JP5034277B2 - Of 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoic acid ester and 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanohydrazide Production method - Google Patents

Description

  The present invention relates to 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoic acid ester and 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxo The present invention relates to a novel method for producing propanohydrazide. 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoic acid ester and 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanohydrazide are These are useful compounds as raw materials and synthetic intermediates for pharmaceuticals and agricultural chemicals. The present invention also relates to novel synthetic intermediates for producing these compounds and their novel production methods.

Conventionally, methods for producing 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoic acid ester include, for example, lithium bromide, concentrated sulfuric acid and dibromobis (triphenylphosphine) palladium. In the presence of carbon monoxide (57 kg / cm ² ), cycloheptylcarboxamide and 4-formyltetrahydropyran were reacted at 120 ° C. for 10 hours to give 2-cycloheptylcarbonylamino-2- (4-tetrahydro). Pyranyl) acetic acid, which is then reacted with methyl 2-chloro-2-oxoacetate to produce methyl 3-cycloheptylcarbonylamino-3- (4-tetrahydropyranyl) -2-oxopropionate Is disclosed (for example, see Patent Document 1). Further, a method for producing 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanohydrazide by reacting with hydrazine monohydrate is also disclosed (for example, patents). Reference 1). However, in these methods, a highly toxic carbon monoxide must be used for a long time under high pressure, and 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2- It was disadvantageous as an industrial production method of oxopropanoic acid ester and 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanohydrazide.
International Publication No. 03/91202 Pamphlet

  The object of the present invention is to solve the above-mentioned problems and to produce 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoate and 3- (N- The present invention provides an industrially suitable method for producing these compounds, which can produce (acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanohydrazide in high yield. Another object of the present invention is to provide a novel 2-acyloxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoic acid ester and a novel 3 which are useful synthetic intermediates that can be used in the method for producing the above compound. To provide an industrially suitable production method capable of producing-(N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoic acid ester and these compounds in high yield. It is.

  In view of the above problems, as a result of intensive studies by the present inventors, 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoate, and Discovered methods capable of producing 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanohydrazide in high yield, and novel synthetic intermediate compounds which can be used in these production methods And the manufacturing method was discovered, and this invention was completed.

  That is, the present invention relates to the general formula (2)

(In the formula, R represents a hydrocarbon group, and R ¹ represents a hydrogen atom or a hydrocarbon group.)
-Acyloxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoic acid ester (hereinafter referred to as compound (2)).

The present invention also provides a general formula (1)

(In the formula, R and R ¹ are as defined above.)
Wherein the aminating agent is reacted with 2-acyloxy-3- (4-tetrahydropyranyl) -3-oxopropanoic acid ester represented by the general formula (2). )

（式中、Ｒ及びＲ¹は、前記と同義である。）
で示される化合物（２）の製造方法に関する。

(In the formula, R and R ¹ are as defined above.)
To a method for producing the compound (2) represented by formula (1).

（式中、Ｒは、炭化水素基、Ｒ¹は、水素原子又は炭化水素基、Ｒ²は、水素原子又は炭化水素基を示す。）
で示される３−（Ｎ−アシルアミノ）−２−アシルオキシ−３−（４−テトラヒドロピラニル）−２−プロペン酸エステル（以下、化合物（３）と称する）に関する。 The present invention also provides a general formula (3)

(In the formula, R represents a hydrocarbon group, R ¹ represents a hydrogen atom or a hydrocarbon group, and R ² represents a hydrogen atom or a hydrocarbon group.)
-(N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoic acid ester (hereinafter referred to as compound (3)).

（式中、Ｒ及びＲ¹は、前記と同義である。）
で示される化合物（２）と、一般式（６） The present invention also provides a compound of the general formula (2) in the presence of a base.

(In the formula, R and R ¹ are as defined above.)
And a compound represented by the general formula (6)

(Wherein R ² has the same meaning as described above, and X represents a halogen atom.)
A general formula (3), characterized by reacting with an acyl halide represented by formula (hereinafter referred to as compound (6))

（式中、Ｒ、Ｒ¹及びＲ²は、前記と同義である。）
で示される化合物（３）の製造方法にも関する。

(In the formula, R, R ¹ and R ² are as defined above.)
It relates also to the manufacturing method of the compound (3) shown by these.

The present invention also provides a general formula (2)

(In the formula, R represents a hydrocarbon group, and R ¹ represents a hydrogen atom or a hydrocarbon group.)
A compound represented by the general formula (4), wherein the compound (2) is reacted with a base.

(In the formula, R has the same meaning as described above, and R ^A has the same meaning as R ^1. )
Is a process for producing 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoic acid ester (hereinafter referred to as compound (4)).

The present invention also provides a general formula (3)

(In the formula, R represents a hydrocarbon group, R ¹ represents a hydrogen atom or a hydrocarbon group, and R ² represents a hydrogen atom or a hydrocarbon group.)
The compound (3) represented by the general formula (4) is subjected to a solvolysis reaction in a solvent.

(In the formula, R has the same meaning as described above, and R ^A has the same meaning as R ^2. )
To a method for producing the compound (4) represented by

The present invention also provides a general formula (2)

(In the formula, R represents a hydrocarbon group, and R ¹ represents a hydrogen atom or a hydrocarbon group.)
Compound (2) represented by the general formula (6)

(In the formula, R ² represents a hydrogen atom or a hydrocarbon group, and X represents a halogen atom.)
The compound (6) represented by the general formula (5) is reacted in the presence of the first base, and then the second base and hydrazine are sequentially added thereto for reaction.

(In the formula, R ^A has the same meaning as R ^2. )
The present invention relates to a process for producing 3- (N-acylamino) -3- (4-tetrahydropyranyl) -3-oxopropanohydrazide (hereinafter referred to as compound (5)).

The present invention also provides a general formula (3)

(In the formula, R represents a hydrocarbon group, R ¹ represents a hydrogen atom or a hydrocarbon group, and R ² represents a hydrogen atom or a hydrocarbon group.)
The compound (3) represented by general formula (5) is reacted with hydrazine.

（式中、Ｒ^Aは、Ｒ²と同義である。）
で示される化合物（５）の製造方法に関する。

(In the formula, R ^A has the same meaning as R ^2. )
It relates to the manufacturing method of the compound (5) shown by these.

  By a convenient method, 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoic acid ester and 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2- Industrially suitable production methods capable of producing oxopropanohydrazide in high yield, useful intermediate compounds that can be used in these production methods, and methods for producing the same can be provided.

  In the present specification, the hydrocarbon group refers to an organic group composed of a carbon atom and a hydrogen atom, and specifically includes an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group, and the like exemplified below. it can.

  The alkyl group refers to a linear or branched saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms. Specific examples include groups such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group.

  The cycloalkyl group refers to a cyclic saturated aliphatic hydrocarbon group having 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, and a cyclodecyl group.

  The aryl group refers to a monocyclic or polycyclic aromatic hydrocarbon group having 6 to 20 carbon atoms (the aryl group may be mono- or polysubstituted by an alkyl group having 1 to 4 carbon atoms). Specific examples include groups such as a phenyl group, a tolyl group, a xylyl group, and a naphthyl group.

  An aralkyl group refers to an alkyl group as defined above substituted with an aryl group as defined above. Specific examples include groups such as a benzyl group and a phenethyl group.

で示される（なお、化合物（２）は、Ｅ体及びＺ体のいずれの構造もとり得る。）。このような一般式（２）において、Ｒは、炭化水素基であり、具体的には、例えば、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基等のアルキル基；シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、シクロヘプチル基、シクロオクチル基、シクロノニル基、シクロデシル基等のシクロアルキル基；ベンジル基、フェネチル基等のアラルキル基；フェニル基、トリル基、キシリル基、ナフチル基等のアリール基が挙げられるが、好ましくはメチル基、エチル基である。なお、これらの基は、各種異性体を含む。 Compound (2)
The novel compound (2) of the present invention has the general formula (2)

(Note that the compound (2) can take any structure of E-form and Z-form). In such general formula (2), R is a hydrocarbon group, specifically, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, Alkyl groups such as nonyl and decyl groups; cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl; aralkyl such as benzyl and phenethyl Group; aryl groups such as phenyl group, tolyl group, xylyl group, naphthyl group and the like can be mentioned, and methyl group and ethyl group are preferable. These groups include various isomers.

R ¹ is a hydrogen atom or a hydrocarbon group, specifically a hydrogen atom and, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, Alkyl groups such as nonyl and decyl groups; cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl; aralkyl such as benzyl and phenethyl Groups; aryl groups such as phenyl, tolyl, xylyl, and naphthyl groups; R ¹ is preferably a hydrogen atom, a methyl group, a t-butyl group, or a cycloheptyl group. These groups include various isomers.

Specific examples of the compound (2) of the present invention include the following compounds.
Methyl 2-acetoxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoate;
Methyl 2-pivaloyloxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoate; and 2-cycloheptylcarbonyloxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoic acid Methyl.

（式中、Ｒは、炭化水素基を示し、Ｒ¹は、水素原子又は炭化水素基を示す。）
で示される化合物（１）にアミノ化剤を反応させることを特徴とする本発明の方法によって得ることができる。 Production Method of Compound (2) from Compound (1) The compound (2) of the present invention has the general formula (1)

(In the formula, R represents a hydrocarbon group, and R ¹ represents a hydrogen atom or a hydrocarbon group.)
It can obtain by the method of this invention characterized by making an aminating agent react with the compound (1) shown by these.

The compound (1) used in the reaction of the present invention is a reaction process formula (1).

(In the formula, X represents a halogen atom, and R and R ¹ are as defined above.)
As shown, 4-acetyltetrahydropyran (compound (A)) and carbonic acid diester (compound (B)) are reacted to produce 3- (4-tetrahydropyranyl) -3-oxopropanoic acid ester (compound ( C)), and then a halogenating agent is reacted with this to obtain 2-halogeno-3- (4-tetrahydropyranyl) -3-oxopropanoic acid ester (compound (D)), and then an organic carboxylic acid It is a compound that can be obtained by reacting (Compound (E)) or a salt thereof.

