JPS6172753A - Pyridyl ketone derivative - Google Patents

Abstract

NEW MATERIAL:A pyridylketone derivative shown by the formula I (X is halo gen; Y and Z are halogen, hydroxy, amino, mono- or di-lower alkylamino, cycloalkyl, cycloalkylamino, cyclic amino, lower alkylthio, arylthio, lower alkylsulfinyl, arylsulfinyl, etc.; R1 and R2 are H, halogen, lower alkyl oxycarbonyl, cyano, etc.). EXAMPLE:2,6-Dichloro-5-fluoronicotinoylmalonic acid diethyl ester. USE:Useful as an intermediate for preparing naphthyridine-based pyridone carboxylic acid derivative having improved antibacterial activity. PREPARATION:A carboxylic acid derivative shown by the formula II (Y1 and Z1 are halogen, etc.) is reacted with a halogenating agent to give a compound shown by the formula III (Hal is F, etc.), which is reacted with an enolate anion of a compound shown by the formula IV (R1a and R2a are cyano, etc.) to give a compound shown by the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel pyridylketone derivatives which are valuable intermediates in the production of compounds with excellent antimicrobial activity.

More specifically, the compound of the present invention has the following general formula (wherein X
means a halogen atom, and Y and Z are the same or different and are a halogen atom, a hydroxy group, an amine group, a mono- or di-lower alkylamino group, a cycloalkylamino group, or a cyclic amine group.

Lower alkylthio group, arylthio group, lower alkylsulfinyl group, arylsulfinyl group, lower alkylsulfonyl group, arylsulfonyl M, lower alkylsulfonyloxy group.

Rs means an arylsulfonyloxy group, a lower alkyloxy group or an aryloxy group;

R2's are the same or different and mean a hydrogen atom, a norogen atom, a lower alkyloxycarbonyl group, an /ano group, a nitro group or an acetyl group. ) is a pyridyl ketone derivative represented by

Among the compounds represented by the general formula []], R+, R
At least one of 2 is a lower alkyloxy/carbonyl group.

Compounds that are cyanogen, nitro or acetyl are
The following formula (wherein,
group or acetyl group. ), and such tautomers are also included in the compounds of the present invention.

In this specification, a halogen atom means fluorine.

It means chlorine, bromine, and iodine, lower alkyl* means straight chain or branched alkyl having 1 to 6 carbon atoms, and 7-chloroalkyl means cycloalkyl having 3 to 7 carbon atoms. However, aryl means phenyl or substituted phenyl (for example, p-t'Jl, etc.). Also,
Cyclic amine group refers to 4 which may contain another heteroatom.
to 7-membered ring cyclic amino group (for example, 1-pyrrolidinyl group, piperidino group, 6-morpholino group, 1-piperazinyl group, etc.), and the ring is a lower alkyl group, hydroquine group, or amine group.

Acylamino group (for example, acetylamino group, etc.).

It may be substituted with an acyl group (eg, acetyl group, etc.).

Hitherto, various production methods have been disclosed for the synthesis of naphthyridine-based pyridonecarboxylic acids (for example, Japanese Patent Application No. 5S
-13sooo-h. However, a method for producing naphthyridine-based pyridone carboxylic acids using the pyridyl ketone derivative of the present invention as an intermediate has not been disclosed so far.

The method for producing the compound of the present invention will be explained below.

(1) The compound of the present invention in which R1 and R2 in the general formula [1] are the above-mentioned groups other than halogen atoms, , halogen atom, amide, ) group.

Mono- or di-lower alkylamino group, cycloalkylamino group, cyclic amino group, lower alkylthio group, arylthio group, lower alkylsulfinyl group, arylsulfinyl group, lower alkylsulfonyl group, arylsulfonyl group, lower alkylsulfonyloxy group, arylsulfonyl It means an oxy group, a lower alkyloxy group or an aryloxy group. ) A halogenating agent is applied to the carboxylic acid derivative represented by the following general formula (where Hal means fluorine, chlorine or bromine,
, Y4 and Zi are the same as above. ), and further combine this with the following general formula % formula %) (wherein R+a and R2a are the same or different and represent a lower alkyl group, a cyano group, a nitro group or an acetyl group) K can be produced by reacting a compound represented by the following formula with the erlate anion and, if necessary, further treating with an acid.

