SU545250A3 - Method for preparing substituted biphenylyl butyric acid or its esters or its salts - Google Patents

Description

compounds. D.H. of their preparation, acetoacetic ester is reacted by known methods with an alkali metal alcoholate solution. Acetoacetic acid ethyl ester is used in the form of a sodium derivative. Compounds of general formula I, which are obtained from non-optically active intermediates, are obtained in the form of rapemes, c, which can be easily split in 110s ;;) sdst;} m (Lpc. Of crystallization of IL with (, leu from optically active). mi base1: au 15: mp on; uu optically active, ex, e.) 1l of compass. This cleavage of the quinine racemate was especially useful. The starting compounds of general formula II can be easily obtained by reducing the ketones of the general formula IV-cn complex metal hydrides, in particular with borohydride n the three oxo compounds obtained in a known manner, for example by treating a halo-substituted hydrogen hydrogen with β-1 acids, a phosphorus halide with a thionyl halide, are converted into compounds 5; with the general formula I. Ketov obnay IV of formula IV can be easily obtained by corresponding to the substituted blothenyl by temp 15modG: STB: 1 with apetylchlorpdum is present without an anhydride (; d: 1st chloro |) nd aluminum. Example 1. A. Ethyl ester of (2-fluoro-4-bffeppleyl) -1-ethyl-acetosuxenoic acid. To a solution of 2.53 g of sodium in 70 ml of absolute ethanol was added dropwise, transferring 14.3 g (0.11 mol) of ethyl ester of acetosuccinic acid, stirring was continued for another 30 minutes, then 27.9 g (0.1 mol) were added dropwise 1- (2-fluoro-4-biphenyl) -1-bromoethaca (with product) and then heated for 30 mpn under reflux. After cooling, the resulting sodium hydroxide is filtered off with suction and the solvent is distilled off under a filtrate under vacuum. The remaining residue is mixed with 250 ml of water and absorbed in ether. The ether solution is then washed with water, dissolved and freed from the solvent, a liquid residue being obtained, which is distilled off under vacuum. The above is obtained as a colorless liquid. T. Kip. 155 ° C (0.2 mmHg); yield 24.5 g (75% of theory). B. Ethyl ester of 3- (2-fluoro-4-bifepilit) oil acid. To a solution of 75 mg of sodium B4 g (0.088 mol) of absolute ethanol, 11.8 g (0.036 mol) of ethyl ester (2-fluoro4-biffeptil) -1-ltp-acetosuxenoic acid are fed and the starting reaction mixture is heated so that the mixture is ethanol-acetic ester goes dropwise through a 10 cm Vigre column. After about 2i / 2 hours, 4 g of absolute ethanol is added again. The reaction ends after 5 hours. After this time, the excess ethanol is distilled off, the remaining residue is mixed with 150 ml of 5% hydrochloric acid and taken up in ether. The ether solution extracted by shaking with water and the solvent is recovered. The remaining residue is distilled under vacuum and 9 g (87% of theory) of ethyl 3- (2-fluoro-4-bifepylyl) - butyric acid ethyl acetate are obtained with a boil. 139 - (0.15 mm Hg. Art.), So pl. 32-33 0. B. 3- (2-fluoro-4-biphenyl) o-acid. 9 g (0.0314 mol) of 3- (2-fluoro-4-biphephenyl) butyric acid ethyl ester is dissolved in 150 ml of methanol, a 30% potassium hydroxide solution is added until a strongly alkaline reaction is obtained and the reaction mixture is heated during 30 min with reverse refrigeration. The solvent is then distilled off, the solid residue is dissolved in water and acidified with dilute hydrochloric acid. The acid that is separated out is filtered off with suction, washed with water, dried and recrystallized from cyclohexane. 3- (2-fluoro-4 - bifepilil) ma l 1k; acid plasites at JUS-101 ° 0, its cyclohexylamine salt at 165 ° C. The yield is 6.9 g (85% of theory). PRI mme R 2. A. Ethyl ester of (2-fluoro-4-bifepilit) -1-ethyl-acetosuccinic acid. 42.6 g (0.28 mol) of acetoacetic acid ethyl ester sodium salt are dissolved in 200 ml of absolute ethanol, then 59.5 g (0.254 mol) of 1- (2-fluoro-4-bnophenylpl) -1-chloro is added dropwise. ethane (crude product) and then heated for 30 minutes under reflux. After cooling, the sodium chloride obtained is settled and the solvent is distilled off from the filtrate under vacuum. The remaining residue is shifted with 300 ml of water and then taken up in ether. The ethereal solution is diluted with water, dissolved and the solvent is removed from it, and a liquid residue remains, which is distilled under vacuum. Receive the above ester as a continuous-flow liquid with a t. Cue. 165 - 67 ° C / 0.2 l: m. Hg Art. with the release of 61.5 g (73.8% of theory). B. Ethyl ester of 3- (2-fluoro-4-bifepilit) oil acid. To a solution of 450 mg of sodium ethoxide in 8 g (0.175 mol) of absolute ethanol, 16.4 g (0.05 mol) of (2-fluor-4-biphenylyl) - - -ethyl acetoxuspe acid ethyl ester are fed and the initial reaction mixture is heated, that the resulting mixture of ethanol - acetic acid passes dropwise through a Vigre column measuring 10 cm. After about 2/2 hours, 8 g of absolute ethanol is added again. The reaction ends after 5 hours. After this time, excess ethanol is distilled off, the remaining residue is mixed.

