Method for preparing pregabalin intermediate (r)-3-(carbamoylmethyl)-5-methylhexanoic acid

Patent metadata

Field	Value
Publication number	US-2021114970-A1
Application number	US-202017112891-A
Country	US
Kind code	A1
Filing date	Dec 4, 2020
Priority date	Jun 6, 2018
Publication date	Apr 22, 2021
Grant date	—

Abstract

A method for preparing pregabalin chiral intermediate (R)-3-(carbamoylmethyl)-5-methylhexanoic acid by a biological enzyme method. In particular, the method comprises: reacting compound (I) 3-isobutylglutaric acid, as a raw material, with a nitrogen-containing agent to produce compound (II) 3-isobutylglutarimide; and performing stereoselective ring-opening of compound (II) under the action of a biological enzyme to produce compound (III) (R)-3 -(carbamoylmethyl)-5-methylhexanoic acid:

First claim

1 . A method for preparing (R)-3-(carbamoylmethyl)-5-methylhexanoic acid comprising:
reacting 3-isobutylglutaric acid with a nitrogen-containing reagent to produce 3-isobutylglutarimide; reacting the 3-isobutylglutarimide in a solvent with a biological enzyme to perform stereoselective ring-opening to produce (R)-3-(carbamoylmethyl)-5-methylhexanoic acid; wherein: the biological enzyme is a hydrolase.

2 . The method of claim 1 , wherein the hydrolase is a lipase or an esterase.

3 . The method of claim 2 , wherein the lipase is selected from the group consisting of plant lipase, animal lipase, bacterial lipase, and fungal lipase.

4 . The method of claim 2 , wherein the lipase is from carica papaya, porcine pancreas, Burkholderia cepacia, Pseudomonas cepacia, candida rugosa, rhizomucor miehei, aspergillus oryzae.

5 . The method of claim 2 , wherein the esterase is selected from the group consisting of thermophilic esterase APE1547, ethyl chrysanthemate esterase, esterase EST12-7, liver esterase, and carboxylesterase.

6 . The method of claim 1 , wherein the nitrogen-containing reagent is selected from the group consisting of ammonia water, urea, a basic ammonium salt, and thiourea.

7 . The method of claim 1 , wherein the biological enzyme is in the form of immobilized enzyme particles, enzyme powder, cells or organelles containing the biological enzyme, or crude enzymes obtained by culturing enzyme-producing microorganisms.

8 . The method of claim 1 , wherein the biological enzyme and the 3-isobutylglutarimide have a mass ratio of 1:1-1:20.

9 . The method of claim 8 , wherein the biological enzyme and the 3-isobutylglutarimide have a mass ratio of 1:5-1:10.

10 . The method of claim 1 , wherein the solvent is a miscible system of water and an organic solvent.

11 . The method of claim 10 , wherein the organic solvent is selected from the group consisting of ethanol, tetrahydrofuran, and acetone.

12 . The method of claim 10 , wherein the water and the organic solvent have a mass ratio of 1:1-1:5.

13 . The method of claim 1 , wherein the 3-isobutylglutarimide and the solvent have a mass ratio of 1:5-1:50.

14 . The method of claim 13 , wherein the 3-isobutylglutarimide and the solvent have a mass ratio of 1:5-1:10.

15 . The method of claim 1 , wherein the reacting the 3-isobutylglutarimide is at a temperature range from 25° C. to 55° C.

16 . The method of claim 15 , wherein the reacting the 3-isobutylglutarimide is at a temperature range from 30° C. to 45° C.

17 . The method of claim 1 , wherein the reacting the 3-isobutylglutarimide is for a time from 8 h to 20 h.

18 . The method of claim 17 , wherein the reacting the 3-isobutylglutarimide is for a time from 8 h to 20 h.

19 . The method of claim 1 further comprising reacting the (R)-3-(carbamoylmethyl)-5-methylhexanoic acid with bromine under basic conditions to produce pregabalin.

Assignees

• Zhejiang Huahai Pharm Co Ltd

Inventors

• Yang Changming
• Guo Pan
• Wang Yifeng
• Zhang Wenling
• Wang Peng

Classifications

• C12P7/40

  containing a carboxyl group {including Peroxycarboxylic acids} · CPC title

• C12P13/02 Primary

  Amides, e.g. chloramphenicol {or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes (peptides C12P21/00 or C07K)} · CPC title

• C07C227/04

  Formation of amino groups in compounds containing carboxyl groups · CPC title

• C07C227/06 Primary

  by addition or substitution reactions, without increasing the number of carbon atoms in the carbon skeleton of the acid · CPC title