Method for synthesizing key intermediate of apixaban

Patent metadata

Field	Value
Publication number	US-9656958-B2
Application number	US-201414902286-A
Country	US
Kind code	B2
Filing date	Jul 29, 2014
Priority date	Aug 2, 2013
Publication date	May 23, 2017
Grant date	May 23, 2017

Abstract

The invention relates to a method for synthesizing an intermediate of Apixaban comprising reacting a compound of formula I with 5-chloro-valeryl chloride in the presence of inorganic base in an inert solvent to obtain a compound of formula II, with the reaction formula of (A), wherein R is selected from nitro group and the group (B). The method is mild in reaction condition, simple in operation, easy in purification, inexpensive in production cost, environmental-friendly, and suitable for industrial production.

First claim

The invention claimed is:

1. A method for synthesizing an intermediate of Apixaban of formula II, characterized in that, the method comprises the step of: reacting a compound of formula I with 5-chloro-valeryl chloride in an inert solvent in the presence of an inorganic base to obtain a compound of formula II, with the reaction scheme of:

wherein R is selected from nitro group or

 group;
the inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, or potassium bicarbonate.

2. The method according to claim 1 , characterized in that, the inert solvent is selected from the group consisting of tetrahydrofuran, acetonitrile, dichloromethane, N,N-dimethylformamide, or 1,2-dichloroethane.

3. The method according to claim 1 , characterized in that, the inorganic base is sodium hydroxide.

4. The method according to claim 1 , characterized in that, the inert solvent is acetonitrile.

5. The method according to claim 1 , characterized in that, the molar ratio of 5-chloro-valeryl chloride to the compound of formula I is 1.0 -3.0:1.

6. The method according to claim 1 , characterized in that, the inorganic base is sodium hydroxide, and the molar ratio of sodium hydroxide to the compound of formula I is 2.0 - 10.0:1.

7. The method according to claim 1 , characterized in that, the inert solvent is acetonitrile, and the ratio of the volume of the solvent to the weight of the reactant is 25 - 40:1.

8. The method according to claim 1 , wherein 5-chloro-valeryl chloride is added dropwise, and the reaction temperature when dropwise adding 5-chloro-valeryl chloride is controlled to -10° C. to 10° C.

9. The method according to claim 1 , wherein 5-chloro-valeryl chloride is added dropwise, and the reaction temperature after completing the addition of 5-chloro-valeryl chloride is 0° C. to 50° C.

10. The method according to claim 2 , characterized in that, the inert solvent is acetonitrile.

11. The method according to claim 5 , characterized in that, the molar ratio of 5-chloro-valeryl chloride to the compound of formula I is 1.5 -2.3:1.

12. The method according to claim 6 , characterized in that, the molar ratio of sodium hydroxide to the compound of formula I is 5.0 - 6.5:1.

13. The method according to claim 7 , characterized in that, the ratio of the volume of the solvent to the weight of the reactant is 28 - 35:1.

14. The method according to claim 2 , characterized in that, the inert solvent is acetonitrile, and the ratio of the volume of the solvent to the weight of the reactant is 25 - 40:1.

15. The method according to claim 8 , wherein the reaction temperature when dropwise adding 5-chloro-valeryl chloride is controlled to -5° C. to 5° C.

16. The method according to claim 9 , wherein the reaction temperature after completing the addition of 5-chloro-valeryl chloride is 15° C. to 40° C.

Assignees

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

Inventors

• Wang Boyu
• Yao Jinfeng
• Huang Luning
• Zhang Jeannie

Classifications

• C07D211/02

  Preparation by ring-closure or hydrogenation · CPC title

• C07D211/76

  attached in position 2 or 6 · CPC title

• C07D211/88 Primary

  attached in positions 2 and 6, e.g. glutarimide · CPC title

• C07D211/40

  Oxygen atoms · CPC title