JPWO2014142308A1 - Bicyclic pyrazolinone derivatives and herbicides containing them as active ingredients - Google Patents

Abstract

A bicyclic pyrazolinone derivative represented by the general formula (1) [Chemical formula 1] (wherein Ar, R1 and Y represent the definitions described in the specification) and a herbicide containing it as an active ingredient.

Description

  The present invention relates to a novel bicyclic pyrazolinone derivative and a herbicide containing it as an active ingredient.

So far, research and development for controlling harmful weeds that hinder the growth of crops has been widely promoted, and many compounds having a weed control effect have been found that are useful as active ingredients of herbicides. However, these compounds cannot be said to be sufficiently satisfactory in performance desirable as a herbicide such as a weed control effect, persistence of the effect or selectivity between crops and weeds, and these existing herbicides. Some of them have already been confirmed to be resistant, and therefore new herbicides are still desired.
Conventionally, acetyl CoA carboxylase (ACCase) -inhibiting herbicidal compounds such as pinoxaden are known as herbicides having a bicyclic pyrazolinone as a basic skeleton (see Patent Documents 1 to 3). In such an ACCase-inhibiting herbicide, the hydroxyl group on the bicyclic pyrazolinone that is the basic skeleton is an essential substituent for the expression of activity, and further, as a substituent on the benzene ring, a methyl group or It has been suggested that substitution of an electron donating group typified by an ethyl group at the ortho or para position is important for the expression of ACCase inhibitory activity.

  Further, as herbicides having a condensed phenyl group such as a benzoxazinone ring, flumioxazin and the like are known, but these compounds have a substituent at the 6-position via a nitrogen atom such as tetrahydrophthalimide. It is a ring structure (see Patent Documents 4 to 5).

JP 2002-506870 A JP-A-5-117240 International Publication No. 1996-021652 Pamphlet JP 61-076486 JP-A 61-152683

  The object of the present invention is to provide a compound useful as an active ingredient of a herbicide that has desirable performance as a herbicide such as the sustainability of the effect and the selectivity between crops and weeds in addition to an excellent weed control effect. It is in.

｛式中、
Ｒ^１は、ハロゲン原子を表し、
Ｙは、メチレン基、フルオロメチレン基、ジメチレン基、トリメチレン基、テトラメチレン基、オキサメチレン基又はオキサジメチレン基を表し、
Ａｒは、下記一般式（Ａｒ−１）

［式中、
Ｘ^１は、水素原子又はハロゲン原子を表し、
Ｘ^２及びＸ^３は、各々独立に、同一又は相異なって、水素原子；ハロゲン原子；Ｃ_１−Ｃ_４アルキル基；Ｃ_１−Ｃ_４ハロアルキル基；Ｃ_１−Ｃ_４アルキルオキシ基；又はハロゲン原子及びＣ_１−Ｃ_４アルキル基からなる群より選択される１種以上の置換基で置換されていてもよいフェニル基を表し、
Ｒ^２ａは、水素原子；Ｃ_１−Ｃ_４アルキルオキシ基、シアノ基、（Ｃ_１−Ｃ_４アルキル）オキシカルボニル基及び（Ｃ_２−Ｃ_４アルケニル）オキシカルボニル基からなる群より選択される１種以上の置換基で置換されていてもよいＣ_１−Ｃ_６アルキル基；Ｃ_１−Ｃ_６ハロアルキル基；Ｃ_３−Ｃ_６シクロアルキル基；グリシジル基；ハロゲン原子で置換されていてもよいＣ_２−Ｃ_６アルケニル基；ハロゲン原子又はトリメチルシリル基で置換されていてもよいＣ_２−Ｃ_６アルキニル基；又は、ハロゲン原子、Ｃ_１−Ｃ_４アルキル基、Ｃ_１−Ｃ_４アルキルオキシ基、（Ｃ_１−Ｃ_４アルキル）オキシカルボニル基、トリフルオロメチル基、シアノ基及びニトロ基からなる群より選択される１種以上の置換基で置換されていてもよいＣ_７−Ｃ_８アラルキル基を表し、
Ｚは、酸素原子又は硫黄原子を表す。］で示される２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル基又は２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾチアジン−６−イル基；
下記一般式（Ａｒ−２）

［式中、Ｘ^１は、水素原子又はハロゲン原子を表し、
Ｘ^２ｄは、水素原子；Ｃ_１−Ｃ_４アルキル基；Ｃ_１−Ｃ_４ハロアルキル基；又はハロゲン原子及びＣ_１−Ｃ_４アルキル基からなる群より選択される１種以上の置換基で置換されていてもよいフェニル基を表し、
Ｒ^２ｃは、水素原子；Ｃ_１−Ｃ_６アルキル基；Ｃ_１−Ｃ_６ハロアルキル基；Ｃ_３−Ｃ_６シクロアルキル基；Ｃ_２−Ｃ_６アルケニル基；Ｃ_２−Ｃ_６アルキニル基；又は、ハロゲン原子、Ｃ_１−Ｃ_４アルキル基、Ｃ_１−Ｃ_４アルキルオキシ基、（Ｃ_１−Ｃ_４アルキル）オキシカルボニル基、トリフルオロメチル基、シアノ基及びニトロ基からなる群より選択される１種以上の置換基で置換されていてもよいＣ_７−Ｃ_８アラルキル基を表す。］で示される１，２−ジヒドロ−２−オキソキノキサリン−７−イル基；又は
下記一般式（Ａｒ−３）

［式中、Ｘ^１は、水素原子又はハロゲン原子を表し、
Ｘ^２ｄは、水素原子；Ｃ_１−Ｃ_４アルキル基；Ｃ_１−Ｃ_４ハロアルキル基；又はハロゲン原子及びＣ_１−Ｃ_４アルキル基からなる群より選択される１種以上の置換基で置換されていてもよいフェニル基を表し、
Ｒ^２ｃは、水素原子；Ｃ_１−Ｃ_６アルキル基；Ｃ_１−Ｃ_６ハロアルキル基；Ｃ_３−Ｃ_６シクロアルキル基；Ｃ_２−Ｃ_６アルケニル基；Ｃ_２−Ｃ_６アルキニル基；又は、ハロゲン原子、Ｃ_１−Ｃ_４アルキル基、Ｃ_１−Ｃ_４アルキルオキシ基、（Ｃ_１−Ｃ_４アルキル）オキシカルボニル基、トリフルオロメチル基、シアノ基及びニトロ基からなる群より選択される１種以上の置換基で置換されていてもよいＣ_７−Ｃ_８アラルキル基を表す。］で示されるベンゾイミダゾール−６−イル基；を表す。｝
で示される二環性ピラゾリノン誘導体；As a result of diligent research to solve the above-mentioned problems, the present inventors have found that the bicyclic pyrazolinone compound that has not been known so far has an excellent weed control effect, and is desirable as an effective ingredient of a herbicide. The present inventors have found that there are those having a different profile, and have completed the present invention.
That is, the present invention
(I) General formula (1)

{Where,
R ¹ represents a halogen atom,
Y represents a methylene group, a fluoromethylene group, a dimethylene group, a trimethylene group, a tetramethylene group, an oxamethylene group or an oxadimethylene group;
Ar represents the following general formula (Ar-1)

[Where:
X ¹ represents a hydrogen atom or a halogen atom,
X ² and X ³ are each independently the same or different and represent a hydrogen atom; a halogen atom; a C ₁ -C ₄ alkyl group; a C ₁ -C ₄ haloalkyl group; a C ₁ -C ₄ alkyloxy group; represents an atom or C ₁ -C ₄ 1 or more substituents phenyl group which may be substituted with a group selected from the group consisting of alkyl groups,
R ^2a is a hydrogen atom; ₁ selected from the group consisting of a C ₁ -C ₄ alkyloxy group, a cyano group, a (C ₁ -C ₄ alkyl) oxycarbonyl group and a (C ₂ -C ₄ alkenyl) oxycarbonyl group seed or more optionally substituted _C 1 -C ₆ alkyl group optionally substituted with a _group; C 1 -C ₆ haloalkyl _group; C 3 -C ₆ cycloalkyl group; glycidyl group; a C be substituted by a halogen atom _{A 2-} C ₆ alkenyl group; a C ₂ -C ₆ alkynyl group optionally substituted with a halogen atom or a trimethylsilyl group; or a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkyloxy group, ( C ₁ -C ₄ alkyl) substituted with one or more substituents selected from the group consisting of oxycarbonyl group, trifluoromethyl group, cyano group and nitro group Represents a good C ₇ -C ₈ aralkyl group,
Z represents an oxygen atom or a sulfur atom. 2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl group or 2,3-dihydro-3-oxo-4H-1,4-benzothiazin-6-yl group ;
The following general formula (Ar-2)

[Wherein, X ¹ represents a hydrogen atom or a halogen atom,
X ^2d is substituted with one or more substituents selected from the group consisting of a hydrogen atom; a C ₁ -C ₄ alkyl group; a C ₁ -C ₄ haloalkyl group; or a halogen atom and a C ₁ -C ₄ alkyl group. Represents an optionally substituted phenyl group,
R ^2c represents a hydrogen atom; a C ₁ -C ₆ alkyl group; a C ₁ -C ₆ haloalkyl group; a C ₃ -C ₆ cycloalkyl group; a C ₂ -C ₆ alkenyl group; a C ₂ -C ₆ alkynyl group; halogen _atom, C 1 -C ₄ alkyl _group, C 1 -C ₄ alkyl _group, 1 is selected from the group consisting of _(C 1 -C ₄ alkyl) oxycarbonyl group, a trifluoromethyl group, a cyano group and a nitro group It represents a C ₇ -C ₈ aralkyl group which may be substituted with one or more substituents. Or a 1,2-dihydro-2-oxoquinoxalin-7-yl group represented by general formula (Ar-3):

[Wherein, X ¹ represents a hydrogen atom or a halogen atom,
X ^2d is substituted with one or more substituents selected from the group consisting of a hydrogen atom; a C ₁ -C ₄ alkyl group; a C ₁ -C ₄ haloalkyl group; or a halogen atom and a C ₁ -C ₄ alkyl group. Represents an optionally substituted phenyl group,
R ^2c represents a hydrogen atom; a C ₁ -C ₆ alkyl group; a C ₁ -C ₆ haloalkyl group; a C ₃ -C ₆ cycloalkyl group; a C ₂ -C ₆ alkenyl group; a C ₂ -C ₆ alkynyl group; halogen _atom, C 1 -C ₄ alkyl _group, C 1 -C ₄ alkyl _group, 1 is selected from the group consisting of _(C 1 -C ₄ alkyl) oxycarbonyl group, a trifluoromethyl group, a cyano group and a nitro group It represents a C ₇ -C ₈ aralkyl group which may be substituted with one or more substituents. A benzimidazol-6-yl group represented by the formula: }
A bicyclic pyrazolinone derivative represented by:

(Ii) In general formula (1), Ar is general formula (Ar-1), and X ² and X ³ are each independently the same or different and are each a hydrogen atom, a methyl group, a methoxy group or a fluorine atom Y is a methylene group, a dimethylene group, a trimethylene group or an oxadimethylene group, and Z is an oxygen atom, The bicyclic pyrazolinone derivative according to (i) above;
(Iii) In the general formula (1), Ar is the general formula (Ar-1), X ¹ is a fluorine atom or a chlorine atom, and X ² and X ³ are both hydrogen atoms or both fluorine atoms, Alternatively, X ² is a methyl group or a methoxy group, X ³ is a hydrogen atom, R ¹ is a chlorine atom, Y is a dimethylene group or an oxadimethylene group, and Z is an oxygen atom. a bicyclic pyrazolinone derivative according to ii);
In (iv) Formula (1), Ar is a formula ^{(Ar-1), R 2a} _is, C 1 -C ₄ alkyloxy group, a cyano _{group, (C} 1 -C ₄ alkyl) oxycarbonyl group and A C ₁ -C ₆ alkyl group optionally substituted with one or more substituents selected from the group consisting of (C ₂ -C ₄ alkenyl) oxycarbonyl groups; C ₁ -C ₆ haloalkyl groups; C _2- A bicyclic pyrazolinone derivative according to any one of (i) to (iii) above, which is a C ₆ alkenyl group; or a C ₂ -C ₆ alkynyl group;
(V) In the general formula (1), Ar is the general formula (Ar-1), and R ^2a is a C ₂ -C ₆ alkenyl group or a C ₂ -C ₆ alkynyl group. ) A bicyclic pyrazolinone derivative according to any one of
(Vi) The compound represented by the general formula (1) is
5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one,
5-chloro-4- (7-fluoro-4-methyl-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin- 3-on,
4- (4-Allyl-7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -5-chloro-1,2-tetramethylene-4-pyrazolin- 3-on,
5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4-propargyl-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin- 3-on,
5-chloro-4- (7-fluoro-2,3-dihydro-4-isobutyl-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene- 4-pyrazolin-3-one,
5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo-4-propargyl-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene- 4-pyrazolin-3-one,
(S) -5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo-4-propargyl-4H-1,4-benzoxazin-6-yl) -1,2 -Tetramethylene-4-pyrazolin-3-one,
4- [4- (2-Butynyl) -7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl] -5-chloro-1,2 -Tetramethylene-4-pyrazolin-3-one,
5-chloro-4- (7-chloro-2,3-dihydro-3-oxo-4-propargyl-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin- 3-on,
5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4-propargyl-4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin- 3-on,
5-Chloro-1,2-tetramethylene-4- (2,2,7-trifluoro-2,3-dihydro-3-oxo-4-propargyl-4H-1,4-benzoxazin-6-yl) -4-pyrazolin-3-one and 5-chloro-1,2-oxadiethylene-4- (2,2,7-trifluoro-2,3-dihydro-3-oxo-4-propargyl-4H-1, The bicyclic pyrazolinone derivative according to (i) above, which is one compound selected from the group consisting of 4-benzoxazin-6-yl) -4-pyrazolin-3-one;
(Vii) In the general formula (1), Ar is the general formula (Ar-2), X ¹ is a fluorine atom, X ^2d is a methyl group or a trifluoromethyl group, and Y is a dimethylene group or an oxa group. The bicyclic pyrazolinone derivative according to the above (i), which is a dimethylene group, R ¹ is a chlorine atom, and R ^2c is a C ₂ -C ₆ alkenyl group or a C ₂ -C ₆ alkynyl group.
(Viii) In the general formula (1), Ar is the general formula (Ar-3), X ¹ is a fluorine atom, X ^2d is a methyl group or a trifluoromethyl group, and Y is a dimethylene group or an oxa group. The bicyclic pyrazolinone derivative according to the above (i), which is a dimethylene group, R ¹ is a chlorine atom, and R ^2c is a C ₂ -C ₆ alkenyl group or a C ₂ -C ₆ alkynyl group.
(Ix) a herbicide containing the bicyclic pyrazolinone derivative according to any one of (i) to (viii) as an active ingredient;
(X) the herbicide as described in (ix) above, which is for upland weed control or paddy field weed control;
(Xi) The herbicide according to (x), which is for upland field weed control, and wherein the crop in the upland field is wheat, soybean, or corn;
(Xii) the herbicide according to any one of (ix) to (xi), which is a foliage and / or a soil treatment agent;
(Xiii) Use of the bicyclic pyrazolinone derivative according to any one of (i) to (viii) for controlling weeds;
(Xiv) a weed control method comprising applying an effective amount of the bicyclic pyrazolinone derivative according to any one of (i) to (viii) above;
Etc.

  The novel bicyclic pyrazolinone derivative of the present invention exhibits an excellent weed control effect, and has an excellent profile desirable as a herbicide such as the sustainability of the effect and the selectivity between crops and weeds. For this reason, it is useful as an active ingredient of a herbicide.

Hereinafter, the present invention will be described in detail.
First, R ¹ , R ^2a , R ^2b , R ^2c , R ³ , R ⁴ , X ¹ , X ² , X ^2a , X ^2b , X ^2c used in the general formula (1) and other general formulas described later. , X ^2d , X ³ , X ^3a , X ^3b , X ^3c , X ⁴ , Y and Z will be described.
Examples of the halogen atom represented by R ¹ include a fluorine atom, a chlorine atom and a bromine atom. From the viewpoint of high herbicidal activity, a chlorine atom or a fluorine atom is preferable, and a chlorine atom is more preferable.

The C ₁ -C ₆ alkyl group represented by R ^2a and R ^2b may be linear or branched, and is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, or an isobutyl group. , Sec-butyl group, tert-butyl group, pentyl group, hexyl group and the like. The alkyl _group, C 1 -C ₄ alkyloxy group, a cyano _{group, (C} 1 -C ₄ alkyl) oxycarbonyl group and _(C 2 -C ₄ alkenyl) one or more selected from the group consisting of oxycarbonyl group In particular, an alkyloxy group-substituted alkyl group such as a methoxymethyl group, an ethoxymethyl group, a 1- (methoxy) ethyl group, and a 1- (ethoxy) ethyl group; a cyanomethyl group Cyano group-substituted alkyl groups such as 1-cyanoethyl group and 2-cyanoethyl group; methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propyloxycarbonylmethyl group, isopropyloxycarbonylmethyl group, 1- (methoxycarbonyl) ethyl group, 1 -(Ethoxycarbonyl) ethyl group, 1- (isopropyloxycarbonyl) ethyl Group, alkyloxycarbonyl group-substituted alkyl groups such as 2- (methoxycarbonyl) ethyl group, 2- (ethoxycarbonyl) ethyl group, 2- (isopropyloxycarbonyl) ethyl group; vinyloxycarbonyl group, allyloxycarbonyl group, meta Examples thereof include alkenyloxycarbonyl group-substituted alkyl groups such as a aryloxycarbonyl group and a crotyloxycarbonyl group. _C 1 -C ₄ alkyl group is preferred from the viewpoint herbicidal activity is high, among them, an isopropyl group, sec- butyl group, a methoxymethyl group, more preferably a cyanomethyl group.
The C ₁ -C ₆ alkyl group represented by R ^2c may be linear or branched, and may be a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec- Examples thereof include a butyl group, a tert-butyl group, a pentyl group, and a hexyl group.

The C ₁ -C ₆ haloalkyl group represented by R ^2a , R ^2b and R ^2c may be linear or branched, and may be a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, 2 2,2-trifluoroethyl group, pentafluoroethyl group, 3-fluoropropyl group, dichloromethyl group, trichloromethyl group and the like.
^Examples of the C ₃ -C ₆ cycloalkyl group represented by R ^2a , R ^2b and R ^2c include a cyclopropyl group, a cyclopropylmethyl group, a cyclobutyl group, a cyclobutylmethyl group, a cyclopentyl group, a cyclopentylmethyl group, and a cyclohexyl group. Can be illustrated.
^Examples of the C ₂ -C ₆ alkenyl group represented by R ^2a and R ^2b include a vinyl group, an allyl group, a crotyl group, a methallyl group, a 1-buten-3-yl group, a prenyl group, a 3-butenyl group, 2- A hexenyl group etc. can be illustrated. The alkenyl group may be substituted with a halogen atom such as a chlorine atom or a fluorine atom. An allyl group, a crotyl group, and a methallyl group are preferable in terms of high herbicidal activity.
^Examples of the C ₂ -C ₆ alkenyl group represented by R ^2c include a vinyl group, an allyl group, a crotyl group, a methallyl group, a 1-buten-3-yl group, a prenyl group, a 3-butenyl group, and a 2-hexenyl group. Can be illustrated.
^Examples of the C ₂ -C ₆ alkynyl group represented by R ^2a and R ^2b include ethynyl group, propargyl group, 1-butyn-3-yl group, 2-butynyl group, 3-butynyl group, 2-pentynyl group and the like. It can be illustrated. The alkynyl group may be substituted with a halogen atom such as a chlorine atom or a fluorine atom, or a trimethylsilyl group. From the viewpoint of high herbicidal activity, a propargyl group, 2-butynyl group and 1-butyn-3-yl group are preferred.
Examples of the C ₂ -C ₆ alkynyl group represented by R ^2c include an ethynyl group, a propargyl group, a 1-butyn-3-yl group, a 2-butynyl group, a 3-butynyl group, and a 2-pentynyl group. Can do.

Examples of the C ₇ -C ₈ aralkyl group represented by R ^2a , R ^2b and R ^2c include benzyl group, α-phenethyl group, β-phenethyl group and the like. The aralkyl group is a halogen atom such as a chlorine atom or a fluorine atom; a C ₁ -C ₄ alkyl group such as a methyl group, an ethyl group, an isopropyl group, a sec-butyl group, or a tert-butyl group; a methoxy group, an ethoxy group, or an isopropyl group. C ₁ -C ₄ alkyloxy groups such as oxy group, sec-butyloxy group and tert-butyloxy group; (C ₁ -C ₄ such as methoxycarbonyl group, ethoxycarbonyl group, isopropyloxycarbonyl group and tert-butyloxycarbonyl group) Alkyl) oxycarbonyl group; trifluoromethyl group; cyano group; and optionally substituted by one or more substituents selected from the group consisting of nitro group. More specifically, 2-fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2,4-difluorobenzyl group, 2,6-difluorobenzyl group, 2,4,6-trifluorobenzyl group, 2,3,4,5,6-pentafluorobenzyl group, 2,4-dichlorobenzyl group, 3,5-dichlorobenzyl group, 2- (trifluoromethyl) benzyl group, 3- (trifluoromethyl) benzyl group, 4- (trifluoromethyl) benzyl group, 2,6-dimethylbenzyl group, 2,6-diethylbenzyl group, 2,4, 6-trimethylbenzyl group, 4- (tert-butyl) benzyl group, 4-methoxybenzyl group, 4- (tert-butyloxy) benzyl group, 4- ( Butoxycarbonyl) benzyl group, 4-cyanobenzyl group, can be exemplified 4-nitrobenzyl group.
Examples of the C ₁ -C ₄ alkyl group represented by R ³ include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. . A methyl group or an ethyl group is preferred from the viewpoint of good production efficiency.
The C ₁ -C ₄ alkyl group represented by R ⁴ may be linear or branched, and may be a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec- Examples thereof include a butyl group and a tert-butyl group. An ethyl group is preferable in terms of production efficiency.

Examples of the halogen atom represented by X ¹ include a fluorine atom, a chlorine atom, and a bromine atom. In terms of high herbicidal activity, a fluorine atom or a chlorine atom is preferable, and a fluorine atom is more preferable.
When Ar represents a group represented by the general formula (Ar-1), the halogen atom represented by X ¹ is preferably a fluorine atom or a chlorine atom. Further, when Ar represents a group represented by the general formula (Ar-2) or (Ar-3), the halogen atom represented by X ¹ is preferably a fluorine atom.

Examples of the halogen atom represented by X ² , X ^2b , X ^2c , X ³ , X ^3b and X ^3c include a fluorine atom, a chlorine atom and a bromine atom. A fluorine atom is preferable in terms of high herbicidal activity.
The C ₁ -C ₄ alkyl group represented by X ² , X ^2a , X ^2b , X ^2d , X ³ , X ^3a and X ^3b may be either linear or branched. Examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. From the viewpoint of high herbicidal activity, a methyl group, an ethyl group, and an isopropyl group are preferable, and a methyl group is more preferable.
The C ₁ -C ₄ haloalkyl group represented by X ² , X ^2a , X ^2b , X ^2d , X ³ , X ^3a and X ^3b may be either linear or branched. Examples thereof include a difluoromethyl group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a 3-fluoropropyl group, a chloromethyl group, a dichloromethyl group, and a trichloromethyl group.
The C ₁ -C ₄ alkyloxy group represented by X ² , X ^2a , X ³ and X ^3a may be either linear or branched, for example, methoxy group, ethoxy group, propyloxy Group, isopropyloxy group, butyloxy group, isobutyloxy group, sec-butyloxy group, tert-butyloxy group and the like. From the viewpoint of high herbicidal activity, a methoxy group, an ethoxy group, a propyloxy group, and an isopropyloxy group are preferable.
The phenyl group which may be substituted with a halogen atom represented by X ² , X ^2a , X ^2b , X ^2d , X ³ , X ^3a and X ^3b or a C ₁ -C ₄ alkyl group includes a phenyl group, 2 -Fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2,4-difluorophenyl group, 2,4,6-trifluorophenyl group 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl Examples include groups.

X ² and X ³ are preferably a hydrogen atom, a fluorine atom, a methoxy group or a methyl group in terms of high herbicidal activity.
Examples of the halogen atom represented by X ⁴ include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
Y represents a methylene group (—CH ₂ —), a fluoromethylene group (—CHF— or —CF ₂ —), a dimethylene group (—CH ₂ CH ₂ —), a trimethylene group (—CH ₂ CH ₂ CH ₂ —), Tetramethylene group (—CH ₂ CH ₂ CH ₂ CH ₂ —), oxamethylene group (—OCH ₂ — or —CH ₂ O—), or oxadimethylene group (—OCH ₂ CH ₂ —, —CH ₂ OCH ₂₎ - or it represents a _-CH 2 _CH 2 O-). From the viewpoint of high herbicidal activity, Y is preferably a methylene group, a dimethylene group, a trimethylene group or an oxadimethylene group, more preferably a dimethylene group or an oxadimethylene group.

Z represents an oxygen atom or a sulfur atom, and an oxygen atom is preferable in terms of high herbicidal activity.
In addition, in the compound represented by the general formula (1), when X ² and X ³ are different substituents, the absolute configuration of the resulting asymmetric carbon is not particularly limited, and individual optically active substances and their racemic forms are not limited. Any body is included in the present invention.
Ar used in the general formula (1) and other general formulas described later will be described. Ar represents a group represented by the general formula (Ar-1), (Ar-2) or (Ar-3). . Of these groups, the group represented by the general formula (Ar-1) is preferable, and the group in which Z is an oxygen atom is more preferable.

The above groups in the compound of the present invention will be further described below.
(A) R ¹ , X ¹ , X ² , X ³ , R ^2a , Y and Z when Ar represents a group represented by the general formula (Ar-1)
As described above, R ¹ represents a halogen atom, preferably a chlorine atom or a fluorine atom, and more preferably a chlorine atom.
X ¹ is preferably a halogen atom, more preferably a fluorine atom or a chlorine atom.
X ² and X ³ are each independently the same or different and are preferably a hydrogen atom, a C ₁ -C ₄ alkyl group or a halogen atom, more preferably a hydrogen atom, a methyl group, a methoxy group or a fluorine atom. And more preferably a hydrogen atom or a fluorine atom.
R ^2a is preferably _one selected from the group consisting of a C ₁ -C ₄ alkyloxy group, a cyano group, a (C ₁ -C ₄ alkyl) oxycarbonyl group, and a (C ₂ -C ₄ alkenyl) oxycarbonyl group. A C ₁ -C ₆ alkyl group optionally substituted with the above substituents; a C ₁ -C ₆ haloalkyl group; a C ₂ -C ₆ alkenyl group; or a C ₂ -C ₆ alkynyl group, more preferably C is ₂ -C ₆ alkenyl or _C 2 -C ₆ alkynyl group.
Y is preferably a methylene group, a dimethylene group, a trimethylene group or an oxadimethylene group, more preferably a dimethylene group or an oxadimethylene group.
Z is preferably an oxygen atom.

In the case where Ar represents a group represented by the general formula (Ar-1), two or three preferable atoms or groups in the above R ¹ , X ¹ , X ² , X ³ , R ^2a , Y and Z are used. The compound of the present invention comprising the above simultaneously is preferred. For example, the following compounds are preferred:
(Ii) X ² and X ³ are each independently the same or different and are a hydrogen atom, a methyl group, a methoxy group or a fluorine atom, and Y is a methylene group, a dimethylene group, a trimethylene group or an oxadimethylene group. And Z is an oxygen atom, and (iv) R ^2a is a C ₁ -C ₄ alkyloxy group, a cyano group, a (C ₁ -C ₄ alkyl) oxycarbonyl group and (C ₂ -C ₄ alkenyl) oxy. one or more optionally substituted with a substituent _C 1 -C ₆ alkyl group selected from the group consisting of a carbonyl _group; C 1 -C ₆ haloalkyl _group; C 2 -C ₆ alkenyl; or _{C 2} - a C ₆ alkynyl group, compound. In the compound, (v) a compound in which R ^2a is a C ₂ -C ₆ alkenyl group or a C ₂ -C ₆ alkynyl group is more preferable.
(Iii) X ¹ is a fluorine atom or a chlorine atom, X ² and X ³ are both hydrogen atoms or both fluorine atoms, or X ² is a methyl group or a methoxy group and X ³ is a hydrogen atom, R ¹ is a chlorine atom, Y is a dimethylene group or an oxadimethylene group, Z is an oxygen atom, and (iv) R ^2a is a C ₁ -C ₄ alkyloxy group, a cyano group, (C ₁ -C ₄ alkyl) oxycarbonyl group and _(C 2 -C ₄ alkenyl) one or more optionally substituted with a substituent _C 1 -C ₆ alkyl group selected from the group consisting of oxycarbonyl group; _{C 1} -C ₆ haloalkyl _group; C 2 -C ₆ alkenyl group; or _C 2 -C ₆ alkynyl group, compound. In the compound, (v) a compound in which R ^2a is a C ₂ -C ₆ alkenyl group or a C ₂ -C ₆ alkynyl group is more preferable.

(B) R ¹ , X ¹ , X ^2d , R ^2c and Y when Ar represents a group represented by the general formula (Ar-2) or (Ar-3)
As described above, R ¹ represents a halogen atom, preferably a chlorine atom or a fluorine atom, and more preferably a chlorine atom.
X ¹ is preferably a halogen atom, more preferably a fluorine atom.
X ^2d is preferably a hydrogen atom, a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ haloalkyl group, more preferably a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ haloalkyl group, and even more A methyl group or a trifluoromethyl group is preferred.
R ^2c is preferably a C ₁ -C ₆ alkyl group; a C ₂ -C ₆ alkenyl group; or a C ₂ -C ₆ alkynyl group, more preferably a C ₂ -C ₆ alkenyl group or C ₂ -C _6. Alkynyl group.
Y is preferably a methylene group, a dimethylene group, a trimethylene group or an oxadimethylene group, more preferably a dimethylene group or an oxadimethylene group.

In the case where Ar represents a group represented by the general formula (Ar-2) or (Ar-3), two or three preferable atoms or groups in the above R ¹ , X ¹ , X ^2d , R ^2c and Y are used. The compounds of the present invention comprising more than one species simultaneously are preferred. For example, the following compounds are preferred:
R ¹ is a chlorine atom or a fluorine atom,
X ¹ is a halogen atom,
X ^2d is a C ₁ -C ₄ alkyl group or a C ₁ -C ₄ haloalkyl group,
A compound wherein R ^2c is a C ₁ -C ₆ alkyl group; a C ₂ -C ₆ alkenyl group; or a C ₂ -C ₆ alkynyl group, and Y is a methylene group, a dimethylene group, a trimethylene group or an oxadimethylene group .
In the above compound,
R ¹ is a chlorine atom,
X ¹ is a fluorine atom,
X ^2d is a methyl group or a trifluoromethyl group,
R ^2c is a C ₂ -C ₆ alkenyl group (preferably allyl group); or C ₂ -C ₆ alkynyl group (preferably propargyl group) and Y is a dimethylene group or an oxadimethylene group, preferable.

［式中、Ｒ^１、Ｘ^１、Ｘ^２、Ｘ^３、Ｙ及びＺは前記と同じ意味を表す。Ｒ^２ｂは、Ｃ_１−Ｃ_４アルキルオキシ基、シアノ基，（Ｃ_１−Ｃ_４アルキル）オキシカルボニル基及び（Ｃ_２−Ｃ_４アルケニル）オキシカルボニル基からなる群より選択される１種以上の置換基で置換されていてもよいＣ_１−Ｃ_６アルキル基；Ｃ_１−Ｃ_６ハロアルキル基；Ｃ_３−Ｃ_６シクロアルキル基；グリシジル基；ハロゲン原子で置換されていてもよいＣ_２−Ｃ_６アルケニル基；ハロゲン原子又はトリメチルシリル基で置換されていてもよいＣ_２−Ｃ_６アルキニル基；又は、ハロゲン原子、Ｃ_１−Ｃ_４アルキル基、Ｃ_１−Ｃ_４アルキルオキシ基、（Ｃ_１−Ｃ_４アルキル）オキシカルボニル基、トリフルオロメチル基、シアノ基及びニトロ基からなる群より選択される１種以上の置換基で置換されていてもよいＣ_７−Ｃ_８アラルキル基を表す。Ｒ^３は、Ｃ_１−Ｃ_４アルキル基を表す。Ｌ^ａは脱離基を表す。］Next, typical production methods of the bicyclic pyrazolinone derivative of the present invention (hereinafter also referred to as “the compound of the present invention”) will be described, but the present invention is not limited to these production methods.
Bicyclic pyrazolinone derivatives represented by the following general formulas (1a) and (1b), which are part of the compound of the present invention, can be produced, for example, by the following production method-1.
Manufacturing method-1

[Wherein, R ¹ , X ¹ , X ² , X ³ , Y and Z represent the same meaning as described above. R ^2b is one or more selected from the group consisting of a C ₁ -C ₄ alkyloxy group, a cyano group, a (C ₁ -C ₄ alkyl) oxycarbonyl group, and a (C ₂ -C ₄ alkenyl) oxycarbonyl group. optionally substituted with a substituent _C 1 -C ₆ alkyl _group; C 1 -C ₆ haloalkyl _group; C 3 -C ₆ cycloalkyl group; glycidyl group; optionally _C 2 -C be substituted by a halogen atom ₆ alkenyl group; a halogen atom or an optionally substituted _C 2 -C ₆ alkynyl group with trimethylsilyl group; or a halogen _atom, C 1 -C ₄ alkyl _group, C 1 -C ₄ alkyl group, _{(C 1} - C ₄ alkyl) oxycarbonyl group, a trifluoromethyl group, optionally substituted with one or more substituents selected from the group consisting of cyano group and a nitro group C -C represents an ₈ aralkyl group. R ³ represents a C ₁ -C ₄ alkyl group. La represents ^a leaving group. ]

Production method-1 is a bicyclic pyrazolinone which is a part of the compound of the present invention by reduction of the nitro group on the benzene ring of the bicyclic pyrazolinone derivative (2) to an amino group and subsequent intramolecular cyclization reaction. Step 1-1 for producing the derivative (1a), and then reacting the bicyclic pyrazolinone derivative (1a) with the compound (3) in the presence of a base to form a bicyclic pyrazolinone derivative which is a part of the compound of the present invention It consists of process 1-2 which manufactures (1b).
Step 1-1 is a reduction of the nitro group on the benzene ring of the bicyclic pyrazolinone derivative (2) to an amino group, followed by an intramolecular cyclization reaction, which is part of the compound of the present invention. This is a process for producing a pyrazolinone derivative (1a).
For reduction of the nitro group, catalytic reduction using hydrogen gas or hydrazine, or metal reduction using a metal or a metal compound such as iron, tin, or zinc can be used.
In catalytic reduction, a metal catalyst such as palladium, platinum, nickel, ruthenium, rhodium, or osmium is used. Palladium catalysts include palladium black, palladium-supported carbon, platinum catalysts include platinum-supported carbon, platinum (IV) oxide hydrate, etc., nickel catalysts include Raney nickel, ruthenium, rhodium, and osmium metals. Examples of the catalyst include ruthenium-supported carbon, rhodium-supported carbon, and osmium-supported carbon. The addition amount of the metal catalyst is usually about 0.0001 to 10 mol%, preferably about 0.1 to 1.0 mol% with respect to the bicyclic pyrazolinone derivative (2).
When hydrogen gas is used as the reducing agent, the pressure of the hydrogen gas is not particularly limited and may be pressurized as necessary. In that case, it is usually in the range of 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa. The reaction may be carried out at a pressure selected as appropriate. When hydrazine is used as the reducing agent, the target product can be obtained in good yield by using 1 to 25 mol of hydrazine with respect to 1 mol of the bicyclic pyrazolinone derivative (2).

The reduction reaction may be carried out at a reaction temperature appropriately selected in the range of usually 20 to 100 ° C., preferably 40 to 80 ° C.
In the catalytic reduction reaction, a reaction solvent is appropriately used as necessary. Examples of the reaction solvent include water, alcohol solvents such as methanol, ethanol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, dichloromethane, 1,2-dichloroethane, chloroform. , Halogen solvents such as carbon tetrachloride, ether solvents such as diethyl ether, dimethoxyethane (hereinafter abbreviated as DME), diethoxyethane, tetrahydrofuran (hereinafter abbreviated as THF), and hydrocarbons such as hexane, heptane and cyclohexane And organic solvents such as aromatic solvents such as benzene, toluene and xylene, and ester solvents such as ethyl acetate and butyl acetate. Methanol, ethyl acetate, THF, toluene and the like are preferable. These reaction solvents may be used alone or in appropriate combination of two or more.
In metal reduction using a metal such as iron, tin, or zinc, or a metal compound, the target product can be obtained in high yield by carrying out the reaction by appropriately selecting reaction conditions suitable for each metal. For example, iron-acetic acid, iron-hydrochloric acid, tin-hydrochloric acid, zinc-hydrochloric acid, etc. may be used. In the reaction, a reaction solvent is appropriately used as necessary.

After completion of the reaction, the desired product can be produced by isolating the desired product from the reaction system containing the desired product by a conventional method and purifying the product by recrystallization, distillation, column chromatography or the like as necessary. In some cases, the obtained target product can be used as it is as a raw material for the next step without purification.
In Step 1-2, the bicyclic pyrazolinone derivative (1a) which is a part of the compound of the present invention is reacted with the compound (3) in the presence of a base to thereby form the bicyclic compound which is a part of the compound of the present invention. This is a step for producing a pyrazolinone derivative (1b).
Step 1-2 is performed in the presence of a base. Bases include organic bases such as triethylamine, tributylamine and pyridine, sodium hydride and sodium amide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and other inorganic bases, sodium methoxide, sodium ethoxide And alkali metal alkoxides such as potassium tert-butoxide, lithium bases such as methyl lithium and butyl lithium, and the like.
Process 1-2 reaction can be implemented in an organic solvent. Any organic solvent that does not harm the reaction can be used as the organic solvent, and ether solvents such as 1,4-dioxane, THF, DME, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, benzene, toluene, Aromatic hydrocarbon solvents such as chlorobenzene, hydrocarbon solvents such as hexane and octane, ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone and cyclohexanone, ester solvents such as ethyl acetate and ethyl propionate, acetonitrile and propio Nitrile solvents such as nitrile, amide solvents such as N, N-dimethylformamide (hereinafter abbreviated as DMF) and N, N-dimethylacetamide, sulfoxide solvents such as dimethyl sulfoxide (hereinafter abbreviated as DMSO), and these Mixed solvent It can be exemplified. Moreover, what is necessary is just to select and use an organic solvent suitably suitable for the base to be used.

［式中、Ｒ^１、Ｘ^１、Ｙ、及びＺは前記と同じ意味を表す。Ｘ^２ａ及びＸ^３ａは、各々独立に、同一又は相異なって、水素原子；Ｃ_１−Ｃ_４アルキル基；Ｃ_１−Ｃ_４ハロアルキル基；Ｃ_１−Ｃ_４アルキルオキシ基；ハロゲン原子及びＣ_１−Ｃ_４アルキル基からなる群より選択される１種以上の置換基で置換されていてもよいフェニル基を表す。Ｘ^４は、ハロゲン原子を表す。Ｒ^３及びＲ^４は、各々独立に、同一又は相異なって、Ｃ_１−Ｃ_４アルキル基を表す。］Although there is no restriction | limiting in particular in reaction temperature, What is necessary is just to make it react at the temperature chosen suitably in the range from -78 degreeC to the reflux temperature of the solvent to be used.
Formula (3) compounds represented by the (R ^{2b -L a),} as the leaving group represented by L ^a, a chlorine atom, a bromine atom, a halogen atom such as iodine atom, a methylsulfonyloxy group, trifluoromethyl Examples thereof include substituted sulfonyloxy groups such as a sulfonyloxy group, a phenylsulfonyloxy group, and a 4-methylphenylsulfonyloxy group. Here, some of the compounds represented by the general formula (3) which are not commercially available can be easily prepared by a general chemical method in the art.
After completion of the reaction, the desired product can be isolated from the reaction system containing the desired product by a conventional method, and can be purified by recrystallization, distillation, column chromatography or the like, if necessary.
In the method shown in Production Method-1, the bicyclic pyrazolinone derivative (2a) among the bicyclic pyrazolinone derivative (2) as a starting material can be produced by the method shown in the following Production Method-2. .
Manufacturing method-2

[Wherein, R ¹ , X ¹ , Y, and Z represent the same meaning as described above. X ^2a and X ^3a are each independently the same or different and represent a hydrogen atom; a C ₁ -C ₄ alkyl group; a C ₁ -C ₄ haloalkyl group; a C ₁ -C ₄ alkyloxy group; a halogen atom and C ₁ A phenyl group which may be substituted with one or more substituents selected from the group consisting of —C ₄ alkyl groups. X ⁴ represents a halogen atom. R ³ and R ⁴ are each independently the same or different and each represents a C ₁ -C ₄ alkyl group. ]

Production method-2 is a step of producing 2-substituted phenyl-2-oxoacetic acid ester (6a) by reacting Grignard reagent prepared from benzene bromide (4a) with oxalic acid diester (5). Treat the α-carbonyl group of the 2-1,2-substituted phenyl-2-oxoacetic acid ester (6a) with Wittig reagent prepared from triphenylphosphine and R ¹ ₂ CX ⁴ ₂ (7). Step 2-2 for producing an acrylic acid derivative (8a) by dihalomethyleneation, Step 2-3 for producing a bicyclic pyrazolinone derivative (10a) by reacting the acrylic acid derivative (8a) with a cyclic hydrazine (9), Step 2 of producing a bicyclic pyrazolinone derivative (11a) by nitrating the benzene ring of the bicyclic pyrazolinone derivative (10a) And Step 2-5 for producing the bicyclic pyrazolinone derivative (2a) by reacting the bicyclic pyrazolinone derivative (11a) with the glycolic acid ester or thioglycolic acid ester (12a) in the presence of a base. .
Step 2-1 is a step for producing a 2-substituted phenyl-2-oxoacetic acid ester (6a) by reacting an oxalic acid diester (5) with a Grignard reagent prepared from bromobenzenes (4a).

The Grignard reagent of benzene bromides (4a) can be prepared according to a general Grignard reagent preparation method. It can be easily prepared by adding an organic solvent to magnesium metal, then adding benzene bromides (4a) and stirring. As the organic solvent, an ether solvent such as THF, DME, and diethyl ether can be used, and THF is preferable in terms of a good yield. There is no restriction | limiting in particular in reaction temperature, Although reaction advances fully at room temperature, you may heat as needed. Further, the reaction can be promoted by adding a catalytic amount of iodine.
The Grignard reagent of benzene bromides (4a) can also be prepared by a Grignard exchange reaction, which is a general chemical technique, and can be prepared by, for example, a reaction with isopropyl magnesium chloride. By adding a THF solution of isopropylmagnesium chloride to a solution of benzene bromides (4a) (for example, THF solution) at a low temperature and reacting while gradually raising the temperature to room temperature, Grignard of benzene bromides (4a) Reagents can be prepared. As the organic solvent, in addition to THF, an ether solvent such as DME or diethyl ether can be used, and THF is preferable in terms of a good yield.
Furthermore, it is well known to those skilled in the art that a Grignard reagent can be prepared even when a substituted phenyl iodide is used in place of the bromobenzenes (4a), and it can be easily obtained from a commercially available substituted phenyl iodide or a commercially available raw material. Prepared substituted phenyl iodides can be used.

The prepared Grignard reagent of benzene bromides (4a) can be reacted with the oxalic acid diester (5) in the solution without isolation. That is, for example, by adding the prepared Grignard reagent to a THF solution of diethyl oxalate, for example, at a low temperature and reacting while gradually raising the temperature to room temperature, the target 2-substituted phenyl-2-oxoacetic acid ester ( 6a) can be produced. In addition, a solution of the oxalic acid diester (5) (for example, a THF solution) is added to the prepared Grignard reagent solution at a low temperature, and the reaction is performed while gradually raising the temperature to room temperature, whereby the target 2-substituted phenyl-2 is obtained. -Oxoacetic acid ester (6a) can be prepared. As the organic solvent, an ether solvent such as THF, DME, and diethyl ether can be used, and THF is preferable in terms of a good yield. The reaction temperature is not particularly limited, but in order to suppress an extreme reaction, the initial reaction is performed at a low temperature of about −40 to −78 ° C., and the reaction is performed while gradually raising the temperature to room temperature. Is preferable in terms of good.
Among the benzene bromides (4a) used in Step 2-1, some of the non-commercially-available compounds are generally known to those skilled in the art from appropriate commercially-available compounds so as to have a desired substituent on the benzene ring. Can be easily prepared by various chemical methods.
After completion of the reaction, the desired product can be produced by isolating the desired product from the reaction system containing the desired product by a conventional method and purifying the product by recrystallization, distillation, column chromatography or the like as necessary. In some cases, the obtained target product can be used as it is as a raw material for the next step without purification.

In Step 2-2, the carbonyl group at the α-position of the 2-substituted phenyl-2-oxoacetic acid ester (6a) was treated with a Wittig reagent prepared from triphenylphosphine and R ¹ ₂ CX ⁴ ₂ (7) to obtain a dihalomethylene. Is a step of producing an acrylic acid derivative (8a).
The 2-substituted phenylacrylic acid ester (8a) in which R ¹ is a chlorine atom is a dichloromethylene triphenylphosphorane (phosphorus ylide) of Wittig reagent prepared from triphenylphosphine and carbon tetrachloride (R ¹ = X ⁴ = Cl). And 2-substituted phenyl-2-oxoacetic acid ester (6a) can be easily produced.
Dichloromethylenetriphenylphosphorane can be easily prepared by reacting triphenylphosphine and carbon tetrachloride in an organic solvent such as dichloromethane at a temperature of about 0 ° C. to room temperature. The reaction of dichloromethylenetriphenylphosphorane and 2-substituted phenyl-2-oxoacetic acid ester (6a) can be carried out under heating conditions from room temperature to about 100 ° C. The reaction can be carried out in an organic solvent, and any solvent that does not adversely affect the reaction can be used without particular limitation. Halogen solvents such as dichloromethane and chloroform are preferred in terms of good yield. After completion of the reaction, the 2-substituted phenylacrylic acid ester (8a) can be obtained by ordinary post-treatment and can be purified by silica gel column chromatography or distillation.
The tertiary phosphine used for the preparation of phosphorus ylide is not limited to triphenylphosphine, but triphenylphosphine is preferable because it is easily available and has a good yield.
The 2-substituted phenylacrylic acid ester (8a) in which R ¹ is a fluorine atom is obtained by reacting the Wittig reagent difluoromethylenetriphenylphosphorane with the 2-substituted phenyl-2-oxoacetic acid ester (6a). It can be manufactured easily.

As the difluoromethylene reaction of α-ketoesters using difluoromethylenetriphenylphosphorane, a method using difluoromethylenetriphenylphosphorane prepared from sodium chlorodifluoroacetate and triphenylphosphine (US Pat. No. 4,001,301, International Publication No. 2001-095721 pamphlet and JP-A-2004-503475). In addition, dibromodifluoromethane and triphenylphosphine are reacted in an N, N-dimethylacetamide solution to form a phosphonium salt, and then powdered zinc is added to prepare difluoromethylenetriphenylphosphorane, which is a difluoromethylene of α-ketoesters. A method (Japanese Patent Application Laid-Open No. 2008-195678 and Japanese Patent Application Laid-Open No. 2008-195679) used for the methyleneation reaction is disclosed. In Step 2-2, by carrying out the reaction according to the methods described in these patent documents, the target R ¹ can easily produce a 2-substituted phenylacrylate (8a) having a fluorine atom. it can.
In Step 2-2, chlorofluoromethylenetriphenylphosphorane was prepared using trichlorofluoromethane instead of dibromodifluoromethane as the compound represented by the general formula (7), and 2-substituted phenyl-2- By reacting oxoacetic acid ester (6a), 2-substituted phenylacrylic acid ester (8a) in which ^one of two R ¹ is a chlorine atom and the other is a fluorine atom can be produced.
After completion of the reaction, the desired product can be produced by isolating the desired product from the reaction system containing the desired product by a conventional method and purifying the product by recrystallization, distillation, column chromatography or the like as necessary. In some cases, the obtained target product can be used as it is as a raw material for the next step without purification.

Step 2-3 is a step of producing the bicyclic pyrazolinone derivative (10a) by reacting the acrylic acid derivative (8a) with the cyclic hydrazines (9).
Step 2-3 comprises reacting 2-substituted phenylacrylic acid ester (8a) with cyclic hydrazine (9) or a chemically acceptable salt thereof, optionally in the presence of a base, to give a bicyclic pyrazolinone. This is a step of producing the derivative (10a).
Specific examples of the cyclic hydrazine (9) include pyrazolidine, 4-fluoropyrazolidine, hexahydropyridazine, 1,2-diazacycloheptane, 1,3,4-oxadiazolidine, 1,4,5 -Oxadiazepane, 4-methyl-1,2,4-triazolidine, 5-methyl-1,2,5-triazepane and the like can be exemplified. These cyclic hydrazines can be used in the reaction as they are, but chemically acceptable salts such as hydrochloride and sulfate can also be used in the reaction. A part of the cyclic hydrazine (9) is commercially available. For example, hexahydropyridazine can be produced by a known method (Japanese Patent Laid-Open Nos. 8-109170 and 10-29981).

The reaction of step 2-3 can be carried out in a solvent. As the solvent, any solvent that does not harm the reaction can be used. Ether solvents such as 1,4-dioxane, THF, DME, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, benzene, toluene, chlorobenzene, etc. Aromatic hydrocarbon solvents, hydrocarbon solvents such as hexane and octane, ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone and cyclohexanone, ester solvents such as ethyl acetate and ethyl propionate, acetonitrile and propionitrile, etc. Nitrile solvents, amide solvents such as DMF and N, N-dimethylacetamide, sulfoxide solvents such as DMSO, water, and mixed solvents thereof. Preferably, ether solvents such as 1,4-dioxane and THF can be exemplified.
There is no restriction | limiting in particular in reaction temperature, It can implement at the temperature chosen suitably in the range from room temperature to the reflux temperature of the solvent to be used.
The reaction can also be promoted by adding a base during the reaction. Examples of the base include organic bases such as triethylamine, tributylamine and pyridine, inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide, sodium methoxide, sodium ethoxide and potassium tert-butoxide. Alkali metal alkoxides can be exemplified. Preferably, organic bases, such as a triethylamine, and inorganic bases, such as potassium carbonate and sodium hydroxide, can be illustrated. Moreover, when using the salt of cyclic hydrazine (9), it is preferable from the point that reaction time is short and a yield is good to make it react by adding the base more than the quantity corresponding to the acid which forms a salt.
After completion of the reaction, the desired product can be produced by isolating the desired product from the reaction system containing the desired product by a conventional method and purifying the product by recrystallization, distillation, column chromatography or the like as necessary. In some cases, the obtained target product can be used as it is as a raw material for the next step without purification.

Step 2-4 is a step of producing a bicyclic pyrazolinone derivative (11a) by nitration of the benzene ring of the bicyclic pyrazolinone derivative (10a).
Nitration in step 2-4 is, for example, nitration using a mixed acid prepared from concentrated nitric acid and concentrated sulfuric acid in concentrated sulfuric acid, or nitration using fuming nitric acid in a solvent such as no solvent or dichloromethane. The method can be used. The reaction conditions are not particularly limited, and the target bicyclic pyrazolinone derivative (11a) is produced with good yield and regioselectivity by carrying out according to a general method of nitrating a benzene ring. Can do.
After completion of the reaction, the desired product can be produced by isolating the desired product from the reaction system containing the desired product by a conventional method and purifying the product by recrystallization, distillation, column chromatography or the like as necessary. In some cases, the obtained target product can be used as it is as a raw material for the next step without purification.

Step 2-5 is a step of producing a bicyclic pyrazolinone derivative (2a) by reacting the bicyclic pyrazolinone derivative (11a) with a glycolic acid ester or thioglycolic acid ester (12a) in the presence of a base. is there. In this step, a bicyclic pyrazolinone derivative (2a, Z = O) having a benzoxazine ring can be produced by using a glycolic acid ester in which Z in the general formula (12a) is an oxygen atom. By using a thioglycolic acid ester in which Z in (12a) is a sulfur atom, a bicyclic pyrazolinone derivative (2a, Z = S) having a benzothiazine ring can be produced.
Step 2-5 is performed in the presence of a base. Examples of the base include amine bases such as triethylamine, tributylamine, N-methylmorpholine, and pyridine, alkyllithium bases such as butyllithium and methyllithium, alkali metal hydrides such as sodium hydride and potassium hydride, and potassium fluoride. Inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide can be used. Sodium hydride is preferable in terms of good yield.
Step 2-5 can be performed in the absence of a solvent, but can also be performed in an organic solvent that does not harm the reaction. Examples of the solvent include ether solvents such as THF, 1,4-dioxane, diethyl ether and DME, amide solvents such as DMF and dimethylacetamide, sulfoxide solvents such as DMSO, and nitrile solvents such as acetonitrile and propionitrile. Solvents, ketone solvents such as acetone and methyl ethyl ketone, aliphatic hydrocarbon solvents such as hexane, heptane, and octane, aromatic hydrocarbon solvents such as benzene, toluene, and chlorobenzene, and mixed solvents thereof can be exemplified. . As the organic solvent, a suitable organic solvent may be appropriately selected depending on the base to be used. From the viewpoint of good yield, ether solvents are preferable, and THF and 1,4-dioxane are more preferable.
The reaction in Step 2-5 can be carried out at a reaction temperature appropriately selected in the range of −78 to 150 ° C., depending on the base and solvent to be used.

  The glycolic acid ester or thioglycolic acid ester (12a) as a raw material can be easily obtained or can be easily prepared from a commercially available raw material. For example, methyl glycolate, ethyl glycolate, butyl glycolate, 2- Glycolic acid esters such as methyl (trifluoromethyl) glycolate and ethyl 2- (trifluoromethyl) glycolate; Lactic acid esters such as methyl lactate, ethyl lactate and butyl lactate; methyl 2-hydroxybutyrate, ethyl 2-hydroxybutyrate, 2-hydroxybutyric acid esters such as butyl 2-hydroxybutyrate; 2-hydroxyisobutyric acid esters such as methyl 2-hydroxyisobutyrate, ethyl 2-hydroxyisobutyrate, butyl 2-hydroxyisobutyrate; methyl 2-hydroxyvalerate, 2 2-hydroxy such as ethyl hydroxyvalerate Droxy valerate; 2-hydroxyisovalerate such as methyl 2-hydroxyisovalerate and ethyl 2-hydroxyisovalerate; methyl 2-hydroxy-3-methylpentanoate, 2-hydroxy-3-methylpentanoic acid 2-hydroxy-3-methylpentanoic acid esters such as ethyl; 2-hydroxy-4-methylpentanoic acid esters such as methyl 2-hydroxy-4-methylpentanoate and ethyl 2-hydroxy-4-methylpentanoate; Alkoxy-substituted glycolic acid esters such as methyl methoxyglycolate, methyl 2-ethoxyglycolate, methyl 2- (isopropyloxy) glycolate; methyl 2-phenylglycolate, methyl 2- (2-chlorophenyl) glycolate, 2- ( 3-chlorophenyl) glycolic acid methyl , Methyl 2- (4-chlorophenyl) glycolate, methyl 2- (2-fluorophenyl) glycolate, methyl 2- (3-fluorophenyl) glycolate, methyl 2- (4-fluorophenyl) glycolate, 2- Methyl (2-methylphenyl) glycolate, methyl 2- (3-methylphenyl) glycolate, methyl 2- (4-methylphenyl) glycolate, methyl 2- (2-isopropylphenyl) glycolate, 2- (3 -Glycolic acid esters such as 2-substituted phenylglycolic acid esters such as methyl isopropylphenyl) glycolate and methyl 2- (4-isopropylphenyl) glycolate; or methyl thioglycolate, ethyl thioglycolate, butyl thioglycolate Thioglycolate such as thiomilk Thiolactic acid esters such as methyl acid, ethyl thiolactate and butyl thiolactate; 2-mercaptobutyric acid esters such as methyl 2-mercaptobutyrate and ethyl 2-mercaptobutyrate; methyl 2-mercaptoisobutyrate and ethyl 2-mercaptoisobutyrate Thioglycolic acid esters such as 2-mercaptoisobutyric acid ester; 2-mercaptovaleric acid ester such as methyl 2-mercaptovalerate and ethyl 2-mercaptovalerate;

  After completion of the reaction, the desired product can be produced by isolating the desired product from the reaction system containing the desired product by a conventional method and purifying the product by recrystallization, distillation, column chromatography or the like as necessary. In some cases, the obtained target product can be used as it is as a raw material for the next step without purification.

［式中、Ｒ^１、Ｒ^３、Ｒ^４、Ｘ^１、Ｘ^２ａ、Ｘ^３ａ、Ｘ^４、Ｙ、及びＺは前記と同じ意味を表す。］In addition, in the method shown in Production Method-1, the bicyclic pyrazolinone derivative (2a) among the bicyclic pyrazolinone derivative (2) as a starting material is produced by the method shown in the following Production Method-3. You can also.
Production method-3

[Wherein, R ¹ , R ³ , R ⁴ , X ¹ , X ^2a , X ^3a , X ⁴ , Y, and Z represent the same meaning as described above. ]

In Production Method-3, 2-substituted phenyl-2-oxoacetic acid ester (6b) obtained in Step 2-1 of Production Method-2 is nitrated to produce 2-substituted phenyl-2-oxoacetic acid ester (6b). Step 3-1, 2-Substituted phenyl-2-oxoacetic acid ester (6c) by nucleophilic substitution of the fluorine atom on the benzene ring of the benzene ring with compound (12a) The benzylic carbonyl group of step 2-2, 2-substituted phenyl-2-oxoacetic acid ester (6c) is prepared with Wittig reagent prepared from triphenylphosphine and R ¹ ₂ CX ⁴ ₂ (7). Step 3-3 for producing acrylic acid derivative (8b) by treatment with dihalomethylene, reacting acrylic acid derivative (8b) with cyclic hydrazine (9), Comprising the step 3-4 to produce a bicyclic pyrazolinone derivative (2a).
Step 3-1 is a step of producing 2-substituted phenyl-2-oxoacetic acid ester (6b) by nitration of the benzene ring of 2-substituted phenyl-2-oxoacetic acid ester (6a).
Step 3-1 is the same reaction as Step 2-4 of Production Method-2 described above, and details thereof are as described in the description of Step 2-4. However, in the description of Step 2-4, the bicyclic pyrazolinone derivative (10a) is converted to 2-substituted phenyl-2-oxoacetic acid ester (6a), and the bicyclic pyrazolinone derivative (11a) is converted to 2-substituted phenyl-2-oxo Read as oxoacetic acid ester (6b).
Step 3-2 includes nucleophilic substitution of the fluorine atom on the benzene ring of the 2-substituted phenyl-2-oxoacetate ester (6b) with the compound (12a) to give a 2-substituted phenyl-2-oxoacetate ester (6c) Is a process of manufacturing.
Step 3-2 is the same reaction as Step 2-5 of Production Method-2 described above, and details thereof are as described in the description of Step 2-5. However, in the explanation of Step 2-5, the bicyclic pyrazolinone derivative (11a) is converted to 2-substituted phenyl-2-oxoacetic acid ester (6b), and the bicyclic pyrazolinone derivative (2a) is converted to 2-substituted phenyl-2-oxo. Read as oxoacetic acid ester (6c).
Step 3-3 treats the benzylic carbonyl group of 2-substituted phenyl-2-oxoacetic acid ester (6c) with Wittig reagent prepared from triphenylphosphine and R ¹ ₂ CX ⁴ ₂ (7). And dihalomethylene to produce an acrylic acid derivative (8b).
Step 3-3 is the same reaction as step 2-2 of the above-described production method-2, and details thereof are as described in the description of step 2-2. However, in the description of Step 2-2, the bicyclic pyrazolinone derivative (6a) is converted to 2-substituted phenyl-2-oxoacetic acid ester (6c), and the bicyclic pyrazolinone derivative (8a) is converted to 2-substituted phenyl-2-oxo. Read as oxoacetic acid ester (8b).
Step 3-4 is a step of producing the bicyclic pyrazolinone derivative (2a) by reacting the acrylic acid derivative (8b) with the cyclic hydrazine (9).
Step 3-4 is the same reaction as Step 2-3 of Production Method-2 described above, and details are as described in the description of Step 2-3. However, in the description of Step 2-3, the acrylic acid derivative (8a) is read as the acrylic acid derivative (8b), and the bicyclic pyrazolinone derivative (10a) is read as the bicyclic pyrazolinone derivative (2a).

［式中、Ｒ^１、Ｘ^１及びＹは前記と同じ意味を表す。Ｘ^２ｂ及びＸ^３ｂは、各々独立に、同一又は相異なって、水素原子；ハロゲン原子；Ｃ_１−Ｃ_４アルキル基；Ｃ_１−Ｃ_４ハロアルキル基；又はハロゲン原子及びＣ_１−Ｃ_４アルキル基からなる群より選択される１種以上の置換基で置換されていてもよいフェニル基を表す。Ｒ^３は、Ｃ_１−Ｃ_４アルキル基を表す。Ｌ^ａは、脱離基を表す。］Furthermore, in the method shown in Production Method-1, the bicyclic pyrazolinone derivative (2b) in which Z is an oxygen atom among the bicyclic pyrazolinone derivatives (2) as starting materials is shown in the following Production Method-4. It can also be manufactured by other methods.
Manufacturing method-4

[Wherein R ¹ , X ¹ and Y represent the same meaning as described above. X ^2b and X ^3b are each independently the same or different and represent a hydrogen atom; a halogen atom; a C ₁ -C ₄ alkyl group; a C ₁ -C ₄ haloalkyl group; or a halogen atom and a C ₁ -C ₄ alkyl group. Represents a phenyl group which may be substituted with one or more substituents selected from the group consisting of R ³ represents a C ₁ -C ₄ alkyl group. L ^a represents a leaving group. ]

Production method-4 includes Step 4-1 in which the bicyclic pyrazolinone derivative (11b) obtained by methoxylation of the bicyclic pyrazolinone derivative (11a) obtained in Step 2-4 of Production Method-2 is produced, Bicyclic pyrazolinone Step 4-2 for producing a bicyclic pyrazolinone derivative (11c) by converting a methoxy group on the benzene ring of the derivative (11b) to a hydroxyl group, a bicyclic pyrazolinone derivative (11c) and an acetate having a leaving group ( It consists of the process 4-3 which manufactures the said bicyclic pyrazolinone derivative (2b) by making 12b) react in presence of a base.
Step 4-1 is a step of producing a bicyclic pyrazolinone derivative (11b) by reacting the bicyclic pyrazolinone derivative (11a) with methanol in the presence of a base.
Step 4-1 is performed in the presence of a base. Examples of the base include triethylamine, tributylamine, N-methylmorpholine, amine bases such as pyridine, alkyllithium bases such as butyllithium and methyllithium, alkali metal hydrides such as sodium hydride and potassium hydride, sodium carbonate, Inorganic bases such as potassium carbonate, sodium hydroxide and potassium hydroxide can be used. Sodium hydride is preferable in terms of good yield.
Step 4-1 can be performed in the absence of a solvent, but can also be performed in an organic solvent that does not harm the reaction. Examples of the solvent include ether solvents such as THF, 1,4-dioxane, diethyl ether and DME, amide solvents such as DMF and dimethylacetamide, sulfoxide solvents such as DMSO, and nitrile solvents such as acetonitrile and propionitrile. Solvents, ketone solvents such as acetone and methyl ethyl ketone, aliphatic hydrocarbon solvents such as hexane, heptane, and octane, aromatic hydrocarbon solvents such as benzene, toluene, and chlorobenzene, and mixed solvents thereof can be exemplified. . Moreover, what is necessary is just to select and use an organic solvent suitably suitable for the base to be used. Further, methanol as a reaction reagent may be used as a solvent. From the viewpoint of good yield, ether solvents are preferable, and THF and 1,4-dioxane are more preferable.

The reaction in Step 4-1 can be carried out at a reaction temperature appropriately selected in the range of −78 to 80 ° C., depending on the base and solvent to be used.
After completion of the reaction, the desired product can be produced by isolating the desired product from the reaction system containing the desired product by a conventional method and purifying the product by recrystallization, distillation, column chromatography or the like as necessary. In some cases, the obtained target product can be used as it is as a raw material for the next step without purification.

Step 4-2 is a step of producing a bicyclic pyrazolinone derivative (11c) by deprotecting the hydroxyl protecting group (methyl group) on the benzene ring of the bicyclic pyrazolinone derivative (11b) and converting it to a hydroxyl group. is there.
The deprotection in Step 4-2 is performed by a known method effective for cleaving methyl ether bonds (for example, PGM Wuts and TW Greene, Protective Groups in Organic Synthesis, A John Wiley & Sons, Inc., p.25-30, p.370-382), the desired bicyclic pyrazolinone derivative (11c) can be produced by appropriately using an effective method. Among them, deprotection using boron tribromide is preferable in terms of yield and selectivity.
The deprotection reaction using boron tribromide can be carried out in an organic solvent such as dichloromethane or ethyl acetate. A method using dichloromethane is preferable in terms of a good yield. The reaction can be carried out at a temperature appropriately selected from -78 ° C to 60 ° C. There is no restriction | limiting in particular in the usage-amount of boron tribromide, What is necessary is just to use about 1-5 mol with respect to 1 mol of bicyclic pyrazolinone derivatives (11b) normally.
After completion of the reaction, the desired product can be produced by isolating the desired product from the reaction system containing the desired product by a conventional method and purifying the product by recrystallization, distillation, column chromatography or the like as necessary. In some cases, the obtained target product can be used as it is as a raw material for the next step without purification.

Step 4-3 is a step of producing a bicyclic pyrazolinone derivative (2b) by reacting a bicyclic pyrazolinone derivative (11c) with an acetate ester (12b) having a leaving group in the presence of a base. is there.
Step 4-3 is performed in the presence of a base. Examples of the base include triethylamine, tributylamine, N-methylmorpholine, amine bases such as pyridine, alkyllithium bases such as butyllithium and methyllithium, alkali metal hydrides such as sodium hydride and potassium hydride, sodium carbonate, Inorganic bases such as potassium carbonate, sodium hydroxide and potassium hydroxide can be used. Sodium hydride is preferable in terms of good yield.
Step 4-3 can be performed in the absence of a solvent, but can also be performed in an organic solvent that does not harm the reaction. Examples of the solvent include ether solvents such as THF, 1,4-dioxane, diethyl ether and DME, amide solvents such as DMF and dimethylacetamide, sulfoxide solvents such as DMSO, and nitrile solvents such as acetonitrile and propionitrile. Solvents, ketone solvents such as acetone and methyl ethyl ketone, aliphatic hydrocarbon solvents such as hexane, heptane, and octane, aromatic hydrocarbon solvents such as benzene, toluene, and chlorobenzene, and mixed solvents thereof can be exemplified. . Moreover, what is necessary is just to select and use an organic solvent suitably suitable for the base to be used. From the viewpoint of good yield, ether solvents are preferable, and THF and 1,4-dioxane are more preferable.
The reaction in Step 4-3 can be carried out at a reaction temperature appropriately selected in the range of −78 to 150 ° C., depending on the base and solvent to be used.
In acetate (12b) which is a raw material, as the leaving group represented by L ^a, a chlorine atom, a bromine atom, a halogen atom such as iodine atom, a methylsulfonyloxy group, a trifluoromethylsulfonyloxy group, a phenylsulfonyloxy group And substituted sulfonyloxy groups such as 4-methylphenylsulfonyloxy group.
The acetate ester (12b) can be easily obtained or can be easily prepared from commercially available raw materials, such as methyl chloroacetate, ethyl chloroacetate, methyl bromoacetate, ethyl bromoacetate, methyl bromofluoroacetate, bromofluoroacetate. Ethyl acetate, methyl bromodifluoroacetate, ethyl bromodifluoroacetate, methyl 2-chloropropionate, ethyl 2-chloropropionate, methyl 2-bromopropionate, ethyl 2-bromopropionate, methyl 2-bromobutyrate, 2-bromo Examples include α-halocarboxylic acid esters such as ethyl butyrate, butyl 2-bromobutyrate, methyl 2-bromoisobutyrate, ethyl 2-bromoisobutyrate, and butyl 2-bromoisobutyrate. In addition, the hydroxyl group of the α-hydroxycarboxylic acid ester exemplified in the above step 2-5 is substituted with a substituted sulfonyloxy such as methylsulfonyloxy group, trifluoromethylsulfonyloxy group, phenylsulfonyloxy group, 4-methylphenylsulfonyloxy group, etc. A compound converted into a group can also be exemplified as an acetate (12b) having a leaving group.

  After completion of the reaction, the desired product can be produced by isolating the desired product from the reaction system containing the desired product by a conventional method and purifying the product by recrystallization, distillation, column chromatography or the like as necessary. In some cases, the obtained target product can be used as it is as a raw material for the next step without purification.

