Preparation method of pregabalin

A technology of pregabalin and chiral ester, applied in the field of preparation of pregabalin, can solve problems such as low yield and severe reaction conditions, and achieve the effects of improving purity, convenient operation, and safe and environmentally friendly preparation method

Inactive Publication Date: 2019-03-22
ZHUOHE PHARM GRP CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The preparation methods of pregabalin mainly include asymmetric synthesis and chemical resolution. Chemical resolution is the mainstream method of production today, but the yield is low and the reaction conditions are severe. The development of a mild resolution method has important application value

Method used

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  • Preparation method of pregabalin

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Experimental program
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preparation example Construction

[0020] The present invention provides a kind of preparation method of pregabalin, and the structural formula of pregabalin is as follows:

[0021]

[0022] Wherein, the preparation method of the pregabalin shown in the above structural formula is: using the pregabalin racemate as the starting material, under the action of lipase to prepare the pregabalin chiral ester, and the pregabalin chiral ester is hydrolyzed The reaction gives pregabalin.

[0023] The structural formula of pregabalin chiral ester is as follows:

[0024]

[0025] Wherein, R is selected from methyl, ethyl or isopropyl.

[0026] The reaction process of the chiral ester of pregabalin is as follows: adding solvent and pregabalin racemate to the reaction bottle, then adding lipase, constant temperature shaker, 200rpm reaction for 24h, suction filtration, the filtrate is concentrated by silica gel column chromatography, and the corresponding eluted solution, concentrated to give pregabalin chiral ester. ...

Embodiment 1

[0029] This embodiment discloses a kind of pregabalin prepared according to the above method, wherein R is selected from ethyl, and the specific reaction steps are as follows:

[0030] Add 100ml of ethanol and 12.5g of pregabalin racemate to a 500ml round bottom flask, then add 1g of lipase, react in a constant temperature shaker at 40°C, 200rpm for 24h, filter with suction, concentrate the filtrate by silica gel column chromatography, and collect the corresponding eluent. After concentration, 6.1 g of chiral ester of pregabalin was obtained.

[0031] Add 5g of pregabalin chiral ester and 10ml of concentrated hydrochloric acid into a 50ml reaction bottle, stir at reflux for 3h, adjust to PH5 with 2M sodium hydroxide, dissolve and dry dichloromethane after concentration, then remove dichloromethane under reduced pressure, and recrystallize with ethanol / acetone , to obtain high-purity pregabalin 3.2g.

[0032] The purity of the high-purity pregabalin finally prepared in this ex...

Embodiment 2

[0034] This embodiment discloses a kind of pregabalin prepared according to the above method, wherein R is selected from isopropyl, and the specific reaction steps are as follows:

[0035] Add 100ml of isopropanol and 12.5g of pregabalin racemate to a 500ml round bottom flask, then add 1g of lipase, and react on a constant temperature shaker at 40°C at 200rpm for 24h. After suction filtration, the filtrate was concentrated by silica gel column chromatography, and the corresponding eluate was collected and concentrated to obtain 6.2 g of pregabalin chiral ester.

[0036] Add 5g of pregabalin chiral ester and 20ml of 2M sodium hydroxide to a 50ml reaction bottle, stir at 80°C for 6h, adjust to PH5 with 6M hydrochloric acid, dissolve ethyl acetate after concentration and dry, then remove dichloromethane under reduced pressure, ethanol / acetone weight Crystallized to obtain 3.3 g of high-purity pregabalin.

[0037] The purity of the high-purity pregabalin finally prepared in this ...

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Abstract

The invention provides a preparation method of pregabalin. The method comprises the following steps: taking pregabalin racemate as an initiator, forming pregabalin chiral ester under the action of lipase, and ensuring that the pregabalin chiral ester is subjected to hydrolysis reaction, so as to form the pregabalin. The preparation method ensures that the pregabalin is high in purity, convenient to operate, and safer and more environmentally friendly.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a preparation method of pregabalin. Background technique [0002] Pregabalin is an analogue of the neurotransmitter GABA, a follow-up to gabapentin. The mechanism of action of pregabalin is similar to that of gabapentin, and it has shown anticonvulsant and analgesic effects in different animal models, but the detailed mechanism of action is still unclear. Pregabalin is structurally similar to the neurotransmitter GABA, but it does not act directly through the GABA mechanism. At the same time, this product is different from traditional antiepileptic drugs. It does not interact with GABAA or GABAB receptors within the effective concentration range. It is not metabolized into GABA or GABA agonist, nor does it inhibit the uptake and degradation of GABA, nor does it act on sodium or calcium channels, nor the release and uptake of glutamate. At the same time, pregabalin d...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/18C07C229/08
CPCC07B2200/07C07C227/18C12P13/005C07C229/08
Inventor 王涛李晓明王庆林王彬彬孙益林
Owner ZHUOHE PHARM GRP CO LTD
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