Method for preparing brivaracetam and intermediate thereof

Patent metadata

Field	Value
Publication number	US-12516021-B2
Application number	US-202017922140-A
Country	US
Kind code	B2
Filing date	Apr 30, 2020
Priority date	Apr 30, 2020
Publication date	Jan 6, 2026
Grant date	Jan 6, 2026

Abstract

Disclosed is a method for preparing a brivaracetam intermediate shown in formula B—R, comprising: reacting a compound shown in formula B—P and a resolving agent to prepare a compound shown in formula B-Q; and converting the compound shown in formula B-Q into the brivaracetam intermediate shown in formula B—R, wherein the resolving agent is a (1S,2S)-(+)-1,2-diaminocyclohexane compound. Also provided is a method for preparing brivaracetam. According to the method, a mixture of two diastereoisomers of(S)-2-3-propylpyrrolidine-1-yl butyric acid can be conveniently and effectively resolved, and the use of a chiral HPLC column is avoided, thereby greatly shortening the process time, simplifying the operation, reducing the process cost, and facilitating industrial production and environmental protection.

First claim

The invention claimed is:

1 . A method for preparing a brivaracetam intermediate represented by Formula B—R,

wherein the preparation method comprises:
(1) reacting a compound represented by Formula B—P with a resolving reagent to obtain a compound represented by Formula B-Q,

(2) converting the compound represented by Formula B-Q to the brivaracetam intermediate represented by Formula B—R;
wherein the resolving reagent is a (1S,2S)-(+)-1,2-cyclohexanediamine compound having Formula (I),

wherein, in Formula (I), R 1 , R 2 , and R 5 are each independently selected from the group consisting of H, CH 3 , and Ts, and R 1 , R 2 , and R 5 are not Ts simultaneously.

2 . The method according to claim 1 , wherein the resolving reagent is selected from the group consisting of 1S,2S-cyclohexanediamine, 1S,2S—N,N-dimethyl-1,2-cyclohexanediamine, (1S,2S)—N1,N1,N2,N2-tetramethyl-cyclohexane-1,2-diamine and N-((1S,2S)-2-(dimethylamino)cyclohexyl)-4-toluenesulfonamide, or any combination thereof.

3 . The method for preparing according to claim 1 , wherein a molar ratio of the compound represented by Formula B—P to the resolving reagent is 1:0.8 to 1.5.

4 . The method for preparing according to claim 1 , wherein the step (1) comprises:
a. adding the compound represented by Formula B—P and the resolving reagent to a resolving solvent, dissolving the solids at a resolving temperature to obtain a clear solution, cooling the solution to crystallize, and separating crystals to obtain a solid crude product of the compound represented by Formula B-Q; and b. recrystallizing the solid crude product in a recrystallization solvent, and separating crystals to obtain the compound represented by Formula B-Q.

5 . The method according to claim 4 , wherein the resolving solvent is selected from the group consisting of methyl tert-butyl ether (MTBE), isopropyl ether, tetrahydrofuran (THF), acetonitrile, ethyl acetate (EA), isopropyl acetate (IPAC), isopropanol and dimethyl ether (DME), or any combination thereof.

6 . The method according to claim 4 , wherein a ratio of a volume of the resolving solvent to a mass of the compound represented by Formula B—P is 1 mL to 30 mL:1 g.

7 . The method according to claim 4 , wherein the recrystallization solvent is selected from the group consisting of methyl tert-butyl ether, acetonitrile, ethyl acetate, isopropyl acetate and dimethyl ether, or any combination thereof.

8 . The method according to claim 4 , wherein a ratio of a volume of the recrystallization solvent to a mass of the compound represented by Formula B-Q is 1 mL to 30 mL:1 g.

9 . The method according to claim 1 , wherein the step (2) comprises: converting the compound represented by Formula B-Q to the brivaracetam intermediate represented by Formula B—R in a reaction solvent, in the presence of an acid.

10 . The method according to claim 9 , wherein the acid in the step (2) is dilute hydrochloric acid, trifluoroacetic acid or a combination thereof.

11 . The method according to claim 9 , wherein the reaction solvent in the step (2) is selected from the group consisting of isopropanol, ethyl acetate, isopropyl acetate and water.

12 . A method for preparing brivaracetam, wherein the method comprises:
preparing the brivaracetam intermediate represented by Formula B—R according to the method of claim 1 ; and aminating the brivaracetam intermediate represented by Formula B—R to brivaracetam.

13 . The method according to claim 3 , wherein the molar ratio of the compound represented by Formula B—P to the resolving reagent is 1:1.

14 . The method according to claim 6 , wherein the ratio of the volume of the resolving solvent to the mass of the compound represented by Formula B—P is 1 mL to 10 mL:1 g.

15 . The method according to claim 6 , wherein the ratio of the volume of the resolving solvent to the mass of the compound represented by Formula B—P is 3 mL to 6 mL:1 g.

16 . The method according to claim 7 , wherein the recrystallization solvent is selected from the group consisting of isopropyl acetate, acetonitrile, ethyl acetate and dimethyl ether, or any combination thereof.

17 . The method according to claim 8 , wherein the ratio of the volume of the recrystallization solvent to the mass of the compound represented by Formula B-Q is 1 mL to 10 mL:1 g.

18 . The method according to claim 8 , wherein the ratio of the volume of the recrystallization solvent to the mass of the compound represented by Formula B-Q is 3 mL: 1 g.

19 . The method according to claim 4 , wherein the resolving temperature is 50° C. to 75° C.

Assignees

• Shanghai Syncores Tech Inc Ltd
• Zhejiang Huahai Pharm Co Ltd

Inventors

• Zhan Yipeng
• Fan Haisheng
• Yin Kai
• Ji Xiang
• Liu Boyang
• Guo Xiaowen
• Huang Luning
• Tao Anping
• An Jianguo
• Gu Hong

Classifications

• C07B2200/07

  Optical isomers · CPC title

• C07B57/00

  Separation of optically-active compounds · CPC title

• C07D207/27 Primary

  with substituted hydrocarbon radicals directly attached to the ring nitrogen atom · CPC title