［式中、Ｒ^１、Ｒ^４、Ｘ^１、Ｘ^４及びＹは前記と同じ意味を表す。］The bicyclic pyrazolinone derivative (11b), which is a production intermediate in the method shown in Production method-4, can also be produced by the method shown in the following production method-5.
Manufacturing method-5

[Wherein, R ¹ , R ⁴ , X ¹ , X ⁴ and Y represent the same meaning as described above. ]

Production Method-5 is a step 5-1 for producing 2-substituted phenyl-2-oxoacetic acid ester (6d) by reacting oxalic acid diester (5) with Grignard reagent prepared from bromobenzenes (4b). Step 5-2 for producing 2-substituted phenyl-2-oxoacetate ester (6e) by nitration on the benzene ring of 2-substituted phenyl-2-oxoacetate ester (6d) step producing the α-position of the carbonyl group of the oxo acid ester (6e), triphenylphosphine and _{^{R 1 2 CX 4 2 (7}} ) and Jiharomechiren by treatment with Wittig reagent prepared from acrylic acid derivative (8c) 5 -3, reacting acrylic acid derivative (8c) with cyclic hydrazines (9) to produce bicyclic pyrazolinone derivative (11b), which is a production intermediate Comprising the step 5-4.
Step 5-1 is the same reaction as step 2-1 of the above-described production method-2, and details thereof are as described in the description of step 2-1. However, in the description of Step 2-1, bromobenzenes (4a) are changed to benzenes (4b) and 2-substituted phenyl-2-oxoacetic acid ester (6a) is substituted to 2-substituted phenyl-2-oxoacetic acid. Read as ester (6d).
Step 5-2 is the same reaction as Step 2-4 of Production Method-2 described above, and details thereof are as described in the description of Step 2-4. However, in the description of Step 2-4, the bicyclic pyrazolinone derivative (10a) is converted to 2-substituted phenyl-2-oxoacetic acid ester (6d), and the bicyclic pyrazolinone derivative (11a) is converted to 2-substituted phenyl-2-oxo Read as oxoacetic acid ester (6e).

Step 5-3 is the same reaction as in Step 2-2 of Production Method-2 described above, and details thereof are as described in the description of Step 2-2. However, in the description of Step 2-2, 2-substituted phenyl-2-oxoacetic acid ester (6a) is converted to 2-substituted phenyl-2-oxoacetic acid ester (6e), and acrylic acid derivative (8a) is converted to acrylic acid derivative ( Read as 8c).
Step 5-4 is the same reaction as Step 2-3 of Production Method-2 described above, and details thereof are as described in the description of Step 2-3. However, in the description of Step 2-3, acrylic acid derivative (8a) is read as acrylic acid derivative (8c), and bicyclic pyrazolinone derivative (10a) is read as bicyclic pyrazolinone derivative (11b).

［式中、Ｒ^１、Ｘ^１及びＹは、前記と同じ意味を表す。Ｘ^２ｃ及びＸ^３ｃは、 ハロゲン原子を表す。Ｌ^ｂ及びＬ^ｃは、脱離基を表す。］The following bicyclic pyrazolinone derivative (1c), which is a part of the compound of the present invention, uses the bicyclic pyrazolinone derivative (11c) that can be produced by the method shown in Step 4-2 of Production Method-4 as a starting material. For example, it can also manufacture by the method shown to the following manufacturing methods-6.
Manufacturing method-6

[Wherein R ¹ , X ¹ and Y represent the same meaning as described above. X ^2c and X ^3c represent a halogen atom. L ^b and L ^c represent a leaving group. ]

  Production method-6 includes step 6-1 for producing a bicyclic pyrazolinone derivative (11d) by reducing the nitro group on the benzene ring of the bicyclic pyrazolinone derivative (11c), and the bicyclic pyrazolinone derivative (11d) Step 6-2 for producing a bicyclic pyrazolinone derivative (11e) by reacting an acetic acid derivative (12c) having a leaving group in the presence of a base, and the bicyclic pyrazolinone derivative (11e) in the presence of a base. It consists of the process 6-3 which cyclizes and manufactures the bicyclic pyrazolinone derivative (1c) which is a part of this invention compound.

Step 6-1 is a step of producing the bicyclic pyrazolinone derivative (11d) by reducing the nitro group on the benzene ring of the bicyclic pyrazolinone derivative (11c) to an amino group.
For reduction of the nitro group, catalytic reduction using hydrogen gas or hydrazine, or metal reduction using a metal or a metal compound such as iron, tin, or zinc can be used.
In catalytic reduction, a metal catalyst such as palladium, platinum, nickel, ruthenium, rhodium, or osmium is used. Palladium catalysts include palladium black, palladium-supported carbon, platinum catalysts include platinum-supported carbon, platinum (IV) oxide hydrate, etc., nickel catalysts include Raney nickel, ruthenium, rhodium, and osmium metals. Examples of the catalyst include ruthenium-supported carbon, rhodium-supported carbon, and osmium-supported carbon. The addition amount of the metal catalyst is usually 0.0001 to 10 mol%, preferably about 0.1 to 1.0 mol%, relative to the bicyclic pyrazolinone derivative (11c).
When hydrogen gas is used as the reducing agent, the pressure of the hydrogen gas is not particularly limited and may be pressurized as necessary. In that case, it is usually in the range of 0.1 to 1 MPa, preferably 0.1 to 0.5 MPa. The reaction may be carried out at a pressure selected as appropriate. When hydrazine is used as the reducing agent, the target product can be obtained in good yield by using 1 to 25 mol of hydrazine with respect to 1 mol of the bicyclic pyrazolinone derivative (11c).
The reduction reaction may be carried out at a reaction temperature appropriately selected in the range of usually 20 to 100 ° C., preferably 40 to 80 ° C.

In the catalytic reduction reaction, a reaction solvent is appropriately used as necessary. Examples of the reaction solvent include water, alcohol solvents such as methanol, ethanol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, dichloromethane, 1,2-dichloroethane, chloroform. , Halogen solvents such as carbon tetrachloride, ether solvents such as diethyl ether, DME, diethoxyethane, and THF, hydrocarbon solvents such as hexane, heptane, and cyclohexane, and aromatic hydrocarbons such as benzene, toluene, and xylene Examples thereof include organic solvents such as solvents and ester solvents such as ethyl acetate and butyl acetate, and methanol, ethyl acetate, THF, toluene and the like are preferable. These reaction solvents may be used alone or in appropriate combination of two or more.
In metal reduction using a metal such as iron, tin, or zinc, or a metal compound, the target product can be obtained in high yield by carrying out the reaction by appropriately selecting reaction conditions suitable for each metal. For example, iron-acetic acid, iron-hydrochloric acid, tin-hydrochloric acid, zinc-hydrochloric acid, etc. may be used. In the reaction, a reaction solvent is appropriately used as necessary.

  After completion of the reaction, the desired product can be produced by isolating the desired product from the reaction system containing the desired product by a conventional method and purifying the product by recrystallization, distillation, column chromatography or the like as necessary. In some cases, the obtained target product can be used as it is as a raw material for the next step without purification.

Step 6-2 is a step of producing a bicyclic pyrazolinone derivative (11e) by reacting the bicyclic pyrazolinone derivative (11d) with an acetic acid derivative (12c) having a leaving group in the presence of a base.
Step 6-2 is performed in the presence of a base. Bases include organic bases such as triethylamine, tributylamine and pyridine, sodium hydride and sodium amide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide and other inorganic bases, sodium methoxide, sodium ethoxide And alkali metal alkoxides such as potassium tert-butoxide, lithium bases such as methyl lithium and butyl lithium, and the like.
The reaction of step 6-2 can be carried out in an organic solvent. Any organic solvent that does not harm the reaction can be used as the organic solvent, and ether solvents such as 1,4-dioxane, THF, DME, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, benzene, toluene, Aromatic hydrocarbon solvents such as chlorobenzene, hydrocarbon solvents such as hexane and octane, ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone and cyclohexanone, ester solvents such as ethyl acetate and ethyl propionate, acetonitrile and propio Examples thereof include nitrile solvents such as nitriles, amide solvents such as DMF and N, N-dimethylacetamide, sulfoxide solvents such as DMSO, and mixed solvents thereof. Moreover, what is necessary is just to select and use an organic solvent suitably suitable for the base to be used.
Although there is no restriction | limiting in particular in reaction temperature, What is necessary is just to make it react at the temperature chosen suitably in the range from -30 degreeC to the reflux temperature of the solvent to be used.

In acetic acid derivative represented by the general formula (12c), as the leaving group represented by L ^b, it can be exemplified a chlorine atom, a bromine atom, a halogen atom such as iodine atom. In addition, examples of the leaving group represented by L ^c include C ₁ -C ₄ alkyloxy groups such as methoxy group, ethoxy group, isopropyl group, and butyl group, or halogen atoms such as chlorine atom and bromine atom. Can do.
Among the acetic acid derivatives (12c), some of the commercially available compounds can be easily prepared by a general chemical method in the art. Examples of the acetic acid derivative (12c) include methyl bromodifluoroacetate, ethyl bromodifluoroacetate, methyl chlorodifluoroacetate, ethyl chlorodifluoroacetate, bromofluoroacetic acid chloride, bromodifluoroacetic acid chloride, chlorofluoroacetic acid chloride, and chlorodifluoroacetic acid chloride. can do.
After completion of the reaction, the desired product can be produced by isolating the desired product from the reaction system containing the desired product by a conventional method and purifying the product by recrystallization, distillation, column chromatography or the like as necessary. In some cases, the obtained target product can be used as it is as a raw material for the next step without purification.

Step 6-3 is a step of producing a bicyclic pyrazolinone derivative (1c) which is a part of the compound of the present invention by cyclizing the bicyclic pyrazolinone derivative (11e) in the presence of a base.
Step 6-3 is performed in the presence of a base. Examples of the base include organic bases such as triethylamine, tributylamine, N-methylmorpholine, 4- (dimethylamino) pyridine, diazabicycloundecene (hereinafter abbreviated as DBU), and diazabicyclononene (hereinafter abbreviated as DBN). , Inorganic bases such as sodium hydride and sodium amide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide and potassium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, methyllithium And lithium bases such as butyl lithium and the like. From the viewpoint of good yield, strong base DBU and DBN having low nucleophilicity are preferred.
The reaction in Step 6-3 can be carried out in an organic solvent. Any organic solvent that does not harm the reaction can be used as the organic solvent, and ether solvents such as 1,4-dioxane, THF, DME, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, benzene, toluene, Aromatic hydrocarbon solvents such as chlorobenzene, hydrocarbon solvents such as hexane and octane, ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone and cyclohexanone, ester solvents such as ethyl acetate and ethyl propionate, acetonitrile and propio Examples thereof include nitrile solvents such as nitriles, amide solvents such as DMF and N, N-dimethylacetamide, sulfoxide solvents such as DMSO, and mixed solvents thereof. Moreover, what is necessary is just to select and use an organic solvent suitably suitable for the base to be used.
Although there is no restriction | limiting in particular in reaction temperature, What is necessary is just to make it react at the temperature chosen suitably in the range from room temperature to the reflux temperature of the solvent to be used.

  After completion of the reaction, the desired product can be produced by isolating the desired product from the reaction system containing the desired product by a conventional method and purifying the product by recrystallization, distillation, column chromatography or the like as necessary. In some cases, the obtained target product can be used as it is as a raw material for the next step without purification.

［式中、Ｒ^１、Ｒ^３、Ｘ^１及びＹは、前記と同じ意味を表す。Ｒ^２ｃは、水素原子；Ｃ_１−Ｃ_６アルキル基；Ｃ_１−Ｃ_６ハロアルキル基；Ｃ_３−Ｃ_６シクロアルキル基；Ｃ_２−Ｃ_６アルケニル基；Ｃ_２−Ｃ_６アルキニル基；又はハロゲン原子、Ｃ_１−Ｃ_４アルキル基、Ｃ_１−Ｃ_４アルキルオキシ基、（Ｃ_１−Ｃ_４アルキル）オキシカルボニル基、トリフルオロメチル基、シアノ基及びニトロ基からなる群より選択される１種以上の置換基で置換されていてもよいＣ_７−Ｃ_８アラルキル基を表す。Ｘ^２ｄは、水素原子；Ｃ_１−Ｃ_４アルキル基；Ｃ_１−Ｃ_４ハロアルキル基；又はハロゲン原子及びＣ_１−Ｃ_４アルキル基からなる群より選択される１種以上の置換基で置換されていてもよいフェニル基を表す。］The following bicyclic pyrazolinone derivative (1d) having a 1,2-dihydro-2-oxoquinoxalin-7-yl group, which is a part of the compound of the present invention, is shown in Production Method-2 and Production Method-3. The bicyclic pyrazolinone derivative (11f) that can be produced according to the above method can be used as a starting material, for example, by the method shown in the following production method-7.
Manufacturing method-7

[Wherein R ¹ , R ³ , X ¹ and Y represent the same meaning as described above. R ^2c is a hydrogen atom; a C ₁ -C ₆ alkyl group; a C ₁ -C ₆ haloalkyl group; a C ₃ -C ₆ cycloalkyl group; a C ₂ -C ₆ alkenyl group; a C ₂ -C ₆ alkynyl group; _atom, C 1 -C ₄ alkyl _group, C 1 -C ₄ alkyl _{group, (C} 1 -C ₄ alkyl) oxycarbonyl group, a trifluoromethyl group, one selected from the group consisting of cyano group and a nitro group It represents a C ₇ -C ₈ aralkyl group which may be substituted with the above substituents. X ^2d is substituted with one or more substituents selected from the group consisting of a hydrogen atom; a C ₁ -C ₄ alkyl group; a C ₁ -C ₄ haloalkyl group; or a halogen atom and a C ₁ -C ₄ alkyl group. Represents an optionally substituted phenyl group. ]

Production method-7 is a step 7-1 of producing a bicyclic pyrazolinone derivative (11g) by nitrating the 4-position of the benzene ring of the bicyclic pyrazolinone derivative (11f), the benzene ring of the bicyclic pyrazolinone derivative (11g). Step 7-2 for producing a bicyclic pyrazolinone derivative (11h) by nucleophilic substitution of the 5-position fluorine atom with an amine represented by the general formula R ^2c —NH ₂ (13), bicyclic pyrazolinone derivative (11h) Step 7-3 for producing a bicyclic pyrazolinone derivative (11i) by reducing the nitro group at the 4-position of the benzene ring, and 2-oxo represented by the bicyclic pyrazolinone derivative (11i) and the general formula X ^2d COCOOR ³ It consists of process 7-4 which condenses carboxylic acid ester (14) and manufactures the bicyclic pyrazolinone derivative (1d) which is a part of this invention compound.
Step 7-1 is a step of selectively nitration of the 4-position of the benzene ring of the bicyclic pyrazolinone derivative (11f) to produce a bicyclic pyrazolinone derivative (11g).
Step 7-1 is a reaction similar to Step 2-4 of Production Method-2 described above, and details thereof are as described in the description of Step 2-4. However, in the explanation of Step 2-4, the bicyclic pyrazolinone derivative (10a) is read as the bicyclic pyrazolinone derivative (11f), and the bicyclic pyrazolinone derivative (11a) is read as the bicyclic pyrazolinone derivative (11g).
In Step 7-2, the fluorine atom activated by the adjacent nitro group at the 5-position of the benzene ring of the bicyclic pyrazolinone derivative (11 g) is converted with an amine (13) represented by the general formula R ^2c —NH ₂ . This is a step of producing a bicyclic pyrazolinone derivative (11h) by nucleophilic substitution.
Examples of amines (13) that are raw materials for Step 7-2 include ammonia; methylamine, ethylamine, propylamine, isopropylamine, butylamine, tert-butylamine, isobutylamine, pentylamine, isopentylamine, hexylamine, isohexyl. Alkylamines such as amines; cycloalkylamines such as cyclopropylamine, cyclopropylmethylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine; alkenylamines such as allylamine, methallylamine, crotylamine, geranylamine; propargylamine, 3- Alkynylamines such as amino-1-butyne and 1-amino-2-butyne; benzylamine, 2-fluorobenzylamine, 4-fluorobenzylamine, 4-chloro Benzylamine, 2,4-difluorobenzylamine, 3,5-dichlorobenzylamine, 2-methylbenzylamine, 4-methylbenzylamine, 4-isopropylbenzylamine, 4-tert-butylbenzylamine, 2- (methyloxy ) Benzylamine, 4- (methyloxy) benzylamine, 4- (isopropyloxy) benzylamine, 4- (tert-butyloxy) benzylamine, 4- (methyloxycarbonyl) benzylamine, 4- (ethyloxycarbonyl) benzyl Amine, 4- (isopropyloxycarbonyl) benzylamine, 4- (tert-butyloxycarbonyl) benzylamine, 2- (trifluoromethyl) benzylamine, 3- (trifluoromethyl) benzylamine, 4- (trifluoro Til) benzylamine, 2-cyanobenzylamine, 4-cyanobenzylamine, 2-nitrobenzylamine, 4-nitrobenzylamine, aralkylamines such as α-phenethylamine, β-phenethylamine; and chemically acceptable Examples of these amines include hydrochlorides and sulfates.

The reaction in Step 7-2 can be promoted by adding a base. Bases include organic bases such as triethylamine, diisopropylethylamine, tributylamine, pyridine, inorganic bases such as sodium hydride, sodium amide, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium ethoxide, potassium tert-butoxide. Examples thereof include alkali metal alkoxides such as lithium bases such as methyl lithium and butyl lithium.
The amount of the base used is not particularly limited, and the amine (13) used as a raw material also acts as a base, so that the reaction can proceed sufficiently without adding a base, and the target product can be obtained with good yield. it can. In the case of using salts of amines such as hydrochlorides or sulfates in amines (13), it is preferable to add an equal amount or more of a base in order to capture hydrochloric acid or sulfuric acid.
The reaction of step 7-2 can be carried out in a solvent. As the solvent, any solvent that does not harm the reaction can be used. Ether solvents such as 1,4-dioxane, THF, DME, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, benzene, toluene, chlorobenzene, etc. Aromatic hydrocarbon solvents, hydrocarbon solvents such as hexane and octane, nitrile solvents such as acetonitrile and propionitrile, amide solvents such as DMF and N, N-dimethylacetamide, sulfoxide solvents such as DMSO, Furthermore, these mixed solvents can be illustrated. Preferably, ether solvents such as 1,4-dioxane and THF can be exemplified.
The reaction in Step 7-2 can be performed at a temperature appropriately selected in the range of 0 ° C to 100 ° C.

Step 7-3 is a step of producing the bicyclic pyrazolinone derivative (11i) by reducing the nitro group at the 4-position of the benzene ring of the bicyclic pyrazolinone derivative (11h).
Step 7-3 is the same reaction as Step 6-1 in the above-mentioned production method-6, and details thereof are as described in the description of Step 6-1. However, in the description of Step 6-1, the bicyclic pyrazolinone derivative (11c) is replaced with the bicyclic pyrazolinone derivative (11h), and the bicyclic pyrazolinone derivative (11d) is replaced with the bicyclic pyrazolinone derivative (11i). However, in the step 7-3, when the nitro group is reduced by catalytic reduction, when the substituent R ^{2c of the} bicyclic pyrazolinone derivative (11h) is an alkenyl group or an alkynyl group, a double bond of the substituent or Since the triple bond may be reduced, and when the substituent R ^2c is an aralkyl group, the aralkyl group may be hydrocracked. Metal reduction using iron-acetic acid, iron-hydrochloric acid, tin-hydrochloric acid, zinc-hydrochloric acid and the like is preferable, and the target product can be obtained at a low yield with good yield. Therefore, metal reduction using reduced iron is more preferable.

Step 7-4 is a step of condensing the bicyclic pyrazolinone derivative (1d) of the present invention by condensing the bicyclic pyrazolinone derivative (11i) and the 2-oxocarboxylic acid ester (14) represented by the general formula X ^2d COCOOR ^3. It is a manufacturing process.
Examples of the 2-oxocarboxylic acid ester (14) as a raw material of Step 7-4 include glyoxylic acid, pyruvic acid, 2-oxobutanoic acid, 3-methyl-2-oxobutanoic acid, 2-oxopentanoic acid, 3-methyl- 2-oxopentanoic acid, 4-methyl-2-oxopentanoic acid, 3,3-dimethyl-2-oxobutanoic acid, 3-fluoropyruvic acid, 3-chloropyruvic acid, 3-bromopyruvic acid, trifluoropyruvic acid, Examples thereof include methyl esters such as 4-chloro-3,3-dimethyl-2-oxobutanoic acid, ethyl esters, and tert-butyl esters. Furthermore, as 2-oxocarboxylic acid ester (14), benzoyl formic acid, 2-fluorobenzoyl formic acid, 3-fluorobenzoyl formic acid, 4-fluorobenzoyl formic acid, 2-chlorobenzoyl formic acid, 3-chlorobenzoyl formic acid, 4-chloro Benzoyl formic acid, 2,4-difluorobenzoyl formic acid, 2,6-difluorobenzoyl formic acid, 2,4-dichlorobenzoyl formic acid, 2,6-dichlorobenzoyl formic acid, 2-methylbenzoyl formic acid, 3-methylbenzoyl formic acid, 4-methyl Examples include methyl esters, ethyl esters, tert-butyl esters, etc. such as benzoylformic acid, 4-isopropylbenzoylformic acid, 4-tert-butylbenzoylformic acid, 2,4-dimethylbenzoylformic acid, 2,6-dimethylbenzoylformic acid, etc. it can. A part of the 2-oxocarboxylic acid ester (14) is commercially available, but can be easily produced according to a known method.

Step 7-4 is performed in the presence of a base. Examples of the base include triethylamine, tributylamine, N-methylmorpholine, 4- (dimethylamino) pyridine, DBU, DBN and other organic bases, sodium hydride and sodium amide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, Examples thereof include inorganic bases such as potassium hydroxide, alkali metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, and lithium bases such as methyl lithium and butyl lithium. From the viewpoint of good yield, strong base DBU and DBN having low nucleophilicity are preferred.
The reaction in Step 7-4 can be carried out in an organic solvent. Any organic solvent that does not harm the reaction can be used as the organic solvent, and ether solvents such as 1,4-dioxane, THF, DME, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, benzene, toluene, Aromatic hydrocarbon solvents such as chlorobenzene, hydrocarbon solvents such as hexane and octane, nitrile solvents such as acetonitrile and propionitrile, amide solvents such as DMF and N, N-dimethylacetamide, sulfoxides such as DMSO Examples of the solvent and a mixed solvent thereof can be given. Moreover, what is necessary is just to select and use an organic solvent suitably suitable for the base to be used.
Although there is no restriction | limiting in particular in reaction temperature, What is necessary is just to make it react at the temperature chosen suitably in the range from room temperature to the reflux temperature of the solvent to be used.
The reaction of step 7-4 can improve the yield by reacting in the presence of a dehydrating agent. Examples of the dehydrating agent include sodium sulfate, magnesium sulfate, niline pentoxide, molecular sieve and the like. The yield can also be improved by azeotropically removing water produced by the reaction using Dean Stark.
In Steps 7-1 to 7-4, after completion of the reaction, the target product is isolated from the reaction system containing the target product by a conventional method, and purified by recrystallization, distillation, column chromatography or the like as necessary. The target product can be manufactured. In some cases, the obtained target product can be used as it is as a raw material for the next step without purification.

［式中、Ｒ^１、Ｒ^２ｃ、Ｘ^１、Ｘ^２ｄ及びＹは、前記と同じ意味を表す。Ｌ^ｄは、脱離基を表す。］In addition, the following bicyclic pyrazolinone derivative (1e) having a benzimidazol-6-yl group, which is a part of the compound of the present invention, is a bicyclic pyrazolinone derivative that can be produced according to the method shown in Production Method-7 ( 11i) can be used as a starting material, for example, by the method shown in the following production method-8.
Manufacturing method-8

[Wherein, R ¹ , R ^2c , X ¹ , X ^2d and Y represent the same meaning as described above. L ^d represents a leaving group. ]

Production method-8 is a part of the compound of the present invention by condensing the bicyclic pyrazolinone derivative (11i) and the carboxylic acid derivative (15) represented by the general formula X ^2d CO-L ^d in the presence of a base. It consists of process 8-1 which manufactures a bicyclic pyrazolinone derivative (1e).
In the carboxylic acid derivative (15) represented by the general formula X ^2d CO-L ^d which is the raw material of the step 8-1, examples of the leaving group represented by L ^d include a methoxy group, an ethoxy group, and an isopropyloxy group And a halogen atom such as a chlorine atom or a bromine atom. In addition, the carboxylic acid derivative (15) may be a carboxylic acid anhydride. In this case, the leaving group represented by L ^d is X ^2d COO (wherein X ^2d represents the same meaning as described above). )), And examples thereof include an acetyloxy group, a propionyloxy group, a pivaloyloxy group, and a trifluoroacetyloxy group.
More specifically, the carboxylic acid derivative (15) that is the raw material of Step 8-1 includes formic acid, acetic acid, propionic acid, 2-methylpropionic acid, butyric acid, isobutyric acid, 3-methylbutanoic acid, valeric acid, Methyl esters, ethyl esters, such as valeric acid, pivalic acid, fluoroacetic acid, chloroacetic acid, bromoacetic acid, trifluoroacetic acid, trichloroacetic acid, difluorochloroacetic acid, difluorobromoacetic acid, 3-chloro-2,2-dimethylpropionic acid, Examples thereof include esters such as tert-butyl ester; chemically acceptable acid chlorides and bromides of these carboxylic acids; chemically acceptable anhydrides of these carboxylic acids; and the like. Examples of the carboxylic acid derivative (15) include benzoic acid, 2-fluorobenzoic acid, 3-fluorobenzoic acid, 4-fluorobenzoic acid, 2-chlorobenzoic acid, 3-chlorobenzoic acid, 4-chlorobenzoic acid, 2,4-difluorobenzoic acid, 2,6-difluorobenzoic acid, 2,4-dichlorobenzoic acid, 2,6-dichlorobenzoic acid, 2-methylbenzoic acid, 3-methylbenzoic acid, 4-methylbenzoic acid, Esters such as 4-isopropylbenzoic acid, 4-tert-butylbenzoic acid, 2,4-dimethylbenzoic acid, 2,6-dimethylbenzoic acid, and the like, such as methyl ester, ethyl ester, and tert-butyl ester; Examples thereof include acceptable acid chlorides and acid bromides of these carboxylic acids; chemically acceptable anhydrides of these carboxylic acids; and the like. Some of the carboxylic acid derivatives (15) are commercially available, but can be easily produced according to known methods.

Step 8-1 is performed in the presence of a base. Examples of the base include organic bases such as triethylamine, tributylamine, N-methylmorpholine, 4- (dimethylamino) pyridine, DBU and DBN, and inorganic bases such as sodium carbonate, potassium carbonate and cesium carbonate.
The reaction of step 8-1 can be carried out in an organic solvent. Any organic solvent that does not harm the reaction can be used as the organic solvent, such as ether solvents such as 1,4-dioxane, THF, DME, diethyl ether, diisopropyl ether, cyclopentyl methyl ether, chloroform, dichloromethane, etc. Halogen solvents such as benzene, toluene and chlorobenzene, hydrocarbon solvents such as hexane and octane, nitrile solvents such as acetonitrile and propionitrile, DMF and N, N-dimethylacetamide, etc. Examples thereof include amide solvents, sulfoxide solvents such as DMSO, and mixed solvents thereof. Moreover, what is necessary is just to select and use an organic solvent suitably suitable for the base to be used.
Although there is no restriction | limiting in particular in reaction temperature, What is necessary is just to make it react at the temperature chosen suitably in the range from 0 degreeC to the reflux temperature of the solvent to be used.
After completion of the reaction, the desired product can be produced by isolating the desired product from the reaction system containing the desired product by a conventional method and purifying the product by recrystallization, distillation, column chromatography or the like as necessary.

Next, the herbicide of this invention which uses the bicyclic pyrazolinone derivative of this invention as an active ingredient, and its usage method are demonstrated.
The bicyclic pyrazolinone derivative of the present invention has an excellent weed control effect and can be used as an active ingredient of a herbicide. Moreover, it has excellent profiles such as good residual effect and selectivity between crops and weeds.
The bicyclic pyrazolinone derivative of the present invention is useful for controlling annual, perennial and perennial weeds occurring in paddy fields, fields, orchards, wetlands and the like. More specifically, barb, enokirogusa, barnyard grass, sparrow burdock, oats, abalone, black-bellied, blue-headed toe, ichibibi, white-blossoms, intagade, marba morning glory, green-billed moth, red-bellied grasshopper, red-breasted moth, red-bellied, red-bucked, red-bucked Field weeds such as Giant pufferfish, Tainubie, Tamagayatsuri, Matsubai, Inuhotarui, Mitsugayatsuri, Kurogwai, Konagi, Azena, Kakishigusa, Mizuaoi, Himesohagi, Mizohakobe, Urikawa, Omodaka, Azaena it can.
The bicyclic pyrazolinone derivative of the present invention has good selectivity for cultivated crops such as corn, wheat, soybean, etc., and various cultivated crops (for example, corn, wheat, barley, rice, soybean, It has an excellent profile as a herbicide using rapeseed, sugar beet, cotton, etc.) as an applied crop.

Since the bicyclic pyrazolinone derivative of the present invention exhibits an excellent herbicidal effect on weeds before and after emergence, when used as a herbicide, the bicyclic pyrazolinone derivative is pre-treated on a planting planned site such as a crop or a crop. After planting, etc., the characteristic physiological activity of the bicyclic pyrazolinone derivative of the present invention can be more effectively exhibited by treating from the initial generation stage of weeds to the growing stage. However, the herbicide of the present invention is not limited to use in such an embodiment, for example, upland, paddy fields, paddy cuttings, fallow paddy fields, ridges, farm roads, waterways, grassland, cemeteries, parks. It can also be used for extermination of weeds such as roads, playgrounds, vacant lots around buildings, open land, track ends or forests. In this case, it is economically most advantageous and effective to carry out the treatment before the beginning of weed generation, but it is not necessarily limited to this, and weeds in the growing season can be controlled.
When the bicyclic pyrazolinone derivative of the present invention is used as a herbicide, it may be used after being formulated into a convenient shape according to a conventional method for agricultural chemical formulations. In general, the bicyclic pyrazolinone derivative of the present invention is blended in an appropriate ratio in an appropriate liquid carrier or solid carrier and dissolved, dispersed, suspended, mixed, impregnated or adsorbed, and a dosage form suitable for the intended use. It is formulated and used.

Examples of the pharmaceutical form of the herbicide of the present invention include, for example, wettable powder, granular wettable powder, aqueous solvent, emulsion, liquid, oil, spray, powder, DL (driftless) type powder, granule, fine granule, A fine granule F, a fine granule F, a flowable agent, a dry flowable agent, a jumbo agent, a tablet, a paste agent, etc. can be mentioned.
These preparations may contain, as necessary, auxiliary agents such as emulsifiers, dispersants, spreading agents, penetrants, wetting agents, binders, thickeners, preservatives, antioxidants, and coloring agents in appropriate proportions. And can be prepared by a known method.
Examples of the liquid carrier used for formulation include water; alcohols such as methanol, ethanol, propyl alcohol, isopropyl alcohol, and ethylene glycol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, diisobutyl ketone, and cyclohexanone. Ethers such as dioxane, tetrahydrofuran, dipropyl ether, ethylene glycol monomethyl ether, diethylene glycol monomethyl ether, and propylene glycol monomethyl ether; aliphatic hydrocarbons such as hexane, octane, cyclohexane, kerosene, fuel oil, and machine oil; benzene and Aromatic hydrocarbons such as toluene, xylene, solvent naphtha and methylnaphthalene: Halogenated carbon such as dichloromethane, chloroform and carbon tetrachloride Hydrogens; acid amides such as DMF, dimethylacetamide and N-methylpyrrolidone; esters such as ethyl acetate and butyl acetate, diisopropyl phthalate, dibutyl phthalate and fatty acid glycerin esters; nitriles such as acetonitrile and propionitrile; Sulfoxides such as dimethyl sulfoxides; and the like. These liquid carriers can be used alone or in admixture of two or more at an appropriate ratio.

Solid carriers used in the formulation include minerals such as kaolin, bentonite, clays such as acid clay, clay, talc such as talc and wax stone powder, silicas such as diatomaceous earth, white carbon and mica powder Plant powders such as soybean powder, CMC, tobacco powder, wheat flour (grain flour), and wood flour; inorganic salts such as calcium carbonate, sodium bicarbonate, potassium chloride, ammonium sulfate, and potassium sulfate; sugars such as lactose and glucose And other solid carriers such as alumina and activated carbon. These solid carriers can be used alone or in admixture of two or more at an appropriate ratio.
The liquid carrier or solid carrier used for formulation is usually 1 to 99% by weight, preferably about 10 to 99% by weight, based on the whole preparation.
When formulating, adjuvants such as emulsifiers, dispersants, spreading agents, penetrants, wetting agents and the like are used depending on the purpose. One type or two or more types of auxiliary agents may be used in combination depending on the application, but it is also possible to not use them at all. Surfactants are usually used for the purpose of emulsifying, dispersing, solubilizing and / or wetting the active ingredient in the carrier.

Examples of the surfactant include polyoxyethylene alkyl ether, polyoxyethylene alkyl aryl ether, polyoxyethylene alkyl polyoxypropylene block copolymer, polyethylene glycol fatty acid ester, polyoxyethylene polyhydric alcohol fatty acid ester, sucrose fatty acid ester, sorbitan Nonionic surfactants such as fatty acid esters; alkyl sulfate esters, alkylaryl sulfonates, dialkyl sulfosuccinates, polyoxyalkylene allyl phenyl ether sulfonates, polyoxyethylene alkyl phenyl ether sulfonates, polyoxyethylene An alkyl aryl ether phosphate ester salt, lignin sulfonate, naphthalene sulfonate formaldehyde polycondensate, etc. Emissions surfactant, alkyl trimethyl ammonium chloride _{(C 12 to 18),} methyl polyoxyethylene alkyl ammonium chloride _{(C 12 to 18),} alkyl-N-methyl pyridium bromide _{(C 12 to 18),} mono or Ammonium type surfactants such as dialkyl (C _12-18 ) methylated ammonium chloride, alkyl (C _12-18 ) pentamethylpropylenediamine dichloride, alkyldimethylbenzalkonium chloride (C _12-18 ), benzethonium chloride (octyl) phenoxy cationic surfactants such as benzalkonium-type surfactants such as ethoxyethyl dimethyl benzyl ammonium chloride); dialkyl (C _{8 to 12)} diamino ethyl betaines, alkyl (C _{12 to 18)} Jimechirube Jirubetain, dialkyl _{(C 8 to 12)} diamino ethyl glycine, alkyl _{(C 12 to 18)} such as amphoteric surfactants dimethylbenzyl glycine and the like. These surfactants may be used alone or in combination of two or more depending on the application. The surfactant is usually used in a proportion of 0.1 to 50% by weight, preferably about 0.1 to 25% by weight, based on the whole preparation.

  Examples of the binder and thickener include dextrin, sodium salt of carboxymethyl cellulose, polycarboxylic acid polymer compound, polyvinyl pyrrolidone, polyvinyl alcohol, sodium lignin sulfonate, calcium lignin sulfonate, sodium polyacrylate, gum arabic , Sodium alginate, mannitol, sorbitol, bentonite mineral, polyacrylic acid and its derivatives, white carbon, natural sugar derivatives (for example, xanthan gum, guar gum, etc.), and the like.

  The content ratio of the bicyclic pyrazolinone derivative of the present invention in the herbicide of the present invention is not particularly limited because it may be appropriately adjusted depending on the purpose of use, but is usually about 0.01 to 90% by weight, for example, emulsion, water It is a ratio of 1 to 90% by weight for a powder, a wettable powder, a liquid, an aqueous solvent, a flowable, etc., and a ratio of 0.01 to 10% by weight is usually used for an oil, a powder, a DL powder, etc. In the case of fine granules, fine granules F, fine granules F, granules, etc., the proportion is usually 0.05 to 10% by weight. Emulsions, wettable powders, granular wettable powders, liquids, aqueous solvents, flowables and the like are usually used by appropriately diluting with water or the like, and usually diluted about 100 to 100,000 times.

Next, the usage method of the herbicide of this invention is demonstrated. The herbicide of this invention can be used with the application method of well-known agricultural chemicals, such as soil spraying, water surface spraying, foliage spraying, and air spraying.
When the herbicide of the present invention is used as a herbicide for upland fields or paddy fields, the amount to be used (that is, effective amount) is appropriately set in consideration of the application area, application time, application method, target grass species, cultivated crops, etc. Usually, the compound of the present invention is about 1 to 5000 g, preferably about 10 to 1000 g, per hectare of a field or paddy field.
The herbicide of the present invention is usually used as a pre-emergence soil admixture treatment agent, a pre-emergence soil treatment agent, or a post-emergence foliar treatment agent for upland weed control. For paddy field weed control, it is usually used as a flooded soil treatment agent or a foliage and soil treatment agent.

  Further, the herbicide of the present invention may be used in combination with one or more other herbicides, insecticides, acaricides, nematicides, fungicides, plant growth regulators, etc., if necessary. Or it can also use together. The herbicide of the present invention may contain other active ingredients such as one or more herbicides, insecticides, acaricides, nematicides, fungicides, plant growth regulators and the like. It may be used in combination with these other active ingredients.

As an active ingredient of other herbicides that can be applied and / or mixed with the compound of the present invention and used, for example,
(1) Phenoxy fatty acid-based herbicidal compounds [2,4-PA, MCP, MCPB, phenothiol, mecoprop, fluroxypyr, triclopyr, clomeprop, naproanilide, etc.],
(2) Benzoic acid herbicidal compounds [2,3,6-TBA, dicamba, clopyralid, picloram, aminopyralide, quinclolac, quinmelac, etc.],
(3) Urea-based herbicidal compounds [diuron, linuron, chlortoluron, isoproturon, fluometuron, isouron, tebuthiuron, metabenzthiazurone, cumyluron, diimron, methyldaimiron]
(4) Triazine herbicidal compounds [atrazine, amethrin, cyanazine, simazine, propazine, simethrin, dimetamethrin, promethrin, metribudine, triadifram, etc.]

(5) Bipyridinium herbicidal compounds [paraquat, diquat, etc.]
(6) Hydroxybenzonitrile-based herbicidal compounds [bromoxynyl, ioxinyl, etc.]
(7) dinitroaniline herbicidal compound [pendimethalin, prodiamine, trifluralin, etc.],
(8) Organophosphorus herbicidal compounds [amiprophos methyl, butamifos, benzulide, piperophos, anilophos, glyphosate, glufosinate, glufosinate-P, bialaphos, etc.]
(9) Carbamate herbicidal compounds [dialate, trialate, EPTC, butyrate, bencho curve, esprocarb, molinate, dimethylpiperate, swep, chlorprofam, fenmedifam, phenicofam, pyribuchicarb, ashram, etc.],
(10) Acid amide-based herbicidal compounds [propanyl, propyzamide, bromobutide, ettobenzanide, etc.]

(11) Chloroacetanilide herbicidal compounds [acetochlor, alachlor, butachlor, dimethenamide, propachlor, metazachlor, metolachlor, pretilachlor, tenyl chlor, petoxamide, etc.]
(12) Diphenyl ether type herbicidal compounds [acifluorfen, biphenox, oxyfluorfen, lactofen, fomesafen, clomethoxynil, acloniphen, etc.],
(13) Cyclic imide-based herbicidal compounds [oxadiazone, sinidoneethyl, carfentrazoneethyl, sulfentrazone, flumicrolacpentyl, flumioxazin, pyraflufenethyl, oxadialgyl, pentoxazone, fluthiaset methyl, butaphenacyl, benzphene Dizone, bencarbazone, saflufenacil, etc.],
(14) Pyrazole-based herbicidal compounds [benzophenap, pyrazolate, pyrazoxifene, topramezone, pyrasulfol, etc.]
(15) Triketone herbicidal compounds [isoxafurtol, benzobicyclone, sulcotrione, mesotrione, tembotrione, tefryltrione, etc.]

(16) Aryloxyphenoxypropionic acid herbicidal compounds [clodinahop propargyl, cihalohop butyl, diclohop methyl, phenoxaprop ethyl, fluazif butyl, haloxy hop methyl, quizalofop ethyl, metamihop, etc.] ,
(17) Trione oxime herbicidal compounds [aloxidim, cetoxydim, butroxidim, cresodymium, cloproxydim, cycloxydim, teplaloxidim, tolalkoxydim, propoxydim, etc.],
(18) Sulfonylurea-based herbicidal compounds [chlorsulfuron, sulfometuron methyl, metsulfuron methyl, chlorimuron ethyl, tribenuron methyl, trisulfuron, bensulfuron methyl, thifensulfuron methyl, pyrazosulfuron ethyl , Primissulfuron methyl, nicosulfuron, amidosulfuron, sinosulfuron, imazosulfuron, rimsulfuron, halosulfuronmethyl, prosulfuron, ethamethsulfuronmethyl, triflusulfuronmethyl, flazasulfuron, cyclosulfamuron, flupirsulfuron, Sulfosulfuron, azimusulfuron, ethoxysulfuron, oxasulfuron, iodosulfuron methyl sodium, foramsulfuron, mesosulfuron methyl, trifloxysulfuron, Tosurufuron, ortho-Sul Pham Ron, flucetosulfuron, professional Pires iodosulfuron, etc.],
(19) Imidazolinone herbicidal compounds [imazametabenzmethyl, imazametapyr, imazamox, imazapill, imazaquin, imazetapyr, etc.],
(20) Sulfonamide-based herbicidal compounds [flumethoslam, methoslam, diclosram, florasuram, chloransrammethyl, penoxsulam, pyroxusram, etc.]

(21) Pyrimidinyloxybenzoic acid herbicidal compound [pyrithiobac sodium, bispyribac sodium, pyriminobacmethyl, pyribenzoxime, pyriphthalide, pyrimisulphan, etc.],
(22) Herbicidal compounds of other strains [bentazone, bromacil, terbacil, chlorthiamid, isoxaben, dinosebu, amitrol, cinmethyline, tridiphan, dalapon, diflufenzopyr sodium, dithiopyr, thiazopyr, sodium flucarbazone, propoxycarbazone sodium , Mefenacet, flufenacet, fentolazamide, fentorazol, indanophan, oxadiclomephone, benfrecetate, ACN, pyridate, chloridazone, norflurazon, flurtamone, diflufenican, picolinaphene, beflubutamide, cromazone, amicarbazone, pinoxaden, pyraclonene, carbaclosonth Aminocyclopyrachlor, ipfencarbazone, etc.] Gerare,

  Examples of the active ingredient of the plant growth regulator include, for example, hymexazole, paclobutrazol, uniconazole-P, inabenfide, prohexadione calcium, abiglycine, 1-naphthylacetamide, abscisic acid, indolebutyric acid, ethiclozate, ethephone, cloxiphonac , Chlormequat, dichloroprop, gibberellin, prohydrojasmon, benzylaminopurine, forchlorphenuron, maleic acid hydrazide, calcium peroxide, mepicoat chloride, 4-CPA, etc.

As an active ingredient of a fungicide,
(1) Polyhaloalkylthio-based bactericidal compounds [captan, phorpet, etc.]
(2) Organophosphorous fungicidal compounds [IBP, EDDP, torquelophosmethyl, etc.]
(3) Benzimidazole bactericidal compounds [benomyl, carbendazim, thiophanate methyl, thiabendazole, etc.]
(4) Carboxamide-based bactericidal compounds [Carboxin, mepronil, flutolanil, tifluzamide, furametopyr, boscalid, pentiopyrad, etc.]
(5) Dicarboximide-based bactericidal compounds [procymidone, iprodione, vinclozoline, etc.],

(6) Acylalanine fungicidal compound [metalaxyl etc.],
(7) Azole fungicidal compounds [triadimephone, triadimenol, propiconazole, tebuconazole, cyproconazole, epoxiconazole, prothioconazole, ipconazole, triflumizole, prochloraz, penconazole, flusilazole, diniconazole, brom Conazole, difenoconazole, metconazole, tetraconazole, microbutanyl, fenbuconazole, hexaconazole, fluquinconazole, triticonazole, viteltanol, imazalyl, flutriahol, etc.],
(8) Morpholine-based bactericidal compounds [dodemorph, tridemorph, fenpropimorph, etc.]
(9) Strobilurin-based bactericidal compounds [azoxystrobin, cresoxime methyl, metminostrobin, trifloxystrobin, picoxystrobin, pyraclostrobin, floxastrobin, dimoxystrobin, etc.],
(10) Antibiotic bactericidal compounds [validamycin A, blasticidin S, kasugamycin, polyoxins, etc.]

(11) Dithiocarbamate bactericidal compounds [mancozeb, maneb, thiuram, etc.]
(12) Other bactericidal compounds [fusalide, probenazole, isoprothiolane, tricyclazole, pyroxilone, ferimzone, acibenzoral S methyl, carpropamide, diclocimet, phenoxanyl, thiazinyl, dichromedin, teclophthalam, pencyclon, oxolinic acid, TPN, trifolin, fenpropidin , Spiroxamine, fluazinam, iminooctazine, fenpicuronyl, fludioxonil, quinoxyphene, fenhexamide, silthiofam, proquinazide, cyflufenamide, basic copper calcium sulfate, diclofluuride, cyprodinil, pyrimethanil, mepanipyrim, dietofencarb, pyrbencarbamido, famoxadone , Ethaboxam, amisulbrom, y Robarikarubu, benthiavalicarb, cyazofamid, mandipropamid, metrafenone, fluopyram, bixafen and the like] and the like,

As an active ingredient of an insecticide, for example,
(1) Organophosphorus insecticidal compounds [fenthion, fenitrothion, pyrimiphosmethyl, diazinon, quinalphos, isoxathion, pyridafenthion, chlorpyrifos, chlorpyrifosmethyl, bamidione, malathion, phentoate, dimethoate, disulfotone, monocrotophos, tetrachlorbinphos, chlorfenvin Phos, propaphos, acephate, trichlorfone, EPN, pyracrofos, butathiophos, chloroethoxyphos, cyanophos, diclofenthion, dichlorvos, dimethylvinphos, ethion, etoprophos, etrimphos, formimothione, isofenphos, mesulfenphos, metidathion, nared, oxydeprophos, parathion, Hosalon, Hosmet, Profenofos, Prothiofos, Sa Thione, sulprofos, tebupirimfos, temephos, terbufos, thiometon, folate, etc.],
(2) Carbamate insecticidal compounds [carbaryl, metorcarb, isoprocarb, BPMC, propoxyl, XMC, carbofuran, carbosulfan, benfuracarb, furthiocarb, mesomil, thiodicarb, alanib, bendiocarb, cloetocarb, etiophencarb, fenocarb, oxamyl, pyramib , Xylylcarb, aldicarb, etc.]
(3) Synthetic pyrethroid insecticidal compounds [tefluthrin, bifenthrin, cycloprotorin, etofenprox, acrinathrin, allethrin, benfluthrin, beta-cyfluthrin, cyfluthrin, cyhalothrin, cypermethrin, deltamethrin, esfenvalerate, fenpropatoline, fenvalerate Rate, flucitrinate, flufenprox, flumethrin, fulvalinate, halfenprox, imiprotrine, permethrin, praretrin, pyrethrin, resmethrin, sigma-cypermethrin, silafluophene, tralomethrin, transfluthrin, tetramethrin, phenothrin, ciphenothrin, alpha Permethrin, zeta permethrin, lambda cihalothrin, gamma cyhalothrin Furamethrin, tau full burrs sulfonates, metofluthrin, profluthrin, dimefluthrin, protrifenbute and the like],
(4) Nereistoxin-based insecticidal compounds [cartap, bensultap, thiocyclam, etc.]
(5) Neonicotinoid insecticidal compounds [imidacloprid, nitenpyram, acetamiprid, thiamethoxam, thiacloprid, dinotefuran, clothianidin, etc.],

(6) Benzoylphenylurea insecticidal compounds [chlorfluazuron, fluazuron, flufenoxuron, hexaflumuron, lufenuron, novallon, bistrifluron, diflubenzuron, flucycloxuron, nobiflumuron, teflubenzuron, triflumuron, etc.],
(7) Macrolide insecticidal compounds [emamectin, abamectin, milbemectin, lepimectin, spinosad, spinetoram, etc.]
(8) Other insecticidal compounds [buprofezin, tebufenozide, chromafenozide, halofenozide, methoxyphenozide, fipronil, etiprole, acetoprole, vaniliprol, pyriprole, pyrafluprolol, pymetrozine, pyrifluquinazone, diafenthiuron, indoxacarb, metaflumizone, tolfenpyrazone , Fluphenerium, pyridalyl, flonicamid, spiromesifene, spirotetramat, flubendiamide, chlorantraniliprole, pyriproxyfen, cyromazine, methoxadiazone, triazemate, chlordane, nicotine sulfate, tralopyril, Bt toxin insecticides, etc.] Etc.

As an active ingredient of an acaricide, for example, hexothiazox, pyridaben, fenpyroximate, tebufenpyrad, chlorfenapyr, etoxazole, pyrimidifen, acequinosyl, biphenazate, spirodiclofen, phenazaquin, bromopropyrate, formethanate, amitraz, benzoximate, quinomethionate, Benzylate, chlorfenson, clofentezin, cyflumetofene, dicofol, phenbutadium oxide, phenothiocarb, fluacrylpyrim, propargite, polynactin complex, tetradiphone, amidoflumet, sienopyrafen, etc.
Examples of the active ingredient of the nematicide include fostiazeate, kazusafos, bencrothiaz, metam ammonium, metam sodium, DCIP, levamisole hydrochloride, methyl isothiocyanate, morantel tartrate, and imisiaphos.

The compounds represented by the above general names are known literatures (for example, “The Pesticide Manual, 16th Edition, 2012”), “Narumi Shibuya, 2 others, SHIBUYA INDEX-2012-16th Edition, "May 2012", etc.)).
Above all, from the viewpoint of synergistic effect on the weed spectrum and weed control weeds, amidosulfuron, azimusulfuron, bensulfuron methyl, chlorimuron, cyclosulfamuron, ethoxysulfuron, frazasulfuron, flucetsulfuron, flupirus Ruflon, horamsulfuron, halosulfuron methyl, imazosulfuron, mesosulfuron, nicosulfuron, orthosulfamuron, oxasulfuron, pyrimisulfuron, pyrazosulfuron ethyl, rimsulfuron, sulfometuron, sulfosulfuron, trifloxysulfuron, chlor Sulflon, Shinosulfuron, Etamesulfuron, Iodosulfuron, Metosulfuron, Prosulfuron, Thifensulfuron, Triasulfuron, Tribenuron, Triflusulfuron, Tri Surufuron, bispyribac, pyriminobac-methyl, pyridyl-thio back sodium salt, pyriftalid, pyridinium miss Le fan, penoxsulam, ALS inhibitory herbicides such as pro Pires iodosulfuron;
Isonorlon, isouron, metabenzthiazulone, monisouron, norlon, anisulone, butulon, clobromulone, chlorethuron, clotorulone, chloroxuron, diemron, cumylron, diphenoxuron, dimeflon, diuron, fenulon, flumeturon, fluothiuron, isoproturumuron, linthuron Photosynthesis-inhibiting herbicides such as, methbenzuron, metobromulone, methoxuron, monolinuron, monuron, nebulon, atrazine, dimetamethrin, mesoprotorin, promethrin, cimethrin;

Chlorajhop, clodinahop, clofop, cyhalohop butyl, diclohop, phenoxaprop, phenoxaprop-P, fenthiaprop, fluazihop, fluazihop-P, haloxyhop, haloxyhop-P, isoxapyrihop, metamihop, propoxahop, Fatty acid biosynthesis-inhibiting herbicides such as quizalofop, quizalofop-P, alloxidim, butoxydim, cretodim, cloproxidim, cycloxydim, proxoxime, cetoxydim, tepraxidim, and tralcoxidim;
PDS-inhibiting herbicides such as beflubutamide, picolinaphen, diflufenican, etc .;
HPPD-inhibiting herbicides such as benzophenap, pyrasulfotol, pyrazolate, pyrazoxifene, mesotrione, sulcotrione, tefuryltrione, tembotrione, benzobicyclone, isoxacrotol, isoxaflutol;
PPO-inhibiting herbicides such as pentoxazone, azaphenidin, full microlac, flumioxazin, flumipropine, pyraflufenethyl, oxadiargyl, oxadiazone;
Indanophan, oxadichromemephone, butachlor, pretilachlor, tenylchlor, naproanilide, clomeprop, fentrazamide, ipfencarbazone, mefenacet, bromobutide, anilophos, esprocarb, pyributicarb, thiobencarb, benfrecetate, molinate, quinoclamin, MCPA ethyl, MCPA thiop Other action mechanism type herbicides such as fenfentrol, pyraclonil, phenoxasulfone and the like are preferable.

  In addition, when used as a herbicide for paddy fields, azimusulfuron, bensulfuronmethyl, cyclosulfamlone, flucetosulfuron, orthosulfamlone, ethoxysulfuron, halosulfuronmethyl, bispyribac sodium salt, pyriminobacmethyl , Pyriphthalide, Penoxsulam, Pyrisulfuran, Pyrazosulfuron ethyl, Imazosulfuron, Daimron, Cumyllon, Cimetrine, Cihalohop butyl, Metamihop, Benzophenap, Pyrazolate, Pyrazoxifene, Benzobicyclon, Tefriltrione, Pentoxazone, Oxadiazone, Indanophan , Oxadichromemephone, butachlor, pretilachlor, tenylchlor, naproanilide, clomeprop, fentolazamide, mefenacet, bro Buchido, cafenstrole, anilofos, esprocarb, pyributicarb, thiobencarb, benfuresate, molinate, quinoclamine, MCPA thioethyl, MCPB, pyraclonil and pro Pires chlorsulfuron, phenoxy suspension sulfone is particularly preferred.

The herbicide containing the compound of the present invention as an active ingredient further includes a safener (for example, flirazole, dichlormid, benoxacol, aridocrol, isoxadifenethyl, fenchlorazoleethyl, mefenpyrdiethyl, croquintoset mexil, Fencrolim, cyprosulfamide, ciomethrinyl, oxabetrinyl, floxophenim, flurazole, 2-dichloromethyl-2-methyl-1,3-dioxolane, 1,8-naphthalic anhydride, etc.), pigment, fertilizer (eg, urea, etc.) Etc. may be mixed as appropriate.
The herbicide containing the compound of the present invention as an active ingredient can be used as a herbicide for agricultural land such as fields, paddy fields, lawns, orchards, or non-agricultural land. The herbicide containing the compound of the present invention as an active ingredient is useful, for example, as a herbicide in agricultural land or the like where the “crop” or the like listed below is cultivated.

Agricultural crops: corn, rice, wheat, barley, rye, oat, sorghum, cotton, soybean, peanut, buckwheat, sugar beet, rapeseed, sunflower, sugar cane, tobacco, etc.
Vegetables: Solanum vegetables (eggplants, tomatoes, peppers, peppers, potatoes, etc.), cucurbits (cucumbers, pumpkins, zucchini, watermelons, melons, etc.), cruciferous vegetables (radish, turnip, horseradish, kohlrabi, Chinese cabbage, cabbage) , Mustard, broccoli, cauliflower, etc.), asteraceae vegetables (burdock, shungiku, artichoke, lettuce, etc.), lily family vegetables (eg, leek, onion, garlic, asparagus, etc.), celery family vegetables (carrot, parsley, celery, American redfish) Etc.), red crustacean vegetables (spinach, chard, etc.), persimmon vegetables (perilla, mint, basil, etc.), strawberry, sweet potato, yam, taro, etc.
Fruit trees: berries (apples, pears, Japanese pears, quince, quince, etc.), nuclear fruits (peaches, plums, nectarines, ume, sweet cherry, apricots, prunes, etc.), citrus (satsuma mandarin, orange, lemon, lime, grapefruit) ), Nuts (chestnut, walnut, hazel, almond, pistachio, cashew nut, macadamia nut, etc.), berries (blueberry, cranberry, blackberry, raspberry, etc.), grape, oyster, olive, loquat, banana, coffee, Date palm, coconut palm, oil palm, etc.
Trees other than fruit trees: Cha, mulberry, flowering trees, street trees (ash, birch, dogwood, eucalyptus, ginkgo, lilac, maple, oak, poplar, redwood, fu, sycamore, zelkova, black bean, peach tree, Tsuga, rat, pine, Spruce, yew) etc.
Other: Flowers (Rose, Carnation, Chrysanthemum, Eustoma, Gypsophila, Gerbera, Marigold, Salvia, Petunia, Verbena, Tulip, Aster, Gentian, Lily, Pansy, Cyclamen, Orchid, Lily of the valley, Lavender, Stock, Habutton, Primula, Poinsettia, gladiolus, cattleya, daisy, cymbidium, begonia, etc.), foliage plants, etc.

The above "crop" includes HPPD inhibitors such as isoxaflutol, ALS inhibitors such as imazetapyr and thifensulfuron methyl, EPSP synthase inhibitors such as glyphosate, glutamine synthase inhibitors such as glufosinate, cetoxydim and the like Rapeseed, wheat, sunflower tolerant to acetyl-CoA carboxylase inhibitors, PPO inhibitors such as flumioxazin, herbicides such as bromoxynil, dicamba, 2,4-D, etc. by classical breeding methods or genetic recombination techniques , Crops such as rice, corn and soybeans are also included.
Examples of “crop” tolerated by classical breeding methods include rapeseed, wheat, sunflower, rice, corn resistant to imidazolinone ALS-inhibiting herbicides; resistant to sulfonylurea ALS-inhibiting herbicides Examples of crops to which tolerance is imparted to soybean; an acetyl-CoA carboxylase inhibitor include SR corn;
Examples of “crop” to which tolerance has been imparted by genetic engineering techniques include glyphosate-resistant maize, soybean, cotton, rapeseed, sugar beet varieties; glufosinate-tolerant maize, soybean, cotton, rapeseed varieties; Crop can be mentioned.
In addition, the above “crop” can be produced by using a genetic recombination technique, for example, a crop capable of synthesizing a selective toxin known in the genus Bacillus or an anti-disease having a selective action. Also included are crops that have been given the ability to produce protogenic substances, and crops that have been given useful traits such as oil component modification and amino acid content enhancing traits.

In addition, the above-mentioned classic herbicide traits or herbicide resistance genes, insecticidal pest resistance genes, antipathogenic substance production genes, useful traits such as oil component modification and amino acid content enhancement traits Multiple “stacked varieties” are also included in the “crop”.
When the compound of the present invention is used for a crop that has become herbicide-tolerant, the herbicide to which the crop is tolerated (for example, glyphosate or a salt thereof, glufosinate or a salt thereof, dicamba or a salt thereof, imazetapyr or a salt thereof, it can be used to control the overall weed by systematic processing and / or mixing process of isoxaflutole, etc.) with the compound of the present invention.

アルゴンガス雰囲気下、マグネシウム（６１．８ｇ，２．５３ｍｏｌ）とヨウ素（５０ｍｇ）のＴＨＦ（１０００ｍＬ）懸濁液に、１−ブロモ−２，４−ジフルオロベンゼン（４８９ｇ，２．４８ｍｏｌ）とＴＨＦ（７００ｍＬ）の混合溶液を、反応溶液の温度が４０℃を超えないように維持しながら、２．５時間かけて滴下し、２，４−ジフルオロフェニルマグネシウムブロミドのＴＨＦ溶液を調製した。このＴＨＦ溶液を、しゅう酸ジエチル（３６３ｇ，２．４３ｍｏｌ）のＴＨＦ（２５０ｍＬ）溶液に−４０℃以下で２．５時間かけて滴下した後、氷冷下で１時間攪拌した。反応終了後、反応溶液に飽和塩化アンモニウム水（５００ｍＬ）と水（１５００ｍＬ）を加え、酢酸エチル（２００ｍＬ×３）で抽出した。合一した有機層を飽和食塩水（５００ｍＬ）で洗浄した後、有機層を無水硫酸マグネシウム（５０ｇ）で乾燥した。有機層から減圧下で溶媒を留去した後、減圧蒸留することにより、２−（２，４−ジフルオロフェニル）−２−オキソ酢酸エチルの淡黄色固体（３８９ｇ，収率：７３％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．４０（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），４．４３（ｑ，Ｊ＝７．２Ｈｚ，３Ｈ），６．９１（ｄｄｄ，Ｊ＝２．３，８．６ ａｎｄ １０．８Ｈｚ，１Ｈ），７．０４（ｄｄｄｄ，Ｊ＝０．９，２．３，８．６ ａｎｄ １０．８Ｈｚ，１Ｈ），７．９９（ｄｄｄ，Ｊ＝６．５，８．２ ａｎｄ ８．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１０６（ｄ，Ｊ＝１３．５Ｈｚ，１Ｆ），−９７．２（ｄ，Ｊ＝１３．５Ｈｚ，１Ｆ）．
トリフェニルホスフィン（９７３ｇ，３．６０ｍｏｌ）のジクロロメタン（７２０ｍＬ）溶液に、氷冷下で四塩化炭素（５５７ｇ，３．６０ｍｏｌ）を加えて５分間撹拌した後、２−（２，４−ジフルオロフェニル）−２−オキソ酢酸エチル（３８６ｇ，１．８０ｍｏｌ）のジクロロメタン（１８０ｍＬ）溶液を滴下し、３０℃以下で２０時間攪拌した。反応終了後、反応液から減圧下で溶媒を留去した。得られた残渣をヘキサン（１５００ｍＬ）に懸濁させ、不溶物をろ過により取り除き、ろ液を減圧下で濃縮する操作を２回繰り返した。得られた油状物を減圧蒸留することにより、３，３−ジクロロ−２−（２，４−ジフルオロフェニル）アクリル酸エチルの淡黄色油状物（４５５ｇ，収率：９０％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．２６（ｔ，Ｊ＝７．１Ｈｚ，３Ｈ），４．２５（ｑ，Ｊ＝７．１Ｈｚ，２Ｈ），６．８７（ｄｄｄ，Ｊ＝２．１，８．８ ａｎｄ １０．４Ｈｚ，１Ｈ），６．９２（ｄｄｄｄ，Ｊ＝１．０，２．１，６．７ ａｎｄ ９．６Ｈｚ，１Ｈ），７．３１（ｄｄｄ，Ｊ＝６．７，８．４ ａｎｄ ８．４Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１０８（ｄ，Ｊ＝７．５Ｈｚ，１Ｆ），−１０７（ｄ，Ｊ＝７．５Ｈｚ，１Ｆ）．EXAMPLES Hereinafter, although an Example, a reference example, a comparative example, a formulation example, and a test example demonstrate this invention further in detail, this invention is not limited to these.
Reference Example-1

Under an argon gas atmosphere, a suspension of magnesium (61.8 g, 2.53 mol) and iodine (50 mg) in THF (1000 mL) was added to 1-bromo-2,4-difluorobenzene (489 g, 2.48 mol) and THF ( 700 mL) was added dropwise over 2.5 hours while maintaining the temperature of the reaction solution so as not to exceed 40 ° C. to prepare a THF solution of 2,4-difluorophenylmagnesium bromide. This THF solution was added dropwise to a solution of diethyl oxalate (363 g, 2.43 mol) in THF (250 mL) at −40 ° C. or lower over 2.5 hours, and then stirred under ice cooling for 1 hour. After completion of the reaction, saturated aqueous ammonium chloride (500 mL) and water (1500 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 3). The combined organic layer was washed with saturated brine (500 mL), and then the organic layer was dried over anhydrous magnesium sulfate (50 g). The solvent was distilled off from the organic layer under reduced pressure, followed by distillation under reduced pressure to obtain a pale yellow solid (389 g, yield: 73%) of ethyl 2- (2,4-difluorophenyl) -2-oxoacetate. It was. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.40 (t, J = 7.2 Hz, 3H), 4.43 (q, J = 7.2 Hz, 3H), 6.91 (ddd, J = 2) .3, 8.6 and 10.8 Hz, 1H), 7.04 (dddd, J = 0.9, 2.3, 8.6 and 10.8 Hz, 1H), 7.99 (ddd, J = 6) .5, 8.2 and 8.7 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-106 (d, J = 13.5 Hz, 1F), −97.2 (d, J = 13.5 Hz, 1F).
Carbon tetrachloride (557 g, 3.60 mol) was added to a solution of triphenylphosphine (973 g, 3.60 mol) in dichloromethane (720 mL) under ice cooling, and the mixture was stirred for 5 minutes, and then 2- (2,4-difluorophenyl). ) A solution of ethyl 2-oxoacetate (386 g, 1.80 mol) in dichloromethane (180 mL) was added dropwise, and the mixture was stirred at 30 ° C. or lower for 20 hours. After completion of the reaction, the solvent was distilled off from the reaction solution under reduced pressure. The obtained residue was suspended in hexane (1500 mL), insolubles were removed by filtration, and the operation of concentrating the filtrate under reduced pressure was repeated twice. The obtained oil was distilled under reduced pressure to obtain a light yellow oil (455 g, yield: 90%) of ethyl 3,3-dichloro-2- (2,4-difluorophenyl) acrylate. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.26 (t, J = 7.1 Hz, 3H), 4.25 (q, J = 7.1 Hz, 2H), 6.87 (ddd, J = 2) .1, 8.8 and 10.4 Hz, 1H), 6.92 (dddd, J = 1.0, 2.1, 6.7 and 9.6 Hz, 1H), 7.31 (ddd, J = 6 .7, 8.4 and 8.4 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108 (d, J = 7.5 Hz, 1F), −107 (d, J = 7.5 Hz, 1F).

ヘキサヒドロピリダジン二臭化水素塩（３０６ｇ，１．２３ｍｏｌ）及び３，３−ジクロロ−２−（２，４−ジフルオロフェニル）アクリル酸エチル（３１５ｇ，１．１２ｍｏｌ）の１，４−ジオキサン（１１２１ｍＬ）溶液に、トリエチルアミン（３７８ｇ，３．７０ｍｏｌ）を加え、１５時間加熱還流した。反応終了後、反応液から減圧下で溶媒を留去し、得られた残渣に水（１０００ｍＬ）を加え、析出した固体をろ取した。得られた固体を水（１０００ｍＬ）及びジエチルエーテル（１０００ｍＬ）で洗浄した後、減圧乾燥することにより、５−クロロ−４−（２，４−ジフルオロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの淡黄色固体（２４１ｇ，収率：７６％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８９−１．９２（ｍ，２Ｈ），２．００−２．０５（ｍ，２Ｈ），３．５８−３．６３（ｍ，２Ｈ），３．８０−３．８４（ｍ，２Ｈ），６．８６−６．９６（ｍ，２Ｈ），７．４８（ｄｔ，Ｊ＝６．５ ａｎｄ ８．４Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１０（ｄ，Ｊ＝７．８Ｈｚ，１Ｆ），−１０７（ｄ，Ｊ＝７．８Ｈｚ，１Ｆ）．
５−クロロ−４−（２，４−ジフルオロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（２４０ｇ，０．８４３ｍｏｌ）の濃硫酸（１６８８ｍＬ）懸濁液に、６９％硝酸（９２．４ｇ，１．０１ｍｏｌ）と濃硫酸（５６．３ｍＬ）から調製した混酸を氷冷下で１時間以上かけて加え、同温にて４時間攪拌した。反応終了後、反応液を氷水（７５００ｇ）中に注ぎ、クロロホルム（６００ｍＬ×６）で抽出した。合一した有機層を５％水酸化ナトリウム水溶液（５００ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥した。有機層を減圧下に溶媒を留去することにより、５−クロロ−４−（２，４−ジフルオロ−５−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの黄色固体（２０２ｇ，収率：７３％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．９１−１．９６（ｍ，２Ｈ），２．０２−２．０７（ｍ，２Ｈ），３．６５−３．７０（ｍ，２Ｈ），３．８１−３．８６（ｍ，２Ｈ），７．１０（ｄｄ，Ｊ＝９．１ ａｎｄ １０．４Ｈｚ，１Ｈ），８．３４（ｄｄ，Ｊ＝７．２ ａｎｄ ８．３Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１２（ｄ，Ｊ＝１５．８Ｈｚ，１Ｆ），−９５．６（ｄ，Ｊ＝１５．８Ｈｚ，１Ｆ）．Reference example-2

1,4-dioxane (1121 mL) of hexahydropyridazine dibromide salt (306 g, 1.23 mol) and ethyl 3,3-dichloro-2- (2,4-difluorophenyl) acrylate (315 g, 1.12 mol) ) To the solution was added triethylamine (378 g, 3.70 mol), and the mixture was heated to reflux for 15 hours. After completion of the reaction, the solvent was distilled off from the reaction solution under reduced pressure, water (1000 mL) was added to the resulting residue, and the precipitated solid was collected by filtration. The obtained solid was washed with water (1000 mL) and diethyl ether (1000 mL), and then dried under reduced pressure to give 5-chloro-4- (2,4-difluorophenyl) -1,2-tetramethylene-4- A pale yellow solid (241 g, yield: 76%) of pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.89-1.92 (m, 2H), 2.00-2.05 (m, 2H), 3.58-3.63 (m, 2H), 3.80-3.84 (m, 2H), 6.86-6.96 (m, 2H), 7.48 (dt, J = 6.5 and 8.4 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-110 (d, J = 7.8 Hz, 1F), −107 (d, J = 7.8 Hz, 1F).
To a suspension of 5-chloro-4- (2,4-difluorophenyl) -1,2-tetramethylene-4-pyrazolin-3-one (240 g, 0.843 mol) in concentrated sulfuric acid (1688 mL) was added 69% nitric acid. (92.4 g, 1.01 mol) and a mixed acid prepared from concentrated sulfuric acid (56.3 mL) were added over 1 hour under ice cooling, and the mixture was stirred at the same temperature for 4 hours. After completion of the reaction, the reaction solution was poured into ice water (7500 g) and extracted with chloroform (600 mL × 6). The combined organic layers were washed with 5% aqueous sodium hydroxide solution (500 mL × 3) and dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure to give a yellow solid of 5-chloro-4- (2,4-difluoro-5-nitrophenyl) -1,2-tetramethylene-4-pyrazolin-3-one. (202 g, yield: 73%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.91-1.96 (m, 2H), 2.02-2.07 (m, 2H), 3.65-3.70 (m, 2H), 3.81-3.86 (m, 2H), 7.10 (dd, J = 9.1 and 10.4 Hz, 1H), 8.34 (dd, J = 7.2 and 8.3 Hz, 1H) . ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-112 (d, J = 15.8 Hz, 1F), −95.6 (d, J = 15.8 Hz, 1F).