with 200 ml of 5% hydrochloric acid and absorbed in zfira. The solvent was distilled off from the ethereal solution extracted by shaking with water. The remaining residue consists of 3- (2-fluoro-4-biphenylyl) -based ethyl ester.

B. 3- (2-fluoro-4-biphenylyl) -buttonic acid. The ethyl ester of 3- (2-fluoro-4-biphenylyl) butyric acid obtained in p. B is dissolved in 300 ml of methanol, a 30% potassium hydroxide solution is added to the strong alkaline reaction and the reaction mixture is heated for 30 min. reflux condenser. The solvent is then distilled off, the remaining solid residue is dissolved in water and acidified with dilute hydrochloric acid. The separated acid is filtered off with suction, washed with water and dissolved in ethyl acetate. The solution of ethyl acetate is dried.

By adding cyclohexylamine to this solution, a salt of cyclohexylamine 3- (2-fluoro-4-biphenylyl) -based acid is precipitated before alkaline, which melts at 164-165 ° C. Yield 14 g (78.3% of theory).

Example 3

A. (2-Chloro-4-biphenylyl) -1-ethyl-acetoacetic acid ethyl ester. To a solution of 2.53 g of sodium in 70 ml of absolute ethanol was added dropwise, stirring, 14.3 g (0.11 mol) of ethyl acetoacetate, and the stirring was continued for another 30 minutes, then dropwise from 25.1 g (0.1 mol) 1- (2-chloro-4-biphenylyl) -1-chloro-ethane (crude product) and then heated for 30 minutes under reflux. After cooling, the resulting sodium chloride is sucked off and the solvent is distilled off from the filtrate under vacuum. The remaining residue is mixed with 250 ml of water and then taken up in ether. The ether solution is then washed with water, the solvent is extracted and the solvent is extracted, and a liquid residue remains, which is distilled off in vacuo.

The above ester is obtained as a colorless liquid with m.p. 166-168 ° C (0.1 mm Hg. Art.); yield 24.3 g (70.5% of theory).

B. 3- (2-chloro-4-biphenylyl) -based acid. To a solution of 140 mg of sodium in 8 g (0.177 mol) of absolute ethanol, 17.3 g (0.05 mol) of ethyl ester (2-chloro-4-biphenylyl) -1 - ethyl acetoacetic acid are fed and the initial reaction mixture is heated so that the resulting mixture of ethanol-acetic ether goes dropwise through a Vigre column measuring 10 cm. After about 2V2 hours, 8 g of absolute ethanol is added again. The reaction ends after 5 hours. Then 250 ml of methanol are added and the solution is shifted with a 30% potassium hydroxide solution to a strongly alkaline reaction. It is then heated under reflux for 30 minutes and the solvent is distilled off. The rest is shifted

with 250 ml of water and shake with ether. The aqueous alkaline solution is acidified with dilute hydrochloric acid and extracted with ether. The ether solution is washed with water, dried and the solvent is removed. The remaining solid precipitate is dissolved in 200 ml of acetone-acetic ether (1: 1) and before the onset of alkali; cyclohexylamine is added to the reaction. The precipitate formed is filtered off with suction and washed with ethyl acetate. The cyclohexylamine salt melts irie 180-182 ° C. Yield 15 g (80% of theory).