  The compound (2) of the present invention can be obtained by reacting the compound (1) with an aminating agent. Examples of the aminating agent include ammonia; 1,1,1,3,3,3-hexamethyldisilazane; ammonium carboxylates such as ammonium formate, ammonium acetate, ammonium propionate, and ammonium benzoate. Preferably, 1,1,1,3,3,3-hexamethyldisilazane, ammonium formate, and ammonium acetate are used. In addition, you may use these aminating agents individually or in mixture of 2 or more types.

  The amount of the aminating agent to be used is preferably 1 to 30 mol, more preferably 1 to 15 mol, per 1 mol of compound (1).

  The reaction of the present invention is preferably carried out in a solvent, and the solvent used is not particularly limited as long as it does not inhibit the reaction. For example, water; methanol, ethanol, isopropyl alcohol, n-propyl alcohol, Alcohols such as isobutyl alcohol and t-butyl alcohol; amines such as triethylamine and tributylamine; pyridines such as pyridine, methylpyridine and dimethylaminopyridine; quinolines such as quinoline, isoquinoline and methylisoquinoline; N, N-dimethyl Amides such as formamide, N, N-dimethylacetamide, N-methylpyrrolidone; Ureas such as N, N′-dimethylimidazolidinone; Sulfoxides such as dimethyl sulfoxide; Sulfones such as sulfolane; Tetrahydrofuran, dioxane, Examples include ethers such as lopentyl methyl ether; aromatic hydrocarbons such as toluene and xylene; carboxylic acid esters such as ethyl acetate and butyl acetate, preferably alcohols, ethers, more preferably methanol and ethanol. Tetrahydrofuran is used. In addition, you may use these solvents individually or in mixture of 2 or more types.

  Although the usage-amount of the said solvent is suitably adjusted with the uniformity and stirring property of a reaction liquid, Preferably it is 1-50g with respect to 1g of compounds (1), More preferably, it is 1-20g.

  The reaction of the present invention is carried out, for example, by a method of mixing the compound (1), an aminating agent and a solvent and reacting them with stirring. The reaction temperature at that time is preferably −50 to 150 ° C., more preferably −20 to 100 ° C., and the reaction pressure is not particularly limited.

  In the reaction of the present invention, an acid may be present in the reaction system in order to increase the reactivity. Examples of the acid used include carboxylic acids such as formic acid, acetic acid and trifluoroacetic acid; Organic sulfonic acids such as acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenebenzenesulfonic acid; mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid; phosphomolybdic acid, phosphotungstic acid, silicomolybdic acid, silicotungstic acid, etc. Heteropolyacids; solid acids such as ion exchange resins and activated clays; and chlorinated substances such as trimethylsilyl chloride, dibutylsilyl chloride, acetyl chloride, chlorosilane and the like. In addition, you may use these acids individually or in mixture of 2 or more types.

  The amount of the acid to be used is preferably 0.001 to 10 g, more preferably 0.01 to 5 g, per 1 g of compound (1).

  In addition, compound (2) is obtained by the reaction of the present invention, which can be performed by a general method such as neutralization, extraction, filtration, concentration, distillation, recrystallization, crystallization, column chromatography after the reaction is completed. Isolated and purified. In addition, the compound (2) has the general formula (2 ′)

（式中、Ｒ及びＲ¹は、前記と同義である。）
で示されるイミン体の構造もとり得る。

(In the formula, R and R ¹ are as defined above.)
The structure of the imine body shown by can be also taken.

で示される。一般式（３）においては、Ｒは、炭化水素基であり、具体的には、例えば、メチル基、エチル基、プロピル基、ブチル基、ペンチル基、ヘキシル基、ヘプチル基、オクチル基、ノニル基、デシル基等のアルキル基；ベンジル基、フェネチル基等のアラルキル基；フェニル基、トリル基、キシリル基、ナフチル基等のアリール基が挙げられるが、好ましくはメチル基、エチル基である。なお、これらの基は、各種異性体を含む。 Compound (3)
The novel compound (3) of the present invention has the general formula (3)

Indicated by In the general formula (3), R is a hydrocarbon group, and specifically includes, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, and a nonyl group. And alkyl groups such as decyl group; aralkyl groups such as benzyl group and phenethyl group; and aryl groups such as phenyl group, tolyl group, xylyl group and naphthyl group, preferably methyl group and ethyl group. These groups include various isomers.

R ¹ is a hydrogen atom or a hydrocarbon group. Specific examples of the hydrocarbon group include, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, Alkyl groups such as nonyl and decyl groups; cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl; aralkyl such as benzyl and phenethyl Group; aryl groups such as phenyl group, tolyl group, xylyl group, naphthyl group and the like can be mentioned, and a hydrogen atom, methyl group, t-butyl group, and cycloheptyl group are preferable. These groups include various isomers.

R ² is a hydrogen atom or a hydrocarbon group, preferably an alkyl group, a cycloalkyl group or an aryl group. Specifically, for example, alkyl groups such as methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group; cyclopropyl group, cyclobutyl group, cyclopentyl group Cycloalkyl groups such as cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group and cyclodecyl group; and aryl groups such as phenyl group, tolyl group, xylyl group and naphthyl group. These groups include various isomers.

Specific examples of the compound represented by the general formula (3) include the following compounds.
Methyl 3- (N-cycloheptylcarbonylamino) -2-acetoxy-3- (4-tetrahydropyranyl) -2-propenoate and 3- (N-acetylamino) -2-acetoxy-3- (4- Tetrahydropyranyl) -2-propenoic acid methyl ester.

（式中、Ｒは、炭化水素基を示し、Ｒ¹は、水素原子又は炭化水素基を示す。）
で示される化合物（２）と、一般式（６） Production Method of Compound (3) from Compound (2) Compound (3) of the present invention is represented by the general formula (2) in the presence of a base.

(In the formula, R represents a hydrocarbon group, and R ¹ represents a hydrogen atom or a hydrocarbon group.)
And a compound represented by the general formula (6)

（式中、Ｒ²は、水素原子又は炭化水素基を示し、Ｘは、ハロゲン原子を示す。）
で示される化合物（６）とを反応させることを特徴とする本発明の方法によって得ることができる。

(In the formula, R ² represents a hydrogen atom or a hydrocarbon group, and X represents a halogen atom.)
It can obtain by the method of this invention characterized by making it react with the compound (6) shown by these.

  The compound (2) used in the method of the present invention can be obtained by the method described above.

The compound (6) used in the reaction of the present invention is represented by the general formula (6). In the general formula (6), R ² is a hydrogen atom or a hydrocarbon group, preferably an alkyl group, a cycloalkyl group or an aryl group. X is a halogen atom, and specifically represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

The amount of compound (6) to be used is preferably 1.0 to 10 mol, more preferably 1.0 to 5.0 mol, per 1 mol of compound (2).
Examples of the base used in the reaction of the present invention include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkalis such as sodium hydrogen carbonate and potassium hydrogen carbonate Metal hydrogen carbonates; alkali metal alkoxides such as sodium methoxide and potassium methoxide; alkali metal hydrides such as sodium hydride and potassium hydride; methyl lithium, n-butyl lithium, sec-butyl lithium, t-butyl lithium and the like Alkali metal alkyls of the following: Alkali metal amides such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium amide, sodium bis (trimethylsilyl) amide; amines such as triethylamine, tributylamine; pyridine, Chirupirijin, pyridine such as dimethylamino pyridine; quinoline, isoquinoline, including but quinolines such as methyl isoquinoline, preferably an alkali metal hydride, amines, pyridines are used. In addition, you may use these bases individually or in mixture of 2 or more types.

  The amount of the base to be used is preferably 1.0 to 10 mol, more preferably 1.0 to 5.0 mol, per 1 mol of compound (2).

  The reaction of the present invention is preferably carried out in a solvent, and the solvent to be used is not particularly limited as long as it does not inhibit the reaction. For example, water; amines such as triethylamine and tributylamine; pyridine, methyl Pyridines such as pyridine and dimethylaminopyridine; Quinolines such as quinoline, isoquinoline and methylisoquinoline; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; N, N′-dimethyl Ureas such as imidazolidinone; Sulfoxides such as dimethyl sulfoxide and sulfolane; Ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane and cyclopentyl methyl ether; Aromatic hydrocarbons such as toluene and xylene; Acetonitrile and propionite Le, butyronitrile, nitriles such as benzonitrile; ethyl acetate, although carboxylic acid esters such as butyl acetate, preferably ethers, aromatic hydrocarbons, nitriles is used. In addition, you may use these solvents individually or in mixture of 2 or more types.

  Although the usage-amount of the said solvent is suitably adjusted with the uniformity and stirring property of a reaction liquid, Preferably it is 0.5-50g with respect to 1g of compounds (2), More preferably, it is 1-20g.

  The reaction of the present invention is performed by, for example, a method of mixing the compound (2), the compound (6), a base and a solvent and reacting them with stirring. The reaction temperature at that time is preferably −30 to 110 ° C., more preferably −20 to 80 ° C., particularly preferably −10 to 60 ° C., and the reaction pressure is not particularly limited.

  In addition, compound (3) is obtained by the reaction of the present invention, which can be obtained by a general method such as neutralization, extraction, filtration, concentration, distillation, recrystallization, crystallization, column chromatography after the reaction is completed. Isolated and purified.

