JPH02215749A - 2-amino-2-substituted-acrylic acid derivative - Google Patents

Abstract

NEW MATERIAL:The 3-amino-2-snbstituted-acrylic acid derivative of formula I [A is N or C-R5 (R5 is H or halogen); R1 is H, halogen, methyl or amino which may be substituted with one or two lower alkyl, acyl or benzyl groups; R2 is lower alkyloxycarbonyl or cyano; R3 and R4 are lower alkyl or together with bonded N form a cyclic amino: X1, X2 and X3 are halogen; R1 is not H when A is C-R5]. EXAMPLE:2-Pentafluorobenzoyl-3-dimethylaminoacrylic acid methyl ester. USE:Useful as an intermediate for the synthesis of a compound having excellent antibacterial activity. PREPARATION:The compound of formula I can be produced by reacting a carboxylic acid halide of formula II (X is halogen) with an aminoacrylic acid derivative of formula N in an inert solvent in the presence of a base at 0-200 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel 3-amino-2-substituted acrylic acid derivatives which are valuable intermediates in the production of compounds with excellent antimicrobial activity.

[Prior Art] Some 3-amino-2-be/silyl acrylic al!
m-bodies are known (Japanese Patent Application Laid-Open No. 131-112051,
However, these compounds do not have a substituent corresponding to the substituent R+ in the compound of the present invention.

Furthermore, 3-amino-2-dicotinoyl acrylic acid derivatives are not known.

[Object of the invention] The present invention provides novel 3-amino-2-22 substituted-
The present invention provides acrylic acid derivatives.

[Structure of the invention] The compound of the present invention has the following general formula: [In the formula, A means N or CR8.

R11 means a hydrogen atom or a halogen If atom; RI means a hydrogen atom, a halogen atom, a methyl group, or a lower alkyl group.

means an amino group which may be substituted with 1 or 2 acyl groups or benodyl groups, R2 means a lower alkyloxycarbonyl group or a sia/group, R3 and R4 are the same or different and represent a lower alkyl group; or may together with the nitrogen atom to which they are attached form a cyclic ami7 group (which may also contain other heteroatoms), Xb Xt and X3 are the same or different means a halogen atom.

However, when A is C-R5, RI is not a hydrogen atom. ] Novel 3-amino-2-substituted-acrylic acid V represented by
It is a k conductor.

In this specification, examples of the halogen atom include fluorine and chlorine. Examples of lower alkyl include methyl, ethyl, and propyl.

Isopropyl, butyl, isobutyl, t-butyl.

Examples include beethyl and neopentyl. Examples of the acyl group include formyl, acetyl, propionyl, butyryl, imbutyryl, and pivaloyl.

Examples include chloroacetyl and trifluoroacetyl. Examples of the cyclic amine 7 group include pyrrolidinyl, piperidino, piperazinyl, homopiperazinyl, morpholino,
Examples include 5- to 7-membered ring groups such as thiomorpholif.

Next, a method for producing the compound of the present invention will be explained.

The compound of the present invention comprises a carboxylic acid halide represented by the following general formula (wherein, X means a halogen atom, and A, RI, XI,
In the formula, R2, R3 and R4 are the same as @. ) can be produced by reacting with an amide/acrylic ffi derivative represented by

In this reaction, starting compounds (■) and (III) are mixed in an inert solvent in the presence of a base at 0 to 200°C, preferably at 10 to 100°C.
This can be carried out by stirring at 50°C for 1 to 24 hours.

As a solvent, for example, methylene chloride, chloroform, 1
, halogenated hydrocarbons such as 2-dichloroethane, aromatic compounds such as benzene, toluene, xylene, diethyl ether, tetrahydrochloride, dioxa7.1.
Examples include ethers such as 2-dimethoxyethane. Examples of the base include inorganic bases such as potassium carbonate, sodium bicarbonate, potassium carbonate, and sodium carbonate;
Examples include bases such as triethylamine, N-methylmorpholine, N-ethylmorpholine, N-methylpiperidine, and pyridine. Raw material compound 11) and (Iff) are 1
It is preferable to use a stoichiometric amount of :1.

After the reaction is completed, the product is isolated and purified by conventional methods.

[Effects of the Invention] The compounds (I) thus obtained are all new compounds, and are valuable compounds as intermediates in the production of pyridonecarboxylic acid derivatives having excellent antibacterial activity.

