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Method for asymmetric preparation of (S)-3-aminomethyl-5-methylcaproic acid

A methyl hexanoic acid, asymmetric technology, applied in the field of chemical medicine, can solve the problems of difficult recovery and recycling, hindered industrial production, expensive catalysts, etc., and achieve the effect of cheap raw materials, short reaction steps and mild reaction conditions

Inactive Publication Date: 2018-08-28
SYNCOZYMES SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The catalyst used in this method is expensive, recovery and recycling are relatively difficult, the reaction conditions are harsh, and industrial production is hindered

Method used

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  • Method for asymmetric preparation of (S)-3-aminomethyl-5-methylcaproic acid
  • Method for asymmetric preparation of (S)-3-aminomethyl-5-methylcaproic acid
  • Method for asymmetric preparation of (S)-3-aminomethyl-5-methylcaproic acid

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] The synthesis of embodiment 1 (S)-3-aminomethyl-5-methylhexanoic acid

[0029] (1) Preparation of compound III

[0030] Add 3-isobutylglutaric acid (1kg) and urea (0.64kg) in the 5L round bottom flask, react the reaction mixture at 180 ℃ for 2 hours, cool to 80 ℃, add water (1L), ethanol (2L), Activated carbon (50 g), heated at 80° C. for 0.5 hour, filtered hot, cooled to crystallize, filtered, and dried to obtain white crystalline compound III (0.83 kg, yield: 92%).

[0031] (2) Preparation of Compound IV

[0032] Toluene (2.7L), (S)-(+)-1-phenethylamine (0.88kg) and DMAP (5.9g) were added in a 6L round bottom flask, and compound III (0.83 kg) were added to the flask in batches (the addition was completed in 1 hour), and the reaction was stirred at -20 to -10°C for 3 hours. The reaction solution was washed with water, dried, concentrated under reduced pressure, and then crystallized with toluene to obtain compound IV (1.42 kg, yield: 90%), with ee of 99.4%.

[0033...

Embodiment 2

[0037] The synthesis of embodiment 2 (S)-3-aminomethyl-5-methylhexanoic acid

[0038] (1) Preparation of compound III

[0039] Add 3-isobutylglutaric acid (1kg) and 40% ammonia water (0.68kg) in the 5L round bottom flask, react the reaction mixture at 100 ℃ for 2 hours, cool to 80 ℃, add water (1L), ethanol (2L ), activated carbon (50 g), heated at 80° C. for 0.5 hour, hot filtered, cooled to crystallize, filtered, and dried to obtain white crystalline compound III (0.81 kg, yield: 90%).

[0040] (2) Preparation of Compound IV

[0041] Toluene (2.7L), (S)-(+)-1-phenethylamine (0.88kg) and DMAP (5.9g) were added in a 6L round bottom flask, and compound III (0.81 kg) were added to the flask in batches (the addition was completed in 1 hour), and the reaction was stirred at -20 to -10°C for 3 hours. The reaction solution was washed with water, dried, concentrated under reduced pressure, and then crystallized with toluene to obtain compound IV (1.39 kg, yield: 90%), with ee of 9...

Embodiment 3

[0046] The synthesis of embodiment 3 (S)-3-aminomethyl-5-methylhexanoic acid

[0047] (1) Preparation of compound III

[0048]Add 3-isobutylglutaric acid (1kg) and ammonium bicarbonate (1.26kg) to a 5L round bottom flask, react the reaction mixture at 180°C for 2 hours, cool to 90°C, add water (1L), ethanol (2L ), activated carbon (50 g), heated at 80° C. for 0.5 hour, hot filtered, cooled to crystallize, filtered, and dried to obtain white crystalline compound III (0.82 kg, yield: 91%).

[0049] (2) Preparation of compound IV

[0050] Toluene (2.7L), (S)-(+)-1-phenethylamine (0.88kg) and DMAP (5.9g) were added in a 6L round bottom flask, and compound III (0.82 kg) into the flask in batches (the addition was completed in 1 hour), and the reaction was stirred at -20 to -10°C for 3 hours. The reaction solution was washed with water, dried, concentrated under reduced pressure, and then crystallized with toluene to obtain compound IV (1.45 kg, yield: 93%), with ee of 99.1%.

...

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Abstract

The invention discloses a method for asymmetric preparation of (S)-3-aminomethyl-5-methylcaproic acid. The method is characterized by comprising the following four synthesis steps: with 3-isobutylglutaric acid as a raw material, subjecting 3-isobutylglutaric acid and a nitrogen-containing reagent to a ring-closure reaction; subjecting a reaction product and (S)-(+)-1-phenylethylamine to asymmetricring opening; carrying out Huffman rearrangement; and then carrying out amide hydrolysis so as to obtain (S)-3-aminomethyl-5-methylcaproic acid. Compared with the prior art, the method provided by the invention has the advantages of usage of cheap and easily available raw materials, short reaction steps, mild reaction conditions, and no usage of reagents easily leading to poisoning and explosion;the overall yield of method is as high as 72%; the purity of the product pregabalin is greater than 99%, and an ee value is greater than 99%; and the method has good application prospects in industrial large-scale production.

Description

technical field [0001] The invention belongs to the field of chemistry and medicine, and in particular relates to a method for asymmetrically preparing (S)-3-aminomethyl-5-methylhexanoic acid. Background technique [0002] (S)-3-aminomethyl-5-methylhexanoic acid, commonly known as pregabalin, is a kind of aminobutyric acid (GABA) receptor antagonist developed by Pfizer for the treatment of peripheral neuralgia and Partial seizures. In July 2004, it was approved by the European Union and launched in the UK for the first time. In December 2004, it was approved by the FDA for marketing, and the trade name was Lyrica. (S)-3-Aminomethyl-5-methylhexanoic acid mainly acts by regulating pressure-dependent calcium channels in the central nervous system. After oral administration, it is absorbed through the intestinal transport mechanism mediated by neutral amino acid carriers. High bioavailability. Compared with gabapentin used clinically, pregabalin has stronger anticonvulsant ef...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/18C07C229/08C07D211/88C07C231/10C07C233/05C07C231/12C07C237/32
CPCC07B2200/07C07C227/18C07C231/10C07C231/12C07D211/88C07C229/08C07C233/05C07C237/32
Inventor 竺伟王波何明刚
Owner SYNCOZYMES SHANGHAI
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