Method for preparing (S)- or (R)-2-aminobutanamide through transaminase biocatalysis

A technology of aminobutanamide and biocatalysis, which is applied in the direction of fermentation, etc., can solve the problems of large environmental pollution, low S-2-aminobutanamide ee value, high cost, etc., and achieve low product yield and high reaction selectivity , the effect of reducing production costs

Active Publication Date: 2017-06-13
HAINAN UNIVERSITY
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0003] As can be seen from the above-mentioned prior art, at present most of the synthetic methods of S-2-aminobutyramide are to synthesize mixed-rotation 2-aminobutanamide, and then adopt chemical or biological methods to split. The steps are complex, the environment is polluted, the cost is relatively high, the resolution yield is low, and the ee value of the obtained S-2-aminobutanamide is low, below 95%, it is difficult to meet the preparation requirements of the drug ee value

Method used

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  • Method for preparing (S)- or (R)-2-aminobutanamide through transaminase biocatalysis
  • Method for preparing (S)- or (R)-2-aminobutanamide through transaminase biocatalysis
  • Method for preparing (S)- or (R)-2-aminobutanamide through transaminase biocatalysis

Examples

Experimental program
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Effect test

Embodiment 1

[0046] In a 25ml three-neck round bottom flask, add 1.5ml of water, then add 0.2ml of DMSO, then measure 0.5mmol of methyl ethyl ketone into the round bottom flask, stir well, then add 2mmol of ammonium chloride, 2mmol of NaHCO 3 , and then added 0.01 mmol of tetrabutylammonium iodide, condensed and refluxed at 50°C for half an hour. Then, a hydrogen peroxide solution (containing 2.5 mmol of H 2 o 2 , 1ml of water), the dropwise addition was completed in 2 hours. After dripping, reflux reaction was carried out at 50°C for 16 hours, during which time the progress of the reaction was monitored by TLC silica gel plate or high performance liquid chromatography. After the reaction was completed, 20 mL of ethyl acetate was added for extraction, and then the ethyl acetate was removed under reduced pressure to obtain a yellow solid. The obtained yellow solid was purified, and then its structure was identified, and its NMR data are as follows:

[0047] 1 H NMR (400 MHz, CDCl 3 )...

Embodiment 2

[0050] In a 25ml three-neck round bottom flask, add 1.5ml of water, then add 0.2ml of DMSO, then measure 0.5mmol of methyl ethyl ketone into the round bottom flask, stir well, then add 2mmol of ammonium chloride, 2mmol of NaHCO 3 , and then added 0.01 mmol of tetrabutylammonium iodide, condensed and refluxed at 70°C for half an hour. Then, a hydrogen peroxide solution (containing 2.5 mmol of H 2 o 2 , 1ml of water), the dropwise addition was completed in 2 hours. After dripping, the reaction was condensed and refluxed at 70° C. for 16 hours, during which time the progress of the reaction was monitored by TLC silica gel plate or high performance liquid chromatography. After the reaction was completed, 20 mL of ethyl acetate was added for extraction, and then the ethyl acetate was removed under reduced pressure to obtain a yellow solid, which was 2-carbonylbutyramide. In terms of butanone, the yield of 2-carbonylbutyramide is 80%, and the purity of the product tested by HPLC...

Embodiment 3

[0052] In a 25ml three-neck round bottom flask, add 1.5ml of water, then add 0.2ml of DMSO, then measure 0.5mmol of methyl ethyl ketone into the round bottom flask, stir well, then add 2mmol of ammonium chloride, 2mmol of K 2 CO 3 , and then added 0.01 mmol of CuI, condensed and refluxed at 70°C for half an hour. Then, a hydrogen peroxide solution (containing 2.5 mmol of H 2 o 2 , 1ml of water), the dropwise addition was completed in 2 hours. After dripping, it was condensed and refluxed at 70°C for 14 hours. During the period, the progress of the reaction was monitored by TLC silica gel plate or high performance liquid chromatography. After the reaction was completed, 20 mL of ethyl acetate was added for extraction, and then the ethyl acetate was removed under reduced pressure to obtain a yellow solid, which was 2-carbonylbutyramide. In terms of butanone, the yield of 2-carbonylbutyramide is 73%, and the purity of the product tested by HPLC is 97%.

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Abstract

The invention discloses a method for preparing (S)- or (R)-2-aminobutanamide through transaminase biocatalysis. The method comprises the following steps: taking transaminase as a biocatalyst and catalyzing carbonyl on 2-carbonylbutylamide into amino in the presence of an amino donor, thereby obtaining the (S)- or (R)-2-aminobutanamide. The used transaminase refers to any one of Cv-omega-TA WT, Cv-omega-TA W60C, Vf-omega-TA, ATA-117 and ATA S9. According to the method disclosed by the invention, the (S)- or (R)-2-aminobutanamide is prepared by taking the 2-carbonylbutylamide as a raw material through a biocatalysis method. The transaminase is used for catalysis of carbonyl amide substances first, the transaminase with high efficiency and high selectivity can be successfully screened, the reaction selectivity is high, the product yield is 85% or higher, the ee value of the product is more than 99.5% or higher, and the problems in the prior art that the product yield is low and the ee value is not high are completely solved.

Description

technical field [0001] The present invention relates to a synthesis method of (S)- or (R)-2-aminobutyramide, in particular to a green synthesis method for preparing (S)- or (R)-2-aminobutanamide by transaminase biocatalysis . Background technique [0002] Levetiracetam is a new type of antiepileptic drug with high efficiency and less toxic side effects. Compared with most antiepileptic drugs, it shows stronger antiepileptic properties and can effectively control epileptic seizures, which is of great development value . S-2-aminobutanamide ((S)-2-aminobutanamide) is a key chiral intermediate for the synthesis of levetiracetam. There have been many reports on the synthesis and preparation of S-2-aminobutanamide. For example, Zheng Renchao et al. published an article titled "A Preliminary Study on the Preparation of Levetiracetam Chiral Intermediate (S)-2-Aminobutyramide by Amidase Resolution" (Fermentation Technology Communication, FAJIAO KEJITONGXUN2015, 44(3) ), the artic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P13/02
CPCC12P13/02
Inventor 王博王丹张宽陈祎平张德拉
Owner HAINAN UNIVERSITY
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