Method for preparing pregabalin

Patent metadata

Field	Value
Publication number	US-2021114972-A1
Application number	US-202017112917-A
Country	US
Kind code	A1
Filing date	Dec 4, 2020
Priority date	Jun 6, 2018
Publication date	Apr 22, 2021
Grant date	—

Abstract

The present invention relates to a method for preparing pregabalin by a biological enzyme method. In particular, the method comprises producing pregabalin B and an R-configuration compound C by using a compound A as a raw material under the action of a biological enzyme; performing configuration inversion of the separated and recovered R-configuration compound C under the action of an isomerase to produce an S-configuration compound D; and producing pregabalin B from the compound D under the action of a biological enzyme

First claim

1 . A method for preparing pregabalin comprising:
reacting a compound of formula (I) in a first solvent with a biological enzyme to produce a target compound of formula (III) and a by-product of formula (II); reacting the by-product of formula (II) in a second solvent with an isomerase to perform a configuration inversion to produce a compound of formula (IV); reacting the compound of formula (IV) in a third solvent with the biological enzyme to produce the target compound of formula (III);

wherein:
R 1 and R 2 are independently hydrogen or an alkyl group; and
the biological enzyme is a hydrolase.

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

3 . The method of claim 2 , wherein the lipase is a mold lipase, a yeast lipase, or a bacterial lipase.

4 . The method of claim 3 , wherein the mold lipase is from a Rhizopus delemar, an Aspergillus niger, a Rhizomucor miehei, or a Gertrichum candidum.

5 . The method of claim 3 , wherein the yeast lipase is from Candida antarctica B, Candida cylindracea, or Rhodoaorula glutinis.

6 . The method of claim 3 , wherein the bacterial lipase is from Burkholderia cepacia, Pseudomonas, or Staphylococcus epidermidis.

7 . The method of claim 1 , wherein the isomerase is an epimerase.

8 . The method of claim 7 , wherein the epimerase is selected from the group consisting of glucose isomerase, sucrose isomerase, D-tagatose 3-epimerase, D-psicose 3-epimerase, cellobiose 2-epimerase and 2-ketogluconate epimerase.

9 . The method of claim 1 , wherein the biological enzyme, the isomerase, or both are in the form of immobilized enzyme particles, enzyme powder, or cells or organelles containing the biological enzyme or the isomerase.

10 . The method of claim 1 , wherein R 1 and R 2 are independently a C 1 -C 4 branched or straight chain alkyl group.

11 . The method of claim 1 , wherein R 1 is H and R 2 is methyl.

12 . The method of claim 1 , wherein
the biological enzyme and the compound of formula (I) have a mass ratio of 1:2-1:20; and/or the isomerase and the compound of formula (II) have a mass ratio of 1:1-1:20; and/or the biological enzyme and the compound of formula (IV) have a mass ratio of 1:2-1:20.

12 . The method of claim 1 , wherein the first solvent and the third solvent is water or a miscible system of water and an organic solvent.

13 . The method of claim 1 , wherein the mass-volume ratio of the compound of formula (I) to the first solvent or the compound of formula (IV) to the third solvent is 1 g:10 mL-1 g:50 mL.

14 . The method of claim 1 , wherein the second solvent is an organic solvent.

15 . The method of claim 1 , wherein the mass-volume ratio of the compound of formula (II) to the second solvent is 1 g:10 mL-1 g:50 mL.

16 . The method of claim 1 , wherein the reacting a compound of formula (I), the reacting the by-product of formula (II), and/or the reacting the compound of formula (IV) is at a temperature range from 25° C. to 55° C.

17 . The method of claim 1 , wherein the reacting a compound of formula (I), the reacting the by-product of formula (II), and/or the reacting the compound of formula (IV) is for a time from 5 h to 20 h.

18 . The method of claim 1 further comprising extracting the by-product of formula (II) before the reacting with the isomerase.

19 . The method of claim 18 , wherein the extracting is with a fourth organic solvent selected from the group consisting of toluene, dichloromethane, methyl tert-butyl ether, and ethyl acetate.

Assignees

• Zhejiang Huahai Pharm Co Ltd

Inventors

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

Classifications

• C12Y301/01003

  Triacylglycerol lipase (3.1.1.3) · CPC title

• C12P13/005

  Amino acids other than alpha- or beta amino acids, e.g. gamma amino acids · CPC title

• C12P41/006

  by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures · CPC title

• C12Y504/99011

  Isomaltulose synthase (5.4.99.11) · CPC title

• C12Y501/03011

  Cellobiose epimerase (5.1.3.11) · CPC title