JPH0223554B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides intermediate products of the formula (wherein one of R ¹ and R ² is a hydrogen atom, the other is a hydroxyl group, or both may be taken together to form an oxo group, and R is an alkyl group) The present invention relates to a method for producing glycidic acid derivatives.

The present invention is based on the formula By reacting the compound with haloacetate in the presence of an alkali metal alcoholate catalyst, the formula A method for producing a glycidic acid derivative of the formula (wherein R is an alkyl group) is provided.

According to the invention, the process described above is carried out by reacting a compound of formula (1) and a haloacetic ester, such as chloroacetic acid methyl or ethyl ester, under the conditions of Dalzen condensation. The condensation is carried out under anhydrous conditions in an aprotic solvent at temperatures from 0 DEG C. to -40 DEG C. in an inert atmosphere and catalyzed by an alkali metal alcoholate such as sodium methoxide. On this occasion,
By adjusting the reaction temperature and the quantitative ratio of the base used and the haloacetic acid ester, it is possible to selectively cause the reaction to occur only on the carbonyl group on the methyl ketone side in the formula (1). In the above method, the obtained formula (In the formula, R represents the above-mentioned meaning) The glycidic acid derivative of the formula It may be converted into a compound represented by (wherein R represents the above-mentioned meaning).

In this case, an aqueous solution of sodium hypochlorite is used as the oxidizing agent, a halogenated hydrocarbon such as dichloroethane or dichloromethane is used in the organic layer, the reaction temperature is 10°C to 40°C, and tetra-n is used as the phase transfer catalyst. - Using a quaternary ammonium salt such as butylammonium hydrogen sulfate or benzyltrimethylammonium hydroxide.

The starting compound for the method of the present invention has the formula (wherein R ¹ and R ² are each an alkyl group or can be taken together to form a cyclic alkylene group) is reacted with benzaldehyde to form a compound of the formula (In the formula, R ¹ and R ² represent the above meanings.)
It can be produced by producing a secondary alcohol and then deacetalizing it (Japanese Patent Application No. 1983-
No. 50128), and compounds in which R ¹ and R ² together form an oxo group can be prepared by reacting the Grignard reagent type compound with cyanobenzene or benzoyl halide, followed by deacetalization.

The above-mentioned 2-(3-benzoylphenyl)-propionic acid, which is useful as a medicine, can be obtained according to the present invention by subjecting the compound of formula (2) obtained as described above to aromatic carbonization, preferably using benzene, toluene, etc. By adding a catalytic amount of methanesulfonic acid, p-toluenesulfonic acid, sulfuric acid, etc. in a hydrogen solvent and stirring at a temperature of 60 to 65°C for 60 minutes, the epoxy ring is cleaved to form the formula 2-hydroxy-3-(3-benzoylphenyl)-3-butenoic acid ester (wherein R represents the above meaning) is produced, and then this ester is
By treatment with an alkali metal alcoholate in an alcohol such as methanol, ethanol etc. at 60-80°C followed by hydrolysis, the formula A pyruvic acid derivative represented by the formula 2-(3-benzoylphenyl)-propionic acid.

Conventional methods for producing 2-(3-benzoylphenyl)-propionic acid include Japanese Patent Publication No. 45-19287;
The method described in Publications No. 47-7024 and No. 52-8301 is known, and one example is to react m-bromomethylbenzophenone with sodium cyanide to form an acetonitrile derivative, and then convert this into a metal alcoholate. React with diethyl carbonate in the presence of a catalyst to form the sodium salt of ethyl 2-cyano-(m-benzoylphenyl)acetate,
Furthermore, this sodium salt is reacted with methyl iodide to form ethyl 2-cyano-2-(m-benzoylphenyl)propionate, which is then hydrolyzed.
Examples include a method of producing (m-benzoylphenyl)propionitrile by decarboxylation and producing the desired 3-benzoylphenyl-propionic acid by alkaline hydrolysis (see Japanese Patent Publication No. 19287-1987). .