The process of producing a pyrido/carboxylic acid derivative, for example, in which the 1-position is a cyclopropyl group and the 7-position is a piperazine/derivative, using the compound of the present invention is as follows.

I O (wherein R8 means a 1-piperazinyl group which may have a substituent, A, R1,R2゜Rs, R4,
Xl, X2 and X3 are the same as above. ) According to this reaction formula, compound (I) of the present invention is reacted with cyclopropylamine to form 3-cyclopropylamino-2-substituted acrylic acid derivative W (fV), and a base is allowed to act on this. A closed ring body (V) is obtained. Hydrolyze this to create carvone!
I (Vl) and then reacted with a piperazine derivative to produce compound (■).

The compound of formula (■) thus obtained has extremely excellent antibacterial activity and is a valuable compound as an antibacterial agent.

[Examples] Next, the present invention will be explained in more detail by giving examples and reference examples.

Example 1 2-pentafluorobenzoyl-3-dimethylaminoacrylic acid methyl ester: 2.8 g of methyl 3-dimethylaminoacrylate
- Dissolve in methylmorpholine, and add 4.6 g of pentafluorobenzoyl chloride dropwise to the solution while stirring while cooling with water. Heat the reaction solution to 70-80℃
After heating and stirring for 2 hours, the mixture was cooled to room temperature. After washing with water and drying, the solvent is distilled off under reduced pressure. Separate and purify the residue using silica gel column chromatography (eluent: methylene chloride). The resulting crystals are recrystallized from isopropyl ether to obtain 5.0 g of the desired product as pale yellow crystals.

m. p. 04~65℃! R spectrum (Knr) cm-': 188
8, 1038, 1578, 1522. 1499
NMR spectrum (CDCD3) δ: 3,02 (
3H, s, N-CH3)3,41 (3H, s,
N-CD3) 3,59 (3H, s, O-(jL+) 7,98 (IH, s, =CII-N) Mass spectrum m/z: 323 (M”) Elemental analysis %
(As CD3HIOFIINQ3) Calculated value C:
48.31 H: 3.12 N+4.33 F:
29.39 min 4fr value C: 48.35 H: 2.
92 N: 4.29 F: 29.07 Example 2 2-pentafluorobenzoyl-3-dimethylaminoacrylic acid methyl ester: Reacted in the same manner as in Example 1 by using 3.1 g of ethyl 3-dimethylaminoacrylate. Process and obtain the object5.
4 g are obtained as a pale yellow oil.

IR spectrum (liquid film) Ql-': 1894.1634.157B, 1520.1499
NMR spectrum (CDC1*) δ: 1.07 (3
H, t, 0CH2CH3)3.02 (3)1. s
, N-CD5) 3.41 (3H,s, N-CD5
)4.04 (2H,Q, OCH*CH3)7.97
(IH, s, =CH-N) Mass spectrum m/z: 337 (M+) Example 3 2-pentafluorobe/Syl-3-dimethylaminoacrylonitrile: 2.0 g of methyl 3-dimethylaminoacrylate and N
- 2.1 g of methylmorpholine is dissolved in 461 g of toluene, and 4.0 g of pentafluorobenzoyl chloride is added dropwise thereto while stirring while cooling with water. After stirring overnight at room temperature, the reaction solution was washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methyl chloride/
) for separation and purification. The resulting crystals are recrystallized from ethanol-inpropyl ether to obtain 2.8 g of the desired product as pale yellow crystals.

m, 9.120-129°C IR spectrum (Knr) cs-': 2208,
1003.1007.1597.1522.1502N
MR spectrum (CDC1a) δ: 3.35 (3H
,s, N-Cl5) 3.40 (3H,S, N-C
I (G) 7.95 (11-L s, =CH-N) Mass spectrum m/z: 290 (M”) Elemental analysis % (as CZH7FsN20) Calculated value C:
49. ff7 H: 2.43 N: 9.65 F
F2.73 analysis value C:49.70 11:2.41
N: 9.07 F: 32.8+Example 4 2-pentafluorobenzoyl-3-(1-pyrrolidinyl)acrylic acid methyl ester: 3.8 g of methyl 3-(1-pyrrolidinyl)acrylate and N-methyl morpholif 2. 2 g of the solution was dissolved in 1,2-dimethoxyethano 451, and 4.6 g of pentafluorobenzoyl chloride was added dropwise thereto while stirring while cooling with water. After heating the reaction solution under reflux for 1.5 hours, the solvent was distilled off under reduced pressure. The residue is extracted with methyl chloride, and the extract is washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
Separation and purification with methyl chloride/) yields 5.7 g of the desired product as an orange oil.

