Synthesis method for cariprazine

Patent metadata

Field	Value
Publication number	US-11420948-B2
Application number	US-201917266955-A
Country	US
Kind code	B2
Filing date	Aug 6, 2019
Priority date	Aug 29, 2018
Publication date	Aug 23, 2022
Grant date	Aug 23, 2022

Abstract

The present application relates to a synthesis method for cariprazine, comprising performing an acylation reaction between a compound represented by formula (I) and dimethylcarbamoyl chloride in a reaction solvent in the presence of an aqueous solution of an inorganic base, so as to obtain the cariprazine compound represented by formula (II). The synthesis method overcomes defects in the prior art such as a long reaction time, large size impurities and the difficulty of purification, and provides a new method suitable for commercial production wherein the reaction is fast, impurity sizes are small, the product is easily purified, the purity of the product can reach 99.0% or more, and the yield is high.

First claim

The invention claimed is:

1. A method of synthesizing cariprazine represented by formula (II), comprising: in a reaction solvent, in the presence of an aqueous solution of an inorganic base, acylating a compound represented by formula (I) with dimethylcarbamoyl chloride to obtain cariprazine represented by formula (II), as shown in the reaction formula:

wherein the aqueous solution of the inorganic base is Na 2 CO 3 aqueous solution or K 2 CO 3 aqueous solution.

2. The method according to claim 1 , wherein the inorganic base has a concentration of 5-30% by weight in the aqueous solution of the inorganic base.

3. The method according to claim 1 , wherein the reaction solvent is a solvent that is immiscible with water.

4. The method according to claim 3 , wherein the reaction solvent is one or at least two selected from the group consisting of dichloromethane, toluene, tetrahydrofuran and 2-methyltetrahydrofuran.

5. The method according to claim 3 , wherein the reaction solvent is dichloromethane or 2-methyltetrahydrofuran.

6. The method according to claim 1 , wherein a reaction temperature of the acylation reaction is 0-100° C.

7. The method according to claim 6 , wherein the reaction temperature of the acylation reaction is 10-70° C.

8. The method according to claim 6 , wherein the reaction temperature of the acylation reaction is 15-30° C.

9. The method according to claim 1 , wherein a ratio in mole of the inorganic base to a sum of the compound represented by formula (I) and dimethylcarbamoyl chloride is greater than or equal to 1.

10. The method according to claim 1 , further comprising: after completing the acylation reaction, removing a water phase, adding a crystallization solvent to an organic phase to precipitate cariprazine, and then filtering.

11. The method according to claim 10 , wherein, before adding the crystallization solvent, if the reaction solvent in the organic phase is not dichloromethane, the reaction solvent in the organic phase is replaced with dichloromethane.

12. The method according to claim 10 , wherein the crystallization solvent is n-heptane and/or cyclohexane.

13. The method according to claim 1 , wherein the compound represented by formula (I) is added to the reaction solvent in the form of itself or salt thereof.

14. The method according to claim 9 , wherein a ratio in mole of the inorganic base to the sum of the compound represented by formula (I) and dimethylcarbamoyl chloride is 2-6:1.

15. The method according to claim 12 , wherein the crystallization solvent is n-heptane.

16. The method according to claim 13 , wherein the salt of the compound represented by formula (I) is one or at least two selected from the group consisting of the dihydrochloride, sulfate, and dihydrobromide of the compound represented by formula (I).

17. The method according to claim 13 , wherein the salt of the compound represented by formula (I) is dihydrochloride of the compound represented by formula (I).

Assignees

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

Inventors

• Liao Wenjing
• Ge Jianfeng
• Zhang Jicheng
• Huang Luning
• Tao Anping
• Gu Eric

Classifications

• C07D295/135 Primary

  with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings · CPC title

• C07B43/06

  of amide groups · CPC title

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title