However, this method requires the use of toxic sodium cyanide, making it unsuitable for industrial production, and there are problems in that the starting material, m-substituted product, is relatively difficult to obtain.

As a result of repeated research to improve these drawbacks, the present inventors have completed the above-mentioned synthesis method via the new process of the present invention. These methods have been researched and developed with the aim of firstly using readily available raw materials and secondly as being a method advantageous for industrialization. Each step in this method has a high yield, does not require complicated operations, and is extremely suitable for industrialization.

The present invention will be further explained with reference to examples below.
The present invention is not limited to these. Reference Examples 1 to 3 are for explaining the method of producing 2-(3-benzoylphenyl)-propionic acid from the raw material compound of the present invention, and Reference Examples 4 to 6 are for explaining the method for producing 2-(3-benzoylphenyl)-propionic acid from the target compound of the present invention. be.

Example m-Phenylhydroxymethylacetophenone (8.3 g, 37 mmol) and methyl chloroacetate (8.0 g, 74 mmol) are dissolved in toluene (76 ml) and dimethylformamide (13 ml) is added thereto. Powdered sodium methoxide (4.0 g, 74 mmol) was added while keeping the temperature in the reaction tank at -20°C and being careful not to increase the temperature, and then
The mixture was stirred for 1 hour at a temperature below .degree. Next, add water (50
ml) and extracted with ethyl acetate (60 ml x 3 times). The ethyl acetate layer was washed with water, then with saturated brine, dried over magnesium sulfate, and concentrated to give crude 3-
Methyl-3-(m-phenylhydroxymethylphenyl)-methylglycidate was obtained.

νmax (cm ^-1 ): 3500 (m), 3060 (w), 3040 (w)
,
2980 (m), 2880 (w), 1755 (s), 1735 (sh),
1495 (m), 1440 (m), 1400 (m), 1380 (m),
1290 (m), 1210 (s), 1180 (m), 1110 (w),
1080 (m), 1025 (m), 870 (m), 795 (m), 760
(m), 700 (s) δ (60MHz, CDCl ₃ ): 1.68 (3H, br, s) 2.78
(1H, -OH), 3.44 and 3.75 (3H, 2 singlets), 3.50 and 3.67 (1H, 2 singlets), 5.31 (1H, s), 7.20 (9H, br, aromatic) n ¹⁹ _D 1.5307.

This compound was used in the next reaction without further purification.

The crude methyl 3-methyl-3-(m-phenylhydroxymethylphenyl)-glycidate (11.2
g, 37.5 mmol) in dichloroethane (100 ml)
Further, add 10% aqueous solution of sodium hypozinc oxide (100 ml), and add tetra-n as a catalyst.
-Butyl-ammonium hydrogen sulfate (2.0 g) was added and stirred at room temperature for 5 hours. Separate the organic layer;
After washing with water and saturated brine, it was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
9.0 g (82.2%) of methyl 3-methyl-3-(m-benzoylphenyl)glycidate was obtained.

n ¹⁹ _D 1.5718 νmax (cm ^-1 ): 1755 (s), 1735 (sh), 1660 (s)
,
1600 (m), 1580 (w) δ (60MHz, CDCl ₃ ): 1.75 (3H, d, J = 2Hz),
~3.55 (1H, 2 singlets), ~3.60~
(3H, 2 singlets, COO Me ), 7.50
(9H, m, aromatic) MS: m/e296 (M ⁺ ) Reference example 1 (m-phenylhydroxymethyl)acetophenone ethylene acetal (21.4 g, 79 mmol)
was dissolved in dichloroethane (210 ml), and 10% aqueous hypochlorous acid solution (210 ml) was added. Tetra-n-butylammonium hydrosulfite (1.5 g) was added as a phase transfer catalyst, and the mixture was stirred at room temperature for 6 hours. After separating the dichloroethane layer, the aqueous layer was extracted with methylene chloride (50 ml x 2). Combine the dichloroethane solutions, wash with water, wash with saturated saline,
After drying (MgSO ₄ ) and concentration, crude 3-benzoylacetophenone monoethylene acetal was obtained. This compound was not purified further and was dissolved in acetone (100ml).
Concentrated hydrochloric acid (10 ml) was added thereto, and the mixture was stirred at room temperature for 1 hour.

After adding saturated sodium bicarbonate solution (200ml) to the reaction mixture, extraction with isopropyl ether (60ml x 3 times)
did. The combined organic layers were washed with water, washed with saturated brine, dried (MgSO ₄ ), concentrated, and the residue was distilled to obtain 13.5 g (78.0%) of 3-benzoylacetophenone.

bp151~154゜(0.2mmHg). n ²⁰⁵ _D 1.6065.

νmax (cm ^-1 ): 3050, 2980, 2910, 1695, 1660 δ (60MHz, CDCl ₃ ): 2.50 (3H, s), 7.30 to 8.17
(9H, m) Reference Example 2 In the same manner as in Reference Example 1 above, a Grignard reagent was prepared from m-bromoacetophenone ethylene acetal (5 g, 21 mmol) and metallic magnesium (600 mg). In this, benzonitrile (2.12 g) dissolved in tetrahydrofuran (10 ml)
g, 20.6 mmol) was added thereto, and the mixture was further heated under reflux for 1 hour. After cooling, concentrated hydrochloric acid (10 ml) dissolved in water (40 ml) was added to the reaction solution, and the mixture was further stirred at 60°C for 1 hour. After cooling, the reaction solution was transferred to a separatory funnel and extracted with benzene (30 ml x 3). Wash the benzene layer with water, wash with saturated sodium bicarbonate solution, wash with saturated saline solution,
After drying (MgSO ₄ ) and concentration, the residue was distilled to give 3.5 g.
(76.0%) of 3-benzoylacetophenone was obtained. The instrumental analysis results were consistent with those of Reference Example 1 above.

Reference Example 3 In the same manner as in Reference Example 1, a Grignard reagent was prepared from m-bromoacetophenone ethylene acetal (5 g, 20.6 mmol) and metallic magnesium (600 mg). Benzoyl chloride (1.6 g) dissolved in tetrahydrofuran (10 ml) was gradually added to the mixture at -30°C, and after further stirring at -30°C for 3 hours, the temperature was gradually returned to room temperature. Then add 2NHCl (20ml) and acetone (20ml) into this
was added and stirred at room temperature for 30 minutes. reaction mixture 50
ml of water, the organic layer was separated and the aqueous layer was extracted with benzene. The benzene layer and the first separated organic layer were combined and washed with water, saturated sodium bicarbonate solution, saturated brine, dried (MgSO ₄ ), concentrated, and the residue was purified by silica gel column chromatography. 2.4 g (52.1%) of 3-benzoylacetophenone was obtained. The results of various instrumental analyzes were consistent with those of Reference Example 1 above.

Reference example 4 3-methyl-3-(m-benzoylphenyl)
Methyl glycidate (8.8 g, 29.7 mmol) was dissolved in anhydrous benzene (60 ml), methanesulfonic acid (0.2 ml) was added, and the mixture was stirred at 60-65°C for 1 hour.
After cooling, 450 mg of solid sodium carbonate was added and stirred at room temperature for 15 minutes. After filtration, the liquid was concentrated, and the residue was subjected to silica gel column chromatography [80 g of SiO ₂ , n-hexane/ethyl acetate (9:
7.0g (80%) of 2-hydroxy-
Methyl 3-(m-benzoylphenyl)-3-butenoate was obtained.

n ²⁴ _D 1.5714 νmax (cm ^-1 ): 3330 (m), 1735 (s), 1660 (s)
,
1600 (m), 1570 (w) δ (60MHz, CDCl ₃ ): 3.48 (1H, d, J = 6Hz),
3.67 (3H, s), 5.05 (1H, d, J=6Hz),
5.48 (1H, s), 5.51 (1H, s), 7.20-7.90
(9H, m, aromatic).

Reference Example 5 Methyl 2-hydroxy-3-(m-benzoylphenyl)-3-butenoate (7.0 g, 23.6 mmol) was dissolved in anhydrous benzene (50 ml), and 28% sodium methylate (6.9 ml) was added. 30 at 40-55℃
Stir for a minute. After cooling, acetic acid (3.3 ml) was added to neutralize. After diluting with water, extracting with ethyl acetate, washing the ethyl acetate layer with water, washing with saturated sodium bicarbonate solution, washing with saturated brine, drying (MgSO ₄ ), and concentrating.
The residue was purified by silica gel column chromatography [SiO ₂ 80 g, solvent: n-hexane/ethyl acetate (9:1)] to obtain 5.1 g (73.0%) of 3-methyl-3-(m-benzoylphenyl)- Methyl pyruvate was obtained.

n ²⁰ _D 1.5797 νmax (cm ^-1 ): 1730 (s), 1660 (s), 1600 (m)
,
1580 (w), 1280 (s), 1040 (m) δ (60MHz, CDCl ₃ ): 1.82 (3H, d, J = 6.5
Hz), 3.72 (3H, s), 4.58 (1H, q, J=7
Hz), 7.2 to 7.9 (9H, m, aromatic) Reference example 6 3-methyl-3-(m-benzoylphenyl)-
Methyl pyruvate (4.8 g, 16.2 mmol) was dissolved in methanol (32 ml) and isopropyl ether (32 ml) and further dissolved in water (48 ml).
KOH (1.6 g) was added in one portion and stirred at room temperature for 15 minutes. Transfer the reaction mixture to a separatory funnel, separate the organic layer, wash the aqueous layer with isopropyl ether, acidify with concentrated hydrochloric acid, and extract with ethyl acetate (50 ml x 3).
did. The ethyl acetate extract was washed with water, washed with saturated brine, dried (MgSO ₄ ), concentrated, and the crude 3
-Methyl-3-(m-benzoylphenyl)pyruvic acid (4.6 g) was obtained. This was used in the next reaction without further purification.

Crude 3-methyl-3-(m-benzoylphenyl)
Pyruvic acid (4.6 g) was dissolved in methanol (20 ml), 28% sodium alcoholate (6.5 ml) was added, and water (38 ml) was added. Dilute 30% H ₂ O ₂ (1.9 ml) with water (11.5 ml) under ice-water cooling and stirring.
It was dripped in minutes. After the dropwise addition, the mixture was stirred for 5 minutes, and the reaction solution was extracted with isopropyl ether. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (3x30ml). The extract was washed with water and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and 2-
3.24 g of crude crystals of (3-benzoylphenyl)-propionic acid were obtained. Isopropyl ether was recrystallized to obtain 2.4 g (58.3%) of the desired product.

mp91.6~92.3℃ νmax (cm ^-1 ): ~3400 (br), ~2800 (br), 1695
(s), 1660 (s), 1290 (s) δ (60MHz, CDCl ₃ ): 1.53 (3H, d, J = 7Hz),
3.80 (1H, q, J = 6.5Hz), 7.20-8.00 (9H, aromatic, m), 11.03 (1H, s) MS: m/e255 (M ⁺ +1), 210

Claims (1)

[Claims] 1 formula wherein a compound represented by the formula is reacted with a haloacetate in the presence of an alkali metal alcoholate catalyst. A method for producing a glycidic acid derivative represented by the formula (wherein R is an alkyl group). 2 formulas The formula obtained by reacting the compound represented by with haloacetic acid ester in the presence of an alkali metal alcoholate catalyst (wherein R is an alkyl group) is subjected to a two-phase oxidation reaction in the presence of a phase transfer catalyst. A method for producing a glycidic acid derivative represented by the formula (wherein R is an alkyl group).