JPS5953906B2 - 3-Methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl]pyruvic acid - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 3-methyl-3-[4-(1-oxo-2-
It relates to isoindolinyl)phenyl]pyruvic acid.

The compound of formula (I) can be used to prepare 2-[4-(1-oxo-2-isoindolinyl)fe-le]propionic acid of formula M) which has activity as an anti-inflammatory agent and analgesic. It is a useful intermediate and has pharmacological effects itself.

Hy゛゛゜゜゛... Conventionally, methods for synthesizing the compound represented by the formula (capital) include JP-A-51-11627, JP-A-48-57965, JP-A-51-6959, JP-A-51-34147, etc. The method described in is known.

These methods are expressed as follows. The present inventors have now completed the present invention by using the method shown in the following formula, which is completely different from these known methods, and found that the desired product can be obtained in higher yield than conventional known methods. .

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. be able to. Also 4
It can also be easily obtained by aminating -chloroacetophenone. In this way, the known method is expensive 2-(4-
This is a method for producing indoprofen, which is famous as an anti-inflammatory analgesic, using aminophenyl) propionic acid, but the present inventors have developed a method for producing indoprofen using 4-aminoacetophenone, which can be obtained industrially at low cost. Therefore, the desired product can be produced 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-amisoacetophenone and phthalaldehyde are reacted to form 4,4'-(0-phenylenebismethyleneamino)diacetophenone, and then 4-(
1-oxo-2-isoindolinyl)acetophenone. The method for synthesizing the novel intermediate (1) of the present invention begins with the synthesis of 4-(1-oxo-2
2-cyano-3 represented by the general formula (5) by heating and dehydrating acetophenone and cyanacetic acid or its esters in the presence of a catalyst such as ammonium acetate, generally in a solvent. -methyl-3-[4
1-(1-oxo-2-isoindolinyl)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 organic acid salts of amines such as morpholine, triethylamine, aniline, and diethylamine 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 (5) is obtained as a mixture of geometric isomers. Next, by oxidizing and hydrolyzing (5), 2-carbamoyl-3-methyl-3-[4-(1-oxo-2
-isoindolinyl)phenyl]glycidic acid can be produced.

The oxidation conditions include hydrogen peroxide in the presence of alkali tungstate, alkali phosphate, alkali molybdate, etc. Or in the presence of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, etc.
Oxidation is carried out using acetonitrile and hydrogen peroxide.

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. Hydrochloric acid, sulfuric acid, etc. can be used as the acid agent. Obtained 2
-Carbamoyl-3-methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl]glycidic acid is decarboxylated to produce 3-methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl] of the formula ()
4-(1-oxo-2-isoindolinyl)phenyl]
Pyruvate 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. Also, hydrochloric acid, etc.
Decarboxylation can also be performed with an acid agent. Furthermore, by hydrolyzing (1), 3-methyl-
3-[4-(1-oxo-2-isoindolinyl)phenyl]pyruvic acid can be produced.

The conditions for hydrolysis may be alkaline conditions or acidic conditions.

For alkaline conditions, it is desirable to use alkaline agents such as sodium hydroxide and potassium hydroxide, and for acidic conditions, it is desirable to use mineral acids such as hydrochloric acid and sulfuric acid, but any means commonly used for hydrolysis can be used. But that's fine. The reaction time is about 1 to 5 hours. Reaction temperature is room temperature to 200℃
That's about it. Known means for treatment in each reaction,
For example, it can be purified by recrystallization, column chromatography, distillation, etc.

Compounds (1) and (5) are a mixture of geometric isomers, and the desired compound (1) can be obtained using any of the geometric isomers. 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)phenyl] Method for producing ethyl acrylate 4-(1-oxo-2-isoindolinyl)acetophenone 1.25 g 1 ethyl cyanacetate 056 g 1 ammonium acetate 1 g 1 21 L of glacial acetic acid and 30 d of benzene were heated under 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.
1 g of pale yellow powder of ~165°C was obtained. −
Single element analysis value C2lHl8O,
N2・7H,0 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(CDCl,
) 1.40 (3H, triplet, CH2C horse) 2.70 (3H, singlet, CH,) 4.35 (2H1 quartet, CH without C,) 4.85 (2H1 singlet, CH,) Infrared absorption spectrum C1! L-! (KBr)172
0(C=O)1680(C=0) Further, nuclear magnetic resonance spectroscopy of the recrystallized mother liquor revealed that it was a mixture of the above substance and its geometric isomer.