IR spectrum (liquid film) ca-': +(198,1032,15B0.1520.1499
．． 138ONMR spectrum (CDCl3) δ: 1.
80-2.20 (4H, m, C-C)IzCHt-
C) 3.25 (2H, t, N-Cl-1t) 3.8
0 (2H,t, N-CHl)3.55 (3H,m
, 0-CHs)8.10 (IH,s, =CH-N
) Mass spectrum m/z: 349 (M”) Example
5 2-Pentafluorobe/Si-3-piperidinoacrylic acid methyl ester: 3.2* Methyl 3-piperidinoacrylate and 1.9 g of N-methylmorpholine were mixed with 1,2-dimethoxyethane 3
913.9 g of pentafluorobe/diylchloro was added dropwise to the solution under water-cooling and stirring.

After stirring the reaction solution at room temperature for 17 hours, the solvent was distilled off under reduced pressure. The following treatment was carried out in the same manner as in Example 4, and 5.2 g of the target product was obtained.
, is obtained as an orange oil.

Summer R spectrum (liquid film) c++-': +098. 1032. 1500. 1520
．． 14HNMR spectrum (CDCl3) δ:1
．． 50-2.00 (ON, m, C-(CH
2) 3-C) 3.20-3.80 (41L
m, CH2-N-Cl+2)3.55 (31-
1,s, 0-C1h)? ,90 (1)1.
s, =CH-N) mass spectrum m/z:
303 (M”) Example 6 2-(2,8-dichloro-5-fluoronicotinoyl)
-3-dimethylaminoacrylic acid methyl ester: 1.4 g of methyl 3-dimethylaminoacrylate and N
-Methylmorpholinia 1. Ig was dissolved in 23 parts of toluene, and 2.3 g of 2,6-dichloro-5-fluoronicotinoyl chloride was added dropwise to the solution while stirring while cooling with water. After heating the reaction solution at 70-80°C for 1 hour, it is cooled to room temperature. After washing with water and drying, the solvent is distilled off under reduced pressure. The residue was recrystallized from toluene-ethyl ether to obtain 2.5 g of the desired product.
is obtained as pale yellow crystals.

m, p, 145-146°C IR spectrum (Kn r ) cs-': 1 (t9
0.1042.157[3,1383,13137NM
R spectrum (do-DMSO) δ: 2.93 (311
, s, N-C1,) 3.40 (3H, s, N-CI-h) 3.47 (
31-f, s, 0-CD5) 7.93 (IH, s
, =Cl-1-N)7.97 (IH,d, JII
F=81(Z) Mass Spectiv m/z: 32
0 (M”) elemental analysis% (Cl2H1lCIgFN2o3
Calculated value C: 44.88 H: 3.45
N: 8.72 F: 5.92 C]: 2
2.08 Analysis value C: 44.81 H: 3.2'7
N: 8.72 F + 5.84 CI: 2
2.00 Example 7 2-(2,6-dichloro-5-fluoronicotinoyl)
-3-dimethylaminoacrylic acid ethyl ester: A reaction treatment was carried out in the same manner as in Example 6 by using 1.5 g of 3-dimethylaminoacrylic acid ethyl ester to obtain the desired product 2.
Obtain 0 g as pale yellow crystals. Recrystallize from ethyl ether.

m, 9.94-95°C IR spectrum (Knr) cs-': +088.
lG24.15CIE, 1427.1394NMR
Spectrum (CDCl3) δ: 1.00 (3H, t
, 0-CH2Ctf3)2.90 (311,s,
N-CD5)3, (io (311,s, N-C)1
3) 4.00 (2H,Q, 0-CIIzCl-h)
7.50 (III, d, JllF=8112)7
．． 95 (LLI, s, =CH-N) Mass spectrum m/z: 334 (M”) Elemental analysis % (C
H31-(13c 12FN203 IIo, 25+1
(as zO) Calculated value C: 45.97 H: 4.0
1 N: 8.25 F: 5.59 CI +
20.88 Analysis value C: 4G, 17H: 4.00
N: 8.3 [IF: 5.31 Cl:
20.94 Example 8 2-(2,017chloro0-5-fluoronicotinoyl)-3-dimethylaminoacrylonitrile: Dissolve 1.1 g of 3-dimethylaminoacrylonitrile and 1.1 g of N-methylmorpholin in 23 ml of toluene. , 2.3 g of 46-dichloro-5-fluoronicotinoyl chloride was added dropwise to the mixture under water-cooling and stirring. The mixture is stirred overnight, then washed with water and dried. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl ether to obtain 2.6 g of the desired product as pale yellow crystals.

