JPS5953905B2 - 3-Methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl]pyruvic acid amide - Google Patents

Description

Detailed Description of the Invention The present invention provides 3-methyl-3-[4-(1-oxo2-
This invention relates to isoindolinyl)phenyl]pyruvic acid amide.

The compounds of formula (I) are useful intermediates in the preparation of 2-[4-(1-oxo-2-isoindolinyl)phenynolipropionic acid of formula M, which has activity as an anti-inflammatory agent and analgesic. body, and has its own pharmacological effects.

袢□或HC0oH■ Conventionally, methods for synthesizing the compound represented by the formula M include Japanese Patent Publication No. 51-11627, Japanese Patent Publication No. 48-57965, and Japanese Patent Application Publication No. 51/1989.
-6959, JP-A-51-34147, etc. are known.

These methods can be expressed as follows.

Convexity: ゛゛〇〇) O This time, the present inventors have discovered that the desired product can be obtained using the method shown in the formula below, which is completely different from these known methods, and in a higher yield than the conventional known methods. This was discovered and the present invention was completed.

Cl4. That is, various methods are known for producing 2-(4-aminophenyl)propionic acid, which is the starting material in the known method, but all of them require a long production process of 5 to 8 steps, and are not economically inexpensive. It is difficult to manufacture and is not suitable for industrial manufacturing methods.

However, 4-aminoacetophenone, which is the starting material of the present invention, can be produced in a high yield and economically at low cost in one step by using, for example, Friedel-Crafts reaction from inexpensive acetanilide. I can do it. Also 4-
It can also be easily obtained by aminating chloroacetophenone. As described above, the known method uses expensive 2-(4-aminophenyl)propionic acid to produce indoprofen, which is famous as an anti-inflammatory analgesic.
The present inventors use a method of manufacturing using 4-aminoacetophenone, which can be obtained industrially at low cost, and can manufacture the desired product more advantageously than known methods. By using this 4-aminoacetophenone and phthalaldehyde, phthalic anhydride, phthalic acid, benzaldehyde, 0-halogenomethylbenzoic acid esters, etc., it can be induced to 4-(1-oxo-2-isoindolinyl)acetophenone. .

For example, 4-aminoacetophenone and phthalaldehyde are reacted to form 4,4'-(0-phenylenebismethyleneamino)diacetophenone, and then 4-(
It can be derived into 1-oxo-2-isoindolinino(c)acetophenone. New intermediate of the present invention (1)
The synthesis method is to first heat 4-(1-oxo-2-isoindolinyl)acetophenone represented by formula (5) and cyanacetic acid or its esters in the presence of a catalyst such as ammonium acetate, generally in a solvent. By dehydration, 2-cyano-3-methyl-3-[
4-(1-oxo-2-isoindolininorifhenyl)
Acrylic acids can be produced.

The most preferred catalyst is a mixture of ammonium acetate and glacial acetic acid, but other organic acid salts of amines such as piperidine acetate, piperidine benzoate, piperazine,
Various amino acids such as morpholine, triethylamine, aniline, diethylamine, etc. Organic acid salts can be used. Amino acids can also be used as catalysts.
The solvent may be any solvent that does not participate in the reaction, such as benzene, toluene, xylene, chloroform, cyclohexane, etc. It is preferable to carry out the reaction while removing water produced during the reaction as an azeotrope together with the solvent. The reaction time is about 1 to 48 hours, and the reaction temperature is preferably near the boiling point of the solvent used. Note that (auto) is obtained as a mixture of geometric isomers. Next, by oxidizing and hydrolyzing (auto), 2-carbamoyl-3-methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl]glycidic acid represented by formula 01) can be produced. I can do it.

The oxidation conditions include hydrogen in the presence of alkali tungstate, alkali octaphosphate, alkali octamolybdate, and the like. Alternatively, oxidation is carried out using acetonitrile and hydrogen peroxide in the presence of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, or the like.

In addition, oxidation can be performed using peracids such as perbenzoic acid, peracetic acid, perphthalic acid, percamphoric acid, and the like. Any solvent that does not participate in the reaction may be used, but alcohol-based solvents such as methanol, ethanol, propanol, and butanol are preferred. The reaction temperature is about 0 to 200°C, preferably 20 to 100°C.
That's about it. In this reaction, a carboxylic acid ester is usually obtained, but it can be hydrolyzed to produce a carboxylic acid. As the hydrolyzing agent, an alkaline agent and an acid agent can be used. Examples of alkaline agents include sodium hydroxide, potassium hydroxide, sodium carbonate, and potassium carbonate.
As the solvent, water or an alcoholic solvent is preferable.
Methanol, ethanol, propanol, etc. can be used. As the acid agent, hydrochloric acid disulfuric acid, etc. can be used. Obtained 2
-carbamoylni-3-methyl-3-[4-(1-oxo-2-isoindolinyl)phenynoliglycidic acid is decarboxylated to give the 3-methyl-3-
[4-(1-oxo-2-isoindolinyl)phenyl]pyruvic acid amide can be produced.

As conditions for decarboxylation, the objective can be achieved by directly heating compound (1).

The heating temperature is preferably 70 to 250°C. The purpose can also be achieved by heating in a solvent. The solvent at this time may be any solvent as long as it does not participate in the reaction, preferably a solvent having a boiling point of 80°C or higher. The purpose can be achieved in a short reaction time of 3 minutes to several hours, preferably about 30 minutes. As for the treatment in each reaction, purification can be carried out by known means such as recrystallization, column chromatography, distillation, etc.

