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A kind of preparation method of lacosamide chemical enzymatic method

A chemical enzymatic method, lacosamide technology, applied in biochemical equipment and methods, methods based on microorganisms, microorganisms, etc., can solve problems such as unsuitable for industrial production, unsuitable for industrial production, product racemization, etc., to avoid amino protection and deprotection steps, good economic benefits and social benefits, reducing the effect of environmental protection

Active Publication Date: 2016-01-20
NANJING UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The total yield of this method is low, and it is not suitable for industrialized production;
[0006] (3) D-serine first reacts with acetic anhydride to generate acetylated D-serine, then condenses acetylated D-serine with benzylamine to form the corresponding intermediate product, and finally the intermediate product is produced by methylation of methyl iodide under the catalysis of silver oxide The final product, lacosamide, has a simple synthetic route, but the reagents are expensive, unsuitable for industrial production, and the product is partially racemized (about 25%);
This method is cumbersome to operate, high in cost and low in total yield

Method used

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  • A kind of preparation method of lacosamide chemical enzymatic method

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Effect test

Embodiment 1

[0027] Embodiment one: single enzyme conversion reaction

[0028] Centrifuge 1000mL of Bacillus pallidus CICC10363 fermentation broth to obtain 20g of wet bacteria, add it to 1000mL of transformation liquid, the transformation liquid contains 60g of racemic 2-amino-3-methoxypropionamide (mass concentration 6%), 1.0g / L Tween-80, pH11, enzymatic reaction at 55°C for 5h. After the reaction, the transformation solution was centrifuged at 4000r / min for 15 minutes to remove the bacterial cells, the supernatant was adjusted to pH 5.0 with 6mol / L hydrochloric acid, added 5 grams of activated carbon, stirred and heated to 70°C for decolorization, and suction filtered; the decolorization solution was concentrated in vacuum to precipitate out , cooled and crystallized, vacuum filtered, rinsed with pure water, stirred with 80% ethanol, and dried to obtain (R)-2-amino-3-methoxypropionic acid 22.1g, (R)-2-amino The conversion rate of -3-methoxypropionamide is about 80%, ee=98.1%.

Embodiment 2

[0029] Embodiment two: single enzyme conversion reaction

[0030] Centrifuge 1000mL of the fermentation broth of Bacillus pallidum NCCB10026 to obtain 19g of wet bacteria, and add it to 1000mL of transformation liquid, which contains 60g of racemic 2-amino-3-methoxypropionamide (mass concentration 6%), 0.05g / LCTAB , pH6, 25 ℃ enzymatic reaction 1h. After the reaction, the transformation solution was centrifuged at 4000r / min for 15 minutes to remove the bacterial cells, the supernatant was adjusted to pH 5.0 with 6mol / L hydrochloric acid, added 5 grams of activated carbon, stirred and heated to 70°C for decolorization, and suction filtered; the decolorization solution was concentrated in vacuum to precipitate out , cooled and crystallized, vacuum filtered, rinsed with pure water, stirred with 80% ethanol, and dried to obtain (R)-2-amino-3-methoxypropionic acid 13.8g, (R)-2-amino The conversion rate of -3-methoxypropionamide is about 50%, ee=97.7%.

Embodiment 3

[0031] Embodiment three: single enzyme transformation reaction

[0032] Centrifuge 1000mL of Bacillus pallidus CICC10363 fermentation broth to obtain 22g of wet bacteria, add it to 1000mL of transformation liquid, the transformation liquid contains 60g of racemic 2-amino-3-methoxypropionamide (mass concentration 6%), 0.2g / LOP , pH9, enzymatic reaction at 45°C for 4.5h. After the reaction, the transformation solution was centrifuged at 4000r / min for 15 minutes to remove the bacterial cells, the supernatant was adjusted to pH 5.0 with 6mol / L hydrochloric acid, added 5 grams of activated carbon, stirred and heated to 70°C for decolorization, and suction filtered; the decolorization solution was concentrated in vacuum to precipitate out , cooled and crystallized, vacuum filtered, rinsed with pure water, stirred with 80% ethanol, and dried to obtain 26.3g of (R)-2-amino-3-methoxypropionic acid, (R)-2-amino - The conversion rate of 3-methoxypropionamide is about 95%, ee=98.5%.

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Abstract

The invention belongs to the technical field of biochemical engineering and particularly relates to a method for preparing lacosamide by virtue of a chemoenzymatic method. With racemic 2-amino-3-methoxy acrylic amide as a raw material, the method comprises the following steps: mixing wet cells or crude enzyme with D type amide hydrolase activity or mixed wet cells or mixed crude enzyme with D type amide hydrolase activity and amide racemase activity with the racemic 2-amino-3-methoxy acrylic amide, and performing an enzymatic conversion reaction under a certain temperature and a certain pH, wherein the enzymatic conversion product is (R)-2-amino-3-methoxy propionic acid, the (R)-2-amino-3-methoxy propionic acid is condensed to the final product lacosamide under the DCC catalysis after being acetylated. The technical route of the invention has the advantages of simple preparation process, mild reaction conditions, high yield, low cost and high product optical purity.

Description

1. Technical field [0001] The invention belongs to the technical field of biochemical industry, and in particular relates to a chemical and enzymatic preparation method of lacosamide. 2. Background technology [0002] Lacosamide, whose chemical name is (R)-2-acetamido-N-benzyl-3-methoxypropionamide, is a drug developed by SchwarzPharma in Germany for the treatment of epilepsy and neuropathic pain. In September 2008, the European Union approved the marketing of Lacosamide Tablets of Belgian UCB Company for the auxiliary treatment of partial epileptic seizures in patients over 16 years old with or without secondary epileptic seizures. In October 2008, the U.S. FDA approved lacosamide to be listed as an adjuvant drug in combination with other drugs for the treatment of partial epileptic seizures. The trade name is Vimpat. The drug model of lacosamide shows that it has dual regulatory effects of amplifying and preventing the inactivation of sodium channels and regulating the cl...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C12P13/02C12R1/025C12R1/01
Inventor 焦庆才王治元刘均忠刘茜高亮
Owner NANJING UNIV
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