When producing compound (III) which is an acid chloride, compound (II) and a chlorinating agent (for example, thionyl chloride, phosphorus oxychloride, phosgene, phosphorus trichloride, phosphorus pentachloride, etc.)
in a solvent or without a solvent at 10 to 150°C for 20 minutes to 5
By reacting for a long time, a compound which is an acid chloride is obtained. As the solvent, chloroform, benzene, toluene, etc. are used.

When phosphorus tribromide is used as a halogenating agent, an acid bromide compound (Ill) is obtained.

When the acid chloride compound [old] is further treated with hydrogen fluoride, the acid fluoride compound ([1)] is produced.

The reaction between compound ([) and the erulate anion of compound (IV) can be carried out using ether, tetrahydrofuran, dioxa/
, in an inert solvent such as benzene, toluene, quinolene, etc.
This is carried out by stirring at ~120°C for 30 minutes to 3 hours.

The erulate anion of compound [IV] is
) with reagents such as magnesium methoxide, magnesium ethoxide, sodium, sodium ethoxide, sodium hydride, sodium amide, triphenylmethyl sodium, and potassium L-butoxide.

When a compound in which one or both of R+a and Rza is a lower alkyloxycarbonyl group is obtained by the above reaction, the compound is treated with water or water-ethanol gel.
Hydrolytic decarboxylation is caused by heating under reflux for 30 minutes to 6 hours in the presence of an acid in a water-containing solvent such as
It can be converted to the compound (1) of the present invention in which one or both of R1 and R2 is a hydrogen atom. As the acid, hydrochloric acid, sulfuric acid + p-toluenesulfo/acid, etc. are used.

Moreover, the compound of the present invention in which X and Y are hydroxy groups,
X and Y obtained by the above reaction are a halogen atom, a lower alkylthio group, an arylthio group, a lower alkylsulfinyl group, an arylsulfinyl group, a low R alkylsulfonyl group, an arylsulfonyl group, a lower alkylsulfonyloxy group, an arylsulfonyloxy group, It can be produced by hydrolyzing a compound having a lower alkyloxy group or an aryloxy group by a conventional method.

The raw material compound [■] can be produced by the method described in Reference Examples 1 to 3 or a method analogous thereto.

(2) In general formula [1], at least one of X and Y is an amino group, a mono- or di-lower alkylamino group.

The compound of the present invention which is a cycloalkylamino group or a cyclic amino group also has the following general formula (wherein, X means the same as defined above, Y2, Zz
are the same or different, a halogen atom, a hydroxy group,
Amino group, mono- or di-lower alkylamino group, cycloalkylamino group, cyclic amine group, lower alkylthio group, arylthio group, lower alkylsulfinyl group, arylsulfinyl group, lower alkylsulfonyl group, 7-arylsulfonyl group, lower alkylsulfonyloxy group, arylsulfonyloxy group, lower alkyloxy group or aryloxy group, Rib, R2b
are the same or different and are hydrogen atoms.

Lower alkyloxycarbonyl group, cyano group.

It means a nitro group or an acetyl group. However, Y2 and 2
2 are the same or different and are not a hydroxy group, an amine group, a mono- or di-lower alkylamino group, a cycloalkylamino group, a cyclic amino group, a lower alkylthio group or an aryloxy group. ) and a compound represented by the following general formula % formula % [) (wherein W means an amine group, a mono- or di-lower alkylamino group, a /chloroalkylamino group, or a cyclic amine group). It can be produced by reacting amines.

This reaction uses ethanol, acetonitrile, dioxane,
The raw material compound (V
) and (Vl) are mixed and stirred for 30 minutes to 24 hours. This reaction is generally carried out in the presence of an acid acceptor using 1 to 1.2 equivalents of starting compound (Vl) relative to (V).

A raw material compound in which both Y2 and Zz are halogen atoms [
v] and reacting it with 1 to 1.2 equivalents of the starting compound (Vl), this reaction proceeds regioselectively to obtain a compound in which Zz is converted to W. However, in general, a compound having a group that is relatively more easily substituted than the other group at the position of Y2 or Zz to be converted should be used as a raw material compound. v], Y2 and Zz are the same or different and are a halogen atom, lower alkylthio group, arylthio group, lower alkylsulfinyl group, arylsulfinyl group, lower alkylsulfonyl group, arylsulfonyl group, (l alkylsulfonyloxy group or arylsulfonyloxy group) Using a raw material compound having 7 groups, reacting it with a compound (Vl'l) of 2 or more equivalents to form Y2 and 2
It is also possible to obtain compounds in which both 2 are substituted with W.