水素化ナトリウムの５５％油分散（０．５４０ｇ，１３．５ｍｍｏｌ）の１，４−ジオキサン（６０ｍＬ）懸濁液に、５−クロロ−４−（２，４−ジフルオロ−５−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（２．９７ｇ，９．０ｍｍｏｌ）及びグリコール酸エチル（１．２９ｍＬ，１３．５ｍｍｏｌ）を加え、室温で３０分間攪拌した。反応終了後、反応液を飽和塩化アンモニウム水溶液（６０ｍＬ）に注ぎ、酢酸エチル（５０ｍＬ×３）で抽出した。合一した有機層を飽和食塩水（５０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］酢酸エチルの淡黄色固体（３．４８ｇ，収率：９３％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．３１（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．９０−１．９４（ｍ，２Ｈ），２．００−２．０５（ｍ，２Ｈ），３．６２−３．６７（ｍ，２Ｈ），３．８１−３．８６（ｍ，２Ｈ），４．３０（ｑ，Ｊ＝７．２Ｈｚ，２Ｈ），４．７７（ｓ，２Ｈ），６．７５（ｄ，Ｊ＝１０．７Ｈｚ，１Ｈ），８．１７（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−９８．９（ｓ，１Ｆ）．Reference example-3

To a suspension of sodium hydride in 55% oil dispersion (0.540 g, 13.5 mmol) in 1,4-dioxane (60 mL), 5-chloro-4- (2,4-difluoro-5-nitrophenyl)- 1,2-tetramethylene-4-pyrazolin-3-one (2.97 g, 9.0 mmol) and ethyl glycolate (1.29 mL, 13.5 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (60 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate) to give 2- [4- (5-chloro-3-oxo-1,2-tetramethylene-4-pyrazolin-4-yl). A light yellow solid (3.48 g, yield: 93%) of ethyl -5-fluoro-2-nitrophenyloxy] acetate was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.31 (t, J = 7.2 Hz, 3H), 1.90-1.94 (m, 2H), 2.00-2.05 (m, 2H) ), 3.62-3.67 (m, 2H), 3.81-3.86 (m, 2H), 4.30 (q, J = 7.2 Hz, 2H), 4.77 (s, 2H) ), 6.75 (d, J = 10.7 Hz, 1H), 8.17 (d, J = 7.3 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-98.9 (s, 1F).

水素化ナトリウムの５５％油分散（２９．３ｇ，０．６７１ｍｏｌ）をヘキサン（１００ｍＬ×２）で洗浄し、減圧乾燥させた後、氷冷下で１，４−ジオキサン（３６５１ｍＬ）、５−クロロ−４−（２，４−ジフルオロ−５−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（２０１ｇ，０．６１０ｍｏｌ）、グリコール酸メチル（８０．１ｍＬ，０．８５４ｍｏｌ）を順次加え、室温で２時間攪拌した。反応終了後、反応液を氷水（５０００ｇ）に注ぎ、クロロホルム（５００ｍＬ×８）で抽出した。合一した有機層を飽和食塩水（５００ｍＬ×２）で洗浄後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた粗生成物をクロロホルム（３００ｍＬ）に溶解した後、ヘキサンを加えて再結晶により精製することにより、２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］酢酸メチルの淡黄色固体（１６８ｇ，収率：６９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８８−１．９４（ｍ，２Ｈ），２．００−２．０６（ｍ，２Ｈ），３．６２−３．６７（ｍ，２Ｈ），３．８０−３．８６（ｍ，２Ｈ），３．８３（ｓ，３Ｈ），４．８０（ｓ，２Ｈ），６．７６（ｄ，Ｊ＝１０．９Ｈｚ，１Ｈ），８．１６（ｄ，Ｊ＝６．９Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−９８．３（ｓ，１Ｆ）．Reference example-4

A 55% oil dispersion (29.3 g, 0.671 mol) of sodium hydride was washed with hexane (100 mL × 2), dried under reduced pressure, and then 1,4-dioxane (3651 mL), 5-chloro under ice-cooling. -4- (2,4-difluoro-5-nitrophenyl) -1,2-tetramethylene-4-pyrazolin-3-one (201 g, 0.610 mol), methyl glycolate (80.1 mL, 0.854 mol) Were sequentially added and stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was poured into ice water (5000 g) and extracted with chloroform (500 mL × 8). The combined organic layer was washed with saturated brine (500 mL × 2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was dissolved in chloroform (300 mL), and then purified by recrystallization after adding hexane to give 2- [4- (5-chloro-3-oxo-1,2-tetramethylene-4]. -Pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] methyl acetate pale yellow solid (168 g, yield: 69%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.88-1.94 (m, 2H), 2.00-2.06 (m, 2H), 3.62-3.67 (m, 2H), 3.80-3.86 (m, 2H), 3.83 (s, 3H), 4.80 (s, 2H), 6.76 (d, J = 10.9 Hz, 1H), 8.16 ( d, J = 6.9 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-98.3 (s, 1F).

Reference Example-5
5-Chloro-4- (2,4-difluoro-5-nitrophenyl) -1,2-tetramethylene-4 in the same manner as in Reference Example 4 except that potassium fluoride was used instead of sodium hydride. Reaction of pyrazolin-3-one with methyl glycolate to give 2- [4- (5-chloro-3-oxo-1,2-tetramethylene-4-pyrazolin-4-yl) -5-fluoro-2 -Nitrophenyloxy] methyl acetate was obtained in 58% yield.

２−［５−フルオロ−４−（５−クロロ−１，２−テトラメチレン−３−オキソ−４−ピラゾリン−４−イル）−２−ニトロフェニルオキシ］酢酸メチル（１６８ｇ，０．４２１ｍｏｌ）の酢酸エチル（８２８ｍＬ）溶液に、水（７５．９ｇ）及び酢酸（４１６ｍＬ）を加えた後、還元鉄（１３１ｇ，２．１１ｍｏｌ）を加え、８０℃で５時間攪拌した。反応終了後、反応液を室温まで冷却し、不溶物をろ別し、固体を酢酸エチル（４００ｍＬ）と酢酸（１００ｍＬ）の混合溶媒で洗浄した。合一した有機層を減圧濃縮した後、残渣を氷水（１５００ｍＬ）に注ぎ、析出した固体をろ取した。得られた固体をエーテル（５００ｍＬ）で洗浄した後、減圧乾燥することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの淡黄色固体（１２９ｇ，収率：９０％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．９７−１．９６（ｍ，２Ｈ），１．９８−２．０７（ｍ，２Ｈ），３．５７−３．６８（ｍ，２Ｈ），３．８２−３．９２（ｍ，２Ｈ），４．５０（ｓ，２Ｈ），６．７３（ｄ，Ｊ＝９．７Ｈｚ，１Ｈ），７．１２（ｄ，Ｊ＝６．２Ｈｚ，１Ｈ），９．３４（ｂｒｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．８（ｓ，１Ｆ）．Example-1

Of methyl 2- [5-fluoro-4- (5-chloro-1,2-tetramethylene-3-oxo-4-pyrazolin-4-yl) -2-nitrophenyloxy] acetate (168 g, 0.421 mol) After adding water (75.9 g) and acetic acid (416 mL) to an ethyl acetate (828 mL) solution, reduced iron (131 g, 2.11 mol) was added, and the mixture was stirred at 80 ° C. for 5 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, insolubles were filtered off, and the solid was washed with a mixed solvent of ethyl acetate (400 mL) and acetic acid (100 mL). The combined organic layers were concentrated under reduced pressure, the residue was poured into ice water (1500 mL), and the precipitated solid was collected by filtration. The obtained solid was washed with ether (500 mL) and then dried under reduced pressure to give 5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazine- A pale yellow solid (129 g, yield: 90%) of 6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.97-1.96 (m, 2H), 1.98-2.07 (m, 2H), 3.57-3.68 (m, 2H), 3.82-3.92 (m, 2H), 4.50 (s, 2H), 6.73 (d, J = 9.7 Hz, 1H), 7.12 (d, J = 6.2 Hz, 1H) ), 9.34 (brs, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.8 (s, 1F).

２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］酢酸エチル（２．４８ｇ，６．０ｍｍｏｌ）の酢酸エチル（３０ｍＬ）溶液に、水（３０ｍＬ）及び酢酸（３０ｍＬ）を加えた後、還元鉄（３．３５ｇ，６０．０ｍｍｏｌ）を加え、８０℃で１時間攪拌した。反応終了後、反応液を室温まで冷却し、不溶物をろ別後、ろ液に飽和炭酸水素ナトリウム水溶液（３００ｍＬ）を加え、酢酸エチル（１００ｍＬ×３）で抽出した。有機層を飽和炭酸水素ナトリウム水溶液（１００ｍＬ）及び飽和食塩水（１００ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた固体にヘキサン（５０ｍＬ）を加え、ろ過することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの灰白色固体（１．３９ｇ，収率：６８％）を得た。Example-2

2- [4- (5-Chloro-3-oxo-1,2-tetramethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] ethyl acetate (2.48 g, 6.0 mmol) After adding water (30 mL) and acetic acid (30 mL) to an ethyl acetate (30 mL) solution, reduced iron (3.35 g, 60.0 mmol) was added, and the mixture was stirred at 80 ° C. for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, insoluble matters were filtered off, saturated aqueous sodium hydrogen carbonate solution (300 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane (50 mL) was added to the obtained solid and filtered to give 5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl. ) -1,2-tetramethylene-4-pyrazolin-3-one was obtained as an off-white solid (1.39 g, yield: 68%).

５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（２００ｍｇ，０．５９ｍｍｏｌ）のＤＭＦ（２ｍＬ）溶液に、氷冷下で水素化ナトリウムの５５％油分散（２６ｍｇ，０．６５ｍｍｏｌ）及びヨウ化メチル（９４．１ｍｇ，０．６５ｍｍｏｌ）を加え、室温で２２時間攪拌した。反応終了後、反応液に水を注ぎ、析出した固体を吸引ろ過し、水、次いでヘキサンとジエチルエーテルの混合溶媒で洗浄した後、乾燥することにより、５−クロロ−４−（７−フルオロ−４−メチル−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（１６２ｍｇ，収率：８３％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８８−１．９４（ｍ，２Ｈ），２．００−２．０６（ｍ，２Ｈ），３．３６（ｓ，３Ｈ），３．６０−３．６３（ｍ，２Ｈ），３．８３−３．８６（ｍ，２Ｈ），４．６３（ｓ，２Ｈ），６．８０（ｄ，Ｊ＝１０．０Ｈｚ，１Ｈ），７．１３（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１６（ｓ，１Ｆ）．Example-3

5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one ( 200 mg, 0.59 mmol) in DMF (2 mL) was added with a 55% oil dispersion of sodium hydride (26 mg, 0.65 mmol) and methyl iodide (94.1 mg, 0.65 mmol) under ice-cooling. For 22 hours. After completion of the reaction, water is poured into the reaction solution, and the precipitated solid is suction filtered, washed with water and then with a mixed solvent of hexane and diethyl ether, and dried to give 5-chloro-4- (7-fluoro- 4-Methyl-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one as a white solid (162 mg, yield) : 83%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.88-1.94 (m, 2H), 2.00-2.06 (m, 2H), 3.36 (s, 3H), 3.60- 3.63 (m, 2H), 3.83-3.86 (m, 2H), 4.63 (s, 2H), 6.80 (d, J = 10.0 Hz, 1H), 7.13 ( d, J = 6.7 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-116 (s, 1F).

５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（２００ｍｇ，０．５９ｍｍｏｌ）のＤＭＦ（２ｍＬ）溶液に、氷冷下で水素化ナトリウムの５５％油分散（２６ｍｇ，０．６５ｍｍｏｌ）及びヨウ化エチル（１０３ｍｇ，０．６５ｍｍｏｌ）を加え、室温で２２時間攪拌した。反応終了後、反応液に水を注ぎ、析出した固体を吸引ろ過し、水で洗浄後、ヘキサンとジエチルエーテルの混合溶媒で洗浄し、乾燥することにより、５−クロロ−４−（４−エチル−７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの淡黄色固体（１５１ｍｇ，収率：７０％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．２９（ｔ，Ｊ＝７．０Ｈｚ，３Ｈ），１．８８−１．９４（ｍ，２Ｈ），２．００−２．０６（ｍ，２Ｈ），３．６１−３．６３（ｍ，２Ｈ），３．８３−３．８６（ｍ，２Ｈ），３．９９（ｑ，Ｊ＝７．０Ｈｚ，１Ｈ），４．６１（ｓ，２Ｈ），６．８０（ｄ，Ｊ＝１０．０Ｈｚ，１Ｈ），７．１７（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１６（ｓ，１Ｆ）．Example-4

5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one ( To a solution of 200 mg, 0.59 mmol) in DMF (2 mL), 55% oil dispersion of sodium hydride (26 mg, 0.65 mmol) and ethyl iodide (103 mg, 0.65 mmol) were added under ice-cooling. Stir for hours. After completion of the reaction, water is poured into the reaction solution, and the precipitated solid is suction filtered, washed with water, washed with a mixed solvent of hexane and diethyl ether, and dried to give 5-chloro-4- (4-ethyl). -7-Fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one as a pale yellow solid (151 mg, Yield: 70%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.29 (t, J = 7.0 Hz, 3H), 1.88-1.94 (m, 2H), 2.00-2.06 (m, 2H) ), 3.61-3.63 (m, 2H), 3.83-3.86 (m, 2H), 3.99 (q, J = 7.0 Hz, 1H), 4.61 (s, 2H) ), 6.80 (d, J = 10.0 Hz, 1H), 7.17 (d, J = 6.7 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-116 (s, 1F).

５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（２００ｍｇ，０．５９ｍｍｏｌ）のＤＭＦ（２ｍＬ）溶液に、氷冷下で水素化ナトリウムの５５％油分散（２６ｍｇ，０．６５ｍｍｏｌ）及びイソブチルブロミド（９１．８ｍｇ，０．６５ｍｍｏｌ）を加え、室温で２１時間攪拌した。反応終了後、反応液に水を注ぎ、析出した固体を吸引ろ過し、水で洗浄後、ヘキサンとジエチルエーテルの混合溶媒で洗浄し、乾燥することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−４−イソブチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（１４３ｍｇ，収率：６１％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ０．９４（ｄ，Ｊ＝７．０Ｈｚ，６Ｈ），１．８８−１．９４（ｍ，２Ｈ），２．００−２．０５（ｍ，２Ｈ），２．１３（ｔ ａｎｄ ｓｅｐｔ，Ｊ＝７．０ ａｎｄ ７．０Ｈｚ，１Ｈ），３．６１−３．６４（ｍ，２Ｈ），３．８０（ｄ，Ｊ＝７．４Ｈｚ，２Ｈ），３．８３−３．８５（ｍ，２Ｈ），４．６１（ｓ，２Ｈ），６．８０（ｄ，Ｊ＝９．６Ｈｚ，１Ｈ），７．１４（ｄ，Ｊ＝７．０Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１６（ｓ，１Ｆ）．Example-5

5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one ( 200 mg, 0.59 mmol) in DMF (2 mL) was added with 55% oil dispersion of sodium hydride (26 mg, 0.65 mmol) and isobutyl bromide (91.8 mg, 0.65 mmol) under ice-cooling. Stir for 21 hours. After completion of the reaction, water is poured into the reaction solution, and the precipitated solid is suction filtered, washed with water, washed with a mixed solvent of hexane and diethyl ether, and dried to give 5-chloro-4- (7-fluoro). -2,3-dihydro-4-isobutyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one as a white solid (143 mg, yield) Rate: 61%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.94 (d, J = 7.0 Hz, 6H), 1.88-1.94 (m, 2H), 2.00-2.05 (m, 2H) ), 2.13 (t and sept, J = 7.0 and 7.0 Hz, 1H), 3.61-3.64 (m, 2H), 3.80 (d, J = 7.4 Hz, 2H) , 3.83-3.85 (m, 2H), 4.61 (s, 2H), 6.80 (d, J = 9.6 Hz, 1H), 7.14 (d, J = 7.0 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-116 (s, 1F).

５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（２００ｍｇ，０．５９ｍｍｏｌ）のＤＭＦ（２ｍＬ）溶液に、氷冷下で水素化ナトリウムの５５％油分散（２６ｍｇ，０．６５ｍｍｏｌ）及び４−フルオロベンジルブロミド（１２３ｍｇ，０．６５ｍｍｏｌ）を加え、室温で１９時間攪拌した。反応終了後、反応液に水を注ぎ、析出した固体を吸引ろ過し、水で洗浄後、ヘキサンとジエチルエーテルの混合溶媒で洗浄し、乾燥することにより、５−クロロ−４−［７−フルオロ−４−（４−フルオロベンジル）−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体物（２０４ｍｇ，収率：７７％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８６−１．９２（ｍ，２Ｈ），１．９８−２．０３（ｍ，２Ｈ），３．５７−３．６０（ｍ，２Ｈ），３．８０−３．８１（ｍ，２Ｈ），４．７２（ｓ，２Ｈ），５．１２（ｓ，２Ｈ），６．８１（ｄ，Ｊ＝９．７Ｈｚ，１Ｈ），７．００（ｄｄ，Ｊ＝８．８ ａｎｄ ８．８，２Ｈ），７．０９（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ），７．２９（ｄｄ，Ｊ＝５．８ ａｎｄ ８．８，２Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１４．７（ｓ，１Ｆ），−１１４．８（ｓ，１Ｆ）．Example-6

5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one ( 200 mg, 0.59 mmol) in DMF (2 mL) was added with a 55% oil dispersion of sodium hydride (26 mg, 0.65 mmol) and 4-fluorobenzyl bromide (123 mg, 0.65 mmol) under ice-cooling. For 19 hours. After completion of the reaction, water is poured into the reaction solution, and the precipitated solid is suction filtered, washed with water, washed with a mixed solvent of hexane and diethyl ether, and dried to give 5-chloro-4- [7-fluoro. White of -4- (4-fluorobenzyl) -2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl] -1,2-tetramethylene-4-pyrazolin-3-one A solid substance (204 mg, yield: 77%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.86-1.92 (m, 2H), 1.98-2.03 (m, 2H), 3.57-3.60 (m, 2H), 3.80-3.81 (m, 2H), 4.72 (s, 2H), 5.12 (s, 2H), 6.81 (d, J = 9.7 Hz, 1H), 7.00 ( dd, J = 8.8 and 8.8, 2H), 7.09 (d, J = 6.7 Hz, 1H), 7.29 (dd, J = 5.8 and 8.8, 2H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.7 (s, 1F), -114.8 (s, 1F).

実施例−３と同様にして、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンと（クロロメチル）メチルエーテルとの反応により、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−４−メトキシメチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンを収率６８％で得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８６−１．９３（ｍ，２Ｈ），１．９８−２．０５（ｍ，２Ｈ），３．４０（ｓ，３Ｈ），３．５８−３．６２（ｍ，２Ｈ），３．８０−３．８５（ｍ，２Ｈ），４．６５（ｓ，２Ｈ），５．３２（ｓ，２Ｈ），６．８０（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．３９（ｄ，Ｊ＝６．９Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１４．９（ｓ，１Ｆ）．Example-7

In the same manner as in Example-3, 5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene Reaction of -4-pyrazolin-3-one with (chloromethyl) methyl ether yields 5-chloro-4- (7-fluoro-2,3-dihydro-4-methoxymethyl-3-oxo-4H-1, 4-Benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained in a yield of 68%. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.86-1.93 (m, 2H), 1.98-2.05 (m, 2H), 3.40 (s, 3H), 3.58-3 .62 (m, 2H), 3.80-3.85 (m, 2H), 4.65 (s, 2H), 5.32 (s, 2H), 6.80 (d, J = 9.9 Hz) , 1H), 7.39 (d, J = 6.9 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-114.9 (s, 1F).

実施例−３と同様にして、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンとアリルブロミドとの反応により、４−（４−アリル−７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンを収率８３％で得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８６−１．９４（ｍ，２Ｈ），１．９８−２．０６（ｍ，２Ｈ），３．５８−３．６３（ｍ，２Ｈ），３．８０−３．８５（ｍ，２Ｈ），４．５４−４．５８（ｍ，２Ｈ），４．６５（ｓ，２Ｈ），５．２４（ｍ，１Ｈ），５．２５（ｍ，１Ｈ），５．８８（ｍ，１Ｈ），６．８０（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．１３（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１５．３（ｓ，１Ｆ）．Example-8

In the same manner as in Example-3, 5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene 4- (4-Allyl-7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) by reaction of -4-pyrazolin-3-one with allyl bromide -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one was obtained in a yield of 83%. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.86-1.94 (m, 2H), 1.98-2.06 (m, 2H), 3.58-3.63 (m, 2H), 3 .80-3.85 (m, 2H), 4.54-4.58 (m, 2H), 4.65 (s, 2H), 5.24 (m, 1H), 5.25 (m, 1H) ), 5.88 (m, 1H), 6.80 (d, J = 9.9 Hz, 1H), 7.13 (d, J = 6.7 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-115.3 (s, 1F).

実施例−３と同様にして、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンとメタリルブロミドとの反応により、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−４−メタリル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンを収率７８％で得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．７７（ｓ，３Ｈ），１．８６−１．９４（ｍ，２Ｈ），１．９８−２．０６（ｍ，２Ｈ），３．５８−３．６４（ｍ，２Ｈ），３．７９−３．８５（ｍ，２Ｈ），４．４７（ｓ，２Ｈ），４．６６（ｓ，２Ｈ），４．８１（ｓ，１Ｈ），４．９４（ｓ，１Ｈ），６．８０（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．０６（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１５．２（ｓ，１Ｆ）．Example-9

In the same manner as in Example-3, 5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene Reaction of -4-pyrazolin-3-one with methallyl bromide yields 5-chloro-4- (7-fluoro-2,3-dihydro-4-methallyl-3-oxo-4H-1,4-benzoxazine -6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained in a yield of 78%. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.77 (s, 3H), 1.86-1.94 (m, 2H), 1.98-2.06 (m, 2H), 3.58-3 .64 (m, 2H), 3.79-3.85 (m, 2H), 4.47 (s, 2H), 4.66 (s, 2H), 4.81 (s, 1H), 4. 94 (s, 1H), 6.80 (d, J = 9.9 Hz, 1H), 7.06 (d, J = 6.8 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-115.2 (s, 1F).

水素化ナトリウムの５５％油分散（２９．１ｇ，０．６６８ｍｏｌ）をヘキサン（１００ｍＬ×２）で洗浄し、減圧乾燥させた後、ＤＭＦ（１１７４ｍＬ）を加えた。この懸濁液に、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（２０５ｇ，０．６０７ｍｏｌ）、次いでプロパルギルブロミド（１３２ｇ，０．６６８ｍｏｌ）を４０℃以下で３０分かけて加えた後、室温で２４時間攪拌した。反応終了後、反応液を氷水（５０００ｇ）に注ぎ入れ、析出した固体をろ取した。得られた固体をエーテル（１０００ｍＬ）で洗浄、減圧乾燥した。得られた粗生成物をメタノール（５００ｍＬ）で洗浄することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの淡黄色固体（２０２ｇ，収率：８８％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８８−１．９４（ｍ，２Ｈ），２．００−２．０６（ｍ，２Ｈ），２．２７（ｔ，Ｊ＝２．５Ｈｚ，１Ｈ），３．６０−３．６５（ｍ，２Ｈ），３．８１−３．８７（ｍ，２Ｈ），４．６５（ｓ，２Ｈ），４．７１（ｄ，Ｊ＝２．５Ｈｚ，２Ｈ），６．８２（ｄ，Ｊ＝９．８Ｈｚ，１Ｈ），７．３１（ｄ，Ｊ＝６．６Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１４．９（ｓ，１Ｆ）．Example-10

Sodium hydride 55% oil dispersion (29.1 g, 0.668 mol) was washed with hexane (100 mL × 2), dried under reduced pressure, and DMF (1174 mL) was added. To this suspension, 5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4- Pyrazolin-3-one (205 g, 0.607 mol) and then propargyl bromide (132 g, 0.668 mol) were added at 40 ° C. or lower over 30 minutes, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was poured into ice water (5000 g), and the precipitated solid was collected by filtration. The obtained solid was washed with ether (1000 mL) and dried under reduced pressure. The resulting crude product was washed with methanol (500 mL) to give 5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4-propargyl-4H-1,4-benzoxazine A pale yellow solid (202 g, yield: 88%) of -6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.88-1.94 (m, 2H), 2.00-2.06 (m, 2H), 2.27 (t, J = 2.5 Hz, 1H ), 3.60-3.65 (m, 2H), 3.81-3.87 (m, 2H), 4.65 (s, 2H), 4.71 (d, J = 2.5 Hz, 2H ), 6.82 (d, J = 9.8 Hz, 1H), 7.31 (d, J = 6.6 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.9 (s, 1F).

５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（２００ｍｇ，０．５９ｍｍｏｌ）のＤＭＦ（２ｍＬ）溶液に、氷冷下で水素化ナトリウムの５５％油分散（２６ｍｇ，０．６５ｍｍｏｌ）及び１−ブロモ−２−ブチン（９０ｍｇ，０．６５ｍｍｏｌ）を加え、室温で２１時間攪拌した。反応終了後、反応液に水を注ぎ、析出した固体を吸引ろ過し、水で洗浄後、ヘキサンとジエチルエーテルの混合溶媒で洗浄し、乾燥することにより、４−［４−（２−ブチニル）−７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの薄茶色固体（１９７ｍｇ，収率：８５％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．７８（ｄ，Ｊ＝２．３Ｈｚ，３Ｈ），１．８８−１．９４（ｍ，２Ｈ），２．００−２．０６（ｍ，２Ｈ），３．６１−３．６４（ｍ，２Ｈ），３．８３−３．８６（ｍ，２Ｈ），４．６３（ｄ，Ｊ＝２．３Ｈｚ，２Ｈ），４．６４（ｓ，２Ｈ），６．８１（ｄ，Ｊ＝９．８Ｈｚ，１Ｈ），７．２９（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５（ｓ，１Ｆ）．Example-11

5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one ( 200 mg, 0.59 mmol) in DMF (2 mL) was added with 55% oil dispersion of sodium hydride (26 mg, 0.65 mmol) and 1-bromo-2-butyne (90 mg, 0.65 mmol) under ice-cooling. And stirred at room temperature for 21 hours. After completion of the reaction, water is poured into the reaction solution, and the precipitated solid is suction filtered, washed with water, washed with a mixed solvent of hexane and diethyl ether, and dried to give 4- [4- (2-butynyl) Light brown of -7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl] -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one A solid (197 mg, yield: 85%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.78 (d, J = 2.3 Hz, 3H), 1.88-1.94 (m, 2H), 2.00-2.06 (m, 2H) ), 3.61-3.64 (m, 2H), 3.83-3.86 (m, 2H), 4.63 (d, J = 2.3 Hz, 2H), 4.64 (s, 2H) ), 6.81 (d, J = 9.8 Hz, 1H), 7.29 (d, J = 6.7 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115 (s, 1F).

５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（２００ｍｇ，０．５９ｍｍｏｌ）のＤＭＦ（２ｍＬ）溶液に、氷冷下で水素化ナトリウムの５５％油分散（２６ｍｇ，０．６５ｍｍｏｌ）及びブロモアセトニトリル（８０ｍｇ，０．６５ｍｍｏｌ）を加え、室温で２１時間攪拌した。反応終了後、反応液に水を注ぎ、析出した固体を吸引ろ過し、水で洗浄後、ヘキサンとジエチルエーテルの混合溶媒で洗浄し、乾燥することにより、５−クロロ−４−（４−シアノメチル−７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（１９６ｍｇ，収率：８８％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．９０−１．９５（ｍ，２Ｈ），２．０１−２．０７（ｍ，２Ｈ），３．６４−３．６７（ｍ，２Ｈ），３．８４−３．８６（ｍ，２Ｈ），４．７０（ｓ，２Ｈ），４．８８（ｓ，２Ｈ），６．８７（ｄ，Ｊ＝９．１Ｈｚ，１Ｈ），７．２１（ｄ，Ｊ＝６．６Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１３（ｓ，１Ｆ）．Example-12

5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one ( 200 mg, 0.59 mmol) in DMF (2 mL) was added with a 55% oil dispersion of sodium hydride (26 mg, 0.65 mmol) and bromoacetonitrile (80 mg, 0.65 mmol) under ice cooling, and the mixture was stirred at room temperature for 21 hours. Stir. After completion of the reaction, water is poured into the reaction solution, and the precipitated solid is suction filtered, washed with water, washed with a mixed solvent of hexane and diethyl ether, and dried to give 5-chloro-4- (4-cyanomethyl). -7-Fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one as a white solid (196 mg, yield) Rate: 88%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.90-1.95 (m, 2H), 2.01-2.07 (m, 2H), 3.64-3.67 (m, 2H), 3.84-3.86 (m, 2H), 4.70 (s, 2H), 4.88 (s, 2H), 6.87 (d, J = 9.1 Hz, 1H), 7.21 ( d, J = 6.6 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-113 (s, 1F).

水素化ナトリウムの５５％油分散（０．１８０ｇ，４．５ｍｍｏｌ）の１，４−ジオキサン（２０ｍＬ）懸濁液に、５−クロロ−４−（２，４−ジフルオロ−５−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（０．９９ｇ，３．０ｍｍｏｌ）及び乳酸エチル（０．５３ｍＬ，４．５ｍｍｏｌ）を加え、室温で３０分間攪拌した。反応終了後、反応液を飽和塩化アンモニウム水溶液（２０ｍＬ）に注ぎ、酢酸エチル（３０ｍＬ×３）で抽出した。合一した有機層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製したのち、得られた生成物を酢酸エチルから再結晶することにより、２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］プロピオン酸エチルの淡黄色固体（０．７ｇ，収率：５５％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．２７（ｔ，Ｊ＝７．１Ｈｚ，３Ｈ），１．７１（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．９０−１．９３（ｍ，２Ｈ），２．０１−２．０５（ｍ，２Ｈ），３．６０−３．６５（ｍ，２Ｈ），３．８０−３．８５（ｍ，２Ｈ），４．２５（ｑ，Ｊ＝７．１Ｈｚ，２Ｈ），４．８０（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），６．７３（ｄ，Ｊ＝１０．９Ｈｚ，１Ｈ），８．１２（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−９８．９（ｓ，１Ｆ）．
１Ｆ）．Reference Example-6

To a suspension of 55% oil dispersion of sodium hydride (0.180 g, 4.5 mmol) in 1,4-dioxane (20 mL), 5-chloro-4- (2,4-difluoro-5-nitrophenyl)- 1,2-tetramethylene-4-pyrazolin-3-one (0.99 g, 3.0 mmol) and ethyl lactate (0.53 mL, 4.5 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (ethyl acetate), and then the obtained product is recrystallized from ethyl acetate to give 2- [4- (5-chloro-3-oxo-1). , 2-tetramethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] light yellow solid (0.7 g, yield: 55%) of ethyl propionate. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.27 (t, J = 7.1 Hz, 3H), 1.71 (d, J = 6.8 Hz, 3H), 1.90-1.93 (m , 2H), 2.01-1.05 (m, 2H), 3.60-3.65 (m, 2H), 3.80-3.85 (m, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.80 (q, J = 6.8 Hz, 1H), 6.73 (d, J = 10.9 Hz, 1H), 8.12 (d, J = 7.3 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-98.9 (s, 1F).
1F).

２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］プロピオン酸エチル（１．２８ｇ，３．０ｍｍｏｌ）の酢酸エチル（１５ｍＬ）溶液に、水（１５ｍＬ）及び酢酸（１５ｍＬ）を加えた後、還元鉄（１．６８ｇ，３０．０ｍｍｏｌ）を加え、８０℃で１時間攪拌した。反応終了後、反応液を室温へ戻し、不溶物をろ別後、ろ液に飽和炭酸水素ナトリウム水溶液（１５０ｍＬ）を加え、酢酸エチル（１００ｍＬ×３）で抽出した。有機層を飽和炭酸水素ナトリウム水溶液（１００ｍＬ）及び飽和食塩水（１００ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた固体にヘキサン（５０ｍＬ）を加え、ろ過することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの灰白色固体（１．０５ｇ，収率：９８％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５５（ｄ，Ｊ＝６．９Ｈｚ，３Ｈ），１．８９−１．９４（ｍ，２Ｈ），１．９９−２．０５（ｍ，２Ｈ），３．６０−３．６５（ｍ，２Ｈ），３．８３−３．８８（ｍ，２Ｈ），４．６１（ｑ，Ｊ＝６．９Ｈｚ，１Ｈ），６．７５（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．０７（ｄ，Ｊ＝６．９Ｈｚ，１Ｈ），８．８０（ｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．８（ｓ，１Ｆ）．Example-13

Ethyl 2- [4- (5-chloro-3-oxo-1,2-tetramethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] propionate (1.28 g, 3. After adding water (15 mL) and acetic acid (15 mL) to a solution of 0 mmol) in ethyl acetate (15 mL), reduced iron (1.68 g, 30.0 mmol) was added, and the mixture was stirred at 80 ° C. for 1 hour. After completion of the reaction, the reaction solution was returned to room temperature, insoluble materials were filtered off, saturated aqueous sodium hydrogen carbonate solution (150 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane (50 mL) is added to the obtained solid and filtered to give 5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazine. An off-white solid (1.05 g, yield: 98%) of -6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.55 (d, J = 6.9 Hz, 3H), 1.89-1.94 (m, 2H), 1.99-2.05 (m, 2H) ), 3.60-3.65 (m, 2H), 3.83-3.88 (m, 2H), 4.61 (q, J = 6.9 Hz, 1H), 6.75 (d, J = 9.9 Hz, 1H), 7.07 (d, J = 6.9 Hz, 1H), 8.80 (s, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.8 (s, 1F).

水素化ナトリウムの５５％油分散（４１ｍｇ，０．９４ｍｍｏｌ）のＤＭＦ（３ｍＬ）懸濁液に、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（３００ｍｇ，０．８５３ｍｍｏｌ）及びヨードメタン（１３３ｍｇ，０．９４ｍｍｏｌ）を加え、室温で１６時間攪拌した。反応液にさらにヨードメタン（１３３ｍｇ，０．９４ｍｍｏｌ）を加え、室温でさらに２４時間攪拌した。反応終了後、反応液に水（１０ｍＬ）を加え、酢酸エチル（１０ｍＬ×１）で抽出し、有機層を蒸留水（１０ｍＬ×３）次いで飽和食塩水（１０ｍＬ）で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製した後、得られた生成物を酢酸エチルとヘキサンの混合溶媒から再結晶することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２，４−ジメチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（１２０ｍｇ，収率：３８％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５７（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．８９−１．９４（ｍ，２Ｈ），２．００−２．０４（ｍ，２Ｈ），３．３５（ｓ，３Ｈ），３．６０−３．６４（ｍ，２Ｈ），３．８２−３．８６（ｍ，２Ｈ），４．６７（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），６．８０（ｄ，Ｊ＝９．８Ｈｚ，１Ｈ），７．１２（ｄ，Ｊ＝６．６Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．８（ｓ，１Ｆ）．Example-14

To a suspension of sodium hydride in 55% oil dispersion (41 mg, 0.94 mmol) in DMF (3 mL) was added 5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (300 mg, 0.853 mmol) and iodomethane (133 mg, 0.94 mmol) were added at room temperature for 16 Stir for hours. To the reaction solution was further added iodomethane (133 mg, 0.94 mmol), and the mixture was further stirred at room temperature for 24 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, followed by extraction with ethyl acetate (10 mL × 1), and the organic layer was washed with distilled water (10 mL × 3) and then with saturated brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate), and then the obtained product was recrystallized from a mixed solvent of ethyl acetate and hexane to give 5-chloro-4- (7-fluoro). -2,3-Dihydro-2,4-dimethyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one as a white solid (120 mg Yield: 38%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.57 (d, J = 6.8 Hz, 3H), 1.89-1.94 (m, 2H), 2.00-2.04 (m, 2H) ), 3.35 (s, 3H), 3.60-3.64 (m, 2H), 3.82-3.86 (m, 2H), 4.67 (q, J = 6.8 Hz, 1H) ), 6.80 (d, J = 9.8 Hz, 1H), 7.12 (d, J = 6.6 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.8 (s, 1F).

水素化ナトリウムの５５％油分散（５６ｍｇ，１．２８ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（３００ｍｇ，０．８５３ｍｍｏｌ）、次いでヨードエタン（２００ｍｇ，１．２８ｍｍｏｌ）のＤＭＦ溶液を加え、室温で終夜攪拌した。反応終了後、反応液に水（１０ｍＬ）を加え、酢酸エチル（１０ｍＬ×１）で抽出し、有機層を蒸留水（１０ｍＬ×３）及び飽和食塩水（１０ｍＬ）で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた固体をシリカゲルカラムクロマトグラフィー（酢酸エチル）により精製することにより、５−クロロ−４−（４−エチル−７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（１７０ｍｇ，収率：５２％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．２７（ｔ，Ｊ＝７．１Ｈｚ，３Ｈ），１．５６（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．８６−１．９５（ｍ，２Ｈ），１．９９−２．０７（ｍ，２Ｈ），３．６０−３．６４（ｍ，２Ｈ），３．８２−３．８７（ｍ，２Ｈ），３．９７（ｑ，Ｊ＝７．１Ｈｚ，１Ｈ），３．９８（ｑ，Ｊ＝７．１Ｈｚ，１Ｈ），４．６４（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），６．８０（ｄ，Ｊ＝１０．０Ｈｚ，１Ｈ），７．１５（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．８（ｓ，１Ｆ）．Example-15

To a suspension of sodium hydride in 55% oil dispersion (56 mg, 1.28 mmol) in DMF (2 mL) was added 5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (300 mg, 0.853 mmol) followed by iodoethane (200 mg, 1.28 mmol) in DMF And stirred at room temperature overnight. After completion of the reaction, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL × 1), and the organic layer was washed with distilled water (10 mL × 3) and saturated brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained solid was purified by silica gel column chromatography (ethyl acetate) to give 5-chloro-4- (4-ethyl-7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H- A white solid (170 mg, yield: 52%) of 1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.27 (t, J = 7.1 Hz, 3H), 1.56 (d, J = 6.8 Hz, 3H), 1.86-1.95 (m , 2H), 1.99-2.07 (m, 2H), 3.60-3.64 (m, 2H), 3.82-3.87 (m, 2H), 3.97 (q, J = 7.1 Hz, 1H), 3.98 (q, J = 7.1 Hz, 1H), 4.64 (q, J = 6.8 Hz, 1H), 6.80 (d, J = 10.0 Hz, 1H), 7.15 (d, J = 6.7 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.8 (s, 1F).

水素化ナトリウムの５５％油分散（４１ｍｇ，０．９４ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（３００ｍｇ，０．８５３ｍｍｏｌ）、次いでイソブチルブロミド（１３０ｍｇ，０．９４ｍｍｏｌ）のＤＭＦ溶液を加え、室温で終夜攪拌した。反応終了後、反応液に水（１０ｍＬ）を加え、酢酸エチル（１０ｍＬ×１）で抽出し、有機層を蒸留水（１０ｍＬ×３）及び飽和食塩水（１０ｍＬ）で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた組成生物をシリカゲルカラムクロマトグラフィー（酢酸エチル）により精製することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−４−イソブチル−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（９０ｍｇ，収率：２５％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ０．９１−０．９６（ｍ，６Ｈ），１．５６（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．８８−１．９４（ｍ，２Ｈ），２．００−２．０５（ｍ，２Ｈ），２．１３（ｍ，１Ｈ），３．６０−３．６５（ｍ，２Ｈ），３．７１−３．８４（ｍ，２Ｈ），３．８２−３．８７（ｍ，２Ｈ），４．６５（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），６．８０（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．１２（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．８（ｓ，１Ｆ）．Example-16

To a suspension of sodium hydride in 55% oil dispersion (41 mg, 0.94 mmol) in DMF (2 mL) was added 5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (300 mg, 0.853 mmol), then isobutyl bromide (130 mg, 0.94 mmol) in DMF In addition, the mixture was stirred overnight at room temperature. After completion of the reaction, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL × 1), and the organic layer was washed with distilled water (10 mL × 3) and saturated brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting compositional organism was purified by silica gel column chromatography (ethyl acetate) to give 5-chloro-4- (7-fluoro-2,3-dihydro-4-isobutyl-2-methyl-3-oxo-4H A white solid (90 mg, yield: 25%) of -1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.91-0.96 (m, 6H), 1.56 (d, J = 6.8 Hz, 3H), 1.88-1.94 (m, 2H) ), 2.00-2.05 (m, 2H), 2.13 (m, 1H), 3.60-3.65 (m, 2H), 3.71-3.84 (m, 2H), 3.82-3.87 (m, 2H), 4.65 (q, J = 6.8 Hz, 1H), 6.80 (d, J = 9.9 Hz, 1H), 7.12 (d, J = 6.8 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.8 (s, 1F).

水素化ナトリウムの５５％油分散（４１ｍｇ，０．９４ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（３００ｍｇ，０．８５３ｍｍｏｌ）、次いでアリルブロミド（１１６ｍｇ，０．９４ｍｍｏｌ）のＤＭＦ溶液を加え、室温で終夜攪拌した。反応終了後、反応液に水（１０ｍＬ）を加え、酢酸エチル（１０ｍＬ×１）で抽出し、有機層を蒸留水（１０ｍＬ×３）及び飽和食塩水（１０ｍＬ）で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた固体にジエチルエーテル（１０ｍＬ）を加え、ろ過することにより、４−（４−アリル−７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（１７７ｍｇ，収率：５３％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５９（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．８７−１．９３（ｍ，２Ｈ），１．９９−２．０５（ｍ，２Ｈ），３．５８−３．６２（ｍ，２Ｈ），３．８１−３．８６（ｍ，２Ｈ），４．４８−４．５９（ｍ，２Ｈ），４．７０（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），５．１９−５．２５（ｍ，２Ｈ），５．８２−５．９２（ｍ，１Ｈ），６．８０（ｄ，Ｊ＝９．６Ｈｚ，１Ｈ），７．１１（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．４（ｓ，１Ｆ）．Example-17

To a suspension of sodium hydride in 55% oil dispersion (41 mg, 0.94 mmol) in DMF (2 mL) was added 5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (300 mg, 0.853 mmol), then allyl bromide (116 mg, 0.94 mmol) in DMF In addition, the mixture was stirred overnight at room temperature. After completion of the reaction, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL × 1), and the organic layer was washed with distilled water (10 mL × 3) and saturated brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diethyl ether (10 mL) was added to the obtained solid and filtered to give 4- (4-allyl-7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoate. A white solid (177 mg, yield: 53%) of oxazin-6-yl) -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.59 (d, J = 6.8 Hz, 3H), 1.87-1.93 (m, 2H), 1.99-2.05 (m, 2H) ), 3.58-3.62 (m, 2H), 3.81-3.86 (m, 2H), 4.48-4.59 (m, 2H), 4.70 (q, J = 6) .8 Hz, 1H), 5.19-5.25 (m, 2H), 5.82-5.92 (m, 1H), 6.80 (d, J = 9.6 Hz, 1H), 7.11 (D, J = 6.8 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.4 (s, 1F).

水素化ナトリウムの５５％油分散（４１ｍｇ，０．９４ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（３００ｍｇ，０．８５３ｍｍｏｌ）、次いでメタリルブロミド（１３１ｍｇ，０．９４ｍｍｏｌ）のＤＭＦ溶液を加え、室温で終夜攪拌した。反応終了後、反応液に水（１０ｍＬ）を加え、酢酸エチル（１０ｍＬ×１）で抽出し、有機層を蒸留水（１０ｍＬ×３）及び飽和食塩水（１０ｍＬ）で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた固体にジエチルエーテル（１０ｍＬ）を加え、ろ過することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−４−メタリル−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（１８４ｍｇ，収率：５３％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５９（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．７６（ｓ，３Ｈ），１．８７−１．９３（ｍ，２Ｈ），１．９９−２．０５（ｍ，２Ｈ），３．５７−３．６２（ｍ，２Ｈ），３．８０−３．８５（ｍ，２Ｈ），４．４４（ｓ，２Ｈ），４．７１（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），４．７８（ｓ，１Ｈ），４．９２（ｓ，１Ｈ），６．８０（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．０４（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．４（ｓ，１Ｆ）．Example-18

To a suspension of sodium hydride in 55% oil dispersion (41 mg, 0.94 mmol) in DMF (2 mL) was added 5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (300 mg, 0.853 mmol), then methallyl bromide (131 mg, 0.94 mmol) in DMF And stirred at room temperature overnight. After completion of the reaction, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL × 1), and the organic layer was washed with distilled water (10 mL × 3) and saturated brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diethyl ether (10 mL) was added to the obtained solid and filtered to give 5-chloro-4- (7-fluoro-2,3-dihydro-4-methallyl-2-methyl-3-oxo-4H-1 , 4-Benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained as a white solid (184 mg, yield: 53%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.59 (d, J = 6.8 Hz, 3H), 1.76 (s, 3H), 1.87-1.93 (m, 2H), 1. 99-2.05 (m, 2H), 3.57-3.62 (m, 2H), 3.80-3.85 (m, 2H), 4.44 (s, 2H), 4.71 ( q, J = 6.8 Hz, 1H), 4.78 (s, 1H), 4.92 (s, 1H), 6.80 (d, J = 9.9 Hz, 1H), 7.04 (d, J = 6.8 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.4 (s, 1F).

水素化ナトリウムの５５％油分散（４１ｍｇ，０．９４ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（３００ｍｇ，０．８５３ｍｍｏｌ）、次いでプロパルギルブロミド（１１８ｍｇ，０．９４ｍｍｏｌ）のＤＭＦ溶液を加え、室温で終夜攪拌した。反応終了後、反応液に水（１０ｍＬ）を加え、酢酸エチル（１０ｍＬ×１）で抽出し、有機層を蒸留水（１０ｍＬ×３）及び飽和食塩水（１０ｍＬ）で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた固体にジエチルエーテル（１０ｍＬ）を加え、ろ過することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの黄土色固体（２００ｍｇ，収率：６０％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５９（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．９０−１．９４（ｍ，２Ｈ），２．００−２．０６（ｍ，２Ｈ），２．２６（ｔ，Ｊ＝２．５Ｈｚ，１Ｈ），３．６０−３．６５（ｍ，２Ｈ），３．８２−３．８８（ｍ，２Ｈ），４．６３（ｄｄ，Ｊ＝２．５ ａｎｄ １７．５Ｈｚ，１Ｈ），４．６８（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），４．７６（ｄｄ，Ｊ＝２．５ ａｎｄ １７．５Ｈｚ，１Ｈ），６．８２（ｄ，Ｊ＝９．８Ｈｚ，１Ｈ），７．２９（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．１（ｓ，１Ｆ）．Example-19

To a suspension of sodium hydride in 55% oil dispersion (41 mg, 0.94 mmol) in DMF (2 mL) was added 5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (300 mg, 0.853 mmol), then propargyl bromide (118 mg, 0.94 mmol) in DMF In addition, the mixture was stirred overnight at room temperature. After completion of the reaction, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL × 1), and the organic layer was washed with distilled water (10 mL × 3) and saturated brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diethyl ether (10 mL) was added to the obtained solid and filtered to give 5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo-4-propargyl-4H-1 , 4-Benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained as an ocherous solid (200 mg, yield: 60%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.59 (d, J = 6.8 Hz, 3H), 1.90-1.94 (m, 2H), 2.00-2.06 (m, 2H) ), 2.26 (t, J = 2.5 Hz, 1H), 3.60-3.65 (m, 2H), 3.82-3.88 (m, 2H), 4.63 (dd, J = 2.5 and 17.5 Hz, 1H), 4.68 (q, J = 6.8 Hz, 1H), 4.76 (dd, J = 2.5 and 17.5 Hz, 1H), 6.82 ( d, J = 9.8 Hz, 1H), 7.29 (d, J = 6.7 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.1 (s, 1F).

水素化ナトリウムの５５％油分散（４１ｍｇ，０．９４ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（３００ｍｇ，０．８５３ｍｍｏｌ）、次いで２−ブチニルブロミド（１３０ｍｇ，０．９４ｍｍｏｌ）のＤＭＦ溶液を加え、室温で終夜攪拌した。反応終了後、反応液に水（１０ｍＬ）を加え、酢酸エチル（１０ｍＬ×１）で抽出し、有機層を蒸留水（１０ｍＬ×３）及び飽和食塩水（１０ｍＬ）で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた固体にジエチルエーテル（１０ｍＬ）を加え、ろ過することにより、４−［４−（２−ブチニル）−７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（２１３ｍｇ，収率：６２％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５８（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．７８（ｔ，Ｊ＝２．３Ｈｚ，３Ｈ），１．９０−１，９３（ｍ，２Ｈ），２．０１−２．０５（ｍ，２Ｈ），３．６０−３．６５（ｍ，２Ｈ），３．８２−３．８７（ｍ，２Ｈ），４．５４（ｑ，Ｊ＝２．３ ａｎｄ １７．２Ｈｚ，１Ｈ），４．６６（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），４．６９（ｑ，Ｊ＝２．３ ａｎｄ １７．２Ｈｚ，１Ｈ），６．８０（ｄ，Ｊ＝９．８Ｈｚ，１Ｈ），７．２７（ｄ，Ｊ＝６．１Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．５（ｓ，１Ｆ）．Example-20

To a suspension of sodium hydride in 55% oil dispersion (41 mg, 0.94 mmol) in DMF (2 mL) was added 5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (300 mg, 0.853 mmol) followed by 2-butynyl bromide (130 mg, 0.94 mmol) in DMF And stirred at room temperature overnight. After completion of the reaction, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL × 1), and the organic layer was washed with distilled water (10 mL × 3) and saturated brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diethyl ether (10 mL) was added to the obtained solid and filtered to give 4- [4- (2-butynyl) -7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1 , 4-Benzoxazin-6-yl] -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one was obtained as a white solid (213 mg, yield: 62%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.58 (d, J = 6.8 Hz, 3H), 1.78 (t, J = 2.3 Hz, 3H), 1.90-1, 93 (m , 2H), 2.01-2.05 (m, 2H), 3.60-3.65 (m, 2H), 3.82-3.87 (m, 2H), 4.54 (q, J = 2.3 and 17.2 Hz, 1H), 4.66 (q, J = 6.8 Hz, 1H), 4.69 (q, J = 2.3 and 17.2 Hz, 1H), 6.80 ( d, J = 9.8 Hz, 1H), 7.27 (d, J = 6.1 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.5 (s, 1F).

水素化ナトリウムの５５％油分散（４１ｍｇ，０．９４ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（３００ｍｇ，０．８５３ｍｍｏｌ）、次いでブロモアセトニトリル（１１６ｍｇ，０．９４ｍｍｏｌ）のＤＭＦ溶液を加え、室温で終夜攪拌した。反応終了後、反応液に水（１０ｍＬ）を加え、酢酸エチル（１０ｍＬ×１）で抽出し、有機層を蒸留水（１０ｍＬ×３）及び飽和食塩水（１０ｍＬ）で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた固体にジエチルエーテル（１０ｍＬ）を加え、ろ過することにより、５−クロロ−４−（４−シアノメチル−７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの黄土色固体（２６２ｍｇ，収率：７８％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．６２（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．９１−１．９５（ｍ，２Ｈ），２．０１−２．０６（ｍ，２Ｈ），３．６３−３．６８（ｍ，２Ｈ），３．８１−３．８６（ｍ，２Ｈ），４．７０（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），４．８３（ｄ，Ｊ＝１７．５Ｈｚ，１Ｈ），４．９２（ｄ，Ｊ＝１７．５Ｈｚ，１Ｈ），６．８６（ｄ，Ｊ＝９．８Ｈｚ，１Ｈ），７．１９（ｄ，Ｊ＝６．４Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１３．６（ｓ，１Ｆ）．Example-21

To a suspension of sodium hydride in 55% oil dispersion (41 mg, 0.94 mmol) in DMF (2 mL) was added 5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (300 mg, 0.853 mmol) followed by bromoacetonitrile (116 mg, 0.94 mmol) in DMF. In addition, the mixture was stirred overnight at room temperature. After completion of the reaction, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL × 1), and the organic layer was washed with distilled water (10 mL × 3) and saturated brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diethyl ether (10 mL) was added to the obtained solid and filtered to give 5-chloro-4- (4-cyanomethyl-7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1 , 4-Benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained as an ocher solid (262 mg, yield: 78%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.62 (d, J = 6.8 Hz, 3H), 1.91-1.95 (m, 2H), 2.01 to 2.06 (m, 2H) ), 3.63-3.68 (m, 2H), 3.81-3.86 (m, 2H), 4.70 (q, J = 6.8 Hz, 1H), 4.83 (d, J = 17.5 Hz, 1H), 4.92 (d, J = 17.5 Hz, 1H), 6.86 (d, J = 9.8 Hz, 1H), 7.19 (d, J = 6.4 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-113.6 (s, 1F).

水素化ナトリウムの５５％油分散（４１ｍｇ，０．９４ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（３００ｍｇ，０．８５３ｍｍｏｌ）、次いでクロロメチルメチルエーテル（８０ｍｇ，０．９４ｍｍｏｌ）のＤＭＦ溶液を加え、室温で終夜攪拌した。反応終了後、反応液に水（１０ｍＬ）を加え、酢酸エチル（１０ｍＬ×１）で抽出し、有機層を蒸留水（１０ｍＬ×３）及び飽和食塩水（１０ｍＬ）で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた固体にジエチルエーテル（１０ｍＬ）を加え、ろ過することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−４−メトキシメチル−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（１０５ｍｇ，収率：３１％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．６０（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．８７−１．９１（ｍ，２Ｈ），１．９８−２．０５（ｍ，２Ｈ），３．３８（ｓ，３Ｈ），３．５８−３．６３（ｍ，２Ｈ），３．８０−３．８５（ｍ，２Ｈ），４．６８（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），５．２５（ｄ，Ｊ＝１０．６Ｈｚ，１Ｈ），５．３８（ｄ，Ｊ＝１０．６Ｈｚ，１Ｈ），６．８０（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．３８（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．０（ｓ，１Ｆ）．Example-22

To a suspension of sodium hydride in 55% oil dispersion (41 mg, 0.94 mmol) in DMF (2 mL) was added 5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (300 mg, 0.853 mmol) followed by chloromethyl methyl ether (80 mg, 0.94 mmol) in DMF The solution was added and stirred at room temperature overnight. After completion of the reaction, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL × 1), and the organic layer was washed with distilled water (10 mL × 3) and saturated brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Diethyl ether (10 mL) was added to the obtained solid and filtered to give 5-chloro-4- (7-fluoro-2,3-dihydro-4-methoxymethyl-2-methyl-3-oxo-4H- A white solid (105 mg, yield: 31%) of 1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.60 (d, J = 6.8 Hz, 3H), 1.87-1.91 (m, 2H), 1.98-2.05 (m, 2H) ), 3.38 (s, 3H), 3.58-3.63 (m, 2H), 3.80-3.85 (m, 2H), 4.68 (q, J = 6.8 Hz, 1H) ), 5.25 (d, J = 10.6 Hz, 1H), 5.38 (d, J = 10.6 Hz, 1H), 6.80 (d, J = 9.9 Hz, 1H), 7.38. (D, J = 6.8 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.0 (s, 1F).

水素化ナトリウムの５５％油分散（０．１９９ｇ，４．５５ｍｍｏｌ）の１，４−ジオキサン（２０ｍＬ）懸濁液に、５−クロロ−４−（２，４−ジフルオロ−５−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（１．０ｇ，３．０３ｍｍｏｌ）及び２−ヒドロキシ酪酸エチル（０．６２ｍＬ，４．５５ｍｍｏｌ）を加え、室温で３０分間攪拌した。反応終了後、反応液を飽和塩化アンモニウム水溶液（２０ｍＬ）に注ぎ、酢酸エチル（３０ｍＬ×３）で抽出した。合一した有機層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し、得られた固体を酢酸エチルとヘキサンの混合溶媒から再結晶することにより、２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］ブタン酸エチルの淡黄色固体（０．５１５ｇ，収率：３８％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．１２（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．２７（ｔ，Ｊ＝７．１Ｈｚ，３Ｈ），１．８７−１．９５（ｍ，２Ｈ），１．９９−２．０６（ｍ，２Ｈ），２．０８（ｄｑ，Ｊ＝５．９ ａｎｄ ７．３Ｈｚ，２Ｈ），３．６０−３．６５（ｍ，２Ｈ），３．８１−３．８５（ｍ，２Ｈ），４．２５（ｑ，Ｊ＝７．１Ｈｚ，２Ｈ），４．６４（ｔ，Ｊ＝５．９Ｈｚ，１Ｈ），６．６８（ｄ，Ｊ＝１１．０Ｈｚ，１Ｈ），８．１１（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−９８．９（ｓ，１Ｆ）．Reference Example-7

To a suspension of sodium hydride in 55% oil dispersion (0.199 g, 4.55 mmol) in 1,4-dioxane (20 mL), 5-chloro-4- (2,4-difluoro-5-nitrophenyl)- 1,2-tetramethylene-4-pyrazolin-3-one (1.0 g, 3.03 mmol) and ethyl 2-hydroxybutyrate (0.62 mL, 4.55 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate), and the obtained solid was recrystallized from a mixed solvent of ethyl acetate and hexane to give 2- [4- (5-chloro-3- A light yellow solid (0.515 g, yield: 38%) of ethyl oxo-1,2-tetramethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] butanoate was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.12 (t, J = 7.3 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H), 1.87-1.95 (m , 2H), 1.99-2.06 (m, 2H), 2.08 (dq, J = 5.9 and 7.3 Hz, 2H), 3.60-3.65 (m, 2H), 3 81-3.85 (m, 2H), 4.25 (q, J = 7.1 Hz, 2H), 4.64 (t, J = 5.9 Hz, 1H), 6.68 (d, J = 11.0 Hz, 1H), 8.11 (d, J = 7.4 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-98.9 (s, 1F).

２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］ブタン酸エチル（０．５１５ｇ，１．１６ｍｍｏｌ）の酢酸エチル（１０ｍＬ）溶液に、水（１０ｍＬ）及び酢酸（１０ｍＬ）を加えた後、還元鉄（０．６５ｇ，１１．６ｍｍｏｌ）を加え、８０℃で１時間攪拌した。反応終了後、反応液を室温へ戻し、不溶物をろ別後、ろ液に飽和炭酸水素ナトリウム水溶液（７０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を飽和炭酸水素ナトリウム水溶液（５０ｍＬ）及び飽和食塩水（５０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた固体にヘキサン（３０ｍＬ）を加え、ろ過することにより、５−クロロ−４−（２−エチル−７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（０．４０４ｇ，収率：９５％）を灰白色固体物として得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．０６（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ），１．８０−１．９７（ｍ，４Ｈ），１．９９−２．０７（ｍ，２Ｈ），３．６０−３．６５（ｍ，２Ｈ），３．８２−３．８６（ｍ，２Ｈ），４．４５（ｄｄ，Ｊ＝４．６ ａｎｄ ８．０Ｈｚ，１Ｈ），６．７５（ｄ，Ｊ＝１０．０Ｈｚ，１Ｈ），７．０７（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ），８．９５（ｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．８（ｓ，１Ｆ）．Example-23

Ethyl 2- [4- (5-chloro-3-oxo-1,2-tetramethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] butanoate (0.515 g, 1. After adding water (10 mL) and acetic acid (10 mL) to a solution of 16 mmol) in ethyl acetate (10 mL), reduced iron (0.65 g, 11.6 mmol) was added, and the mixture was stirred at 80 ° C. for 1 hour. After completion of the reaction, the reaction solution was returned to room temperature, insolubles were filtered off, saturated aqueous sodium hydrogen carbonate solution (70 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane (30 mL) was added to the obtained solid and filtered to give 5-chloro-4- (2-ethyl-7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazine. -6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (0.404 g, yield: 95%) was obtained as an off-white solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.06 (t, J = 7.4 Hz, 3H), 1.80-1.97 (m, 4H), 1.99-2.07 (m, 2H) ), 3.60-3.65 (m, 2H), 3.82-3.86 (m, 2H), 4.45 (dd, J = 4.6 and 8.0 Hz, 1H), 6.75. (D, J = 10.0 Hz, 1H), 7.07 (d, J = 6.8 Hz, 1H), 8.95 (s, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.8 (s, 1F).

水素化ナトリウムの５５％油分散（２２ｍｇ，０．５１ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、５−クロロ−４−（２−エチル−７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（１７０ｍｇ，０．４６５ｍｍｏｌ）、次いでプロパルギルブロミド（６４ｍｇ，０．５１ｍｍｏｌ）のＤＭＦ溶液を加え、室温で終夜攪拌した。反応終了後、反応液に水（１０ｍＬ）を加え、酢酸エチル（１０ｍＬ×１）で抽出し、有機層を蒸留水（１０ｍＬ×３）及び飽和食塩水（１０ｍＬ）で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた固体をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、５−クロロ−４−（２−エチル−７−フルオロ−２，３−ジヒドロ−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（１１１ｍｇ，収率：５９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．０８（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ），１．８７−１．９７（ｍ，４Ｈ），１．９７−２．０６（ｍ，２Ｈ），２．２５（ｔ，Ｊ＝２．５Ｈｚ，１Ｈ），３．６１−３．６６（ｍ，２Ｈ），３．８２−３．８７（ｍ，２Ｈ），４．５４（ｍ，１Ｈ），４．７０（ｄ，Ｊ＝２．５Ｈｚ，２Ｈ），６．８３（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．２７（ｄ，Ｊ＝６．６Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．１（ｓ，１Ｆ）．Example-24

To a suspension of sodium hydride in 55% oil dispersion (22 mg, 0.51 mmol) in DMF (2 mL) was added 5-chloro-4- (2-ethyl-7-fluoro-2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (170 mg, 0.465 mmol) and then propargyl bromide (64 mg, 0.51 mmol) in DMF. In addition, the mixture was stirred overnight at room temperature. After completion of the reaction, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL × 1), and the organic layer was washed with distilled water (10 mL × 3) and saturated brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained solid was purified by silica gel column chromatography (ethyl acetate) to give 5-chloro-4- (2-ethyl-7-fluoro-2,3-dihydro-3-oxo-4-propargyl-4H- A white solid (111 mg, yield: 59%) of 1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.08 (t, J = 7.4 Hz, 3H), 1.87-1.97 (m, 4H), 1.97-2.06 (m, 2H) ), 2.25 (t, J = 2.5 Hz, 1H), 3.61-3.66 (m, 2H), 3.82-3.87 (m, 2H), 4.54 (m, 1H) ), 4.70 (d, J = 2.5 Hz, 2H), 6.83 (d, J = 9.9 Hz, 1H), 7.27 (d, J = 6.6 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.1 (s, 1F).

水素化ナトリウムの５５％油分散（０．１９９ｇ，４．５５ｍｍｏｌ）の１，４−ジオキサン（２０ｍＬ）懸濁液に、５−クロロ−４−（２，４−ジフルオロ−５−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（１．０ｇ，３．０３ｍｍｏｌ）及び２−ヒドロキシ吉草酸エチル（０．６９ｍＬ，４．５５ｍｍｏｌ）を加え、室温で３０分間攪拌した。反応終了後、反応液を飽和塩化アンモニウム水溶液（２０ｍＬ）に注ぎ、酢酸エチル（３０ｍＬ×３）で抽出した。合一した有機層を飽和食塩水（３０ｍＬ）で洗浄後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］吉草酸エチルの淡黄色固体（０．５４０ｇ，収率：３９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ０．９９（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．２７（ｔ，Ｊ＝７．０Ｈｚ，３Ｈ），１．５５−１．６４（ｍ，２Ｈ），１．８９−１．９３（ｍ，２Ｈ），１．９４−２．０５（ｍ，４Ｈ），３．６０−３．６５（ｍ，２Ｈ），３．８１−３．８５（ｍ，２Ｈ），４．２４（ｑ，Ｊ＝７．３Ｈｚ，２Ｈ），４．６７（ｄｄ，Ｊ＝４．５ ａｎｄ ７．８Ｈｚ，１Ｈ），６．６７（ｄ，Ｊ＝１０．９Ｈｚ，１Ｈ），８．１１（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−９８．９（ｓ，１Ｆ）．Reference Example-8

To a suspension of sodium hydride in 55% oil dispersion (0.199 g, 4.55 mmol) in 1,4-dioxane (20 mL), 5-chloro-4- (2,4-difluoro-5-nitrophenyl)- 1,2-tetramethylene-4-pyrazolin-3-one (1.0 g, 3.03 mmol) and ethyl 2-hydroxyvalerate (0.69 mL, 4.55 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate) to give 2- [4- (5-chloro-3-oxo-1,2-tetramethylene-4-pyrazolin-4-yl). A light yellow solid (0.540 g, yield: 39%) of ethyl -5-fluoro-2-nitrophenyloxy] valerate was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ0.99 (t, J = 7.3 Hz, 3H), 1.27 (t, J = 7.0 Hz, 3H), 1.55-1.64 (m , 2H), 1.89-1.93 (m, 2H), 1.94-2.05 (m, 4H), 3.60-3.65 (m, 2H), 3.81-3.85 (M, 2H), 4.24 (q, J = 7.3 Hz, 2H), 4.67 (dd, J = 4.5 and 7.8 Hz, 1H), 6.67 (d, J = 10. 9 Hz, 1 H), 8.11 (d, J = 7.4 Hz, 1 H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-98.9 (s, 1F).

２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］吉草酸エチル（０．４６８ｇ，１．０３ｍｍｏｌ）の酢酸エチル（１０ｍＬ）溶液に、水（１０ｍＬ）及び酢酸（１０ｍＬ）を加えた後、還元鉄（０．５７５ｇ，１０．３ｍｍｏｌ）を加え、８０℃で１時間攪拌した。反応終了後、反応液を室温へ戻し、不溶物をろ別後、ろ液に飽和炭酸水素ナトリウム水溶液（７０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を飽和炭酸水素ナトリウム水溶液（５０ｍＬ）及び飽和食塩水（５０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた固体にヘキサン（３０ｍＬ）を加え、ろ過することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−２−プロピル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの灰白色固体（０．３５１ｇ，収率：９０％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ０．９５（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ），１．４６−１．６１（ｍ，２Ｈ），１．８０−１．８５（ｍ，２Ｈ），１．８８−１．９４（ｍ，２Ｈ），１．９９−２．０５（ｍ，２Ｈ），３．６０−３．６５（ｍ，２Ｈ），３．８１−３．８６（ｍ，２Ｈ），４．５２（ｔ，Ｊ＝６．３Ｈｚ，１Ｈ），６．７４（ｄ，Ｊ＝１０．１Ｈｚ，１Ｈ），７．０６（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ），８．８５（ｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．８（ｓ，１Ｆ）．Example-25

2- [4- (5-Chloro-3-oxo-1,2-tetramethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] ethyl valerate (0.468 g, 1. 03 mmol) in ethyl acetate (10 mL) was added water (10 mL) and acetic acid (10 mL), and then reduced iron (0.575 g, 10.3 mmol) was added, followed by stirring at 80 ° C. for 1 hour. After completion of the reaction, the reaction solution was returned to room temperature, insolubles were filtered off, saturated aqueous sodium hydrogen carbonate solution (70 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Hexane (30 mL) was added to the obtained solid and filtered to give 5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-2-propyl-4H-1,4-benzoxazine. An off-white solid (0.351 g, yield: 90%) of -6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.95 (t, J = 7.4 Hz, 3H), 1.46-1.61 (m, 2H), 1.80-1.85 (m, 2H) ), 1.88-1.94 (m, 2H), 1.99-2.05 (m, 2H), 3.60-3.65 (m, 2H), 3.81-3.86 (m) , 2H), 4.52 (t, J = 6.3 Hz, 1H), 6.74 (d, J = 10.1 Hz, 1H), 7.06 (d, J = 6.7 Hz, 1H), 8 .85 (s, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.8 (s, 1F).

