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Preparation method of pregabalin

A pregabalin and solvent technology, applied in the field of pregabalin preparation, can solve the problems of unfavorable industrial production, high corrosion of equipment, long reaction time, etc., and achieve the advantages of large-scale industrial production, lower production cost and easy operation Effect

Inactive Publication Date: 2014-11-12
NANTONG CHANGYOO PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method uses a large amount of hydrochloric acid, the reaction time is long, and the equipment is highly corrosive, which is not conducive to large-scale industrial production.

Method used

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  • Preparation method of pregabalin
  • Preparation method of pregabalin
  • Preparation method of pregabalin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] A preparation method of formula I pregabalin, characterized in that the preparation method comprises the following steps:

[0023] (a) In 250mL of isopropyl ether, add 45g of 3-(carbamoylmethyl)-5-methylhexanoic acid of formula II, stir to dissolve, and heat up to 45°C; 22.8g of chiral resolving agent (R)-(+)-α-Phenylethylamine was dissolved in 120mL tetrahydrofuran, and slowly added dropwise to the above reaction solution; after dropping, reacted at 45°C for 2 hours; then cooled to room temperature, and gradually solids precipitated. Stir, cool to 5°C to crystallize, filter with suction, place the resulting solid in 300 mL of ether for slurry, and dry to obtain 46 g of 3-(carbamoylmethyl)-5-methylhexanoic acid (R)- (+)-α-Phenylethylamine salt, white solid, yield: 58%; the resulting filtrate was added to 10 times the amount of 5% sodium hydroxide solution, stirred for 30 minutes, the aqueous phase was separated, and adjusted with hydrochloric acid When the pH reached 2...

Embodiment 2

[0029] A preparation method of formula I pregabalin, characterized in that the preparation method comprises the following steps:

[0030] (a) In 700mL of chloroform, add 60g of 3-(carbamoylmethyl)-5-methylhexanoic acid of formula II, stir to dissolve, and heat up to 45°C; 54.8g of chiral resolving agent (R )-(+)-α-Phenylethylamine was dissolved in 200mL tetrahydrofuran, and slowly added dropwise to the above reaction solution; after dropping, reacted at 45°C for 2 hours; then cooled to room temperature, gradually solids were precipitated, stirred, Cool to 5°C for crystallization, filter with suction, place the resulting solid in 400 mL of ether for slurry, and dry to obtain 59.2 g of 3-(carbamoylmethyl)-5-methylhexanoic acid (R)-( +)-α-phenylethylamine salt, white solid, yield: 56%; the obtained filtrate was added to 10 times the amount of 5% sodium hydroxide solution, stirred for 30 minutes, the water phase was separated, and the pH was adjusted with hydrochloric acid To 2-3...

Embodiment 3

[0036] A preparation method of formula I pregabalin, characterized in that the preparation method comprises the following steps:

[0037] (a) In 220mL of toluene, add 20g of 3-(carbamoylmethyl)-5-methylhexanoic acid of formula II, stir to dissolve, and heat up to 45°C; 22.8g of chiral resolving agent (R )-(+)-α-Phenylethylamine was dissolved in 80mL of tetrahydrofuran, and slowly added dropwise to the above reaction solution; after dropping, reacted at 45°C for 2 hours; then cooled to room temperature, gradually solids were precipitated, stirred, Cool to 5°C to crystallize, filter with suction, place the resulting solid in 220 mL of ether for slurry, and dry to obtain 18.3 g of 3-(carbamoylmethyl)-5-methylhexanoic acid (R)-( +)-α-phenylethylamine salt, white solid, yield: 52%; the obtained filtrate was added to 10 times the amount of 5% sodium hydroxide solution, stirred for 30 minutes, the water phase was separated, and the pH was adjusted with hydrochloric acid To 2-3, a so...

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Abstract

The invention provides a preparation method of pregabalin. The preparation method comprises the following steps: performing chiral separation reaction, dissociation reaction and Hofmann degradation reaction with 3-(carbamoyl methyl)-5-methylhexanoic acid serving as raw material to prepare pregabalin, wherein a pregabalin chiral isomer generated in the process reacts under the action of an alkali reagent so as to obtain a hydrolysis product, and the hydrolysis product is hydrolyzed further and recycled to obtain the raw material 3-(carbamoyl methyl)-5-methylhexanoic acid. Compared with the prior art, the preparation method is convenient to carry out; the prepared pregabalin is high in purity; the used raw material can be recycled, so that the production cost is greatly reduced; the preparation method is favorable for large-scale industrial production.

Description

technical field [0001] The invention relates to a preparation method of pregabalin. Background technique [0002] Pregabalin (Pregabalin, trade name Lyrica) is a novel C-aminobutyric acid (GABA) receptor agonist developed by Warner-Lambert Company. In August 2003, Pfizer filed a registration application in the United States for use in Anticonvulsant and adjuvant treatment of partial seizures, and then applied for the treatment of pain caused by diabetic peripheral neuropathy (DPN) and neuralgia caused by herpes virus infection. [0003] Pregabalin is a structural analog of the inhibitory neurotransmitter GABA, but its antiepileptic effect is similar to that of GABA A or GABA B Receptor independent and independent of other GABA receptor-related drug targets. Pregabalin has no direct effect on sodium channels, it passes through the cell membrane of the blood-brain barrier through specific transport channels for transporting leucine, isoleucine and valine, specific and P / Q-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/08C07C227/04
Inventor 林燕峰李泽标吕连岭马甜甜
Owner NANTONG CHANGYOO PHARMATECH CO LTD
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