JPS6051465B2 - 3-Methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl]pyruvic acid esters - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to 3 represented by the general formula (I) HCOCOORI 0 (I) (wherein R represents a lower alkyl group)
-Methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl]pyruvic acid esters.

The compound represented by the formula (I) has pharmacological action itself, and further has an anti-inflammatory and analgesic action. 2-[4-(1-oxo-2-isoindolinyl)phenyl] represented by the formula (■) ゜・:: It is a useful intermediate in the production of propionic acid (common name: indoprofen).

Conventionally, as a method for synthesizing the compound represented by formula (■), the method described in JP-A-47-997 & JP-A-51-6575 is known. These methods can be expressed as follows. However, the starting material of these known methods, 2-(
The various methods known for producing 4-aminophenyl)propionic acid all involve 5 to 8 steps, and the long production steps make it difficult to produce it economically and at low cost.

Therefore, these known methods are not suitable as industrial production methods. This time, the present inventors have developed a method as shown in Scheme 1, which is completely different from these known methods, has fewer steps than the known methods, has a better reaction yield in each step, and most of them can be done in the same reaction vessel. Because reactions can also be carried out,
It was found that this method is extremely advantageous as an industrial method, and the present invention was completed.

Scheme 1 The new substance 4-(1-oxo-2-isoindolinyl)acetophenone (■), which is a starting material, has already been patented by the present inventors (Japanese Patent Application No. 51-73849)
-156857), 51-126791 (Unexamined Japanese Patent Publication No. 53
-53633), 51-140650 (Unexamined Japanese Patent Publication No. 1983-
65871), 51-144672 (Unexamined Japanese Patent Publication No. 53-7
1063), 51-144673 (Unexamined Japanese Patent Publication No. 53-71)
064), it can be obtained industrially at low cost.

That is, 4-aminoacetophenone can be obtained easily and economically in a high yield by first subjecting acetanilide, which is an inexpensive industrial raw material, to the Friedel-Crafts reaction or by aminating 4-chloroacetophenone. The desired 4-( It can be derived into 1-oxo2-isoindolinyl)acetophenone (■). Specifically, for example, 4-aminoacetophenone and phthalaldehyde are condensed to form 4●4''-(0-phenylenebismethyleneamino)diacetophenone, and then treated in acetic acid (Japanese Patent Application No. 73849/1989). 4-(1-
A method in which 4-aminoacetophenone and o-halogenomethylbenzoic acid esters are condensed,
There are methods such as one-step method (Japanese Patent Application No. 51-140650), but all of them can obtain 4-(1-oxo-2-isoindolinyl)acetophenone (■) in high yield. The new 4-(1
-oxo2-isoindolinyl)acetophenone (V
) and α-halogenoacetic acid esters under the conditions of Dalzene condensation to obtain 3-methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl]glycidic acid esters (■).

