Method for performing catalytic stereoselective separation on 2,3-diphenylpropionic acid enantiomer by adopting bio-enzyme

Abstract

The invention discloses a new chiral separation method of a 2,3-diphenylpropionic acid single enantiomer, i.e., a method for synthesizing the 2,3-diphenylpropionic acid single enantiomer by performing enzyme-catalyzed enantioselective hydrolysis on a 2,3-diphenylpropionic acid enantiomer. 2,3-diphenylpropionate enantiomer is hydrolyzed by utilizing high selectivity and high catalysis efficiency of Candida antarctica lipase A and a solubilization effect of cyclodextrin on a 2,3-diphenylpropionate enantiomer is utilized, so that hydrolysis reaction of the 2,3-diphenylpropionate enantiomer in a phosphate buffering solution is enhanced; the conversion rate of a substrate and the optical purity of a product are respectively up to 44.79 percent and 98.24 percent, and the stereoselectivity E is greater than 276. According to the method disclosed by the invention, the problems of low optical purity, low yield, environment pollution and the like in a general separation technique are overcome; by adopting the method, the high conversion rate and the high selectivity required by hydrolysis of the 2,3-diphenylpropionate enantiomer can be realized, so that the aims of no-toxicity and no-harmlessness of a separation chiral compound, mild reaction conditions, simpleness of equipment, convenience in operation, low cost and the like are fulfilled.

Description

technical field

[0001] The invention belongs to the preparation of chiral compounds by biological methods, and relates to the synthesis of single-configuration 2,3-diphenyl by using Candida antarctica lipase A stereoselectively to catalyze the hydrolysis of 2,3-diphenyl propionate enantiomer method for the enantiomers of propionic acid. Candida antarctica lipase A was used to hydrolyze racemic 2,3-diphenylpropionate of the structure shown in (1) to synthesize (2) in a single configuration.

[0002]

[0003] (1) (2)

Background technique

[0004] 2,3-diphenylpropionic acid (2,3-2-PPA), also known as β-phenylpropionic acid, is an intermediate in the synthesis of effective VLA-4 antagonistic activity body, and results in better oral bioavailability and metabolic stability due to its non-peptidyl structure. Small molecules that antagonize VLA-4 may be useful in the treatment of chronic inflammatory diseases such as asthma, multiple sclerosis, and the like due to their p...

Examples

Embodiment 1

[0021] Mix 40 mmol of methyl 2,3-diphenylpropionate enantiomer with 10 mg of several commercially available lipases (Candida rugosa lipase, Candida antarctica lipase A, Pseudomonas fluorescens lipase, Pseudomonas cepacia lipase, Aspergillus oryzae, Thermomyces lanuginosus lipase, Candida antarctica lipase B, Rhizomucor miehei, porcine pancreas lipase, and Rhizopus nigra) were added to 1 mL of sodium dihydrogen phosphate buffer solution with a pH of 6.5; heat the reaction in a 25 mL reaction tube at 400 rpm and 40°C for 16 h; and analyze the progress of the reaction and the optical purity of the product by high performance liquid chromatography. The results showed that when Candida antarctica lipase A was used as a catalyst, the substrate conversion rate was 6.30%, and the optical purity of the product was 94.18%.

Embodiment 2

[0023] Add 40 mmol of methyl 2,3-diphenylpropionate enantiomer and 20 mg of Candida antarctica lipase A to 1 mL of sodium dihydrogen phosphate buffer solution at pH 6.5; in a 25 mL reaction tube In 400 rpm, the reaction temperature is 60 ℃, heat the reaction for 4 h; and the reaction progress and the optical purity of the product are analyzed by high performance liquid chromatography; at this time, the conversion rate of the substrate is 20.35%, and the optical purity of the product is 95.70% .

Embodiment 3

[0025] Add 40 mmol of methyl 2,3-diphenylpropionate enantiomer and 10 mg of Candida antarctica lipase A to 1 mL of sodium dihydrogen phosphate buffer solution at pH 5.5; in a 25 mL reaction tube The reaction was heated at 400 rpm and 60°C for 24 hours; and the reaction progress and the optical purity of the product were analyzed by high performance liquid chromatography; at this time, the conversion rate of the substrate was 35.75%, and the optical purity of the product was 95.44%.

technical field

[0001] The invention belongs to the preparation of chiral compounds by biological methods, and relates to the synthesis of single-configuration 2,3-diphenyl by using Candida antarctica lipase A stereoselectively to catalyze the hydrolysis of 2,3-diphenyl propionate enantiomer method for the enantiomers of propionic acid. Candida antarctica lipase A was used to hydrolyze racemic 2,3-diphenylpropionate of the structure shown in (1) to synthesize (2) in a single configuration.

[0002]

[0003] (1) (2)

Background technique

[0004] 2,3-diphenylpropionic acid (2,3-2-PPA), also known as β-phenylpropionic acid, is an intermediate in the synthesis of effective VLA-4 antagonistic activity body, and results in better oral bioavailability and metabolic stability due to its non-peptidyl structure. Small molecules that antagonize VLA-4 may be useful in the treatment of chronic inflammatory diseases such as asthma, multiple sclerosis, and the like due to their p...

Examples

Embodiment 1

[0021] Mix 40 mmol of methyl 2,3-diphenylpropionate enantiomer with 10 mg of several commercially available lipases (Candida rugosa lipase, Candida antarctica lipase A, Pseudomonas fluorescens lipase, Pseudomonas cepacia lipase, Aspergillus oryzae, Thermomyces lanuginosus lipase, Candida antarctica lipase B, Rhizomucor miehei, porcine pancreas lipase, and Rhizopus nigra) were added to 1 mL of sodium dihydrogen phosphate buffer solution with a pH of 6.5; heat the reaction in a 25 mL reaction tube at 400 rpm and 40°C for 16 h; and analyze the progress of the reaction and the optical purity of the product by high performance liquid chromatography. The results showed that when Candida antarctica lipase A was used as a catalyst, the substrate conversion rate was 6.30%, and the optical purity of the product was 94.18%.

Embodiment 2

[0023] Add 40 mmol of methyl 2,3-diphenylpropionate enantiomer and 20 mg of Candida antarctica lipase A to 1 mL of sodium dihydrogen phosphate buffer solution at pH 6.5; in a 25 mL reaction tube In 400 rpm, the reaction temperature is 60 ℃, heat the reaction for 4 h; and the reaction progress and the optical purity of the product are analyzed by high performance liquid chromatography; at this time, the conversion rate of the substrate is 20.35%, and the optical purity of the product is 95.70% .

Embodiment 3

[0025] Add 40 mmol of methyl 2,3-diphenylpropionate enantiomer and 10 mg of Candida antarctica lipase A to 1 mL of sodium dihydrogen phosphate buffer solution at pH 5.5; in a 25 mL reaction tube The reaction was heated at 400 rpm and 60°C for 24 hours; and the reaction progress and the optical purity of the product were analyzed by high performance liquid chromatography; at this time, the conversion rate of the substrate was 35.75%, and the optical purity of the product was 95.44%.