Bio-catalytic deracemization preparation method of non-natural L-amino acid

A technology of biocatalysis and biocatalyst, which is applied in the field of preparation of chiral pharmaceutical intermediates by biocatalytic asymmetric oxidation, can solve the problems of sensitivity, easy decomposition, unreported non-natural L-amino acid method, etc., and achieve simple process and environmental friendliness , good versatility

Inactive Publication Date: 2011-09-07
CHONGQING UNIV OF POSTS & TELECOMM +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In these methods using NaBH 4 or NaCNBH 3 Combination with D-amino acid oxidase to deracemize DL-amino acids to unnatural L-amino acids has 3 disadvantages: 1) NaBH 4 Sensitive to water, easy to decompose under pH (acidic or neutral) co

Method used

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  • Bio-catalytic deracemization preparation method of non-natural L-amino acid

Examples

Experimental program
Comparison scheme
Effect test

Example Embodiment

[0021] Example 1: L-2-aminobutyric acid

[0022] 2.06g (0.02mol) DL-2-aminobutyric acid is dissolved in 50ml of ammonium formate (1.0mol / L, adjust the pH to 7.2 with ammonia water) solution, add 2.06g immobilized D-amino acid oxidase (58U / g), 1ml of catalase solution (50000U / ml), 1g of Pd-C catalyst (10%), oxygen is continuously introduced, and the reaction is stirred at 30°C for 16h, the optical rotation of the reaction solution no longer increases. Filter to remove immobilized D-amino acid oxidase and Pd-C, concentrate the filtrate to about 10ml, adjust the isoelectric point, freeze to precipitate white crystals, and dry to obtain 1.8g L-2-aminobutyric acid, the yield is 87%, ee>99 %.

Example Embodiment

[0023] Example 2: L-2-aminovaleric acid

[0024] 2.90g (0.025mol) DL-2-aminovaleric acid is dissolved in 50ml of ammonium formate (1.0mol / L, adjust the pH to 7.2 with ammonia) solution, add 2.90g immobilized D-amino acid oxidase (58U / g), 1.5ml of catalase solution (50000U / ml), 1g of Pd-C catalyst (10%), oxygen was continuously introduced, and the reaction was stirred at 30°C for 16h, and the optical rotation of the reaction solution no longer increased. The immobilized D-amino acid oxidase and Pd-C were removed by filtration, the filtrate was concentrated to about 10ml, the isoelectric point was adjusted, white crystals were precipitated by freezing, and dried to obtain 2.6g L-2-aminovaleric acid, the yield was 90%, ee>99 %.

Example Embodiment

[0025] Example 3: L-2-Aminoadipic acid

[0026] 3.22g (0.02mol) DL-2-aminoadipate was dissolved in 50ml ammonium formate (1.0mol / L, adjust the pH to 7.2 with ammonia) solution, and 3.22g immobilized D-amino acid oxidase (58U / g) was added , 1ml catalase solution (50000U / ml), 1g Pd-C catalyst (10%), oxygen is continuously introduced, and the reaction is stirred at 30°C for 20h, the optical rotation of the reaction solution no longer increases. The immobilized D-amino acid oxidase and Pd-C were removed by filtration, the filtrate was concentrated to about 10ml, the isoelectric point was adjusted, white crystals were precipitated by freezing, and dried to obtain 2.8g L-2-aminoadipate, the yield was 87%, ee> 99%.

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Abstract

The invention provides a bio-catalytic deracemization preparation method of non-natural L-amino acid. In the method, immobilized D-amino acid oxidase with high enantioselectivity is used as a biocatalyst, D-enantiomer oxide in DL-amino acid catalytically and chemically synthesized in the presence of molecular oxygen is used as imino acid, and the L-amino acid is reserved. Pd-C is used as a catalyst, HCOONH4 is used as a hydrogen donor, and the formed imino acid is converted into DL-amino acid in situ by chemical catalytic hydrogen transfer reaction, so that continuous conversion from the DL-amino acid to the L-amino acid is realized. The hydrogen peroxide generated in the reaction process is efficiently decomposed into water and molecular oxygen in situ by using catalase. The method is used for preparing chiral medicament intermediates such as L-2-aminobutyric acid, L-2-aminovaleric acid, L-2-aminoadipic acid, L-tert-leucine, L-cyclohexyl glycine, L-o-chlorobenzene glycine, L-p-fluorobenzene glycine, L-2-amino-4-phenyl butyric acid, L-piperidine-2-carboxylic acid and L-piperazine-2-carboxylic acid; the yield is 75 to 95 percent; and the ee is more than 99 percent.

Description

technical field [0001] The invention relates to a biocatalytic deracemization preparation method of unnatural L-amino acid, and belongs to the technical field of biocatalytic asymmetric oxidation preparation of chiral pharmaceutical intermediates. Background technique [0002] Unnatural L-amino acids are non-protein amino acids that do not occur in nature. Unnatural L-amino acids and their derivatives such as protected unnatural L-amino acids and unnatural L-amino alcohols are key intermediates of chiral drugs and are widely used in the field of medicine. For example, L-2-aminobutyric acid is the intermediate of antiepileptic drug levetiracetam, L-2-aminovaleric acid is the intermediate of antihypertensive drug perindopril, and L-2-aminoadipic acid is the intermediate of gluten Aminoamide synthetase inhibitor intermediate, L-tert-leucine is an intermediate of antiviral, anti-tumor and anti-inflammatory drugs, L-cyclohexylglycine is an intermediate of cyclooxygenase (COX-2) ...

Claims

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Application Information

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IPC IPC(8): C12P41/00C12P13/04
Inventor 夏仕文方国兰徐红梅葛超郭丽娟李阳杨智慧
Owner CHONGQING UNIV OF POSTS & TELECOMM
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