Method for preparing dabigatran etexilate intermediate, and intermediate compound

Patent metadata

Field	Value
Publication number	US-10112901-B2
Application number	US-201415323709-A
Country	US
Kind code	B2
Filing date	Jul 3, 2014
Priority date	Jul 3, 2014
Publication date	Oct 30, 2018
Grant date	Oct 30, 2018

Abstract

Disclosed are a method for preparing a dabigatran etexilate intermediate, and an intermediate compound. The method for preparing a dabigatran etexilate intermediate 4 comprises: reacting a compound 3 with a C 1 -C 3 alkyl alcohol solution of methylamine in an organic solvent, wherein, X=chlorine, bromine, or iodine. Also disclosed are an intermediate compound 3 and a preparation method thereof. The method for preparing a dabigatran etexilate intermediate of the present invention has the advantages of simple process, easy operation, high yield, and easy purification, thus being suitable for industrial production.

First claim

What is claimed is:

1. A preparation method of a dabigatran etexilate intermediate 4, comprising: reacting a compound 3 with a C 1 -C 3 alkyl alcohol solution of methylamine in an organic solvent, wherein the organic solvent is a erotic organic solvent or an aprotic organic solvent; and

wherein, X=chlorine, bromine, or iodine.

2. The preparation method according to claim 1 , wherein the protic organic solvent is methanol and/or ethanol, and the aprotic organic solvent is an aprotic polar organic solvent.

3. The preparation method according to claim 2 , wherein the aprotic organic solvent is one or more of dimethyl sulfoxide, N,N-dimethyl formamide, N,N-dimethyl acetamide, and N-methyl pyrrolidone.

4. The preparation method according to claim 1 , wherein the C 1 -C 3 alkyl alcohol solution of methylamine is one or more of a methanol solution of methylamine, an ethanol solution of methylamine, and a propanol solution of methylamine; and the concentration of the C 1 -C 3 alkyl alcohol solution of methylamine is 27-32% by weight.

5. The preparation method according to claim 1 , wherein the molar ratio of the compound 3 to methylamine is 1:1.98-1:2.35.

6. The preparation method according to claim 1 , wherein the C 1 -C 3 alkyl alcohol solution of methylamine is added by dripping the C alkyl alcohol solution of methylamine into a mixture of the compound 3 and the organic solvent.

7. The preparation method according to claim 1 , wherein when the organic solvent is a prone organic solvent, the reaction temperature is 30-40° C.; and when the organic solvent is an aprotic organic solvent, the reaction temperature is 60-90° C.

8. The preparation method according to claim 7 , wherein when the organic solvent is an aprotic organic solvent, the reaction temperature is 70° C.

9. The preparation method according to claim 1 , wherein the compound 3 is prepared through a method comprising: acylating a compound 2 with ethyl 3-(pyridin-2-yl-amino)propionate in dichloromethane and/or tetrahydrofuran in the presence of an organic base; and then the dabigatran etexilate intermediate 4 is prepared following the preparation method according to claim 1 ,

wherein, X=chlorine, bromine, or iodine.

10. The preparation method according to claim 9 , wherein the organic base is triethylamine and/or N,N-diisopropylethylamine.

11. The preparation method according to claim 9 , wherein the molar ratio of the compound 2 to ethyl 3-(pyridin-2-yl-amino)propionate is 1:1; the molar ratio of the organic base to the compound 2 is 1:1-2:1; and the acylation temperature is 0-30° C.

12. The preparation method according to claim 9 , wherein the volume/weight ratio of dichloromethane and/or tetrahydrofuran to the compound 2 is 4-7 ml/g.

13. The preparation method according to claim 9 , wherein the compound 2 is added by dripping a mixture of the compound 2 and dichloromethane and/or tetrahydrofuran into a mixture of ethyl 3-(pyridin-2-yl-amino)propionate and the organic base.

14. A compound having a structure represented by

wherein, X=chlorine, bromine, or iodine.

15. A preparation method of the compound 3, represented by:

the preparation method comprising: acylating a compound 2 with ethyl 3-(pyridin-2-yl-amino)propionate in dichloromethane and/or tetrahydrofuran in the presence of an organic base,

wherein, X=chlorine, bromine, or iodine; and
the reaction conditions in the preparation method are as defined in claim 9 .

Assignees

• Shanghai Inst Pharmaceutical Ind
• China State Inst Pharm Ind
• Chia Tai Tianqing Pharmaceutical Group Co Ltd

Inventors

• Guo Yajun
• Shan Hanbin
• Zhu Xueyan
• Yuan Zhedong
• Yu Xiong
• Guo Meng
• Hu Mingtong
• Wang Duzheng
• Huang Yu

Classifications

• C07D213/75 Primary

  Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates · CPC title