m, 9.138-139°C IR spectrum (KDr) cs-': 2214, 1
049.1597.1557.1427.1394NM
R spectrum (CDCl3) δ: 3.35 (31-
1,s, N-CD5) 3.50 (3H,s, N-
CD5) 7.45 (IH, d, JIIF=6) Iris 2) 7
．． 90 (IH,s, =CH-N) Mass Spect/I/ m/z: 320 (M”) Elemental Analysis % (
C eyes H! 1cI2FN30) Calculated value C: 45.
80) 1: 2.80 N: 14.59 F
:[1,59C1: 24.01 Analysis value C: 45.8
5 H: 2.01 N: 14.52 F: 0
．． 02 C1: 24.71 Example 9 2-[2-(N-7 cetyl-N-benzylamino)-3
,4,6-)lifluorobenzoyl] -3-dimethylaminoacrylic acid ethyl ester = (1) 2-(N-
Acetyl-N-benzylamino)-3,4,6-) refluorobenzoic fl! A mixture of 22.0 g and 4.1 parts of oxalyl chloride was heated under reflux for 5 hours. Excess oxalyl chloride is distilled off under reduced pressure to obtain 2.1 g of crude 2-(N-acetyl-N-benzylamino)-3,,'l,El-)lifluorobenzoic acid chloride.

■ Add 2.1 g of the above compound to 1 1,2-dimethoxyethane
0.9 g of ethyl 3-dimethylaminoacrylate and 70 g of N-methyl sulfolyl were dissolved in 0.0 g of yam and stirred with water cooling.
．． A mixture of 1 g and 10 ml of 1,2-dimethoxyethane is added dropwise. After stirring overnight at room temperature, the reaction solution was concentrated under reduced pressure and the residue was extracted with methylene chloride. The extract is washed with water, dried, and then concentrated under reduced pressure. The residue is separated and purified by silica gel column chromatography (eluent: methylene chloride) to obtain 0.3 g of the desired product as a yellow oil.

IR spectrum (liquid film) am-': 1080, 1830.1572.1377 NMR spectrum (CDCl3) δ: 1.10 (3H, t, 0
-CHzCH3)2.00 (3H,s, C0CHs
)3.00 (3H,s, N-CH5)3.35 (
3H,s, N-C)h)4.04 (2H,Q, 0
CHzCH3) 4.07 (IH, d, J=14+1
z, NC1■*r'h)5.45 (IH,d,
J=14Hz, NCH2Ph) [i, 85 (
IH, m, arom, )7.22 (5H, m,
C) fzPh) 7.97 (IH,s, =Cl-
1-N) vs. X vector m/z: 448 (M”)
Reference example 1 1-cyclopropyl-5,8,8-)refluoro-7-
(cis-3,5-dimethyl-1-piperazinyl)-1,
4-dihydro-4-okifukinori/-3-carboxylic acid: +1) 24 g of 2-pe/tafluorobenzoyl-3-dimethylamino methyl acrylate in toluene + 0011
cyclopropylamine 4, dissolved in water-cooled and stirred,
．． Drop 7g. After stirring the reaction solution at room temperature for 1 hour,
Toluene is distilled off under reduced pressure and isopropyl alcohol is added. The precipitated crystals are subjected to ih2 Ri to obtain 20 g of methyl 2-pentafluorope/silyl-3-cyclopropylaminoacrylate.

m, P, 149~+51'C.

(2) Add 20g of this compound to 1,2-dimethoxyethane 7
I001, and 7 g of potassium t-butoxide is added thereto at 2 to 5° C. while cooling with water. After stirring the reaction solution at room temperature for 1 hour, 300 ml of ice water was added, and the precipitated crystals were collected by filtration to give 1-cyclopropyl-5,6°7,8-tetrafluoro-1,4-dihydro-4- Oxoquinoline-3
-17.9 g of methyl carboxylate are obtained. m, p,
198-200℃.