The 3- (2-chloro-4-biphenylyl) -buttoned acid obtained from it melts after recrystallization from cyclohexane and 128-.

Example 4

A. (4-Fluoro-4-biphenylyl) -1-ethyl-acetoacetic acid ethyl ester. To a solution of 22.8 g (0.15 mol) of sodium acetoacetic acid ethyl ester in 70 ml of absolute ethanol was added dropwise, while stirring, 23.4 g (0.1 mol) of 1- (4-fluoro-4-biphenylyl) bchloroban (crude product) in 60 ml of benzene and heated for 30 minutes on a reflux condenser. After cooling, the resulting sodium chloride is filtered off with suction and the solvent is distilled off under a filtrate under vacuum. The remaining residue is mixed with 250 ml of water and taken up in ether. The ether solution is then washed with water, dried and the solvent is removed, and 28 g (85.5% of theory) of the crude product are obtained.

The colorless ethyl ester (4-fluoro-4biphenylyl) -1-ethyl-acetoacetic acid boils at 172С and a pressure of 0.15 mm Hg. Art.

B. 3- (4-fluoro-4-biphenylyl) -button acid. The process is carried out analogously to Example 3B, but using 16.4 g (0.05 mol) of (4-fluoro-4-biphenylyl) 1-ethyl acetoacetic acid ethyl ester. Obtain 14 g (78.5% of theory) of cyclohexylamine salt with m. Pl. 182-184С. The 3- (4-fluoro-4-biphenylyl) - butyric acid liberated from it melts after recrystallization from ethanol at 141-HZC.

In a similar manner, a 3- (3-chloro-4-biphenylyl) -based acid compound is prepared; T. Il. .

Example 5. Separation of racemic 3- (2-fluoro-4-biphenylyl) -butyric acid into optically active constituents.

Claims (2)

77.5 g (0.3 mol) of 3- (2-fluoro-4-biphenylyl) butyric acid are dissolved in 1.5 liters of ethanol and mixed with a solution of 97.2 g (0.3 mol) of quinine (to cleave the Merck racemate) in 1.5 liters of ethanol. A colorless precipitate A is obtained, which is filtered off with suction, and the filtrate B. The precipitate A is recrystallized 15 times from ethanol (30 l in total), and a pravovshr is obtained, which is 3- (2-fluoro-4biphenylyl) butyric acid with a m.p. 87-88 ° C (from cyclohexane); a - | -34.5 °; yield 5.5 g. P1z filtrate B removes the solvent and absorbs the residue in hot methanol (500 ml). Upon cooling, the osal is precipitated, which is sucked off and discarded. The filtrate is treated 4 more times in the same manner with methanol. The residue remaining upon evaporation of methanol is dissolved in 500 ml of warm acetic ether and a precipitate is obtained on standing, which is filtered off with suction and recrystallized from 500 ml of ethyl acetate. A levorotating 3- (2-fluoro-4biphenylyl) -based acid is obtained with a melting point. 85-87 ° C (from cyclohexane); -33.5 °; Yield Formula of the Invention A method for producing a substituted biphenylyl butyric acid acid or its esters of the general formula L N cn-ns where R 1 is a halogen atom and B is a hydroxy group or an alkoxy group with 1 to 4 carbon atoms, or its salts, about 1 and 4 h P1 and the fact that the compound of the general formula where RI has the above meaning and Hal is a halogen atom is reacted with an alkali metal salt of acetoacetic acid ester in a solvent followed by cleavage of the obtained p-ketocarboxylic acid ester of the general formula SI, COCH, 1 1 CH - SI When heated in the presence of catalytic amounts of alcoholate in an anhydrous alcohol, and isolating the product pelevogo in free form or in the form ranematov or as optically active components or as a salt. 2. A method according to claim 1, characterized in that the solvent used is an alcohol that is esterified with apetoacetic acid. Sources of information, attributed to the examination: 1. "Preparative Organic Chemistry, M.-L., 1964, p. 632-635 (prototype). Priority signs: 17.08.72: halogen RI-atom; B-hydroxy or alkoxy group with 1-4 carbon atoms. 01/05/73: A process for the preparation of substitution biphenylyl butyric acid of general formula I or its esters or its salts.