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Novel method for preparing pregabalin raceme hydrochloride

A technology of pregabalin and racemate, applied in the field of chemical pharmacy, can solve the problems of cumbersome routes, difficult industrialization, harsh reaction conditions, etc., and achieves the effects of simple operation, low cost and mild reaction conditions

Active Publication Date: 2011-07-06
ZHEJIANG HUAHAI PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has a long synthetic route, uses butyllithium in the reaction, and the reaction conditions are harsh, making it difficult to realize industrial production
[0004] Marvin S.Hoekstra etc. disclose several methods for preparing pregabalin in Organic Process Research & Development (1997,1,26-28), some method routes are loaded down with trivial details, and yield is not high, and some method intermediates are difficult to separate, and dismantle The optical purity of the obtained product is not ideal, and some methods use highly toxic reagents in some steps, which makes industrialization difficult
[0005] Patent WO2008 / 007145 discloses a method for synthesizing pregabalin with chloroacetate and isovaleraldehyde as raw materials. This method is not conducive to industrial promotion due to expensive raw materials and high cost.

Method used

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  • Novel method for preparing pregabalin raceme hydrochloride
  • Novel method for preparing pregabalin raceme hydrochloride
  • Novel method for preparing pregabalin raceme hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0074] Add 16g of sodium hydride to a 500ml three-necked flask, then add 70ml of dimethyl carbonate, and stir. Then add 20g of 4-methyl-2-pentanone, heat up to reflux reaction, and the system temperature is about 80°C. After refluxing for about 2 hours, the reaction of 4-methyl-2-pentanone was complete. Stop the reaction, add 200ml of ice water after cooling to room temperature, adjust the pH of the system to about 2-3 with concentrated hydrochloric acid, first extract with 80ml of dichloromethane, and then extract the aqueous phase with 40×2ml of dichloromethane. The combined organic phases were washed with brine and dried over anhydrous sodium sulfate for 2 hours. The desiccant was filtered off, and the solvent was distilled off under reduced pressure to obtain compound (1) as a light brown oil weighing 28.8 g with a yield of about 91%.

Embodiment 2

[0076] Add 16g of sodium hydroxide to a 500ml three-necked flask, then add 70ml of dibutyl carbonate, and stir. Then add 20g of 4-methyl-2-pentanone, heat up to reflux reaction, and the system temperature is about 80°C. After refluxing for about 2 hours, the reaction of 4-methyl-2-pentanone was complete. Stop the reaction, add 200ml of ice water after cooling to room temperature, adjust the pH of the system to about 2-3 with concentrated hydrochloric acid, first extract with 80ml of dichloromethane, and then extract the aqueous phase with 40×2ml of dichloromethane. The combined organic phases were washed with brine and dried over anhydrous sodium sulfate for 2 hours. The desiccant was filtered off, and the solvent was distilled off under reduced pressure to obtain compound (1) as a light brown oil weighing 26.5 g with a yield of about 84%.

Embodiment 3

[0078] Add 21.6g of sodium methoxide to a 500ml three-necked flask, then add 70ml of diethyl carbonate, and stir. Then add 20g of 4-methyl-2-pentanone, heat up to reflux reaction, and the system temperature is about 80°C. After refluxing for about 2 hours, the reaction of 4-methyl-2-pentanone was complete. Stop the reaction, add 200ml of ice water after cooling to room temperature, adjust the pH of the system to about 2-3 with concentrated hydrochloric acid, first extract with 80ml of dichloromethane, and then extract the aqueous phase with 40×2ml of dichloromethane. The combined organic phases were washed with brine and dried over anhydrous sodium sulfate for 2 hours. The desiccant was filtered off, and the solvent was distilled off under reduced pressure to obtain compound (1) as a light brown oil with a yield of about 76%.

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Abstract

The invention discloses a route and method for preparing 3-aminomethyl-5-methylhexanoic acid, namely pregabalin raceme hydrochloride. The method comprises the following steps of: performing condensation on 4-methyl-2-pentanone to obtain a compound in a formula (1), and performing reduction to obtain a compound in a formula (2); performing halogenation or esterification to obtain a compound in a formula (3a), and performing substitution to obtain a compound in a formula (4), or performing elimination on the compound in the formula (3a) to obtain a compound in a formula (3b) and performing addition to obtain a compound in the formula (4); and performing reduction and acidolysis on the compound in the formula (4) to obtain a pregabalin hydrochloride compound in a formula (6). The method is easy to operate, mild in reaction conditions, and low in cost, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to a synthetic route and a preparation method for preparing pregabalin racemate 3-aminomethyl-5-methylhexanoic acid hydrochloride, belonging to the field of chemical pharmacy. Background technique [0002] Pregabalin is a gamma-aminobutyric acid (GABA) receptor blocker developed by Pfizer, and it is a new drug that has been used clinically as an anti-epilepsy and neuroma treatment. The drug has no drug-drug interaction with the existing antiepileptic drugs, and it is convenient to be used in conjunction with other antiepileptic drugs to achieve synergistic antiepileptic effects. Therefore, it is reasonable to think that the drug has a very broad antiepileptic prospect. [0003] The preparation of this compound has been reported in many literatures. Yuen PW et al. disclosed a method for preparing pregabalin in Bioorganic & Medicinal Chemistry Letters [1994, 4(6) 823-826]. This method has a long synthetic route, uses butyllithium ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/08C07C227/22
Inventor 王立新徐小英甘立新李先国黄青春王文田芳贺光云
Owner ZHEJIANG HUAHAI PHARMA CO LTD
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