（式中、Ｒは、炭化水素基、Ｒ¹は、水素原子又は炭化水素基を示す。）
で示される化合物（２）と塩基とを反応させることにより、一般式（４） Production Method of Compound (4) from Compound (2) According to the method of the present invention, the compound represented by the general formula (2)

(In the formula, R represents a hydrocarbon group, and R ¹ represents a hydrogen atom or a hydrocarbon group.)
By reacting the compound (2) represented by general formula (4) with a base, general formula (4)

（式中、Ｒは、前記と同義であり、Ｒ^Aは、Ｒ¹と同義である。）
で示される化合物（４）を得ることができる。また、化合物（４）は、一般式（４′）

(In the formula, R has the same meaning as described above, and R ^A has the same meaning as R ^1. )
(4) can be obtained. In addition, the compound (4) has the general formula (4 ′)

（式中、Ｒ及びＲ^Aは、前記と同義である。）
で示されるイミン体の構造もとり得る。

(In the formula, R and ^RA are as defined above.)
The structure of the imine body shown by can be also taken.

  The compound (2) used in the reaction of the present invention is represented by the general formula (2) (note that the compound (2) can take any structure of E-form and Z-form). In the general formula (2), R is a hydrocarbon group, specifically, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group. And alkyl groups such as decyl group; aralkyl groups such as benzyl group and phenethyl group; and aryl groups such as phenyl group, tolyl group, xylyl group and naphthyl group, preferably methyl group and ethyl group. These groups include various isomers.

R ¹ is a hydrogen atom or a hydrocarbon group. Specific examples of the hydrocarbon group include, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, Alkyl groups such as nonyl group and decyl group; cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group and cycloheptyl group; aralkyl groups such as benzyl group and phenethyl group; phenyl group, tolyl group, xylyl group and naphthyl group An aryl group such as a hydrogen atom, a methyl group, a t-butyl group, and a cycloheptyl group are preferable. These groups include various isomers.

  The compound (2) used in the method of the present invention can be obtained by the method described above.

  Examples of the base used in the reaction of the present invention include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; alkalis such as sodium hydrogen carbonate and potassium hydrogen carbonate Metal hydrogen carbonates; alkali metal alkoxides such as sodium methoxide and potassium methoxide; alkali metal hydrides such as sodium hydride and potassium hydride; methyl lithium, n-butyl lithium, sec-butyl lithium, t-butyl lithium and the like Alkali metal alkyls of the following: Alkali metal amides such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium amide, sodium bis (trimethylsilyl) amide; amines such as triethylamine, tributylamine; pyridine, Pyridines such as tilpyridine and dimethylaminopyridine; quinolines such as quinoline, isoquinoline, and methylisoquinoline are preferable, and alkali metal carbonates, alkali metal hydrogen carbonates, and more preferably alkali metal hydrogen carbonates are used. . In addition, you may use these bases individually or in mixture of 2 or more types.

  The amount of the base to be used is preferably 0.01 to 10 mol, more preferably 0.05 to 5.0 mol, per 1 mol of compound (2).

  The reaction of the present invention is preferably carried out in a solvent, and the solvent used is not particularly limited as long as it does not inhibit the reaction. For example, water; alcohols such as methanol, ethanol, isopropyl alcohol and t-butyl alcohol Amines such as triethylamine and tributylamine; pyridines such as pyridine, methylpyridine and dimethylaminopyridine; quinolines such as quinoline, isoquinoline and methylisoquinoline; N, N-dimethylformamide, N, N-dimethylacetamide, N- Amides such as methylpyrrolidone; Ureas such as N, N′-dimethylimidazolidinone; Sulfoxides such as dimethyl sulfoxide; Sulfones such as sulfolane; Ethers such as dioxane, cyclopentylmethyl ether and tetrahydrofuran; Toluene Aromatic hydrocarbons such as xylene; carboxylic acid esters such as ethyl acetate and butyl acetate; nitriles such as acetonitrile, propionitrile, butyronitrile, benzonitrile, etc. are preferable, but alcohols, amides, urea are preferable. Amides are used, more preferably amides. In addition, you may use these solvents individually or in mixture of 2 or more types.

  Although the usage-amount of the said solvent is suitably adjusted with the uniformity and stirring property of a reaction liquid, Preferably it is 0.5-50g with respect to 1g of compounds (2), More preferably, it is 1-20g.

  The reaction of the present invention is performed, for example, by a method of mixing the compound (2), a base and a solvent and reacting them while stirring. The reaction temperature at that time is preferably −30 to 110 ° C., more preferably −20 to 90 ° C., and the reaction pressure is not particularly limited.

  In addition, compound (4) is obtained by the reaction of the present invention, which can be obtained by a general method such as neutralization, extraction, filtration, concentration, distillation, recrystallization, crystallization, column chromatography after the reaction is completed. Isolated and purified.

（式中、Ｒは、炭化水素基、Ｒ¹は、水素原子又は炭化水素基、Ｒ²は、水素原子又は炭化水素基を示す。）
で示される化合物（３）を溶媒中で加溶媒分解反応させることにより、一般式（４） Production Method of Compound (4) from Compound (3) According to the method of the present invention, the compound represented by the general formula (3)

(In the formula, R represents a hydrocarbon group, R ¹ represents a hydrogen atom or a hydrocarbon group, and R ² represents a hydrogen atom or a hydrocarbon group.)
The compound (3) represented by general formula (4) is subjected to a solvolysis reaction in a solvent.

（式中、Ｒは、前記と同義であり、Ｒ^Aは、Ｒ²と同義である。）
で示される化合物（４）を得ることができる。

(In the formula, R has the same meaning as described above, and R ^A has the same meaning as R ^2. )
(4) can be obtained.

  The compound (3) used in the solvolysis reaction of the present invention is represented by the general formula (3) (note that the compound (3) can take any structure of E-form and Z-form). In the general formula (3), R is a hydrocarbon group, specifically, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group. And alkyl groups such as decyl group; aralkyl groups such as benzyl group and phenethyl group; and aryl groups such as phenyl group, tolyl group, xylyl group and naphthyl group, preferably methyl group and ethyl group. These groups include various isomers.

R ¹ is a hydrogen atom or a hydrocarbon group. Specific examples of the hydrocarbon group include, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, Alkyl groups such as nonyl and decyl groups; cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl; aralkyl such as benzyl and phenethyl Group; aryl groups such as phenyl group, tolyl group, xylyl group, naphthyl group and the like can be mentioned, and a hydrogen atom, methyl group, t-butyl group, and cycloheptyl group are preferable. These groups include various isomers.

R ² is a hydrogen atom or a hydrocarbon group, preferably an alkyl group, a cycloalkyl group or an aryl group. Specifically, for example, alkyl groups such as methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group; cyclopropyl group, cyclobutyl group, cyclopentyl group Cycloalkyl groups such as cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group and cyclodecyl group; and aryl groups such as phenyl group, tolyl group, xylyl group and naphthyl group. These groups include various isomers.

  The compound (3) used in the method of the present invention can be obtained by the method described above.

  The solvolysis reaction of the present invention is preferably carried out in the presence of a base. Examples of the base used include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; sodium carbonate, potassium carbonate and the like. Alkali metal carbonates; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; alkali metal alkoxides such as sodium methoxide and potassium methoxide; alkali metal hydrides such as sodium hydride and potassium hydride; methyl lithium; Alkali metal alkyls such as n-butyl lithium, sec-butyl lithium and t-butyl lithium; Alkali metal amides such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium amide and sodium bis (trimethylsilyl) amide; triethylamine Amines such as tributylamine; pyridines such as pyridine, methylpyridine, dimethylaminopyridine; quinolines such as quinoline, isoquinoline, methylisoquinoline, and the like, preferably alkali metal carbonates, alkaline earth metal bicarbonates, Amines, pyridines, more preferably amines, pyridines, particularly preferably amines are used. In addition, you may use these bases individually or in mixture of 2 or more types.

  The amount of the base to be used is preferably 0.01 to 10 mol, more preferably 0.05 to 5.0 mol, per 1 mol of compound (3).

  Examples of the solvent used in the solvolysis reaction of the present invention include water; alcohols such as methanol, ethanol, isopropyl alcohol, and t-butyl alcohol. In addition, you may use these solvents individually or in mixture of 2 or more types.

  Although the usage-amount of the said solvent is suitably adjusted with the uniformity and stirring property of a reaction liquid, Preferably it is 0.5-50g with respect to 1g of compounds (3), More preferably, it is 1-20g.

  In the solvolysis reaction of the present invention, a second solvent can be used in addition to the above-mentioned solvent, and the second solvent is not particularly limited as long as it does not inhibit the reaction. Amines such as butylamine; pyridines such as pyridine, methylpyridine and dimethylaminopyridine; quinolines such as quinoline, isoquinoline and methylisoquinoline; N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and the like Amides; Ureas such as N, N'-dimethylimidazolidinone; Sulfoxides such as dimethyl sulfoxide and sulfolane; Ethers such as dioxane, cyclopentylmethyl ether and tetrahydrofuran; Aromatic hydrocarbons such as toluene and xylene; Acetic acid Carbos such as ethyl and butyl acetate Esters; acetonitrile, propionitrile, butyronitrile, nitriles such as benzonitrile is used. In addition, you may use these solvents individually or in mixture of 2 or more types.

  Although the usage-amount of said 2nd solvent is suitably adjusted with the uniformity and stirring property of a reaction liquid, Preferably it is 0.5-50g with respect to 1g of compounds (3), More preferably, it is 1-20g.

  The reaction of the present invention is carried out, for example, by a method of mixing the compound (3), a solvent and, if necessary, a base and reacting while stirring. The reaction temperature at that time is preferably −30 to 110 ° C., more preferably −20 to 80 ° C., particularly preferably −10 to 60 ° C., and the reaction pressure is not particularly limited.

  In addition, compound (4) is obtained by the reaction of the present invention, which can be obtained by a general method such as neutralization, extraction, filtration, concentration, distillation, recrystallization, crystallization, column chromatography after the reaction is completed. Isolated and purified.