The condensation is preferably carried out under anhydrous conditions in the presence of an alkaline condensing agent. As the condensing agent, any of the condensing agents commonly used in Dalzene condensation, such as metal alkoxides, metal amides, and metal hydrides, may be used. Typical examples include sodium ethoxide, sodium isopropoxide, potassium ethoxide, potassium isopropoxide, sodium amide, potassium amide, sodium hydride, potassium hydride, and the like. A solvent can also be used if desired. Suitable solvents include ethanol, isopropanol, butanol, ether,
Tetrahydrofuran, dioxane, benzene, toluene and the like can be mentioned. The reaction temperature is -80℃ to 20℃
The temperature is about 0°C. Preferably the reflux temperature of the mixture is from -20°C. The reaction time ranges from 1 hour to 1 hour, but it is sufficient to carry out the entire reaction for 1 minute. Next, by heating these glycidic acid esters, a novel 2-substituted -3-[4-(1-oxo-2-isoindolinyl)
Phenyl]-3-butenoic acid esters (■) can be obtained. It is preferable to use an acid catalyst as the conditions at this time. Specifically, mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, or organic acids such as formic acid, acetic acid, and propionic acid can be used as the acids. A reaction time of about 3 times is sufficient. A solvent may or may not be used, and when used, organic acids such as acetic acid, hydrated acetic acid, propionic acid, and hydrated propionic acid, as well as organic solvents having a relatively high boiling point such as benzene, toluene, and xylene are preferred. The reaction temperature is from 50°C to the boiling point of the reaction solvent, preferably from 100 to 200'C in the case of no solvent. Furthermore, by heating this butenoic acid ester (■) for a long time, a novel 3-methyl[4-(1-oxo-2-isoindolinyl)phenyl]pyruvic acid ester (1) shown in Scheme 1 is obtained. be able to. As for the conditions at this time, it is preferable to use an acid or basic catalyst. For the acid, the conditions were exactly the same as for the synthesis of butenoic acid esters (■),
That is, mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, and phosphoric acid, organic acids such as formic acid, acetic acid, and propionic acid, or a mixture of both are used. Therefore, in the case of acidic conditions, pyruvate ester (1) can be obtained from glycidate ester (■) by simply carrying out a long reaction during the synthesis of butenoate ester (■). As basic conditions, metal alkoxides, metal amides, metal hydrides, etc. can be used. Specifically, sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, potassium methoxide, potassium ethoxide, potassium propoxide, potassium isopropoxide, sodium amide, potassium amide, sodium hydride, potassium hydride, etc. It is. In addition, in the case of these basic catalysts, the ester can be replaced with a metal salt. In this case, it is possible to obtain pyruvate (■) directly. Any solvent can be used as long as it does not participate in the reaction. For example, benzene, toluene, xylene, ethanol, isopropanol, butanol,
Ether, tetrahydrofuran, etc. The reaction temperature is preferably room temperature to 200°C. The reaction time ranges from 1 hour to 1 hour, but it is sufficient to carry out the entire reaction for two intervals.
It is also possible to conduct this reaction in the open or to finally add water to lead to pyruvic acid (■), which is the next step reactant shown in Scheme 1. In this way, in the present invention, pyruvic acid is produced continuously from glycidic acid (■) through butenoic acid (■) and pyruvic acid ester (1) in the same reaction vessel without isolating the reaction products of each step. It is possible to do so. In addition, glycidic acid, its salts, and its esters, which are unknown in the literature and obtained by the present invention, are mixtures of geometric isomers, but no matter which isomer is used or the mixture is used as it is, butenoic acid ester derivatives can be obtained. As for the treatment in each reaction, purification can be performed by known means such as recrystallization, column chromatography, etc. Next, the present invention will be explained with reference to examples, but the present invention is not limited thereto. Example 1 Process for producing 3-methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl]glycidic acid ethyl ester 4-(1-oxo-2-isoindolinyl)acetophenone 4.5y1 Mixture of sodium amide 4y and tetrahydrofuran 1e While stirring at 10-20°C, 10 ml of ethyl chloroacetate is added dropwise.

After stirring for 6 hours while keeping the liquid temperature at 10 to 20°C, the mixture is further stirred at room temperature for 16 hours. Finally, after stirring at 40° C. for 1 hour, insoluble materials were removed by filtration, and the solvent was distilled off. Recrystallized with a mixed solvent of tetrahydrofuran and ethanol, melting point 183
Colorless needles (4) at ~185°C and melting point 141-14
Geometric isomers of colorless needles (B) at 3°C are obtained in a ratio of 2.4:1. Elemental analysis value C2OHl9O4N Calculated value: Cl7l. 2O: Hl5.68; Nl4. l
5 Experimental value (A): Cl7l. 43; Hl5.56; Nl
4.3l experimental value (B): Cl7l. 48; Hl5.32
;Nl4.22 infrared absorption spectrum νρ1. (KB
r) 1680 (C=O), 1710 (C=0) nuclear magnetic resonance spectra δ (CDCl3) 1.0 and 1.35
(3H1 each triplet, J=7Hz1CFI2C river, diisomers A and B) 1.90 (3H1 singlet, CH3) 3.5 and 3.7 (1H1 each singlet, '.CUl diisomers A and B) 4 .0 and 4.3 (2H1 quartet each, J=7Hz,,C?CH3, diisomers A and B)
4.9 (2111 singlet, N-CH2) 7.8-8.0 (8FI1 multiplet, aromatic proton) Example 22-Hydroxy 3-[4-(1-oxo2
-isoindolinyl)phenyl]-3-methyl-3- obtained in Example 1 of the method for producing ethyl-3-butenoic acid ester
Mixture of geometric isomers of [4-(1-oxo-2-isoindolinyl)phenyl]glycidic acid ethyl ester (2
．． Add 5 ml of p-xylene to 4:1) 1y, and heat and reflux the three powders while continuously introducing hydrochloric acid gas.