Nuclear magnetic resonance spectrum δ(CDCl,)1 of recrystallization mother liquor
．． 40, 1.20 (3H, each triplet, CH2qb, diisomer) 2.70, 2.60 (3H, each singlet, CH,
diisomer) 4.35, 4.10 (2H1 each quartet, Cj
CH,, diisomer) 4.85 (2H, singlet, CH,) Example 2 2-carbamoyl-3-methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl]glycidic acid ethyl ester Production method of 2-cyano-3-methyl-3-[4
-(1-oxo-2-isoindolinyl)phenylacrylic acid ethyl ester 25j France 1.5 d of 30% hydrogen peroxide solution is added dropwise to a solution of 100 η of trisodium phosphate and 201 t1 of ethanol, and the mixture is stirred at room temperature for 24 hours.

After the reaction, the solvent was distilled off, the residue was washed with water, and then recrystallized from ethanol to obtain colorless granular crystal 1707!1y, one of the geometric isomers, having a melting point of 220°C (decomposed). Infrared absorption spectrum I-1 (KBr) 1740 (C=0) 1670 (C=0) Nuclear magnetic resonance spectrum δ (D6-DMSO) 1.30
(3H1 triplet, CH2C) 1.70 (3H1 singlet, CH3) 4.30 (2H1 quartet, CH2CH3) 5.00 (2
H1 singlet, CH2) 7.1-8.1 (8H1 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; H, 7.62 The crystals obtained from the ethanol mother liquor were recrystallized from isopropanol to give a melting point of 1.
The other crystal of the geometric isomer, 50r11fi1, was obtained as colorless granular crystals at 93°C (decomposed).

Infrared absorption spectrum Cm-1 (KBr) 1730 (
C=O) 1680 (C=O) Nuclear magnetic resonance spectrum δ(D6-DMSO) 0.90
(3H1 triplet, CH2C&) 1.75 (3H1 singlet, CH3) 3.80 (2H1 quartet, C-shaped CH3) 4.95 (2H1 singlet, CH2) 7.3-8.1 (8H1 multiplet line, aromatic nuclear hydrogen) Example
Process for producing 32-carbamoyl-3-methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl]glycidic acid 2-carbamoyl-3-methyl-3-[4-(1
-Oxo-2-isoindolinyl) Feni (Incorporated) glycidic acid ethyl ester 100 watts 1% sodium hydroxide 5
Dissolve in a mixture of mj and 5 ml of ethanol and leave 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.
I got 1!9. Infrared absorption spectrum I-1 (KBr)
1720 (C=0) 1690 (C=O) 1670 (C=O) Nuclear magnetic resonance spectrum δ (D6-DMSO) 1.70
(3H1 singlet, CH3) 5.00 (2H1 singlet, C
H2) 7.1-8.1 (8H1 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-isoindolinyl) glycidic acid ethyl ester 400 ~ 2 to 30 ml of ethanol
Add to the solution containing sodium hydroxide from 00 to 60°C.
Heat for 2 hours.

After cooling, the crystals were collected to obtain 390η of sodium salt. Add 5% hydrochloric acid aqueous solution to this to make it acidic, remove the crystals,
Colorless granular crystals 330W9 with a melting point of 230-235°C were obtained. 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 acid amide 2-carbamoyl-3-methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl]
isoindolinyl) glycidic acid 300η 1
Heat at 60°C to decarboxylate.

After cooling, recrystallize with ethyl acetate to obtain a melting point of 204-20.
220η of light yellow granular crystals were obtained at 6°C. Infrared absorption spectrum 礪-1 (KBr) 3400 (NH2) 1680 (C=O) Nuclear magnetic resonance spectrum δ (CDCl3-CD3OD)
1.50 (3H1 doublet, CH3) 4.95 (2H1 singlet, 9H2) 7.2-8.1 (8H1 multiplet, aromatic nuclear hydrogen) Mass spectrum m/E236 (reference peak) m/E3O8 ( M+) Example 6 Method for producing 3-methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl]pyruvic acid 3-methyl-3
-[4-(1-nioxo-2-isoindolinyl)phenyl]pyruvic acid amide 300W9 is heated at 100°C for 1 hour in 10% sodium hydroxide 10W11, and after cooling, it is washed with chloroform.

The aqueous layer is made acidic with a 10% aqueous hydrochloric acid solution and extracted with chloroform. Wash the chloroform layer with water, dry (Na, SO4),
The solvent was distilled off, and the residue was recrystallized from ethyl acetate to give colorless granular crystals 23071If with a melting point of 202-205°C.
get. Infrared absorption spectrum I-1 (KBr) 176
0,1720,1650 (C=0) Nuclear magnetic resonance spectrum δ (CDCl3-CD3OD) 1.50 (3H1 doublet, CH3) 5.00 (2H1 singlet, CH2)

Claims (1)

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