水素化ナトリウムの５５％油分散（２５ｍｇ，０．５７９ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−２−プロピル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（２００ｍｇ，０．５２７ｍｍｏｌ）、次いでプロパルギルブロミド（７３ｍｇ，０．５７９ｍｍｏｌ）のＤＭＦ溶液を加え、室温で終夜攪拌した。反応終了後、反応液に水（１０ｍＬ）を加え、酢酸エチル（１０ｍＬ×１）で抽出し、有機層を蒸留水（１０ｍＬ×３）及び飽和食塩水（１０ｍＬ）で洗浄した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた固体をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４−プロパルギル−２−プロピル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（１０１ｍｇ，収率：４７％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ０．９８（ｔ，Ｊ＝７．５Ｈｚ，３Ｈ），１．４６−１．５７（ｍ，２Ｈ），１．８３−１．８５（ｍ，２Ｈ）１．８７−１．９４（ｍ，２Ｈ），２．００−２．０６（ｍ，２Ｈ），２．２５（ｔ，Ｊ＝２．５Ｈｚ，１Ｈ），３．６１−３．６６（ｍ，２Ｈ），３．８１−３．８６（ｍ，２Ｈ），４．６１（ｔ，Ｊ＝６．８Ｈｚ，１Ｈ），４．７０（ｄ，Ｊ＝２．５Ｈｚ，２Ｈ），６．８１（ｄ，Ｊ＝９．８Ｈｚ，１Ｈ），７．２７（ｄ，Ｊ＝６．５Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．１（ｓ，１Ｆ）．Example-26

To a suspension of sodium hydride in 55% oil dispersion (25 mg, 0.579 mmol) in DMF (2 mL) was added 5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-2-propyl- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (200 mg, 0.527 mmol), then propargyl bromide (73 mg, 0.579 mmol) in DMF In addition, the mixture was stirred overnight at room temperature. After completion of the reaction, water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL × 1), and the organic layer was washed with distilled water (10 mL × 3) and saturated brine (10 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained solid was purified by silica gel column chromatography (ethyl acetate) to give 5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4-propargyl-2-propyl-4H- A white solid (101 mg, yield: 47%) of 1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.98 (t, J = 7.5 Hz, 3H), 1.46 to 1.57 (m, 2H), 1.83 to 1.85 (m, 2H) ) 1.87-1.94 (m, 2H), 2.00-2.06 (m, 2H), 2.25 (t, J = 2.5 Hz, 1H), 3.61-3.66 ( m, 2H), 3.81-3.86 (m, 2H), 4.61 (t, J = 6.8 Hz, 1H), 4.70 (d, J = 2.5 Hz, 2H), 6. 81 (d, J = 9.8 Hz, 1H), 7.27 (d, J = 6.5 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.1 (s, 1F).

参考例−６と同様にして、５−クロロ−４−（２，４−ジフルオロ−５−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オンと２−ヒドロキシイソカプロン酸エチルとの反応により、２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］イソカプロン酸エチルの淡黄色固体（０．５４０ｇ，収率：３９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ０．９５（ｄ，Ｊ＝６．７Ｈｚ，３Ｈ），１．００（ｄ，Ｊ＝６．５Ｈｚ，３Ｈ），１．２７（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．７１−１．７８（ｍ，２Ｈ），１．８８−２．０９（ｍ，５Ｈ），３．６２−３．６６（ｍ，２Ｈ），３．８１−３．８６（ｍ，２Ｈ），４．２５（ｑ，Ｊ＝７．２Ｈｚ，２Ｈ），４．７０（ｍ，１Ｈ），６．６７（ｄ，Ｊ＝１０．９Ｈｚ，１Ｈ），８．１２（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−９８．８（ｓ，１Ｆ）．Reference Example-9

In the same manner as in Reference Example-6, 5-chloro-4- (2,4-difluoro-5-nitrophenyl) -1,2-tetramethylene-4-pyrazolin-3-one and ethyl 2-hydroxyisocaproate Reaction with ethyl 2- [4- (5-chloro-3-oxo-1,2-tetramethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] isocaproate. A yellow solid (0.540 g, yield: 39%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.95 (d, J = 6.7 Hz, 3H), 1.00 (d, J = 6.5 Hz, 3H), 1.27 (t, J = 7. 2Hz, 3H), 1.71-1.78 (m, 2H), 1.88-2.09 (m, 5H), 3.62-3.66 (m, 2H), 3.81-3. 86 (m, 2H), 4.25 (q, J = 7.2 Hz, 2H), 4.70 (m, 1H), 6.67 (d, J = 10.9 Hz, 1H), 8.12 ( d, J = 7.4 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-98.8 (s, 1F).

実施例−２５と同様にして、２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］イソカプロン酸エチルから５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−イソブチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンを得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ０．９７（ｄ，Ｊ＝６．６Ｈｚ，３Ｈ），０．９８（ｄ，Ｊ＝６．６Ｈｚ，３Ｈ），１．６１−１．８１（ｍ，２Ｈ），１．８７−２．０６（ｍ，５Ｈ），３．５９−３．６４（ｍ，２Ｈ），３．８４−３．８９（ｍ，２Ｈ），４．５９（ｍ，１Ｈ），６．７４（ｄ，Ｊ＝１０．１Ｈｚ，１Ｈ），７．０６（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ），８．７０（ｂｒｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１５．６（ｓ，１Ｆ）．Example-27

2- [4- (5-Chloro-3-oxo-1,2-tetramethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] isocaprone as in Example-25 Ethyl acetate to 5-chloro-4- (7-fluoro-2,3-dihydro-2-isobutyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4 -Pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.97 (d, J = 6.6 Hz, 3H), 0.98 (d, J = 6.6 Hz, 3H), 1.61-1.81 (m, 2H), 1.87-2.06 (m, 5H), 3.59-3.64 (m, 2H), 3.84-3.89 (m, 2H), 4.59 (m, 1H) 6.74 (d, J = 10.1 Hz, 1H), 7.06 (d, J = 6.8 Hz, 1H), 8.70 (brs, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-115.6 (s, 1F).

実施例−２６と同様にして、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−イソブチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンとアリルブロミドとの反応により、４−（４−アリル−７−フルオロ−２，３−ジヒドロ−２−イソブチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンを得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ０．９８（ｄ，Ｊ＝６．７Ｈｚ，３Ｈ），０．９９（ｄ，Ｊ＝６．６Ｈｚ，３Ｈ），１．６２−１．８３（ｍ，２Ｈ），１．８６−２．０６（ｍ，５Ｈ），３．５８−３．６４（ｍ，２Ｈ），３．８０−３．８６（ｍ，２Ｈ），４．４５（ｍ，１Ｈ），４．６１（ｍ，１Ｈ），４．６９（ｄｄ，Ｊ＝３．７ ａｎｄ １０．２Ｈｚ，１Ｈ），５．１６−５．２５（ｍ，２Ｈ），５．８７（ｍ，１Ｈ），６．７８（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．０９（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１５．５（ｓ，１Ｆ）．Example-28

In the same manner as in Example 26, 5-chloro-4- (7-fluoro-2,3-dihydro-2-isobutyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1, Reaction of 2-tetramethylene-4-pyrazolin-3-one with allyl bromide yields 4- (4-allyl-7-fluoro-2,3-dihydro-2-isobutyl-3-oxo-4H-1,4. -Benzoxazin-6-yl) -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.98 (d, J = 6.7 Hz, 3H), 0.99 (d, J = 6.6 Hz, 3H), 1.62-1.83 (m, 2H), 1.86-2.06 (m, 5H), 3.58-3.64 (m, 2H), 3.80-3.86 (m, 2H), 4.45 (m, 1H) 4.61 (m, 1H), 4.69 (dd, J = 3.7 and 10.2 Hz, 1H), 5.16-5.25 (m, 2H), 5.87 (m, 1H) , 6.78 (d, J = 9.9 Hz, 1H), 7.09 (d, J = 6.7 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-115.5 (s, 1F).

実施例−２６と同様にして、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−イソブチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンとメタリルブロミドとの反応により、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−イソブチル−４−メタリル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンを得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ０．９８（ｄ，Ｊ＝６．７Ｈｚ，３Ｈ），０．９９（ｄ，Ｊ＝６．５Ｈｚ，３Ｈ），１．６４−１．８４（ｍ，５Ｈ），１．８５−２．０６（ｍ，５Ｈ），３．５８−３．６３（ｍ，２Ｈ），３．８０−３．８５（ｍ，２Ｈ），４．３０（ｄ，Ｊ＝１６．９Ｈｚ，１Ｈ），４．５７（ｄ，Ｊ＝１６．９Ｈｚ，１Ｈ），４．７１（ｄｄ，Ｊ＝３．９ ａｎｄ １０．４Ｈｚ，１Ｈ），４．７７（ｓ，１Ｈ），４．９２（ｍ，１Ｈ），６．７８（ｄ，Ｊ＝１０．０Ｈｚ，１Ｈ），７．０２（ｄ，Ｊ＝７．２Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１５．５（ｓ，１Ｆ）．Example-29

In the same manner as in Example 26, 5-chloro-4- (7-fluoro-2,3-dihydro-2-isobutyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1, Reaction of 2-tetramethylene-4-pyrazolin-3-one with methallyl bromide gave 5-chloro-4- (7-fluoro-2,3-dihydro-2-isobutyl-4-methallyl-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.98 (d, J = 6.7 Hz, 3H), 0.99 (d, J = 6.5 Hz, 3H), 1.64-1.84 (m, 5H), 1.85-2.06 (m, 5H), 3.58-3.63 (m, 2H), 3.80-3.85 (m, 2H), 4.30 (d, J = 16.9 Hz, 1H), 4.57 (d, J = 16.9 Hz, 1H), 4.71 (dd, J = 3.9 and 10.4 Hz, 1H), 4.77 (s, 1H), 4.92 (m, 1H), 6.78 (d, J = 10.0 Hz, 1H), 7.02 (d, J = 7.2 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-115.5 (s, 1F).

実施例−２６と同様にして、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−イソブチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンとプロパルギルブロミドとの反応により、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−イソブチル−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンを得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ０．９８（ｄ，Ｊ＝６．６Ｈｚ，３Ｈ），０．９９（ｄ，Ｊ＝６．６Ｈｚ，３Ｈ），１．６２−１．８３（ｍ，２Ｈ），１．８７−２．０６（ｍ，５Ｈ），２．２５（ｔ，Ｊ＝２．４Ｈｚ，１Ｈ），３．６０−３．６５（ｍ，２Ｈ），３．８２−３．８８（ｍ，２Ｈ），４．６５−４．７０（ｍ，３Ｈ），６．８１（ｄ，Ｊ＝１０．０Ｈｚ，１Ｈ），７．２７（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１５．１（ｓ，１Ｆ）．Example-30

In the same manner as in Example 26, 5-chloro-4- (7-fluoro-2,3-dihydro-2-isobutyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1, Reaction of 2-tetramethylene-4-pyrazolin-3-one with propargyl bromide yields 5-chloro-4- (7-fluoro-2,3-dihydro-2-isobutyl-3-oxo-4-propargyl-4H. -1,4-Benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.98 (d, J = 6.6 Hz, 3H), 0.99 (d, J = 6.6 Hz, 3H), 1.62-1.83 (m, 2H), 1.87-2.06 (m, 5H), 2.25 (t, J = 2.4 Hz, 1H), 3.60-3.65 (m, 2H), 3.82-3. 88 (m, 2H), 4.65-4.70 (m, 3H), 6.81 (d, J = 10.0 Hz, 1H), 7.27 (d, J = 6.7 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-115.1 (s, 1F).

実施例−２６と同様にして、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−イソブチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンと１−ブロモ−２−ブチンとの反応により、４−［４−（２−ブチニル）−７−フルオロ−２，３−ジヒドロ−２−イソブチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンを得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ０．９８（ｄ，Ｊ＝６．７Ｈｚ，３Ｈ），０．９９（ｄ，Ｊ＝６．５Ｈｚ，３Ｈ），１．６２−１．８３（ｍ，５Ｈ），１．８５−２．０７（ｍ，５Ｈ），３．６０−３．６４（ｍ，２Ｈ），３．８２−３．８８（ｍ，２Ｈ），４．６０−４．６９（ｍ，３Ｈ），６．７９（ｄ，Ｊ＝９．８Ｈｚ，１Ｈ），７．２５（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１５．５（ｓ，１Ｆ）．Example-31

In the same manner as in Example 26, 5-chloro-4- (7-fluoro-2,3-dihydro-2-isobutyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1, Reaction of 2-tetramethylene-4-pyrazolin-3-one with 1-bromo-2-butyne gives 4- [4- (2-butynyl) -7-fluoro-2,3-dihydro-2-isobutyl- to give 3-oxo-4H-1,4-benzoxazin-6-yl] -5-chloro-1,2-tetramethylene-4-pyrazoline-3-one. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.98 (d, J = 6.7 Hz, 3H), 0.99 (d, J = 6.5 Hz, 3H), 1.62-1.83 (m, 5H), 1.85-2.07 (m, 5H), 3.60-3.64 (m, 2H), 3.82-3.88 (m, 2H), 4.60-4.69 ( m, 3H), 6.79 (d, J = 9.8Hz, 1H), 7.25 (d, J = 6.7Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-115.5 (s, 1F).

実施例−２６と同様にして、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−イソブチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンと３−ブロモ−１−（トリメチルシリル）プロピンとの反応により、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−イソブチル−３−オキソ−４−（３−トリメチルシリル−２−プロピニル）−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンを得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ０．０９（ｓ，９Ｈ），０．９８（ｄ，Ｊ＝６．７Ｈｚ，６Ｈ），１．６３−１．８３（ｍ，２Ｈ），１．８７−２．０６（ｍ，５Ｈ），３．５４−３．６５（ｍ，２Ｈ），３．８０−３．８８（ｍ，２Ｈ），４．５９−４．８０（ｍ，３Ｈ），６．８０（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．２４（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１５．６（ｓ，１Ｆ）．Example-32

In the same manner as in Example 26, 5-chloro-4- (7-fluoro-2,3-dihydro-2-isobutyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1, Reaction of 2-tetramethylene-4-pyrazolin-3-one with 3-bromo-1- (trimethylsilyl) propyne gives 5-chloro-4- (7-fluoro-2,3-dihydro-2-isobutyl-3. -Oxo-4- (3-trimethylsilyl-2-propynyl) -4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 0.09 (s, 9H), 0.98 (d, J = 6.7 Hz, 6H), 1.63-1.83 (m, 2H), 1.87 -2.06 (m, 5H), 3.54-3.65 (m, 2H), 3.80-3.88 (m, 2H), 4.59-4.80 (m, 3H), 6 .80 (d, J = 9.9 Hz, 1H), 7.24 (d, J = 6.8 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-115.6 (s, 1F).

水素化ナトリウムの５５％油分散（０．６５ｇ，１５．０ｍｍｏｌ）の１，４−ジオキサン（５０ｍＬ）溶液に、氷冷下で５−クロロ−４−（２，４−ジフルオロ−５−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（３．３０ｇ，１０．０ｍｍｏｌ）及び２−ヒドロキシ−２−メトキシ酢酸メチル（１．８６ｇ，１５．０ｍｍｏｌ）を順次加え、室温で１時間撹拌した。反応終了後、反応液を氷水（１００ｇ）に注ぎ、酢酸エチル（１００ｍＬ×３）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：クロロホルム＝１：１）で精製することにより、２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］−２−メトキシ酢酸メチルの黄色固体（１．４４ｇ，収率：３４％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８８−１．９６（ｍ，２Ｈ），１．９８−２．０８（ｍ，２Ｈ），３．６１（ｓ，３Ｈ），３．６３−３．６８（ｍ，２Ｈ），３．８０−３．８６（ｍ，２Ｈ），３．８６（ｓ，３Ｈ），５．５７（ｓ，１Ｈ），７．１１（ｄ，Ｊ＝１０．８Ｈｚ，１Ｈ），８．１３（ｄ，Ｊ＝７．２Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−９８．５（ｓ，１Ｆ）．Reference Example-10

To a solution of sodium hydride in 55% oil dispersion (0.65 g, 15.0 mmol) in 1,4-dioxane (50 mL) under ice-cooling, 5-chloro-4- (2,4-difluoro-5-nitrophenyl) was added. ) -1,2-tetramethylene-4-pyrazolin-3-one (3.30 g, 10.0 mmol) and methyl 2-hydroxy-2-methoxyacetate (1.86 g, 15.0 mmol) were added successively at room temperature. Stir for 1 hour. After completion of the reaction, the reaction solution was poured into ice water (100 g) and extracted with ethyl acetate (100 mL × 3). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: chloroform = 1: 1) to give 2- [4- (5-chloro-3-oxo-1,2-tetramethylene-4- A yellow solid (1.44 g, yield: 34%) of pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] -2-methoxyacetate was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.88-1.96 (m, 2H), 1.98-2.08 (m, 2H), 3.61 (s, 3H), 3.63-3 .68 (m, 2H), 3.80-3.86 (m, 2H), 3.86 (s, 3H), 5.57 (s, 1H), 7.11 (d, J = 10.8 Hz) , 1H), 8.13 (d, J = 7.2 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-98.5 (s, 1F).

２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］−２−メトキシ酢酸メチル（１．２０ｇ，２．７９ｍｍｏｌ）の酢酸エチル（５．６ｍＬ）溶液に、酢酸（２．８ｍＬ）及び水（０．５ｍＬ）を加えた後、０℃で還元鉄（１．５６ｇ，２７．９ｍｍｏｌ）を加え、８０℃で１時間撹拌した。反応終了後、反応液を室温まで冷却し、不溶物をろ別後、ろ液に飽和炭酸水素ナトリウム水溶液（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥した後、減圧濃縮することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メトキシ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（１．２１ｇ，収率：定量的）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８５−１．９７（ｍ，２Ｈ），１．９７−２．０９（ｍ，２Ｈ），３．５４（ｓ，３Ｈ），３．５６−３．７１（ｍ，２Ｈ），３．８０−３．９７（ｍ，２Ｈ），５．２２（ｓ，１Ｈ），６．８４（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．１９（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ），９．５１（ｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１５．６（ｓ，１Ｆ）．Example-33

2- [4- (5-Chloro-3-oxo-1,2-tetramethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] -2-methoxyacetate methyl (1.20 g) , 2.79 mmol) in ethyl acetate (5.6 mL), acetic acid (2.8 mL) and water (0.5 mL) were added, and then reduced iron (1.56 g, 27.9 mmol) was added at 0 ° C. , And stirred at 80 ° C. for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, insolubles were filtered off, saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-chloro-4- (7-fluoro-2,3-dihydro-2-methoxy-3-oxo-4H-1,4. A white solid (1.21 g, yield: quantitative) of -benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.85-1.97 (m, 2H), 1.97-2.09 (m, 2H), 3.54 (s, 3H), 3.56-3 .71 (m, 2H), 3.80-3.97 (m, 2H), 5.22 (s, 1H), 6.84 (d, J = 9.9 Hz, 1H), 7.19 (d , J = 6.8 Hz, 1H), 9.51 (s, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-115.6 (s, 1F).

水素化ナトリウムの５５％油分散（０．０４ｇ，０．９０ｍｍｏｌ）のＤＭＦ（３ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メトキシ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（０．３ｇ，０．８２ｍｍｏｌ）及びプロパルギルブロミド（０．０７ｍＬ，０．９０ｍｍｏｌ）を順次加え、室温で２４時間攪拌した。反応終了後、反応液を飽和塩化アンモニウム水溶液（３０ｍＬ）に注ぎ入れ、酢酸エチル（３０ｍＬ×３）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メトキシ−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（０．２０ｇ，収率：６１％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８７−１．９５（ｍ，２Ｈ），１．９９−２．０６（ｍ，２Ｈ），２．２６（ｔ，Ｊ＝２．５Ｈｚ，１Ｈ），３．５５（ｓ，３Ｈ），３．６０−３．６６（ｍ，２Ｈ），３．８２−３．８８（ｍ，２Ｈ），４．７３（ｑ，Ｊ＝１７．６Ｈｚ，２Ｈ），４．７４（ｑ，Ｊ＝１７．６Ｈｚ，２Ｈ），５．３４（ｓ，１Ｈ），６．９２（ｄ，Ｊ＝９．７Ｈｚ，１Ｈ），７．３３（ｄ，Ｊ＝６．６Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１４．８（ｓ，１Ｆ）．Example-34

To a suspension of sodium hydride in 55% oil dispersion (0.04 g, 0.90 mmol) in DMF (3 mL) under ice-cooling, 5-chloro-4- (7-fluoro-2,3-dihydro-2- Methoxy-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (0.3 g, 0.82 mmol) and propargyl bromide (0.07 mL) , 0.90 mmol) was sequentially added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate) to give 5-chloro-4- (7-fluoro-2,3-dihydro-2-methoxy-3-oxo-4-propargyl- A white solid (0.20 g, yield: 61%) of 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.87-1.95 (m, 2H), 1.99-2.06 (m, 2H), 2.26 (t, J = 2.5 Hz, 1H) , 3.55 (s, 3H), 3.60-3.66 (m, 2H), 3.82-3.88 (m, 2H), 4.73 (q, J = 17.6 Hz, 2H) , 4.74 (q, J = 17.6 Hz, 2H), 5.34 (s, 1H), 6.92 (d, J = 9.7 Hz, 1H), 7.33 (d, J = 6. 6 Hz, 1 H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-114.8 (s, 1F).

水素化ナトリウムの５５％油分散（０．０６ｇ，１．３１ｍｍｏｌ）のＤＭＦ（３ｍＬ）溶液に、氷冷下で５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メトキシ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（０．３ｇ，０．８２ｍｍｏｌ）及び１−ブロモ−２−ブチン（０．１３ｍＬ，１．３１ｍｍｏｌ）を順次加え、室温で４８時間撹拌した。反応終了後、反応液を飽和塩化アンモニウム水溶液（３０ｍＬ）に注ぎ入れ、酢酸エチル（３０ｍＬ×３）で抽出した。合一した有機層を水（３０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、４−［４−（２−ブチニル）−７−フルオロ−２，３−ジヒドロ−２−メトキシ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（０．１８ｇ，収率：５３％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．７７（ｔ，Ｊ＝２．４Ｈｚ，３Ｈ），１．８８−１．９５（ｍ，２Ｈ），１．９９−２．０６（ｍ，２Ｈ），３．５４（ｓ，３Ｈ），３．６０−３．６５（ｍ，２Ｈ），３．８２−３．８８（ｍ，２Ｈ），４．５６−４．７７（ｍ，２Ｈ），５．３３（ｓ，１Ｈ），６．９０（ｄ，Ｊ＝９．７Ｈｚ，１Ｈ），７．３１（ｄ，Ｊ＝６．６Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１５．２（ｓ，１Ｆ）．Example-35

To a solution of sodium hydride in 55% oil dispersion (0.06 g, 1.31 mmol) in DMF (3 mL) under ice cooling, 5-chloro-4- (7-fluoro-2,3-dihydro-2-methoxy- 3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (0.3 g, 0.82 mmol) and 1-bromo-2-butyne ( 0.13 mL, 1.31 mmol) was sequentially added, and the mixture was stirred at room temperature for 48 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layer was washed with water (30 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate) to give 4- [4- (2-butynyl) -7-fluoro-2,3-dihydro-2-methoxy-3-oxo- 4H-1,4-benzoxazin-6-yl] -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one was obtained as a white solid (0.18 g, yield: 53%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.77 (t, J = 2.4 Hz, 3H), 1.88-1.95 (m, 2H), 1.99-2.06 (m, 2H) , 3.54 (s, 3H), 3.60-3.65 (m, 2H), 3.82-3.88 (m, 2H), 4.56-4.77 (m, 2H), 5 .33 (s, 1H), 6.90 (d, J = 9.7 Hz, 1H), 7.31 (d, J = 6.6 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-115.2 (s, 1F).

水素化ナトリウムの５５％油分散（０．９９ｇ，２２．８ｍｍｏｌ）の１，４−ジオキサン（７５ｍＬ）溶液に、氷冷下で５−クロロ−４−（２，４−ジフルオロ−５−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（５．００ｇ，１５．２ｍｍｏｌ）及びＤＬ−マンデル酸エチル（３．９ｍＬ，２２．８ｍｍｏｌ）を順次加え、室温で１時間撹拌した。反応終了後、反応液を氷水（１００ｇ）に注ぎ、酢酸エチル（１００ｍＬ×３）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］−２−フェニル酢酸エチルの白色固体（２．６０ｇ，収率：３５％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．２１（ｔ，Ｊ＝７．１Ｈｚ，３Ｈ），１．８７−１．９５（ｍ，２Ｈ），１．９９−２．０７（ｍ，２Ｈ），３．６１−３．６６（ｍ，２Ｈ），３．８０−３．８６（ｍ，２Ｈ），４．１４−４．２９（ｍ，２Ｈ），５．６９（ｓ，１Ｈ），６．７７（ｄ，Ｊ＝１０．８Ｈｚ，１Ｈ），７．３８−７．４６（ｍ，３Ｈ），７．６１−７．６６（ｍ，２Ｈ），８．１８（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−９８．４（ｓ，１Ｆ）．Reference Example-11

To a solution of sodium hydride in 55% oil dispersion (0.99 g, 22.8 mmol) in 1,4-dioxane (75 mL) under ice-cooling, 5-chloro-4- (2,4-difluoro-5-nitrophenyl) was added. ) -1,2-tetramethylene-4-pyrazolin-3-one (5.00 g, 15.2 mmol) and ethyl DL-mandelate (3.9 mL, 22.8 mmol) were sequentially added and stirred at room temperature for 1 hour. . After completion of the reaction, the reaction solution was poured into ice water (100 g) and extracted with ethyl acetate (100 mL × 3). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 2- [4- (5-chloro-3-oxo-1,2-tetramethylene-4-pyrazoline). A white solid (2.60 g, yield: 35%) of ethyl-4-yl) -5-fluoro-2-nitrophenyloxy] -2-phenylacetate was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.21 (t, J = 7.1 Hz, 3H), 1.87-1.95 (m, 2H), 1.99-2.07 (m, 2H) 3.61-3.66 (m, 2H), 3.80-3.86 (m, 2H), 4.14-4.29 (m, 2H), 5.69 (s, 1H), 6 .77 (d, J = 10.8 Hz, 1H), 7.38-7.46 (m, 3H), 7.61-7.66 (m, 2H), 8.18 (d, J = 7. 3Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-98.4 (s, 1F).

２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］−２−フェニル酢酸エチル（２．２０ｇ，４．４９ｍｍｏｌ）の酢酸エチル（２０ｍＬ）溶液に、酢酸（９ｍＬ）及び水（１．６ｍＬ）を加えた後、０℃で還元鉄（２．５１ｇ，４４．９ｍｍｏｌ）を加え、８０℃で４時間撹拌した。反応終了後、反応液を室温まで冷却し、不溶物をろ別後、ろ液に飽和炭酸水素ナトリウム水溶液（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥した後、減圧濃縮することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−２−フェニル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（１．４６ｇ，収率：７９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８５−１．９４（ｍ，２Ｈ），１．９７−２．０６（ｍ，２Ｈ），３．５７−３．６５（ｍ，２Ｈ），３．８２−３．８９（ｍ，２Ｈ），５．６４（ｓ，１Ｈ），６．８１（ｄ，Ｊ＝１０．１Ｈｚ，１Ｈ），７．１０（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ），７．３３−７．３８（ｍ，３Ｈ），７．４１−７．４４（ｍ，２Ｈ），８．９０（ｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１５．０（ｓ，１Ｆ）．Example-36

2- [4- (5-Chloro-3-oxo-1,2-tetramethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] -2-phenylacetate (2.20 g , 4.49 mmol) in ethyl acetate (20 mL), acetic acid (9 mL) and water (1.6 mL) were added, and then reduced iron (2.51 g, 44.9 mmol) was added at 0 ° C. and at 80 ° C. Stir for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, insolubles were filtered off, saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-2-phenyl-4H-1,4. A white solid (1.46 g, yield: 79%) of -benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.85-1.94 (m, 2H), 1.97-2.06 (m, 2H), 3.57-3.65 (m, 2H), 3 .82-3.89 (m, 2H), 5.64 (s, 1H), 6.81 (d, J = 10.1 Hz, 1H), 7.10 (d, J = 6.7 Hz, 1H) , 7.33-7.38 (m, 3H), 7.41-7.44 (m, 2H), 8.90 (s, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-115.0 (s, 1F).

水素化ナトリウムの５５％油分散（０．０３４ｇ，０．７９ｍｍｏｌ）のＤＭＦ（２ｍＬ）溶液に、氷冷下で５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−２−フェニル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（０．３ｇ，０．７２ｍｍｏｌ）及びクロロ酢酸アリル（０．０９２ｍＬ，０．７９ｍｍｏｌ）を順次加え、室温で２４時間撹拌した。反応終了後、反応液を飽和塩化アンモニウム水溶液（３０ｍＬ）に注ぎ入れ、酢酸エチル（５０ｍＬ×３）で抽出した。合一した有機層を水（３０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、２−［６−（５−クロロ−１，２−テトラメチレン−３−オキソ−４−ピラゾリン−４−イル）−７−フルオロ−２，３−ジヒドロ−３−オキソ−２−フェニル−４Ｈ−１，４−ベンゾオキサジン−４−イル］酢酸アリルの白色固体（０．２９ｇ，収率：８０％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８４−１．９３（ｍ，２Ｈ），１．９５−２．０４（ｍ，２Ｈ），３．５２−３．６５（ｍ，２Ｈ），３．７５−３．８７（ｍ，２Ｈ），４．５９（ｍ，１Ｈ），４．６４−４．７１（ｍ，２Ｈ），４．９４（ｍ，１Ｈ），５．２３（ｍ，１Ｈ），５．３０（ｍ，１Ｈ），５．７９（ｓ，１Ｈ），５．８９（ｍ，１Ｈ），６．８２（ｄ，Ｊ＝９．８Ｈｚ，１Ｈ），６．９３（ｄ，Ｊ＝６．５Ｈｚ，１Ｈ），７．３２−７．３８（ｍ，３Ｈ），７．４３−７．４９（ｍ，２Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１４．６（ｓ，１Ｆ）．Example-37

To a solution of sodium hydride in 55% oil dispersion (0.034 g, 0.79 mmol) in DMF (2 mL) under ice-cooling, 5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo- 2-phenyl-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (0.3 g, 0.72 mmol) and allyl chloroacetate (0.092 mL, 0.79 mmol) was sequentially added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layer was washed with water (30 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate) to give 2- [6- (5-chloro-1,2-tetramethylene-3-oxo-4-pyrazolin-4-yl). -7-Fluoro-2,3-dihydro-3-oxo-2-phenyl-4H-1,4-benzoxazin-4-yl] Allyl acetate white solid (0.29 g, yield: 80%) was obtained. It was. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.84-1.93 (m, 2H), 1.95-2.04 (m, 2H), 3.52-3.65 (m, 2H), 3 .75-3.87 (m, 2H), 4.59 (m, 1H), 4.64-4.71 (m, 2H), 4.94 (m, 1H), 5.23 (m, 1H) ), 5.30 (m, 1H), 5.79 (s, 1H), 5.89 (m, 1H), 6.82 (d, J = 9.8 Hz, 1H), 6.93 (d, J = 6.5 Hz, 1H), 7.32-7.38 (m, 3H), 7.43-7.49 (m, 2H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-114.6 (s, 1F).

水素化ナトリウムの５５％油分散（０．０４ｇ，０．９３ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−２−フェニル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（０．３ｇ，０．７２ｍｍｏｌ）及びアリルブロミド（０．０９２ｍＬ，０．７９ｍｍｏｌ）を順次加え、室温で２３時間撹拌した。反応終了後、反応液を飽和塩化アンモニウム水溶液（３０ｍＬ）に注ぎ入れ、酢酸エチル（５０ｍＬ×３）で抽出した。合一した有機層を水（３０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）で精製することにより、４−（４−アリル−７−フルオロ−２，３−ジヒドロ−３−オキソ−２−フェニル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（０．２２ｇ，収率：６６％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８３−１．９４（ｍ，２Ｈ），１．９５−２．０４（ｍ，２Ｈ），３．５３−３．６６（ｍ，２Ｈ），３．７５−３．８７（ｍ，２Ｈ），４．４８（ｍ，１Ｈ），４．７４（ｍ，１Ｈ），５．１４−５．２６（ｍ，２Ｈ），５．７８（ｓ，１Ｈ），５．８９（ｍ，１Ｈ），６．８６（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．１１（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ），７．２９−７．３９（ｍ，３Ｈ），７．３９−７．４６（ｍ，２Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１５．０（ｓ，１Ｆ）．Example-38

To a suspension of sodium hydride in 55% oil dispersion (0.04 g, 0.93 mmol) in DMF (2 mL) under ice-cooling, 5-chloro-4- (7-fluoro-2,3-dihydro-3- Oxo-2-phenyl-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (0.3 g, 0.72 mmol) and allyl bromide (0.092 mL) , 0.79 mmol) was added sequentially, and the mixture was stirred at room temperature for 23 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layer was washed with water (30 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 4- (4-allyl-7-fluoro-2,3-dihydro-3-oxo-2- Phenyl-4H-1,4-benzoxazin-6-yl) -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one was obtained as a white solid (0.22 g, yield: 66%). It was. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.83-1.94 (m, 2H), 1.95-2.04 (m, 2H), 3.53-3.66 (m, 2H), 3 .75-3.87 (m, 2H), 4.48 (m, 1H), 4.74 (m, 1H), 5.14-5.26 (m, 2H), 5.78 (s, 1H) ), 5.89 (m, 1H), 6.86 (d, J = 9.9 Hz, 1H), 7.11 (d, J = 6.7 Hz, 1H), 7.29-7.39 (m , 3H), 7.39-7.46 (m, 2H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-115.0 (s, 1F).

水素化ナトリウムの５５％油分散（０．０３４ｇ，０．７９ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−２−フェニル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（０．３ｇ，０．７２ｍｍｏｌ）及びプロパルギルブロミド（０．０６３ｍＬ，０．７９ｍｍｏｌ）を順次加え、室温で２８時間撹拌した。反応終了後、反応液を飽和塩化アンモニウム水溶液（３０ｍＬ）に注ぎ入れ、酢酸エチル（５０ｍＬ×３）で抽出した。合一した有機層を水（３０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィーで精製することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−２−フェニル−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（０．２３ｇ，収率：７０％）を得た^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８７−１．９４（ｍ，２Ｈ），１．９８−２．０６（ｍ，２Ｈ），２．２７（ｔ，Ｊ＝２．５Ｈｚ，１Ｈ），３．５６−３．６６（ｍ，２Ｈ），３．７８−３．８８（ｍ，２Ｈ），４．６９（ｄｄ，Ｊ＝２．５ ａｎｄ １７．５Ｈｚ，１Ｈ），４．８５（ｄｄ，Ｊ＝２．５ ａｎｄ １７．５Ｈｚ，１Ｈ），５．７５（ｓ，１Ｈ），６．８５（ｄ，Ｊ＝１０．０Ｈｚ，１Ｈ），７．３０（ｄ，Ｊ＝６．５Ｈｚ，１Ｈ），７．３２−７．４２（ｍ，５Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１４．６（ｓ，１Ｆ）．Example-39

To a suspension of sodium hydride in 55% oil dispersion (0.034 g, 0.79 mmol) in DMF (2 mL) under ice-cooling, 5-chloro-4- (7-fluoro-2,3-dihydro-3- Oxo-2-phenyl-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (0.3 g, 0.72 mmol) and propargyl bromide (0.063 mL) , 0.79 mmol) was added sequentially, and the mixture was stirred at room temperature for 28 hours. After completion of the reaction, the reaction solution was poured into a saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layer was washed with water (30 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to give 5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-2-phenyl-4-propargyl-4H-1, ¹ H-NMR (400 MHz, CDCl ₃ ) obtained white solid (0.23 g, yield: 70%) of 4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one ) Δ 1.87-1.94 (m, 2H), 1.98-2.06 (m, 2H), 2.27 (t, J = 2.5 Hz, 1H), 3.56-3.66 ( m, 2H), 3.78-3.88 (m, 2H), 4.69 (dd, J = 2.5 and 17.5 Hz, 1H), 4.85 (dd, J = 2.5 and 17). .5 Hz, 1 H), 5.75 (s, 1 H), 6.85 (d, J = 1) .0Hz, 1H), 7.30 (d, J = 6.5Hz, 1H), 7.32-7.42 (m, 5H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-114.6 (s, 1F).

アルゴン雰囲気下、金属マグネシウム（１．１ｇ，４４．２ｍｍｏｌ）にＴＨＦ（４０ｍＬ）を加え、次いで１−ブロモ−２−フルオロ−４−メトキシベンゼン（８．４ｇ，４４．２ｍｍｏｌ）を、溶液の温度が４０℃を超えないように加え、２−フルオロ−４−メトキシフェニルマグネシウムブロミドのＴＨＦ溶液を調製した。このＴＨＦ溶液を、シュウ酸ジエチル（４．９ｍＬ，４４．２ｍｍｏｌ）のＴＨＦ（４０ｍＬ）溶液に−４０℃で滴下した。反応溶液を、徐々に室温まで昇温しながら２４時間攪拌した。反応溶液に飽和塩化アンモニウム水溶液（１００ｍＬ）と水（２００ｍＬ）を加え、酢酸エチル（２００ｍＬ×２）で抽出した。混合した有機層を硫酸マグネシウムで乾燥させた後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１）で精製することにより、２−（２−フルオロ−４−メトキシフェニル）−２−オキソ酢酸エチルの黄色液体（７．３ｇ，７３％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．３９（ｔ，Ｊ＝７．１Ｈｚ，３Ｈ），３．８９（ｓ，３Ｈ），４．４１（ｑ，Ｊ＝７．１Ｈｚ，２Ｈ），６．６３（ｄｄ，Ｊ＝２．３ ａｎｄ １２．９Ｈｚ，１Ｈ），６．８２（ｄｄ，Ｊ＝２．３ ａｎｄ ８．８Ｈｚ，１Ｈ），７．９１（ｔ，Ｊ＝８．８Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１０８．１（ｓ，１Ｆ）．
トリフェニルホスフィン（１５．０ｇ，５７．５ｍｍｏｌ）のジクロロメタン（５０ｍＬ）溶液に、四塩化炭素（６．５ｇ，２８．７ｍｍｏｌ）を０℃で加えて、１５分攪拌した。その後、２−（２−フルオロ−４−メトキシフェニル）−２−オキソ酢酸エチル（３．８ｇ，１６．４ｍｍｏｌ）を加えて、室温で１５時間攪拌した。反応終了後、反応液を減圧濃縮し、析出した固体をろ過し、クロロホルムとエーテルの混合溶媒で洗浄した。ろ液を減圧濃縮して得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１）で精製することにより、３，３−ジクロロ−２−（２−フルオロ−４−メトキシフェニル）アクリル酸エチルの無色液体（７．４ｇ，８８％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．２７（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），３．８２（ｓ，３Ｈ），４．２５（ｑ，Ｊ＝７．２Ｈｚ，２Ｈ），６．６５（ｄｄ，Ｊ＝２．５ ａｎｄ １１．６Ｈｚ，１Ｈ），６．７２（ｄｄ，Ｊ＝２．５ ａｎｄ ８．６Ｈｚ，１Ｈ），７．２５（ｔ，Ｊ＝８．６Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１０．２（ｓ，１Ｆ）．Reference Example-12

Under argon atmosphere, THF (40 mL) was added to magnesium metal (1.1 g, 44.2 mmol), followed by 1-bromo-2-fluoro-4-methoxybenzene (8.4 g, 44.2 mmol) at the temperature of the solution. Was added so as not to exceed 40 ° C., and a THF solution of 2-fluoro-4-methoxyphenylmagnesium bromide was prepared. This THF solution was added dropwise at −40 ° C. to a solution of diethyl oxalate (4.9 mL, 44.2 mmol) in THF (40 mL). The reaction solution was stirred for 24 hours while gradually warming to room temperature. A saturated aqueous ammonium chloride solution (100 mL) and water (200 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give a yellow liquid of ethyl 2- (2-fluoro-4-methoxyphenyl) -2-oxoacetate (7 .3 g, 73%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.39 (t, J = 7.1 Hz, 3H), 3.89 (s, 3H), 4.41 (q, J = 7.1 Hz, 2H), 6.63 (dd, J = 2.3 and 12.9 Hz, 1H), 6.82 (dd, J = 2.3 and 8.8 Hz, 1H), 7.91 (t, J = 8.8 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.1 (s, 1F).
Carbon tetrachloride (6.5 g, 28.7 mmol) was added to a solution of triphenylphosphine (15.0 g, 57.5 mmol) in dichloromethane (50 mL) at 0 ° C., and the mixture was stirred for 15 minutes. Then, ethyl 2- (2-fluoro-4-methoxyphenyl) -2-oxoacetate (3.8 g, 16.4 mmol) was added and stirred at room temperature for 15 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the precipitated solid was filtered and washed with a mixed solvent of chloroform and ether. The crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give 3,3-dichloro-2- (2-fluoro-4-methoxy). A colorless liquid (7.4 g, 88%) of ethyl phenyl) acrylate was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.27 (t, J = 7.2 Hz, 3H), 3.82 (s, 3H), 4.25 (q, J = 7.2 Hz, 2H), 6.65 (dd, J = 2.5 and 11.6 Hz, 1H), 6.72 (dd, J = 2.5 and 8.6 Hz, 1H), 7.25 (t, J = 8.6 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-110.2 (s, 1F).

３，３−ジクロロ−２−（２−フルオロ−４−メトキシフェニル）アクリル酸エチル（２．５ｇ，８．５ｍｍｏｌ）の１，４−ジオキサン（３０ｍＬ）溶液に、ヘキサヒドロピリダジン二臭化水素塩（２．５ｇ，１０．２ｍｍｏｌ）とトリエチルアミン（３．６ｍＬ，２５．６ｍｍｏｌ）を室温で加えた後、加熱還流しながら２４時間攪拌した。反応終了後、反応液を減圧濃縮し、蒸留水（８０ｍＬ）を加え、酢酸エチル（１５０ｍＬ×２）で抽出した。有機層を無水硫酸マグネシウムで乾燥した後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）で精製することにより、５−クロロ−４−（２−フルオロ−４−メトキシフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（２．０ｇ，７９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８４−１．９２（ｍ，２Ｈ），１．９７−２．０４（ｍ，２Ｈ），３．６２−３．６４（ｍ，２Ｈ），３．８１（ｓ，３Ｈ），３．８２−３．８５（ｍ，２Ｈ），６．６９（ｄｄ，Ｊ＝２．４ ａｎｄ １１．７Ｈｚ，１Ｈ），６．７６（ｄ，Ｊ＝２．４ ａｎｄ ８．５Ｈｚ，１Ｈ），７．３９（ｄｄ，Ｊ＝８．５ ａｎｄ ８．５Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１０．１（ｓ，１Ｆ）．
５−クロロ−４−（２−フルオロ−４−メトキシフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（８８０ｍｇ，３．０ｍｍｏｌ）のジクロロメタン（１０ｍＬ）溶液に、−４０℃で三臭化ホウ素のジクロロメタン１Ｍ溶液（６．０ｍＬ）を加えた。反応温度を室温までゆっくり上昇させながら、反応液を８時間攪拌した。反応終了後、反応液を氷水に滴下した後、１Ｎ−ＨＣｌ水溶液（５０ｍＬ）を加えた。析出した固体をろ過して、十分乾燥させることにより、５−クロロ−４−（２−フルオロ−４−ヒドロキシフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（７７８ｍｇ，９３％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ｄ−ＤＭＳＯ）：δ１．７４−１．８２（ｍ，２Ｈ），１．８７−１．９５（ｍ，２Ｈ），３．５４−３．５９（ｍ，２Ｈ），３．６２−３．６８（ｍ，２Ｈ），６．６２（ｄｄ，Ｊ＝２．４ ａｎｄ １１．９Ｈｚ，１Ｈ），６．６６（ｄｄ，Ｊ＝２．４ ａｎｄ ８．５Ｈｚ，１Ｈ），７．１８（ｄｄ，Ｊ＝８．５ ａｎｄ ８．５Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１０．６（ｓ，１Ｆ）．Reference Example-13

To a solution of ethyl 3,3-dichloro-2- (2-fluoro-4-methoxyphenyl) acrylate (2.5 g, 8.5 mmol) in 1,4-dioxane (30 mL) was added hexahydropyridazine dihydrobromide. (2.5 g, 10.2 mmol) and triethylamine (3.6 mL, 25.6 mmol) were added at room temperature, followed by stirring for 24 hours while heating under reflux. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, distilled water (80 mL) was added, and the mixture was extracted with ethyl acetate (150 mL × 2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 5-chloro-4- (2-fluoro-4-methoxyphenyl) -1,2-tetramethylene. A white solid (2.0 g, 79%) of -4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.84-1.92 (m, 2H), 1.97-2.04 (m, 2H), 3.62-3.64 (m, 2H), 3.81 (s, 3H), 3.82-3.85 (m, 2H), 6.69 (dd, J = 2.4 and 11.7 Hz, 1H), 6.76 (d, J = 2) .4 and 8.5 Hz, 1H), 7.39 (dd, J = 8.5 and 8.5 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-110.1 (s, 1F).
To a solution of 5-chloro-4- (2-fluoro-4-methoxyphenyl) -1,2-tetramethylene-4-pyrazolin-3-one (880 mg, 3.0 mmol) in dichloromethane (10 mL) at −40 ° C. A 1M solution of boron tribromide in dichloromethane (6.0 mL) was added. The reaction solution was stirred for 8 hours while slowly raising the reaction temperature to room temperature. After completion of the reaction, the reaction mixture was added dropwise to ice water, and 1N-HCl aqueous solution (50 mL) was added. The precipitated solid was filtered and sufficiently dried to give a white solid (778 mg) of 5-chloro-4- (2-fluoro-4-hydroxyphenyl) -1,2-tetramethylene-4-pyrazolin-3-one. 93%). ¹ H-NMR (400 MHz, d-DMSO): δ 1.74-1.82 (m, 2H), 1.87-1.95 (m, 2H), 3.54-3.59 (m, 2H) , 3.62-3.68 (m, 2H), 6.62 (dd, J = 2.4 and 11.9 Hz, 1H), 6.66 (dd, J = 2.4 and 8.5 Hz, 1H) ), 7.18 (dd, J = 8.5 and 8.5 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-110.6 (s, 1F).

アルゴン雰囲気下、金属マグネシウム（１．１ｇ，４４．２ｍｍｏｌ）のＴＨＦ（４０ｍＬ）懸濁液に、１−ブロモ−２−フルオロ−４−メトキシベンゼン（８．４ｇ，４４．２ｍｍｏｌ）を、溶液の温度が４０℃を超えないように加え、２−フルオロ−４−メトキシフェニルマグネシウムブロミドのＴＨＦ溶液を調製した。このＴＨＦ溶液を、シュウ酸ジエチル（４．９ｍＬ，４４．２ｍｍｏｌ）のＴＨＦ（４０ｍＬ）溶液に、−４０℃で滴下した。反応溶液を、徐々に室温まで昇温しながら２４時間攪拌した。反応終了後、反応溶液に飽和塩化アンモニウム水溶液（１００ｍＬ）と水（２００ｍＬ）を加え、酢酸エチル（２００ｍＬ×２）で抽出した。混合した有機層を硫酸マグネシウムで乾燥させた後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１）で精製することにより、２−（２−フルオロ−４−メトキシフェニル）−２−オキソ酢酸エチルの黄色液体（７．３ｇ，収率：７３％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．３９（ｔ，Ｊ＝７．１Ｈｚ，３Ｈ），３．８９（ｓ，３Ｈ），４．４１（ｑ，Ｊ＝７．１Ｈｚ，２Ｈ），６．６３（ｄｄ，Ｊ＝２．３ ａｎｄ １２．９Ｈｚ，１Ｈ），６．８２（ｄｄ，Ｊ＝２．３ ａｎｄ ８．８Ｈｚ，１Ｈ），７．９１（ｄｄ，Ｊ＝８．８ ａｎｄ ８．８Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１０８．１（ｓ，１Ｆ）．
２−（２−フルオロ−４−メトキシフェニル）−２−オキソ酢酸エチル（７００ｍｇ，３．０９ｍｍｏｌ）の濃硫酸（３ｍＬ）懸濁液に、濃硝酸（０．１９ｍＬ，６．１８ｍｍｏｌ）と濃硫酸（１ｍＬ）から調製した混酸を氷冷下でゆっくり加え、さらに３時間攪拌した。反応終了後、反応液を氷水中に注ぎ、酢酸エチル（２０ｍＬ×２，１０ｍＬ×１）で抽出した。有機層を飽和食塩水で洗浄し無水硫酸マグネシウムで乾燥した後に減圧濃縮し、茶褐色油状の粗生成物（７１１ｍｇ）を得た。同じ操作を繰り返して、２−（２−フルオロ−４−メトキシフェニル）−２−オキソ酢酸エチル（９３３ｍｇ，４．１２ｍｍｏｌ）から茶褐色油状の粗生成物（９９９ｍｇ）を得た。これらの粗生成物を合わせてシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１）で精製することにより、２−（２−フルオロ−４−メトキシ−５−ニトロフェニル）−２−オキソ酢酸エチルの茶色油状物（１．０７ｇ，収率：５５％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．４１（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），４．０６（ｓ，３Ｈ），４．４４（ｑ，Ｊ＝７．２Ｈｚ，２Ｈ），６．８５（ｄ，Ｊ＝１１．２Ｈｚ，１Ｈ），８．５６（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−９９．１（ｓ，１Ｆ）．
トリフェニルホスフィン（３．１１ｇ，１１．９ｍｍｏｌ）のジクロロメタン溶液に、氷冷下で四塩化炭素（１．２２ｇ，７．９ｍｍｏｌ）と２−（２−フルオロ−４−メトキシ−５−ニトロフェニル）−２−オキソ酢酸エチル（１．０７ｇ，３．９５ｍｍｏｌ）を加え、室温で２２時間攪拌した。反応終了後、反応液に水（５０ｍＬ）を加え、クロロホルム（３０ｍＬ×２，２０ｍＬ×１）で抽出した。有機層を、飽和食塩水（１０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥した後に減圧濃縮することにより、茶褐色固体の粗生成物（５．３９ｇ）を得た。このものをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１）で精製することにより、３，３−ジクロロ−２−（２−フルオロ−４−メトキシ−５−ニトロフェニル）アクリル酸エチルの淡黄色油状物（９０９ｍｇ，収率：６８％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．２７（ｔ，Ｊ＝７．１Ｈｚ，３Ｈ），３．９９（ｓ，３Ｈ），４．２６（ｑ，Ｊ＝７．１Ｈｚ，２Ｈ），６．８４（ｄ，Ｊ＝１０．９Ｈｚ，１Ｈ），７．９９（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−９９．９（ｓ，１Ｆ）．Reference Example-14

Under an argon atmosphere, 1-bromo-2-fluoro-4-methoxybenzene (8.4 g, 44.2 mmol) was added to a suspension of metallic magnesium (1.1 g, 44.2 mmol) in THF (40 mL). The solution was added so that the temperature did not exceed 40 ° C., and a THF solution of 2-fluoro-4-methoxyphenylmagnesium bromide was prepared. This THF solution was added dropwise at −40 ° C. to a solution of diethyl oxalate (4.9 mL, 44.2 mmol) in THF (40 mL). The reaction solution was stirred for 24 hours while gradually warming to room temperature. After completion of the reaction, a saturated aqueous ammonium chloride solution (100 mL) and water (200 mL) were added to the reaction solution, and the mixture was extracted with ethyl acetate (200 mL × 2). The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to give a yellow liquid of ethyl 2- (2-fluoro-4-methoxyphenyl) -2-oxoacetate (7 .3 g, yield: 73%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.39 (t, J = 7.1 Hz, 3H), 3.89 (s, 3H), 4.41 (q, J = 7.1 Hz, 2H), 6.63 (dd, J = 2.3 and 12.9 Hz, 1H), 6.82 (dd, J = 2.3 and 8.8 Hz, 1H), 7.91 (dd, J = 8.8 and 8.8 Hz, 1 H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.1 (s, 1F).
To a suspension of ethyl 2- (2-fluoro-4-methoxyphenyl) -2-oxoacetate (700 mg, 3.09 mmol) in concentrated sulfuric acid (3 mL), concentrated nitric acid (0.19 mL, 6.18 mmol) and concentrated sulfuric acid were added. The mixed acid prepared from (1 mL) was slowly added under ice cooling, and the mixture was further stirred for 3 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate (20 mL × 2, 10 mL × 1). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a brown oily crude product (711 mg). The same operation was repeated to obtain a brown oily crude product (999 mg) from ethyl 2- (2-fluoro-4-methoxyphenyl) -2-oxoacetate (933 mg, 4.12 mmol). These crude products were combined and purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give ethyl 2- (2-fluoro-4-methoxy-5-nitrophenyl) -2-oxoacetate. Of a brown oil (1.07 g, yield: 55%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.41 (t, J = 7.2 Hz, 3H), 4.06 (s, 3H), 4.44 (q, J = 7.2 Hz, 2H), 6.85 (d, J = 11.2 Hz, 1H), 8.56 (d, J = 7.3 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-99.1 (s, 1F).
To a dichloromethane solution of triphenylphosphine (3.11 g, 11.9 mmol) under ice cooling, carbon tetrachloride (1.22 g, 7.9 mmol) and 2- (2-fluoro-4-methoxy-5-nitrophenyl) were added. Ethyl-2-oxoacetate (1.07 g, 3.95 mmol) was added and stirred at room temperature for 22 hours. After completion of the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with chloroform (30 mL × 2, 20 mL × 1). The organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain a brown solid crude product (5.39 g). This was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give a light ethyl ethyl 3,3-dichloro-2- (2-fluoro-4-methoxy-5-nitrophenyl) acrylate. A yellow oil (909 mg, yield: 68%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.27 (t, J = 7.1 Hz, 3H), 3.99 (s, 3H), 4.26 (q, J = 7.1 Hz, 2H), 6.84 (d, J = 10.9 Hz, 1H), 7.9 (d, J = 7.4 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-99.9 (s, 1F).

３，３−ジクロロ−２−（２−フルオロ−４−メトキシ−５−ニトロフェニル）アクリル酸エチル（９０９ｍｇ，２．６９ｍｍｏｌ）の１，４−ジオキサン（２０ｍＬ）溶液に、トリエチルアミン（１．０１ｇ，９．９５ｍｍｏｌ）及びヘキサヒドロピリダジン二臭化水素塩（７２３ｍｇ，４．９５ｍｍｏｌ）を加え、１８時間還流した。反応終了後、反応液に水（５０ｍＬ）を加え、酢酸エチル（３０ｍＬ×２，２０ｍＬ×１）で抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた橙色固体の粗生成物（１．２１ｇ）をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝３０：１）で精製することにより、５−クロロ−４−（２−フルオロ−４−メトキシ−５−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの黄色固体物（７３２ｍｇ，収率：８０％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８８−１．９５（ｍ，２Ｈ），１．９９−２．０６（ｍ，２Ｈ），３．６１−３．６５（ｍ，２Ｈ），３．８１−３．８６（ｍ，２Ｈ），３．９８（ｓ，３Ｈ），６．８６（ｄ，Ｊ＝１１．２Ｈｚ，１Ｈ），８．１４（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−９８．５（ｓ，１Ｆ）．Reference Example-15

To a solution of ethyl 3,3-dichloro-2- (2-fluoro-4-methoxy-5-nitrophenyl) acrylate (909 mg, 2.69 mmol) in 1,4-dioxane (20 mL) was added triethylamine (1.01 g, 9.95 mmol) and hexahydropyridazine dihydrobromide (723 mg, 4.95 mmol) were added and refluxed for 18 hours. After completion of the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 2, 20 mL × 1). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained orange solid crude product (1.21 g) was purified by silica gel column chromatography (ethyl acetate: methanol = 30: 1) to give 5-chloro-4- (2-fluoro-4-methoxy-). A yellow solid (732 mg, yield: 80%) of 5-nitrophenyl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.88-1.95 (m, 2H), 1.99-2.06 (m, 2H), 3.61-3.65 (m, 2H), 3 81-3.86 (m, 2H), 3.98 (s, 3H), 6.86 (d, J = 11.2 Hz, 1H), 8.14 (d, J = 7.4 Hz, 1H) . ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-98.5 (s, 1F).

水素化ナトリウムの５５％油分散（０．４７５ｇ，１０．９ｍｍｏｌ）の１，４−ジオキサン（４６ｍＬ）溶液に、５−クロロ−４−（２，４−ジフルオロ−５−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（３．０１ｇ，９．１０ｍｍｏｌ）を加え、次いで、メタノール（０．９２０ｍＬ，２２．８ｍｍｏｌ）を滴下し、室温で２時間撹拌した。反応終了後、反応液を氷水（１００ｇ）に注ぎ入れ、クロロホルム（１００ｍＬ×４）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：酢酸エチル＝１：１）で精製することにより、５−クロロ−４−（２−フルオロ−４−メトキシ−５−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの黄色固体（２．２７ｇ，収率：７３％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８８−１．９５（ｍ，２Ｈ），１．９９−２．０６（ｍ，２Ｈ），３．６１−３．６５（ｍ，２Ｈ），３．８１−３．８６（ｍ，２Ｈ），３．９８（ｓ，３Ｈ），６．８６（ｄ，Ｊ＝１１．２Ｈｚ，１Ｈ），８．１４（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−９８．５（ｓ，１Ｆ）．Reference Example-16

To a solution of sodium hydride in 55% oil dispersion (0.475 g, 10.9 mmol) in 1,4-dioxane (46 mL), 5-chloro-4- (2,4-difluoro-5-nitrophenyl) -1, 2-tetramethylene-4-pyrazolin-3-one (3.01 g, 9.10 mmol) was added, then methanol (0.920 mL, 22.8 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 hr. After completion of the reaction, the reaction solution was poured into ice water (100 g) and extracted with chloroform (100 mL × 4). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: ethyl acetate = 1: 1) to give 5-chloro-4- (2-fluoro-4-methoxy-5-nitrophenyl) -1, A yellow solid (2.27 g, yield: 73%) of 2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.88-1.95 (m, 2H), 1.99-2.06 (m, 2H), 3.61-3.65 (m, 2H), 3 81-3.86 (m, 2H), 3.98 (s, 3H), 6.86 (d, J = 11.2 Hz, 1H), 8.14 (d, J = 7.4 Hz, 1H) . ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-98.5 (s, 1F).

５−クロロ−４−（２−フルオロ−４−メトキシ−５−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（４．００ｇ，１１．７ｍｍｏｌ）のジクロロメタン（４７ｍＬ）溶液に、−４０℃で三臭化ホウ素のジクロロメタン１Ｍ溶液（２９．３ｍＬ）を滴下し、室温まで徐々に昇温させながら５時間撹拌した。反応終了後、反応液に水（１５０ｍＬ）を注ぎ入れ、１時間撹拌した。析出した固体をろ取し、ジエチルエーテルで洗浄することにより、５−クロロ−４−（２−フルオロ−４−ヒドロキシ−５−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの黄色固体（３．８２ｇ，収率：定量的）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８８−１．９６（ｍ，２Ｈ），２．００−２．０７（ｍ，２Ｈ），３．６２，−３．６６（ｍ，２Ｈ），３．８２−３．８７（ｍ，２Ｈ），６．９１（ｄ，Ｊ＝１０．４Ｈｚ，１Ｈ），８．３４（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ），１０．８（ｄ，Ｊ＝１．５Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−９４．８（ｓ，１Ｆ）．Reference Example-17

A solution of 5-chloro-4- (2-fluoro-4-methoxy-5-nitrophenyl) -1,2-tetramethylene-4-pyrazolin-3-one (4.00 g, 11.7 mmol) in dichloromethane (47 mL). To the solution, 1M solution of boron tribromide in dichloromethane (29.3 mL) was added dropwise at −40 ° C., and the mixture was stirred for 5 hours while gradually warming to room temperature. After completion of the reaction, water (150 mL) was poured into the reaction solution and stirred for 1 hour. The precipitated solid was collected by filtration and washed with diethyl ether to give 5-chloro-4- (2-fluoro-4-hydroxy-5-nitrophenyl) -1,2-tetramethylene-4-pyrazolin-3- An on-yellow solid (3.82 g, yield: quantitative) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.88-1.96 (m, 2H), 2.00-2.07 (m, 2H), 3.62, -3.66 (m, 2H), 3.82-3.87 (m, 2H), 6.91 (d, J = 10.4 Hz, 1H), 8.34 (d, J = 7.3 Hz, 1H), 10.8 (d, J = 1.5 Hz, 1 H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-94.8 (s, 1F).

５−クロロ−４−（２−フルオロ−４−ヒドロキシ−５−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（７０２ｍｇ，２．１４ｍｍｏｌ）のＤＭＦ（５ｍＬ）溶液に、炭酸セシウム（１．３９ｇ，４．２８ｍｍｏｌ）とブロモ酢酸メチル（６５５ｍｇ，４．２８ｍｍｏｌ）を加え、８０℃で６時間攪拌した。反応終了後、反応液に水（３０ｍＬ）を加え、酢酸エチル（３０ｍＬ×１、２０ｍＬ×２）で抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた橙色油状の粗生成物（１．０７ｇ）をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、２−［４−（５−クロロ−１，２−テトラメチレン−３−オキソ−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］酢酸メチルの黄色固体物（４５０ｍｇ，収率：５１％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８９−１．９６（ｍ，２Ｈ），２．００−２．０６（ｍ，２Ｈ），３．６１−３．６６（ｍ，２Ｈ），３．８３（ｓ，３Ｈ），３．８０−３．８６（ｍ，２Ｈ），４．７９（ｓ，２Ｈ），６．７５（ｄ，Ｊ＝１０．７Ｈｚ，１Ｈ），８．１６（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−９８．４（ｓ，１Ｆ）．Reference Example-18

To a solution of 5-chloro-4- (2-fluoro-4-hydroxy-5-nitrophenyl) -1,2-tetramethylene-4-pyrazolin-3-one (702 mg, 2.14 mmol) in DMF (5 mL), Cesium carbonate (1.39 g, 4.28 mmol) and methyl bromoacetate (655 mg, 4.28 mmol) were added, and the mixture was stirred at 80 ° C. for 6 hours. After completion of the reaction, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 1, 20 mL × 2). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained orange oil crude product (1.07 g) was purified by silica gel column chromatography (ethyl acetate) to give 2- [4- (5-chloro-1,2-tetramethylene-3-oxo- 4-Pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] methyl acetate yellow solid (450 mg, yield: 51%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.89-1.96 (m, 2H), 2.00-2.06 (m, 2H), 3.61-3.66 (m, 2H), 3.83 (s, 3H), 3.80-3.86 (m, 2H), 4.79 (s, 2H), 6.75 (d, J = 10.7 Hz, 1H), 8.16 ( d, J = 7.3 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-98.4 (s, 1F).

５−クロロ−４−（２−フルオロ−４−ヒドロキシ−５−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（１．０１ｇ，３．０５ｍｍｏｌ）のエタノール（１２ｍＬ）溶液に、１０％パラジウム／炭素（６４．９ｍｇ，０．０６１ｍｍｏｌ）を加え、水素雰囲気下、室温で１６時間撹拌した。反応終了後、反応液へクロロホルムとメタノールの混合溶媒（クロロホルム：メタノール＝１０：１）を加えた後、ろ過により触媒をろ別し、ろ液を減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、４−（５−アミノ−２−フルオロ−４−ヒドロキシフェニル）−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの青緑色固体（０．６８７ｇ，収率：７６％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８９−１．９７（ｍ，２Ｈ），１．９９−２．０７（ｍ，２Ｈ），３．６０−３．６５（ｍ，２Ｈ），３．８５−３．９１（ｍ，２Ｈ），６．２６（ｄ，Ｊ＝１０．８Ｈｚ，１Ｈ），６．４９（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１４２．３（ｓ，１Ｆ）．Reference Example-19

A solution of 5-chloro-4- (2-fluoro-4-hydroxy-5-nitrophenyl) -1,2-tetramethylene-4-pyrazolin-3-one (1.01 g, 3.05 mmol) in ethanol (12 mL) Was added with 10% palladium / carbon (64.9 mg, 0.061 mmol), and the mixture was stirred at room temperature for 16 hours in a hydrogen atmosphere. After completion of the reaction, a mixed solvent of chloroform and methanol (chloroform: methanol = 10: 1) was added to the reaction solution, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 4- (5-amino-2-fluoro-4-hydroxyphenyl) -5-chloro-1,2 -A blue-green solid (0.687 g, yield: 76%) of tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.89-1.97 (m, 2H), 1.99-2.07 (m, 2H), 3.60-3.65 (m, 2H), 3 .85-3.91 (m, 2H), 6.26 (d, J = 10.8 Hz, 1H), 6.49 (d, J = 7.3 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-142.3 (s, 1F).

４−（５−アミノ−２−フルオロ−４−ヒドロキシフェニル）−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オン（４．５０ｇ，１５．１ｍｍｏｌ）のＴＨＦ（５０ｍＬ）溶液に、氷冷下で水素化ナトリウムの５５％油分散（０．６６０ｇ，１５．１ｍｍｏｌ）を加え、−１５℃で１時間撹拌した後、２−ブロモ−２，２−ジフルオロ酢酸エチル（２．２２ｍＬ，１６．６ｍｍｏｌ）を滴下し、０℃で２時間、室温で１５時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（５０ｍＬ）を加え、クロロホルム（１００ｍＬ×２）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物を（クロロホルム：メタノール＝１０：１）で洗浄することにより、２−ブロモ−Ｎ−［５−（５−クロロ−１，２−テトラメチレン−３−オキソ−４−ピラゾリン−４−イル）−４−フルオロ−２−ヒドロキシフェニル］−２，２−ジフルオロアセトアミド（４．５８ｇ，収率：６７％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ）δ１．８３−１．７４（ｍ，２Ｈ），１．９６−１．８７（ｍ，２Ｈ），３．６２−３．５７（ｍ，２Ｈ），３．６９−３．６３（ｍ，２Ｈ），６．７９（ｄ，Ｊ＝１１．２Ｈｚ，１Ｈ），７．２８（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），１０．３９（ｓ，１Ｈ），１０．５９（ｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＤＭＳＯ）δ−１１１．４（ｓ，１Ｆ），−６０．０（ｓ，２Ｆ）．Reference Example-20

4- (5-amino-2-fluoro-4-hydroxyphenyl) -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one (4.50 g, 15.1 mmol) in THF (50 mL) To the mixture was added 55% oil dispersion (0.660 g, 15.1 mmol) of sodium hydride under ice-cooling, and the mixture was stirred at −15 ° C. for 1 hour, and then ethyl 2-bromo-2,2-difluoroacetate (2. 22 mL, 16.6 mmol) was added dropwise, and the mixture was stirred at 0 ° C. for 2 hours and at room temperature for 15 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution, and the mixture was extracted with chloroform (100 mL × 2). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was washed with (chloroform: methanol = 10: 1) to give 2-bromo-N- [5- (5-chloro-1,2-tetramethylene-3-oxo-4-pyrazoline). -4-yl) -4-fluoro-2-hydroxyphenyl] -2,2-difluoroacetamide (4.58 g, yield: 67%) was obtained. ¹ H-NMR (400 MHz, DMSO) δ 1.83-1.74 (m, 2H), 1.96-1.87 (m, 2H), 3.62-3.57 (m, 2H), 3. 69-3.63 (m, 2H), 6.79 (d, J = 11.2 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 10.39 (s, 1H), 10.59 (s, 1H). ¹⁹ F-NMR (376 MHz, DMSO) δ-111.4 (s, 1F), -60.0 (s, 2F).

２−ブロモ−Ｎ−［５−（５−クロロ−１，２−テトラメチレン−３−オキソ−４−ピラゾリン−４−イル）−４−フルオロ−２−ヒドロキシフェニル］−２，２−ジフルオロアセトアミド（３．７６ｇ，８．２７ｍｍｏｌ）のトルエン（６０ｍＬ）溶液に、ＤＢＵ（１．２３ｍＬ，８．２７ｍｍｏｌ）を加え、８０℃で３時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（５０ｍＬ）を加え、クロロホルム（１００ｍＬ×３）で抽出した。合一した有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をクロロホルムで洗浄することにより、５−クロロ−４−（２，２，７−トリフルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（１．３６ｇ，収率：４４％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ）δ１．７７−１．８５（ｍ，２Ｈ），１．８９−１．９７（ｍ，２Ｈ），３．６３−３．７２（ｍ，４Ｈ），７．１８（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ），７．４６（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），１２．１（ｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＤＭＳＯ）δ−１１４．７（ｓ，１Ｆ），−７５．７（ｓ，２Ｆ）．Example-40

2-Bromo-N- [5- (5-chloro-1,2-tetramethylene-3-oxo-4-pyrazolin-4-yl) -4-fluoro-2-hydroxyphenyl] -2,2-difluoroacetamide DBU (1.23 mL, 8.27 mmol) was added to a toluene (60 mL) solution of (3.76 g, 8.27 mmol), and the mixture was stirred at 80 ° C. for 3 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution, and the mixture was extracted with chloroform (100 mL × 3). The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was washed with chloroform to give 5-chloro-4- (2,2,7-trifluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazine-6. A white solid (1.36 g, yield: 44%) of -yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, DMSO) δ 1.77-1.85 (m, 2H), 1.89-1.97 (m, 2H), 3.63-3.72 (m, 4H), 7. 18 (d, J = 6.8 Hz, 1H), 7.46 (d, J = 9.9 Hz, 1H), 12.1 (s, 1H). ¹⁹ F-NMR (376 MHz, DMSO) δ-114.7 (s, 1F), -75.7 (s, 2F).