(3) 10g of this compound, 11g of wood vinegar! ! 0011. A mixture of 500 parts of water and 7 parts of concentrated sulfuric acid is heated under reflux for 30 minutes.

The reaction mixture is poured into ice water, and the precipitated crystals are collected by filtration and washed with water. Recrystallized from chloroform to give 1-cyclopropyl-5,8,7,8-tetrafluoro-1,4-dihydro
8.8 g of -4-okinegyunorin-3-carboxylic acid is obtained. m, p, 181-182°C.

(4) A mixture of 2.0 g of this compound, 2.5 g of cis-2,6-dimethylbiverazine, and 301 pyridine was heated and stirred at 80°C for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, and the residue was Dissolve in dilute ammonia water and treat with activated carbon. The liquid is concentrated under reduced pressure to give pi-17 to pi-8. #r
The resulting crystals are collected by filtration, washed with water, and dried to obtain 1.9 g of the desired product. Chloroform-recrystallized from ethanol-m
, p, 2ti9-260°C.

Reference example 2 5-amino-1-7 cloprovir-8-difluoro-
7-(cis-3,5-dimethyl-1-piperazinyl)-
1,4-dihydro-4-oxoquinoline-3-carboxylic acid: (1) 1-cyclopropyl-5,8,7,8-tetrafluoro-1, obtained in the same manner as in Reference Example 1 (+)■ 4-
28.2 g of dihydro-4-oxoquinoline-3-carbo/ethyl acid, 9.8 ml of benzylamine, fm
21.0 g of glacial potassium hydroxide and 140 g of acetonitrile
ml of the mixture was heated at 100-110°C for 1 hour,
5-be/dylamino-1-cyclopropyl-8,7,8
21.7 Lg of ethyl -trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate are obtained. Recrystallize from ethanol. m, 9.134-135°C.

(2) Add 20g of this compound to vinegar! 0.5 g of 5% palladium-carbon dissolved in lOOml and ethanol 1501
Hydrolysis in the presence of ethyl 5-amino-1-cyclopropyl-8,7,8-)lifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate 14.1
get g. Recrystallize from chloroform-ethanol.

m, p, 230-237°C.

■ 12.8g of this compound, 1.180ml of vinegar. water 5
A mixture of 9 I and 1 sulfuric acid was heated to 100-110°C.
After heating and stirring for 40 minutes at
11.1 g of -okinki/su/-3-carboxylic acid are obtained. Recrystallize from chloroform-ethanol.

m, p, 294-295°C.

(4) A mixture of 1.5 g of this compound, 2.3 g of cis-2,6-dimethylbiperazine and 20 I of pyridine is heated under reflux for 4 hours. The reaction solution is concentrated under reduced pressure, and ethanol is added to the residue. The crystals are collected by filtration, washed with water, and then recrystallized from chloroform-ethyl acetate to obtain 1.6 g of the desired product. m, 9.258-260°C.

Reference example 3 5-amino-1-cyclobuvir-6,8-difluoro-7-(cis-15-dimethyl-1-piperazinyl)-
1,,4-dihydro-4-oxoquinoline-3-carboxylic acid: 1-cyclopropyl-5,8,8-trifluoro-7-(cis-3,5-dimethyl-1- piperazinyl)-1,4-dihydro-4-oxo-quinol/-
3-carboxylic acid and 20% ammonia water in a sealed tube! 00~
Heat at 110°C for 48 hours. After opening, treated with activated carbon,
Concentrate the solution under reduced pressure. Add ethanol to the residue and collect the crystals by filtration. The desired product is obtained by recrystallization from chloroform-ethyl acetate.

m, p, 258-260°C.

Hoko Example 4 1-Cyclopropyl-6-fluoro-7-(1-piperazinyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid: fl)2-('26- Dissolve 3.5 g of ethyl dichloro(5-fluoronicotinoyl)-3-dimethylaminoacrylate in a mixed solvent of 71 ethanol and 1 O 1 of ethyl ether, and stir while cooling with water.
0.7 g of cyclopropylamine is added dropwise to this. After stirring the reaction solution at room temperature for 1 hour, 6 precipitated crystals were collected and 3 g of ethyl 2-(2,6-dichloro-5-fluoronicotinoyl)-3-cyclopropylaminoacrylate was collected.
get. m, p, 130-133°C.