(3) The compound of the present invention in which one or both of R+ and R2 in the general formula [1] is a halogen atom is a compound represented by the following general formula (wherein x, y, z and Rlb are the same as above). Manufactured by halogenating 1
can be built.

This reaction is carried out in a solvent such as acetic acid, chloroform, carbon tetrachloride, benzene, toluene, quinolene, etc. or in the absence of a solvent.
This can be carried out by treating the compound [■] with a halogenating agent such as chlorine, sulfuryl chloride, bromine, or N-bromosuccinimide at 150°C.

The thus obtained compounds [ ] are all new compounds and are valuable as intermediates for the production of naphthyridine-based pyridonecarboxylic acid conductors having excellent antibacterial activity.

In the general formula [1], X is fluorine, Y and Z are chlorine,
Taking as an example the compound of the present invention in which R+ is hydrogen and R2 is an ethoxy7carbonyl group, the conversion to a naphthyridine-based pyridonecarboxylic acid derivative is illustrated as follows.

(Left below) [Kari] [Kari] Let ethyl formate and acetic anhydride react to form a compound [■],
This was reacted with cyclopropylamine to form the compound (IX
). The compound ([X] is converted into a ring-closed form (X) in the presence of a base.
'], this can be reacted with a pyrrolidine conductor to obtain an ester of the formula [Kari], which can be further hydrolyzed to produce naphthyridine carboxylic acid hydrochloride [Kari].

Next, the method for producing the compound of the present invention will be explained with reference to Examples and Reference Examples.

Reference Example 1 Heat 2.6-cyclo-5-fluoronicotinic acid. Add water and further heat at 100-110°C for 2 hours.
6.0y of 2,6-dichloro-5-fluoronicotinic acid is obtained. Example 1 2.6-cyclo-5-fluoronicotinoylmalonic acid diethyl ester (1) 2,6-dichloro-5-fluoronicotinic acid 2
A mixture of 2.6y and thionyl chloride 113- is heated to reflux for 1 hour. Concentrate to dryness under reduced pressure to obtain oily 2,6-dichloro-5-fluoronicotinic acid chloride 24.6Pt! 4!
Ru.

(2) Metal magnesium 2.91? , malonic acid diethyl ester 19.8y, absolute ethanol 18rne
Anhydrous ether (100 ml) of ethoxymagnesium diethyl malonate prepared from
50mt') Distill the chill to form an oily 2,6-dichloro-5-7,f fluoronicotinoyl malonic acid diethyl ester 34.1
Get 2.

MS m/z: 316 (M”-CI), 30
6.288. 270.242°192°NMR (CDCI3) δ: 1.06 (
3H, t, J-7Hz, -(H2CH3).

1.40 (3H, t, J-7H2, -CH2CH3),
4.08 (2H, q.

J=7H2, -(1:H2CH3), 4.42(2
H,q, J-7Hz.

-CH2CH3), 7.55 (LH, d, J-7H
z, C4-H) Example 2 2.6-dichloro-5-fluoronicotinoyl acetic acid ethyl ester 2.6-dichloro-5-fluoronicotinoyl acetic acid ethyl ester 34.1 jil', water 100 me
, a mixture of a small amount of p-toluenesulfonic acid is heated to reflux for 2 hours. Next, extract with isopropyl ether and dry the extract with anhydrous sodium sulfate. The isopropyl ether was distilled off, and the resulting crude crystals were recrystallized from ether-hexane to yield 22.2 g of ethyl 2,6-dichloro-5-fluoronicotinoyl acetate! tlj!
Ru. m, p, 69-70"C Example 3 3-7 cetyl-2.6-)chloro-5-fluoropyridi/2,6->chloro-5-fluoronicotinoyl acetic acid ethyl ester O,: 1M', 10% A mixture of 4-hydrochloric acid and 2-me methanol was heated under reflux for 1.5 hours. Extracted with chloroform, and dried the extract over anhydrous sodium sulfate.
Distill chloroform to obtain oily 3-acetyl-2,6
-Dichloro-5-fluoropyridine 0.13 is obtained.