水素化ナトリウムの５５％油分散（０．０４ｇ，０．８８ｍｍｏｌ）のＤＭＦ（２．５ｍＬ）溶液に、氷冷下で５−クロロ−４−（２，２，７−トリフルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８０ｍｍｏｌ）を加え、１５分撹拌した後、ベンジルブロミド（０．１１ｍＬ，０．８８ｍｍｏｌ）を加え、室温で４５時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。合一した有機層を水（５０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製し、得られた固体をメタノールで洗浄することにより、４−（４−ベンジル−２，２，７−トリフルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（０．２２ｇ，収率：５９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８７−１．９３（ｍ，２Ｈ），１．９７−２．０４（ｍ，２Ｈ），３．５８−３．６２（ｍ，２Ｈ），３．７８−３．８３（ｍ，２Ｈ），５．２３（ｓ，２Ｈ），７．０２（ｄ，Ｊ＝９．２Ｈｚ，１Ｈ），７．２３−７．３７（ｍ，６Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１２（ｓ，１Ｆ），−７７．５（ｓ，２Ｆ）．Example-41

To a solution of sodium hydride in 55% oil dispersion (0.04 g, 0.88 mmol) in DMF (2.5 mL) under ice-cooling, 5-chloro-4- (2,2,7-trifluoro-2,3 -Dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (0.30 g, 0.80 mmol) was added and stirred for 15 minutes. After that, benzyl bromide (0.11 mL, 0.88 mmol) was added and stirred at room temperature for 45 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layer was washed with water (50 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1), and the obtained solid was washed with methanol to give 4- (4-benzyl-2,2,7-trimethyl). Fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one (0. 22 g, yield: 59%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.87-1.93 (m, 2H), 1.97-2.04 (m, 2H), 3.58-3.62 (m, 2H), 3 .78-3.83 (m, 2H), 5.23 (s, 2H), 7.02 (d, J = 9.2 Hz, 1H), 7.23-7.37 (m, 6H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-112 (s, 1F), −77.5 (s, 2F).

水素化ナトリウムの５５％油分散（０．０４ｇ，０．８８ｍｍｏｌ）のＤＭＦ（２．５ｍＬ）溶液に、氷冷下で５−クロロ−４−（２，２，７−トリフルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８０ｍｍｏｌ）を加え、１５分撹拌した後、アリルブロミド（０．０７４ｍＬ，０．８８ｍｍｏｌ）を加え、室温で４３時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。合一した有機層を水（５０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製し、得られた固体をメタノールで洗浄することにより、４−（４−アリル−２，２，７−トリフルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（０．１８ｇ，収率：５４％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８８−１．９６（ｍ，２Ｈ），２．００−２．０７（ｍ，２Ｈ），３．６２−３．６７（ｍ，２Ｈ），３．８１−３．８６（ｍ，２Ｈ），４．６４（ｍ，２Ｈ），５．２４−５．３４（ｍ，２Ｈ），５．８９（ｄｄｔ，Ｊ＝５．０，１０．５ ａｎｄ １７．２Ｈｚ，１Ｈ），７．０２（ｄ，Ｊ＝９．２Ｈｚ，１Ｈ），７．３０（ｄ，Ｊ＝６．４Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１３（ｓ，１Ｆ），−７７．５（ｓ，２Ｆ）．Example-42

To a solution of sodium hydride in 55% oil dispersion (0.04 g, 0.88 mmol) in DMF (2.5 mL) under ice-cooling, 5-chloro-4- (2,2,7-trifluoro-2,3 -Dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (0.30 g, 0.80 mmol) was added and stirred for 15 minutes. After that, allyl bromide (0.074 mL, 0.88 mmol) was added, and the mixture was stirred at room temperature for 43 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layer was washed with water (50 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1), and the obtained solid was washed with methanol to give 4- (4-allyl-2,2,7-trimethyl). Fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one (0. 18 g, yield: 54%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.88-1.96 (m, 2H), 2.00-2.07 (m, 2H), 3.62-3.67 (m, 2H), 3 81-3.86 (m, 2H), 4.64 (m, 2H), 5.24-5.34 (m, 2H), 5.89 (ddt, J = 5.0, 10.5 and 17.2 Hz, 1H), 7.02 (d, J = 9.2 Hz, 1H), 7.30 (d, J = 6.4 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-113 (s, 1F), -77.5 (s, 2F).

水素化ナトリウムの５５％油分散（０．０４ｇ，０．８８ｍｍｏｌ）のＤＭＦ（２．５ｍＬ）溶液に、氷冷下で５−クロロ−４−（２，２，７−トリフルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８０ｍｍｏｌ）を加え、１５分撹拌した後、プロパルギルブロミド（０．０７０ｍＬ，０．８８ｍｍｏｌ）を加え、室温で５０時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。合一した有機層を水（３０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製し、得られた固体をジエチルエーテルとヘキサンの混合溶媒（ジエチルエーテル：ヘキサン＝１：１）で洗浄することにより、５−クロロ−１，２−テトラメチレン−４−（２，２，７−トリフルオロ−２，３−ジヒドロ−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−４−ピラゾリン−３−オンの白色固体（０．２０９ｇ，収率：６３％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．９６−１．８９（ｍ，２Ｈ），２．０８−２．００（ｍ，２Ｈ），２．３４（ｔ，Ｊ＝２．５Ｈｚ，１Ｈ），３．６９−３．６４（ｍ，２Ｈ），３．８８−３．８３（ｍ，２Ｈ），４．８０（ｄ，Ｊ＝２．５Ｈｚ，２Ｈ），７．０５（ｄ，Ｊ＝９．２Ｈｚ，１Ｈ），７．４８（ｄ，Ｊ＝６．３Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１２（ｓ，１Ｆ），−７７．３（ｓ，２Ｆ）．Example-43

To a solution of sodium hydride in 55% oil dispersion (0.04 g, 0.88 mmol) in DMF (2.5 mL) under ice-cooling, 5-chloro-4- (2,2,7-trifluoro-2,3 -Dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (0.30 g, 0.80 mmol) was added and stirred for 15 minutes. Then, propargyl bromide (0.070 mL, 0.88 mmol) was added and stirred at room temperature for 50 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layer was washed with water (30 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (chloroform: methanol = 10: 1), and the obtained solid is washed with a mixed solvent of diethyl ether and hexane (diethyl ether: hexane = 1: 1). 5-chloro-1,2-tetramethylene-4- (2,2,7-trifluoro-2,3-dihydro-3-oxo-4-propargyl-4H-1,4-benzoxazine-6- Yl) -4-pyrazolin-3-one was obtained as a white solid (0.209 g, yield: 63%). ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.96-1.89 (m, 2H), 2.08-2.00 (m, 2H), 2.34 (t, J = 2.5 Hz, 1H) 3.69-3.64 (m, 2H), 3.88-3.83 (m, 2H), 4.80 (d, J = 2.5 Hz, 2H), 7.05 (d, J = 9.2 Hz, 1H), 7.48 (d, J = 6.3 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-112 (s, 1F), −77.3 (s, 2F).

水素化ナトリウムの５５％油分散（０．０４ｇ，０．８８ｍｍｏｌ）のＤＭＦ（２．５ｍＬ）溶液に、氷冷下で５−クロロ−４−（２，２，７−トリフルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８０ｍｍｏｌ）を加え、１５分撹拌した後、１−ブロモ−２−ブチン（０．０８３ｍＬ，０．８８ｍｍｏｌ）を加え、室温で４２時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。合一した有機層を水（５０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、４−［４−（２−ブチニル）−２，２，７−トリフルオロ−２，３−ジヒドロ−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル］−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（０．２６ｇ，収率：７６％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８０（ｔ，Ｊ＝２．４Ｈｚ，３Ｈ），１．８９−１．９６（ｍ，２Ｈ），２．０１−２．０８（ｍ，２Ｈ），３．６３−３．６８（ｍ，２Ｈ），３．８３−３．８８（ｍ，２Ｈ），４．７２（ｑ，Ｊ＝２．４Ｈｚ，２Ｈ），７．０３（ｄ，Ｊ＝９．２Ｈｚ，１Ｈ），７．４５（ｄ，Ｊ＝６．４Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１３（ｓ，１Ｆ），−７７．１（ｓ，２Ｆ）．Example-44

To a solution of sodium hydride in 55% oil dispersion (0.04 g, 0.88 mmol) in DMF (2.5 mL) under ice-cooling, 5-chloro-4- (2,2,7-trifluoro-2,3 -Dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (0.30 g, 0.80 mmol) was added and stirred for 15 minutes. After that, 1-bromo-2-butyne (0.083 mL, 0.88 mmol) was added and stirred at room temperature for 42 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layer was washed with water (50 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 4- [4- (2-butynyl) -2,2,7-trifluoro-2,3- Dihydro-3-oxo-4-propargyl-4H-1,4-benzoxazin-6-yl] -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one as a white solid (0.26 g, Yield: 76%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.80 (t, J = 2.4 Hz, 3H), 1.89-1.96 (m, 2H), 2.01-2.08 (m, 2H) 3.6-3.68 (m, 2H), 3.83-3.88 (m, 2H), 4.72 (q, J = 2.4 Hz, 2H), 7.03 (d, J = 9.2 Hz, 1H), 7.45 (d, J = 6.4 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-113 (s, 1F), −77.1 (s, 2F).

水素化ナトリウムの５５％油分散（０．１８ｇ，４．５ｍｍｏｌ）の１，４−ジオキサン（１５ｍＬ）溶液に、５−クロロ−４−（２，４−ジフルオロ−５−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（０．９８９ｇ，３．０ｍｍｏｌ）及びチオグリコール酸メチル（０．４１ｍＬ，４．５ｍｍｏｌ）を順次加え、室温で３０分間撹拌した。反応終了後、反応液を氷水（５０ｇ）に注ぎ、酢酸エチル（５０ｍＬ×３）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、２−［４−（５−クロロ−１，２−テトラメチレン−３−オキソ−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルスルファニル］酢酸メチルの淡黄色固体（０．５９ｇ，収率：４７％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８９−１．９６（ｍ，２Ｈ），２．００−２．０８（ｍ，２Ｈ），３．６３−３．７０（ｍ，２Ｈ），３．７５（ｓ，２Ｈ），３．８０（ｓ，３Ｈ），３．８２−３．８７（ｍ，２Ｈ），７．２７（ｄ，Ｊ＝１０．５Ｈｚ，１Ｈ），８．５０（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１００．１（ｓ，１Ｆ）．Reference Example-21

To a solution of sodium hydride in 55% oil dispersion (0.18 g, 4.5 mmol) in 1,4-dioxane (15 mL), 5-chloro-4- (2,4-difluoro-5-nitrophenyl) -1, 2-tetramethylene-4-pyrazolin-3-one (0.989 g, 3.0 mmol) and methyl thioglycolate (0.41 mL, 4.5 mmol) were sequentially added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was poured into ice water (50 g) and extracted with ethyl acetate (50 mL × 3). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate) to give 2- [4- (5-chloro-1,2-tetramethylene-3-oxo-4-pyrazolin-4-yl). A light yellow solid (0.59 g, yield: 47%) of methyl -5-fluoro-2-nitrophenylsulfanyl] acetate was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.89-1.96 (m, 2H), 2.00-2.08 (m, 2H), 3.63-3.70 (m, 2H), 3 .75 (s, 2H), 3.80 (s, 3H), 3.82-3.87 (m, 2H), 7.27 (d, J = 10.5 Hz, 1H), 8.50 (d , J = 6.7 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-100.1 (s, 1F).

２−［４−（５−クロロ−１，２−テトラメチレン−３−オキソ−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルスルファニル］酢酸メチル（０．４１６ｇ，１．００ｍｍｏｌ）の酢酸エチル（５ｍＬ）溶液に、酢酸（５ｍＬ）及び水（５ｍＬ）を順次加えた後、０℃で還元鉄（０．５６ｇ，１０．０ｍｍｏｌ）を加え、８０℃で１時間撹拌した。反応終了後、反応液を室温まで冷却し、不溶物をろ別後、ろ液に飽和炭酸水素ナトリウム水溶液（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥した後、減圧濃縮することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾチオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（０．３０６ｇ，８６％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８７−１．９６（ｍ，２Ｈ），１．９８−２．０８（ｍ，２Ｈ），３．３６（ｓ，２Ｈ），３．６１−３．６８（ｍ，２Ｈ），３．８２−３．９０（ｍ，２Ｈ），７．０８（ｄ，Ｊ＝９．３Ｈｚ，１Ｈ），７．１３（ｄ，Ｊ＝３．９Ｈｚ，１Ｈ），８．６３（ｂｒｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１６．９（ｓ，１Ｆ）．Example-45

Methyl 2- [4- (5-chloro-1,2-tetramethylene-3-oxo-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenylsulfanyl] acetate (0.416 g, 1.00 mmol) Acetic acid (5 mL) and water (5 mL) were sequentially added to an ethyl acetate (5 mL) solution, and then reduced iron (0.56 g, 10.0 mmol) was added at 0 ° C., followed by stirring at 80 ° C. for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, insolubles were filtered off, saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzothioxazine. A white solid (0.306 g, 86%) of -6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.87-1.96 (m, 2H), 1.98-2.08 (m, 2H), 3.36 (s, 2H), 3.61-3 .68 (m, 2H), 3.82-3.90 (m, 2H), 7.08 (d, J = 9.3 Hz, 1H), 7.13 (d, J = 3.9 Hz, 1H) , 8.63 (brs, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-116.9 (s, 1F).

水素化ナトリウムの５５％油分散（０．０４ｇ，０．８８ｍｍｏｌ）のＤＭＦ（２．５ｍＬ）溶液に、氷冷下で５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾチオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８０ｍｍｏｌ）を加え、１５分撹拌した後、プロパルギルブロミド（０．０７０ｍＬ，０．８８ｍｍｏｌ）を加え、室温で５０時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。合一した有機層を水（３０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製し、得られた固体をジエチルエーテルとヘキサンの混合溶媒（ジエチルエーテル：ヘキサン＝１：１）で洗浄することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾチオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（０．２０９ｇ，収率：６３％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８８−１．９６（ｍ，２Ｈ），１．９９−２．０７（ｍ，２Ｈ），２．２８（ｔ，Ｊ＝２．４Ｈｚ，１Ｈ），３．４６（ｓ，２Ｈ），３．６２−３．６７（ｍ，２Ｈ），３．８２−３．８７（ｍ，２Ｈ），４．７１（ｄ，Ｊ＝２．４Ｈｚ，２Ｈ），７．１６（ｄ，Ｊ＝９．２Ｈｚ，１Ｈ），７．５１（ｄ，Ｊ＝６．２Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）δ−１１６．３（ｓ，１Ｆ）．Example-46

To a solution of sodium hydride in 55% oil dispersion (0.04 g, 0.88 mmol) in DMF (2.5 mL) under ice-cooling, 5-chloro-4- (7-fluoro-2,3-dihydro-3- Oxo-4H-1,4-benzothioxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (0.30 g, 0.80 mmol) was added and stirred for 15 minutes before propargyl. Bromide (0.070 mL, 0.88 mmol) was added and stirred at room temperature for 50 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layer was washed with water (30 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product is purified by silica gel column chromatography (chloroform: methanol = 10: 1), and the obtained solid is washed with a mixed solvent of diethyl ether and hexane (diethyl ether: hexane = 1: 1). 5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4-propargyl-4H-1,4-benzothioxazin-6-yl) -1,2-tetramethylene-4 -A white solid (0.209 g, yield: 63%) of pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.88-1.96 (m, 2H), 1.99-2.07 (m, 2H), 2.28 (t, J = 2.4 Hz, 1H) 3.46 (s, 2H), 3.62-3.67 (m, 2H), 3.82-3.87 (m, 2H), 4.71 (d, J = 2.4 Hz, 2H) 7.16 (d, J = 9.2 Hz, 1H), 7.51 (d, J = 6.2 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ) δ-116.3 (s, 1F).

４−フルオロ−３−ニトロベンゾイルギ酸エチル（１．００ｇ，４．１５ｍｍｏｌ）のＴＨＦ（２０ｍＬ）溶液にグリコール酸エチル（０．４８ｍＬ，４．９８ｍｍｏｌ）を加えた後、氷冷下で水素化ナトリウムの５５％油分散（０．２０ｇ，４．５７ｍｍｏｌ）を少量ずつ加え、室温で１時間撹拌した。反応終了後、反応液を氷水（１００ｇ）に注ぎ入れ、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝２：１）で精製することにより、４−（エトキシカルボニル）メトキシ−３−ニトロベンゾイルギ酸エチルの黄色固体（１．０５ｇ，収率：７８％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．３０（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．４４（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），４．２８（ｑ，Ｊ＝７．２Ｈｚ，２Ｈ），４．４６（ｑ，Ｊ＝７．２Ｈｚ，２Ｈ），４．８８（ｓ，２Ｈ），７．０５（ｄ，Ｊ＝８．９Ｈｚ，１Ｈ），８．２７（ｄｄ，Ｊ＝８．９ ａｎｄ ２．２Ｈｚ，１Ｈ），８．６３（ｄ，Ｊ＝２．２Ｈｚ，１Ｈ）．Reference Example-22

Ethyl glycolate (0.48 mL, 4.98 mmol) was added to a solution of ethyl 4-fluoro-3-nitrobenzoylformate (1.00 g, 4.15 mmol) in THF (20 mL), and then sodium hydride under ice cooling. 55% oil dispersion (0.20 g, 4.57 mmol) was added in small portions and stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into ice water (100 g) and extracted with ethyl acetate (50 mL × 3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give a yellow solid (1.05 g, yield of ethyl 4- (ethoxycarbonyl) methoxy-3-nitrobenzoylformate). Rate: 78%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.30 (t, J = 7.2 Hz, 3H), 1.44 (t, J = 7.2 Hz, 3H), 4.28 (q, J = 7) .2 Hz, 2H), 4.46 (q, J = 7.2 Hz, 2H), 4.88 (s, 2H), 7.05 (d, J = 8.9 Hz, 1H), 8.27 (dd , J = 8.9 and 2.2 Hz, 1H), 8.63 (d, J = 2.2 Hz, 1H).

トリフェニルホスフィン（１０．９ｇ，４１．４ｍｍｏｌ）のジクロロメタン（８１ｍＬ）溶液に、氷冷下で四塩化炭素（２．７ｍＬ）を加えた後、４−（エトキシカルボニル）メトキシ−３−ニトロベンゾイルギ酸エチル（４．４９ｇ，１３．８ｍｍｏｌ）を加えて、室温で１９時間撹拌した。反応溶液から減圧下に溶液を除去した後、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１）で精製することにより、２−［４−（エトキシカルボニル）メトキシ−３−ニトロフェニル］−３，３−ジクロロアクリル酸エチルの淡黄色固体（４．６２ｇ，収率：８５％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．２９（ｔ，Ｊ＝７．１Ｈｚ，３Ｈ），１．３１（ｔ，Ｊ＝７．１Ｈｚ，３Ｈ），４．２８（ｑ，Ｊ＝７．１Ｈｚ，２Ｈ），４．２８（ｑ，Ｊ＝７．１Ｈｚ，２Ｈ），４．８０（ｓ，２Ｈ），６．９９（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．５４（ｄｄ，Ｊ＝８．８ ａｎｄ ２．３Ｈｚ，１Ｈ），７．９４（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）．Reference Example-23

Carbon tetrachloride (2.7 mL) was added to a solution of triphenylphosphine (10.9 g, 41.4 mmol) in dichloromethane (81 mL) under ice cooling, and then 4- (ethoxycarbonyl) methoxy-3-nitrobenzoylformic acid. Ethyl (4.49 g, 13.8 mmol) was added and stirred at room temperature for 19 hours. After removing the solution from the reaction solution under reduced pressure, 2- [4- (ethoxycarbonyl) methoxy-3-nitrophenyl] -3 was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1). , Ethyl 3-dichloroacrylate was obtained as a pale yellow solid (4.62 g, yield: 85%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.29 (t, J = 7.1 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 4.28 (q, J = 7) .1 Hz, 2H), 4.28 (q, J = 7.1 Hz, 2H), 4.80 (s, 2H), 6.99 (d, J = 8.8 Hz, 1H), 7.54 (dd , J = 8.8 and 2.3 Hz, 1H), 7.94 (d, J = 2.3 Hz, 1H).

２−［４−（エトキシカルボニル）メトキシ−３−ニトロフェニル］−３，３−ジクロロアクリル酸エチル（５．４９ｇ，１４．０ｍｍｏｌ）の１，４−ジオキサン（２８ｍＬ）溶液にヘキサヒドロピリダジン二臭化水素塩（３．８２ｇ，１５．４ｍｍｏｌ）およびトリエチルアミン（６．３ｍＬ，４６．２ｍｍｏｌ）を室温で加えた後、加熱還流しながら６時間撹拌した。反応終了後、反応液に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）で精製することにより、２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−２−ニトロフェニルオキシ］酢酸エチルの黄色固体（４．９４ｇ，収率：８９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．２９（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．８７−１．９４（ｍ，２Ｈ），１．９９−２．０６（ｍ，２Ｈ），３．５９−３．６３（ｍ，２Ｈ），３．８１−３．８５（ｍ，２Ｈ），４．２７（ｑ，Ｊ＝７．２Ｈｚ，２Ｈ），４．７８（ｓ，２Ｈ），７．０２（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），８．１６（ｄｄ，Ｊ＝８．８Ｈｚ，２．２Ｈｚ，１Ｈ），８．３９（ｄ，Ｊ＝２．２Ｈｚ，１Ｈ）．Reference Example-24

Diethyl hexahydropyridazine was added to a solution of ethyl 2- [4- (ethoxycarbonyl) methoxy-3-nitrophenyl] -3,3-dichloroacrylate (5.49 g, 14.0 mmol) in 1,4-dioxane (28 mL). Hydrogen fluoride salt (3.82 g, 15.4 mmol) and triethylamine (6.3 mL, 46.2 mmol) were added at room temperature, followed by stirring for 6 hours while heating under reflux. After completion of the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 2- [4- (5-chloro-3-oxo-1,2-tetramethylene-4- A yellow solid (4.94 g, yield: 89%) of ethyl pyrazolin-4-yl) -2-nitrophenyloxy] acetate was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.29 (t, J = 7.2 Hz, 3H), 1.87-1.94 (m, 2H), 1.99-2.06 (m, 2H) ), 3.59-3.63 (m, 2H), 3.81-3.85 (m, 2H), 4.27 (q, J = 7.2 Hz, 2H), 4.78 (s, 2H) ), 7.02 (d, J = 8.8 Hz, 1H), 8.16 (dd, J = 8.8 Hz, 2.2 Hz, 1H), 8.39 (d, J = 2.2 Hz, 1H) .

２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−２−ニトロフェニルオキシ］酢酸エチル（１．２０ｇ，３．０３ｍｍｏｌ）の酢酸エチル（６ｍＬ）溶液に、酢酸（３ｍＬ）および水（０．６ｍＬ）を加えた後、氷冷下で還元鉄（０．８５ｇ，１５．２ｍｍｏｌ）を加え、８０℃で３時間撹拌した。反応終了後、反応液を室温まで冷却し、不溶物をろ別後、ろ液を水（５０ｍＬ×２）、飽和炭酸水素ナトリウム水溶液（５０ｍＬ×３）で洗浄し、有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮することによって５−クロロ−４−（２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（０．５８ｇ，収率：６０％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８７−１．９４（ｍ，２Ｈ），１．９８−２．０５（ｍ，２Ｈ），３．５５−３．６０（ｍ，２Ｈ），３．８６−３．９０（ｍ，２Ｈ），４．５６（ｓ，２Ｈ），６．９６（ｄ，Ｊ＝８．５Ｈｚ，１Ｈ），７．３４（ｄｄ，Ｊ＝８．５ ａｎｄ ２．０Ｈｚ，１Ｈ），７．６３（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ），８．９４（ｓ，１Ｈ）．Example-47

Ethyl acetate of ethyl 2- [4- (5-chloro-3-oxo-1,2-tetramethylene-4-pyrazolin-4-yl) -2-nitrophenyloxy] acetate (1.20 g, 3.03 mmol) (6 mL) To the solution, acetic acid (3 mL) and water (0.6 mL) were added, and then reduced iron (0.85 g, 15.2 mmol) was added under ice cooling, followed by stirring at 80 ° C. for 3 hours. After completion of the reaction, the reaction solution is cooled to room temperature, insolubles are filtered off, and the filtrate is washed with water (50 mL × 2) and saturated aqueous sodium hydrogen carbonate solution (50 mL × 3), and the organic layer is washed with anhydrous magnesium sulfate. After drying, it is concentrated under reduced pressure to give 5-chloro-4- (2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin- A 3-one white solid (0.58 g, yield: 60%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.87-1.94 (m, 2H), 1.98-2.05 (m, 2H), 3.55-3.60 (m, 2H), 3.86-3.90 (m, 2H), 4.56 (s, 2H), 6.96 (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 8.5 and 2 .0Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 8.94 (s, 1H).

水素化ナトリウムの５５％油分散（０．０４５ｇ，１．０３ｍｍｏｌ）のＤＭＦ（２．４ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．９４ｍｍｏｌ）および１−ヨード−２−メチルプロパン（０．１２ｍＬ，１．０３ｍｍｏｌ）を順次加え、室温で２４時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×２）で抽出した。有機層を水（５０ｍＬ×４）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）で精製することにより、５−クロロ−４−［２，３−ジヒドロ−４−イソブチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（０．２３ｇ，収率：６６％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ０．９５−０．９８（ｍ，６Ｈ），１．８６−１．９３（ｍ，２Ｈ），１．９８−２．０６（ｍ，２Ｈ），２．１８（ｍ，１Ｈ），３．５５−３．６０（ｍ，２Ｈ），３．８１−３．８６（ｍ，４Ｈ），４．６１（ｓ，２Ｈ），７．０１（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．４５（ｄｄ，Ｊ＝８．４ ａｎｄ １．９Ｈｚ，１Ｈ），７．６７（ｄ，Ｊ＝１．９Ｈｚ，１Ｈ）．Example-48

To a suspension of sodium hydride in 55% oil dispersion (0.045 g, 1.03 mmol) in DMF (2.4 mL) under ice-cooling, 5-chloro-4- (2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (0.30 g, 0.94 mmol) and 1-iodo-2-methylpropane (0.12 mL) , 1.03 mmol) was added sequentially, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic layer was washed with water (50 mL × 4), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 5-chloro-4- [2,3-dihydro-4-isobutyl-3-oxo-4H- A white solid (0.23 g, yield: 66%) of 1,4-benzoxazin-6-yl] -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.95-0.98 (m, 6H), 1.86-1.93 (m, 2H), 1.98-2.06 (m, 2H), 2.18 (m, 1H), 3.55-3.60 (m, 2H), 3.81-3.86 (m, 4H), 4.61 (s, 2H), 7.01 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 8.4 and 1.9 Hz, 1H), 7.67 (d, J = 1.9 Hz, 1H).

水素化ナトリウムの５５％油分散（０．０４５ｇ，１．０３ｍｍｏｌ）のＤＭＦ（２．４ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．９４ｍｍｏｌ）およびアリルブロミド（０．０８７ｍＬ，１．０３ｍｍｏｌ）を順次加え、室温で２０時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×２）で抽出した。有機層を水（３０ｍＬ×４）、飽和食塩水（１０ｍＬ×１）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）で精製することにより、４−（４−アリル−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（０．２５ｇ，収率：７４％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８５−１．９２（ｍ，２Ｈ），１．９８−２．０５（ｍ，２Ｈ），３．５４−３．５８（ｍ，２Ｈ），３．８０−３．８５（ｍ，２Ｈ），４．５８−４．６１（ｍ，２Ｈ），４．６５（ｓ，２Ｈ），５．２５（ｍ，１Ｈ），５．２８（ｍ，１Ｈ），５．９２（ｍ，１Ｈ），７．０１（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．４８（ｄｄ，Ｊ＝８．４ ａｎｄ ２．０Ｈｚ，１Ｈ），７．６５（ｄ，Ｊ＝１．９Ｈｚ，１Ｈ）．Example-49

To a suspension of sodium hydride in 55% oil dispersion (0.045 g, 1.03 mmol) in DMF (2.4 mL) under ice-cooling, 5-chloro-4- (2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (0.30 g, 0.94 mmol) and allyl bromide (0.087 mL, 1.03 mmol). Sequentially added and stirred at room temperature for 20 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic layer was washed with water (30 mL × 4) and saturated brine (10 mL × 1), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 4- (4-allyl-2,3-dihydro-3-oxo-4H-1,4- A white solid (0.25 g, yield: 74%) of benzoxazin-6-yl) -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.85-1.92 (m, 2H), 1.98-2.05 (m, 2H), 3.54-3.58 (m, 2H), 3.80-3.85 (m, 2H), 4.58-4.61 (m, 2H), 4.65 (s, 2H), 5.25 (m, 1H), 5.28 (m, 1H), 5.92 (m, 1H), 7.01 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 8.4 and 2.0 Hz, 1H), 7.65 ( d, J = 1.9 Hz, 1H).

水素化ナトリウムの５５％油分散（０．０４５ｇ，１．０３ｍｍｏｌ）のＤＭＦ（２．４ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．９４ｍｍｏｌ）およびプロパルギルブロミド（０．０８２ｍＬ，１．０３ｍｍｏｌ）を順次加え、室温で１８時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、クロロホルム（１００ｍＬ×２）で抽出した。有機層を水（５０ｍＬ×４）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をヘキサンで洗浄することにより、５−クロロ−４−（２，３−ジヒドロ−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（０．２８ｇ，収率：８２％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８６−１．９３（ｍ，２Ｈ），１．９８−２．０６（ｍ，２Ｈ），２．２７（ｔ，Ｊ＝２．５Ｈｚ，１Ｈ），３．５６−３．６０（ｍ，２Ｈ），３．８２−３．８６（ｍ，２Ｈ），４．６５（ｓ，２Ｈ），４．７４（ｄ，Ｊ＝２．５Ｈｚ，２Ｈ），７．０３（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．５２（ｄｄ，Ｊ＝８．４ ａｎｄ １．９Ｈｚ，１Ｈ），７．７８（ｄ，Ｊ＝１．９Ｈｚ，１Ｈ）．Example-50

To a suspension of sodium hydride in 55% oil dispersion (0.045 g, 1.03 mmol) in DMF (2.4 mL) under ice-cooling, 5-chloro-4- (2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (0.30 g, 0.94 mmol) and propargyl bromide (0.082 mL, 1.03 mmol). Sequentially added and stirred at room temperature for 18 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with chloroform (100 mL × 2). The organic layer was washed with water (50 mL × 4), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was washed with hexane to give 5-chloro-4- (2,3-dihydro-3-oxo-4-propargyl-4H-1,4-benzoxazin-6-yl) -1 , 2-tetramethylene-4-pyrazolin-3-one was obtained as a white solid (0.28 g, yield: 82%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.86-1.93 (m, 2H), 1.98-2.06 (m, 2H), 2.27 (t, J = 2.5 Hz, 1H ), 3.56-3.60 (m, 2H), 3.82-3.86 (m, 2H), 4.65 (s, 2H), 4.74 (d, J = 2.5 Hz, 2H) ), 7.03 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 8.4 and 1.9 Hz, 1H), 7.78 (d, J = 1.9 Hz, 1H) .

水素化ナトリウムの５５％油分散（０．０４５ｇ，１．０３ｍｍｏｌ）のＤＭＦ（２．４ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．９４ｍｍｏｌ）および１−ブロモ−２−ブチン（０．０９７ｍＬ，１．０３ｍｍｏｌ）を順次加え、室温で１８時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、４−［４−（２−ブチニル）−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（０．２８ｇ，収率：８０％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．７９（ｔ，Ｊ＝２．４Ｈｚ，３Ｈ），１．８６−１．９３（ｍ，２Ｈ），１．９９−２．０６（ｍ，２Ｈ），３．５６−３．６０（ｍ，２Ｈ），３．８２−３．８６（ｍ，２Ｈ），４．６４（ｓ，２Ｈ），４．６６（ｑ，Ｊ＝２．４Ｈｚ，２Ｈ），７．０２（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．５２（ｄｄ，Ｊ＝８．４ ａｎｄ ２．０Ｈｚ，１Ｈ），７．７２（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ）．Example-51

To a suspension of sodium hydride in 55% oil dispersion (0.045 g, 1.03 mmol) in DMF (2.4 mL) under ice-cooling, 5-chloro-4- (2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (0.30 g, 0.94 mmol) and 1-bromo-2-butyne (0.097 mL, 1.03 mmol) was sequentially added and stirred at room temperature for 18 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with water (50 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 4- [4- (2-butynyl) -2,3-dihydro-3-oxo-4H-1 , 4-Benzoxazin-6-yl] -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one was obtained as a white solid (0.28 g, yield: 80%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.79 (t, J = 2.4 Hz, 3H), 1.86-1.93 (m, 2H), 1.99-2.06 (m, 2H) ), 3.56-3.60 (m, 2H), 3.82-3.86 (m, 2H), 4.64 (s, 2H), 4.66 (q, J = 2.4 Hz, 2H) ), 7.02 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 8.4 and 2.0 Hz, 1H), 7.72 (d, J = 2.0 Hz, 1H) .

水素化ナトリウムの５５％油分散（０．０９０ｇ，２．０６ｍｍｏｌ）のＤＭＦ（２．４ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．９４ｍｍｏｌ）および２−（クロロメチル）ピリジン塩酸塩（０．１７ｇ，１．０３ｍｍｏｌ）を順次加え、室温で２０時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×２）で抽出した。有機層を水（５０ｍＬ×４）、飽和食塩水（１０ｍＬ×１）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）で精製することにより、５−クロロ−４−［２，３−ジヒドロ−３−オキソ−４−（２−ピリジルメチル）−４Ｈ−１，４−ベンゾオキサジン−６−イル］−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（０．２４ｇ，収率：６２％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８２−１．８８（ｍ，２Ｈ），１．９４−２．０１（ｍ，２Ｈ），３．４０−３．６０（ｍ，２Ｈ），３．７６−３．８０（ｍ，２Ｈ），４．７５（ｓ，２Ｈ），５．３０（ｓ，２Ｈ），７．０４（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．１７（ｄｄｄ，Ｊ＝７．７，４．９ ａｎｄ １．０Ｈｚ，１Ｈ），７．２３（ｄｄｄ，Ｊ＝７．７，１．０ ａｎｄ ０．９Ｈｚ，１Ｈ），７．４１（ｄ，Ｊ＝１．９Ｈｚ，１Ｈ），７．５３（ｄｄ，Ｊ＝８．４ ａｎｄ １．９Ｈｚ，１Ｈ），７．６２（ｄｄｄ，Ｊ＝７．７，７．７ ａｎｄ １．８Ｈｚ，１Ｈ），８．５７（ｄｄｄ，Ｊ＝４．９，１．８ ａｎｄ ０．９Ｈｚ，１Ｈ）．Example-52

To a suspension of sodium hydride in 55% oil dispersion (0.090 g, 2.06 mmol) in DMF (2.4 mL) under ice-cooling, 5-chloro-4- (2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (0.30 g, 0.94 mmol) and 2- (chloromethyl) pyridine hydrochloride (0. 17 g, 1.03 mmol) was sequentially added, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic layer was washed with water (50 mL × 4) and saturated brine (10 mL × 1), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 5-chloro-4- [2,3-dihydro-3-oxo-4- (2-pyridyl). A white solid (0.24 g, yield: 62%) of (methyl) -4H-1,4-benzoxazin-6-yl] -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.82-1.88 (m, 2H), 1.94-2.01 (m, 2H), 3.40-3.60 (m, 2H), 3.76-3.80 (m, 2H), 4.75 (s, 2H), 5.30 (s, 2H), 7.04 (d, J = 8.4 Hz, 1H), 7.17 ( ddd, J = 7.7, 4.9 and 1.0 Hz, 1H), 7.23 (ddd, J = 7.7, 1.0 and 0.9 Hz, 1H), 7.41 (d, J = 1.9 Hz, 1H), 7.53 (dd, J = 8.4 and 1.9 Hz, 1H), 7.62 (ddd, J = 7.7, 7.7 and 1.8 Hz, 1H), 8 .57 (ddd, J = 4.9, 1.8 and 0.9 Hz, 1H).

水素化ナトリウムの５５％油分散（０．４３ｇ，９．８５ｍｍｏｌ）の１，４−ジオキサン（３８ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（２，４−ジフルオロ−５−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（２．５０ｇ，９．５８ｍｍｏｌ）を加え、Ｌ−（−）−乳酸メチル（１．１０ｍＬ，１１．４ｍｍｏｌ）を滴下し、室温で５時間撹拌した。反応終了後、反応液を氷水（１５０ｇ）に注ぎ入れ、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた粗生成物を酢酸エチルに溶かし、ヘキサンを加えて析出した固体をろ取することにより、（Ｓ）−２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］プロピオン酸メチルの白色固体（１．６２ｇ，収率：５２％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．７１（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．８８−１．９５（ｍ，２Ｈ），１．９８−２．０６（ｍ，２Ｈ），３．６１−３．６６（ｍ，２Ｈ），３．８１−３．８５（ｍ，２Ｈ），３．８１（ｓ，３Ｈ），４．８２（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），６．７２（ｄ，Ｊ＝１０．９Ｈｚ，１Ｈ），８．１１（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−９８．８（ｓ，１Ｆ）．Reference Example-25

To a suspension of sodium hydride in 55% oil dispersion (0.43 g, 9.85 mmol) in 1,4-dioxane (38 mL) under ice-cooling, 5-chloro-4- (2,4-difluoro-5- Nitrophenyl) -1,2-tetramethylene-4-pyrazolin-3-one (2.50 g, 9.58 mmol) was added, and L-(−)-methyl lactate (1.10 mL, 11.4 mmol) was added dropwise. And stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution was poured into ice water (150 g) and extracted with ethyl acetate (50 mL × 3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was dissolved in ethyl acetate, hexane was added, and the precipitated solid was collected by filtration to give (S) -2- [4- (5-chloro-3-oxo-1,2-tetramethylene). A white solid (1.62 g, yield: 52%) of methyl-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] propionate was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.71 (d, J = 6.8 Hz, 3H), 1.88-1.95 (m, 2H), 1.98-2.06 (m, 2H) ), 3.61-3.66 (m, 2H), 3.81-3.85 (m, 2H), 3.81 (s, 3H), 4.82 (q, J = 6.8 Hz, 1H) ), 6.72 (d, J = 10.9 Hz, 1H), 8.11 (d, J = 7.3 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-98.8 (s, 1F).

（Ｓ）−２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］プロピオン酸メチル（１．４０ｇ，３．３８ｍｍｏｌ）の酢酸エチル（６．８ｍＬ）溶液に、酢酸（３．４ｍＬ）および水（０．６ｍＬ）を加えた後、氷冷下で還元鉄（０．９４ｇ，１６．９ｍｍｏｌ）を加え、８０℃で３時間撹拌した。反応終了後、反応液を室温まで冷却し、酢酸エチル：酢酸＝１：１の混合溶媒を加えた後、不溶物をろ別した。ろ液に水（１００ｍＬ）を加えてクロロホルム（１００ｍＬ×３）で抽出した。有機層を水（１００ｍＬ×１）、飽和炭酸水素ナトリウム水溶液（５０ｍＬ×３）で洗浄し、無水硫酸ナトリウムで乾燥後、減圧濃縮することにより、（Ｓ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（１．１０ｇ，収率：９２％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５５（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．８７−１．９４（ｍ，２Ｈ），１．９８−２．０５（ｍ，２Ｈ），３．５９−３．６４（ｍ，２Ｈ），３．８３−３．８８（ｍ，２Ｈ），４．６１（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），６．７５（ｄ，Ｊ＝１０．１Ｈｚ，１Ｈ），７．０６（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ），８．５８（ｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．６（ｓ，１Ｆ）．Example-53

(S) -2- [4- (5-Chloro-3-oxo-1,2-tetramethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] propionate methyl (1. Acetic acid (3.4 mL) and water (0.6 mL) were added to a solution of 40 g, 3.38 mmol) in ethyl acetate (6.8 mL), and then reduced iron (0.94 g, 16.9 mmol) was added under ice cooling. And stirred at 80 ° C. for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature, a mixed solvent of ethyl acetate: acetic acid = 1: 1 was added, and insoluble matters were filtered off. Water (100 mL) was added to the filtrate and extracted with chloroform (100 mL × 3). The organic layer was washed with water (100 mL × 1) and saturated aqueous sodium hydrogen carbonate solution (50 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (S) -5-chloro-4- (7- Fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one as a white solid (1. 10 g, yield: 92%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.55 (d, J = 6.8 Hz, 3H), 1.87-1.94 (m, 2H), 1.98-2.05 (m, 2H) ), 3.59-3.64 (m, 2H), 3.83-3.88 (m, 2H), 4.61 (q, J = 6.8 Hz, 1H), 6.75 (d, J = 10.1 Hz, 1 H), 7.06 (d, J = 6.8 Hz, 1 H), 8.58 (s, 1 H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.6 (s, 1F).

（Ｓ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（１８３ｍｇ，０．５２ｍｍｏｌ）のアセトン（１０ｍＬ）溶液に炭酸カリウム（１０８ｍｇ，０．７８ｍｍｏｌ）および（ブロモメチル）シクロプロパン（１４４ｍｇ，０．７８ｍｍｏｌ）を順次加え、５０℃で２４時間撹拌した。反応終了後、反応液へ水（１０ｍＬ）を加え、酢酸エチル（１５ｍＬ×３）で抽出した。有機層を水（２０ｍＬ×２）で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９５／５）で精製することにより、（Ｓ）−５−クロロ−４−（４−シクロプロピルメチル−７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（７２ｍｇ，収率：３４％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ０．３５−０．５５（ｍ，４Ｈ），１．１４−１．２９（ｍ，１Ｈ），１．５６（ｄ，Ｊ＝６．７Ｈｚ，３Ｈ），１．８７−１．９６（ｍ，２Ｈ），１．９８−２．０８（ｍ，２Ｈ），３．５８−３．６６（ｍ，２Ｈ），３．８３（ｄ，Ｊ＝７．１Ｈｚ，２Ｈ），３．８３−３．８７（ｍ，２Ｈ），４．６６（ｑ，Ｊ＝６．７Ｈｚ，１Ｈ），６．８０（ｄ，Ｊ＝１０．０Ｈｚ，１Ｈ），７．２６（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．９（ｓ，１Ｆ）．Example-54

(S) -5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene- To a solution of 4-pyrazolin-3-one (183 mg, 0.52 mmol) in acetone (10 mL), potassium carbonate (108 mg, 0.78 mmol) and (bromomethyl) cyclopropane (144 mg, 0.78 mmol) were added sequentially, Stir for 24 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic layer was washed with water (20 mL × 2), dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 95/5) to give (S) -5-chloro-4- (4-cyclopropylmethyl-7-fluoro-2, White solid (72 mg, yield: 34) of 3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one %). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.35-0.55 (m, 4H), 1.14-1.29 (m, 1H), 1.56 (d, J = 6.7 Hz, 3H ), 1.87-1.96 (m, 2H), 1.98-2.08 (m, 2H), 3.58-3.66 (m, 2H), 3.83 (d, J = 7) .1 Hz, 2H), 3.83-3.87 (m, 2H), 4.66 (q, J = 6.7 Hz, 1H), 6.80 (d, J = 10.0 Hz, 1H), 7 .26 (d, J = 6.7 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.9 (s, 1F).

（Ｓ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（１８３ｍｇ，０．５２ｍｍｏｌ）のアセトン（１０ｍＬ）溶液に炭酸カリウム（１０８ｍｇ，０．７８ｍｍｏｌ）およびブロモ酢酸メチル（１２２ｍｇ，０．７８ｍｍｏｌ）を順次加え、５０℃で２４時間撹拌した。反応終了後、反応液へ水（１０ｍＬ）を加え、酢酸エチル（１５ｍＬ×３）で抽出した。有機層を水（２０ｍＬ×２）で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９５／５）で精製することにより、２−［（Ｓ）−６−（５−クロロ−１，２−テトラメチレン−３−オキソピラゾリン−４−イル）−７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−４−イル］酢酸メチルの白色固体（１７３ｍｇ，収率：７８％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．６０（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．８６−１．９４（ｍ，２Ｈ），１．９８−２．０６（ｍ，２Ｈ），３．５８−３．６４（ｍ，２Ｈ），３．７７（ｓ，３Ｈ），３．８０−３．８５（ｍ，２Ｈ），４．６１（ｄｄ，Ｊ＝１７．５Ｈｚ，１Ｈ），４．７０（ｑ，Ｊ＝１７．５Ｈｚ，１Ｈ），４．７３（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），６．８３（ｄ，Ｊ＝９．８Ｈｚ，１Ｈ），６．９０（ｄ，Ｊ＝６．５Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．１（ｓ，１Ｆ）．Example-55

(S) -5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene- To a solution of 4-pyrazolin-3-one (183 mg, 0.52 mmol) in acetone (10 mL), potassium carbonate (108 mg, 0.78 mmol) and methyl bromoacetate (122 mg, 0.78 mmol) were sequentially added, and the mixture was stirred at 50 ° C. for 24 hours. Stir. After completion of the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic layer was washed with water (20 mL × 2), dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 95/5) to give 2-[(S) -6- (5-chloro-1,2-tetramethylene-3- Oxopyrazolin-4-yl) -7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-4-yl] methyl acetate white solid (173 mg, yield: 78 %). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.60 (d, J = 6.8 Hz, 3H), 1.86-1.94 (m, 2H), 1.98-2.06 (m, 2H) ), 3.58-3.64 (m, 2H), 3.77 (s, 3H), 3.80-3.85 (m, 2H), 4.61 (dd, J = 17.5 Hz, 1H) ), 4.70 (q, J = 17.5 Hz, 1H), 4.73 (q, J = 6.8 Hz, 1H), 6.83 (d, J = 9.8 Hz, 1H), 6.90. (D, J = 6.5 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.1 (s, 1F).

（Ｓ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（１８３ｍｇ，０．５２ｍｍｏｌ）のアセトン（５ｍＬ）溶液に炭酸カリウム（１０８ｍｇ，０．７８ｍｍｏｌ）およびブロモ酢酸エチル（１３７ｍｇ，０．７８ｍｍｏｌ）を順次加え、５０℃で２０時間撹拌した。反応終了後、反応液へ水（１０ｍＬ）を加え、酢酸エチル（１５ｍＬ×３）で抽出した。有機層を水（２０ｍＬ×２）で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９５／５）で精製することにより、２−［（Ｓ）−６−（５−クロロ−１，２−テトラメチレン−３−オキソピラゾリン−４−イル）−７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−４−イル］酢酸エチルの白色固体（２１０ｍｇ，収率：９２％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．２６（ｄ，Ｊ＝７．２Ｈｚ，３Ｈ），１．５９（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．８５−１．９４（ｍ，２Ｈ），１．９７−２．０４（ｍ，２Ｈ），３．５７−３．６３（ｍ，２Ｈ），３．８０−３．８５（ｍ，２Ｈ），４．２２（ｑ，Ｊ＝７．２Ｈｚ，２Ｈ），４．６１（ｄ，Ｊ＝１７．６Ｈｚ，１Ｈ），４．６６（ｄ，Ｊ＝１７．６Ｈｚ，２Ｈ），４．７３（ｑ，Ｊ＝６．８Ｈｚ，２Ｈ），６．８２（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），６．９０（ｄ，Ｊ＝６．５Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．２（ｓ，１Ｆ）．Example-56

(S) -5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene- To a solution of 4-pyrazolin-3-one (183 mg, 0.52 mmol) in acetone (5 mL) were sequentially added potassium carbonate (108 mg, 0.78 mmol) and ethyl bromoacetate (137 mg, 0.78 mmol), and then at 50 ° C. for 20 hours. Stir. After completion of the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic layer was washed with water (20 mL × 2), dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 95/5) to give 2-[(S) -6- (5-chloro-1,2-tetramethylene-3- Oxopyrazolin-4-yl) -7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-4-yl] ethyl acetate white solid (210 mg, yield: 92 %). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.26 (d, J = 7.2 Hz, 3H), 1.59 (d, J = 6.8 Hz, 3H), 1.85-1.94 (m , 2H), 1.97-2.04 (m, 2H), 3.57-3.63 (m, 2H), 3.80-3.85 (m, 2H), 4.22 (q, J = 7.2 Hz, 2H), 4.61 (d, J = 17.6 Hz, 1H), 4.66 (d, J = 17.6 Hz, 2H), 4.73 (q, J = 6.8 Hz, 2H), 6.82 (d, J = 9.9 Hz, 1H), 6.90 (d, J = 6.5 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.2 (s, 1F).

（Ｓ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（１８３ｍｇ，０．５２ｍｍｏｌ）のアセトン（１０ｍＬ）溶液に炭酸カリウム（１０８ｍｇ，０．７８ｍｍｏｌ）および２−ブロモプロピオン酸メチル（１３４ｍｇ，０．７８ｍｍｏｌ）を順次加え、５０℃で２４時間撹拌した。反応終了後、反応液へ水（１０ｍＬ）を加え、酢酸エチル（１５ｍＬ×３）で抽出した。有機層を水（２０ｍＬ×２）で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９５／５）で精製することにより、２−［（Ｓ）−６−（５−クロロ−１，２−テトラメチレン−３−オキソピラゾリン−４−イル）−７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−４−イル］プロピオン酸メチルの白色固体（１０４ｍｇ，収率：４６％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５２（ｄ，Ｊ＝６．８Ｈｚ，１．５Ｈ），１．６１（ｄ，Ｊ＝６．８Ｈｚ，１．５Ｈ），１．６４（ｄ，Ｊ＝７．２Ｈｚ，３Ｈ），１．８６−１．９４（ｍ，２Ｈ），１．９８−２．０５（ｍ，２Ｈ），３．５８−３．６６（ｍ，２Ｈ），３．７４（ｄ，Ｊ＝３．６Ｈｚ，１Ｈ），３．８０−３．８５（ｍ，２Ｈ），４．５８（ｑ，Ｊ＝６．８Ｈｚ，０．５Ｈ），４．７１（ｑ，Ｊ＝６．８Ｈｚ，０．５Ｈ），５．２５（ｑ，Ｊ＝７．２Ｈｚ，０．５Ｈ），５．２６（ｑ，Ｊ＝７．２Ｈｚ，０．５Ｈ），６．８３（ｄ，Ｊ＝９．８Ｈｚ，０．５Ｈ），６．８４（ｄ，Ｊ＝９．８Ｈｚ，０．５Ｈ），６．９７（ｄ，Ｊ＝６．９Ｈｚ，０．５Ｈ），６．９９（ｄ，Ｊ＝６．９Ｈｚ，０．５Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１４．９３（ｓ，０．５Ｆ），−１１４．９２（ｓ，０．５Ｆ）．Example-57

(S) -5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene- To a solution of 4-pyrazolin-3-one (183 mg, 0.52 mmol) in acetone (10 mL), potassium carbonate (108 mg, 0.78 mmol) and methyl 2-bromopropionate (134 mg, 0.78 mmol) were added successively, For 24 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic layer was washed with water (20 mL × 2), dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 95/5) to give 2-[(S) -6- (5-chloro-1,2-tetramethylene-3- Oxopyrazolin-4-yl) -7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-4-yl] methyl propionate white solid (104 mg, yield: 46%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.52 (d, J = 6.8 Hz, 1.5H), 1.61 (d, J = 6.8 Hz, 1.5H), 1.64 (d , J = 7.2 Hz, 3H), 1.86-1.94 (m, 2H), 1.98-2.05 (m, 2H), 3.58-3.66 (m, 2H), 3 .74 (d, J = 3.6 Hz, 1H), 3.80-3.85 (m, 2H), 4.58 (q, J = 6.8 Hz, 0.5H), 4.71 (q, J = 6.8 Hz, 0.5H), 5.25 (q, J = 7.2 Hz, 0.5H), 5.26 (q, J = 7.2 Hz, 0.5H), 6.83 (d , J = 9.8 Hz, 0.5H), 6.84 (d, J = 9.8 Hz, 0.5H), 6.97 (d, J = 6.9 Hz, 0.5H), 6.99 ( d, J = 6.9 Hz, 0.5H . ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.93 (s, 0.5F), -114.92 (s, 0.5F).

（Ｓ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（１８３ｍｇ，０．５２ｍｍｏｌ）のアセトン（５ｍＬ）溶液に炭酸カリウム（１０８ｍｇ，０．７８ｍｍｏｌ）および２−ブロモプロピオン酸エチル（１４４ｍｇ，０．７８ｍｍｏｌ）を順次加え、５０℃で２０時間撹拌した。反応終了後、反応液へ水（１０ｍＬ）を加え、酢酸エチル（１５ｍＬ×３）で抽出した。有機層を水（２０ｍＬ×２）で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９５／５）で精製することにより、２−［（Ｓ）−６−（５−クロロ−１，２−テトラメチレン−３−オキソピラゾリン−４−イル）−７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−４−イル］プロピオン酸エチルの白色固体（１０７ｍｇ，収率：４５％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．１８（ｔ，Ｊ＝７．１Ｈｚ，１．５Ｈ），１．２０（ｔ，Ｊ＝７．１Ｈｚ，１．５Ｈ），１．５２（ｄ，Ｊ＝６．８Ｈｚ，１．５Ｈ），１．６０（ｄ，Ｊ＝６．８Ｈｚ，１．５Ｈ），１．６４（ｄ，Ｊ＝７．１Ｈｚ，１．５Ｈ），１．６４２（ｄ，Ｊ＝７．１Ｈｚ，１．５Ｈ），１．８６−１．９５（ｍ，２Ｈ），１．９８−２．０５（ｍ，２Ｈ），３．５８−３．６５（ｍ，２Ｈ），３．８０−３．８７（ｍ，２Ｈ），４．２０（ｍ，２Ｈ），４．５８（ｑ，Ｊ＝６．８Ｈｚ，０．５Ｈ），４．７１（ｑ，Ｊ＝６．８Ｈｚ，０．５Ｈ），５．１４（ｑ，Ｊ＝７．１Ｈｚ，０．５Ｈ），５．２６（ｑ，Ｊ＝７．１Ｈｚ，０．５Ｈ），６．８３（ｄ，Ｊ＝９．８Ｈｚ，０．５Ｈ），６．８４（ｄ，Ｊ＝９．８Ｈｚ，０．５Ｈ），６．８４（ｄ，Ｊ＝９．８Ｈｚ，０．５Ｈ），６．９９（ｄ，Ｊ＝６．４Ｈｚ，０．５Ｈ），７．００（ｄ，Ｊ＝６．４Ｈｚ，０．５Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．１（ｓ，０．５Ｆ），−１１５．０（ｓ，０．５Ｆ）．Example-58

(S) -5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene- To a solution of 4-pyrazolin-3-one (183 mg, 0.52 mmol) in acetone (5 mL) were added potassium carbonate (108 mg, 0.78 mmol) and ethyl 2-bromopropionate (144 mg, 0.78 mmol) successively, and 50 ° C. For 20 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic layer was washed with water (20 mL × 2), dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 95/5) to give 2-[(S) -6- (5-chloro-1,2-tetramethylene-3- Oxopyrazolin-4-yl) -7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-4-yl] ethyl propionate white solid (107 mg, yield: 45%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.18 (t, J = 7.1 Hz, 1.5H), 1.20 (t, J = 7.1 Hz, 1.5H), 1.52 (d , J = 6.8 Hz, 1.5H), 1.60 (d, J = 6.8 Hz, 1.5H), 1.64 (d, J = 7.1 Hz, 1.5H), 1.642 ( d, J = 7.1 Hz, 1.5H), 1.86-1.95 (m, 2H), 1.98-2.05 (m, 2H), 3.58-3.65 (m, 2H) ), 3.80-3.87 (m, 2H), 4.20 (m, 2H), 4.58 (q, J = 6.8 Hz, 0.5H), 4.71 (q, J = 6) .8 Hz, 0.5 H), 5.14 (q, J = 7.1 Hz, 0.5 H), 5.26 (q, J = 7.1 Hz, 0.5 H), 6.83 (d, J = 9.8 Hz, 0.5 H), 6.8 (D, J = 9.8 Hz, 0.5H), 6.84 (d, J = 9.8 Hz, 0.5H), 6.99 (d, J = 6.4 Hz, 0.5H), 7. 00 (d, J = 6.4 Hz, 0.5H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.1 (s, 0.5F), -115.0 (s, 0.5F).

（Ｓ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（１８３ｍｇ，０．５２ｍｍｏｌ）のアセトン（１０ｍＬ）溶液に炭酸カリウム（１０８ｍｇ，０．７８ｍｍｏｌ）および２−クロロ−２−エトキシ酢酸エチル（１４４ｍｇ，０．７８ｍｍｏｌ）を順次加え、５０℃で２０時間撹拌した。反応終了後、反応液へ水（１０ｍＬ）を加え、酢酸エチル（１５ｍＬ×３）で抽出した。有機層を水（２０ｍＬ×２）で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９５／５）で精製することにより、２−［（Ｓ）−６−（５−クロロ−１，２−テトラメチレン−３−オキソピラゾリン−４−イル）−７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−４−イル］−２−エトキシ酢酸エチルの白色固体（１５５ｍｇ，収率：６２％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．０４（ｔ，Ｊ＝７．１Ｈｚ，１．５Ｈ），１．１０（ｔ，Ｊ＝７．１Ｈｚ，１．５Ｈ），１．２７（ｔ，Ｊ＝７．１Ｈｚ，１．５Ｈ），１．２９（ｔ，Ｊ＝７．１Ｈｚ，１．５Ｈ），１．５５（ｄ，Ｊ＝６．８Ｈｚ，１．５Ｈ），１．６５（ｄ，Ｊ＝６．８Ｈｚ，１．５Ｈ），１．８５−１．９３（ｍ，２Ｈ），１．９６−２．０４（ｍ，２Ｈ），３．５２−３．８９（ｍ，６Ｈ），４．１５（ｍ，２Ｈ），４．６０（ｑ，Ｊ＝６．８Ｈｚ，０．５Ｈ），４．８１（ｑ，Ｊ＝６．８Ｈｚ，０．５Ｈ），６．５１（ｓ，０．５Ｈ），６．５３（ｓ，０．５Ｈ），６．８２（ｄ，Ｊ＝９．７Ｈｚ，０．５Ｈ），６．８２（ｄ，Ｊ＝９．７Ｈｚ，０．５Ｈ），６．８３（ｄ，Ｊ＝９．７Ｈｚ，０．５Ｈ），７．３４（ｄ，Ｊ＝６．８Ｈｚ，０．５Ｈ），７．３９（ｄ，Ｊ＝６．８Ｈｚ，０．５Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１４．３０（ｓ，０．５Ｆ），−１１４．２６（ｓ，０．５Ｆ）．Example-59

(S) -5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene- To a solution of 4-pyrazolin-3-one (183 mg, 0.52 mmol) in acetone (10 mL), potassium carbonate (108 mg, 0.78 mmol) and ethyl 2-chloro-2-ethoxyacetate (144 mg, 0.78 mmol) were sequentially added. And stirred at 50 ° C. for 20 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic layer was washed with water (20 mL × 2), dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 95/5) to give 2-[(S) -6- (5-chloro-1,2-tetramethylene-3- Oxopyrazolin-4-yl) -7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-4-yl] -2-ethoxyacetate white solid (155 mg, Yield: 62%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.04 (t, J = 7.1 Hz, 1.5H), 1.10 (t, J = 7.1 Hz, 1.5H), 1.27 (t , J = 7.1 Hz, 1.5H), 1.29 (t, J = 7.1 Hz, 1.5H), 1.55 (d, J = 6.8 Hz, 1.5H), 1.65 ( d, J = 6.8 Hz, 1.5H), 1.85-1.93 (m, 2H), 1.96-2.04 (m, 2H), 3.52-3.89 (m, 6H) ), 4.15 (m, 2H), 4.60 (q, J = 6.8 Hz, 0.5H), 4.81 (q, J = 6.8 Hz, 0.5H), 6.51 (s) , 0.5H), 6.53 (s, 0.5H), 6.82 (d, J = 9.7 Hz, 0.5H), 6.82 (d, J = 9.7 Hz, 0.5H) 6.83 (d, J = 9.7 Hz, .5H), 7.34 (d, J = 6.8Hz, 0.5H), 7.39 (d, J = 6.8Hz, 0.5H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.30 (s, 0.5 F), −114.26 (s, 0.5 F).

（Ｓ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（１８３ｍｇ，０．５２ｍｍｏｌ）のアセトン（１０ｍＬ）溶液に炭酸カリウム（１０８ｍｇ，０．７８ｍｍｏｌ）および２，３−ジクロロ−１−プロペン（１１０ｍｇ，０．７８ｍｍｏｌ）を順次加え、５０℃で２４時間撹拌した。反応終了後、反応液へ水（１０ｍＬ）を加え、酢酸エチル（１５ｍＬ×３）で抽出した。有機層を水（２０ｍＬ×２）で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９５／５）で精製することにより、（Ｓ）−５−クロロ−４−［４−（２−クロロアリル）−７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（５５ｍｇ，収率：２５％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．６０（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．８６−１．９５（ｍ，２Ｈ），１．９８−２．０６（ｍ，２Ｈ），３．５８−３．６５（ｍ，２Ｈ），３．８０−３．８６（ｍ，２Ｈ），４．６８（ｓ，２Ｈ），４．７１（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），５．２８（ｍ，１Ｈ），５．３９（ｍ，１Ｈ），６．８２（ｄ，Ｊ＝９．７Ｈｚ，１Ｈ），７．０８（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１４．７（ｓ，１Ｆ）．Example-60

(S) -5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene- To a solution of 4-pyrazolin-3-one (183 mg, 0.52 mmol) in acetone (10 mL), potassium carbonate (108 mg, 0.78 mmol) and 2,3-dichloro-1-propene (110 mg, 0.78 mmol) were sequentially added. And stirred at 50 ° C. for 24 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic layer was washed with water (20 mL × 2), dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 95/5) to give (S) -5-chloro-4- [4- (2-chloroallyl) -7-fluoro- 2,3-Dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl] -1,2-tetramethylene-4-pyrazolin-3-one as a white solid (55 mg, yield) : 25%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.60 (d, J = 6.8 Hz, 3H), 1.86-1.95 (m, 2H), 1.98-2.06 (m, 2H) ), 3.58-3.65 (m, 2H), 3.80-3.86 (m, 2H), 4.68 (s, 2H), 4.71 (q, J = 6.8 Hz, 1H) ), 5.28 (m, 1H), 5.39 (m, 1H), 6.82 (d, J = 9.7 Hz, 1H), 7.08 (d, J = 6.8 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.7 (s, 1F).

（Ｓ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（１８３ｍｇ，０．５２ｍｍｏｌ）のアセトン（１０ｍＬ）溶液に炭酸カリウム（１０８ｍｇ，０．７８ｍｍｏｌ）および３−ブロモ−２−メチル−１−プロペン（１０９ｍｇ，０．７８ｍｍｏｌ）を順次加え、５０℃で２４時間撹拌した。反応終了後、反応液へ水（１０ｍＬ）を加え、酢酸エチル（１５ｍＬ×３）で抽出した。有機層を水（２０ｍＬ×２）で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９５／５）で精製することにより、（Ｓ）−５−クロロ−４−［７−フルオロ−２，３−ジヒドロ−２−メチル−４−（２−メチルプロペニル）−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（１７８ｍｇ，収率：８４％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５８（ｄ，Ｊ＝６．９Ｈｚ，３Ｈ），１．７６（ｓ，３Ｈ），１．８５−１．９４（ｍ，２Ｈ），１．９７−２．０６（ｍ，２Ｈ），３．５７−３．６４（ｍ，２Ｈ），３．８０−３．８５（ｍ，２Ｈ），４．４４（ｂｒｓ，２Ｈ），４．７１（ｑ，Ｊ＝６．９Ｈｚ，１Ｈ），４．７８（ｍ，１Ｈ），４．９２（ｍ，１Ｈ），６．８０（ｄ，Ｊ＝９．８Ｈｚ，１Ｈ），７．０４（ｄ，Ｊ＝６．９Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．４（ｓ，１Ｆ）．Example-61

(S) -5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene- To a solution of 4-pyrazolin-3-one (183 mg, 0.52 mmol) in acetone (10 mL) was added potassium carbonate (108 mg, 0.78 mmol) and 3-bromo-2-methyl-1-propene (109 mg, 0.78 mmol). Sequentially added and stirred at 50 ° C. for 24 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic layer was washed with water (20 mL × 2), dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 95/5) to give (S) -5-chloro-4- [7-fluoro-2,3-dihydro-2- Methyl-4- (2-methylpropenyl) -3-oxo-4H-1,4-benzoxazin-6-yl] -1,2-tetramethylene-4-pyrazolin-3-one as a white solid (178 mg, yield) Rate: 84%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.58 (d, J = 6.9 Hz, 3H), 1.76 (s, 3H), 1.85-1.94 (m, 2H), 1. 97-2.06 (m, 2H), 3.57-3.64 (m, 2H), 3.80-3.85 (m, 2H), 4.44 (brs, 2H), 4.71 ( q, J = 6.9 Hz, 1H), 4.78 (m, 1H), 4.92 (m, 1H), 6.80 (d, J = 9.8 Hz, 1H), 7.04 (d, J = 6.9 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.4 (s, 1F).

（Ｓ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（１８３ｍｇ，０．５２ｍｍｏｌ）のＤＭＦ（１０ｍＬ）溶液に水素化ナトリウムの５５％油分散（２７ｍｇ，０．６２ｍｍｏｌ）および（Ｅ）−４−クロロ−３−メトキシ−２−ブテン酸メチル（１３５ｍｇ，０．７８ｍｍｏｌ）を順次加え、室温で２４時間撹拌した。反応終了後、反応液へ水（１０ｍＬ）を加え、酢酸エチル（１５ｍＬ×３）で抽出した。有機層を水（２０ｍＬ×２）で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９５／５）で精製することにより、（２Ｅ）−［（Ｓ）−６−（５−クロロ−１，２−テトラメチレン−３−オキソピラゾリン−４−イル）−７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−４−イル］−３−メトキシ−２−ブテン酸メチルの白色固体（１０７ｍｇ，収率：４３％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５７（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．８４−１．９４（ｍ，２Ｈ），１．９６−２．０５（ｍ，２Ｈ），３．５６−３．６２（ｍ，２Ｈ），３．６０（ｓ，３Ｈ），３．７２（ｓ，３Ｈ），３．７７−３．８４（ｍ，２Ｈ），４．７０（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），５．２２（ｍ，１Ｈ），５．３１（ｄｄ，Ｊ＝１７．２ ａｎｄ １．１Ｈｚ，１Ｈ），５．４０（ｄｄ，Ｊ＝１７．２ ａｎｄ ０．７Ｈｚ，１Ｈ），６．７９（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），６．９９（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．６（ｓ，１Ｆ）．Example-62

(S) -5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene- Sodium pyride 55% oil dispersion (27 mg, 0.62 mmol) and (E) -4-chloro-3-methoxy-2 in a solution of 4-pyrazolin-3-one (183 mg, 0.52 mmol) in DMF (10 mL) -Methyl butenoate (135 mg, 0.78 mmol) was sequentially added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic layer was washed with water (20 mL × 2), dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 95/5) to give (2E)-[(S) -6- (5-chloro-1,2-tetramethylene- 3-oxopyrazolin-4-yl) -7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-4-yl] -3-methoxy-2-butenoate methyl Of a white solid (107 mg, yield: 43%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.57 (d, J = 6.8 Hz, 3H), 1.84-1.94 (m, 2H), 1.96-2.05 (m, 2H) ), 3.56-3.62 (m, 2H), 3.60 (s, 3H), 3.72 (s, 3H), 3.77-3.84 (m, 2H), 4.70 ( q, J = 6.8 Hz, 1H), 5.22 (m, 1H), 5.31 (dd, J = 17.2 and 1.1 Hz, 1H), 5.40 (dd, J = 17.2) and 0.7 Hz, 1H), 6.79 (d, J = 9.9 Hz, 1H), 6.99 (d, J = 6.7 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.6 (s, 1F).

水素化ナトリウムの５５％オイルディスパージョン（０．０４１ｇ，０．９４ｍｍｏｌ）のＤＭＦ（２．５ｍＬ）懸濁液に、氷冷下で（Ｓ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８５ｍｍｏｌ）およびプロパルギルブロミド（０．０７４ｍＬ，０．９４ｍｍｏｌ）を順次加え、室温で２０時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、クロロホルム（３０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、（Ｓ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（０．２２ｇ，収率：６７％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５９（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．８７−１．９５（ｍ，２Ｈ），１．９８−２．０７（ｍ，２Ｈ），２．２５（ｔ，Ｊ＝２．５Ｈｚ，１Ｈ），３．６０−３．６５（ｍ，２Ｈ），３．８２−３．８７（ｍ，２Ｈ），４．６３（ｄｄ，Ｊ＝１７．６ ａｎｄ ２．５Ｈｚ，１Ｈ），４．６８（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），４．７５（ｄｄ，Ｊ＝１７．６ ａｎｄ ２．５Ｈｚ，１Ｈ），６．８２（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．２７（ｄ，Ｊ＝６．６Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．１（ｓ，１Ｆ）．Example-63

To a suspension of sodium hydride in 55% oil dispersion (0.041 g, 0.94 mmol) in DMF (2.5 mL) under ice-cooling (S) -5-chloro-4- (7-fluoro-2) , 3-Dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (0.30 g, 0.85 mmol) And propargyl bromide (0.074 mL, 0.94 mmol) were sequentially added, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with chloroform (30 mL × 3). The organic layer was washed with water (50 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give (S) -5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl). White solid (0.22 g, yield: 67%) of -3-oxo-4-propargyl-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one ) ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.59 (d, J = 6.8 Hz, 3H), 1.87-1.95 (m, 2H), 1.98-2.07 (m, 2H) ), 2.25 (t, J = 2.5 Hz, 1H), 3.60-3.65 (m, 2H), 3.82-3.87 (m, 2H), 4.63 (dd, J = 17.6 and 2.5 Hz, 1H), 4.68 (q, J = 6.8 Hz, 1H), 4.75 (dd, J = 17.6 and 2.5 Hz, 1H), 6.82 ( d, J = 9.9 Hz, 1H), 7.27 (d, J = 6.6 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.1 (s, 1F).