After the reaction was completed, the solvent was distilled off and the residue was collected. The product was purified by silica gel column chromatography using loloform as a developing solvent to obtain 850 mg of colorless granular crystals. This product was recrystallized with a mixed solvent of benzene and carbon tetrachloride, and the melting point was 1.
Colorless granular crystals with a temperature of 15-117°C were obtained. Elemental analysis value C2OH
l9NO4 Calculated value: Cl7l. 2O: Hl5.68; Nl4. l5
Experimental value: Cl7l. 4l; Hl5.62; Nl4. O8
Infrared absorption spectrum ν warm range (KBr) 1725 (C
=0), 1680 (C=0) nuclear magnetic resonance spectrum δ
(CDCI3) 1.10 (3H1 triple line, J=7Hz1
-CH29■) 3.60 (1H1 wide single wire, 0H) 4
．． 18 (2H1 quartet, J=7Hz, -CjCH3)4
．． 75 (2H1 single line, N-C) 5.10 (1H1 single line, '/CU-) 5.4015.47 (1H1 each single line,) C=C)) 7.3 ~ 8.00 (81 ( , multiplet, aromatic nuclear proton) Example 3 - Process for producing 2-hydroxy 3-[4-(1-oxo-2-isoindolinyl)phenyl]-3-butyric acid ethyl ester 3-methyl-3- obtained in Example 1 Geometric isomer of [4-(1-oxo-2-isoindolinyl)phenyl]glycidic acid ethyl ester (4)
Add 5 ml of p-xylene to 800 m9, and heat and reflux the three powders while continuously introducing hydrochloric acid gas.

After the reaction was completed, the solvent was distilled off, and the residue was purified by silica gel column chromatography using chloroform as a developing solvent to obtain 700 mg of colorless granular crystals. This product was recrystallized with a mixed solvent of benzene and carbon tetrachloride, and the melting point was 115.
Colorless granular crystals of ~11TC were obtained. This product showed no drop in melting point even when mixed with the specimen obtained in Example 2, and various instrumental analysis data were in complete agreement. Example 4 Process for producing 2-hydroxy 3-[4-(1-oxo-2-isoindolinyl)phenyl]-3-butenoic acid ethyl ester 3-methyl-3-[4- obtained in Example 1
Add 3TrL1 of p-xylene to 500 m9 of the geometric isomer (B) of (1-oxo2-isoindolinyl)phenylglycidate ethyl ester, and heat to reflux while continuously introducing hydrochloric acid gas.

After the reaction was completed, the solvent was distilled off, and the residue was purified by silica gel column chromatography using chloroform as a developing solvent to obtain colorless granular crystals of 380 m9. This product was recrystallized with a mixed solvent of benzene and carbon tetrachloride, and the melting point was 1.
Colorless granular crystals with a temperature of 15-117°C were obtained. This is Example 2
Even when it was mixed with the standard product obtained in , it did not show any drop in melting point, and various instrumental analysis data were in complete agreement. Example 52-acetoxy 3-[4-(1-oxo2-isoindolinyl)
Process for producing ethyl phenyl]-3-butenoic acid A mixture of geometric isomers (2.4 :1) Add 1f of glacial acetic acid to 1f and heat under reflux for 1 hour.