（式中、Ｒは、炭化水素基、Ｒ¹は、水素原子又は炭化水素基を示す。）
で示される化合物（２）と一般式（６） Production Method of Compound (5) from Compound (2) According to the method of the present invention, the compound represented by the general formula (2)

(In the formula, R represents a hydrocarbon group, and R ¹ represents a hydrogen atom or a hydrocarbon group.)
Compound (2) represented by the general formula (6)

（式中、Ｒ²は、水素原子又は炭化水素基、Ｘは、ハロゲン原子を示す。）
で示される化合物（６）とを第一の塩基の存在下で反応させた（第１の反応）後、これに第二の塩基、ヒドラジンを順次加えて反応させる（第２の反応）ことにより、一般式（５）

(In the formula, R ² represents a hydrogen atom or a hydrocarbon group, and X represents a halogen atom.)
By reacting the compound (6) represented by formula (6) in the presence of the first base (first reaction), and then adding the second base and hydrazine to the reaction (second reaction). General formula (5)

（式中、Ｒ^Aは、Ｒ²と同義である。）
で示される化合物（５）を得ることができる。

(In the formula, R ^A has the same meaning as R ^2. )
The compound (5) shown by can be obtained.

(First reaction)
In the first reaction of the present invention, the compound (2) and the compound (6) are reacted in the presence of the first base.

  The compound (2) used in the first reaction of the present invention is represented by the general formula (2) (note that the compound (2) can take any structure of E-form and Z-form). In the general formula (2), R is a hydrocarbon group, specifically, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group. And alkyl groups such as decyl group; aralkyl groups such as benzyl group and phenethyl group; and aryl groups such as phenyl group, tolyl group, xylyl group and naphthyl group, preferably methyl group and ethyl group. These groups include various isomers.

R ¹ is a hydrogen atom or a hydrocarbon group. Specific examples of the hydrocarbon group include, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, Alkyl groups such as nonyl group and decyl group; aralkyl groups such as benzyl group and phenethyl group; and aryl groups such as phenyl group, tolyl group, xylyl group and naphthyl group, preferably methyl group and t-butyl group is there. These groups include various isomers.

The compound (6) used in the first reaction of the present invention is represented by the general formula (6). In the general formula (6), R ² is a hydrogen atom or a hydrocarbon group, preferably an alkyl group, a cycloalkyl group or an aryl group. Specifically, for example, alkyl groups such as methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group; cyclopropyl group, cyclobutyl group, cyclopentyl group Cycloalkyl groups such as cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group and cyclodecyl group; and aryl groups such as phenyl group, tolyl group, xylyl group and naphthyl group. These groups include various isomers.

  X is a halogen atom, and specifically represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

  The amount of compound (6) to be used is preferably 0.8 to 10 mol, more preferably 1.0 to 5.0 mol, per 1 mol of compound (2).

  Examples of the first base used in the first reaction of the present invention include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; sodium hydrogen carbonate, Alkali metal hydrogen carbonates such as potassium hydrogen carbonate; Alkali metal alkoxides such as sodium methoxide and potassium methoxide; Alkali metal hydrides such as sodium hydride and potassium hydride; Methyl lithium, n-butyl lithium, sec-butyl lithium Alkali metal alkyls such as t-butyl lithium; Alkali metal amides such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium amide, sodium bis (trimethylsilyl) amide; Amines such as triethylamine and tributylamine Pyridine, methylpyridine, pyridine such as dimethylamino pyridine; quinoline, isoquinoline, including but quinolines such as methyl isoquinoline, preferably amines, pyridines, more preferably used are pyridines. In addition, you may use these bases individually or in mixture of 2 or more types.

  The amount of the base to be used is preferably 0.8 to 10 mol, more preferably 1.0 to 5.0 mol, per 1 mol of compound (2).

  The first reaction of the present invention is preferably carried out in a solvent, and the solvent used is not particularly limited as long as it does not inhibit the reaction. For example, water; amines such as triethylamine and tributylamine; Pyridines such as pyridine, methylpyridine and dimethylaminopyridine; Quinolines such as quinoline, isoquinoline and methylisoquinoline; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; N, N Ureas such as' -dimethylimidazolidinone; sulfoxides such as dimethyl sulfoxide and sulfolane; ethers such as diethyl ether, tetrahydrofuran, dimethoxyethane, dioxane and cyclopropyl methyl ether; aromatic hydrocarbons such as toluene and xylene; Acetonitrile, propylene , Butyronitrile, nitriles such as benzonitrile; ethyl acetate, although carboxylic acid esters such as butyl acetate, preferably ethers, aromatic hydrocarbons, nitriles is used. In addition, you may use these solvents individually or in mixture of 2 or more types.

  Although the usage-amount of the said solvent is suitably adjusted with the uniformity and stirring property of a reaction liquid, Preferably it is 0.5-50g with respect to 1g of compounds (2), More preferably, it is 1-20g.

The reaction of the present invention is performed by, for example, a method of mixing the compound (2), the compound (6), the first base and the solvent and reacting them with stirring. The reaction temperature at that time is preferably −30 to 110 ° C., more preferably −20 to 80 ° C., particularly preferably −10 to 60 ° C., and the reaction pressure is not particularly limited. The obtained reaction solution is used for the second reaction as it is or after being concentrated.
The compound (2) used in the first reaction can be obtained by the method described above.

(Second reaction)
In the second reaction of the present invention, a compound (5) is obtained by sequentially adding a second base and hydrazine to the reaction solution obtained in the first reaction and reacting them.

  Examples of the second base used in the second reaction of the present invention include alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate; dimethylamine and diethylamine , Aliphatic amines such as dipropylamine, diisopropylamine, dibutylamine, piperidine, morpholine, trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine; aniline, N-methylaniline, N, N-dimethylaniline, etc. Aromatic amines may be mentioned, but alkali metal hydrogen carbonates and aliphatic amines are preferable, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, tripropylamine, and tributylamine are particularly preferable. Triethylamine, tripropylamine, tributylamine are used. In addition, you may use these 2nd bases individually or in mixture of 2 or more types.

  The amount of the base to be used is preferably 0.01 to 10 mol, more preferably 0.05 to 5.0 mol, per 1 mol of compound (2).

  The amount of hydrazine used in the second reaction of the present invention is preferably 0.8 to 10 mol, more preferably 1.0 to 3.0 mol, per 1 mol of compound (2). The hydrazine may be in any form such as a hydrate, an acid salt, or an acid salt neutralized with a base.

  In the second reaction of the present invention, it is desirable to use a solvent, and the solvent to be used is not particularly limited as long as it does not inhibit the reaction. For example, methanol, ethanol, isopropyl alcohol, t-butyl alcohol, etc. Alcohols; Nitriles such as acetonitrile, propionitrile, butyronitrile and benzonitrile; Amines such as triethylamine and tributylamine; Pyridines such as pyridine, methylpyridine and dimethylaminopyridine; Quinolines such as quinoline, isoquinoline and methylisoquinoline Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; ureas such as N, N′-dimethylimidazolidinone; sulfoxides such as dimethyl sulfoxide and sulfolane; Examples include ethers such as sun and cyclopropylmethyl ether; aromatic hydrocarbons such as toluene and xylene; carboxylic acid esters such as ethyl acetate and butyl acetate, preferably alcohols, nitriles, and more preferably methanol. Ethanol, acetonitrile, propionitrile are used. In addition, you may use these solvents individually or in mixture of 2 or more types.

  Although the usage-amount of the said solvent is suitably adjusted with the uniformity and stirring property of a reaction liquid, Preferably it is 0.5-50g with respect to 1g of compounds (2), More preferably, it is 1-20g.

  In the second reaction of the present invention, for example, the reaction liquid (containing the reaction product as a main component) obtained in the first reaction and a solvent are mixed, and then a second base and hydrazine are added in order and stirred. It is carried out by a method such as reacting while The reaction temperature at that time is preferably −30 to 110 ° C., more preferably −20 to 80 ° C., particularly preferably −10 to 60 ° C., and the reaction pressure is not particularly limited.

  The compound (5) is obtained by the second reaction of the present invention, and this is generally performed after the reaction, such as neutralization, extraction, filtration, concentration, distillation, recrystallization, crystallization, column chromatography, etc. Isolated and purified by various methods.

（式中、Ｒは、炭化水素基、Ｒ¹は、水素原子又は炭化水素基、Ｒ²は、水素原子又は炭化水素基を示す。）
で示される化合物（３）とヒドラジンとを反応させることにより、一般式（５） Production Method of Compound (5) from Compound (3) According to the method of the present invention, a compound represented by the general formula (3)

(In the formula, R represents a hydrocarbon group, R ¹ represents a hydrogen atom or a hydrocarbon group, and R ² represents a hydrogen atom or a hydrocarbon group.)
By reacting the compound (3) represented by formula (II) with hydrazine, the general formula (5)

（式中、Ｒ^Aは、Ｒ²と同義である。）
で示される化合物（５）を得ることができる。

(In the formula, R ^A has the same meaning as R ^2. )
The compound (5) shown by can be obtained.

  The compound (3) used in the reaction of the present invention is represented by the general formula (3) (note that the compound (3) can take any structure of E-form and Z-form). In the general formula (3), R is a hydrocarbon group, specifically, for example, methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group. And alkyl groups such as decyl group; aralkyl groups such as benzyl group and phenethyl group; and aryl groups such as phenyl group, tolyl group, xylyl group and naphthyl group, preferably methyl group and ethyl group. These groups include various isomers.

R ¹ is a hydrogen atom or a hydrocarbon group. Specific examples of the hydrocarbon group include, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, Alkyl groups such as nonyl and decyl groups; cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl; aralkyl such as benzyl and phenethyl Group; aryl groups such as phenyl group, tolyl group, xylyl group, naphthyl group and the like can be mentioned, and a hydrogen atom, methyl group, t-butyl group, and cycloheptyl group are preferable. These groups include various isomers.

R ² is a hydrogen atom or a hydrocarbon group, preferably an alkyl group, a cycloalkyl group or an aryl group. Specifically, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group Group, hexyl group, heptyl group, octyl group, nonyl group, decyl group and other alkyl groups; cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, cyclodecyl group and the like Alkyl group; aryl groups such as phenyl group, tolyl group, xylyl group, naphthyl group and the like. These groups include various isomers.