（Ｓ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（１８３ｍｇ，０．５２ｍｍｏｌ）のアセトン（１０ｍＬ）溶液に炭酸カリウム（１０８ｍｇ，０．７８ｍｍｏｌ）および２−クロロベンジルクロリド（１２８ｍｇ，０．７８ｍｍｏｌ）を順次加え、５０℃で２４時間撹拌した。反応終了後、反応液へ水（１０ｍＬ）を加え、酢酸エチル（１５ｍＬ×３）で抽出した。有機層を水（２０ｍＬ×２）で洗浄し、硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９５／５）で精製することにより、（Ｓ）−５−クロロ−４−［４−（４−クロロベンジル）−７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（１８１ｍｇ，収率：７３％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．６２（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．８４−１．９４（ｍ，２Ｈ），１．９６−２．０４（ｍ，２Ｈ），３．５５−３．６２（ｍ，２Ｈ），３．７７−３．８４（ｍ，２Ｈ），４．７５（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），５．０８（ｄ，Ｊ＝１９．２Ｈｚ，１Ｈ），５．１２（ｄ，Ｊ＝１９．２Ｈｚ，１Ｈ），６．８０（ｄ，Ｊ＝９．８Ｈｚ，１Ｈ），７．０３（ｄ，Ｊ＝６．６Ｈｚ，１Ｈ），７．２２（ｄ，Ｊ＝８．６Ｈｚ，２Ｈ），７．２８（ｄ，Ｊ＝８．６Ｈｚ，２Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１４．８（ｓ，１Ｆ）．Example-64

(S) -5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene- To a solution of 4-pyrazolin-3-one (183 mg, 0.52 mmol) in acetone (10 mL) were added potassium carbonate (108 mg, 0.78 mmol) and 2-chlorobenzyl chloride (128 mg, 0.78 mmol) sequentially, and at 50 ° C. Stir for 24 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic layer was washed with water (20 mL × 2), dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 95/5) to give (S) -5-chloro-4- [4- (4-chlorobenzyl) -7-fluoro. -2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl] -1,2-tetramethylene-4-pyrazolin-3-one (181 mg, yield) Rate: 73%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.62 (d, J = 6.8 Hz, 3H), 1.84-1.94 (m, 2H), 1.96-2.04 (m, 2H) ), 3.55-3.62 (m, 2H), 3.77-3.84 (m, 2H), 4.75 (q, J = 6.8 Hz, 1H), 5.08 (d, J = 19.2 Hz, 1H), 5.12 (d, J = 19.2 Hz, 1H), 6.80 (d, J = 9.8 Hz, 1H), 7.03 (d, J = 6.6 Hz, 1H), 7.22 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.8 (s, 1F).

水素化ナトリウムの５５％油分散（０．３６ｇ，８．３４ｍｍｏｌ）の１，４−ジオキサン（３８ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（２，４−ジフルオロ−５−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（２．５０ｇ，７．５８ｍｍｏｌ）を加え、Ｄ−（＋）−乳酸メチル（０．８８ｍＬ，９．１０ｍｍｏｌ）を滴下し、室温で４時間撹拌した。反応終了後、反応液を氷水（１５０ｇ）に注ぎ入れ、クロロホルム（１００ｍＬ×２）で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた粗生成物を酢酸エチルで洗浄することにより、（Ｒ）−２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］プロピオン酸メチルの黄色固体（０．８６ｇ，収率：２７％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．７２（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．８８−１．９５（ｍ，２Ｈ），１．９９−２．０６（ｍ，２Ｈ），３．６１−３．６６（ｍ，２Ｈ），３．８１（ｓ，３Ｈ），３．８１−３．８６（ｍ，２Ｈ），４．８２（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），６．７２（ｄ，Ｊ＝１０．９Ｈｚ，１Ｈ），８．１２（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−９８．８（ｓ，１Ｆ）．Reference Example-26

To a suspension of sodium hydride in 55% oil dispersion (0.36 g, 8.34 mmol) in 1,4-dioxane (38 mL) was added 5-chloro-4- (2,4-difluoro-5- 5 under ice cooling. Nitrophenyl) -1,2-tetramethylene-4-pyrazolin-3-one (2.50 g, 7.58 mmol) is added, and D-(+)-methyl lactate (0.88 mL, 9.10 mmol) is added dropwise. And stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was poured into ice water (150 g) and extracted with chloroform (100 mL × 2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was washed with ethyl acetate to give (R) -2- [4- (5-chloro-3-oxo-1,2-tetramethylene-4-pyrazolin-4-yl) -5. A yellow solid (0.86 g, yield: 27%) of methyl -fluoro-2-nitrophenyloxy] propionate was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.72 (d, J = 6.8 Hz, 3H), 1.88-1.95 (m, 2H), 1.99-2.06 (m, 2H) ), 3.61-3.66 (m, 2H), 3.81 (s, 3H), 3.81-3.86 (m, 2H), 4.82 (q, J = 6.8 Hz, 1H) ), 6.72 (d, J = 10.9 Hz, 1H), 8.12 (d, J = 7.4 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-98.8 (s, 1F).

（Ｒ）−２−［４−（５−クロロ−３−オキソ−１，２−テトラメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］プロピオン酸メチル（０．７０ｇ，１．６９ｍｍｏｌ）の酢酸エチル（３．４ｍＬ）溶液に、酢酸（１．７ｍＬ）および水（０．３ｍＬ）を加えた後、氷冷下で還元鉄（０．４７ｇ，８．４５ｍｍｏｌ）を加え、８０℃で３時間撹拌した。反応終了後、反応液を室温まで冷却し、不溶物をろ別した。ろ液を水（５０ｍＬ×２）、飽和炭酸水素ナトリウム水溶液（５０ｍＬ×２）で洗浄し、有機層を無水硫酸ナトリウムで乾燥後、減圧濃縮した。得られた粗生成物をクロロホルムに溶かし、ヘキサンを加えて析出した固体をろ取することにより、（Ｒ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（０．５６ｇ，収率：９５％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５６（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．８７−１．９５（ｍ，２Ｈ），１．９９−２．０６（ｍ，２Ｈ），３．５９−３．６４（ｍ，２Ｈ），３．８３−３．８８（ｍ，２Ｈ），４．６１（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），６．７５（ｄ，Ｊ＝１０．１Ｈｚ，１Ｈ），７．０６（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ），８．５８（ｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．６（ｓ，１Ｆ）．Example-65

(R) -2- [4- (5-Chloro-3-oxo-1,2-tetramethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] propionate methyl (0. Acetic acid (1.7 mL) and water (0.3 mL) were added to a solution of 70 g, 1.69 mmol) in ethyl acetate (3.4 mL), and then reduced iron (0.47 g, 8.45 mmol) was cooled with ice. And stirred at 80 ° C. for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and insoluble matters were filtered off. The filtrate was washed with water (50 mL × 2) and saturated aqueous sodium hydrogen carbonate solution (50 mL × 2), and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was dissolved in chloroform, hexane was added and the precipitated solid was collected by filtration to give (R) -5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl- A white solid (0.56 g, yield: 95%) of 3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.56 (d, J = 6.8 Hz, 3H), 1.87-1.95 (m, 2H), 1.99-2.06 (m, 2H) ), 3.59-3.64 (m, 2H), 3.83-3.88 (m, 2H), 4.61 (q, J = 6.8 Hz, 1H), 6.75 (d, J = 10.1 Hz, 1 H), 7.06 (d, J = 6.8 Hz, 1 H), 8.58 (s, 1 H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.6 (s, 1F).

水素化ナトリウムの５５％油分散（０．０４１ｇ，０．９４ｍｍｏｌ）のＤＭＦ（２．１ｍＬ）懸濁液に、氷冷下で（Ｒ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８５ｍｍｏｌ）およびプロパルギルブロミド（０．０７４ｍＬ，０．９４ｍｍｏｌ）を順次加え、室温で１５時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、クロロホルム（５０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をクロロホルムに溶かし、ヘキサンを加えて析出した固体をろ取することにより、（Ｒ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（０．２５ｇ，収率：７６％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５８（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．８８−１．９４（ｍ，２Ｈ），１．９９−２．０６（ｍ，２Ｈ），２．２５（ｔ，Ｊ＝２．５Ｈｚ，１Ｈ），３．６０−３．６５（ｍ，２Ｈ），３．８２−３．８７（ｍ，２Ｈ），４．６３（ｄｄ，Ｊ＝１７．６ ａｎｄ ２．５Ｈｚ，１Ｈ），４．６７（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），４．７５（ｄｄ，Ｊ＝１７．６ ａｎｄ ２．５Ｈｚ，１Ｈ），６．８２（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．２８（ｄ，Ｊ＝６．６Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．１（ｓ，１Ｆ）．Example-66

To a suspension of sodium hydride in 55% oil dispersion (0.041 g, 0.94 mmol) in DMF (2.1 mL), (R) -5-chloro-4- (7-fluoro-2, 3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (0.30 g, 0.85 mmol) and Propargyl bromide (0.074 mL, 0.94 mmol) was sequentially added and stirred at room temperature for 15 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with chloroform (50 mL × 3). The organic layer was washed with water (50 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was dissolved in chloroform, hexane was added and the precipitated solid was collected by filtration to give (R) -5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl- White solid (0.25 g, yield: 76%) of 3-oxo-4-propargyl-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one Got. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.58 (d, J = 6.8 Hz, 3H), 1.88-1.94 (m, 2H), 1.99-2.06 (m, 2H) ), 2.25 (t, J = 2.5 Hz, 1H), 3.60-3.65 (m, 2H), 3.82-3.87 (m, 2H), 4.63 (dd, J = 17.6 and 2.5 Hz, 1H), 4.67 (q, J = 6.8 Hz, 1H), 4.75 (dd, J = 17.6 and 2.5 Hz, 1H), 6.82 ( d, J = 9.9 Hz, 1H), 7.28 (d, J = 6.6 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.1 (s, 1F).

３，３−ジクロロ−２−［４−（エトキシカルボニル）メトキシ−２−クロロ−５−ニトロフェニル］アクリル酸エチル（８．５３ｇ，２０．０ｍｍｏｌ）に１，４−ジオキサン（５０ｍＬ）とヘキサヒドロピリダジン二臭化水素塩（５．２１ｇ，２１．０ｍｍｏｌ）を加え、さらにトリエチルアミン（９．２ｍＬ，６６．０ｍｍｏｌ）を加え、２０時間還流した。反応終了後、反応液に水（１００ｍＬ）を加えクロロホルム（５０ｍＬ×３）で抽出した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、２−［５−クロロ−４−（５−クロロ−１，２−テトラメチレン−３−オキソ−４−ピラゾリン−４−イル）−２−ニトロフェニルオキシ］酢酸エチルの黄色固体（６．７５ｇ，収率：７８％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．３２（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．８８−１．９６（ｍ，２Ｈ），１．９９−２．０８（ｍ，２Ｈ），３．６１−３．６７（ｍ，２Ｈ），３．８１−３．８７（ｍ，２Ｈ），４．３０（ｑ，Ｊ＝７．２Ｈｚ，２Ｈ），４．７８（ｓ，２Ｈ），７．０９（ｓ，１Ｈ），７．９４（ｓ，１Ｈ）．Reference Example-27

Ethyl 3,3-dichloro-2- [4- (ethoxycarbonyl) methoxy-2-chloro-5-nitrophenyl] acrylate (8.53 g, 20.0 mmol) to 1,4-dioxane (50 mL) and hexahydro Pyridazine dihydrobromide (5.21 g, 21.0 mmol) was added, triethylamine (9.2 mL, 66.0 mmol) was further added, and the mixture was refluxed for 20 hours. After completion of the reaction, water (100 mL) was added to the reaction solution and extracted with chloroform (50 mL × 3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (ethyl acetate) to give 2- [5-chloro-4- (5-chloro-1,2-tetramethylene-3-oxo-4-pyrazolin-4-yl). A yellow solid (6.75 g, yield: 78%) of ethyl -2-nitrophenyloxy] acetate was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.32 (t, J = 7.2 Hz, 3H), 1.88-1.96 (m, 2H), 1.99-2.08 (m, 2H) ), 3.61-3.67 (m, 2H), 3.81-3.87 (m, 2H), 4.30 (q, J = 7.2 Hz, 2H), 4.78 (s, 2H) ), 7.09 (s, 1H), 7.94 (s, 1H).

２−［５−クロロ−４−（５−クロロ−１，２−テトラメチレン−３−オキソ−４−ピラゾリン−４−イル）−２−ニトロフェニルオキシ］酢酸エチル（６．４５ｇ，１５．０ｍｍｏｌ）の酢酸エチル（６０．０ｍＬ）溶液に、水（２．７ｇ）及び酢酸（６０．０ｍＬ）を加えた後、還元鉄（８．３８ｇ，１５０ｍｍｏｌ）を加え、８０℃で２時間攪拌した。反応終了後、反応液を室温まで冷却し、不溶物をろ別し、固体をを酢酸エチル（２００ｍＬ）と酢酸（２０ｍＬ）の混合溶媒で洗浄した。合一した有機層を水（１００ｍＬ×３）、飽和炭酸水素ナトリウム水溶液（１００ｍＬ×２）、飽和食塩水（１００ｍＬ）で洗浄した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、減圧乾燥することにより、５−クロロ−４−（７−クロロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（定量的）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８７−１．９７（ｍ，２Ｈ），２．００−２．０８（ｍ，２Ｈ），３．５６−３．６９（ｍ，２Ｈ），３．８３−３．９２（ｍ，２Ｈ），４．４６（ｓ，２Ｈ），６．８８（ｓ，１Ｈ），６．９８（ｓ，１Ｈ），９．９５（ｂｒｓ，１Ｈ）．Example-67

2- [5-Chloro-4- (5-chloro-1,2-tetramethylene-3-oxo-4-pyrazolin-4-yl) -2-nitrophenyloxy] ethyl acetate (6.45 g, 15.0 mmol) ) In ethyl acetate (60.0 mL), water (2.7 g) and acetic acid (60.0 mL) were added, and reduced iron (8.38 g, 150 mmol) was added, followed by stirring at 80 ° C. for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, insoluble matters were filtered off, and the solid was washed with a mixed solvent of ethyl acetate (200 mL) and acetic acid (20 mL). The combined organic layer was washed with water (100 mL × 3), saturated aqueous sodium hydrogen carbonate solution (100 mL × 2), and saturated brine (100 mL). The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and dried under reduced pressure to give 5-chloro-4- (7-chloro-2,3-dihydro-3-oxo-4H-1,4-benzoxazine-6. A white solid (quantitative) of -yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.87-1.97 (m, 2H), 2.00-2.08 (m, 2H), 3.56-3.69 (m, 2H), 3.83-3.92 (m, 2H), 4.46 (s, 2H), 6.88 (s, 1H), 6.98 (s, 1H), 9.95 (brs, 1H).

氷冷下で水素化ナトリウムの５５％油分散（５３ｍｇ，１．２ｍｍｏｌ）のＤＭＦ（３ｍＬ）懸濁液に、５−クロロ−４−（７−クロロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（３５５ｍｇ，１．０ｍｍｏｌ）及び（クロロメチル）メチルエーテル（１０２ｍｇ，１．２ｍｍｏｌ）を加え、室温で６時間攪拌した。反応終了後、反応液に氷水を注ぎ、クロロホルム（３０ｍＬ×３）で抽出した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをヘキサンで洗浄した後、減圧乾燥することにより、５−クロロ−４−（７−クロロ−２，３−ジヒドロ−４−メトキシメチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（１４９ｍｇ，収率：３７％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８６−１．９５（ｍ，２Ｈ），１．９８−２．０７（ｍ，２Ｈ），３．３９（ｓ，３Ｈ），３．３７−３．６５（ｍ，２Ｈ），３．７８−３．８９（ｍ，２Ｈ），４．６５（ｓ，２Ｈ），５．３０（ｓ，２Ｈ），７．１１（ｓ，１Ｈ），７．２５（ｓ，１Ｈ）．Example-68

To a suspension of 55% oil dispersion of sodium hydride (53 mg, 1.2 mmol) in DMF (3 mL) under ice-cooling, 5-chloro-4- (7-chloro-2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (355 mg, 1.0 mmol) and (chloromethyl) methyl ether (102 mg, 1.2 mmol). The mixture was further stirred at room temperature for 6 hours. After completion of the reaction, ice water was poured into the reaction solution and extracted with chloroform (30 mL × 3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was washed with hexane and then dried under reduced pressure to give 5-chloro-4- (7-chloro-2,3-dihydro-4-methoxymethyl-3-oxo-4H-1,4-benzoxazine- A white solid (149 mg, yield: 37%) of 6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.86-1.95 (m, 2H), 1.98-2.07 (m, 2H), 3.39 (s, 3H), 3.37-3 .65 (m, 2H), 3.78-3.89 (m, 2H), 4.65 (s, 2H), 5.30 (s, 2H), 7.11 (s, 1H), 7. 25 (s, 1H).

氷冷下で水素化ナトリウムの５５％油分散（５３ｍｇ，１．２ｍｍｏｌ）のＤＭＦ（３ｍＬ）懸濁液に、５−クロロ−４−（７−クロロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（３５５ｍｇ，１．０ｍｍｏｌ）及びブロモアセトニトリル（１４８ｍｇ，１．２ｍｍｏｌ）を加え、室温で６時間攪拌した。反応終了後、反応液に氷水を注ぎ、クロロホルム（３０ｍＬ×３）で抽出した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをヘキサンで洗浄した後、減圧乾燥することにより、５−クロロ−４−（７−クロロ−４−シアノメチル−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（１７０ｍｇ，収率：４３％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８８−１．９８（ｍ，２Ｈ），２．００−２．０９（ｍ，２Ｈ），３．６２−３．６８（ｍ，２Ｈ），３．８１−３．８９（ｍ，２Ｈ），４．４２−５．２５（ｍ，４Ｈ），７．０３（ｓ，１Ｈ），７．１７（ｓ，１Ｈ）．Example-69

To a suspension of 55% oil dispersion of sodium hydride (53 mg, 1.2 mmol) in DMF (3 mL) under ice-cooling, 5-chloro-4- (7-chloro-2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (355 mg, 1.0 mmol) and bromoacetonitrile (148 mg, 1.2 mmol) were added at room temperature. Stir for 6 hours. After completion of the reaction, ice water was poured into the reaction solution and extracted with chloroform (30 mL × 3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was washed with hexane, and then dried under reduced pressure to give 5-chloro-4- (7-chloro-4-cyanomethyl-2,3-dihydro-3-oxo-4H-1,4-benzoxazine-6. A white solid (170 mg, yield: 43%) of -yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.88-1.98 (m, 2H), 2.00-2.09 (m, 2H), 3.62-3.68 (m, 2H), 3.81-3.89 (m, 2H), 4.42-5.25 (m, 4H), 7.03 (s, 1H), 7.17 (s, 1H).

氷冷下で水素化ナトリウムの５５％油分散（５３ｍｇ，１．２ｍｍｏｌ）のＤＭＦ（３ｍＬ）懸濁液に、５−クロロ−４−（７−クロロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（３５５ｍｇ，１．０ｍｍｏｌ）及び（ブロモメチル）シクロプロパン（１６９ｍｇ，１．２ｍｍｏｌ）を加え、室温で６時間攪拌した。反応終了後、反応液に氷水を注ぎ、クロロホルム（３０ｍＬ×３）で抽出した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをヘキサンで洗浄した後、減圧乾燥することにより、４−［７−クロロ−４−（シクロプロピルメチル）−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（１７８ｍｇ，収率：４４％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ０．３８−０．５７（ｍ，４Ｈ），１．１２−１．２５（ｍ，１Ｈ），１．８６−１．９６（ｍ，２Ｈ），１．９９−２．０８（ｍ，２Ｈ），３．５８−３．６６（ｍ，２Ｈ），３．７９−３．９０（ｍ，４Ｈ），４．６３（ｓ，２Ｈ），７．０９（ｓ，１Ｈ），７．１０（ｓ，１Ｈ）．Example-70

To a suspension of 55% oil dispersion of sodium hydride (53 mg, 1.2 mmol) in DMF (3 mL) under ice-cooling, 5-chloro-4- (7-chloro-2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (355 mg, 1.0 mmol) and (bromomethyl) cyclopropane (169 mg, 1.2 mmol) were added. And stirred at room temperature for 6 hours. After completion of the reaction, ice water was poured into the reaction solution and extracted with chloroform (30 mL × 3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was washed with hexane and dried under reduced pressure to give 4- [7-chloro-4- (cyclopropylmethyl) -2,3-dihydro-3-oxo-4H-1,4-benzoxazine-6. A white solid (178 mg, yield: 44%) of -yl] -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.38-0.57 (m, 4H), 1.12-1.25 (m, 1H), 1.86-1.96 (m, 2H), 1.99-2.08 (m, 2H), 3.58-3.66 (m, 2H), 3.79-3.90 (m, 4H), 4.63 (s, 2H), 7. 09 (s, 1H), 7.10 (s, 1H).

氷冷下で水素化ナトリウムの５５％油分散（５３ｍｇ，１．２ｍｍｏｌ）のＤＭＦ（３ｍＬ）懸濁液に、５−クロロ−４−（７−クロロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（３５５ｍｇ，１．０ｍｍｏｌ）及び（ブロモメチル）シクロブタン（１８４ｍｇ，１．２ｍｍｏｌ）を加え、室温で６時間攪拌した。反応終了後、反応液に氷水を注ぎ、クロロホルム（３０ｍＬ×３）で抽出した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをヘキサンで洗浄した後、減圧乾燥することにより、４−［７−クロロ−４−（シクロブチルメチル）−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（１７２ｍｇ，収率：４１％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．７６−２．０８（ｍ，６Ｈ），２．６３−２．７９（ｍ，１Ｈ），３．５７−３．６６（ｍ，２Ｈ），３．８１−３．８８（ｍ，２Ｈ），３．９５−４．０３（ｍ，２Ｈ），４．６０（ｓ，２Ｈ），６．９３（ｓ，１Ｈ），７．０８（ｓ，１Ｈ）．Example-71

To a suspension of 55% oil dispersion of sodium hydride (53 mg, 1.2 mmol) in DMF (3 mL) under ice-cooling, 5-chloro-4- (7-chloro-2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (355 mg, 1.0 mmol) and (bromomethyl) cyclobutane (184 mg, 1.2 mmol) were added, Stir at room temperature for 6 hours. After completion of the reaction, ice water was poured into the reaction solution and extracted with chloroform (30 mL × 3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was washed with hexane and then dried under reduced pressure to give 4- [7-chloro-4- (cyclobutylmethyl) -2,3-dihydro-3-oxo-4H-1,4-benzoxazine-6. A white solid (172 mg, yield: 41%) of -yl] -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.76-2.08 (m, 6H), 2.63-2.79 (m, 1H), 3.57-3.66 (m, 2H), 3.81-3.88 (m, 2H), 3.95-4.03 (m, 2H), 4.60 (s, 2H), 6.93 (s, 1H), 7.08 (s, 1H).

氷冷下で水素化ナトリウムの５５％油分散（５３ｍｇ，１．２ｍｍｏｌ）のＤＭＦ（３ｍＬ）懸濁液に、５−クロロ−４−（７−クロロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（３５５ｍｇ，１．０ｍｍｏｌ）及びアリルブロミド（１４８ｍｇ，１．２ｍｍｏｌ）を加え、室温で６時間攪拌した。反応終了後、反応液に氷水を注ぎ、クロロホルム（３０ｍＬ×３）で抽出した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをヘキサンで洗浄した後、減圧乾燥することにより、４−（４−アリル−７−クロロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの淡黄色固体（２５６ｍｇ，収率：６５％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．８７−１．９５（ｍ，２Ｈ），１．９９−２．０７（ｍ，２Ｈ），３．５８−３．６４（ｍ，２Ｈ），３．８０−３．８７（ｍ，２Ｈ），４．５３（ｂｒｓ，２Ｈ），４．６６（ｓ，２Ｈ），５．１７−５．２６（ｍ，２Ｈ），５．７９−５．９１（ｍ，１Ｈ），６．９４（ｓ，１Ｈ），７．１０（ｓ，１Ｈ）．Example-72

To a suspension of 55% oil dispersion of sodium hydride (53 mg, 1.2 mmol) in DMF (3 mL) under ice-cooling, 5-chloro-4- (7-chloro-2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (355 mg, 1.0 mmol) and allyl bromide (148 mg, 1.2 mmol) were added at room temperature. Stir for 6 hours. After completion of the reaction, ice water was poured into the reaction solution and extracted with chloroform (30 mL × 3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was washed with hexane and dried under reduced pressure to give 4- (4-allyl-7-chloro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl)- A pale yellow solid (256 mg, yield: 65%) of 5-chloro-1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.87-1.95 (m, 2H), 1.99-2.07 (m, 2H), 3.58-3.64 (m, 2H), 3 80-3.87 (m, 2H), 4.53 (brs, 2H), 4.66 (s, 2H), 5.17-5.26 (m, 2H), 5.79-5.91 (M, 1H), 6.94 (s, 1H), 7.10 (s, 1H).

氷冷下で水素化ナトリウムの５５％油分散（５３ｍｇ，１．２ｍｍｏｌ）のＤＭＦ（３ｍＬ）懸濁液に、５−クロロ−４−（７−クロロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（３５５ｍｇ，１．０ｍｍｏｌ）及びメタリルブロミド（１６７ｍｇ，１．２ｍｍｏｌ）を加え、室温で６時間攪拌した。反応終了後、反応液に氷水を注ぎ、クロロホルム（３０ｍＬ×３）で抽出した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９５／５）で精製することにより、５−クロロ−４−［７−クロロ−２，３−ジヒドロ−４−（２−メチルプロペニル）−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−１，２−テトラメチレン−４−ピラゾリン−３−オンの淡黄色固体（２５２ｍｇ，収率：６２％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ１．７６（ｓ，３Ｈ），１．８７−１．９４（ｍ，２Ｈ），１．９８−２．０７（ｍ，２Ｈ），３．５６−３．６４（ｍ，２Ｈ），３．７９−３．８８（ｍ，２Ｈ），４．４４（ｂｒｓ，２Ｈ），４．６７（ｓ，２Ｈ），４．７７（ｓ，１Ｈ），４．９２（ｓ，１Ｈ），６．８８（ｓ，１Ｈ），７．１０（ｓ，１Ｈ）．Example-73

To a suspension of 55% oil dispersion of sodium hydride (53 mg, 1.2 mmol) in DMF (3 mL) under ice-cooling, 5-chloro-4- (7-chloro-2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (355 mg, 1.0 mmol) and methallyl bromide (167 mg, 1.2 mmol) were added at room temperature. For 6 hours. After completion of the reaction, ice water was poured into the reaction solution and extracted with chloroform (30 mL × 3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (ethyl acetate: methanol = 95/5) to give 5-chloro-4- [7-chloro-2,3-dihydro-4- (2-methylpropenyl) -3. A light yellow solid (252 mg, yield: 62%) of -oxo-4H-1,4-benzoxazin-6-yl] -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.76 (s, 3H), 1.87-1.94 (m, 2H), 1.98-2.07 (m, 2H), 3.56-3 .64 (m, 2H), 3.79-3.88 (m, 2H), 4.44 (brs, 2H), 4.67 (s, 2H), 4.77 (s, 1H), 4. 92 (s, 1H), 6.88 (s, 1H), 7.10 (s, 1H).

氷冷下で水素化ナトリウムの５５％油分散（５３ｍｇ，１．２ｍｍｏｌ）のＤＭＦ（３ｍＬ）懸濁液に、５−クロロ−４−（７−クロロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（３５５ｍｇ，１．０ｍｍｏｌ）及びプロパルギルブロミド（１５０ｍｇ，１．２ｍｍｏｌ）を加え、室温で６時間攪拌した。反応終了後、反応液に氷水を注ぎ、クロロホルム（３０ｍＬ×３）で抽出した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９５／５）で精製することにより、５−クロロ−４−（７−クロロ−２，３−ジヒドロ−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（２４２ｍｇ，収率：６２％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８７−１．９６（ｍ，２Ｈ），１．９９−２．０８（ｍ，２Ｈ），２．２６（ｍ，１Ｈ），３．６０−３．６５（ｍ，２Ｈ），３．８２−３．８８（ｍ，２Ｈ），４．４１−４．８７（ｍ，４Ｈ），７．１２（ｓ，１Ｈ），７．１４（ｓ，１Ｈ）．Example-74

To a suspension of 55% oil dispersion of sodium hydride (53 mg, 1.2 mmol) in DMF (3 mL) under ice-cooling, 5-chloro-4- (7-chloro-2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (355 mg, 1.0 mmol) and propargyl bromide (150 mg, 1.2 mmol) were added at room temperature. Stir for 6 hours. After completion of the reaction, ice water was poured into the reaction solution and extracted with chloroform (30 mL × 3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (ethyl acetate: methanol = 95/5) to give 5-chloro-4- (7-chloro-2,3-dihydro-3-oxo-4-propargyl-4H- A white solid (242 mg, yield: 62%) of 1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.87-1.96 (m, 2H), 1.99-2.08 (m, 2H), 2.26 (m, 1H), 3.60- 3.65 (m, 2H), 3.82-3.88 (m, 2H), 4.41-4.87 (m, 4H), 7.12 (s, 1H), 7.14 (s, 1H).

氷冷下で水素化ナトリウムの５５％油分散（５３ｍｇ，１．２ｍｍｏｌ）のＤＭＦ（３ｍＬ）懸濁液に、５−クロロ−４−（７−クロロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（３５５ｍｇ，１．０ｍｍｏｌ）及び１−ブロモ−２−ブチン（１６６ｍｇ，１．２ｍｍｏｌ）を加え、室温で６時間攪拌した。反応終了後、反応液に氷水を注ぎ、クロロホルム（３０ｍＬ×３）で抽出した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをヘキサンで洗浄した後、減圧乾燥することにより、４−［４−（２−ブチニル）−７−クロロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの淡褐色固体（２７７ｍｇ，収率：６８％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．７８（ｍ，３Ｈ），１．８７−１．９６（ｍ，２Ｈ），２．００−２．０８（ｍ，２Ｈ），３．５８−３．６６（ｍ，２Ｈ），３．８１−３．８９（ｍ，２Ｈ），４．４８−４．８０（ｍ，４Ｈ），７．１１（ｓ，１Ｈ），７．１４（ｓ，１Ｈ）．Example-75

To a suspension of 55% oil dispersion of sodium hydride (53 mg, 1.2 mmol) in DMF (3 mL) under ice-cooling, 5-chloro-4- (7-chloro-2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (355 mg, 1.0 mmol) and 1-bromo-2-butyne (166 mg, 1.2 mmol) And stirred at room temperature for 6 hours. After completion of the reaction, ice water was poured into the reaction solution and extracted with chloroform (30 mL × 3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was washed with hexane and dried under reduced pressure to give 4- [4- (2-butynyl) -7-chloro-2,3-dihydro-3-oxo-4H-1,4-benzoxazine-6. A pale brown solid (277 mg, yield: 68%) of -yl] -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.78 (m, 3H), 1.87-1.96 (m, 2H), 2.00-2.08 (m, 2H), 3.58- 3.66 (m, 2H), 3.81-3.89 (m, 2H), 4.48-4.80 (m, 4H), 7.11 (s, 1H), 7.14 (s, 1H).

氷冷下で水素化ナトリウムの５５％油分散（１０９ｍｇ，２．５ｍｍｏｌ）のＤＭＦ（３ｍＬ）懸濁液に、５−クロロ−４−（７−クロロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（３５５ｍｇ，１．０ｍｍｏｌ）及び２−（クロロメチル）ピリジン塩酸塩（２０１ｍｇ，１．２ｍｍｏｌ）を加え、室温で６時間攪拌した。反応終了後、反応液に氷水を注ぎ、クロロホルム（３０ｍＬ×３）で抽出した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをヘキサンで洗浄した後、減圧乾燥することにより、５−クロロ−４−［７−クロロ−４−（ピリジン−２−イルメチル）−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−１，２−テトラメチレン−４−ピラゾリン−３−オンの白色固体（２１６ｍｇ，収率：４８％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８４−１．９２（ｍ，２Ｈ），１．９５−２．０４（ｍ，２Ｈ），３．４９−３．６４（ｍ，２Ｈ），３．７１−３．８７（ｍ，２Ｈ），４．７４（ｓ，２Ｈ），５．２３（ｂｒｓ，２Ｈ），７．０１（ｓ，１Ｈ），７．１１（ｓ，１Ｈ），７．１５−７．２４（ｍ，２Ｈ），７．５９−７．６６（ｍ，１Ｈ），８．５２−８．５６（ｍ，１Ｈ）．Example-76

To a suspension of sodium hydride in 55% oil dispersion (109 mg, 2.5 mmol) in DMF (3 mL) under ice cooling was added 5-chloro-4- (7-chloro-2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one (355 mg, 1.0 mmol) and 2- (chloromethyl) pyridine hydrochloride (201 mg, 1. 2 mmol) was added and stirred at room temperature for 6 hours. After completion of the reaction, ice water was poured into the reaction solution and extracted with chloroform (30 mL × 3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was washed with hexane and then dried under reduced pressure to give 5-chloro-4- [7-chloro-4- (pyridin-2-ylmethyl) -2,3-dihydro-3-oxo-4H-1, A white solid (216 mg, yield: 48%) of 4-benzoxazin-6-yl] -1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.84-1.92 (m, 2H), 1.95-2.04 (m, 2H), 3.49-3.64 (m, 2H), 3.71-3.87 (m, 2H), 4.74 (s, 2H), 5.23 (brs, 2H), 7.01 (s, 1H), 7.11 (s, 1H), 7 15-7.24 (m, 2H), 7.59-7.66 (m, 1H), 8.52-8.56 (m, 1H).

２−［４−（エトキシカルボニル）メトキシ−３−ニトロフェニル］−３，３−ジクロロアクリル酸エチル（５．４９ｇ，１４．０ｍｍｏｌ）の１，４−ジオキサン（２８ｍＬ）溶液に１，２−ジアゼパン二臭化水素塩（４．０３ｇ，１５．４ｍｍｏｌ）およびトリエチルアミン（６．４ｍＬ，４６．２ｍｍｏｌ）を室温で加えた後、加熱還流しながら１７時間撹拌した。反応終了後、反応液に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をクロロホルムに溶かし、酢酸エチルを加えて析出した固体をろ取することにより、２−［４−（５−クロロ−３−オキソ−１，２−ペンタメチレン−４−ピラゾリン−４−イル）−２−ニトロフェニルオキシ］酢酸エチルの黄色固体（４．１１ｇ，収率：７２％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．２９（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．８１−１．８５（ｍ，６Ｈ），４．０９−４．１５（ｍ，４Ｈ），４．２７（ｑ，Ｊ＝７．２Ｈｚ，２Ｈ），４．７７（ｓ，２Ｈ），７．０１（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），８．１７（ｄｄ，Ｊ＝８．８ ａｎｄ ２．３Ｈｚ，１Ｈ），８．３８（ｄ，Ｊ＝２．２Ｈｚ，１Ｈ）．Reference Example-28

1,2-diazepane in a solution of ethyl 2- [4- (ethoxycarbonyl) methoxy-3-nitrophenyl] -3,3-dichloroacrylate (5.49 g, 14.0 mmol) in 1,4-dioxane (28 mL). Dihydrobromide (4.03 g, 15.4 mmol) and triethylamine (6.4 mL, 46.2 mmol) were added at room temperature, and the mixture was stirred for 17 hours while heating to reflux. After completion of the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was dissolved in chloroform, ethyl acetate was added and the precipitated solid was collected by filtration to give 2- [4- (5-chloro-3-oxo-1,2-pentamethylene-4-pyrazoline). -4-yl) -2-nitrophenyloxy] ethyl acetate yellow solid (4.11 g, yield: 72%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.29 (t, J = 7.2 Hz, 3H), 1.81-1.85 (m, 6H), 4.09-4.15 (m, 4H) ), 4.27 (q, J = 7.2 Hz, 2H), 4.77 (s, 2H), 7.01 (d, J = 8.8 Hz, 1H), 8.17 (dd, J = 8) .8 and 2.3 Hz, 1H), 8.38 (d, J = 2.2 Hz, 1H).

２−［４−（５−クロロ−３−オキソ−１，２−ペンタメチレン−４−ピラゾリン−４−イル）−２−ニトロフェニルオキシ］酢酸エチル（３．７０ｇ，９．０３ｍｍｏｌ）の酢酸エチル（１８ｍＬ）溶液に、酢酸（９ｍＬ）および水（１．６ｍＬ）を加えた後、氷冷下で還元鉄（２．５２ｇ，４５．２ｍｍｏｌ）を加え、８０℃で２時間撹拌した。反応終了後、反応液を室温まで冷却し、不溶物をろ別後、ろ液を水（５０ｍＬ×２）で洗浄し、有機層を減圧濃縮した。析出した固体を水で洗浄後、乾燥させることにより、５−クロロ−４−（２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オンの白色固体（２．５７ｇ，収率：８５％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．７８−１．８６（ｍ，６Ｈ），４．０５−４．１０（ｍ，２Ｈ），４．１２−４．１７（ｍ，２Ｈ），４．５７（ｓ，２Ｈ），６．９６（ｄ，Ｊ＝８．５Ｈｚ，１Ｈ），７．３４（ｄｄ，Ｊ＝８．５ ａｎｄ ２．０Ｈｚ，１Ｈ），７．５５（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ），８．３４（ｓ，１Ｈ）．Example-77

2- [4- (5-Chloro-3-oxo-1,2-pentamethylene-4-pyrazolin-4-yl) -2-nitrophenyloxy] ethyl acetate (3.70 g, 9.03 mmol) in ethyl acetate Acetic acid (9 mL) and water (1.6 mL) were added to the (18 mL) solution, and then reduced iron (2.52 g, 45.2 mmol) was added under ice cooling, followed by stirring at 80 ° C. for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, insoluble matters were filtered off, the filtrate was washed with water (50 mL × 2), and the organic layer was concentrated under reduced pressure. The precipitated solid was washed with water and dried to give 5-chloro-4- (2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-penta. A white solid (2.57 g, yield: 85%) of methylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.78-1.86 (m, 6H), 4.05-4.10 (m, 2H), 4.12-4.17 (m, 2H), 4.57 (s, 2H), 6.96 (d, J = 8.5 Hz, 1H), 7.34 (dd, J = 8.5 and 2.0 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H), 8.34 (s, 1H).

水素化ナトリウムの５５％油分散（０．０４３ｇ，０．９９ｍｍｏｌ）のＤＭＦ（２．５ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．９０ｍｍｏｌ）および（ブロモメチル）シクロプロパン（０．１０ｍＬ，０．９９ｍｍｏｌ）を順次加え、室温で３８時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×４）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、５−クロロ−４−（４−シクロプロピルメチル−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オンの白色固体（０．２４ｇ，収率：６９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ０．４２−０．４９（ｍ，２Ｈ），０．４９−０．５６（ｍ，２Ｈ），１．２６−１．３６（ｍ，１Ｈ），１．７９−１．８７（ｍ，６Ｈ），３．８９（ｍ，２Ｈ），４．０６−４．１１（ｍ，２Ｈ），４．１１−４．１５（ｍ，２Ｈ），４．６１（ｓ，２Ｈ），７．００（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．４１（ｄｄ，Ｊ＝８．４ ａｎｄ １．９Ｈｚ，１Ｈ），７．８３（ｄ，Ｊ＝１．９Ｈｚ，１Ｈ）．Example-78

To a suspension of sodium hydride in 55% oil dispersion (0.043 g, 0.99 mmol) in DMF (2.5 mL) under ice-cooling, 5-chloro-4- (2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-pentamethylene-4-pyrazolin-3-one (0.30 g, 0.90 mmol) and (bromomethyl) cyclopropane (0.10 mL,. 99 mmol) were sequentially added and stirred at room temperature for 38 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with water (50 mL × 4), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 5-chloro-4- (4-cyclopropylmethyl-2,3-dihydro-3-oxo-4H A white solid (0.24 g, yield: 69%) of -1,4-benzoxazin-6-yl) -1,2-pentamethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.42 to 0.49 (m, 2H), 0.49 to 0.56 (m, 2H), 1.26 to 1.36 (m, 1H), 1.79-1.87 (m, 6H), 3.89 (m, 2H), 4.06-4.11 (m, 2H), 4.11-4.15 (m, 2H), 4. 61 (s, 2H), 7.00 (d, J = 8.4 Hz, 1H), 7.41 (dd, J = 8.4 and 1.9 Hz, 1H), 7.83 (d, J = 1) .9Hz, 1H).

水素化ナトリウムの５５％油分散（０．０４３ｇ，０．９９ｍｍｏｌ）のＤＭＦ（２．５ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．９０ｍｍｏｌ）およびシクロブチルメチルブロミド（０．１２ｍＬ，０．９９ｍｍｏｌ）を順次加え、室温で４３時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（３０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×４）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）で精製することにより、５−クロロ−４−（４−シクロブチルメチル−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オンの白色固体（０．２８ｇ，収率：７８％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．７９−１．８９（ｍ，１０Ｈ），１．９６−２．０９（ｍ，２Ｈ），２．７９（ｍ，１Ｈ），４．０４−４．１０（ｍ，４Ｈ），４．５９（ｓ，２Ｈ），４．１１−４．１５（ｍ，２Ｈ），６．９８（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．４０（ｄｄ，Ｊ＝８．４ ａｎｄ １．９Ｈｚ，１Ｈ），７．６５（ｄ，Ｊ＝１．９Ｈｚ，１Ｈ）．Example-79

To a suspension of sodium hydride in 55% oil dispersion (0.043 g, 0.99 mmol) in DMF (2.5 mL) under ice-cooling, 5-chloro-4- (2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-pentamethylene-4-pyrazolin-3-one (0.30 g, 0.90 mmol) and cyclobutylmethyl bromide (0.12 mL, 0.99 mmol) ) Were sequentially added and stirred at room temperature for 43 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was washed with water (50 mL × 4), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 5-chloro-4- (4-cyclobutylmethyl-2,3-dihydro-3-oxo- A white solid (0.28 g, yield: 78%) of 4H-1,4-benzoxazin-6-yl) -1,2-pentamethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.79-1.89 (m, 10H), 1.96-2.09 (m, 2H), 2.79 (m, 1H), 4.04- 4.10 (m, 4H), 4.59 (s, 2H), 4.11-4.15 (m, 2H), 6.98 (d, J = 8.4 Hz, 1H), 7.40 ( dd, J = 8.4 and 1.9 Hz, 1H), 7.65 (d, J = 1.9 Hz, 1H).

水素化ナトリウムの５５％油分散（０．０４３ｇ，０．９９ｍｍｏｌ）のＤＭＦ（２．５ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．９０ｍｍｏｌ）およびアリルブロミド（０．０８４ｍＬ，０．９９ｍｍｏｌ）を順次加え、室温で２１時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（３０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×３）、飽和食塩水（１０ｍＬ×１）洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）で精製することにより、４−（４−アリル−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−５−クロロ−１，２−ペンタメチレン−４−ピラゾリン−３−オンの白色固体（０．２９ｇ，収率：８５％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．７９−１．８６（ｍ，６Ｈ），４．０４−４．０９（ｍ，２Ｈ），４．０９−４．１４（ｍ，２Ｈ），４．５７−４．６２（ｍ，２Ｈ），４．６４（ｓ，２Ｈ），５．２５（ｍ，１Ｈ），５．２８（ｍ，１Ｈ），５．９３（ｍ，１Ｈ），７．００（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．４６（ｄｄ，Ｊ＝８．４ ａｎｄ ２．０Ｈｚ，１Ｈ），７．６６（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ）．Example-80

To a suspension of sodium hydride in 55% oil dispersion (0.043 g, 0.99 mmol) in DMF (2.5 mL) under ice-cooling, 5-chloro-4- (2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-pentamethylene-4-pyrazolin-3-one (0.30 g, 0.90 mmol) and allyl bromide (0.084 mL, 0.99 mmol). Sequentially added and stirred at room temperature for 21 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was washed with water (50 mL × 3) and saturated brine (10 mL × 1), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 4- (4-allyl-2,3-dihydro-3-oxo-4H-1,4- A white solid (0.29 g, yield: 85%) of benzoxazin-6-yl) -5-chloro-1,2-pentamethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.79-1.86 (m, 6H), 4.04-4.09 (m, 2H), 4.09-4.14 (m, 2H), 4.57-4.62 (m, 2H), 4.64 (s, 2H), 5.25 (m, 1H), 5.28 (m, 1H), 5.93 (m, 1H), 7 .00 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 8.4 and 2.0 Hz, 1H), 7.66 (d, J = 2.0 Hz, 1H).

水素化ナトリウムの５５％油分散（０．０４３ｇ，０．９９ｍｍｏｌ）のＤＭＦ（２．５ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．９０ｍｍｏｌ）およびプロパルギルブロミド（０．０７８ｍＬ，０．９９ｍｍｏｌ）を順次加え、室温で１８時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、クロロホルム（５０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、５−クロロ−４−（２，３−ジヒドロ−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オンの白色固体（０．２７ｇ，収率：８２％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８０−１．８７（ｍ，６Ｈ），２．２６（ｔ，Ｊ＝２．５Ｈｚ，１Ｈ），４．０６−４．１０（ｍ，２Ｈ），４．１１−４．１５（ｍ，２Ｈ），４．６４（ｓ，２Ｈ），４．７４（ｄ，Ｊ＝２．５Ｈｚ，２Ｈ），７．０２（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．５１（ｄｄ，Ｊ＝８．４ ａｎｄ １．９Ｈｚ，１Ｈ），７．７８（ｄ，Ｊ＝１．９Ｈｚ，１Ｈ）．Example-81

To a suspension of sodium hydride in 55% oil dispersion (0.043 g, 0.99 mmol) in DMF (2.5 mL) under ice-cooling, 5-chloro-4- (2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-pentamethylene-4-pyrazolin-3-one (0.30 g, 0.90 mmol) and propargyl bromide (0.078 mL, 0.99 mmol). Sequentially added and stirred at room temperature for 18 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with chloroform (50 mL × 3). The organic layer was washed with water (50 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 5-chloro-4- (2,3-dihydro-3-oxo-4-propargyl-4H-1 , 4-Benzoxazin-6-yl) -1,2-pentamethylene-4-pyrazolin-3-one was obtained as a white solid (0.27 g, yield: 82%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.80-1.87 (m, 6H), 2.26 (t, J = 2.5 Hz, 1H), 4.06-4.10 (m, 2H) ), 4.11-4.15 (m, 2H), 4.64 (s, 2H), 4.74 (d, J = 2.5 Hz, 2H), 7.02 (d, J = 8.4 Hz) , 1H), 7.51 (dd, J = 8.4 and 1.9 Hz, 1H), 7.78 (d, J = 1.9 Hz, 1H).

水素化ナトリウムの５５％油分散（０．０４３ｇ，０．９９ｍｍｏｌ）のＤＭＦ（２．５ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．９０ｍｍｏｌ）および１−ブロモ−２−ブチン（０．０９３ｍＬ，０．９９ｍｍｏｌ）を順次加え、室温で２０時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をヘキサンで洗浄することにより、４−［４−（２−ブチニル）−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−５−クロロ−１，２−ペンタメチレン−４−ピラゾリン−３−オンの白色固体（０．３１ｇ，収率：８９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．７８（ｔ，Ｊ＝２．４Ｈｚ，３Ｈ），１．８１−１．８７（ｍ，６Ｈ），４．０６−４．１０（ｍ，２Ｈ），４．１１−４．１５（ｍ，２Ｈ），４．６３（ｓ，２Ｈ），４．６６（ｑ，Ｊ＝２．４Ｈｚ，２Ｈ），７．０１（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．５２（ｄｄ，Ｊ＝８．４ ａｎｄ １．９Ｈｚ，１Ｈ），７．７１（ｄ，Ｊ＝１．９Ｈｚ，１Ｈ）．Example-82

To a suspension of sodium hydride in 55% oil dispersion (0.043 g, 0.99 mmol) in DMF (2.5 mL) under ice-cooling, 5-chloro-4- (2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-pentamethylene-4-pyrazolin-3-one (0.30 g, 0.90 mmol) and 1-bromo-2-butyne (0.093 mL, 0.99 mmol) was sequentially added, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with water (50 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was washed with hexane to give 4- [4- (2-butynyl) -2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl] -5. A white solid (0.31 g, yield: 89%) of -chloro-1,2-pentamethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.78 (t, J = 2.4 Hz, 3H), 1.81-1.87 (m, 6H), 4.06-4.10 (m, 2H) ), 4.11-4.15 (m, 2H), 4.63 (s, 2H), 4.66 (q, J = 2.4 Hz, 2H), 7.01 (d, J = 8.4 Hz) , 1H), 7.52 (dd, J = 8.4 and 1.9 Hz, 1H), 7.71 (d, J = 1.9 Hz, 1H).

水素化ナトリウムの５５％油分散（０．３５ｇ，８．００ｍｍｏｌ）の１，４−ジオキサン（３６ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（２，４−ジフルオロ−５−ニトロフェニル）−１，２−ペンタメチレン−４−ピラゾリン−３−オン（２．５０ｇ，７．２７ｍｍｏｌ）を加え、グリコール酸メチル（０．６９ｍＬ，８．７２ｍｍｏｌ）を滴下し、室温で４時間撹拌した。反応終了後、反応液を氷水（１５０ｇ）に注ぎ入れ、クロロホルム（１００ｍＬ×４）で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた粗生成物を酢酸エチルで洗浄することにより、２−［４−（５−クロロ−３−オキソ−１，２−ペンタメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］酢酸メチルの黄色固体（１．９９ｇ，収率：６６％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８２−１．８７（ｍ，６Ｈ），３．８３（ｓ，３Ｈ），４．０９−４．１５（ｍ，４Ｈ），４．７８（ｓ，２Ｈ），６．７５（ｄ，Ｊ＝１０．７Ｈｚ，１Ｈ），８．１７（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−９８．６（ｓ，１Ｆ）．Reference Example-29

To a suspension of sodium hydride in 55% oil dispersion (0.35 g, 8.00 mmol) in 1,4-dioxane (36 mL) under ice cooling, 5-chloro-4- (2,4-difluoro-5- Nitrophenyl) -1,2-pentamethylene-4-pyrazolin-3-one (2.50 g, 7.27 mmol) is added, and methyl glycolate (0.69 mL, 8.72 mmol) is added dropwise at room temperature for 4 hours. Stir. After completion of the reaction, the reaction solution was poured into ice water (150 g) and extracted with chloroform (100 mL × 4). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was washed with ethyl acetate to give 2- [4- (5-chloro-3-oxo-1,2-pentamethylene-4-pyrazolin-4-yl) -5-fluoro-2. A yellow solid (1.99 g, yield: 66%) of methyl nitrophenyloxy] acetate was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.82-1.87 (m, 6H), 3.83 (s, 3H), 4.09-4.15 (m, 4H), 4.78 ( s, 2H), 6.75 (d, J = 10.7 Hz, 1H), 8.17 (d, J = 7.4 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-98.6 (s, 1F).

２−［４−（５−クロロ−３−オキソ−１，２−ペンタメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］酢酸メチル（１．８８ｇ，４．５４ｍｍｏｌ）の酢酸エチル（９ｍＬ）溶液に、酢酸（４．５ｍＬ）および水（０．８ｍＬ）を加えた後、氷冷下で還元鉄（２．５４ｇ，４５．４ｍｍｏｌ）を加え、８０℃で５時間撹拌した。反応終了後、反応液を室温まで冷却し、不溶物をろ別後、ろ液を減圧濃縮した。析出した固体をクロロホルムに溶かし、水（５０ｍＬ×３）で洗浄し、有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮することによって５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オンの白色固体（１．４７ｇ，収率：９２％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．７８−１．９１（ｍ，６Ｈ），４．０５−４．２０（ｍ，４Ｈ），４．４２（ｓ，２Ｈ），６．６７（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．１７（ｄ，Ｊ＝７．０Ｈｚ，１Ｈ），１０．２（ｍ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１６．１（ｓ，１Ｆ）．Example-83

Methyl 2- [4- (5-chloro-3-oxo-1,2-pentamethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] acetate (1.88 g, 4.54 mmol) ) In ethyl acetate (9 mL), acetic acid (4.5 mL) and water (0.8 mL) were added, and then reduced iron (2.54 g, 45.4 mmol) was added under ice-cooling. Stir for hours. After completion of the reaction, the reaction solution was cooled to room temperature, insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The precipitated solid was dissolved in chloroform and washed with water (50 mL × 3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-chloro-4- (7-fluoro-2,3-dihydro- A white solid (1.47 g, yield: 92%) of 3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-pentamethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.78-1.91 (m, 6H), 4.05-4.20 (m, 4H), 4.42 (s, 2H), 6.67 ( d, J = 9.9 Hz, 1H), 7.17 (d, J = 7.0 Hz, 1H), 10.2 (m, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-116.1 (s, 1F).

水素化ナトリウムの５５％油分散（０．０４１ｇ，０．９４ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８５ｍｍｏｌ）およびアリルブロミド（０．０７９ｍＬ，０．９４ｍｍｏｌ）を順次加え、室温で２１時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×３）、飽和食塩水（１０ｍＬ×１）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、４−（４−アリル−７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−５−クロロ−１，２−ペンタメチレン−４−ピラゾリン−３−オンの淡黄色固体（０．２１ｇ，収率：６４％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８２−１．８７（ｍ，６Ｈ），４．０７−４．１４（ｍ，４Ｈ），４．５４−４．５８（ｍ，２Ｈ），４．６５（ｓ，２Ｈ），５．２１−５．２７（ｍ，２Ｈ），５．８８（ｍ，１Ｈ），６．７９（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．１５（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．６（ｓ，１Ｆ）．Example-84

To a suspension of sodium hydride in 55% oil dispersion (0.041 g, 0.94 mmol) in DMF (2 mL) under ice-cooling, 5-chloro-4- (7-fluoro-2,3-dihydro-3- Oxo-4H-1,4-benzoxazin-6-yl) -1,2-pentamethylene-4-pyrazolin-3-one (0.30 g, 0.85 mmol) and allyl bromide (0.079 mL, 0.94 mmol) ) Were added sequentially, and the mixture was stirred at room temperature for 21 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with water (50 mL × 3) and saturated brine (10 mL × 1), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 4- (4-allyl-7-fluoro-2,3-dihydro-3-oxo-4H-1 , 4-Benzoxazin-6-yl) -5-chloro-1,2-pentamethylene-4-pyrazolin-3-one was obtained as a pale yellow solid (0.21 g, yield: 64%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.82-1.87 (m, 6H), 4.07-4.14 (m, 4H), 4.54-4.58 (m, 2H), 4.65 (s, 2H), 5.21-5.27 (m, 2H), 5.88 (m, 1H), 6.79 (d, J = 9.9 Hz, 1H), 7.15 ( d, J = 6.8 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.6 (s, 1F).

水素化ナトリウムの５５％油分散（０．０４１ｇ，０．９４ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８５ｍｍｏｌ）および３−ブロモ−２−メチルプロペン（０．０７９ｍＬ，０．９４ｍｍｏｌ）を順次加え、室温で２０時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×３）、飽和食塩水（１０ｍＬ×１）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、５−クロロ−４−［４−（２−メチルプロペニル）−７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−１，２−ペンタメチレン−４−ピラゾリン−３−オンの白色固体（０．２４ｇ，収率：７１％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．７７（ｓ，３Ｈ），１．８２−１．８７（ｍ，６Ｈ），４．０６−４．１３（ｍ，４Ｈ），４．４７（ｓ，２Ｈ），４．６５（ｓ，２Ｈ），４．８１（ｍ，１Ｈ），４．９３（ｍ，１Ｈ），６．７９（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．０８（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．５（ｓ，１Ｆ）．Example-85

To a suspension of sodium hydride in 55% oil dispersion (0.041 g, 0.94 mmol) in DMF (2 mL) under ice-cooling, 5-chloro-4- (7-fluoro-2,3-dihydro-3- Oxo-4H-1,4-benzoxazin-6-yl) -1,2-pentamethylene-4-pyrazolin-3-one (0.30 g, 0.85 mmol) and 3-bromo-2-methylpropene (0 .079 mL, 0.94 mmol) was sequentially added, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with water (50 mL × 3) and saturated brine (10 mL × 1), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 5-chloro-4- [4- (2-methylpropenyl) -7-fluoro-2,3- A white solid (0.24 g, yield: 71%) of dihydro-3-oxo-4H-1,4-benzoxazin-6-yl] -1,2-pentamethylene-4-pyrazolin-3-one was obtained. It was. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.77 (s, 3H), 1.82-1.87 (m, 6H), 4.06-4.13 (m, 4H), 4.47 ( s, 2H), 4.65 (s, 2H), 4.81 (m, 1H), 4.93 (m, 1H), 6.79 (d, J = 9.9 Hz, 1H), 7.08 (D, J = 6.8 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.5 (s, 1F).

水素化ナトリウムの５５％油分散（０．０４１ｇ，０．９４ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８５ｍｍｏｌ）およびプロパルギルブロミド（０．０７４ｍＬ，０．９４ｍｍｏｌ）を順次加え、室温で２０時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、クロロホルム（５０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オンの白色固体（０．２２ｇ，収率：６７％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８３−１．８８（ｍ，６Ｈ），２．２６（ｔ，Ｊ＝２．５Ｈｚ，１Ｈ），４．０８−４．１５（ｍ，４Ｈ），４．６５（ｓ，２Ｈ），４．７１（ｄ，Ｊ＝２．５Ｈｚ，２Ｈ），６．８１（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．３２（ｄ，Ｊ＝６．６Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．２（ｓ，１Ｆ）．Example-86

To a suspension of sodium hydride in 55% oil dispersion (0.041 g, 0.94 mmol) in DMF (2 mL) under ice-cooling, 5-chloro-4- (7-fluoro-2,3-dihydro-3- Oxo-4H-1,4-benzoxazin-6-yl) -1,2-pentamethylene-4-pyrazolin-3-one (0.30 g, 0.85 mmol) and propargyl bromide (0.074 mL, 0.94 mmol) ) Were added sequentially, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with chloroform (50 mL × 3). The organic layer was washed with water (50 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4-propargyl). -4H-1,4-benzoxazin-6-yl) -1,2-pentamethylene-4-pyrazolin-3-one was obtained as a white solid (0.22 g, yield: 67%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.83-1.88 (m, 6H), 2.26 (t, J = 2.5 Hz, 1H), 4.08-4.15 (m, 4H) ), 4.65 (s, 2H), 4.71 (d, J = 2.5 Hz, 2H), 6.81 (d, J = 9.9 Hz, 1H), 7.32 (d, J = 6) .6 Hz, 1 H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.2 (s, 1F).

水素化ナトリウムの５５％油分散（０．０４１ｇ，０．９４ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８５ｍｍｏｌ）および１−ブロモ−２−ブチン（０．０８８ｍＬ，０．９４ｍｍｏｌ）を順次加え、室温で１９時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×３）、飽和食塩水（１０ｍＬ×１）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、４−［４−（２−ブチニル）−７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−５−クロロ−１，２−ペンタメチレン−４−ピラゾリン−３−オンの白色固体（０．２４ｇ，収率：７１％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．７８（ｔ，Ｊ＝２．４Ｈｚ，３Ｈ），１．８３−１．８８（ｍ，６Ｈ），４．０７−４．１４（ｍ，４Ｈ），４．６３（ｑ，Ｊ＝２．４Ｈｚ，２Ｈ），４．６３（ｓ，２Ｈ），６．７９（ｄ，Ｊ＝９．８Ｈｚ，１Ｈ），７．２９（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．５（ｓ，１Ｆ）．Example-87

To a suspension of sodium hydride in 55% oil dispersion (0.041 g, 0.94 mmol) in DMF (2 mL) under ice-cooling, 5-chloro-4- (7-fluoro-2,3-dihydro-3- Oxo-4H-1,4-benzoxazin-6-yl) -1,2-pentamethylene-4-pyrazolin-3-one (0.30 g, 0.85 mmol) and 1-bromo-2-butyne (0. 088 mL, 0.94 mmol) was sequentially added, and the mixture was stirred at room temperature for 19 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with water (50 mL × 3) and saturated brine (10 mL × 1), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 4- [4- (2-butynyl) -7-fluoro-2,3-dihydro-3-oxo. -4H-1,4-benzoxazin-6-yl] -5-chloro-1,2-pentamethylene-4-pyrazolin-3-one was obtained as a white solid (0.24 g, yield: 71%). . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.78 (t, J = 2.4 Hz, 3H), 1.83 to 1.88 (m, 6H), 4.07-4.14 (m, 4H) ), 4.63 (q, J = 2.4 Hz, 2H), 4.63 (s, 2H), 6.79 (d, J = 9.8 Hz, 1H), 7.29 (d, J = 6) .7Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.5 (s, 1F).

水素化ナトリウムの５５％油分散（０．６１ｇ，１３．９ｍｍｏｌ）の１，４−ジオキサン（６０ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（２，４−ジフルオロ−５−ニトロフェニル）−１，２−ペンタメチレン−４−ピラゾリン−３−オン（４．００ｇ，１１．６ｍｍｏｌ）を加え、乳酸エチル（１．６ｍＬ，１３．９ｍｍｏｌ）を滴下し、室温で３時間撹拌した。反応終了後、反応液を氷水（１００ｇ）に注ぎ入れ、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）で精製した後、酢酸エチルで再結晶することにより、２−［４−（５−クロロ−３−オキソ−１，２−ペンタメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］−２−メチル酢酸メチルの黄色固体（２．５３ｇ，収率：４９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．２７（ｔ，Ｊ＝７．１Ｈｚ，３Ｈ），１．７１（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．８１−１．８７（ｍ，６Ｈ），４．０８−４．１５（ｍ，４Ｈ），４．２５（ｑ，Ｊ＝７．１Ｈｚ，２Ｈ），４．７９（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），６．７２（ｄ，Ｊ＝１０．９Ｈｚ，１Ｈ），８．１２（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−９９．２（ｓ，１Ｆ）．Reference Example-30

To a suspension of 55% oil dispersion of sodium hydride (0.61 g, 13.9 mmol) in 1,4-dioxane (60 mL) under ice-cooling, 5-chloro-4- (2,4-difluoro-5- Nitrophenyl) -1,2-pentamethylene-4-pyrazolin-3-one (4.00 g, 11.6 mmol) is added, ethyl lactate (1.6 mL, 13.9 mmol) is added dropwise, and the mixture is stirred at room temperature for 3 hours. did. After completion of the reaction, the reaction solution was poured into ice water (100 g) and extracted with ethyl acetate (50 mL × 3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) and then recrystallized from ethyl acetate to give 2- [4- (5-chloro-3-oxo-1). , 2-pentamethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] -2-methylacetate yellow solid (2.53 g, yield: 49%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.27 (t, J = 7.1 Hz, 3H), 1.71 (d, J = 6.8 Hz, 3H), 1.81-1.87 (m , 6H), 4.08-4.15 (m, 4H), 4.25 (q, J = 7.1 Hz, 2H), 4.79 (q, J = 6.8 Hz, 1H), 6.72. (D, J = 10.9 Hz, 1H), 8.12 (d, J = 7.4 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-99.2 (s, 1F).

２−［４−（５−クロロ−３−オキソ−１，２−ペンタメチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］−２−メチル酢酸メチル（２．２０ｇ，４．９８ｍｍｏｌ）の酢酸エチル（１０ｍＬ）溶液に、酢酸（５ｍＬ）および水（１ｍＬ）を加えた後、氷冷下で還元鉄（１．３９ｇ，２４．９ｍｍｏｌ）を加え、８０℃で３時間撹拌した。反応終了後、反応液を室温まで冷却し、不溶物をろ別後、ろ液を水（５０ｍＬ×３）、飽和炭酸水素ナトリウム水溶液（５０ｍＬ×３）で洗浄し、有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オンの白色固体（１．９５ｇ，定量的）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５１（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．８０−１．８８（ｍ，６Ｈ），４．０７−４．１８（ｍ，４Ｈ），４．５５（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），６．７０（ｄ，Ｊ＝１０．１Ｈｚ，１Ｈ），７．１５（ｄ，Ｊ＝６．９Ｈｚ，１Ｈ），９．４３（ｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１６．４（ｓ，１Ｆ）．Example-88

2- [4- (5-Chloro-3-oxo-1,2-pentamethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] -2-methyl acetate (2.20 g) , 4.98 mmol) in ethyl acetate (10 mL), acetic acid (5 mL) and water (1 mL) were added, and then reduced iron (1.39 g, 24.9 mmol) was added under ice-cooling. Stir for hours. After completion of the reaction, the reaction solution was cooled to room temperature, insoluble matters were filtered off, the filtrate was washed with water (50 mL × 3) and saturated aqueous sodium hydrogen carbonate solution (50 mL × 3), and the organic layer was washed with anhydrous magnesium sulfate. After drying, it is concentrated under reduced pressure to give 5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1, A white solid (1.95 g, quantitative) of 2-pentamethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.51 (d, J = 6.8 Hz, 3H), 1.80-1.88 (m, 6H), 4.07-4.18 (m, 4H) ), 4.55 (q, J = 6.8 Hz, 1H), 6.70 (d, J = 10.1 Hz, 1H), 7.15 (d, J = 6.9 Hz, 1H), 9.43 (S, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-116.4 (s, 1F).

水素化ナトリウムの５５％油分散（０．０３９ｇ，０．９０ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８２ｍｍｏｌ）およびアリルブロミド（０．０７６ｍＬ，０．９０ｍｍｏｌ）を順次加え、室温で１７時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×２）で抽出した。有機層を水（５０ｍＬ×４）洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）で精製することにより、４−（４−アリル−７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−５−クロロ−１，２−ペンタメチレン−４−ピラゾリン−３−オンの白色固体（０．２３ｇ，収率：７０％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５８（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．８１−１．８７（ｍ，６Ｈ），４．０６−４．１４（ｍ，４Ｈ），４．５１−４．５７（ｍ，２Ｈ），４．６８（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），５．１８−５．２５（ｍ，２Ｈ），５．８８（ｍ，１Ｈ），６．７９（ｄ，Ｊ＝１０．０Ｈｚ，１Ｈ），７．１２（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．７（ｓ，１Ｆ）．Example-89

To a suspension of sodium hydride in 55% oil dispersion (0.039 g, 0.90 mmol) in DMF (2 mL) under ice-cooling, 5-chloro-4- (7-fluoro-2,3-dihydro-2- Methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-pentamethylene-4-pyrazolin-3-one (0.30 g, 0.82 mmol) and allyl bromide (0.076 mL) , 0.90 mmol) was added sequentially, and the mixture was stirred at room temperature for 17 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic layer was washed with water (50 mL × 4), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 4- (4-allyl-7-fluoro-2,3-dihydro-2-methyl-3- Oxo-4H-1,4-benzoxazin-6-yl) -5-chloro-1,2-pentamethylene-4-pyrazolin-3-one was obtained as a white solid (0.23 g, yield: 70%). It was. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.58 (d, J = 6.8 Hz, 3H), 1.81-1.87 (m, 6H), 4.06-4.14 (m, 4H) ), 4.51-4.57 (m, 2H), 4.68 (q, J = 6.8 Hz, 1H), 5.18-5.25 (m, 2H), 5.88 (m, 1H) ), 6.79 (d, J = 10.0 Hz, 1H), 7.12 (d, J = 6.8 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.7 (s, 1F).

水素化ナトリウムの５５％油分散（０．０３９ｇ，０．９０ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８２ｍｍｏｌ）および３−ブロモ−２−メチルプロパン（０．０９４ｍＬ，０．９０ｍｍｏｌ）を順次加え、室温で１８時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×３）、飽和食塩水（１０ｍＬ×１）洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）で精製することにより、５−クロロ−４−［７−フルオロ−２，３−ジヒドロ−２−メチル−４−（２−メチルプロペニル）−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−１，２−ペンタメチレン−４−ピラゾリン−３−オンの白色固体（０．２４ｇ，収率：７１％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５８（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．７７（ｓ，３Ｈ），１．８１−１．８７（ｍ，６Ｈ），４．０５−４．１３（ｍ，４Ｈ），４．４１−４．４８（ｍ，２Ｈ），４．７０（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），４．７８（ｍ，１Ｈ），４．９２（ｍ，１Ｈ），６．７９（ｄ，Ｊ＝１０．０Ｈｚ，１Ｈ），７．０６（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．６（ｓ，１Ｆ）．Example-90

To a suspension of sodium hydride in 55% oil dispersion (0.039 g, 0.90 mmol) in DMF (2 mL) under ice-cooling, 5-chloro-4- (7-fluoro-2,3-dihydro-2- Methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-pentamethylene-4-pyrazolin-3-one (0.30 g, 0.82 mmol) and 3-bromo-2- Methylpropane (0.094 mL, 0.90 mmol) was sequentially added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with water (50 mL × 3) and saturated brine (10 mL × 1), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 5-chloro-4- [7-fluoro-2,3-dihydro-2-methyl-4- White solid (0.24 g, yield: (2-methylpropenyl) -3-oxo-4H-1,4-benzoxazin-6-yl] -1,2-pentamethylene-4-pyrazolin-3-one 71%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.58 (d, J = 6.8 Hz, 3H), 1.77 (s, 3H), 1.81-1.87 (m, 6H), 4. 05-4.13 (m, 4H), 4.41-4.48 (m, 2H), 4.70 (q, J = 6.8 Hz, 1H), 4.78 (m, 1H), 4. 92 (m, 1H), 6.79 (d, J = 10.0 Hz, 1H), 7.06 (d, J = 6.8 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.6 (s, 1F).