After the reaction was completed, the solvent was distilled off, and the residue was recrystallized from a mixed solvent of petroleum ether and ether to give a melting point of 109 to 111°C.
942 mg of colorless needle crystals were obtained. Elemental analysis value C22H2l
NC) =, calculated value: Cl69.64; Hl5.58; N
l3.69 Experimental value: Cl69.47; Hl5.77; N
l3.38 Infrared absorption spectrum ν Demand; 1 (KBr)
1725 (C=0, with shoulder), 1680 (C=0) nuclear magnetic resonance spectrum δ (CDCl3) 1.17 (3H1
Triple line, J = 7Hz1-CH2C equivalent) 2.15 (3H1
Single line, COCH3) 4.12 (21(, quartet, J=7
Hz, -C±CH3) 4.78 (2111 single wire, N-C
ll2) 5.45 and 5.58 (1H1 each single line, =C±) 5.80 (1H1 single line, )CH) 7.3 to 7.9 (measured, multiplet, aromatic proton) Example 62- 3-Methyl-3-[4-(1-
Geometric isomer (A) 1y of oxo-2-isoindolinyl)phenylglycidic acid ethyl ester is added with glacial acetic acid 1y and refluxed for 1 hour.

After the reaction was completed, the solvent was distilled off, and the residue was recrystallized from a mixed solvent of petroleum ether and ether to give a melting point of 109 to 111°C.
colorless needle crystals were obtained. This product showed no drop in melting point even when mixed with the specimen obtained in Example 5, and various instrumental analysis data completely matched. Example 7 Process for producing 2-acetoxy 3-[4-(1-oxo-2-isoindolinyl)phenyl]3-butenoic acid ester 3-methyl-3-[4-(1-oxo-2-isoindolinyl) obtained in Example 1 ) Add glacial acetic acid 1y to geometric isomer (B) 1f of phenyl]glycidic acid ethyl ester and heat under reflux for 1 hour.

After the reaction was completed, the solvent was distilled off, and the residue was recrystallized from a mixed solvent of petroleum ether and ether to give a melting point of 109 to 111°C.
colorless needle crystals were obtained. This product showed no drop in melting point even when mixed with the sample obtained in Example 5, and various instrumental analysis data completely matched. Example 8 Process for producing 3-methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl]pyruvic acid ethyl ester (1) 2-hydroxy 3-[4 obtained in Example 2
-(1-oxo2-isoindolinyl)phenyl]-
5 mt of p-xylene was added to 500 m9 of 3-butenoic acid ethyl ester, and heated under reflux for 2 hours while continuously introducing hydrochloric acid gas.

After the reaction was completed, the solvent was distilled off, and the residue was purified by silica gel column chromatography using chloroform as a developing solvent to obtain 420 mg of colorless needles. This product was recrystallized from carbon tetrachloride to obtain colorless needle crystals with a melting point of 122-123°C. Elemental analysis value C2OHl9O4N Calculated value: Cl7l. 2O; Hl5.68; Nl4. l5
Experimental value: Cl7O. 93; Hl5.65; Nl4. l5
Infrared absorption spectrum ν Tomi (KBr) 1675 (C
=O), 1720 (C=0) nuclear magnetic resonance spectrum δ
(CDCl3)1.26 (3H1 triplet, J=7Hz,
-CH2CHllU) 1.48 (3H1 doublet, J=6
Hz1〉CHC river) 4.27 (2H1 quartet, J=7H
z1-C river CH3) 4.56 (IHL quartet, J=6H
z,]C...CH3) 4.91 (2H1 single plate, N-Cl(
2) 7,2-8.0 (8H1 multiplet, aromatic proton)
(2) 2-acetoxy 3-[4- obtained in Example 5
(1-oxo2-isoindolinyl)phenyl]-3
-butenoic acid ethyl ester 6007?19 to glacial acetic acid 1y
2 while continuously introducing acid gas. Heat to reflux for a while.

After the reaction was completed, the solvent was distilled off, and the residue was purified by silica gel column chromatography using chloroform as a developing solvent to obtain 500 mg of colorless needles. This product was recrystallized from carbon tetrachloride to obtain colorless needle crystals with a melting point of 122-123°C. This product showed no drop in melting point even when mixed with the specimen obtained in Example 8 (1), and various instrumental analysis data completely matched. (3) 5 ml of p-xylene was added to 3-methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl]glycidic acid ethyl ester 1y obtained in Example 1, and while continuously introducing hydrochloric acid gas,
Heat to reflux for an hour.