  The compound (3) used in the method of the present invention can be obtained by the above method.

  The amount of hydrazine used in the reaction of the present invention is preferably 1.0 to 10 mol, more preferably 1.0 to 5.0 mol, per 1 mol of compound (3). The hydrazine may be in any form such as a hydrate, an acid salt, or an acid salt neutralized with a base, or may be used as an aqueous solution thereof.

  The reaction of the present invention is preferably carried out in the presence of a base. Examples of the base used include dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, piperidine, morpholine, trimethylamine, triethylamine, tripropyl. Aliphatic amines such as amine, tributylamine and diisopropylethylamine; Aliphatic amines such as aniline, N-methylaniline and N, N-dimethylaniline; Pyrrolidine, piperidine, piperazine, morpholine, pyridine, methylpyridine, dimethylaminopyridine , Quinoline, isoquinoline, methylisoquinoline, pyridazine, pyrimidine, pyrazine and other heterocyclic amines; sodium hydroxide, potassium hydroxide and other alkali metal hydroxides; sodium carbonate, potassium carbonate Alkali metal carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate, etc .; alkali metal alkoxides such as sodium methoxide and potassium methoxide; alkali metal hydrides such as sodium hydride and potassium hydride; Alkali metal alkyls such as methyl lithium, n-butyl lithium, sec-butyl lithium and t-butyl lithium; alkali metal amides such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium amide and sodium bis (trimethylsilyl) amide Preferably, aliphatic amines, aromatic amines, heterocyclic amines, more preferably aliphatic amines, particularly preferably triethylamine, tripropylamine, tributylamine are used. In addition, you may use these bases individually or in mixture of 2 or more types.

  The amount of the base to be used is preferably 0.01 to 10 mol, more preferably 0.05 to 5.0 mol, per 1 mol of compound (3).

  In the reaction of the present invention, it is desirable to use a solvent, and the solvent used is not particularly limited as long as it does not inhibit the reaction. For example, water; alcohols such as methanol, ethanol, isopropyl alcohol, t-butyl alcohol Nitriles such as acetonitrile, propionitrile, butyronitrile and benzonitrile; amines such as triethylamine and tributylamine; pyridines such as pyridine, methylpyridine and dimethylaminopyridine; quinolines such as quinoline, isoquinoline and methylisoquinoline; Amides such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone; Ureas such as N, N′-dimethylimidazolidinone; Sulfoxides such as dimethyl sulfoxide and sulfolane; Ethers such as ethylene and cyclopropyl methyl ether; aromatic hydrocarbons such as toluene and xylene; and carboxylic acid esters such as ethyl acetate and butyl acetate, preferably water, alcohols and nitriles, more preferably Water, methanol, ethanol, acetonitrile, and propionitrile are used. In addition, you may use these solvents individually or in mixture of 2 or more types.

  Although the usage-amount of the said solvent is suitably adjusted with the uniformity and stirring property of a reaction liquid, Preferably it is 0.5-50g with respect to 1g of compounds (3), More preferably, it is 1-20g.

  The reaction of the present invention is carried out, for example, by a method of mixing the compound (3), hydrazine, a base and a solvent as necessary, and reacting with stirring. The reaction temperature at that time is preferably −30 to 110 ° C., more preferably −20 to 80 ° C., particularly preferably −10 to 60 ° C., and the reaction pressure is not particularly limited.

  Compound (5) is obtained by the reaction of the present invention, which is isolated by a general method such as neutralization, extraction, filtration, concentration, distillation, recrystallization, crystallization, column chromatography after the reaction is completed. -Purified.

  In addition, the process of each method of this invention mentioned above can be attached | subjected to subsequent reaction processes continuously according to reaction conditions, a production | generation substance, etc. For example, after the step of producing compound (2) by reacting compound (1) with an aminating agent, compound (2) and compound (6) were reacted in the presence of the first base. Then, the process of obtaining a compound (5) can be performed by adding a 2nd base and hydrazine to this, and making it react.

  In addition, by reacting compound (2) with compound (6) in the presence of a base, compound (3) is subsequently subjected to a solvolysis reaction in a solvent after the step of producing compound (3). Thus, the step of obtaining the compound (4) can also be performed. In this step, the step of obtaining compound (2) by further reacting compound (1) with an aminating agent may be performed first.

An outline of the compounds and methods of the present invention is shown below.

  In addition, according to the present invention, the compound (5) can be produced by a simple and industrially suitable method, but it can also be easily produced by a known method from the compound (4) which can be produced by the present invention. can do.

  Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.

Reference Example 1 (Compound (C) [R = methyl group]; synthesis of methyl 3- (4-tetrahydropyranyl) -3-oxopropanoate)
Into a 500 ml glass flask equipped with a stirrer, thermometer, dropping funnel and distillation apparatus, 35.0 g (273 mmol) of 4-acetyltetrahydropyran, 280.0 g (3.1 mol) of dimethyl carbonate and sodium methoxide 16 were added. .3 g (302 mmol) was added, and the mixture was reacted at 80 to 85 ° C. for 2 hours while distilling out by-produced methanol. After completion of the reaction, the reaction solution was cooled to 5 to 10 ° C., and 175 ml of toluene, 55 ml of 6 mol / l hydrochloric acid (330 mmol) and 35 ml of water were added to the reaction solution in this order. After separating the organic layer, the aqueous layer was extracted twice with 70 ml of toluene. After the organic layer was concentrated under reduced pressure, the concentrate was purified by silica gel column chromatography (developing solvent; hexane / ethyl acetate = 1/1 (volume ratio)) to obtain a colorless liquid having a purity of 93.9% (differential). 40.9 g of methyl 3- (4-tetrahydropyranyl) -3-oxopropanoate was obtained (isolation yield: 76%).
The physical properties of methyl 3- (4-tetrahydropyranyl) -3-oxopropanoate were as follows.
¹ H-NMR (CDCl ₃ , δ (ppm)); 1.68 to 1.82 (4H, m), 2.66 to 2.72 (1H, m), 3.38 to 3.47 (2H, m), 3.51 (2H, s), 3.75 ( 3H, s), 3.97 to 4.04 (2H, m)
CI-MS (m / e); 187 (M + 1)

Reference Example 2 (Compound (D) [X = chlorine atom, R = methyl group]; synthesis of methyl 2-chloro-3- (4-tetrahydropyranyl) -3-oxopropanoate)
16 g (85.9 mmol) of methyl 3- (4-tetrahydropyranyl) -3-oxopropanoate synthesized in Reference Example 1 was added to a glass flask having an internal volume of 25 ml equipped with a stirrer, a thermometer and a dropping funnel. And cooled to 0 ° C. in an ice-water bath. Next, 11.6 g (85.9 mmol) of sulfuryl chloride was slowly added dropwise, followed by reaction at room temperature for 15 hours. After completion of the reaction, the reaction solution was again cooled to 0 ° C., 32 ml of water and 48 ml of toluene were gently added dropwise, and the mixture was stirred for 10 minutes, and then the organic layer was separated. The aqueous layer was extracted with 16 ml of toluene, and the organic layer and the extract were combined and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 2-chloro-3- (4-tetrahydropyranyl) -3-oxopropanoic acid as a light brown oily liquid with a purity of 94.6% (area percentage by gas chromatography) 18.5 g of methyl were obtained (isolation yield: 92%).
The physical properties of methyl 2-chloro-3- (4-tetrahydropyranyl) -3-oxopropanoate were as follows.
¹ H-NMR (CDCl ₃ , δ (ppm)); 1.74 to 1.83 (4H, m), 3.06 to 3.16 (1H, m), 3.41 to 3.50 (2H, m), 3.85 (2.4H, s), 3.86 (0.6H, s), 3.99 to 4.05 (2H, m), 4.93 (0.8H, s), 12.48 (0.2H, d, J = 1.46Hz)
CI-MS (m / e); 221 (M + 1), 223 (M + 3)

Reference Example 3 (Compound (D) [X = chlorine atom, R = methyl group]; synthesis of methyl 2-chloro-3- (4-tetrahydropyranyl) -3-oxopropanoate)
4.79 g of methyl 3- (4-tetrahydropyranyl) -3-oxopropanoate synthesized in the same manner as in Reference Example 1 in a glass flask having an internal volume of 50 ml equipped with a stirrer, a thermometer and a dropping funnel ( 25.7 mmol) and 4.8 ml of toluene were added and cooled to −15 to −10 ° C. in an ice water bath. Next, 3.65 g (27.0 mmol) of sulfuryl chloride was slowly added dropwise while maintaining the liquid temperature at -15 to -5 ° C, followed by reaction at room temperature for 19 hours. After completion of the reaction, the reaction solution was cooled to −10 to −5 ° C., 14 ml of water was slowly added dropwise and stirred for 30 minutes. Then, after separating the organic layer, 14 ml of saturated aqueous sodium chloride solution, 14 ml of 5% by weight aqueous sodium hydrogen carbonate solution and 4.8 ml of saturated aqueous sodium chloride solution, 9.6 ml of 5% by weight aqueous sodium hydrogen carbonate solution, saturated sodium chloride The solution was washed successively with 4.8 ml of aqueous solution to obtain 4.8 ml of a toluene solution of methyl 2-chloro-3- (4-tetrahydropyranyl) -3-oxopropanoate.

