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

Patent metadata

Field	Value
Publication number	US-11420932-B2
Application number	US-202017112891-A
Country	US
Kind code	B2
Filing date	Dec 4, 2020
Priority date	Jun 6, 2018
Publication date	Aug 23, 2022
Grant date	Aug 23, 2022

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

The invention claimed is:

1. A method for preparing (R)-3-(carbamoylmethyl)-5-methylhexanoic acid, the method 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 lipase from Carica papaya , lipase from Pseudomonas cepacia , lipase from Candida rugosa , ethyl chrysanthemate esterase, or esterase EST12-7 from the deep sea of South China Sea; and
the solvent is a miscible system of water and an organic solvent, and the organic solvent is ethanol, isopropanol, cyclohexanol, tetrahydrofuran, 1,4-dioxane, acetone, cyclohexanone, or a mixture of any two or more thereof.

2. 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.

3. 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.

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

5. The method of claim 4 , wherein the biological enzyme and the 3-isobutylglutarimide have a mass ratio of 1:5-1:10.

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

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

8. The method of claim 7 , wherein the 3-isobutylglutarimide and the solvent have a mass ratio of 1:5-1:10.

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

10. The method of claim 9 , wherein the reacting the 3-isobutylglutarimide is at a temperature range from 30° C. to 45° C.

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

12. The method of claim 11 , wherein the reacting the 3-isobutylglutarimide is for a time from 10 h to 15 h.

13. 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
• Zheijiang Huahai Pharmaceutical Co Ltd

Inventors

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

Classifications

• C07C227/04

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

• 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

• C07C227/06 Primary

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