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Preparation method of levetiracetam

A technology of methyl halobutyrate and quality, applied in the field of preparation of levetiracetam, can solve the problems of low yield and low industrial application value, and achieves increased comprehensive yield, enantioselectivity and regional The effect of high selectivity and less three wastes

Active Publication Date: 2015-11-18
ZHEJIANG CHANGMING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] In recent years, there are also literatures (such as: CN20120283040.2) reporting the separation of levetiracetam by biological enzyme method, but the yield is low, and the industrial application value is not high

Method used

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  • Preparation method of levetiracetam
  • Preparation method of levetiracetam
  • Preparation method of levetiracetam

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] (1) In a 500mL three-necked flask, add 270mL of sodium dihydrogen phosphate / sodium hydrogen phosphate buffer solution with a pH value of 6.5, racemic methyl 2-chlorobutyrate (0.2mol, 27.3g) and lipase ( Novozymes immobilized lipase, CALB-Novazym435) 2.7g, control the reaction temperature at 20-25°C, carry out enantioselective hydrolysis reaction, the reaction is complete after 24 hours, add ethyl acetate for extraction (30mL×3), collect The organic layer was spin-dried to obtain 11.5 g of (R)-methyl 2-chlorobutyrate, with a yield of 84.2%. The pH value of the aqueous layer was adjusted to neutral with 4M hydrochloric acid, and then extracted with ethyl acetate. The organic layer was collected and spin-dried to obtain 9.8 g of by-product (S)-2-chlorobutyric acid, with a yield of 80.0%.

[0044] (2) In a 1L autoclave, add the (R)-2-chlorobutyric acid methyl ester (0.073mol, 10g) obtained in step (1) and 200mL of methanol, dissolve it, cool it down to -10~0℃, pass The amm...

Embodiment 2

[0047] (1) In a 500mL three-necked flask, add 350mL of sodium dihydrogen phosphate / sodium hydrogen phosphate buffer solution with a pH value of 7.0, racemic methyl 2-chlorobutyrate (0.2mol, 27.3g) and lipase ( Novozymes immobilized lipase, CALB-Novazym435) 1.4g, control the reaction temperature at 35-40°C, carry out enantioselective hydrolysis reaction, after 36 hours the reaction is complete, add ethyl acetate for extraction (30mL×3), collect The organic layer was spin-dried to obtain 11.2 g of (R)-methyl 2-chlorobutyrate, with a yield of 82.0%. The pH value of the aqueous layer was adjusted to neutral with 4M hydrochloric acid, then extracted with ethyl acetate, the organic layer was collected, and spin-dried to obtain 9.0 g of by-product (S)-2-chlorobutyric acid, with a yield of 73.4%.

[0048] (2) In a 1L autoclave, add the (R)-2-chlorobutyric acid methyl ester (0.073mol, 10g) obtained in step (1) and 350mL of methanol, dissolve it, cool to -10~0℃, pass The ammonia gas is...

Embodiment 3

[0051] (1) In a 1L three-necked flask, add 410 mL of potassium dihydrogen phosphate / potassium hydrogen phosphate buffer solution with a pH value of 7.5, racemic methyl 2-chlorobutyrate (0.2 mol, 27.3 g) and lipase ( Novozymes immobilized lipase, CALB-Novazym435) 1.9g, control the reaction temperature at 25-30°C, carry out enantioselective hydrolysis reaction, after 48 hours the reaction is complete, add ethyl acetate for extraction (30mL×3), collect The organic layer was spin-dried to obtain 12.0 g of (R)-methyl 2-chlorobutyrate, with a yield of 87.9%. The pH value of the aqueous layer was adjusted to neutral with 4M hydrochloric acid, then extracted with ethyl acetate, the organic layer was collected, and spin-dried to obtain 10.5 g of by-product (S)-2-chlorobutyric acid, with a yield of 85.7%.

[0052] (2) In a 1L autoclave, add the (R)-2-chlorobutyric acid methyl ester (0.073mol, 10g) obtained in step (1) and 500mL of ethanol, dissolve it, cool down to -10~0℃, pass The amm...

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Abstract

The invention provides a preparation method of levetiracetam (I). The method comprises the steps that racemization 2-halogenated butyric acid methyl ester which is in low in cost and easy to obtained is used as a raw material, a biological enzyme method is adopted to synthesize key chiral intermediate (R)-2-halogenated butyric acid methyl ester, the intermediate is subjected to ammonolysis and cyclized with 4-chlorobutyryl chloride, and finally the levetiracetam is obtained. The chiral center is built by the adoption of the enzyme asymmetric catalytic technology, a reaction path is directly reduced to three steps, the comprehensive yield is high, and the cost is low. Compared with a chemical catalyst, a biological enzyme catalyst has the advantages of being high in enantioselectivity and regioselectivity and low in energy consumption, producing few by-products and the three wastes, and the like.

Description

(1) Technical field [0001] The invention relates to a preparation method of levetiracetam, in particular to a method for synthesizing the key chiral intermediate (R)-2-halobutyric acid methyl ester through a biological enzymatic method, and then undergoes aminolysis and cyclization Process for the preparation of levetiracetam. (2) Background technology [0002] Levetiracetam (Formula I) is a second-generation acetylcholine agonist with a structure related to piracetam developed by Belgian UCB Company. It is mainly used for the treatment of localized and secondary generalized epilepsy. It is an efficient, A broad-spectrum antiepileptic drug with less toxic and side effects is of great development value. [0003] [0004] At present, there are many synthetic methods of levetiracetam reported at home and abroad, the most important of which are two synthetic routes: [0005] The route one reported by UCB in patents US4696943 and US4943639 is to use vortexed α-ethyl-2-oxo-1-...

Claims

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Application Information

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IPC IPC(8): C12P17/10C07D207/27
Inventor 季友卫陈斌潜飞何亚文高小根洪星
Owner ZHEJIANG CHANGMING PHARMA
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