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A kind of method for enzymatic synthesis of (s)-2-aminobutanamide

A technology for aminobutanamide and enzymatic synthesis, which is applied in the field of enzymatic synthesis of -2-aminobutanamide, can solve the problems of low yield and few synthesis reports, and achieves high ee value, high stereoselectivity, and high specificity. sexual effect

Active Publication Date: 2022-07-26
江苏八巨药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Such as utilizing nitrile hydratase to hydrate 2-aminobutyronitrile stereoselectively, thereby obtaining S-2-aminobutanamide, the yield and optical purity reach 43% and 89% respectively, but the synthesis report of existing enzymatic method is less, and Yield is also lower

Method used

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  • A kind of method for enzymatic synthesis of (s)-2-aminobutanamide
  • A kind of method for enzymatic synthesis of (s)-2-aminobutanamide
  • A kind of method for enzymatic synthesis of (s)-2-aminobutanamide

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] In a clean reactor, 2.1g (S)-2-aminobutyric acid methyl ester, 1.56g carbamide and 20mL isopropanol were added in sequence, and then 0.2g immobilized lipase was added, and methacrylic acid porous resin was used as Immobilize the material, then control the temperature to stir under the condition of 35 ° C, keep the water bath for 24 h, take samples for HPLC analysis, and the conversion rate is greater than 95% (chromatographic column: ODS-34.6nm×250nm, UV 200nm detection; mobile phase: phosphate buffer solution (PH=2.4), acetonitrile:methanol=80:10), after the reaction, the immobilized lipase was recovered by centrifugal filtration, and the filtrate was subjected to vacuum distillation The solvent was removed to obtain 1.62 g of the corresponding product (S)-2-aminobutanamide with a chiral purity content of 99.5%.

Embodiment 2

[0029] In a 250mL clean round-bottomed flask, 10.3g (S)-2-aminobutyric acid methyl ester, 8g ammonium carbamate and 100mL isopropanol were sequentially added to immobilize lipase 1g, and methacrylic acid porous resin was used as the immobilization material. Then control the temperature to stir at 35°C, keep the water bath for 24 hours, stop the reaction, take samples for HPLC analysis, the conversion rate is greater than 95%, centrifugal filtration to remove the immobilized lipase for recovery, and the collected filtrate is put into another clean In the reaction flask, the filtrate (reaction solution) was heated to 80°C for about 1 hour, and then 1 g of activated carbon was added for decolorization treatment for 15 minutes. After suction filtration, the collected filtrate was distilled under reduced pressure to remove the solvent, and methanol was used to distill the residue. The product was rinsed to remove impurities and dried to obtain 7.63 g of (S)-2-aminobutanamide as a wh...

Embodiment 3

[0031]In a 250mL clean round-bottomed flask, 10.3g (S)-2-aminobutyric acid methyl ester, 8g ammonium carbamate and 100mL tert-butanol were sequentially added to immobilize lipase 1g, and methacrylic acid porous resin was used as the immobilization material. The enzyme activity can reach ≥10000PLU / g, and the particle size of the immobilized lipase is 0.5mm, and then the temperature is controlled at 40°C for stirring, the reaction is kept in a water bath for 20h, the reaction is stopped, and sampling is carried out for HPLC analysis. The conversion rate is greater than 96%, centrifugal filtration to remove the immobilized lipase for recovery, the collected filtrate is put into another clean reaction bottle, the filtrate (reaction solution) is heated to 75°C for about 1h, and then 1.5g of activated carbon is added for decolorization for 15 minutes. , after suction filtration, the collected filtrate was distilled under reduced pressure to remove the solvent, and the distilled resid...

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Abstract

The invention relates to a method for enzymatically synthesizing (S)-2-aminobutanamide, and belongs to the technical field of pharmaceutical intermediate synthesis. In order to solve the existing problem of adopting chemical synthesis method, a method for enzymatic synthesis of (S)-2-aminobutanamide is provided, the method comprises in the presence of an amino donor, under the action of a catalytic amount of lipase, The substrate (S)-2-aminobutyric acid methyl ester is subjected to catalytic aminolysis to obtain the corresponding product (S)-2-aminobutyramide; the gene sequence of the lipase is shown in SEQ ID NO.1. The present invention has high stereoselectivity and specificity, forms a product of S-type chiral configuration, and has the effects of high chiral purity and high ee value of the product.

Description

technical field [0001] The invention relates to a method for synthesizing (S)-2-aminobutanamide by an enzymatic method, and belongs to the technical field of pharmaceutical intermediate synthesis. Background technique [0002] Levetiracetam (LEV, trade name Kaipulan) is a piracetam drug developed by Belgian UCB company, chemical name is (S)-а-ethyl-2-oxo-1- Pyrrolidineacetamide. Compared with traditional drugs for treating epilepsy, LEV has a new mechanism of action and can be used as an additive to treat various epilepsy in children, especially for complex localized seizures and myoclonic seizures. Compared with similar drugs, LEV has the following advantages: (1) There is a large difference between the effective dose and the toxic dose, the drug is safe, and the side effects are small; (2) The main metabolic pathway does not pass through the liver drug enzyme system, and there is no interaction with other antiepileptic drugs. ; (3) Rapid oral absorption, absolute bioavai...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P13/02
CPCC12P13/02
Inventor 杨晶晶谷绪顶程加铭陈恬张锦涛程祖福
Owner 江苏八巨药业有限公司
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