After the reaction was completed, the solvent was distilled off, and the residue was purified by silica gel column chromatography using chloroform as a developing solvent to obtain 800 m9 of colorless needle-like crystals. This product was recrystallized from carbon tetrachloride to obtain colorless needle crystals with a melting point of 122-123°C. This product showed no drop in melting point even when mixed with the specimen obtained in Example 8 (1), and various instrumental analysis data completely matched. Reference Example 1 (1) 3-Methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl]pyruvic acid ethyl ester 5
10 ml of 10% aqueous sodium hydroxide solution and 20 ml of ethanol were added to 00 mg, and the mixture was stirred at 70° C. for 1 min.

Ethanol is distilled off, water is added, and the mixture is washed with chloroform. Insoluble materials in the aqueous layer are removed by filtration, and the aqueous layer is acidified with hydrochloric acid. Precipitated crystals were collected and 470mg of colorless granular crystals were obtained.
get. This product was recrystallized from ethyl acetate to obtain colorless granular crystals with a melting point of 202-205°C. Since this product is unknown in Document 2, the inventor has already applied for a patent (patent application filed in 1973).
Even when mixed with 3-methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl]pyruvic acid synthesized by another method of 1-122905), there was no drop in the melting point, and various instrumental analysis data were completely confirmed. matched. (2) 2-hydroxy 3-[4-(1-oxo-2-isoindolinyl)phenyl]-3-butenoic acid ethyl ester 400m
9 was added to 3 ml of a methanol solution containing sodium methylate prepared from 500 mg of sodium metal, and the mixture was heated under reflux, and then the solvent was distilled off.

Add water to make an aqueous solution, wash with chloroform, and acidify with hydrochloric acid. The precipitated crystals were harvested and recrystallized from ethyl acetate to obtain colorless needle crystals with a melting point of 202-205°C. This sample No. 41 showed no drop in melting point even when mixed with the specimen obtained in Reference Example 1 (1), and the various instrumental analysis data were in complete agreement. (3) Add 2 g of glacial acetic acid to a mixture of geometric isomers of 3-methyl-3-[4-(1-oxo-2-isoindolinyl) phenyl] glycidic acid ethyl ester (2.4:1) 1y, and continuously add hydrochloric acid gas. The mixture is heated under reflux for 24 hours while being introduced into the solution.

Finally, 0.5 ml of water was added, heated under reflux for 1 hour, and the solvent was distilled off. Add chloroform to the residue and extract with 10% aqueous sodium hydroxide solution. The extracted layer is washed with chloroform and then acidified with hydrochloric acid. Crystals that precipitate? The crystals were collected and recrystallized from ethyl acetate to obtain colorless granular crystals with a melting point of 202-205°C. This product showed no drop in melting point even when mixed with the specimen obtained in Reference Example 1 (1), and the various instrumental analysis data completely matched. Reference Example 2 Production method of 2-[4-(1-oxo-2-isoindolinyl)phenyl]propionic acid 3-methyl-3-[4-(
300 Tng of 1-oxo-2-isoindolinyl)phenylpyruvic acid is dissolved in 5 mt of 10% sodium hydroxide, and 1 ml of 30% hydrogen peroxide is added dropwise with stirring under ice cooling.

After standing overnight at room temperature, the aqueous layer was washed with chloroform, acidified with hydrochloric acid, and extracted with chloroform. The chloroform layer was dried (Na2SO4), the solvent was distilled off, and the residue was recrystallized from ethanol to give colorless crystals with a melting point of 213-214°C.
Get mg. Elemental analysis value Cl7Hl5O3N Calculated value: Cl72.58: Hl5.37; Nl4.98
Experimental value: Cl72. l3; Hl5.39; Nl4.94
Infrared absorption spectrum νζ (KBr) 1680 (C=
O) Nuclear magnetic resonance spectrum δ(CDCl3) 1.55(3
111 doublet, CH3) 4.90 (2H1 single line, N-CH2) 7.3-8.2 (8H1 multiplet, aromatic nuclear hydrogen) Mass spectrum m/E28l (M236 (reference peak)

Claims (1)

[Claims] 1 General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R
_1 represents a lower alkyl group) 3-methyl-3-[4-(1-oxo-2-isoindolinyl)phenyl]pyruvic acid esters.