Reference Example 4 (Compound (1) [R = methyl group, R ¹ = methyl group]; Synthesis of methyl 2-acetoxy-3- (4-tetrahydropyranyl) -3-oxopropanoate)
9.46 g of methyl 2-chloro-3- (4-tetrahydropyranyl) -3-oxopropanoate synthesized in Reference Example 2 was added to a glass flask having an internal volume of 100 ml equipped with a stirrer, a thermometer and a dropping funnel. 42.9 mmol), 3.0 g (49.8 mmol) of acetic acid and 30 ml of N, N-dimethylformamide were added. Next, 5.0 g (49.8 mmol) of triethylamine was slowly added dropwise with stirring, and the mixture was reacted at room temperature for 14 hours. After completion of the reaction, 100 ml of toluene was added to the reaction solution, followed by filtration. The residue was washed with 50 ml of toluene, and the filtrate and the washing solution were combined and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (developing solvent; hexane / ethyl acetate = 2/1 (volume ratio)) and, as a colorless liquid, 2-acetoxy having a purity of 99.9% or more (area percentage by gas chromatography) 9.2 g of methyl 3- (4-tetrahydropyranyl) -3-oxopropanoate was obtained (isolation yield: 88%).
The physical properties of methyl 2-acetoxy-3- (4-tetrahydropyranyl) -3-oxopropanoate were as follows.
¹ H-NMR (CDCl ₃ , δ (ppm)); 1.68 to 1.87 (4H, m), 2.24 (3H, s), 2.99 to 3.06 (1H, m), 3.40 to 3.51 (2H, m), 3.83 ( 3H, s), 3.98 to 4.03 (2H, m), 5.66 (1H, s)
CI-MS (m / e); 245 (M + 1)

Reference Example 5 (Compound (1) [R = methyl group, R ¹ = t-butyl group]; Synthesis of methyl 2-pivaloyloxy-3- (4-tetrahydropyranyl) -3-oxopropanoate)
Methyl 2-chloro-3- (4-tetrahydropyranyl) -3-oxopropanoate synthesized in the same manner as in Reference Example 2 in a glass flask having an internal volume of 100 ml equipped with a stirrer, a thermometer and a dropping funnel 8.0 g (36.3 mmol), pivalic acid and 4.7 g (46.3 mmol) and 40 ml of N, N-dimethylformamide were added. Next, 4.7 g (46.3 mmol) of triethylamine was gently added dropwise with stirring, and the mixture was reacted at room temperature for 16 hours. After completion of the reaction, 100 ml of ethyl acetate and 100 ml of water were added to the reaction solution, and the organic layer was separated. Next, the aqueous layer was extracted with 100 ml of ethyl acetate, and the organic layer and the extract were combined and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (developing solvent; hexane / ethyl acetate = 2/1 (volume ratio)) and, as a colorless liquid, 2-pivaloyloxy- with a purity of 99.1% (area percentage by gas chromatography) 10.4 g of methyl 3- (4-tetrahydropyranyl) -3-oxopropanoate was obtained (isolation yield: 99%).
The physical properties of methyl 2-pivaloyloxy-3- (4-tetrahydropyranyl) -3-oxopropanoate were as follows.
¹ H-NMR (CDCl ₃ , δ (ppm)); 1.30 (9H, s), 1.68 to 1.87 (4H, m), 2.96 to 3.03 (1H, m), 3.39 to 3.50 (2H, m), 3.82 ( 3H, s), 3.98 to 4.03 (2H, m), 5.59 (1H, s)
CI-MS (m / e); 287 (M + 1)

Reference Example 6 (Compound (1) [R = methyl group, R ¹ = cycloheptyl group]; synthesis of methyl 2-cycloheptylcarbonyloxy-3- (4-tetrahydropyranyl) -3-oxopropanoate)
A glass flask having an internal volume of 200 ml equipped with a stirrer, a thermometer and a dropping funnel was charged with 4.76 g (33.5 mmol) of cycloheptylcarboxylic acid, 3.38 g (33.4 mmol) of triethylamine and 19 ml of N, N-dimethylformamide. Then, a toluene solution of 5.67 g (25.7 mmol) of methyl 2-chloro-3- (4-tetrahydropyranyl) -3-oxopropanoate synthesized in the same manner as in Reference Example 2 was slowly added dropwise. And allowed to react at room temperature for 18 hours with stirring. After completion of the reaction, 24 ml of water and 24 ml of ethyl acetate were added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with 24 ml of ethyl acetate. Next, the organic layer and the extract were combined, washed with 24 ml of a 5% by mass aqueous sodium hydrogen carbonate solution and 9.8 ml of a saturated aqueous sodium chloride solution in this order, and then concentrated under reduced pressure, and the concentrate was subjected to flash column chromatography (developing solvent; Hexane / ethyl acetate = 10/1 → 10/3 (volume ratio)), and as a colorless liquid, methyl 2-cycloheptylcarbonyloxy-3- (4-tetrahydropyranyl) -3-oxopropanoate 68 g were obtained (isolated yield based on methyl 3- (4-tetrahydropyranyl) -3-oxopropanoate: 44%).
The physical properties of methyl 2-cycloheptylcarbonyloxy-3- (4-tetrahydropyranyl) -3-oxopropanoate were as follows.
¹ H-NMR (CDCl ₃ , δ (ppm)); 1.52 to 2.06 (16H, m), 2.64 to 2.73 (1H, m), 2.97 to 3.07 (1H, m), 3.40 to 3.50 (2H, m), 3.82 (3H, s), 4.00 (2H, d, J = 11.7Hz), 5.63 (1H, s)
CI-MS (m / e); 327 (M + 1)

Example 1 (Compound (2) [R = methyl group, R ¹ = methyl group] Synthesis of methyl 2-acetoxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoate)
In a glass flask having an internal volume of 200 ml equipped with a stirrer, 25.11 g of methyl 2-acetoxy-3- (4-tetrahydropyranyl) -3-oxopropanoate synthesized in the same manner as in Reference Example 4 (102. 8 mmol), 96% pure 1,1,1,3,3,3-hexamethyldisilazane 19.01 g (113.1 mmol), phosphomolybdic acid 3.8 g and tetrahydrofuran 126 ml are added and stirred at room temperature for 24 hours. Reacted for hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and 151 ml of ethyl acetate and 75 ml of saturated aqueous sodium hydrogen carbonate solution were added to the concentrate. The organic layer was separated, washed 4 times with 75 ml of saturated aqueous sodium hydrogen carbonate solution, and concentrated under reduced pressure. To the concentrate, 31 ml of ethyl acetate and 102 ml of hexane were added and stirred, followed by filtration. As a pale yellow solid, 2-acetoxy-3- (4-tetrahydropyrani) having a purity of 99.9% or more (area percentage by high performance liquid chromatography). (L) 4.2 g of methyl 3-amino-2-propenoate was obtained (isolation yield: 17%).
Methyl 2-acetoxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoate is a novel compound represented by the following physical property values.
¹ H-NMR (CDCl ₃ , δ (ppm)); 1.62 to 1.74 (4H, m), 2.22 (3H, s), 2.63 to 2.73 (1H, m), 3.38 to 3.47 (2H, m), 3.70 ( 3H, s), 4.01 to 4.07 (2H, m), 5.50 to 6.50 (1H, brs)
CI-MS (m / e); 244 (M + 1)

Example 2 (Compound (2) [R = methyl group, R ¹ = t-butyl group] Synthesis of methyl 2-pivaloyloxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoate)
5.0 g of methyl 2-pivaloyloxy-3- (4-tetrahydropyranyl) -3-oxopropanoate synthesized in the same manner as in Reference Example 5 in a glass flask equipped with a stirrer and having an internal volume of 50 ml (17. 5 mmol), 96% pure 1,1,1,3,3,3-hexamethyldisilazane (3.23 g, 19.2 mmol), phosphomolybdic acid (250 mg) and tetrahydrofuran (25 ml) were added, and the mixture was reacted at room temperature for 16 hours with stirring. I let you. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and 100 ml of toluene and 50 ml of saturated aqueous sodium hydrogen carbonate solution were added to the concentrate. The organic layer was separated and the aqueous layer was extracted with 50 ml of toluene. The organic layer and the extract were combined, washed twice with 50 ml of water and then concentrated under reduced pressure to give 2-pivaloyloxy-3- (4-) as a white solid with a purity of 93.7% (area percentage by high performance liquid chromatography). 5.3 g of methyl tetrahydropyranyl) -3-amino-2-propenoate was obtained (isolation yield: 100%).
Methyl 2-pivaloyloxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoate is a novel compound represented by the following physical property values.
¹ H-NMR (CDCl ₃ , δ (ppm)); 1.31 (9H, s), 1.63 to 1.69 (4H, m), 2.60 to 2.66 (1H, m), 3.34 to 3.43 (2H, m), 3.68 ( 3H, s), 4.01-4.07 (2H, m), 5.93 (1H, brs)
CI-MS (m / e); 286 (M + 1)

Example 3 (Compound (2) [R = methyl group, R ¹ = t-butyl group] Synthesis of methyl 2-pivaloyloxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoate)
60.6 g of methyl 2-pivaloyloxy-3- (4-tetrahydropyranyl) -3-oxopropanoate synthesized in the same manner as in Reference Example 5 in a glass flask having an internal volume of 500 ml equipped with a stirrer (21. 7 mmol), 85.0 g (1.1 mol) of ammonium acetate and 303 ml of methanol were added and reacted at 40 ° C. for 5 hours with stirring. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and then 606 ml of ethyl acetate and 303 ml of water were added. The organic layer was separated, washed 3 times with 303 ml of saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and 2-pivaloyloxy-3- (4-tetrahydropyranyl) -3-amino having a purity of 81.5% (area percentage by high performance liquid chromatography) as a tan mud. 53.8 g of methyl-2-propenoate was obtained (isolation yield: 73%).

