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Preparation method of pregabalin

A technology of pregabalin and carbamoylmethyl, applied in the field of drug synthesis, can solve the problems of reduced product quality, difficult concentration control, unstable sodium hypochlorite, etc., and achieves the effect of reducing impurity content and improving yield

Active Publication Date: 2014-07-16
ZHEJIANG MENOVO PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

For example: sodium hypochlorite is unstable, and its concentration will gradually change in a slightly higher temperature environment. Therefore, if sodium hypochlorite needs to be stored in a refrigerated environment, it is difficult to control the exact concentration; in addition, the concentration change is not the only problem, even after In order to accurately control the amount of feed, the use of sodium hypochlorite stored for a long time will still lead to a decrease in the quality of the product

Method used

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  • Preparation method of pregabalin
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  • Preparation method of pregabalin

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Add 250mL water and 55g (5equiv) sodium hydroxide to a 500mL flask, stir until dissolved, then cool to -5~0°C, add 45g (1.26equiv) N-chlorosuccinimide (NCS) in batches , Control the temperature below 0°C during the addition process. Then add 50g (0,27mol) (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid (CAS181289-33-8) in batches to the above mixed system. Keep the reaction temperature below 0°C. After the addition, keep the temperature at 0-10°C for reaction (take a sample for TLC to detect the reaction process). After 3 hours, TLC shows that the reaction is complete, and continue to stir at 25°C for 12 hours.

[0028] About 60 mL of concentrated hydrochloric acid was added dropwise to the obtained reaction solution to adjust the pH to 5.0-5.5, and the reaction system was slowly cooled to 0-5° C. within 2 to 3 hours, then stirred for 1 hour and then filtered to obtain a white solid. Add 75mL of water and 75mL of isopropanol to the obtained white solid, immerse at ro...

Embodiment 2

[0030] The operation of this embodiment is basically the same as that of Example 1, except that the substrate (R)-(-)-3-(carbamoylmethyl)-5-methylhexanoic acid and N-chlorobutyl The addition order of diimide is reversed, and the reaction results are shown in Table 1.

Embodiment 3

[0032] The operation of this embodiment is basically the same as that of Example 1, except that potassium hydroxide is used instead of sodium hydroxide, and the amount used is 4.0 equiv. The reaction results are shown in Table 1.

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Abstract

The invention discloses a preparation method of pregabalin. According to the preparation method, (R)-(-)-3-(carbamyl methyl)-5-methylhexanol has a Hofmann degradation reaction under the action of N-chlorosuccinimide in the presence of an alkali to produce pregabalin. By adopting N-chlorosuccinimide as a reagent of Hofmann degradation reaction, the use of bromine is avoided, the reaction yield is improved and the content of impurities in the product is reduced, so that the reaction is suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of pregabalin. Background technique [0002] Pregabalin, whose structure is shown in formula (I), has a chemical name of (S)-(+)-3-aminomethyl-5-methylhexanoic acid, which was developed in the early 1990s for the treatment of GABA (gamma-aminobutyric acid) analogs for epilepsy, neuropathic pain, anxiety, and social phobia. Newer studies have shown that it is effective in the treatment of chronic pain caused by fibromyalgia and spinal cord injury, and its pharmaceutical activity is the S-isomer of this γ-amino acid. [0003] [0004] At present, a number of patents have reported the preparation method of pregabalin, such as U.S. Patent U.S.5656793 (793 patents) and the international publication number is WO2006 / 122258 (258 disclosure), WO2006 / 122255 (255 disclosure) and WO2006 / 121557 ( 257 publication) patent application. In these patent applica...

Claims

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Application Information

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IPC IPC(8): C07C229/08C07C227/04
Inventor 亚罗米尔·托曼姚成志陈为人刘雄丁世雄鲍继胜支浩西廖腾火生
Owner ZHEJIANG MENOVO PHARMA
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