IRv: 1710cm MS m/z: 207 (M+), 192. 1
64°NMR (CDCI 3') δ: 2.73
(3H,S,-CH5), 7.83(LH.

d, J-7,5H2, C4-H) 2,4-dinitrophenylhydrazone: m, p,
175°C (recrystallized from ethanol) Example 4 2.6-Dichloro-5-fluoronicotinoylcyanoacetic acid ethyl ester 1.1y of ethyl cyanoacetate and 0.3911 of 62 sodium thihydride in 20me of anhydrous tetrahydrofuran under water cooling.
react. A solution of 2.17 of 2,6-dichloro-5-fluoronicotinic acid chloride in anhydrous tetrahydrofuran (6-) was added dropwise to this under water cooling, and the mixture was stirred for 2.5 hours. Concentrate to dryness under reduced pressure, add dilute aqueous hydrochloric acid solution to the residue, and extract with chloroform. After drying the extract over anhydrous sodium sulfate, chloroform is distilled off.

The residue was separated and purified by silica gel column chromatography to obtain 2.6-')chloro-5-fluoronicotinoylcyanoacetic acid ethyl ester 1.27% as a viscous liquid.

IR! / : 2200. 1650cmM5m/
z: 269 (M”-CI), 241.209.1
92°NMR (CD30D) δ: 7.90 (L
H, d, J-7~8Hz, C4-H).

4.36 (2H, q, J-7, 5Hz, -CH2CH3
), 1.40 (3H.

q, J = 7.5Hz, -CH2Cl(3)
.

Example 5 A mixture of 2.6-dichloro-5-fluoronicotinoyl acetonitrile 2.6-dichloro-5-fluoronicotinoylcyanoacetic acid ethyl ester 0.64', 2% hydrochloric acid LOme is heated to reflux for 4 hours. Add water, extract with chloroform, and dilute the extract with an aqueous sodium bicarbonate solution.

After successively washing with water, drying with anhydrous sodium sulfate.

After distilling off the chloroform and separating and purifying the residue using gel column chromatography, an oily 2,6-dichloro-
0.34y of 5-fluoronicotinoylacetonitrile is obtained.

IRv H2250, 1710Cm MS m/z: 232 (M+), 192.16
4°NMR (CDC1x) δ: 4.28 (2H,
S, -CH2CN), 797 (LH, d, J=7Hz
, C4-H) Reference Example 2 2.5-difluoro-6-(p-tolylthio)2,
Cotinic acid (1) 2. The er-cyclo-5-fluoronicotine nitrile is reacted with the potassium salt of p-thiocresol to yield 2-chloro-6-(p-tolylthio)-5-fluoronicotine nitrile. m, p, 124-12
5'C (2) This compound was treated with anhydrous potassium fluoride in dimethylsulfokind to form 2,5-difluoro-6-(p
−) ') Lucio) Nicotinoyluryl is obtained.

m, p, 120-121°C (3) Hydrolyze this compound with concentrated sulfuric acid to give 2,5-difluoro-6-(p-t')ruthio)nicotinamide. m, p, 152-153° This was further treated with boron fluoride in anhydrous ethanol to give ethyl nistertosul 2,5-difluoro-6-(p-tolylthio)nicotinate. m, p, 68-70℃ (4) Hydrolyze the above ester with an aqueous sodium hydroxide solution to obtain 2,
5-difluoro-6-(p-1lylthio)nicotinic acid is obtained. m, p, 172-174"C Example 6 2.5-difluoro-6-(p-tolylthio)nicotinoylmalonic acid diethyl ester (1) 2.5-difluoro-6-(p-tolylthio)nicotinic acid 5 .3 f, thionyl chloride 9.5 me
, chloroform 27me is heated to reflux for 3 hours. Concentrate to dryness under reduced pressure and recrystallize the residue from ethenoxxa/ to give 2,5-difluoro-6-(p,-1lylthio)nicotinic acid chloride 4.6y. m, p,
73-75°C.

(2) Using the above acid chloride 4.1y, the following treatment was performed in the same manner as in Example 1-(2) to obtain oily 2,5-difluoro-6-(p-)')ruthio)nicotinoylmalone. 5.51 of the acid diethyl ester is obtained.