(2) Dissolve 3 g of this compound in 15 dioxa/I, and add 11 g of potassium t-butoxide at 2 to 5°C under water cooling.
．． Add 1g. After stirring the reaction solution at room temperature for 1 hour, 151 g of ice water was added, and the precipitated crystals were collected by filtration to give 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carbo/
l! 2.4 g of 2-ethyl are obtained.

m, p, summer 77-180℃.

(3) This compound was hydrolyzed in the same manner as in Reference Example 1 (3), and 1-cyclopropyl-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3 - obtain carboxylic acid. Recrystallize from dimethylformamide.

m, p, 222-223.5°C.

(4) A mixture of this compound, anhydrous piperazine and acetonitrile is heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in dilute aqueous sodium hydroxide solution. This solution is neutralized with an acetic acid aqueous solution, and the precipitated crystals are collected by filtration to obtain the desired product.

m, P, 204-266 (decomposition).

i Example 5 5-amino-1-cyclopropyl-6-fluoro-7-
(cis-3,5-dimethyl-1-piperazinyl)-1,
4-dihydro-4-okinequinoline=3-carboyi!
Il: (1) 2-[2-(N-7cetyl-N-be/dylamino)-3,4,8-trifluorobenzoyl]-3-
Ethyl dimethylaminoacrylate and cyclopropylamine were reacted in the same manner as in Reference Example 1 (1) to obtain 2-[2
-(N-acetyl-N-benzylami/)-3,46,
-) Rif, fluorobenzoyl]-3-cyclopropylaminoethyl acrylate is obtained.

m, l), 119~+21"C.

(2) 28.3 g of this compound was reacted in the same manner as in Reference Example 1 (2). Add ice water to the reaction solution, adjust the pH to 4-5 with hydrochloric acid, and extract with chloroform. The extract is dried and then concentrated under reduced pressure. Ether was added to the residue, the crystals were collected by filtration, and 5
-(N-acetyl-N-benzylamino)-1-cyclopropyl-8,7-difluoro-1,4-dihydro-4
21.4 g of ethyl -oxoquinoline-3-carboxylate are obtained.

m, p, 147~! 50℃.

(3) Dissolve 1.0g of this compound in ethanol,
Catalytic reduction is carried out at 50 to 55°C using palladium-carbon as a catalyst. The catalyst was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure. A mixture of concentrated sulfuric acid, glacial acetic acid and water (1:8:O) was added to the residue.
Add intestine 1 and heat under reflux for 2 hours. Add water to the reaction solution,
The precipitated crystals were collected by filtration and washed with ethanol to give 5-amino-1-cyclopropyl-7-difluoro-1,4-
Dihydro-4-oxoquinol/-3-carboxylic acid 0.3
get g.

m, p, 300℃ or more.

(4) A mixture of 280 g of this compound, 1542 g of cis-2,6-dimethylpiveradi and 10 g of pyridine is heated under reflux for 2.5 hours. The solvent was distilled off under reduced pressure,
Insoluble matter was removed by adding IN sodium hydroxide solution f8 to the residue. A 10% acetic acid aqueous solution is added to the filtrate to adjust the pH to 8, and the mixture is extracted with chloroform. After drying the chloroform layer, concentrate under reduced pressure, add acetonitrile to 1[E], and cool with water. The crystals are collected by filtration and recrystallized from aqueous ammonia to obtain 250 g of the desired product.

m, p, 253-254°C.

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, A means N or C-R_5, and here R_
5 means a hydrogen atom or a halogen atom, and R_1 means a hydrogen atom, a halogen atom, or a methyl group, or an amino group optionally substituted with 1 or 2 lower alkyl groups, acyl groups, or benzyl groups. R_2 means a lower alkyloxycarbonyl group or a cyano group, R_3 and R_4 are the same or different and mean a lower alkyl group, or together with the nitrogen atom to which they are bonded, a cyclic amino group (the cyclic X_1, X_2 and X_3 are the same or different and mean a halogen atom. However, when A is C-R_5, R_1 is not a hydrogen atom. ] A 3-amino-2-substituted-acrylic acid derivative represented by: