SU376940A1 - ALL-UNION I - Google Patents

Description

METHOD OF OBTAINING DERIVATIVE PENYLAXUS DERIVATIVES

one

The invention relates to a process for the preparation of phenylacetic acid derivatives of the general formula CH-C, which are not described in the literature (where Y is oxygen or sulfur; RI is linear or branched Ci-C4-alkyl; Hal is chlorine, bromine or fluorine; and esters of these Acids or their salts possessing valuable pharmacological properties. There is a known method for producing halo-derivatives of phenylacetic acid by reacting a halogenated benzyl halide with an alkali metal cyanide and subsequent hydrolysis of the resulting nitrile to halogen-substituted phenyl. hydrochloric acid. A preferred method for preparing compounds of formula I is that an alkyl ester of a compound of general formula

acids

Hal

7 CH -cooh 10 15 25 where X and Ia1 are as defined above, are treated with alkyl oxalate in anhydrous medium in the presence of an alkaline base, for example, an alcoholic, such as sodium t / e-amylate or potassium hydrate, or amide metal, the resulting condensation product is treated with haloalkyl R / Y, where Ri is of the above meaning, Y is chlorine, bromine or iodine, the compound of the general formula is formed. In R, C-C02 Alft 0 C-C02L1K where X, RI and Hal have the above values, Alk -alkyl, treated with an alkaline base, for example, an alcoholate or an amide m metal, in an anhydrous medium, followed by

saponification of the obtained alkyl ester of the general formula

where X, Hal, and Ri are as defined above, by known means, in the presence of caustic soda or caustic potash in an aqueous-alcoholic medium, and the corresponding target product is isolated as an acid, salt, ester, racemate, or optically active antipode.

Example. a-Methyl-4- (4-tetrahydropyranyl) -3-chlorophenylacetic acid.

Kaliev salt of methyl ester (4 tetrahydropyranyl) -3- - phenylsilane-acetic acid.

3.09 g of methyl 4- (4-tetrahydropyranyl) -3-chlorophenylacetic acid, 2.3 g of t; Potassium 7-butylate, 2.3 g of methyl oxalate and 30 ml of benzene are heated for 4 hours under reflux, cooled evaporated to dryness in vacuo, the residue is treated with 50 ml of anhydrous ether for 10 minutes at room temperature, filtered under vacuum, the precipitate is washed with anhydrous ether and the residue. 5.07 g of the potassium salt of methyl 4 (4-tetrahydropyranyl) -3-chloro-3-phenylsilane-acetic acid, which is a light-brown substance, is soluble in water and insoluble in ether and chloroform.

The starting 4- (4-tetrahydropyranyl) -3-chlorophenylacetic acid methyl ester is obtained from diazomethane and 4- (4-tetrahydropyranyl) -3-chlorophenylacetic acid in 99% yield as an amorphous product. The chlorine content is 13.3% (theoretically 13.19).

2-oxo-4- (4-tetrahydropyranyl) -3-chloro-3-phenyl-3-methyl succinic acid methyl ester.

Transfer 5 g of potassium salt of methyl 4- (4-tetrahydropyranyl) -3-chloro 3-phenylsilane-acetic acid with ml of methyl iodide in 100 ml of dimethylformamide, incubated for 4 hours at room temperature, heated for 3 hours at 95 ° C, evaporated to dryness in vacuum The residue is stirred with 200 ml of methylene chloride for 10 minutes at room temperature, filtered, the filtrate is washed with water, dissolved over sodium sulfate and evaporated to dryness in vacuo. 3.9 g (92%) of crude product is obtained, which is purified by chromatography on silica gel and eluted with ether-petroleum ether (50-50). 1.065 g of methyl 2-oxa-4- (4-tetrahydropyranyl) -3 chloro-3-phenyl-3-methyl succinic acid are obtained in the form of a solid, light brown product, soluble in chloroform, methylene chloride and isopropyl ether and insoluble in water. T. pl. - 50 ° С.

A-methyl-4- (4-tetrahydropyranyl) -3-chlorophenylacetic acid methyl ester.

870 mg of methyl 2-oxo-4- (4-tetrahydropyranyl) -3 - chlorine -3-phenyl-3 - methyl succinic acid in 17 ml of dimethylformamide,

treated with 1.6 ml of sodium methoxide solution (prepared from 50 ml of methyl alcohol and 1.71 g of sodium) for 2 hours at 100 ° C. After cooling, evaporated to dryness in vacuo, the residue is treated with a solution of 1.2 ml of 2N.

hydrochloric acid in 30 ml of water, extracted with methylene chloride, the organic layers are washed with water, dissolved over sodium sulfate and evaporated to dryness in vacuo. The residue is chromatographed on silica gel, eluting with ether-petroleum ether (75-25), to obtain 200 mg of a-methyl-4 (4-tetrahydropyranyl) -3-chlorophenylacetic acid methyl ester as light brown crystals, soluble in chloroform, methanol , live

and methylene chloride and water insoluble. T .. pl. 78 ° C. Yield 30%.

Calculated,%: C 63.71; H 6.77; C1 12.54.

C, 5P19S103 (282.78).

Paideno,%: C 63.5; H 6.6; C1 12.8.

In the IR spectrum, taken up in chloroform, the absorption bands characteristic of the aromatic compound, simple and complex ether are present. a-Methyl - 4- (4-tetrahydropyranyl) -3-chlorophenylacetic acid.

A mixture of 145 mg of a-methyl-4- (4-tetrahydropyranyl) -3-chlorophenylacetic acid methyl ester, 1.5 ml of ethanol and 0.15 ml of potassium hydroxide (48 ° Be) is distilled under reflux for 1 hour, and the ethanol is distilled off in a vacuum. The residue is treated with 2 ml of water, the resulting solution is acidified to RP 1 with 0.15 ml of hydrochloric acid and the precipitate is extracted with methylene chloride. The organic layers are washed with water until the neutral reaction of wash water, it is dissolved over sodium sulfate and evaporated to dryness in a vacuum. To 130 mg of the obtained product is added 0.5 ml of isopropyl ether, filtered under

Under vacuum, rinse with isonpropyl ether and dry under vacuum. 44 mg of a-methyl-4- (4-tetrahydropyranyl) -3-chlorophenylacetic acid are obtained in the form of colorless crystals, soluble in methylene chloride and insoluble in water. T. pl. 121 ° C.

Calculated,%: C 62.57; P 6.37; C1 13.19. Synopsis (268.74).

Found,%: C 62.5; H 6.2; C1 13.1; 13.2. In the IR spectrum, taken up in chloroform, there are absorption bands characteristic of ether and aromatic compounds.

Subject invention

The method of obtaining derivatives of phenylacetic acid of the general formula

Rf

,,

sk-soon

X - oxygen or sulfur;

RI-linear or branched

Ci-C4 alkyl;

Hal is chlorine, bromine or fluorine, as well as esters of these acids or their salts, characterized in that the alkyl ester of a compound of the general formula

6

Hal SNg-COOH

X

where X and Hal are as defined above, are treated with oxalic acid alkyl ester in the presence of an alkaline base,

For example, an alcoholate, in an anhydrous medium, the resulting condensation product is successively treated with haloalkyl of the general formula RiY, where RI has the above meaning, Y is chlorine, bromine or iodine, an alkaline base, such as an alcoholate or metal amide, in an anhydrous medium, washed and isolating the desired product as an acid, salt, or ester, in addition to racemate or optically active antipode in a known manner.