水素化ナトリウムの５５％油分散（０．０３９ｇ，０．９０ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８２ｍｍｏｌ）およびプロパルギルブロミド（０．０７１ｍＬ，０．９０ｍｍｏｌ）を順次加え、室温で１８時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×４）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）で精製することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オンの白色固体（０．１８ｇ，収率：５５％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５８（ｄ，Ｊ＝６．７Ｈｚ，３Ｈ），１．８３−１．８８（ｍ，６Ｈ），２．２４（ｄ，Ｊ＝２．５Ｈｚ，１Ｈ），４．０８−４．１５（ｍ，４Ｈ），４．６４（ｄｄ，Ｊ＝１７．６ ａｎｄ ２．５Ｈｚ，１Ｈ），４．６７（ｑ，Ｊ＝６．７Ｈｚ，１Ｈ），４．７５（ｄｄ，Ｊ＝１７．６ ａｎｄ ２．５Ｈｚ，１Ｈ），６．８０（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．２９（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．３（ｓ，１Ｆ）．Example-91

To a suspension of sodium hydride in 55% oil dispersion (0.039 g, 0.90 mmol) in DMF (2 mL) under ice-cooling, 5-chloro-4- (7-fluoro-2,3-dihydro-2- Methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-pentamethylene-4-pyrazolin-3-one (0.30 g, 0.82 mmol) and propargyl bromide (0.071 mL) , 0.90 mmol) was added sequentially, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with water (50 mL × 4), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3- A white solid (0.18 g, yield: 55%) of oxo-4-propargyl-4H-1,4-benzoxazin-6-yl) -1,2-pentamethylene-4-pyrazolin-3-one was obtained. It was. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.58 (d, J = 6.7 Hz, 3H), 1.83 to 1.88 (m, 6H), 2.24 (d, J = 2.5 Hz) , 1H), 4.08-4.15 (m, 4H), 4.64 (dd, J = 17.6 and 2.5 Hz, 1H), 4.67 (q, J = 6.7 Hz, 1H) , 4.75 (dd, J = 17.6 and 2.5 Hz, 1H), 6.80 (d, J = 9.9 Hz, 1H), 7.29 (d, J = 6.7 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.3 (s, 1F).

水素化ナトリウムの５５％油分散（０．０３９ｇ，０．９０ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８２ｍｍｏｌ）および１−ブロモ−２−ブチン（０．０８５ｍＬ，０．９０ｍｍｏｌ）を順次加え、室温で１４時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×４）、飽和食塩水（１０ｍＬ×１）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、４−［４−（２−ブチニル）−７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−５−クロロ−１，２−ペンタメチレン−４−ピラゾリン−３−オンの白色固体（０．２７ｇ，収率：７９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５８（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．７８（ｔ，Ｊ＝２．４Ｈｚ，３Ｈ），１．８３−１．８８（ｍ，６Ｈ），４．０８−４．１５（ｍ，４Ｈ），４．５５（ｄｑ，Ｊ＝１７．４ ａｎｄ ２．４Ｈｚ，１Ｈ），４．６５（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），４．６９（ｄｑ，Ｊ＝１７．４ ａｎｄ ２．４Ｈｚ，１Ｈ），６．７９（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．２７（ｍ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．７（ｓ，１Ｆ）．Example-92

To a suspension of sodium hydride in 55% oil dispersion (0.039 g, 0.90 mmol) in DMF (2 mL) under ice-cooling, 5-chloro-4- (7-fluoro-2,3-dihydro-2- Methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-pentamethylene-4-pyrazolin-3-one (0.30 g, 0.82 mmol) and 1-bromo-2- Butine (0.085 mL, 0.90 mmol) was sequentially added, and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with water (50 mL × 4) and saturated brine (10 mL × 1), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 4- [4- (2-butynyl) -7-fluoro-2,3-dihydro-2-methyl. -3-Oxo-4H-1,4-benzoxazin-6-yl] -5-chloro-1,2-pentamethylene-4-pyrazolin-3-one as a white solid (0.27 g, yield: 79% ) ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.58 (d, J = 6.8 Hz, 3H), 1.78 (t, J = 2.4 Hz, 3H), 1.83-1.88 (m , 6H), 4.08-4.15 (m, 4H), 4.55 (dq, J = 17.4 and 2.4 Hz, 1H), 4.65 (q, J = 6.8 Hz, 1H) , 4.69 (dq, J = 17.4 and 2.4 Hz, 1H), 6.79 (d, J = 9.9 Hz, 1H), 7.27 (m, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.7 (s, 1F).

水素化ナトリウムの５５％油分散（０．０３９ｇ，０．９０ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−ペンタメチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８２ｍｍｏｌ）およびブロモ酢酸エチル（０．１１ｍＬ，０．９０ｍｍｏｌ）を順次加え、室温で１４時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×４）、飽和食塩水（１０ｍＬ×１）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、５−クロロ−４−［４−（エトキシカルボニルメチル）−７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−１，２−ペンタメチレン−４−ピラゾリン−３−オンの黄色油状物（０．２７ｇ，収率：７３％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．２６（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．５９（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），１．８１−１．８７（ｍ，６Ｈ），４．０６−４．１３（ｍ，４Ｈ），４．２１（ｑ，Ｊ＝７．２Ｈｚ，２Ｈ），４．５８−４．６９（ｍ，２Ｈ），４．７２（ｑ，Ｊ＝６．８Ｈｚ．１Ｈ），６．８１（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），６．９３（ｄ，Ｊ＝６．６Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．５（ｓ，１Ｆ）．Example-93

To a suspension of sodium hydride in 55% oil dispersion (0.039 g, 0.90 mmol) in DMF (2 mL) under ice-cooling, 5-chloro-4- (7-fluoro-2,3-dihydro-2- Methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-pentamethylene-4-pyrazolin-3-one (0.30 g, 0.82 mmol) and ethyl bromoacetate (0. 11 mL, 0.90 mmol) was sequentially added, and the mixture was stirred at room temperature for 14 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with water (50 mL × 4) and saturated brine (10 mL × 1), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 5-chloro-4- [4- (ethoxycarbonylmethyl) -7-fluoro-2,3-dihydro. 2-Methyl-3-oxo-4H-1,4-benzoxazin-6-yl] -1,2-pentamethylene-4-pyrazolin-3-one as a yellow oil (0.27 g, yield: 73 %). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.26 (t, J = 7.2 Hz, 3H), 1.59 (d, J = 6.8 Hz, 3H), 1.81-1.87 (m , 6H), 4.06-4.13 (m, 4H), 4.21 (q, J = 7.2 Hz, 2H), 4.58-4.69 (m, 2H), 4.72 (q , J = 6.8 Hz. 1H), 6.81 (d, J = 9.9 Hz, 1H), 6.93 (d, J = 6.6 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.5 (s, 1F).

２−［４−（エトキシカルボニル）メトキシ−３−ニトロフェニル］−３，３−ジクロロアクリル酸エチル（１．００ｇ，２．５５ｍｍｏｌ）の１，４−ジオキサン（５ｍＬ）溶液に１，４，５−オキサジアゼパン二臭化水素塩（０．７４ｇ，２．８１ｍｍｏｌ）およびトリエチルアミン（１．２ｍＬ，８．４２ｍｍｏｌ）を室温で加えた後、加熱還流しながら７時間撹拌した。反応終了後、反応液に水（５０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、２−［４−（５−クロロ−３−オキソ−１，２−オキサジエチレン−４−ピラゾリン−４−イル）−２−ニトロフェニルオキシ］酢酸エチルの黄色固体（０．６８ｇ，収率：６４％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．２９（ｔ，Ｊ＝７．１Ｈｚ，３Ｈ），３．９０−３．９５（ｍ，４Ｈ），４．２１−４．２４（ｍ，２Ｈ），４．２７（ｑ，Ｊ＝７．１Ｈｚ，２Ｈ），４．２４−４．３０（ｍ，２Ｈ），４．７８（ｓ，２Ｈ），７．０２（ｄ，Ｊ＝８．９Ｈｚ，１Ｈ），８．１４（ｄｄ，Ｊ＝８．８ ａｎｄ ２．３Ｈｚ，１Ｈ），８．３６（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）．Reference Example-31

To a solution of ethyl 2- [4- (ethoxycarbonyl) methoxy-3-nitrophenyl] -3,3-dichloroacrylate (1.00 g, 2.55 mmol) in 1,4-dioxane (5 mL), 1,4,5 -Oxadiazepan dibromide (0.74 g, 2.81 mmol) and triethylamine (1.2 mL, 8.42 mmol) were added at room temperature, and the mixture was stirred for 7 hours while heating under reflux. After completion of the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 2- [4- (5-chloro-3-oxo-1,2-oxadiethylene-4-pyrazoline). -4-yl) -2-nitrophenyloxy] ethyl acetate yellow solid (0.68 g, yield: 64%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.29 (t, J = 7.1 Hz, 3H), 3.90-3.95 (m, 4H), 4.21-4.24 (m, 2H) ), 4.27 (q, J = 7.1 Hz, 2H), 4.24-4.30 (m, 2H), 4.78 (s, 2H), 7.02 (d, J = 8.9 Hz) , 1H), 8.14 (dd, J = 8.8 and 2.3 Hz, 1H), 8.36 (d, J = 2.3 Hz, 1H).

２−［４−（５−クロロ−３−オキソ−１，２−オキサジエチレン−４−ピラゾリン−４−イル）−２−ニトロフェニルオキシ］酢酸エチル（３．８０ｇ，９．２３ｍｍｏｌ）の酢酸エチル（１９ｍＬ）溶液に、酢酸（９．２ｍＬ）および水（２ｍＬ）を加えた後、氷冷下で還元鉄（２．５８ｇ，４６．２ｍｍｏｌ）を加え、８０℃で４時間撹拌した。反応終了後、反応液を室温まで冷却し、クロロホルム：酢酸＝１０：１の混合溶媒を加えた後、不溶物をろ別し、ろ液を水（２００ｍＬ×２）で洗浄し、有機層を減圧濃縮した。得られた粗生成物をクロロホルムに溶かし、ヘキサンを加えて析出した固体をろ取し、乾燥させることにより、５−クロロ−４−（２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（２．６６ｇ，収率：８６％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ３．９０−３．９６（ｍ，４Ｈ），４．１８−４．２２（ｍ，２Ｈ），４．２８−４．３２（ｍ，２Ｈ），４．５７（ｓ，２Ｈ），６．９７（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．３３（ｄｄ，Ｊ＝８．４ ａｎｄ ２．０Ｈｚ，１Ｈ），７．５４（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ），８．４９（ｓ，１Ｈ）．Example-94

2- [4- (5-Chloro-3-oxo-1,2-oxadiethylene-4-pyrazolin-4-yl) -2-nitrophenyloxy] ethyl acetate (3.80 g, 9.23 mmol) in ethyl acetate (19 mL) To the solution, acetic acid (9.2 mL) and water (2 mL) were added, and then reduced iron (2.58 g, 46.2 mmol) was added under ice cooling, followed by stirring at 80 ° C. for 4 hours. After completion of the reaction, the reaction solution was cooled to room temperature, a mixed solvent of chloroform: acetic acid = 10: 1 was added, insoluble matters were filtered off, the filtrate was washed with water (200 mL × 2), and the organic layer was separated. Concentrated under reduced pressure. The obtained crude product was dissolved in chloroform, hexane was added and the precipitated solid was collected by filtration and dried to give 5-chloro-4- (2,3-dihydro-3-oxo-4H-1,4. A white solid (2.66 g, yield: 86%) of -benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.90-3.96 (m, 4H), 4.18-4.22 (m, 2H), 4.28-4.32 (m, 2H), 4.57 (s, 2H), 6.97 (d, J = 8.4 Hz, 1H), 7.33 (dd, J = 8.4 and 2.0 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H), 8.49 (s, 1H).

水素化ナトリウムの５５％油分散（０．０４３ｇ，０．９８ｍｍｏｌ）のＤＭＦ（２．２ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８９ｍｍｏｌ）および（ブロモメチル）シクロプロパン（０．０９９ｍＬ，０．９８ｍｍｏｌ）を順次加え、室温で２０時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（３０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、５−クロロ−４−（４−シクロプロピルメチル−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（０．２６ｇ，収率：７４％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ０．４４−０．５５（ｍ，４Ｈ），１．２３−１．３５（ｍ，１Ｈ），３．８７−３．９１（ｍ，２Ｈ），３．９１−３．９６（ｍ，４Ｈ），４．１８−４．２１（ｍ，２Ｈ），４．２５−４．２９（ｍ，２Ｈ），４．６２（ｓ，２Ｈ），７．０１（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．４０（ｄｄ，Ｊ＝８．４ ａｎｄ ２．０Ｈｚ，１Ｈ），７．７８（ｄ，Ｊ＝１．９Ｈｚ，１Ｈ）．Example-95

To a suspension of sodium hydride in 55% oil dispersion (0.043 g, 0.98 mmol) in DMF (2.2 mL) under ice-cooling, 5-chloro-4- (2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one (0.30 g, 0.89 mmol) and (bromomethyl) cyclopropane (0.099 mL, 0. 0). 98 mmol) was added sequentially, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was washed with water (50 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 5-chloro-4- (4-cyclopropylmethyl-2,3-dihydro-3-oxo-4H A white solid (0.26 g, yield: 74%) of -1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.44-0.55 (m, 4H), 1.23-1.35 (m, 1H), 3.87-3.91 (m, 2H), 3.91-3.96 (m, 4H), 4.18-4.21 (m, 2H), 4.25-4.29 (m, 2H), 4.62 (s, 2H), 7. 01 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 8.4 and 2.0 Hz, 1H), 7.78 (d, J = 1.9 Hz, 1H).

水素化ナトリウムの５５％油分散（０．０４３ｇ，０．９８ｍｍｏｌ）のＤＭＦ（２．２ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８９ｍｍｏｌ）およびアリルブロミド（０．０８３ｍＬ，０．９８ｍｍｏｌ）を順次加え、室温で２０時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（３０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、４−（４−アリル−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−５−クロロ−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（０．２１ｇ，収率：６４％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ３．９０−３．９５（ｍ，４Ｈ），４．１６−４．２０（ｍ，２Ｈ），４．２４−４．２７（ｍ，２Ｈ），４．５８−４．６１（ｍ，２Ｈ），４．６５（ｓ，２Ｈ），５．２５（ｍ，１Ｈ），５．２８（ｍ，１Ｈ），５．９２（ｍ，１Ｈ），７．０１（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．４４（ｄｄ，Ｊ＝８．４ ａｎｄ ２．０Ｈｚ，１Ｈ），７．６２（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ）．Example-96

To a suspension of sodium hydride in 55% oil dispersion (0.043 g, 0.98 mmol) in DMF (2.2 mL) under ice-cooling, 5-chloro-4- (2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one (0.30 g, 0.89 mmol) and allyl bromide (0.083 mL, 0.98 mmol). Sequentially added and stirred at room temperature for 20 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layer was washed with water (50 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 4- (4-allyl-2,3-dihydro-3-oxo-4H-1,4-benzo A white solid (0.21 g, yield: 64%) of oxazin-6-yl) -5-chloro-1,2-oxadiethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.90-3.95 (m, 4H), 4.16-4.20 (m, 2H), 4.24-4.27 (m, 2H), 4.58-4.61 (m, 2H), 4.65 (s, 2H), 5.25 (m, 1H), 5.28 (m, 1H), 5.92 (m, 1H), 7 .01 (d, J = 8.4 Hz, 1H), 7.44 (dd, J = 8.4 and 2.0 Hz, 1H), 7.62 (d, J = 2.0 Hz, 1H).

水素化ナトリウムの５５％油分散（０．０４３ｇ，０．９８ｍｍｏｌ）のＤＭＦ（２．２ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８９ｍｍｏｌ）およびプロパルギルブロミド（０．０７８ｍＬ，０．９８ｍｍｏｌ）を順次加え、室温で２２時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、クロロホルム（５０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×３）、飽和食塩水（１０ｍＬ×１）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、５−クロロ−４−（２，３−ジヒドロ−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（０．２３ｇ，収率：７０％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ２．２７（ｔ，Ｊ＝２．５Ｈｚ，１Ｈ），３．９１−３．９６（ｍ，４Ｈ），４．１８−４．２１（ｍ，２Ｈ），４．２６−４．２９（ｍ，２Ｈ），４．６５（ｓ，２Ｈ），４．７４（ｄ，Ｊ＝２．５Ｈｚ，２Ｈ），７．０４（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．５０（ｄｄ，Ｊ＝８．４ ａｎｄ １．９Ｈｚ，１Ｈ），７．７５（ｄ，Ｊ＝１．９Ｈｚ，１Ｈ）．Example-97

To a suspension of sodium hydride in 55% oil dispersion (0.043 g, 0.98 mmol) in DMF (2.2 mL) under ice-cooling, 5-chloro-4- (2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one (0.30 g, 0.89 mmol) and propargyl bromide (0.078 mL, 0.98 mmol). Sequentially added and stirred at room temperature for 22 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with chloroform (50 mL × 3). The organic layer was washed with water (50 mL × 3) and saturated brine (10 mL × 1), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 5-chloro-4- (2,3-dihydro-3-oxo-4-propargyl-4H-1 , 4-Benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one was obtained as a white solid (0.23 g, yield: 70%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.27 (t, J = 2.5 Hz, 1H), 3.91-3.96 (m, 4H), 4.18-4.21 (m, 2H) ), 4.26-4.29 (m, 2H), 4.65 (s, 2H), 4.74 (d, J = 2.5 Hz, 2H), 7.04 (d, J = 8.4 Hz) , 1H), 7.50 (dd, J = 8.4 and 1.9 Hz, 1H), 7.75 (d, J = 1.9 Hz, 1H).

水素化ナトリウムの５５％油分散（０．０４３ｇ，０．９８ｍｍｏｌ）のＤＭＦ（２．２ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８９ｍｍｏｌ）および１−ブロモ−２−ブチン（０．０９２ｍＬ，０．９８ｍｍｏｌ）を順次加え、室温で２０時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×２）で抽出した。有機層を水（５０ｍＬ×４）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、４−［４−（２−ブチニル）−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−５−クロロ−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（０．２４ｇ，収率：６９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．７９（ｔ，Ｊ＝２．４Ｈｚ，３Ｈ），３．９１−３．９６（ｍ，４Ｈ），４．１８−４．２１（ｍ，２Ｈ），４．２６−４．２９（ｍ，２Ｈ），４．６４（ｓ，２Ｈ），４．６６（ｑ，Ｊ＝２．４Ｈｚ，２Ｈ），７．０２（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．５０（ｄｄ，Ｊ＝８．４ ａｎｄ １．９Ｈｚ，１Ｈ），７．６９（ｄ，Ｊ＝１．９Ｈｚ，１Ｈ）．Example-98

To a suspension of sodium hydride in 55% oil dispersion (0.043 g, 0.98 mmol) in DMF (2.2 mL) under ice-cooling, 5-chloro-4- (2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one (0.30 g, 0.89 mmol) and 1-bromo-2-butyne (0.092 mL, 0.98 mmol) was sequentially added, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic layer was washed with water (50 mL × 4), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 4- [4- (2-butynyl) -2,3-dihydro-3-oxo-4H-1 , 4-Benzoxazin-6-yl] -5-chloro-1,2-oxadiethylene-4-pyrazolin-3-one was obtained as a white solid (0.24 g, yield: 69%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.79 (t, J = 2.4 Hz, 3H), 3.91-3.96 (m, 4H), 4.18-4.21 (m, 2H) ), 4.26-4.29 (m, 2H), 4.64 (s, 2H), 4.66 (q, J = 2.4 Hz, 2H), 7.02 (d, J = 8.4 Hz) , 1H), 7.50 (dd, J = 8.4 and 1.9 Hz, 1H), 7.69 (d, J = 1.9 Hz, 1H).

水素化ナトリウムの５５％油分散（０．４２ｇ，９．５５ｍｍｏｌ）の１，４−ジオキサン（４３ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（２，４−ジフルオロ−５−ニトロフェニル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（３．００ｇ，８．６８ｍｍｏｌ）を加え、グリコール酸メチル（１．０３ｍＬ，１３．０ｍｍｏｌ）を滴下し、室温で６時間撹拌した。反応終了後、反応液を氷水（１５０ｇ）に注ぎ入れ、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）で精製することにより、２−［４−（５−クロロ−３−オキソ−１，２−オキサジエチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］酢酸メチルの淡黄色固体（２．６１ｇ，収率：７２％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ３．８３（ｓ，３Ｈ），３．９２−３．９６（ｍ，４Ｈ），４．２３−４．２６（ｍ，２Ｈ），４．２６−４．３０（ｍ，２Ｈ），４．７９（ｓ，２Ｈ），７．７５（ｄ，Ｊ＝１０．７Ｈｚ，１Ｈ），８．１６（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−９８．６（ｓ，１Ｆ）．Reference Example-32

To a suspension of 55% oil dispersion of sodium hydride (0.42 g, 9.55 mmol) in 1,4-dioxane (43 mL) was added 5-chloro-4- (2,4-difluoro-5- 5 under ice cooling. Nitrophenyl) -1,2-oxadiethylene-4-pyrazolin-3-one (3.00 g, 8.68 mmol) is added, and methyl glycolate (1.03 mL, 13.0 mmol) is added dropwise at room temperature for 6 hours. Stir. After completion of the reaction, the reaction solution was poured into ice water (150 g) and extracted with ethyl acetate (50 mL × 3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 2- [4- (5-chloro-3-oxo-1,2-oxadiethylene-4- A pale yellow solid (2.61 g, yield: 72%) of methyl pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] acetate was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.83 (s, 3H), 3.92-3.96 (m, 4H), 4.23-4.26 (m, 2H), 4.26- 4.30 (m, 2H), 4.79 (s, 2H), 7.75 (d, J = 10.7 Hz, 1H), 8.16 (d, J = 7.4 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-98.6 (s, 1F).

２−［４−（５−クロロ−３−オキソ−１，２−オキサジエチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］酢酸メチル（２．３８ｇ，５．７２ｍｍｏｌ）の酢酸エチル（１１ｍＬ）溶液に、酢酸（５．７ｍＬ）および水（１ｍＬ）を加えた後、氷冷下で還元鉄（３．１９ｇ，５７．２ｍｍｏｌ）を加え、８０℃で３時間撹拌した。反応終了後、反応液を室温まで冷却し、不溶物をろ別後、ろ液を飽和炭酸水素ナトリウム水溶液（５０ｍＬ×１）で洗浄し、有機層を減圧濃縮した。析出した固体を水およびエーテルで洗浄することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（１．６９ｇ，収率：７６％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ３．９２−３．９８（ｍ，４Ｈ），４．２１−４．２５（ｍ，２Ｈ），４．２８−４．３２（ｍ，２Ｈ），４．５２（ｓ，２Ｈ），６．７４（ｄ，Ｊ＝１０．１Ｈｚ，１Ｈ），７．１０（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ），９．０３（ｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．９（ｓ，１Ｆ）．Example-99

Methyl 2- [4- (5-chloro-3-oxo-1,2-oxadiethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] acetate (2.38 g, 5.72 mmol) Acetic acid (5.7 mL) and water (1 mL) were added to an ethyl acetate (11 mL) solution, and then reduced iron (3.19 g, 57.2 mmol) was added under ice cooling, followed by stirring at 80 ° C. for 3 hours. did. After completion of the reaction, the reaction solution was cooled to room temperature, insoluble matters were filtered off, the filtrate was washed with a saturated aqueous sodium hydrogen carbonate solution (50 mL × 1), and the organic layer was concentrated under reduced pressure. The precipitated solid was washed with water and ether to give 5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1, A white solid (1.69 g, yield: 76%) of 2-oxadiethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.92-3.98 (m, 4H), 4.21-4.25 (m, 2H), 4.28-4.32 (m, 2H), 4.52 (s, 2H), 6.74 (d, J = 10.1 Hz, 1H), 7.10 (d, J = 6.8 Hz, 1H), 9.03 (s, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.9 (s, 1F).

水素化ナトリウムの５５％油分散（０．０４１ｇ，０．９４ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８５ｍｍｏｌ）および（ブロモメチル）シクロプロパン（０．０９４ｍＬ，０．９４ｍｍｏｌ）を順次加え、室温で２２時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×３）、飽和食塩水（２０ｍＬ×１）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）で精製することにより、５−クロロ−４−（４−シクロプロピルメチル−７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（０．１５ｇ，収率：４３％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ０．４２−０．４７（ｍ，２Ｈ），０．４９−０．５５（ｍ，２Ｈ），１．１８−１．２９（ｍ，１Ｈ），３．８３−３．８６（ｍ，２Ｈ），３．９３−３．９６（ｍ，４Ｈ），４．２０−４．２４（ｍ，２Ｈ），４．２６−４．２９（ｍ，２Ｈ），４．６２（ｓ，２Ｈ），６．８０（ｄ，Ｊ＝１０．０Ｈｚ，１Ｈ），７．２８（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１６．０（ｓ，１Ｆ）．Example-100

To a suspension of sodium hydride in 55% oil dispersion (0.041 g, 0.94 mmol) in DMF (2 mL) under ice cooling, 5-chloro-4- (7-fluoro-2,3-dihydro-3- Oxo-4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one (0.30 g, 0.85 mmol) and (bromomethyl) cyclopropane (0.094 mL, 0.94 mmol) was sequentially added, and the mixture was stirred at room temperature for 22 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with water (50 mL × 3) and saturated brine (20 mL × 1), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 5-chloro-4- (4-cyclopropylmethyl-7-fluoro-2,3-dihydro- A white solid (0.15 g, yield: 43%) of 3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.42-0.47 (m, 2H), 0.49-0.55 (m, 2H), 1.18-1.29 (m, 1H), 3.83-3.86 (m, 2H), 3.93-3.96 (m, 4H), 4.20-4.24 (m, 2H), 4.26-4.29 (m, 2H) ), 4.62 (s, 2H), 6.80 (d, J = 10.0 Hz, 1H), 7.28 (d, J = 6.8 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-116.0 (s, 1F).

水素化ナトリウムの５５％油分散（０．０４１ｇ，０．９４ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８５ｍｍｏｌ）およびアリルブロミド（０．０７９ｍＬ，０．９４ｍｍｏｌ）を順次加え、室温で４時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×４）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をヘキサンで洗浄することにより、４−（４−アリル−７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−５−クロロ−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（０．２６ｇ，収率：７９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ３．９２−３．９６（ｍ，４Ｈ），４．２０−４．２２（ｍ，２Ｈ），４．２５−４．２８（ｍ，２Ｈ），４．５４−４．５８（ｍ，２Ｈ），４．６６（ｓ，２Ｈ），５．２１−５．２７（ｍ，２Ｈ），５．８８（ｍ，１Ｈ），６．８０（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．１３（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．５（ｓ，１Ｆ）．Example-101

To a suspension of sodium hydride in 55% oil dispersion (0.041 g, 0.94 mmol) in DMF (2 mL) under ice-cooling, 5-chloro-4- (7-fluoro-2,3-dihydro-3- Oxo-4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one (0.30 g, 0.85 mmol) and allyl bromide (0.079 mL, 0.94 mmol) ) Were sequentially added and stirred at room temperature for 4 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with water (50 mL × 4), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was washed with hexane to give 4- (4-allyl-7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -5. A white solid (0.26 g, yield: 79%) of -chloro-1,2-oxadiethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.92-3.96 (m, 4H), 4.20-4.22 (m, 2H), 4.25-4.28 (m, 2H), 4.54-4.58 (m, 2H), 4.66 (s, 2H), 5.21-5.27 (m, 2H), 5.88 (m, 1H), 6.80 (d, J = 9.9 Hz, 1H), 7.13 (d, J = 6.7 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.5 (s, 1F).

水素化ナトリウムの５５％油分散（０．０４１ｇ，０．９４ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８５ｍｍｏｌ）およびプロパルギルブロミド（０．０７４ｍＬ，０．９４ｍｍｏｌ）を順次加え、室温で２時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、クロロホルム（１００ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をヘキサンで洗浄することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（０．２８ｇ，収率：８５％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ２．２６（ｔ，Ｊ＝２．５Ｈｚ，１Ｈ），３．９３−３．９７（ｍ，４Ｈ），４．２１−４．２４（ｍ，２Ｈ），４．２６−４．３０（ｍ，２Ｈ），４．６６（ｓ，２Ｈ），４．７１（ｄ，Ｊ＝２．５Ｈｚ，２Ｈ），６．８２（ｄ，Ｊ＝９．８Ｈｚ，１Ｈ），７．３０（ｄ，Ｊ＝６．６Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．１（ｓ，１Ｆ）．Example-102

To a suspension of sodium hydride in 55% oil dispersion (0.041 g, 0.94 mmol) in DMF (2 mL) under ice-cooling, 5-chloro-4- (7-fluoro-2,3-dihydro-3- Oxo-4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one (0.30 g, 0.85 mmol) and propargyl bromide (0.074 mL, 0.94 mmol) ) Were added sequentially, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with chloroform (100 mL × 3). The organic layer was washed with water (50 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was washed with hexane to give 5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4-propargyl-4H-1,4-benzoxazine-6- Yl) -1,2-oxadiethylene-4-pyrazolin-3-one was obtained as a white solid (0.28 g, yield: 85%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.26 (t, J = 2.5 Hz, 1H), 3.93-3.97 (m, 4H), 4.21-4.24 (m, 2H) ), 4.26-4.30 (m, 2H), 4.66 (s, 2H), 4.71 (d, J = 2.5 Hz, 2H), 6.82 (d, J = 9.8 Hz) , 1H), 7.30 (d, J = 6.6 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.1 (s, 1F).

水素化ナトリウムの５５％油分散（０．０４１ｇ，０．９４ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．８５ｍｍｏｌ）および１−ブロモ−２−ブチン（０．０８８ｍＬ，０．９４ｍｍｏｌ）を順次加え、室温で３時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（５０ｍＬ×３）で抽出した。有機層を水（５０ｍＬ×４）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をヘキサンで洗浄することにより、４−［４−（２−ブチニル）−７−フルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−５−クロロ−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（０．３０ｇ，収率：８８％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．７９（ｔ，Ｊ＝２．４Ｈｚ，３Ｈ），３．９４−３．９７（ｍ，４Ｈ），４．２０−４．２３（ｍ，２Ｈ），４．２６−４．３０（ｍ，２Ｈ），４．６３（ｑ，Ｊ＝２．４Ｈｚ，２Ｈ），４．６４（ｓ，２Ｈ），６．８１（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．２８（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．５（ｓ，１Ｆ）．Example-103

To a suspension of sodium hydride in 55% oil dispersion (0.041 g, 0.94 mmol) in DMF (2 mL) under ice-cooling, 5-chloro-4- (7-fluoro-2,3-dihydro-3- Oxo-4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one (0.30 g, 0.85 mmol) and 1-bromo-2-butyne (0. 088 mL, 0.94 mmol) was sequentially added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layer was washed with water (50 mL × 4), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was washed with hexane to give 4- [4- (2-butynyl) -7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazine-6- Yl] -5-chloro-1,2-oxadiethylene-4-pyrazolin-3-one (0.30 g, yield: 88%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.79 (t, J = 2.4 Hz, 3H), 3.94-3.97 (m, 4H), 4.20-4.23 (m, 2H) ), 4.26-4.30 (m, 2H), 4.63 (q, J = 2.4 Hz, 2H), 4.64 (s, 2H), 6.81 (d, J = 9.9 Hz). , 1H), 7.28 (d, J = 6.7 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.5 (s, 1F).

水素化ナトリウムの５５％油分散（４９０ｍｇ，１１．３ｍｍｏｌ）の１，４−ジオキサン（５３ｍＬ）懸濁液に、５−クロロ−４−（２，４−ジフルオロ−５−ニトロフェニル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（３．００ｇ，８．６８ｍｍｏｌ）及びＬ−（−）−乳酸メチル（１．２６ｍＬ，１３．０ｍｍｏｌ）を加え、室温で３時間撹拌した。反応終了後、反応液を氷水（１００ｇ）に注ぎ入れ、酢酸エチル（１００ｍＬ×２）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９：１）で精製した後、得られた生成物をクロロホルムから再結晶することにより、（Ｓ）−２−［４−（５−クロロ−３−オキソ−１，２−オキサジエチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］プロピオン酸メチルの淡黄色固体（１．９０ｇ，収率：５１％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．７２（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），３．７９（ｓ，３Ｈ），３．９１‐３．９６（ｍ，４Ｈ），４．２１−４．２６（ｍ，２Ｈ），４．２６−４．３０（ｍ，２Ｈ），４．８２（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），６．７２（ｄ，Ｊ＝１０．９Ｈｚ，１Ｈ），８．１１（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−９９．０（ｓ，１Ｆ）．Reference Example-33

To a suspension of sodium hydride in 55% oil dispersion (490 mg, 11.3 mmol) in 1,4-dioxane (53 mL), 5-chloro-4- (2,4-difluoro-5-nitrophenyl) -1, 2-Oxadiethylene-4-pyrazolin-3-one (3.00 g, 8.68 mmol) and L-(−)-methyl lactate (1.26 mL, 13.0 mmol) were added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was poured into ice water (100 g) and extracted with ethyl acetate (100 mL × 2). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 9: 1), and then the obtained product was recrystallized from chloroform to obtain (S) -2- [4- ( Light yellow solid of methyl 5-chloro-3-oxo-1,2-oxadiethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] propionate (1.90 g, yield: 51 %). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.72 (d, J = 6.8 Hz, 3H), 3.79 (s, 3H), 3.91-3.96 (m, 4H), 4. 21-4.26 (m, 2H), 4.26-4.30 (m, 2H), 4.82 (q, J = 6.8 Hz, 1H), 6.72 (d, J = 10.9 Hz) , 1H), 8.11 (d, J = 7.4 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-99.0 (s, 1F).

（Ｓ）−２−［４−（５−クロロ−３−オキソ−１，２−オキサジエチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］プロピオン酸メチル（８００ｍｇ，１．８８ｍｍｏｌ）の酢酸エチル（３．７ｍＬ）溶液に、水（０．３ｍＬ）及び酢酸（３．０ｍＬ）を加えた後、還元鉄（５２０ｍｇ，９．３ｍｍｏｌ）を加え、８０℃で１８時間撹拌した。反応終了後、反応液を室温へし、不溶物をろ別後、ろ液に飽和炭酸水素ナトリウム水溶液（１００ｍＬ）を加え、クロロホルム（１００ｍＬ×２）で抽出した。有機層を飽和炭酸水素ナトリウム水溶液（５０ｍＬ×３）及び飽和食塩水（２０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をクロロホルムに溶かし、ヘキサンを加えて析出した固体をろ取することにより、（Ｓ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン‐３−オンの白色固体（５８０ｍｇ，収率：８５％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５６（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），３．９１−３．９６（ｍ，４Ｈ），４．２０−４．２４（ｍ，２Ｈ），４．２８−４．３１（ｍ，２Ｈ），４．６２（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），６．７６（ｄ，Ｊ＝１０．２Ｈｚ，１Ｈ），７．０５（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ），８．３８（ｂｒｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．７（ｓ，１Ｆ）．Example-104

(S) -2- [4- (5-Chloro-3-oxo-1,2-oxadiethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] methyl propionate (800 mg, 1.88 mmol) in ethyl acetate (3.7 mL), water (0.3 mL) and acetic acid (3.0 mL) were added, and then reduced iron (520 mg, 9.3 mmol) was added, followed by heating at 80 ° C. for 18 hours. Stir. After completion of the reaction, the reaction solution was brought to room temperature, insolubles were filtered off, saturated aqueous sodium hydrogen carbonate solution (100 mL) was added to the filtrate, and the mixture was extracted with chloroform (100 mL × 2). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL × 3) and saturated brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was dissolved in chloroform, hexane was added, and the precipitated solid was collected by filtration to give (S) -5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl- A white solid (580 mg, yield: 85%) of 3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.56 (d, J = 6.8 Hz, 3H), 3.91-3.96 (m, 4H), 4.20-4.24 (m, 2H) ), 4.28-4.31 (m, 2H), 4.62 (q, J = 6.8 Hz, 1H), 6.76 (d, J = 10.2 Hz, 1H), 7.05 (d , J = 6.8 Hz, 1H), 8.38 (brs, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.7 (s, 1F).

水素化ナトリウムの５５％油分散（５２ｍｇ，１．２０ｍｍｏｌ）のＤＭＦ（２．７ｍＬ）懸濁液に、氷冷下で（Ｓ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（４００ｍｇ，１．０９ｍｍｏｌ）及びプロパルギルブロミド（９５μＬ，１．２０ｍｍｏｌ）を順次加え、室温で１７時間撹拌した。反応終了後、反応液に水（５０ｍＬ）を加え、クロロホルム（１００ｍＬ×２）で抽出した。有機層を水（５０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝４：１）で精製することにより、（Ｓ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−５−クロロ−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（３８５ｍｇ，収率：８９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５９（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），２．２５（ｔ，Ｊ＝２．５Ｈｚ，１Ｈ），３．９２−３．９８（ｍ，４Ｈ），４．２０−４．２５（ｍ，２Ｈ），４．２６−４．３０（ｍ，２Ｈ），４．６３（ｄｄ，Ｊ＝１７．６ ａｎｄ ２．５Ｈｚ，１Ｈ），４．６７（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），４．７５（ｄｄ，Ｊ＝１７．６ ａｎｄ ２．５Ｈｚ，１Ｈ），６．８２（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．２８（ｄ，Ｊ＝６．６Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．３（ｓ，１Ｆ）．Example-105

To a suspension of sodium hydride in 55% oil dispersion (52 mg, 1.20 mmol) in DMF (2.7 mL) under ice cooling, (S) -5-chloro-4- (7-fluoro-2,3- Dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one (400 mg, 1.09 mmol) and propargyl bromide (95 μL , 1.20 mmol) were sequentially added, and the mixture was stirred at room temperature for 17 hours. After completion of the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with chloroform (100 mL × 2). The organic layer was washed with water (50 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 4: 1) to give (S) -5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl). -3-Oxo-4-propargyl-4H-1,4-benzoxazin-6-yl) -5-chloro-1,2-oxadiethylene-4-pyrazolin-3-one as a white solid (385 mg, yield: 89%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.59 (d, J = 6.8 Hz, 3H), 2.25 (t, J = 2.5 Hz, 1H), 3.92-3.98 (m , 4H), 4.20-4.25 (m, 2H), 4.26-4.30 (m, 2H), 4.63 (dd, J = 17.6 and 2.5 Hz, 1H), 4 .67 (q, J = 6.8 Hz, 1H), 4.75 (dd, J = 17.6 and 2.5 Hz, 1H), 6.82 (d, J = 9.9 Hz, 1H), 7. 28 (d, J = 6.6 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.3 (s, 1F).

水素化ナトリウムの５５％油分散（４９０ｍｇ，１１．３ｍｍｏｌ）の１，４−ジオキサン（５３ｍＬ）懸濁液に、５−クロロ−４−（２，４−ジフルオロ−５−ニトロフェニル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（３．００ｇ，８．６８ｍｍｏｌ）及びＤ−（＋）−乳酸メチル（１．２６ｍＬ，１３．０ｍｍｏｌ）を加え、室温で４時間撹拌した。反応終了後、反応液を氷水（１００ｇ）に注ぎ入れ、酢酸エチル（１００ｍＬ×２）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９：１）で精製した後、得られた生成物をクロロホルムから再結晶することにより、（Ｒ）−２−［４−（５−クロロ−３−オキソ−１，２−オキサジエチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］プロピオン酸メチルの淡黄色固体（２．２４ｇ，収率：６０％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．７２（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），３．８０（ｓ，３Ｈ），３．９２−３．９５（ｍ，４Ｈ），４．２２−４．２６（ｍ，２Ｈ），４．２６−４．２９（ｍ，２Ｈ），４．８２（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），６．７２（ｄ，Ｊ＝１０．９Ｈｚ，１Ｈ），８．１２（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−９９．０（ｓ，１Ｆ）．Reference Example-34

To a suspension of sodium hydride in 55% oil dispersion (490 mg, 11.3 mmol) in 1,4-dioxane (53 mL), 5-chloro-4- (2,4-difluoro-5-nitrophenyl) -1, 2-Oxadiethylene-4-pyrazolin-3-one (3.00 g, 8.68 mmol) and D-(+)-methyl lactate (1.26 mL, 13.0 mmol) were added, and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was poured into ice water (100 g) and extracted with ethyl acetate (100 mL × 2). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 9: 1), and then the obtained product was recrystallized from chloroform to give (R) -2- [4- ( Light yellow solid of methyl 5-chloro-3-oxo-1,2-oxadiethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] propionate (2.24 g, yield: 60 %). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.72 (d, J = 6.8 Hz, 3H), 3.80 (s, 3H), 3.92-3.95 (m, 4H), 4. 22-4.26 (m, 2H), 4.26-4.29 (m, 2H), 4.82 (q, J = 6.8 Hz, 1H), 6.72 (d, J = 10.9 Hz) , 1H), 8.12 (d, J = 7.4 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-99.0 (s, 1F).

（Ｒ）−２−［４−（５−クロロ−３−オキソ−１，２−オキサジエチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］プロピオン酸メチル（１．００ｇ，２．３３ｍｍｏｌ）の酢酸エチル（４．７ｍＬ）溶液に、水（０．４ｍＬ）及び酢酸（２．３ｍＬ）を加えた後、還元鉄（６５０ｍｇ，１１．７ｍｍｏｌ）を加え、８０℃で６時間撹拌した。反応終了後、反応液を室温へ戻し、不溶物をろ別後、ろ液に飽和炭酸水素ナトリウム水溶液（１００ｍＬ）を加え、クロロホルム（１００ｍＬ×２）で抽出した。有機層を飽和炭酸水素ナトリウム水溶液（１００ｍＬ×３）及び飽和食塩水（２０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮することにより、（Ｒ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（７６９ｍｇ，収率：９０％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５５（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），３．９１−３．９６（ｍ，４Ｈ），４．２０−４．２４（ｍ，２Ｈ），４．２８−４．３２（ｍ，２Ｈ），４．６０（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），６．７５（ｄ，Ｊ＝１０．１Ｈｚ，１Ｈ），７．０８（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ），８．６８（ｂｒｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．９（ｓ，１Ｆ）．Example-106

(R) -2- [4- (5-Chloro-3-oxo-1,2-oxadiethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] methyl propionate (1. 00 g, 2.33 mmol) in ethyl acetate (4.7 mL), water (0.4 mL) and acetic acid (2.3 mL) were added, and then reduced iron (650 mg, 11.7 mmol) was added at 80 ° C. Stir for 6 hours. After completion of the reaction, the reaction solution was returned to room temperature, insoluble material was filtered off, saturated aqueous sodium hydrogen carbonate solution (100 mL) was added to the filtrate, and the mixture was extracted with chloroform (100 mL × 2). The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (100 mL × 3) and saturated brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (R) -5-chloro-4- (7- Fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one as a white solid (769 mg, Yield: 90%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.55 (d, J = 6.8 Hz, 3H), 3.91-3.96 (m, 4H), 4.20-4.24 (m, 2H) ), 4.28-4.32 (m, 2H), 4.60 (q, J = 6.8 Hz, 1H), 6.75 (d, J = 10.1 Hz, 1H), 7.08 (d , J = 6.8 Hz, 1H), 8.68 (brs, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.9 (s, 1F).

水素化ナトリウムの５５％油分散（８０ｍｇ，１．８３ｍｍｏｌ）のＤＭＦ（４．２ｍＬ）懸濁液に、氷冷下で（Ｒ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（６１０ｍｇ，１．６６ｍｍｏｌ）及びプロパルギルブロミド（１４５μＬ，１．８３ｍｍｏｌ）を順次加え、室温で１５時間撹拌した。反応終了後、反応液に水（５０ｍＬ）を加え、クロロホルム（１００ｍＬ×２）で抽出した。有機層を水（５０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝４：１）で精製することにより、（Ｒ）−５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−５−クロロ−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（４１４ｍｇ，収率：６１％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５９（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），２．２５（ｔ，Ｊ＝２．５Ｈｚ，１Ｈ），３．９３−３．９８（ｍ，４Ｈ），４．２０−４．２５（ｍ，２Ｈ），４．２６−４．３０（ｍ，２Ｈ），４．６３（ｄｄ，Ｊ＝１７．７ ａｎｄ ２．５Ｈｚ，１Ｈ），４．６７（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），４．７５（ｄｄ，Ｊ＝１７．７ ａｎｄ ２．５Ｈｚ，１Ｈ），６．８２（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．２８（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．３（ｓ，１Ｆ）．Example-107

To a suspension of sodium hydride in 55% oil dispersion (80 mg, 1.83 mmol) in DMF (4.2 mL) under ice-cooling, (R) -5-chloro-4- (7-fluoro-2,3- Dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one (610 mg, 1.66 mmol) and propargyl bromide (145 μL) , 1.83 mmol) were sequentially added, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with chloroform (100 mL × 2). The organic layer was washed with water (50 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. By purifying the obtained crude product by silica gel column chromatography (chloroform: methanol = 4: 1), (R) -5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl) was obtained. -3-Oxo-4-propargyl-4H-1,4-benzoxazin-6-yl) -5-chloro-1,2-oxadiethylene-4-pyrazolin-3-one as a white solid (414 mg, yield: 61%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.59 (d, J = 6.8 Hz, 3H), 2.25 (t, J = 2.5 Hz, 1H), 3.93-3.98 (m , 4H), 4.20-4.25 (m, 2H), 4.26-4.30 (m, 2H), 4.63 (dd, J = 17.7 and 2.5 Hz, 1H), 4 .67 (q, J = 6.8 Hz, 1H), 4.75 (dd, J = 17.7 and 2.5 Hz, 1H), 6.82 (d, J = 9.9 Hz, 1H), 7. 28 (d, J = 6.7 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.3 (s, 1F).

水素化ナトリウムの５５％油分散（０．６２ｇ，１４．３ｍｍｏｌ）の１，４−ジオキサン（４８ｍＬ）溶液に５−クロロ−４−（２，４−ジフルオロ−５−ニトロフェニル）−１，２−オキサジエチレンチレン−４−ピラゾリン−３−オン（３．３０ｇ，９．５５ｍｍｏｌ）を加え、次いでメタノール（０．９６ｍＬ，２３．９ｍｍｏｌ）を滴下し、室温で４時間撹拌した。反応終了後、反応液を氷水（１５０ｇ）に注ぎ入れ、クロロホルム（１００ｍＬ×３）で抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をクロロホルムに溶かし、ヘキサンを加えて析出した固体をろ取することにより、５−クロロ−４−（２−フルオロ−４−メトキシ−５−ニトロフェニル）−１，２−オキサジエチレン−４−ピラゾリン−３−オンの淡黄色固体（２．７５ｇ，収率：８０％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ３．９２−３．９５（ｍ，４Ｈ），３．９８（ｓ，３Ｈ），４．２２−４．２６（ｍ，２Ｈ），４．２６−４．３０（ｍ，２Ｈ），６．８６（ｄ，Ｊ＝１１．１Ｈｚ，１Ｈ），８．１４（ｄ，Ｊ＝７．４Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−９８．７（ｓ，１Ｆ）．Reference Example-35

To a solution of sodium hydride in 55% oil dispersion (0.62 g, 14.3 mmol) in 1,4-dioxane (48 mL), 5-chloro-4- (2,4-difluoro-5-nitrophenyl) -1,2 -Oxadiethylenetylen-4-pyrazolin-3-one (3.30 g, 9.55 mmol) was added, then methanol (0.96 mL, 23.9 mmol) was added dropwise and stirred at room temperature for 4 hours. After completion of the reaction, the reaction solution was poured into ice water (150 g) and extracted with chloroform (100 mL × 3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was dissolved in chloroform, hexane was added, and the precipitated solid was collected by filtration to give 5-chloro-4- (2-fluoro-4-methoxy-5-nitrophenyl) -1,2- A pale yellow solid (2.75 g, yield: 80%) of oxadiethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.92-3.95 (m, 4H), 3.98 (s, 3H), 4.22-4.26 (m, 2H), 4.26- 4.30 (m, 2H), 6.86 (d, J = 11.1 Hz, 1H), 8.14 (d, J = 7.4 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-98.7 (s, 1F).

５−クロロ−４−（２−フルオロ−４−メトキシ−５−ニトロフェニル）−１，２−オキサジエチレンメチレン−４−ピラゾリン−３−オン（１．００ｇ，２．８０ｍｍｏｌ）のジクロロメタン（１２ｍＬ）溶液に、−４０℃で三臭化ホウ素のジクロロメタン１Ｍ溶液（７ｍＬ）を滴下し、室温まで徐々に昇温させながら１８時間撹拌した。反応終了後、反応液を氷水（１００ｇ）に注ぎ入れ、クロロホルム（１００ｍＬ×３）で抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、５−クロロ−４−（２−フルオロ−４−ヒドロキシ−５−ニトロフェニル）−１，２−オキサジエチレン−４−ピラゾリン−３−オンの黄色固体（０．６１ｇ，収率：６４％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ３．９３−３．９６（ｍ，４Ｈ），４．２３−４．２６（ｍ，２Ｈ），４．２７−４．３０（ｍ，２Ｈ），６．９２（ｄ，Ｊ＝１０．４Ｈｚ，１Ｈ），８．３４（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−９５．０（ｓ，１Ｆ）．Reference Example-36

5-Chloro-4- (2-fluoro-4-methoxy-5-nitrophenyl) -1,2-oxadiethylenemethylene-4-pyrazolin-3-one (1.00 g, 2.80 mmol) in dichloromethane (12 mL) To the solution was added dropwise a 1M solution of boron tribromide in dichloromethane (7 mL) at −40 ° C., and the mixture was stirred for 18 hours while gradually warming to room temperature. After completion of the reaction, the reaction solution was poured into ice water (100 g) and extracted with chloroform (100 mL × 3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 5-chloro-4- (2-fluoro-4-hydroxy-5-nitrophenyl) -1,2 A yellow solid (0.61 g, yield: 64%) of -oxadiethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.93-3.96 (m, 4H), 4.23-4.26 (m, 2H), 4.27-4.30 (m, 2H), 6.92 (d, J = 10.4 Hz, 1H), 8.34 (d, J = 7.3 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-95.0 (s, 1F).

５−クロロ−４−（２−フルオロ−４−メトキシ−５−ニトロフェニル）−１，２−オキサジエチレンメチレン−４−ピラゾリン−３−オン（５．０１ｇ，１４．５ｍｍｏｌ）のＤＭＳＯ（４８ｍＬ）溶液に、１０Ｎ水酸化ナトリウム水溶液（２９ｍＬ）を滴下し、室温で５時間撹拌した。反応終了後、反応液を氷水（４００ｇ）に注ぎ入れ、濃塩酸（２５ｍＬ）を加えて析出した固体をろ取した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：酢酸エチル＝１：１）で精製することにより、５−クロロ−４−（２−フルオロ−４−ヒドロキシ−５−ニトロフェニル）−１，２−オキサジエチレン−４−ピラゾリン−３−オンの黄色固体（３．９６ｇ，収率：８０％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ３．９３−３．９６（ｍ，４Ｈ），４．２３−４．２６（ｍ，２Ｈ），４．２７−４．３０（ｍ，２Ｈ），６．９２（ｄ，Ｊ＝１０．４Ｈｚ，１Ｈ），８．３４（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−９５．０（ｓ，１Ｆ）．Reference Example-37

DMSO (48 mL) of 5-chloro-4- (2-fluoro-4-methoxy-5-nitrophenyl) -1,2-oxadiethylenemethylene-4-pyrazolin-3-one (5.01 g, 14.5 mmol) To the solution was added dropwise 10N aqueous sodium hydroxide solution (29 mL), and the mixture was stirred at room temperature for 5 hours. After completion of the reaction, the reaction solution was poured into ice water (400 g), concentrated hydrochloric acid (25 mL) was added, and the precipitated solid was collected by filtration. The obtained crude product was purified by silica gel column chromatography (chloroform: ethyl acetate = 1: 1) to give 5-chloro-4- (2-fluoro-4-hydroxy-5-nitrophenyl) -1, A yellow solid (3.96 g, yield: 80%) of 2-oxadiethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.93-3.96 (m, 4H), 4.23-4.26 (m, 2H), 4.27-4.30 (m, 2H), 6.92 (d, J = 10.4 Hz, 1H), 8.34 (d, J = 7.3 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-95.0 (s, 1F).

５−クロロ−４−（２−フルオロ−４−ヒドロキシ−５−ニトロフェニル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（１．００ｇ，２．９１ｍｍｏｌ）のエタノール（１２ｍＬ）溶液に、１０％パラジウム／炭素（０．０６２ｇ，０．０５８ｍｍｏｌ）を加え、水素雰囲気下、室温で１５時間撹拌した。反応終了後、反応液へクロロホルム：メタノール＝１０：１の混合溶媒を加えた後、ろ過により触媒をろ別し、ろ液を減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、４−（５−アミノ−２−フルオロ−４−ヒドロキシフェニル）−５−クロロ−１，２−オキサジエチレン−４−ピラゾリン−３−オンの青緑色固体（０．８３ｇ，収率：９１％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ３．９３−３．９８（ｍ，４Ｈ），４．２１−４．２４（ｍ，２Ｈ），４．３１−４．３４（ｍ，２Ｈ），６．２７（ｄ，Ｊ＝１０．８Ｈｚ，１Ｈ），６．５２（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ）．^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ）：δ３．７７−３．８３（ｍ，４Ｈ），４．０９−４．１３（ｍ，２Ｈ），４．１７−４．２１（ｍ，２Ｈ），６．５１（ｄ，Ｊ＝１１．１Ｈｚ，１Ｈ），６．５６（ｄ，Ｊ＝７．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１２４．２（ｓ，１Ｆ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＤＭＳＯ）：δ−１２５．７（ｓ，１Ｆ）．Reference Example-38

5-Chloro-4- (2-fluoro-4-hydroxy-5-nitrophenyl) -1,2-oxadiethylene-4-pyrazolin-3-one (1.00 g, 2.91 mmol) in ethanol (12 mL) Was added with 10% palladium / carbon (0.062 g, 0.058 mmol), and the mixture was stirred at room temperature for 15 hours in a hydrogen atmosphere. After completion of the reaction, a mixed solvent of chloroform: methanol = 10: 1 was added to the reaction solution, the catalyst was filtered off by filtration, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 4- (5-amino-2-fluoro-4-hydroxyphenyl) -5-chloro-1,2 A blue-green solid (0.83 g, yield: 91%) of -oxadiethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.93-3.98 (m, 4H), 4.21-4.24 (m, 2H), 4.31-4.34 (m, 2H), 6.27 (d, J = 10.8 Hz, 1H), 6.52 (d, J = 7.3 Hz, 1H). ¹ H-NMR (400 MHz, DMSO): δ 3.77-3.83 (m, 4H), 4.09-4.13 (m, 2H), 4.17-4.21 (m, 2H), 6 .51 (d, J = 11.1 Hz, 1H), 6.56 (d, J = 7.7 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-124.2 (s, 1F). ¹⁹ F-NMR (376 MHz, DMSO): δ-125.7 (s, 1F).

４−（５−アミノ−２−フルオロ−４−ヒドロキシフェニル）−５−クロロ−１，２−オキサジエチレン−４−ピラゾリン−３−オン（２．００ｇ，６．３８ｍｍｏｌ）のＴＨＦ（３２ｍＬ）とＤＭＦ（３２ｍＬ）混合溶液に−１５℃で水素化ナトリウムの５５％オイルディスパージョン（０．２８ｇ，６．３８ｍｍｏｌ）を加え、−１５℃で１時間撹拌した後、ブロモジフルオロ酢酸エチル（０．９４ｍＬ，７．０２ｍｍｏｌ）を滴下し、０℃で６時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（４０ｍＬ）を加え、クロロホルム（１００ｍＬ×３）で抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、２−ブロモ−Ｎ−［５−（５−クロロ−１，２−オキサジエチレン−３−オキソ−４−ピラゾリン−４−イル）−４−フルオロ−２−ヒドロキシフェニル］−２，２−ジフルオロアセトアミドの白色固体（１．６９ｇ，収率：５６％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ）：δ３．７８−３．８６（ｍ，４Ｈ），４．１１−４．１６（ｍ，２Ｈ），４．２３−２７４．（ｍ，２Ｈ），６．７９（ｄ，Ｊ＝１１．２Ｈｚ，１Ｈ），７．２９（ｄ，Ｊ＝７．９Ｈｚ，１Ｈ），１０．３８（ｓ，１Ｈ），１０．５５（ｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＤＭＳＯ）：δ−５９．９（ｓ，２Ｆ），−１１１．５（ｓ，１Ｆ）．Reference Example-39

4- (5-amino-2-fluoro-4-hydroxyphenyl) -5-chloro-1,2-oxadiethylene-4-pyrazolin-3-one (2.00 g, 6.38 mmol) in THF (32 mL) To a mixed solution of DMF (32 mL), 55% oil dispersion of sodium hydride (0.28 g, 6.38 mmol) was added at −15 ° C., and the mixture was stirred at −15 ° C. for 1 hour, and then ethyl bromodifluoroacetate (0.94 mL). 7.02 mmol) was added dropwise and stirred at 0 ° C. for 6 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (40 mL) was added to the reaction solution, and the mixture was extracted with chloroform (100 mL × 3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 2-bromo-N- [5- (5-chloro-1,2-oxadiethylene-3-oxo. A white solid (1.69 g, yield: 56%) of -4-pyrazolin-4-yl) -4-fluoro-2-hydroxyphenyl] -2,2-difluoroacetamide was obtained. ¹ H-NMR (400 MHz, DMSO): δ 3.78-3.86 (m, 4H), 4.11-4.16 (m, 2H), 4.23-274. (M, 2H), 6.79 (d, J = 11.2 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 10.38 (s, 1H), 10.55 (s , 1H). ¹⁹ F-NMR (376 MHz, DMSO): δ-59.9 (s, 2F), -111.5 (s, 1F).

２−ブロモ−Ｎ−［５−（５−クロロ−１，２−オキサジエチレン−３−オキソ−４−ピラゾリン−４−イル）−４−フルオロ−２−ヒドロキシフェニル］−２，２−ジフルオロアセトアミド（１．００ｇ，２．１２ｍｍｏｌ）のトルエン（１５ｍＬ）溶液にＤＢＵ（０．３２ｍＬ，２．１２ｍｍｏｌ）を加え、８０℃で５時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（５０ｍＬ）を加え、クロロホルム（５０ｍＬ×３）で抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製することにより、５−クロロ−４−（２，２，７−トリフルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（０．４８ｇ，収率：５９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ３．９５−４．００（ｍ，４Ｈ），４．２８−４．３２（ｍ，２Ｈ），４．３４−４．３８（ｍ，２Ｈ），６．９２（ｄ，Ｊ＝９．４Ｈｚ，１Ｈ），７．３４（ｄ，Ｊ＝６．６Ｈｚ，１Ｈ），１０．９（ｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−７７．０（ｓ，２Ｆ），−１１４．１（ｓ，１Ｆ）．
^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ）：δ３．７９−３．８４（ｍ，２Ｈ），３．８４−３．８８（ｍ，２Ｈ），４．１４−４．２０（ｍ，２Ｈ），４．２８−４．３３（ｍ，２Ｈ），７．２０（ｄ，Ｊ＝６．９Ｈｚ，１Ｈ），７．４６（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），１２．１（ｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＤＭＳＯ）：δ−７５．８（ｓ，２Ｆ），−１１４．７（ｓ，１Ｆ）．Example-108

2-Bromo-N- [5- (5-chloro-1,2-oxadiethylene-3-oxo-4-pyrazolin-4-yl) -4-fluoro-2-hydroxyphenyl] -2,2-difluoroacetamide DBU (0.32 mL, 2.12 mmol) was added to a toluene (15 mL) solution of (1.00 g, 2.12 mmol), and the mixture was stirred at 80 ° C. for 5 hours. After completion of the reaction, a saturated aqueous ammonium chloride solution (50 mL) was added to the reaction solution, and the mixture was extracted with chloroform (50 mL × 3). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give 5-chloro-4- (2,2,7-trifluoro-2,3-dihydro-3- A white solid (0.48 g, yield: 59%) of oxo-4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.95-4.00 (m, 4H), 4.28-4.32 (m, 2H), 4.34-4.38 (m, 2H), 6.92 (d, J = 9.4 Hz, 1H), 7.34 (d, J = 6.6 Hz, 1H), 10.9 (s, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-77.0 (s, 2F), -114.1 (s, 1F).
¹ H-NMR (400 MHz, DMSO): δ 3.79-3.84 (m, 2H), 3.84-3.88 (m, 2H), 4.14-4.20 (m, 2H), 4 .28-4.33 (m, 2H), 7.20 (d, J = 6.9 Hz, 1H), 7.46 (d, J = 9.9 Hz, 1H), 12.1 (s, 1H) . ¹⁹ F-NMR (376 MHz, DMSO): δ-75.8 (s, 2F), -114.7 (s, 1F).

水素化ナトリウムの５５％油分散（０．０３７ｇ，０．８５ｍｍｏｌ）のＤＭＦ（２ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（２，２，７−トリフルオロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（０．３０ｇ，０．７７ｍｍｏｌ）を加え、１０分撹拌した後、プロパルギルブロミド（０．０６７ｍＬ，０．８５ｍｍｏｌ）を加え、室温で２４時間撹拌した。反応終了後、反応液へ飽和塩化アンモニウム水溶液（３０ｍＬ）を加え、酢酸エチル（１００ｍＬ×２）で抽出した。有機層を水（５０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９：１）で精製することにより、５−クロロ−１，２−オキサジエチレン−４−（２，２，７−トリフルオロ−２，３−ジヒドロ−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−４−ピラゾリン−３−オンの白色固体（０．１７ｇ，収率：５２％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ２．３４（ｔ，Ｊ＝２．５Ｈｚ，１Ｈ），３．９４−３．９８（ｍ，４Ｈ），４．２４−４．２８（ｍ，２Ｈ），４．２８−４．３１（ｍ，２Ｈ），４．８０（ｄ，Ｊ＝２．５Ｈｚ，２Ｈ），７．０５（ｄ，Ｊ＝９．２Ｈｚ，１Ｈ），７．４７（ｄ，Ｊ＝６．４Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−７７．３（ｓ，２Ｆ），−１１２．５（ｓ，１Ｆ）．Example-109

To a suspension of sodium hydride in 55% oil dispersion (0.037 g, 0.85 mmol) in DMF (2 mL) under ice-cooling, 5-chloro-4- (2,2,7-trifluoro-2,3 -Dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one (0.30 g, 0.77 mmol) was added and stirred for 10 minutes. Then, propargyl bromide (0.067 mL, 0.85 mmol) was added and stirred at room temperature for 24 hours. After completion of the reaction, saturated aqueous ammonium chloride solution (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layer was washed with water (50 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 9: 1) to give 5-chloro-1,2-oxadiethylene-4- (2,2,7-trifluoro- A white solid (0.17 g, yield: 52%) of 2,3-dihydro-3-oxo-4-propargyl-4H-1,4-benzoxazin-6-yl) -4-pyrazolin-3-one Obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.34 (t, J = 2.5 Hz, 1H), 3.94-3.98 (m, 4H), 4.24-4.28 (m, 2H) ), 4.28-4.31 (m, 2H), 4.80 (d, J = 2.5 Hz, 2H), 7.05 (d, J = 9.2 Hz, 1H), 7.47 (d , J = 6.4 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-77.3 (s, 2F), -112.5 (s, 1F).

１−ブロモ−２−クロロ−４−フルオロベンゼン（５６．４７ｇ，２６４ｍｍｏｌ）のＴＨＦ（１１０ｍＬ）溶液に、イソプロピルマグネシウムクロリド溶液（１３９ｍＬ，２Ｍ−ＴＨＦ溶液）を−５０℃以下で加え、室温で３０分間撹拌した。得られたグリニャール試薬のＴＨＦ溶液を、−４０℃以下に冷却した後、シュウ酸ジエチル（３９．０ｍＬ，２７７ｍｍｏｌ）を滴下し、０℃で１時間撹拌した。反応溶液に飽和塩化アンモニウム水溶液（１００ｍＬ）を加え、酢酸エチル（１５０ｍＬ×３）で抽出した。有機層を硫酸マグネシウムで乾燥させ、ろ過、減圧下で溶媒を留去した後、減圧蒸留することにより、２−（２−クロロ−４−フルオロフェニル）−２−オキソ酢酸エチルの無色液体（５０．３５ｇ，収率：８３％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．４０（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），４．４２（ｑ，Ｊ＝７．２Ｈｚ，２Ｈ），７．１３（ｄｄｄ，Ｊ＝１０．１，８．８ ａｎｄ ２．４Ｈｚ，１Ｈ），７．２０（ｄｄ，Ｊ＝８．３ ａｎｄ ２．４Ｈｚ，１Ｈ），７．８４（ｄｄ，Ｊ＝８．８ ａｎｄ ６．０Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１０１．９（ｓ，１Ｆ）．
２−（２−クロロ−４−フルオロフェニル）−２−オキソ酢酸エチル（２３．０６ｇ，１００ｍｍｏｌ）の濃硫酸（５０ｍＬ）の懸濁液に、６９％硝酸（１０．０６ｇ，１１０ｍｍｏｌ）と濃硫酸（６ｍＬ）から調製した混酸を氷冷下で３０分間かけてゆっくり加え、同温にて３０分間攪拌した。反応終了後、氷水（５０ｇ）中に反応液を注ぎ、クロロホルム（１００ｍＬ×３）で抽出した。有機層を飽和食塩水（３０ｍＬ）で洗浄し、硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４／１）で精製することにより、２−（２−クロロ−４−フルオロ−５−ニトロフェニル）−２−オキソ酢酸エチルの淡黄色油状物（定量的）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．４２（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），４．４６（ｑ，Ｊ＝７．２Ｈｚ，２Ｈ），７．４７（ｄ，Ｊ＝９．８Ｈｚ，１Ｈ），８．５３（ｄ，Ｊ＝７．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１０７．１（ｓ，１Ｆ）．
２−（２−クロロ−４−フルオロ−５−ニトロフェニル）−２−オキソ酢酸エチル（１．１０ｇ，４．０ｍｍｏｌ）のテトラヒドロフラン（８ｍＬ）溶液に、氷冷下でグリコール酸エチル（０．４６７ｇ，４．４ｍｍｏｌ）と水素化ナトリウムの５５％油分散（０．２１ｇ，４．８ｍｍｏｌ）を順次加え、室温で１時間攪拌した。反応終了後、反応液を氷水（３０ｇ）に注ぎ、クロロホルム（３０ｍＬ×３）で抽出した。合一した有機層を飽和食塩水（５０ｍＬ）で洗浄後、硫酸マグネシウムで乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝４／１）で精製することにより、２−［４−（エトキシカルボニル）メトキシ−２−クロロ−５−ニトロフェニル］−２−オキソ酢酸エチルの淡黄色固体（０．６７ｇ，収率：４７％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．３２（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．４１（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），４．３１（ｑ，Ｊ＝７．２Ｈｚ，２Ｈ），４．４４（ｑ，Ｊ＝７．２Ｈｚ，２Ｈ），７．０１（ｓ，１Ｈ），８．４１（ｓ，１Ｈ）．
トリフェニルホスフィン（２３．８４ｇ，８８．２ｍｍｏｌ）のジクロロメタン（９０ｍＬ）溶液に、四塩化炭素（１３．６３ｇ，８８．２ｍｍｏｌ）を０℃で加えて、５分攪拌した。この溶液に、２−（４−（エトキシカルボニル）メトキシ−２−クロロ−５−ニトロフェニル）−２−オキソ酢酸エチル（１５．８６ｇ，４４．１ｍｍｏｌ）を加えて、室温で２４時間攪拌した。反応混合物から減圧下に溶媒を除去し、残渣にクロロホルムとエーテルの混合溶媒を加え、固体をろ別した。ろ液を減圧濃縮して得られた粗生成物を減圧蒸留することにより、３，３−ジクロロ−２−［４−（エトキシカルボニル）メトキシ−２−クロロ−５−ニトロフェニル］アクリル酸エチルの無色液体（１４．１９ｇ，収率：７５％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．２５（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．３１（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），４．２４（ｑ，Ｊ＝７．２Ｈｚ，２Ｈ），４．３０（ｑ，Ｊ＝７．２Ｈｚ，２Ｈ），４．８０（ｓ，２Ｈ），７．０５（ｓ，１Ｈ），７．９０（ｓ，１Ｈ）．Reference Example-40

To a solution of 1-bromo-2-chloro-4-fluorobenzene (56.47 g, 264 mmol) in THF (110 mL), an isopropylmagnesium chloride solution (139 mL, 2M-THF solution) is added at −50 ° C. or less, and 30 at room temperature. Stir for minutes. The obtained Grignard reagent in THF was cooled to −40 ° C. or lower, and then diethyl oxalate (39.0 mL, 277 mmol) was added dropwise, followed by stirring at 0 ° C. for 1 hour. A saturated aqueous ammonium chloride solution (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic layer was dried over magnesium sulfate, filtered, the solvent was distilled off under reduced pressure, and then distilled under reduced pressure to give a colorless liquid of ethyl 2- (2-chloro-4-fluorophenyl) -2-oxoacetate (50 .35 g, yield: 83%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.40 (t, J = 7.2 Hz, 3H), 4.42 (q, J = 7.2 Hz, 2H), 7.13 (ddd, J = 10 .1, 8.8 and 2.4 Hz, 1H), 7.20 (dd, J = 8.3 and 2.4 Hz, 1H), 7.84 (dd, J = 8.8 and 6.0 Hz, 1H) ). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-101.9 (s, 1F).
To a suspension of ethyl 2- (2-chloro-4-fluorophenyl) -2-oxoacetate (23.06 g, 100 mmol) in concentrated sulfuric acid (50 mL), 69% nitric acid (10.06 g, 110 mmol) and concentrated sulfuric acid were added. The mixed acid prepared from (6 mL) was slowly added over 30 minutes under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. After completion of the reaction, the reaction solution was poured into ice water (50 g) and extracted with chloroform (100 mL × 3). The organic layer was washed with saturated brine (30 mL), dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (hexane: ethyl acetate = 4/1) to give a light yellow oily substance of ethyl 2- (2-chloro-4-fluoro-5-nitrophenyl) -2-oxoacetate. (Quantitative) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.42 (t, J = 7.2 Hz, 3H), 4.46 (q, J = 7.2 Hz, 2H), 7.47 (d, J = 9 .8 Hz, 1 H), 8.53 (d, J = 7.7 Hz, 1 H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-107.1 (s, 1F).
To a solution of ethyl 2- (2-chloro-4-fluoro-5-nitrophenyl) -2-oxoacetate (1.10 g, 4.0 mmol) in tetrahydrofuran (8 mL) was added ethyl glycolate (0.467 g) under ice-cooling. , 4.4 mmol) and 55% oil dispersion of sodium hydride (0.21 g, 4.8 mmol) were sequentially added and stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into ice water (30 g) and extracted with chloroform (30 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane: ethyl acetate = 4/1) to give 2- [4- (ethoxycarbonyl) methoxy-2-chloro-5-nitrophenyl] -2- A light yellow solid (0.67 g, yield: 47%) of ethyl oxoacetate was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.32 (t, J = 7.2 Hz, 3H), 1.41 (t, J = 7.2 Hz, 3H), 4.31 (q, J = 7 .2 Hz, 2H), 4.44 (q, J = 7.2 Hz, 2H), 7.01 (s, 1H), 8.41 (s, 1H).
Carbon tetrachloride (13.63 g, 88.2 mmol) was added to a solution of triphenylphosphine (23.84 g, 88.2 mmol) in dichloromethane (90 mL) at 0 ° C., and the mixture was stirred for 5 minutes. To this solution was added ethyl 2- (4- (ethoxycarbonyl) methoxy-2-chloro-5-nitrophenyl) -2-oxoacetate (15.86 g, 44.1 mmol), and the mixture was stirred at room temperature for 24 hours. The solvent was removed from the reaction mixture under reduced pressure, a mixed solvent of chloroform and ether was added to the residue, and the solid was filtered off. The crude product obtained by concentrating the filtrate under reduced pressure was distilled under reduced pressure to give ethyl 3,3-dichloro-2- [4- (ethoxycarbonyl) methoxy-2-chloro-5-nitrophenyl] acrylate. A colorless liquid (14.19 g, yield: 75%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.25 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H), 4.24 (q, J = 7) .2 Hz, 2H), 4.30 (q, J = 7.2 Hz, 2H), 4.80 (s, 2H), 7.05 (s, 1H), 7.90 (s, 1H).