Compounds (1) and (self) are a mixture of geometric isomers, and the desired compound (1) can be obtained no matter which one of the geometric isomers is used. Alternatively, a mixture of geometric isomers may be used as is. Next, the present invention will be specifically explained with reference to Examples, but the present invention is not limited thereto. Example 1 2-cyano-3-methyl-3-[4-(1-oxo-2
-isoindolinyl)phenynolyacrylic acid ethyl ester 4 A mixture of 1.259-(1-oxo-2-isoindolinyl)acetophenone, 0.56f1 cyanacetic acid ethyl ester, 19 ammonium acetate, 2d glacial acetic acid and 30d benzene. Heat to reflux for 15 hours.

The water produced is separated using a moisture meter.

After the reaction, the benzene layer was washed with water, dried over sodium sulfate, and the solvent was distilled off. The residue was recrystallized from isopropanol, melting point 163.
A pale yellow powder 19 of ~165°C was obtained. −
Single element analysis value C2lHl8O
, N2・-4H20 Calculated value: C, 7l. 88:H, 5.
3l; N, 7.98 Experimental value: C, 7l. 95; H, 5.
l5; N, 8.28 Nuclear magnetic resonance spectrum δ (CDC
l, ) 1.40 (3H, triple line, CH2C per,) 2.7
0 (3H, singlet, CH,) 4.35 (2H, quartet, CHlCH,) 4.85 (2
H, singlet, CH2) Infrared absorption spectrum (KBr) 1720 (C=0) 1680 (C=0) Furthermore, when the recrystallization mother liquor was measured by nuclear magnetic resonance spectrum, the above substance and its geometric isomer were detected. It turned out to be a mixture of.

Nuclear magnetic resonance spectrum of recrystallized mother liquor δ (CDCl,)
1.40, 1.20 (3H, each Mie WA.CH2CHl
, diisomer) 2.70, 2.60 (3H1 each singlet, C
H3, diisomer) 4.35, 4.10 (2H, each doublet, CH2CH,, diisomer) 4.85 (2H, singlet,
CH,) Example 2 Process for producing 2-carbamoyl-3-methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl]glycidic acid ethyl ester 2-cyano-3-methyl-3-[4
-(1-oxo-2-isoindolininorifhenyl) acrylic acid ethyl ester 250~, trisodium phosphate 10077V and ethanol 20a was added dropwise with 1.51!1i of 30% hydrogen peroxide solution, and 24 hours at room temperature. Stir for an hour.

After the reaction, the solvent was distilled off, the residue was washed with water, and then recrystallized from ethanol to give colorless granular crystals 17 with a melting point of 220°C (decomposition).
Obtained 0wa. Infrared absorption spectrum (1″″1 (KBr)
1740 (C=0) 1670 (C=0) Nuclear magnetic resonance spectrum δ (D3-DMSO) 1.30
(3H, triplet, CH2C melon) 1.70 (3H, singlet, CH3) 4.30 (2H, quartet, CIjCH,) 5,00 (2
H1 singlet, CH,) 7.1-8.1 (8H, multiplet, aromatic nuclear hydrogen) elemental analysis value C2lH2OO5N2 calculated value: C, 66.3O; H
, 5.3O; N, 7.37 Experimental value: C, 66.22; H
, 5.35; N, 7.62 Example 32-Carbamoyl-3-methyl-3-[4-(1-oxo-2-isoindolininotriphenyl)glycidic acid production method 2-carbamoyl-3-methyl-3 - 100 ml of ethyl 4-(1-oxo-2-isoindolinino(ha)phenyl)glycidate is dissolved in a mixture of 1% sodium hydroxide 5N and ethanol 5N and left overnight.

After standing, 10% hydrochloric acid aqueous solution was added to acidify the precipitated crystals, and colorless granular crystals with a melting point of 230-235°C were obtained.
Obtained 77V. Infrared absorption spectrum 傂-1 (KBr) 1
720 (C=O) 1690 (C=0) 1670 (C=0) Nuclear magnetic resonance spectrum δ (D, -DMSO) 1.70
(3H, singlet, CH3) 5.00 (2H, singlet, C
H2) 7.1 to 8.1 (8H, multiplet, aromatic nuclear hydrogen) Examples
Process for producing 42-carbamoyl-3-methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl]glycidic acid 2-carbamoyl-3-methyl-3-[4-(1
-Oxo-2-isoindolinino(ha)phenyl]glycidic acid ethyl ester 400Wi is added to a solution prepared by dissolving 2007nfi of sodium hydroxide in 30d of ethanol, and heated at 60°C for 2 hours.

After cooling, the crystals were collected to obtain 390 mfi of sodium salt. This was made acidic by adding 5% aqueous hydrochloric acid solution, and the crystals were collected to obtain colorless granular crystals having a melting point of 230 to 235°C.
The device data of this substance matched that obtained in Example 3. Example 5 Process for producing 3-methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl]pyruvic amide 2-carbamoyl-3-methyl-3-[4-(1-oxo-2-
Isoindolinyl)phenyl]glycidic acid 300mf!
is heated at 160°C to decarboxylate.

After cooling, recrystallize with ethyl acetate to obtain a melting point of 204-20.
Obtained pale yellow granular crystals 22077V at 6°C. Infrared absorption spectrum! (KBr) 3,400 (NH2) 1,680 (C=0) Nuclear magnetic resonance spectrum δ (CDCl3-CD3OD)
1.50 (3H1 doublet, CH3) 4.95 (2H1 singlet, CH2) 7.2-8.1 (8H, multiplet, aromatic nuclear hydrogen) Mass spectrum m/E236 (reference peak) m/E3O8 (M+)

Claims (1)

[Claims] 1 Formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ 3-Methyl-3-[4-(1-oxo-2-isoindolyl)phenyl]pyruvic acid amide represented by (I) .