Example 4 (Compound (2) [R = methyl group, R ¹ = cycloheptyl group] Synthesis of methyl 2-cycloheptylcarbonyloxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoate)
45.06 g of methyl 2-cycloheptylcarbonyloxy-3- (4-tetrahydropyranyl) -3-oxopropanoate synthesized in the same manner as in Reference Example 6 in a 500 mL glass flask equipped with a stirrer (138 mmol), 96% pure 1,1,1,3,3,3-hexamethyldisilazane 25.53 g (158 mmol), 6.75 g phosphomolybdic acid and 225 ml tetrahydrofuran overnight at room temperature with stirring. Reacted. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and 450 ml of ethyl acetate and 225 ml of 5 mass% aqueous sodium hydrogen carbonate solution were added to the concentrate. The organic layer was separated and the aqueous layer was extracted three times with 225 ml of ethyl acetate. The organic layer and the extract were combined, washed twice with 50 ml of water, and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and 90 ml of cycloheptane was added to the concentrate and stirred, followed by filtration again as a white solid, 2-cycloheptylcarbonyloxy-3- (4-tetrahydropyranyl) -3- 27.31 g of methyl amino-2-propenoate was obtained (isolation yield: 61%).
Methyl 2-cycloheptylcarbonyloxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoate is a novel compound represented by the following physical property values.
¹ H-NMR (CDCl ₃ , δ (ppm)); 1.51 to 1.83 (14H, m), 1.99 to 2.08 (2H, m), 2.61 to 2.72 (2H, m), 3.35 to 3.44 (2H, m), 3.68 (3H, s), 4.04 (2H, d, J = 11.5Hz), 6.00 (2H, brs)
CI-MS (m / e); 326 (M + 1)

Example 5 (compound (3) [R = R ¹ = methyl group, R ² = cycloheptyl group]; 3- (N-cycloheptylcarbonylamino) -2-acetoxy-3- (4-tetrahydropyranyl)- Synthesis of methyl 2-propenoate)
2-acetoxy-3- (4-tetrahydropyranyl) -3-amino-2-synthesized in the same manner as in Example 1 in a glass flask having an internal volume of 5 ml equipped with a stirrer, a thermometer and a dropping funnel. 4.0 g (16.4 mmol) methyl propenoate, 1.55 g (19.7 mmol) pyridine and 20 ml tetrahydrofuran were added. Next, 2.89 g (18.0 mmol) of cycloheptylcarbonyl chloride was gently dropped while maintaining the liquid temperature at 0 ° C., and the mixture was reacted at room temperature for 16 hours with stirring. After completion of the reaction, the reaction solution was concentrated under reduced pressure, 40 ml of ethyl acetate and 40 ml of water were added to the concentrate, and the organic layer and the aqueous layer were separated. The aqueous layer was extracted with 20 ml of ethyl acetate, the organic layer was washed with 20 ml of a saturated aqueous sodium hydrogen carbonate solution, and the extract and the organic layer were combined and concentrated under reduced pressure. To the obtained solid (concentrate), 24 ml of heptane was added and filtered, washed with 24 ml of heptane and dried to obtain flesh-colored crystals having a purity of 99.9% or more (area percentage by high performance liquid chromatography). 4.26 g of methyl N-cycloheptylcarbonylamino) -2-acetoxy-3- (4-tetrahydropyranyl) -2-propenoate was obtained (isolation yield: 71%).
Methyl 3- (N-cycloheptylcarbonylamino) -2-acetoxy-3- (4-tetrahydropyranyl) -2-propenoate is a novel compound represented by the following physical property values.
¹ H-NMR (CDCl ₃ , δ (ppm)); 1.50 to 2.00 (16H, m), 2.13 (3H, s), 2.31 to 2.40 (1H, m), 3.45 to 3.54 (2H, m), 3.68 to 3.83 (1H, m), 3.77 (3H, s), 3.99 to 4.04 (2H, m), 6.27 (1H, s)
CI-MS (m / e); 368 (M + 1)

Example 6 (compound (3) [R = R < ¹ > = R < ² > = methyl group]; methyl 3- (N-acetylamino) -2-acetoxy-3- (4-tetrahydropyranyl) -2-propenoate Synthesis)
2-acetoxy-3- (4-tetrahydropyranyl) -3-amino-2- synthesized in the same manner as in Example 1 in a glass flask having an internal volume of 300 ml equipped with a stirrer, a thermometer and a dropping funnel. Methyl propenoate 50.0 g (205.5 mmol), pyridine 19.5 g (246.6 mmol) and acetonitrile 250 ml were added. Subsequently, 17.8 g (226.1 mmol) of acetyl chloride was slowly dropped while maintaining the liquid temperature at 5 to 15 ° C., and the mixture was reacted at room temperature for 5 hours while stirring. After completion of the reaction, 500 ml of ethyl acetate and 200 ml of saturated brine were added to the reaction solution, and the organic layer and the aqueous layer were separated. The organic layer was washed twice with 200 ml of saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, 50 ml of ethyl acetate and 150 ml of hexane were added to the resulting solid (concentrate), filtered, washed with 50 ml of hexane and dried to obtain a skin color crystal having a purity of 99. 99.7% or more (area percentage by high performance liquid chromatography) of 39.7 g of methyl 3- (N-acetylamino) -2-acetoxy-3- (4-tetrahydropyranyl) -2-propenoate was obtained (isolation) Yield; 68%).
Methyl 3- (N-acetylamino) -2-acetoxy-3- (4-tetrahydropyranyl) -2-propenoate is a novel compound represented by the following physical property values.
¹ H-NMR (CDCl ₃ , δ (ppm)); 1.64 to 1.76 (4H, m), 2.09 (3H, s), 2.15 (3H, s), 3.45 to 3.54 (2H, m), 3.68 to 3.82 ( 1H, m), 3.78 (3H, s), 3.99 to 4.05 (2H, m), 6.27 (1H, s)
CI-MS (m / e); 286 (M + 1)

Example 7 (Compound (4) from Compound (2) [R = methyl group, R ^A = cycloheptyl group]; 3- (N-cycloheptylcarbonylamino) -3- (4-tetrahydropyranyl) -2 -Synthesis of methyl oxopropanoate)
3-Amino-2-cycloheptylcarbonyloxy-3- (4-tetrahydropyranyl) -2-synthesized in the same manner as in Example 4 in a glass flask having an internal volume of 25 ml equipped with a stirrer and a thermometer. Methyl propenoate 1.0 g (3.07 mmol), sodium methoxide 33.2 mg (0.61 mmol) and methanol 18 ml were added, and the mixture was reacted at 65 ° C. for 5 hours with stirring. After completion of the reaction, the reaction mixture was analyzed by high performance liquid chromatography (absolute quantification method). As a result, 238 mg of methyl 3- (N-cycloheptylcarbonylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoate was formed. (Reaction yield; 24%).

Example 8 (compound (4) from compound (3) [R = methyl group, R ^A = cycloheptyl group]; 3- (N-cycloheptylcarbonylamino) -3- (4-tetrahydropyranyl) -2 -Synthesis of methyl oxopropanoate)
3- (N-cycloheptylcarbonylamino) -2-acetoxy-3- (4-tetrahydropyranyl) -2 synthesized in the same manner as in Example 5 in a glass flask having an internal volume of 5 ml equipped with a stirrer. -264 mg (0.72 mmol) of methyl propenoate, 17 mg (0.17 mmol) of triethylamine and 3 ml of methanol were added and reacted at room temperature for 24 hours with stirring. After completion of the reaction, the reaction solution was analyzed by high performance liquid chromatography (absolute quantitative method). As a result, 195 mg of methyl 3- (N-cycloheptylcarbonylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoate was formed. (Reaction yield; 83%).

Example 9 (Compound (4) from Compound (3) [R = methyl group, R ^A = cycloheptyl group]; 3- (N-cycloheptylcarbonylamino) -3- (4-tetrahydropyranyl) -2 -Synthesis of methyl oxopropanoate)
The reaction was conducted in the same manner as in Example 8 except that the amount of triethylamine was changed to 83 mg (0.82 mmol) in Example 8. As a result, 204 mg of methyl 3- (N-cycloheptylcarbonylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoate was produced (reaction yield; 87%).

Example 10 (Compound (4) from Compound (3) [R = methyl group, R ^A = cycloheptyl group]; 3- (N-cycloheptylcarbonylamino) -3- (4-tetrahydropyranyl) -2 -Synthesis of methyl oxopropanoate)
In Example 8, the reaction was performed in the same manner as in Example 8 except that the amount of triethylamine was changed to 207 mg (2.0 mmol). As a result, 200 mg of methyl 3- (N-cycloheptylcarbonylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoate was produced (reaction yield; 85%).

Example 11 (compound (4) from compound (3) [R = methyl group, R ^A = cycloheptyl group]; 3- (N-cycloheptylcarbonylamino) -3- (4-tetrahydropyranyl) -2 -Synthesis of methyl oxopropanoate)
3- (N-cycloheptylcarbonylamino) -2-acetoxy-3- (4-tetrahydropyranyl) -2 synthesized in the same manner as in Example 5 in a glass flask equipped with a stirrer and having an internal volume of 100 ml. -5.00 g (13.6 mmol) of methyl propenoate, 0.99 g (13.6 mmol) of diethylamine and 45 ml of methanol were added and reacted at room temperature for 6 hours with stirring. After completion of the reaction, the reaction solution was analyzed by high performance liquid chromatography (absolute quantitative method). As a result, it was found that methyl 3- (N-cycloheptylcarbonylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoate was 2. .76 g was produced (reaction yield; 62%).

Example 12 (Compound (4) from Compound (3) [R = methyl group, R ^A = cycloheptyl group]; 3- (N-cycloheptylcarbonylamino) -3- (4-tetrahydropyranyl) -2 -Synthesis of methyl oxopropanoate)
3- (N-cycloheptylcarbonylamino) -2-acetoxy-3- (4-tetrahydropyranyl) -2 synthesized in the same manner as in Example 5 in a glass flask equipped with a stirrer and having an internal volume of 100 ml. -5.00 g (13.6 mmol) of methyl propenoate, 1.38 g (13.6 mmol) of diisopropylamine and 45 ml of methanol were added and reacted at room temperature for 6 hours with stirring. After completion of the reaction, the reaction mixture was analyzed by high performance liquid chromatography (absolute quantitative method). As a result, methyl 3- (N-cycloheptylcarbonylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoate was found to be 2. 12 g was produced (reaction yield; 48%).

Example 13 (compound (5) from compound (2) [R ^A = cycloheptyl group]; 3- (N-cycloheptylcarbonylamino) -3- (4-tetrahydropyranyl) -2-oxopropanohydrazide Synthesis)
2-acetoxy-3- (4-tetrahydropyranyl) -3- synthesized in the same manner as in Example 1 in a glass flask having an internal volume of 500 ml equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser. 30.0 g (123.3 mmol) of methyl amino-2-propenoate, 12.68 g (160.3 mmol) of pyridine and 90 ml of acetonitrile were added. Next, 21.79 g (135.6 mmol) of cycloheptylcarbonyl chloride was gently dropped while maintaining the liquid temperature at 5 to 10 ° C., and the mixture was reacted at room temperature for 3 hours while stirring. After completion of the reaction, 150 ml of ethyl acetate and 120 ml of 20% brine were added to the reaction solution to separate the organic layer and the aqueous layer. The obtained organic layer was concentrated under reduced pressure, and 300 ml of methanol and 12.48 g (123.3 mmol) of triethylamine were added to the concentrate, followed by stirring at room temperature for 22 hours. Next, while maintaining the liquid temperature at −7 to −4 ° C., 7.72 g (154.1 mmol) of hydrazine monohydrate was gently added dropwise, and the mixture was reacted at room temperature for 20 hours while stirring. After completion of the reaction, the reaction mixture was filtered, and the resulting solid was dried under reduced pressure to give 3- (N-cycloheptylcarbonylamino) -3- (4-tetrahydropyranyl) -2-oxo as a pale orange solid. 24.37 g of propanohydrazide was obtained (isolation yield: 61%).
The physical properties of 3- (N-cycloheptylcarbonylamino) -3- (4-tetrahydropyranyl) -2-oxopropanohydrazide were as follows.
¹ H-NMR (DMSO-d ₆ , δ (ppm)); 1.10 to 1.80 (16H, m), 2.00 to 2.23 (1H, m), 2.35 to 2.65 (1H, m), 3.10 to 3.40 (2H, m ), 3.70 to 3.95 (2H, m), 4.30 to 4.85 (2H, m), 4.85 to 5.02 (1H, m), 7.98 (1H, d, J = 7.6Hz), 9.10 to 10.20 (1H, brs)

Example 14 (Compound (5) from Compound (3) [R ^A = cycloheptyl]]; 3- (N-cycloheptylcarbonylamino) -3- (4-tetrahydropyranyl) -2-oxopropanohydrazide Synthesis)
3- (N-cycloheptylcarbonylamino) -2-acetoxy-3- (4-) synthesized in the same manner as in Example 5 in a glass flask having an internal volume of 20 ml equipped with a stirrer, a thermometer and a dropping funnel. After adding 300 mg (0.82 mmol) of methyl tetrahydropyranyl) -2-propenoate, 164 mg (1.63 mmol) of triethylamine, 2.4 ml of methanol and 0.6 ml of acetonitrile, 82 mg (1.63 mmol) of hydrazine monohydrate was added. Was slowly dropped and reacted at room temperature for 6 hours with stirring. After completion of the reaction, the reaction solution was analyzed by high performance liquid chromatography (absolute quantitative method). As a result, 194 mg of 3- (N-cycloheptylcarbonylamino) -3- (4-tetrahydropyranyl) -2-oxopropanohydrazide was obtained. Produced (reaction yield; 73%).

Example 15 (Compound (5) from Compound (3) [R ^A = cycloheptyl]]; 3- (N-cycloheptylcarbonylamino) -3- (4-tetrahydropyranyl) -2-oxopropanohydrazide Synthesis)
In Example 14, the reaction was performed in the same manner as in Example 14 except that triethylamine was not added. As a result, 101 mg of 3- (N-cycloheptylcarbonylamino) -3- (4-tetrahydropyranyl) -2-oxopropanohydrazide was formed (reaction yield; 38%).

  3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoic acid ester and 3- (N-acylamino) -3- (4-tetrahydropyranyl) provided by the method of the present invention 2-Oxopropanohydrazide is a useful compound as a raw material and synthetic intermediate for pharmaceuticals and agricultural chemicals. The present invention also provides synthetic intermediates for producing these compounds and methods for synthesizing them.

Claims (22)

General formula (2)

(In the formula, R represents a hydrocarbon group, and R ¹ represents a hydrogen atom or a hydrocarbon group.)
2-Acyloxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoic acid ester represented by Methyl 2-acetoxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoate;
Methyl 2-pivaloyloxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoate; and 2-cycloheptylcarbonyloxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoic acid The 2-acyloxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoic acid ester according to claim 1, which is selected from methyl. General formula (1)

(Wherein R and R ¹ have the same meaning as in claim 1).
And an aminating agent is reacted with 2-acyloxy-3- (4-tetrahydropyranyl) -3-oxopropanoic acid ester represented by the general formula (2)

(In the formula, R and R ¹ are as defined above.)
A process for producing 2-acyloxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoate represented by formula (1).   The method for producing 2-acyloxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoate according to claim 3, wherein the reaction is carried out in a solvent. 3- (N-cycloheptylcarbonylamino) -2-acetoxy-3- (4-tetrahydropyranyl) -2-propenoate methyl or 3- (N-acetylamino) -2-acetoxy-3- (4-tetrahydro pyranyl) -2-propenoic acid methylation. In the presence of a base, general formula (2)

(Wherein R and R ¹ have the same meaning as in claim 1 ).
2-acyloxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoic acid ester represented by the general formula (6)

(In the formula, R ² represents a hydrogen atom or a hydrocarbon group, and X represents a halogen atom.)
A reaction with an acyl halide represented by the general formula (3)

(In the formula, R, R ¹ and R ² are as defined above.)
The manufacturing method of 3- (N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoic acid ester shown by these. The method for producing 3- (N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoate according to claim 6 , wherein the reaction is carried out in a solvent. General formula (2)

(In the formula, R represents a hydrocarbon group, and R ¹ represents a hydrogen atom or a hydrocarbon group.)
2-acyloxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoic acid ester represented by the general formula (4)

(In the formula, R has the same meaning as described above, and R ^A has the same meaning as R ^1. )
The manufacturing method of 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoic acid ester shown by these. The method for producing 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoate according to claim 8 , wherein the reaction is carried out in a solvent. General formula (3)

(In the formula, R represents a hydrocarbon group, R ¹ represents a hydrogen atom or a hydrocarbon group, and R ² represents a hydrogen atom or a hydrocarbon group.)
A solvolysis reaction of 3- (N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoate represented by the general formula (4):

(In the formula, R has the same meaning as described above, and R ^A has the same meaning as R ^2. )
The manufacturing method of 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoic acid ester shown by these. The method for producing 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoic acid ester according to claim 10 , wherein the solvolysis reaction is carried out in the presence of a base. The 3- (N-acylamino) -3 according to claim 10 , wherein the solvolysis reaction is carried out in the presence of a base selected from alkali metal carbonates, alkaline earth metal hydrogen carbonates, amines, and pyridines. A process for producing-(4-tetrahydropyranyl) -2-oxopropanoic acid ester. The method for producing 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoate according to claim 10 , wherein the reaction is carried out in water, alcohols, or a mixed solvent thereof. General formula (2)

(In the formula, R represents a hydrocarbon group, and R ¹ represents a hydrogen atom or a hydrocarbon group.)
2-acyloxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoic acid ester represented by the general formula (6)

(In the formula, R ² represents a hydrogen atom or a hydrocarbon group, and X represents a halogen atom.)
The reaction is carried out in the presence of a first base, followed by the subsequent addition of a second base and hydrazine to the acyl halide represented by the general formula (5).

(In the formula, R ^A has the same meaning as R ^2. )
The manufacturing method of 3- (N-acylamino) -3- (4-tetrahydropyranyl) -3-oxopropanohydrazide shown by these. The method for producing 3- (N-acylamino) -3- (4-tetrahydropyranyl) -3-oxopropanohydrazide according to claim 14 , wherein the first base is pyridines. The 3- (N-acylamino) -3- (4-tetrahydropyranyl)-group according to claim 14 , wherein the second base is at least one base selected from the group consisting of triethylamine, tripropylamine and tributylamine. A method for producing 3-oxopropanohydrazide. General formula (3)

(In the formula, R represents a hydrocarbon group, R ¹ represents a hydrogen atom or a hydrocarbon group, and R ² represents a hydrogen atom or a hydrocarbon group.)
A 3- (N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoate represented by formula (5) is reacted with hydrazine.

(In the formula, R ^A has the same meaning as R ^2. )
The manufacturing method of 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanohydrazide shown by these. The method for producing 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanohydrazide according to claim 17 , wherein the reaction is carried out in the presence of a base. The 3- (N-acylamino) -3- (4-tetrahydropyranyl) -2-oxo according to claim 17 , wherein the reaction is carried out in at least one solvent selected from the group consisting of water, alcohols and nitriles. A method for producing propanohydrazide. 15. The 3- (N-acylamino)-of claim 14 further comprising the step of obtaining 2-acyloxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoic acid ester by the method of claim 3. A process for producing 3- (4-tetrahydropyranyl) -3-oxopropanohydrazide. 11. The 3- (N- (N) of claim 10 further comprising the step of obtaining 3- (N-acylamino) -2-acyloxy-3- (4-tetrahydropyranyl) -2-propenoate by the method of claim 6. -Acylamino) -3- (4-tetrahydropyranyl) -2-oxopropanoic acid ester production method. The 3- (N-acylamino)-of claim 21 further comprising the step of obtaining 2-acyloxy-3- (4-tetrahydropyranyl) -3-amino-2-propenoic acid ester by the method of claim 3. A process for producing 3- (4-tetrahydropyranyl) -2-oxopropanoic acid ester.