IRU: 1750.1730.1690CI11M
S m/z: 423 (M”), 377, 304
．． 264゜Example 7 2.5-difluoro-6-(p-tolylthio)nicotinoyl acetic acid ethyl ester 2.5-difluoro-6-(p-4lylthio)nicotinoylmalonic acid diethyl ester Using 5.5Pt, Example 2 2,5-difluoro-6-(p-
to! J Lucio) Nicotinoyl acetic acid ethyl ester'1.
8 Obtain P m, p, 94-95°C (recrystallized from ether-hexane) Reference example 3 2-ethylamino-5-fluoro-6-(p-tolylthio)nicotinic acid “2,5-difluoro- 6-(p-1 lylthio)nicotinic acid ethyl ester and ethylamine were reacted in ethanol to form 2-ethylamino-5-fluoro-6-(p-1).
−)')ruthio) Nicotinic acid ethyl ester is obtained.

m, p, 68-69°C (recrystallized from ethanol)
. This compound was hydrolyzed with an ethanol-water solution of potassium hydroxide to produce 2-ethylamino-5-fluoro-6-
(p-)lylthio)nicotine e is obtained. m, p,
195-198°C (recrystallized from ether-hexane) Example 8 [2-ethylamino-5-fluoro-6-(p-tolylthio)]nicotinoylmalonic acid diethyl ester (1) 2-ethylamino-5- Fluoro-6-(p-tolylthio)nicotinic acid 2.0p, thionyl chloride 2.
A mixture of 4 me and 10 me of chloroform is heated to reflux for 30 minutes. Concentration to dryness under reduced pressure and recrystallization of the residue from ether-hexane yielded 2-ethylamino-5-fluoro-6-(p-)lylthio)nicotinic acid chloride 1.67
get. m, p, 108 109 °C (2) Using 0.33y of the above acid chloride, the same treatment as in Example 1-(2) was carried out to obtain [2-ethylamino-5-fluoro-6-
(p-t')ruthio)] Nicotinoylmalonic acid diethyl ester 0.28Pl! Ru. m, p, 82-83
°C (recrystallized from ether-hexane) 1 Example 9 6-(3-acetylamino-1-pyrrolidinyl)der-2-chloro 5-fluoronicotinoyl acetic acid ethyl ester 2,6-cyclo5-fluoronicotinoyl acetic acid Ethyl ester 1.4p, hydrogen carbonate 1-'Jum 05g
! , 0.77y of 3-acetylaminopyrrolidine, and acetonitrile L4me is stirred at room temperature for 24 hours.

It was concentrated under reduced pressure, and the residue was separated and purified by 7-force gel column chromatography to obtain an oily 6-(3-acetylamino-
OMS m/z to obtain 0.7 By of 5-fluoronicotinoyl acetic acid ethyl ester (1-pyrrolidinyl)-2-'70 rho: 371 (M''), 312
．． 284. 225°NMR (CDCl3)
δ: 1.29 (3H, t, J-7Hz, -(H
2CH3).

1.98 (3H, S, CH3), 4.22 (2H, Q
, J-7H2゜-CH2CH3) , 4.10 (2
H, s, -CH2CO-).

1.93-2.33 (2H, m, pyrrolidine ring),
3.66-4.73 (2H, m, pyrrolidine ring), ca
4.7(LH,m,-(:H-).

6.44 (IH, d, J-7Hz, -NH-), 7.
70 (IH, d.

J=13Hz, C4-(() Reference example 4 7-(3-amino-1-pyrrolidinyl)-1-fucloprobyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3- Carboxylic hydrochloride (1) 3-(2,6-dichloro-
5-fluoronicotinoyl acetic acid ethyl ester 40y was treated with ethyl orthoformate and acetic anhydride to give 2-(2,6
-cyclo-5-fluoronicotinoyl)-3-ethoxyacrylic acid ethyl ester 422 is obtained as an oil.

(2) This compound is reacted with cyclopropylamine in ethanol to obtain 2-(2,6-dichloro-5-fluoronicotinoyl)-3-cyclopropylaminoacrylic acid ethyl ester 42.4P.

m, p, 129-130°C (3) This compound 21y was reacted with potassium t-butylene in anhydrous dioxane to give 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4 −
Oxo-1,8-cattyridine-3-carboxylic acid ethyl ester L7.5p is obtained. m, p, 176-17
8℃

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula,
Mono- or di-lower alkylamino group, cycloalkylamino group, cyclic amino group, lower alkylthio group, arylthio group, lower alkylsulfinyl group, arylsulfinyl group, lower alkylsulfonyl group, arylsulfonyl group, lower alkylsulfonyloxy group, arylsulfonyl It means an oxy group, a lower alkyloxy group or an aryloxy group, and R_1 and R_2 are the same or different and mean a hydrogen atom, a halogen atom, a lower alkyloxycarbonyl group, a cyano group, a nitro group or an acetyl group. ) Pyridyl ketone derivatives.