３，３−ジクロロ−２−［４−（エトキシカルボニル）メトキシ−２−クロロ−５−ニトロフェニル］アクリル酸エチル（４．２７ｇ，１０．０ｍｍｏｌ）に１，４−ジオキサン（２５ｍＬ）と１，４，５−オキサジアゼパン二臭化水素塩（２．９０ｇ，１１．０ｍｍｏｌ）を加え、さらにトリエチルアミン（４．６ｍＬ，３３．０ｍｍｏｌ）を加え、１５時間還流した。反応終了後、反応液に水（５０ｍＬ）を加えクロロホルム（５０ｍＬ×３）で抽出した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、２−［５−クロロ−４−（５−クロロ−１，２−オキサジエチレン−３−オキソ−４−ピラゾリン−４−イル）−２−ニトロフェニルオキシ］酢酸エチルの淡黄色固体（３．５２ｇ，収率：７９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．３２（ｔ，Ｊ＝７．１Ｈｚ，３Ｈ），３．９０−３．９９（ｍ，４Ｈ），４．２１−４．２８（ｍ，４Ｈ），４．３０（ｑ，Ｊ＝７．１Ｈｚ，２Ｈ），４．７８（ｓ，２Ｈ），７．０９（ｓ，１Ｈ），７．９５（ｓ，１Ｈ）．Reference Example-41

Ethyl 3,3-dichloro-2- [4- (ethoxycarbonyl) methoxy-2-chloro-5-nitrophenyl] acrylate (4.27 g, 10.0 mmol) and 1,4-dioxane (25 mL) and 1, 4,5-oxadiazepan dihydrobromide (2.90 g, 11.0 mmol) was added, and further triethylamine (4.6 mL, 33.0 mmol) was added, followed by refluxing for 15 hours. After completion of the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with chloroform (50 mL × 3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (ethyl acetate) to give 2- [5-chloro-4- (5-chloro-1,2-oxadiethylene-3-oxo-4-pyrazolin-4-yl). A light yellow solid (3.52 g, yield: 79%) of ethyl-2-nitrophenyloxy] acetate was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.32 (t, J = 7.1 Hz, 3H), 3.90-3.99 (m, 4H), 4.21-4.28 (m, 4H) ), 4.30 (q, J = 7.1 Hz, 2H), 4.78 (s, 2H), 7.09 (s, 1H), 7.95 (s, 1H).

２−［５−クロロ−４−（５−クロロ−１，２−オキサジエチレン−３−オキソ−４−ピラゾリン−４−イル）−２−ニトロフェニルオキシ］酢酸エチル（４．０６ｇ，９．１ｍｍｏｌ）の酢酸エチル（４５．０ｍＬ）溶液に、水（２．０ｇ）及び酢酸（１０．０ｍＬ）を加えた後、還元鉄（５．０８ｇ，９１．０ｍｍｏｌ）を加え、８０℃で１時間攪拌した。反応終了後、反応液を室温まで冷却し、不溶物をろ別し、固体をを酢酸エチル（１００ｍＬ）と酢酸（１０ｍＬ）の混合溶媒で洗浄した。合一した有機層を水（５０ｍＬ×３）、飽和炭酸水素ナトリウム水溶液（５０ｍＬ×２）、飽和食塩水（５０ｍＬ）で洗浄した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、減圧乾燥することにより、５−クロロ−４−（７−クロロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（２．５８ｇ，収率：７７％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ３．７５−３．８９（ｍ，４Ｈ），４．０６−４．３３（ｍ，４Ｈ），４．６４（ｓ，２Ｈ），６．８３（ｓ，１Ｈ），７．１５（ｓ，１Ｈ），１０．８９（ｂｒｓ，１Ｈ）．Example-110

2- [5-Chloro-4- (5-chloro-1,2-oxadiethylene-3-oxo-4-pyrazolin-4-yl) -2-nitrophenyloxy] ethyl acetate (4.06 g, 9.1 mmol) ) In ethyl acetate (45.0 mL), water (2.0 g) and acetic acid (10.0 mL) were added, and then reduced iron (5.08 g, 91.0 mmol) was added and stirred at 80 ° C. for 1 hour. did. After completion of the reaction, the reaction solution was cooled to room temperature, insoluble matters were filtered off, and the solid was washed with a mixed solvent of ethyl acetate (100 mL) and acetic acid (10 mL). The combined organic layer was washed with water (50 mL × 3), saturated aqueous sodium hydrogen carbonate solution (50 mL × 2), and saturated brine (50 mL). The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and dried under reduced pressure to give 5-chloro-4- (7-chloro-2,3-dihydro-3-oxo-4H-1,4-benzoxazine-6. A white solid (2.58 g, yield: 77%) of -yl) -1,2-oxadiethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.75-3.89 (m, 4H), 4.06-4.33 (m, 4H), 4.64 (s, 2H), 6.83 ( s, 1H), 7.15 (s, 1H), 10.89 (brs, 1H).

氷冷下で水素化ナトリウムの５５％油分散（５３ｍｇ，１．２ｍｍｏｌ）のＤＭＦ（４ｍＬ）懸濁液に、５−クロロ−４−（７−クロロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（３５５ｍｇ，１．０ｍｍｏｌ）及び（クロロメチル）メチルエーテル（１０２ｍｇ，１．２ｍｍｏｌ）を加え、室温で６時間攪拌した。反応終了後、反応液を氷水を注ぎ、クロロホルム（３０ｍＬ×３）で抽出した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９５／５）で精製することにより、５−クロロ−４−（７−クロロ−２，３−ジヒドロ−４−メトキシメチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（１６１ｍｇ，収率：３９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ３．３９（ｓ，３Ｈ），３．８９−４．０１（ｍ，４Ｈ），４．１６−４．３２（ｍ，２Ｈ），４．６６（ｓ，２Ｈ），５．３１（ｓ，２Ｈ），７．１２（ｓ，１Ｈ），７．２６（ｓ，１Ｈ）．Example-111

To a suspension of 55% oil dispersion of sodium hydride (53 mg, 1.2 mmol) in DMF (4 mL) under ice-cooling, 5-chloro-4- (7-chloro-2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one (355 mg, 1.0 mmol) and (chloromethyl) methyl ether (102 mg, 1.2 mmol). The mixture was further stirred at room temperature for 6 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with chloroform (30 mL × 3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (ethyl acetate: methanol = 95/5) to give 5-chloro-4- (7-chloro-2,3-dihydro-4-methoxymethyl-3-oxo-4H). A white solid (161 mg, yield: 39%) of -1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.39 (s, 3H), 3.89-4.01 (m, 4H), 4.16-4.32 (m, 2H), 4.66 (s , 2H), 5.31 (s, 2H), 7.12 (s, 1H), 7.26 (s, 1H).

氷冷下で水素化ナトリウムの５５％油分散（５３ｍｇ，１．２ｍｍｏｌ）のＤＭＦ（４ｍＬ）懸濁液に、５−クロロ−４−（７−クロロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（３５５ｍｇ，１．０ｍｍｏｌ）及びブロモアセトニトリル（１４８ｍｇ，１．２ｍｍｏｌ）を加え、室温で６時間攪拌した。反応終了後、反応液を氷水を注ぎ、クロロホルム（３０ｍＬ×３）で抽出した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９５／５）で精製することにより、５−クロロ−４−（７−クロロ−４−シアノメチル−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（１５８ｍｇ，収率：３８％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ３．９１−４．０３（ｍ，４Ｈ），４．１７−４．３４（ｍ，４Ｈ），４．５２−５．３３（ｍ，４Ｈ），７．０６（ｓ，１Ｈ），７．１８（ｓ，１Ｈ）．Example-112

To a suspension of 55% oil dispersion of sodium hydride (53 mg, 1.2 mmol) in DMF (4 mL) under ice-cooling, 5-chloro-4- (7-chloro-2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one (355 mg, 1.0 mmol) and bromoacetonitrile (148 mg, 1.2 mmol) were added at room temperature. Stir for 6 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with chloroform (30 mL × 3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (ethyl acetate: methanol = 95/5) to give 5-chloro-4- (7-chloro-4-cyanomethyl-2,3-dihydro-3-oxo-4H- A white solid (158 mg, yield: 38%) of 1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.91-4.03 (m, 4H), 4.17-4.34 (m, 4H), 4.52-5.33 (m, 4H), 7.06 (s, 1H), 7.18 (s, 1H).

氷冷下で水素化ナトリウムの５５％油分散（５３ｍｇ，１．２ｍｍｏｌ）のＤＭＦ（４ｍＬ）懸濁液に、５−クロロ−４−（７−クロロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（３７０ｍｇ，１．０ｍｍｏｌ）及び（ブロモメチル）シクロプロパン（１６９ｍｇ，１．２ｍｍｏｌ）を加え、室温で６時間攪拌した。反応終了後、反応液を氷水を注ぎ、クロロホルム（３０ｍＬ×３）で抽出した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９５／５）で精製することにより、４−［７−クロロ−４−（シクロプロピルメチル）−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル］−５−クロロ−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（８０ｍｇ，収率：１９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ０．３７−０．５８（ｍ，４Ｈ），１．１３−１．２４（ｍ，１Ｈ），３．７８−３．８６（ｍ，２Ｈ），３．９２−４．０１（ｍ，４Ｈ），４．１８−４．３２（ｍ，４Ｈ），４．６３（ｓ，２Ｈ），７．１０（ｓ，１Ｈ），７．１１（ｓ，１Ｈ）．Example-113

To a suspension of 55% oil dispersion of sodium hydride (53 mg, 1.2 mmol) in DMF (4 mL) under ice-cooling, 5-chloro-4- (7-chloro-2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one (370 mg, 1.0 mmol) and (bromomethyl) cyclopropane (169 mg, 1.2 mmol) were added And stirred at room temperature for 6 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with chloroform (30 mL × 3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (ethyl acetate: methanol = 95/5) to give 4- [7-chloro-4- (cyclopropylmethyl) -2,3-dihydro-3-oxo-4H- A white solid (80 mg, yield: 19%) of 1,4-benzoxazin-6-yl] -5-chloro-1,2-oxadiethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.37-0.58 (m, 4H), 1.13-1.24 (m, 1H), 3.78-3.86 (m, 2H), 3.92-4.01 (m, 4H), 4.18-4.32 (m, 4H), 4.63 (s, 2H), 7.10 (s, 1H), 7.11 (s, 1H).

氷冷下で水素化ナトリウムの５５％油分散（５３ｍｇ，１．２ｍｍｏｌ）のＤＭＦ（４ｍＬ）懸濁液に、５−クロロ−４−（７−クロロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（３７０ｍｇ，１．０ｍｍｏｌ）及びアリルブロミド（１４８ｍｇ，１．２ｍｍｏｌ）を加え、室温で１２時間攪拌した。反応終了後、反応液を氷水に注ぎ、クロロホルム（３０ｍＬ×３）で抽出した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９５／５）で精製することにより、４−（４−アリル−７−クロロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−５−クロロ−１，２−オキサジエチレン−４−ピラゾリン−３−オンの淡黄色固体（３３１ｍｇ，収率：８１％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）δ３．９２−３．９９（ｍ，４Ｈ），４．１９−４．２４（ｍ，２Ｈ），４．２５−４．３０（ｍ，２Ｈ），４．４２−４．５９（ｍ，２Ｈ），４．６６（ｓ，２Ｈ），５．１６−５．２８（ｍ，２Ｈ），５．７９−５．９２（ｍ，１Ｈ），６．９４（ｓ，１Ｈ），７．１１（ｓ，１Ｈ）．Example-114

To a suspension of 55% oil dispersion of sodium hydride (53 mg, 1.2 mmol) in DMF (4 mL) under ice-cooling, 5-chloro-4- (7-chloro-2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one (370 mg, 1.0 mmol) and allyl bromide (148 mg, 1.2 mmol) were added at room temperature. Stir for 12 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with chloroform (30 mL × 3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (ethyl acetate: methanol = 95/5) to give 4- (4-allyl-7-chloro-2,3-dihydro-3-oxo-4H-1,4- A pale yellow solid (331 mg, yield: 81%) of benzoxazin-6-yl) -5-chloro-1,2-oxadiethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.92-3.99 (m, 4H), 4.19-4.24 (m, 2H), 4.25-4.30 (m, 2H), 4 .42-4.59 (m, 2H), 4.66 (s, 2H), 5.16-5.28 (m, 2H), 5.79-5.92 (m, 1H), 6.94 (S, 1H), 7.11 (s, 1H).

氷冷下で水素化ナトリウムの５５％油分散（７９ｍｇ，１．８ｍｍｏｌ）のＤＭＦ（６ｍＬ）懸濁液に、５−クロロ−４−（７−クロロ−２，３−ジヒドロ−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（５５５ｍｇ，１．５ｍｍｏｌ）及びプロパルギルブロミド（２２５ｍｇ，１．８ｍｍｏｌ）を加え、室温で１２時間攪拌した。反応終了後、反応液を氷水に注ぎ、クロロホルム（３０ｍＬ×３）で抽出した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをヘキサンで洗浄した後、減圧乾燥することにより、５−クロロ−４−（７−クロロ−２，３−ジヒドロ−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（３９７ｍｇ，収率：６５％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ２．２３−２．２９（ｍ，１Ｈ），３．９２−４．０１（ｍ，４Ｈ），４．２０−４．２５（ｍ，２Ｈ），４．２６−４．３２（ｍ，２Ｈ），４．４２−４．９９（ｍ，４Ｈ），７．１３（ｓ，１Ｈ），７．１５（ｓ，１Ｈ）．Example-115

To a suspension of 55% oil dispersion of sodium hydride (79 mg, 1.8 mmol) in DMF (6 mL) under ice-cooling, 5-chloro-4- (7-chloro-2,3-dihydro-3-oxo- 4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one (555 mg, 1.5 mmol) and propargyl bromide (225 mg, 1.8 mmol) were added at room temperature. Stir for 12 hours. After completion of the reaction, the reaction solution was poured into ice water and extracted with chloroform (30 mL × 3). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was washed with hexane and dried under reduced pressure to give 5-chloro-4- (7-chloro-2,3-dihydro-3-oxo-4-propargyl-4H-1,4-benzoxazine-6. A white solid (397 mg, yield: 65%) of -yl) -1,2-oxadiethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ2.23-2.29 (m, 1H), 3.92-4.01 (m, 4H), 4.20-4.25 (m, 2H), 4.26-4.32 (m, 2H), 4.42-4.99 (m, 4H), 7.13 (s, 1H), 7.15 (s, 1H).

５−クロロ−４−（２，５−ジフルオロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（１．４２ｇ，５．０ｍｍｏｌ）の濃硫酸（５ｍＬ）の懸濁液に、６９％硝酸（５４８ｍｇ，６．０ｍｍｏｌ）と濃硫酸（０．３５ｍＬ）から調製した混酸を氷冷下で１０分間かけてゆっくり加え、室温にて２時間攪拌した。反応終了後、氷水（５０ｇ）中に反応液を注ぎ、クロロホルム（３０ｍＬ×３）で抽出した。有機層を飽和食塩水（３０ｍＬ）で洗浄し、硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、５−クロロ−４−（２，５−ジフルオロ−４−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オンの黄色固体（８５８ｍｇ，収率：５２％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．９０−１．９９（ｍ，２Ｈ），２．０２−２．０９（ｍ，２Ｈ），３．６９−３．７５（ｍ，２Ｈ），３．８２−３．８８（ｍ，２Ｈ），７．６２（ｄｄ，Ｊ＝１１．４ ａｎｄ ５．８Ｈｚ，１Ｈ），７．８７（ｄｄ，Ｊ＝９．１ ａｎｄ ６．３Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１２２．１（ｄ，Ｊ＝１６．３Ｈｚ，１Ｆ），−１１２．０（ｄ，Ｊ＝１６．３Ｈｚ，１Ｆ）．Reference Example-42

To a suspension of 5-chloro-4- (2,5-difluorophenyl) -1,2-tetramethylene-4-pyrazolin-3-one (1.42 g, 5.0 mmol) in concentrated sulfuric acid (5 mL), A mixed acid prepared from 69% nitric acid (548 mg, 6.0 mmol) and concentrated sulfuric acid (0.35 mL) was slowly added over 10 minutes under ice cooling, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was poured into ice water (50 g) and extracted with chloroform (30 mL × 3). The organic layer was washed with saturated brine (30 mL), dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (ethyl acetate) to give 5-chloro-4- (2,5-difluoro-4-nitrophenyl) -1,2-tetramethylene-4-pyrazolin-3-one. Of a yellow solid (858 mg, yield: 52%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.90-1.99 (m, 2H), 2.02-2.09 (m, 2H), 3.69-3.75 (m, 2H), 3.82-3.88 (m, 2H), 7.62 (dd, J = 11.4 and 5.8 Hz, 1H), 7.87 (dd, J = 9.1 and 6.3 Hz, 1H) . ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-122.1 (d, J = 16.3 Hz, 1F), -112.0 (d, J = 16.3 Hz, 1F).

氷冷下、５−クロロ−４−（２，５−ジフルオロ−４−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（２．００ｇ，６．１ｍｍｏｌ）のテトラヒドロフラン（３０ｍＬ）溶液に、アリルアミン（１．０５ｇ，１８．２ｍｍｏｌ）を滴下した。この混合溶液を室温で２４時間撹拌した。反応終了後、減圧下で溶媒を留去した。この粗生成物に水を加えて生じた沈殿をろ取し、ジエチルエーテルで洗浄した後、減圧乾燥することにより、４−［５−（アリルアミノ）−２−フルオロ−４−ニトロフェニル］−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの橙色固体（１．８５ｇ，収率：８３％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８８−１．９８（ｍ，２Ｈ），２．００−２．０９（ｍ，２Ｈ），３．６４−３．７４（ｍ，２Ｈ），３．８０−３．８９（ｍ，２Ｈ），３．９４−４．０４（ｍ，２Ｈ），５．２１−５．３８（ｍ，２Ｈ），５．８９−６．０３（ｍ，１Ｈ），７．０８（ｄ，Ｊ＝６．０Ｈｚ，１Ｈ），７．９６（ｄ，Ｊ＝１０．４Ｈｚ，１Ｈ），８．０６（ｂｒｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１２５．６（ｓ，１Ｆ）．Reference Example-43

Under ice-cooling, 5-chloro-4- (2,5-difluoro-4-nitrophenyl) -1,2-tetramethylene-4-pyrazolin-3-one (2.00 g, 6.1 mmol) in tetrahydrofuran (30 mL) ) Allylamine (1.05 g, 18.2 mmol) was added dropwise to the solution. The mixed solution was stirred at room temperature for 24 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Water was added to the crude product, and the resulting precipitate was collected by filtration, washed with diethyl ether, and then dried under reduced pressure to give 4- [5- (allylamino) -2-fluoro-4-nitrophenyl] -5. An orange solid (1.85 g, yield: 83%) of -chloro-1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.88-1.98 (m, 2H), 2.00-2.09 (m, 2H), 3.64-3.74 (m, 2H), 3.80-3.89 (m, 2H), 3.94-4.04 (m, 2H), 5.21-5.38 (m, 2H), 5.89-6.03 (m, 1H) ), 7.08 (d, J = 6.0 Hz, 1H), 7.96 (d, J = 10.4 Hz, 1H), 8.06 (brs, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-125.6 (s, 1F).

４−［５−（アリルアミノ）−２−フルオロ−４−ニトロフェニル］−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オン（１．４７ｇ，４．０ｍｍｏｌ）の酢酸エチル（２０．０ｍＬ）溶液に、水（０．７２ｇ）及び酢酸（４．０ｍＬ）を加えた後、還元鉄（２．２３ｇ，４０．０ｍｍｏｌ）を加え、８０℃で３時間攪拌した。反応終了後、反応液を室温まで冷却し、不溶物をろ別し、固体をを酢酸エチルで洗浄した。合一した有機層を飽和炭酸水素ナトリウム水溶液（２０ｍＬ×２）、飽和食塩水（５０ｍＬ）で洗浄した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、減圧乾燥することにより、４−［５−（アリルアミノ）−４−アミノ−２−フルオロフェニル］−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの淡黄色固体（１．１６ｇ，収率：８６％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８３−１．９１（ｍ，２Ｈ），１．９５−２．０３（ｍ，２Ｈ），３．４４−３．８７（ｍ，８Ｈ），５．１２−５．３６（ｍ，２Ｈ），５．９４−６．０９（ｍ，１Ｈ），６．５０（ｄ，Ｊ＝１０．７Ｈｚ，１Ｈ），６．７５（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１２２．６（ｓ，１Ｆ）．Reference Example-44

4- [5- (allylamino) -2-fluoro-4-nitrophenyl] -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one (1.47 g, 4.0 mmol) in ethyl acetate ( After adding water (0.72 g) and acetic acid (4.0 mL) to the 20.0 mL) solution, reduced iron (2.23 g, 40.0 mmol) was added and stirred at 80 ° C. for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature, insoluble matters were filtered off, and the solid was washed with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (20 mL × 2) and saturated brine (50 mL). The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and dried under reduced pressure to give 4- [5- (allylamino) -4-amino-2-fluorophenyl] -5-chloro-1,2-tetramethylene-4. -A pale yellow solid (1.16 g, yield: 86%) of pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.83-1.91 (m, 2H), 1.95-2.03 (m, 2H), 3.44-3.87 (m, 8H), 5.12-5.36 (m, 2H), 5.94-6.09 (m, 1H), 6.50 (d, J = 10.7 Hz, 1H), 6.75 (d, J = 6) .7Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-122.6 (s, 1F).

４−［５−（アリルアミノ）−４−アミノ−２−フルオロフェニル］−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オン（２３６ｍｇ，０．７ｍｍｏｌ）のトルエン（７ｍＬ）溶液に、トリエチルアミン（７１ｍｇ，０．７ｍｍｏｌ）とピルビン酸エチル（１６６ｍｇ，１．４ｍｍｏｌ）を加えた。この混合溶液を１００℃で４時間撹拌した。反応終了後、減圧下で溶媒を留去した。残渣に水を加え、クロロホルムで生成物を抽出した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、４−（１−アリル−６−フルオロ−２−オキソ−１Ｈ−３−メチルキノキサリン−７−イル）−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの褐色固体（１４７ｍｇ，収率：５４％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８９−１．９８（ｍ，２Ｈ），２．００−２．１０（ｍ，２Ｈ），２．６１（ｓ，３Ｈ），３．６５−３．７２（ｍ，２Ｈ），３．８３−３．９０（ｍ，２Ｈ），４．９０（ｄ，Ｊ＝５．１Ｈｚ，２Ｈ），５．１９（ｄ，Ｊ＝１７．３Ｈｚ，１Ｈ），５．２８（ｄ，Ｊ＝１０．４Ｈｚ，１Ｈ），５．９５（ｄｄｔ，Ｊ＝１７．３，１０．４ ａｎｄ ５．１Ｈｚ，１Ｈ），７．５０（ｄｄ，Ｊ＝６．２Ｈｚ，１Ｈ），７．５６（ｄ，Ｊ＝１０．０Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１６．８（ｓ，１Ｆ）．Example-116

4- [5- (allylamino) -4-amino-2-fluorophenyl] -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one (236 mg, 0.7 mmol) in toluene (7 mL) Were added triethylamine (71 mg, 0.7 mmol) and ethyl pyruvate (166 mg, 1.4 mmol). The mixed solution was stirred at 100 ° C. for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Water was added to the residue, and the product was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (ethyl acetate) to give 4- (1-allyl-6-fluoro-2-oxo-1H-3-methylquinoxalin-7-yl) -5-chloro-1, A brown solid (147 mg, yield: 54%) of 2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.89-1.98 (m, 2H), 2.00-2.10 (m, 2H), 2.61 (s, 3H), 3.65- 3.72 (m, 2H), 3.83-3.90 (m, 2H), 4.90 (d, J = 5.1 Hz, 2H), 5.19 (d, J = 17.3 Hz, 1H) ), 5.28 (d, J = 10.4 Hz, 1H), 5.95 (ddt, J = 17.3, 10.4 and 5.1 Hz, 1H), 7.50 (dd, J = 6. 2 Hz, 1 H), 7.56 (d, J = 10.0 Hz, 1 H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-116.8 (s, 1F).

４−［５−（アリルアミノ）−４−アミノ−２−フルオロフェニル］−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オン（２３６ｍｇ，０．７ｍｍｏｌ）のトルエン（７ｍＬ）溶液に、トリエチルアミン（７１ｍｇ，０．７ｍｍｏｌ）とトリフルオロピルビン酸エチル（２４３ｍｇ，１．４ｍｍｏｌ）を加えた。この混合溶液を１００℃で４時間撹拌した。反応終了後、減圧下で溶媒を留去した。残渣に水を加え、クロロホルムで生成物を抽出した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、４−［１−アリル−６−フルオロ−２−オキソ−１Ｈ−３−（トリフルオロメチル）キノキサリン−７−イル］−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの黄色固体（１４６ｍｇ，収率：４７％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．９２−２．００（ｍ，２Ｈ），２．０３−２．１２（ｍ，２Ｈ），３．６９−３．７７（ｍ，２Ｈ），３．８４−３．９１（ｍ，２Ｈ），４．９５（ｄ，Ｊ＝５．３Ｈｚ，２Ｈ），５．２８（ｄ，Ｊ＝１７．３Ｈｚ，１Ｈ），５．３４（ｄ，Ｊ＝１０．４Ｈｚ，１Ｈ），５．９６（ｄｄｔ，Ｊ＝１７．３，１０．４ ａｎｄ ５．３Ｈｚ，１Ｈ），７．６９（ｄｄ，Ｊ＝６．２Ｈｚ，１Ｈ），７．７４（ｄ，Ｊ＝９．６Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１４．６（ｓ，１Ｆ），−７０．０（ｓ，３Ｆ）．Example-117

4- [5- (allylamino) -4-amino-2-fluorophenyl] -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one (236 mg, 0.7 mmol) in toluene (7 mL) Were added triethylamine (71 mg, 0.7 mmol) and ethyl trifluoropyruvate (243 mg, 1.4 mmol). The mixed solution was stirred at 100 ° C. for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Water was added to the residue, and the product was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (ethyl acetate) to give 4- [1-allyl-6-fluoro-2-oxo-1H-3- (trifluoromethyl) quinoxalin-7-yl] -5- A yellow solid (146 mg, yield: 47%) of chloro-1,2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.92-2.00 (m, 2H), 2.03-2.12 (m, 2H), 3.69-3.77 (m, 2H), 3.84-3.91 (m, 2H), 4.95 (d, J = 5.3 Hz, 2H), 5.28 (d, J = 17.3 Hz, 1H), 5.34 (d, J = 10.4 Hz, 1 H), 5.96 (ddt, J = 17.3, 10.4 and 5.3 Hz, 1 H), 7.69 (dd, J = 6.2 Hz, 1 H), 7.74 ( d, J = 9.6 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.6 (s, 1F), −70.0 (s, 3F).

５−クロロ−４−（２，５−ジフルオロ−４−ニトロフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（１．４７ｇ，４．４５ｍｍｏｌ）を無水テトラヒドロフラン（２２ｍＬ）に溶解し、氷冷下でプロパルギルアミン（７７６ｍｇ，１３．４ｍｍｏｌ）加え室温で２４時間攪拌した。途中、無水テトラヒドロフラン（２２ｍＬ）、プロパルギルアミン（７７６ｍｇ，１３．４ｍｍｏｌ）、Ｎ，Ｎ−ジイソプロピルエチルアミン（５７５ｍｇ，０．７６ｍｍｏｌ）を追加し、計４日と２２時間攪拌した。反応終了後、溶媒を留去し吸引ろ過後、水とジエチルエーテルで洗浄し乾燥することにより、５−クロロ−４−［２−フルオロ−４−ニトロ−５−（プロパルギルアミノ）フェニル］−１，２−テトラメチレン−４−ピラゾリン−３−オン（１．５１ｇ，収率：９３％）を茶褐色固体物として得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．９１−１．９６（ｍ，２Ｈ），２．０２−２．０７（ｍ，２Ｈ），２．３０（ｔ，Ｊ＝２．４０Ｈｚ，１Ｈ），３．６８−３．７１（ｍ，２Ｈ），３．８４−３．８７（ｍ，２Ｈ），４．１４（ｄｄ，Ｊ＝２．４０ａｎｄ５．６０Ｈｚ，２Ｈ），７．１８（ｄ，Ｊ＝６．０Ｈｚ，１Ｈ），７．９８（ｄ，Ｊ＝１０．０Ｈｚ，１Ｈ），８．０２（ｂｒｓ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１２４（ｓ，１Ｆ）．Reference Example-45

5-Chloro-4- (2,5-difluoro-4-nitrophenyl) -1,2-tetramethylene-4-pyrazolin-3-one (1.47 g, 4.45 mmol) was dissolved in anhydrous tetrahydrofuran (22 mL). Then, propargylamine (776 mg, 13.4 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 24 hours. On the way, anhydrous tetrahydrofuran (22 mL), propargylamine (776 mg, 13.4 mmol) and N, N-diisopropylethylamine (575 mg, 0.76 mmol) were added and stirred for a total of 4 days and 22 hours. After completion of the reaction, the solvent was distilled off, suction filtration, washing with water and diethyl ether and drying to give 5-chloro-4- [2-fluoro-4-nitro-5- (propargylamino) phenyl] -1 , 2-tetramethylene-4-pyrazolin-3-one (1.51 g, yield: 93%) was obtained as a brown solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.91-1.96 (m, 2H), 2.02-2.07 (m, 2H), 2.30 (t, J = 2.40 Hz, 1H ), 3.68-3.71 (m, 2H), 3.84-3.87 (m, 2H), 4.14 (dd, J = 2.40 and 5.60 Hz, 2H), 7.18 (d , J = 6.0 Hz, 1H), 7.98 (d, J = 10.0 Hz, 1H), 8.02 (brs, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-124 (s, 1F).

５−クロロ−４−（２−フルオロ−４−ニトロ−５−プロパルギルアミノフェニル）−１，２−テトラメチレン−４−ピラゾリン−３−オン（１．４６ｇ，４．００ｍｍｏｌ）に酢酸エチル（２０ｍＬ）、酢酸（４．４ｍＬ）、水（０．７２ｍＬ）加えた後、還元鉄（２．２３ｇ，４０．０ｍｍｏｌ）を加え８０℃で２０時間攪拌した。反応終了後、セライトろ過し水酢酸エチルで洗浄後ろ液を酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液で洗浄後、無水硫酸マグネシウムで乾燥し減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）で溶出して精製することにより、４−［４−アミノ−２−フルオロ−５−（プロパルギルアミノ）フェニル］−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オン（８０３ｍｇ，収率：６０％）を橙色固体物として得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８５−１．９０（ｍ，２Ｈ），１．９７−２．０３（ｍ，２Ｈ），２．２７（ｔ，Ｊ＝２．４０Ｈｚ，１Ｈ），３．１８（ｂｒｓ，１Ｈ），３．５４−３．５７（ｍ，２Ｈ），３．７２（ｂｒｓ，２Ｈ），３．８１−３．８４（ｍ，２Ｈ），３．８７（ｂｒｓ，２Ｈ），６．５１（ｄ，Ｊ＝１０．８Ｈｚ，１Ｈ），６．８６（ｄ，Ｊ＝６．８０Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１２１（ｓ，１Ｆ）．Reference Example-46

5-Chloro-4- (2-fluoro-4-nitro-5-propargylaminophenyl) -1,2-tetramethylene-4-pyrazolin-3-one (1.46 g, 4.00 mmol) in ethyl acetate (20 mL) ), Acetic acid (4.4 mL) and water (0.72 mL) were added, and reduced iron (2.23 g, 40.0 mmol) was added, followed by stirring at 80 ° C. for 20 hours. After completion of the reaction, the mixture was filtered through celite, washed with water ethyl acetate, and the back solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 4- [4-amino-2-fluoro-5- (propargylamino) phenyl]- 5-Chloro-1,2-tetramethylene-4-pyrazolin-3-one (803 mg, yield: 60%) was obtained as an orange solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.85-1.90 (m, 2H), 1.97-2.03 (m, 2H), 2.27 (t, J = 2.40 Hz, 1H) ), 3.18 (brs, 1H), 3.54-3.57 (m, 2H), 3.72 (brs, 2H), 3.81-3.84 (m, 2H), 3.87 ( brs, 2H), 6.51 (d, J = 10.8 Hz, 1H), 6.86 (d, J = 6.80 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-121 (s, 1F).

４−［４−アミノ−２−フルオロ−５−（プロパルギルアミノ）フェニル］−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オン（２００ｍｇ，０．６０ｍｍｏｌ）のトルエン（６ｍＬ）溶液に、ＤＢＵ（１０９ｍｇ，０．７０ｍｍｏｌ）とピルビン酸エチル（１４２ｍｇ，１．２ｍｍｏｌ）を加えた。この混合溶液を１００℃で４時間撹拌した。反応終了後、減圧下で溶媒を留去した。残渣に水を加え、クロロホルムで生成物を抽出した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、４−（６−フルオロ−２−オキソ−１Ｈ−１−プロパルギル−３−メチルキノキサリン−７−イル）−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの淡黄色固体（１６ｍｇ，収率：７％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．９０−１．９８（ｍ，２Ｈ），２．０２−２．０９（ｍ，２Ｈ），２．３０（ｔ，Ｊ＝２．５Ｈｚ，１Ｈ），２．６１（ｓ，３Ｈ），３．６６−３．７３（ｍ，２Ｈ），３．８４−３．９１（ｍ，２Ｈ），５．０６（ｄ，Ｊ＝２．５Ｈｚ，２Ｈ），７．５７（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．６４（ｄ，Ｊ＝６．２Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１６．３（ｓ，１Ｆ）．Example-118

4- [4-amino-2-fluoro-5- (propargylamino) phenyl] -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one (200 mg, 0.60 mmol) in toluene (6 mL) To the solution was added DBU (109 mg, 0.70 mmol) and ethyl pyruvate (142 mg, 1.2 mmol). The mixed solution was stirred at 100 ° C. for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Water was added to the residue, and the product was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (ethyl acetate) to give 4- (6-fluoro-2-oxo-1H-1-propargyl-3-methylquinoxalin-7-yl) -5-chloro-1, A pale yellow solid (16 mg, yield: 7%) of 2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.90-1.98 (m, 2H), 2.02-2.09 (m, 2H), 2.30 (t, J = 2.5 Hz, 1H ), 2.61 (s, 3H), 3.66-3.73 (m, 2H), 3.84-3.91 (m, 2H), 5.06 (d, J = 2.5 Hz, 2H) ), 7.57 (d, J = 9.9 Hz, 1H), 7.64 (d, J = 6.2 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-116.3 (s, 1F).

４−［４−アミノ−２−フルオロ−５−（プロパルギルアミノ）フェニル］−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オン（２００ｍｇ，０．６０ｍｍｏｌ）のトルエン（６ｍＬ）溶液に、トリエチルアミン（６１ｍｇ，０．６０ｍｍｏｌ）とトリフルオロピルビン酸エチル（２０８ｍｇ，１．２ｍｍｏｌ）を加えた。この混合溶液を１００℃で４時間撹拌した。反応終了後、減圧下で溶媒を留去した。残渣に水を加え、クロロホルムで生成物を抽出した。有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、５−クロロ−４−［６−フルオロ−２−オキソ−１Ｈ−１−プロパルギル−３−（トリフルオロメチル）キノキサリン−７−イル］−１，２−テトラメチレン−４−ピラゾリン−３−オンの黄色固体（２４２ｍｇ，収率：９２％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．９２−２．００（ｍ，２Ｈ），２．０３−２．１２（ｍ，２Ｈ），２．３５（ｔ，Ｊ＝２．５Ｈｚ，１Ｈ），３．７１−３．７７（ｍ，２Ｈ），３．８５−３．９２（ｍ，２Ｈ），５．１０（ｄ，Ｊ＝２．５Ｈｚ，２Ｈ），７．７５（ｄ，Ｊ＝９．５Ｈｚ，１Ｈ），７．８１（ｄ，Ｊ＝６．１Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１４．１（ｓ，１Ｆ），−７０．０（ｓ，３Ｆ）．Example-119

4- [4-amino-2-fluoro-5- (propargylamino) phenyl] -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one (200 mg, 0.60 mmol) in toluene (6 mL) To the solution were added triethylamine (61 mg, 0.60 mmol) and ethyl trifluoropyruvate (208 mg, 1.2 mmol). The mixed solution was stirred at 100 ° C. for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. Water was added to the residue, and the product was extracted with chloroform. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (ethyl acetate) to give 5-chloro-4- [6-fluoro-2-oxo-1H-1-propargyl-3- (trifluoromethyl) quinoxalin-7-yl. ] -1,2-tetramethylene-4-pyrazolin-3-one yellow solid (242 mg, yield: 92%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.92-2.00 (m, 2H), 2.03-2.12 (m, 2H), 2.35 (t, J = 2.5 Hz, 1H ), 3.71-3.77 (m, 2H), 3.85-3.92 (m, 2H), 5.10 (d, J = 2.5 Hz, 2H), 7.75 (d, J = 9.5 Hz, 1 H), 7.81 (d, J = 6.1 Hz, 1 H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.1 (s, 1F), -70.0 (s, 3F).

４−［５−（アリルアミノ）−４−アミノ−２−フルオロフェニル］−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オン（２３６ｍｇ，０．７ｍｍｏｌ）のジクロロメタン（２ｍＬ）溶液に、トリエチルアミン（３５４ｍｇ，３．５ｍｍｏｌ）とＮ，Ｎ−ジメチルアミノピリジン（８６ｍｇ，０．７ｍｍｏｌ）を加え、さらに氷冷下でトリフルオロ酢酸無水物（０．４ｍＬ，２．８ｍｍｏｌ）を加えた。この混合溶液を室温で１２時間撹拌した。反応終了後、水を加え、クロロホルム（２０ｍＬ×３）で生成物を抽出した。合一した有機層を硫酸マグネシウムで乾燥した後に減圧濃縮し、粗生成物を得た。このものをシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製することにより、２−（１−アリル−５−フルオロ−２−トリフルオロメチル−１Ｈ−ベンゾイミダゾール−６−イル）−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オンの褐色固体（収率：定量的）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．８９−１．９７（ｍ，２Ｈ），２．００−２．０９（ｍ，２Ｈ），３．６３−３．７０（ｍ，２Ｈ），３．８４−３．９０（ｍ，２Ｈ），４．９４（ｄ，Ｊ＝５．２Ｈｚ，２Ｈ），５．１６（ｄ，Ｊ＝１７．２Ｈｚ，１Ｈ），５．２８（ｄ，Ｊ＝１０．１Ｈｚ，１Ｈ），５．９５（ｄｄｔ，Ｊ＝１７．２，１０．１ ａｎｄ ５．２Ｈｚ，１Ｈ），７．５９−７．６５（ｍ，３Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１６．３（ｓ，１Ｆ），−６２．２（ｓ，３Ｆ）．Example-120

4- [5- (allylamino) -4-amino-2-fluorophenyl] -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one (236 mg, 0.7 mmol) in dichloromethane (2 mL) Were added triethylamine (354 mg, 3.5 mmol) and N, N-dimethylaminopyridine (86 mg, 0.7 mmol), and further trifluoroacetic anhydride (0.4 mL, 2.8 mmol) was added under ice cooling. . The mixed solution was stirred at room temperature for 12 hours. After completion of the reaction, water was added and the product was extracted with chloroform (20 mL × 3). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure to obtain a crude product. This was purified by silica gel column chromatography (ethyl acetate) to give 2- (1-allyl-5-fluoro-2-trifluoromethyl-1H-benzimidazol-6-yl) -5-chloro-1, A brown solid (yield: quantitative) of 2-tetramethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.89-1.97 (m, 2H), 2.00-2.09 (m, 2H), 3.63-3.70 (m, 2H), 3.84-3.90 (m, 2H), 4.94 (d, J = 5.2 Hz, 2H), 5.16 (d, J = 17.2 Hz, 1H), 5.28 (d, J = 10.1 Hz, 1H), 5.95 (ddt, J = 17.2, 10.1 and 5.2 Hz, 1H), 7.59-7.65 (m, 3H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-116.3 (s, 1F), -62.2 (s, 3F).

４−（４−アミノ−２−フルオロ−５−プロパルギルアミノフェニル）−５−クロロ−１，２−テトラメチレン−４−ピラゾリン−３−オン（２５０ｍｇ，０．７５ｍｍｏｌ）と４−ジメチルアミノピリジン（９１．１ｍｇ，０．７５ｍｍｏｌ）に無水ジクロロメタン（２ｍＬ）とトリエチルアミン（３７７ｍｇ，３．７３ｍｍｏｌ）を加えた後、氷冷下でトリフルオロ酢酸無水物（６３９ｍｇ，２．９８ｍｍｏｌ）を加え室温で１７時間攪拌した。反応終了後、反応液に水を加えクロロホルムで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝１０：１）で溶出して精製することにより、５−クロロ−４−［５−フルオロ−１−プロパルギル−２−（トリフルオロメチル）ベンズイミダゾール−６−イル］−１，２−テトラメチレン−４−ピラゾリン−３−オン（２７０ｍｇ，収率：８８％）を薄黄色固体物として得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．９０−１．９６（ｍ，２Ｈ），２．０２−２．０８（ｍ，２Ｈ），２．４３（ｔ，Ｊ＝２．４０Ｈｚ，１Ｈ），３．６５−３．６８（ｍ，２Ｈ），３．８６−３．８９（ｍ，２Ｈ），５．０８（ｄ，Ｊ＝２．４０Ｈｚ，２Ｈ），７．６２（ｄ，Ｊ＝１０．０Ｈｚ，１Ｈ），７．７９（ｄ，Ｊ＝６．０Ｈｚ，１Ｈ）．^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１６（ｓ，１Ｆ），−６２．１（ｓ，３Ｆ）．Example-121

4- (4-amino-2-fluoro-5-propargylaminophenyl) -5-chloro-1,2-tetramethylene-4-pyrazolin-3-one (250 mg, 0.75 mmol) and 4-dimethylaminopyridine ( After adding anhydrous dichloromethane (2 mL) and triethylamine (377 mg, 3.73 mmol) to 91.1 mg, 0.75 mmol), trifluoroacetic anhydride (639 mg, 2.98 mmol) was added under ice-cooling for 17 hours at room temperature. Stir. After completion of the reaction, water was added to the reaction solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give 5-chloro-4- [5-fluoro-1-propargyl-2- (trifluoro). Methyl) benzimidazol-6-yl] -1,2-tetramethylene-4-pyrazolin-3-one (270 mg, yield: 88%) was obtained as a pale yellow solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.90-1.96 (m, 2H), 2.02-2.08 (m, 2H), 2.43 (t, J = 2.40 Hz, 1H ), 3.65-3.68 (m, 2H), 3.86-3.89 (m, 2H), 5.08 (d, J = 2.40 Hz, 2H), 7.62 (d, J = 10.0 Hz, 1 H), 7.79 (d, J = 6.0 Hz, 1 H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-116 (s, 1F), -62.1 (s, 3F).

水素化ナトリウムの５５％油分散（３３０ｍｇ，７．５３ｍｍｏｌ）の１，４−ジオキサン（２９ｍＬ）懸濁液に、５−クロロ−４−（２，４−ジフルオロ−５−ニトロフェニル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（２．００ｇ，５．７９ｍｍｏｌ）及び乳酸エチル（１．０３ｍＬ，８．６９ｍｍｏｌ）を加え、室温で３時間撹拌した。反応終了後、反応液を氷水（１００ｇ）に注ぎ入れ、酢酸エチル（５０ｍＬ×３）で抽出した。合一した有機層を無水硫酸マグネシウムで乾燥し、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（酢酸エチル：メタノール＝９：１）で精製することにより、２−［４−（５−クロロ−３−オキソ−１，２−オキサジエチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］プロピオン酸エチルの淡黄色固体（１．２６ｇ，収率：４９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．２８（ｔ，Ｊ＝７．０Ｈｚ，３Ｈ），１．７１（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），３．９２−３．９５（ｍ，４Ｈ），４．２２−４．２５（ｍ，２Ｈ），４．２５（ｑ，Ｊ＝７．０Ｈｚ，２Ｈ），４．２５−４．２９（ｍ，２Ｈ），４．８０（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），６．７３（ｄ，Ｊ＝１０．８Ｈｚ，１Ｈ），８．１１（ｄ，Ｊ＝７．５Ｈｚ，１Ｈ）；^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−９９．２（ｓ，１Ｆ）．Reference Example-47

To a suspension of sodium hydride in 55% oil dispersion (330 mg, 7.53 mmol) in 1,4-dioxane (29 mL), 5-chloro-4- (2,4-difluoro-5-nitrophenyl) -1, 2-Oxadiethylene-4-pyrazolin-3-one (2.00 g, 5.79 mmol) and ethyl lactate (1.03 mL, 8.69 mmol) were added and stirred at room temperature for 3 hours. After completion of the reaction, the reaction solution was poured into ice water (100 g) and extracted with ethyl acetate (50 mL × 3). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate: methanol = 9: 1) to give 2- [4- (5-chloro-3-oxo-1,2-oxadiethylene-4- A pale yellow solid (1.26 g, yield: 49%) of ethyl pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] propionate was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.28 (t, J = 7.0 Hz, 3H), 1.71 (d, J = 6.8 Hz, 3H), 3.92-3.95 (m , 4H), 4.22-4.25 (m, 2H), 4.25 (q, J = 7.0 Hz, 2H), 4.25-4.29 (m, 2H), 4.80 (q , J = 6.8 Hz, 1H), 6.73 (d, J = 10.8 Hz, 1H), 8.11 (d, J = 7.5 Hz, 1H); ¹⁹ F-NMR (376 MHz, CDCl ₃ ) : Δ-99.2 (s, 1F).

２−［４−（５−クロロ−３−オキソ−１，２−オキサジエチレン−４−ピラゾリン−４−イル）−５−フルオロ−２−ニトロフェニルオキシ］プロピオン酸エチル（１．２０ｇ，２．７０ｍｍｏｌ）の酢酸エチル（５．５ｍＬ）溶液に、水（０．５ｍＬ）及び酢酸（３．０ｍＬ）を加えた後、還元鉄（７５０ｍｇ，１３．５ｍｍｏｌ）を加え、８０℃で３時間撹拌した。反応終了後、反応液を室温へし、不溶物をろ別後、ろ液に飽和炭酸水素ナトリウム水溶液（１００ｍＬ）を加え、クロロホルム（５０ｍＬ×２）で抽出した。有機層を飽和炭酸水素ナトリウム水溶液（５０ｍＬ×３）及び飽和食塩水（２０ｍＬ）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をクロロホルムに溶かし、ヘキサンを加えて析出した固体をろ取することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（７５２ｍｇ，収率：７６％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５５（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），３．９１−３．９７（ｍ，４Ｈ），４．２０−４．２５（ｍ，２Ｈ），４．２８−４．３３（ｍ，２Ｈ），４．６１（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），６．７５（ｄ，Ｊ＝１０．３Ｈｚ，１Ｈ），７．０８（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ），８．６５（ｂｒｓ，１Ｈ）；^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．８（ｓ，１Ｆ）．Example-122

Ethyl 2- [4- (5-chloro-3-oxo-1,2-oxadiethylene-4-pyrazolin-4-yl) -5-fluoro-2-nitrophenyloxy] propionate (1.20 g, 2. 70 mmol) in ethyl acetate (5.5 mL) was added water (0.5 mL) and acetic acid (3.0 mL), then reduced iron (750 mg, 13.5 mmol) was added, and the mixture was stirred at 80 ° C. for 3 hours. . After completion of the reaction, the reaction solution was brought to room temperature, insolubles were filtered off, saturated aqueous sodium hydrogen carbonate solution (100 mL) was added to the filtrate, and the mixture was extracted with chloroform (50 mL × 2). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL × 3) and saturated brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was dissolved in chloroform, hexane was added, and the precipitated solid was collected by filtration to give 5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo- A white solid (752 mg, yield: 76%) of 4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.55 (d, J = 6.8 Hz, 3H), 3.91-3.97 (m, 4H), 4.20-4.25 (m, 2H) ), 4.28-4.33 (m, 2H), 4.61 (q, J = 6.8 Hz, 1H), 6.75 (d, J = 10.3 Hz, 1H), 7.08 (d , J = 6.8 Hz, 1H), 8.65 (brs, 1H); ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.8 (s, 1F).

水素化ナトリウムの５５％油分散（５２ｍｇ，１．２０ｍｍｏｌ）のＤＭＦ（６．０ｍＬ）懸濁液に、氷冷下で５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オン（４００ｍｇ，１．０９ｍｍｏｌ）及びプロパルギルブロミド（９５μＬ，１．２０ｍｍｏｌ）を順次加え、室温で１５時間撹拌した。反応終了後、反応液に水（５０ｍＬ）を加え、クロロホルム（１００ｍＬ×２）で抽出した。有機層を水（５０ｍＬ×３）で洗浄し、無水硫酸マグネシウムで乾燥後、減圧濃縮した。得られた粗生成物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝９：１）で精製することにより、５−クロロ−４−（７−フルオロ−２，３−ジヒドロ−２−メチル−３−オキソ−４−プロパルギル−４Ｈ−１，４−ベンゾオキサジン−６−イル）−１，２−オキサジエチレン−４−ピラゾリン−３−オンの白色固体（３４６ｍｇ，収率：７９％）を得た。^１Ｈ−ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ_３）：δ１．５９（ｄ，Ｊ＝６．８Ｈｚ，３Ｈ），２．２５（ｔ，Ｊ＝２．５Ｈｚ，１Ｈ），３．９３−３．９８（ｍ，４Ｈ），４．２０−４．２４（ｍ，２Ｈ），４．２６−４．３０（ｍ，２Ｈ），４．６３（ｄｄ，Ｊ＝１７．６ ａｎｄ ２．５Ｈｚ，１Ｈ），４．６７（ｑ，Ｊ＝６．８Ｈｚ，１Ｈ），４．７５（ｄｄ，Ｊ＝１７．６ ａｎｄ ２．５Ｈｚ，１Ｈ），６．８２（ｄ，Ｊ＝９．９Ｈｚ，１Ｈ），７．２８（ｄ，Ｊ＝６．７Ｈｚ，１Ｈ）；^１９Ｆ−ＮＭＲ（３７６ＭＨｚ，ＣＤＣｌ_３）：δ−１１５．３（ｓ，１Ｆ）．

以上の実施例、参考例に示した方法に準じた方法より製造できる本発明の二環性ピラゾリノン誘導体（１）の具体例を表−１から表−３に例示するが、本発明はこれらに限定されるものではない。Example-123

To a suspension of sodium hydride in 55% oil dispersion (52 mg, 1.20 mmol) in DMF (6.0 mL) under ice-cooling, 5-chloro-4- (7-fluoro-2,3-dihydro-2- Methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one (400 mg, 1.09 mmol) and propargyl bromide (95 μL, 1.20 mmol) ) Were sequentially added and stirred at room temperature for 15 hours. After completion of the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with chloroform (100 mL × 2). The organic layer was washed with water (50 mL × 3), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to give 5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo. A white solid (346 mg, yield: 79%) of -4-propargyl-4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin-3-one was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.59 (d, J = 6.8 Hz, 3H), 2.25 (t, J = 2.5 Hz, 1H), 3.93-3.98 (m , 4H), 4.20-4.24 (m, 2H), 4.26-4.30 (m, 2H), 4.63 (dd, J = 17.6 and 2.5 Hz, 1H), 4 .67 (q, J = 6.8 Hz, 1H), 4.75 (dd, J = 17.6 and 2.5 Hz, 1H), 6.82 (d, J = 9.9 Hz, 1H), 7. 28 (d, J = 6.7 Hz, 1H); ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.3 (s, 1F).

Specific examples of the bicyclic pyrazolinone derivative (1) of the present invention that can be produced by a method according to the methods shown in the above Examples and Reference Examples are shown in Tables 1 to 3, but the present invention is not limited thereto. It is not limited.

Next, the present invention will be described in more detail with reference to herbicide preparation examples containing the compound of the present invention as an active ingredient and test examples using the herbicide of the present invention. It is not limited. In addition, “parts” in formulation examples indicate parts by weight.
Formulation Example-1 (emulsion)
10 parts of the present compound, 31 parts of xylene, 27 parts of N, N-dimethylformamide, 22 parts of 1-methyl-2-pyrrolidone, 1 part of 1,3-dimethyl-2-imidazolidinone, NK. An emulsion was obtained by uniformly mixing 9 parts of ST-30 (Takemoto Oil).
Formulation Example-2 (wettable powder)
A mixture of 50 parts of the compound of the present invention, 25 parts of diatomaceous earth, 22 parts of clay, and 3 parts of LUNOX 1000C (manufactured by Toho Chemical) was uniformly mixed and ground to obtain a wettable powder.
Formulation Example-3 (granule)
A mixture of 5 parts of the present compound, 35 parts of bentonite, 55 parts of talc and 5 parts of lignin sulfonic acid soda was uniformly mixed and ground, then kneaded with water, granulated with an extrusion granulator, and dried. The granules were sized to obtain granules.

  Using the preparation prepared according to the above-described method, the herbicidal effect of the bicyclic pyrazolinone derivative of the present invention was investigated according to the method shown in the following test examples. The herbicidal effect on the test weeds or the phytotoxicity on the test samples was determined according to the criteria shown below, and evaluated with a 6-level score of 0-5.

Criteria for herbicidal effect and phytotoxicity 5: 90% or more herbicidal effect / phytotoxicity 4: 70% to 90% herbicidal effect / phytotoxicity 3: 50% to 70% herbicidal effect / phytotoxicity 2: 30% to 50% weeding Effect / phytotoxicity 1: 10% to 30% herbicidal effect / phytotoxicity 0: 0% to 10% herbicidal effect / phytotoxicity

Test example-1 (herbicidal effect test by pretreatment of weed generation under flooded conditions)
Paddy soil was filled in a 30cm ² plastic cup, and seedlings such as Tainubie, Tamagayatsu, Konagi, Firefly, Matsubai, and other annual broad-leaved weeds were sown and kept in a submerged condition. . On the day of weed seeding, the wettable powder or emulsion of the compound of the present invention prepared according to the preparation example was diluted and subjected to watering treatment so as to obtain a predetermined dosage. About 15 days after the treatment, the herbicidal effect on the test weeds was evaluated based on the above-described 6-step criteria of 0-5. Table 4 shows the results.

Test example-2 (herbicidal effect test by soil treatment before weed generation in field conditions)
Field soil was filled in a vat with an area of 65 cm ^{2 and a} depth of 2 cm, seeds of Aoubi and Shiroza were sown on this, and a 0.5 cm covering soil was placed thereon. On the next day, the wettable powder or emulsion of the compound of the present invention prepared according to the formulation example was diluted and sprayed uniformly on the cover so as to obtain a predetermined dosage. About 21 days after the treatment, the herbicidal effect on the test weeds was evaluated by the above-described 6-step criteria of 0-5. The results are shown in Table-5.

Test example-3 (herbicidal effect and phytotoxicity test by soil treatment before weed generation in field conditions)
A field vat with an area of 81 cm ^{2 and a} depth of 3.5 cm was filled with field soil, and seeds of Maruagaagao, Aoubi, Shiroza and maize and soybean seeds were sown, and a 0.5 cm covering soil was formed thereon. On the next day, the wettable powder or emulsion of the compound of the present invention prepared according to the formulation example was diluted and sprayed uniformly on the cover so as to obtain a predetermined dosage. About 21 days after the treatment, the herbicidal effect on the test weeds and the phytotoxicity on corn and soybean were evaluated by the above-described 6-step criteria of 0-5. The results are shown in Table-6.

Test Example 4 (herbicidal effect test by foliar treatment after weed generation in field conditions)
A bat having an area of 65 cm ^{2 and a} depth of 2 cm was filled with field soil, seeds of aoubi, ichibi and shiroza were sown on it, and 0.5 cm of covering soil was formed thereon. This was sprinkled with water and grown for 14 days. The wettable powder or emulsion of the compound of the present invention prepared according to the formulation example was diluted and sprayed uniformly onto the foliage of the plant at a water volume of 4000 liters per hectare so as to obtain a predetermined dosage. 14 days after the treatment, the herbicidal effect on the test weeds was evaluated according to the above-described 6-step criteria of 0-5. The results are shown in Table-7.

Test example-5 (herbicidal effect and phytotoxicity test by foliar treatment after weed generation in field conditions)
A bat having an area of 81 cm ^{2 and a} depth of 3.5 cm was filled with field soil, and seeds of Malvasagao, Aoubi, Ichibi, Shiroza and corn were sown, and a 0.5 cm covering soil was formed thereon. This was sprinkled with water and grown for 14 days. The wettable powder or emulsion of the compound of the present invention prepared according to the formulation example was diluted and sprayed uniformly onto the foliage of the plant at a water volume of 4000 liters per hectare so as to obtain a predetermined dosage. Fourteen days after the treatment, the herbicidal effect on the test weeds and the phytotoxicity on the corn were evaluated according to the above-described 6-step criteria of 0-5. The results are shown in Table-8.

  By treating an effective amount of the bicyclic pyrazolinone derivative of the present invention in paddy fields or fields, harmful weeds can be effectively controlled.

Claims (14)

General formula (1)

{Where,
R ¹ represents a halogen atom,
Y represents a methylene group, a fluoromethylene group, a dimethylene group, a trimethylene group, a tetramethylene group, an oxamethylene group or an oxadimethylene group;
Ar represents the following general formula (Ar-1)

[Where:
X ¹ represents a hydrogen atom or a halogen atom,
X ² and X ³ are each independently the same or different and represent a hydrogen atom; a halogen atom; a C ₁ -C ₄ alkyl group; a C ₁ -C ₄ haloalkyl group; a C ₁ -C ₄ alkyloxy group; represents an atom or C ₁ -C ₄ 1 or more substituents phenyl group which may be substituted with a group selected from the group consisting of alkyl groups,
R ^2a is a hydrogen atom; ₁ selected from the group consisting of a C ₁ -C ₄ alkyloxy group, a cyano group, a (C ₁ -C ₄ alkyl) oxycarbonyl group and a (C ₂ -C ₄ alkenyl) oxycarbonyl group seed or more optionally substituted _C 1 -C ₆ alkyl group optionally substituted with a _group; C 1 -C ₆ haloalkyl _group; C 3 -C ₆ cycloalkyl group; glycidyl group; a C be substituted by a halogen atom _{A 2-} C ₆ alkenyl group; a C ₂ -C ₆ alkynyl group optionally substituted with a halogen atom or a trimethylsilyl group; or a halogen atom, a C ₁ -C ₄ alkyl group, a C ₁ -C ₄ alkyloxy group, ( C ₁ -C ₄ alkyl) substituted with one or more substituents selected from the group consisting of oxycarbonyl group, trifluoromethyl group, cyano group and nitro group Represents a good C ₇ -C ₈ aralkyl group,
Z represents an oxygen atom or a sulfur atom. 2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl group or 2,3-dihydro-3-oxo-4H-1,4-benzothiazin-6-yl group ;
The following general formula (Ar-2)

[Wherein, X ¹ represents a hydrogen atom or a halogen atom,
X ^2d is substituted with one or more substituents selected from the group consisting of a hydrogen atom; a C ₁ -C ₄ alkyl group; a C ₁ -C ₄ haloalkyl group; or a halogen atom and a C ₁ -C ₄ alkyl group. Represents an optionally substituted phenyl group,
R ^2c represents a hydrogen atom; a C ₁ -C ₆ alkyl group; a C ₁ -C ₆ haloalkyl group; a C ₃ -C ₆ cycloalkyl group; a C ₂ -C ₆ alkenyl group; a C ₂ -C ₆ alkynyl group; halogen _atom, C 1 -C ₄ alkyl _group, C 1 -C ₄ alkyl _group, 1 is selected from the group consisting of _(C 1 -C ₄ alkyl) oxycarbonyl group, a trifluoromethyl group, a cyano group and a nitro group It represents a C ₇ -C ₈ aralkyl group which may be substituted with one or more substituents. Or a 1,2-dihydro-2-oxoquinoxalin-7-yl group represented by:
The following general formula (Ar-3)

[Wherein, X ¹ represents a hydrogen atom or a halogen atom,
X ^2d is substituted with one or more substituents selected from the group consisting of a hydrogen atom; a C ₁ -C ₄ alkyl group; a C ₁ -C ₄ haloalkyl group; or a halogen atom and a C ₁ -C ₄ alkyl group. Represents an optionally substituted phenyl group,
R ^2c represents a hydrogen atom; a C ₁ -C ₆ alkyl group; a C ₁ -C ₆ haloalkyl group; a C ₃ -C ₆ cycloalkyl group; a C ₂ -C ₆ alkenyl group; a C ₂ -C ₆ alkynyl group; halogen _atom, C 1 -C ₄ alkyl _group, C 1 -C ₄ alkyl _group, 1 is selected from the group consisting of _(C 1 -C ₄ alkyl) oxycarbonyl group, a trifluoromethyl group, a cyano group and a nitro group It represents a C ₇ -C ₈ aralkyl group which may be substituted with one or more substituents. A benzimidazol-6-yl group represented by the formula: }
A bicyclic pyrazolinone derivative represented by: In the general formula (1), Ar is the general formula (Ar-1), X ² and X ³ are each independently the same or different and are a hydrogen atom, a methyl group, a methoxy group, or a fluorine atom, The bicyclic pyrazolinone derivative according to claim 1, wherein Y is a methylene group, dimethylene group, trimethylene group or oxadimethylene group, and Z is an oxygen atom. In the general formula (1), Ar is the general formula (Ar-1), X ¹ is a fluorine atom or a chlorine atom, X ² and X ³ are both hydrogen atoms or both fluorine atoms, or X ³ is a methyl group or a methoxy group, X ³ is a hydrogen atom, R ¹ is a chlorine atom, Y is a dimethylene group or an oxadimethylene group, and Z is an oxygen atom. Bicyclic pyrazolinone derivatives. In the general formula (1), Ar is the general formula (Ar-1), R ^2a is a C ₁ -C ₄ alkyloxy group, a cyano group, a (C ₁ -C ₄ alkyl) oxycarbonyl group, and (C C ₁ -C ₆ alkyl group optionally substituted with one or more substituents selected from the group consisting of _2- C ₄ alkenyl) oxycarbonyl groups; C ₁ -C ₆ haloalkyl groups; C ₂ -C ₆ bicyclic pyrazolinone derivative according to any one of claims 1 to 3 or C ₂ -C ₆ alkynyl group; an alkenyl group. In the above Formula (1), Ar is a formula ^{(Ar-1), R 2a} _is, C 2 -C ₆ alkenyl or _C 2 -C ₆ any one of claims 1 to 4, an alkynyl group The bicyclic pyrazolinone derivative according to item. The compound represented by the general formula (1) is
5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin-3-one,
5-chloro-4- (7-fluoro-4-methyl-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin- 3-on,
4- (4-Allyl-7-fluoro-2,3-dihydro-3-oxo-4H-1,4-benzoxazin-6-yl) -5-chloro-1,2-tetramethylene-4-pyrazolin- 3-on,
5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4-propargyl-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin- 3-on,
5-chloro-4- (7-fluoro-2,3-dihydro-4-isobutyl-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene- 4-pyrazolin-3-one,
5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo-4-propargyl-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene- 4-pyrazolin-3-one,
(S) -5-chloro-4- (7-fluoro-2,3-dihydro-2-methyl-3-oxo-4-propargyl-4H-1,4-benzoxazin-6-yl) -1,2 -Tetramethylene-4-pyrazolin-3-one,
4- [4- (2-Butynyl) -7-fluoro-2,3-dihydro-2-methyl-3-oxo-4H-1,4-benzoxazin-6-yl] -5-chloro-1,2 -Tetramethylene-4-pyrazolin-3-one,
5-chloro-4- (7-chloro-2,3-dihydro-3-oxo-4-propargyl-4H-1,4-benzoxazin-6-yl) -1,2-tetramethylene-4-pyrazolin- 3-on,
5-chloro-4- (7-fluoro-2,3-dihydro-3-oxo-4-propargyl-4H-1,4-benzoxazin-6-yl) -1,2-oxadiethylene-4-pyrazolin- 3-on,
5-Chloro-1,2-tetramethylene-4- (2,2,7-trifluoro-2,3-dihydro-3-oxo-4-propargyl-4H-1,4-benzoxazin-6-yl) -4-pyrazolin-3-one and 5-chloro-1,2-oxadiethylene-4- (2,2,7-trifluoro-2,3-dihydro-3-oxo-4-propargyl-4H-1, The bicyclic pyrazolinone derivative according to claim 1, which is one compound selected from the group consisting of 4-benzoxazin-6-yl) -4-pyrazolin-3-one. In the general formula (1), Ar is the general formula (Ar-2), X ¹ is a fluorine atom, X ^2d is a methyl group or a trifluoromethyl group, and Y is a dimethylene group or an oxadimethylene group. The bicyclic pyrazolinone derivative according to claim 1, wherein R ¹ is a chlorine atom, and R ^2c is a C ₂ -C ₆ alkenyl group or a C ₂ -C ₆ alkynyl group. In the general formula (1), Ar is the general formula (Ar-3), X ¹ is a fluorine atom, X ^2d is a methyl group or a trifluoromethyl group, and Y is a dimethylene group or an oxadimethylene group. The bicyclic pyrazolinone derivative according to claim 1, wherein R ¹ is a chlorine atom, and R ^2c is a C ₂ -C ₆ alkenyl group or a C ₂ -C ₆ alkynyl group.   A herbicide containing the bicyclic pyrazolinone derivative according to any one of claims 1 to 8 as an active ingredient.   The herbicide according to claim 9, which is for upland weed control or paddy field weed control.   The herbicide according to claim 10, wherein the herbicide is for upland weed control, and the crop in the upland field is wheat, soybean or corn.   The herbicide according to any one of claims 9 to 11, which is a foliage and / or a soil treatment agent.   Use of the bicyclic pyrazolinone derivative according to any one of claims 1 to 8 for controlling weeds.   A method for controlling weeds comprising applying an effective amount of the bicyclic pyrazolinone derivative according to any one of claims 1 to 8.