Vortioxetine intermediate and synthesis process thereof

Patent metadata

Field	Value
Publication number	US-9926286-B2
Application number	US-201515126890-A
Country	US
Kind code	B2
Filing date	Mar 25, 2015
Priority date	May 9, 2014
Publication date	Mar 27, 2018
Grant date	Mar 27, 2018

Abstract

The present invention provides a new intermediate II and a method for synthesizing the same. The method comprises: (a) firstly diazotizing a compound of formula I as a raw material, and then halogenating to obtain an intermediate II; and (b) reacting the intermediate II with a compound III to obtain a compound IV, hydrolyzing the obtained compound IV directly without being separated to obtain Vortioxetine represented by compound V. The intermediate II can be used for synthesizing Vortioxetine.

First claim

What is claimed is:

1. A method for synthesizing an intermediate II, characterized by firstly diazotizing a compound of formula I as a raw material, and then halogenating to obtain the intermediate II:

in each formula, R is a protective group for amino, and X is halogen.

2. The method of claim 1 , wherein R is selected from: tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, carboxybenzyl, acetyl or trifluoroacetyl.

3. The method of claim 2 , wherein R is tert-butoxycarbonyl or acetyl.

4. The method of claim 1 , wherein X is selected from: chlorine, bromine or iodine.

5. The method of claim 4 , wherein X is bromine.

6. The method of claim 1 , wherein the halogenating agent used in the halogenating reaction is selected from: NaX, KX, LiX, MgX 2 , CuX, CuX 2 , or a mixture of any two thereof, or a mixture of copper sulfate and NaX.

7. The method of claim 6 , wherein the halogenating agent is a mixture of sodium bromide and cuprous bromide, or a mixture of lithium bromide and cuprous bromide.

8. The method of claim 1 , further comprising reacting the intermediate II with a compound III to obtain a compound IV, hydrolyzing the obtained compound IV directly without being separated to obtain Vortioxetine represented by compound V,

9. A compound of following formula

wherein R is 9-fluorenylmethoxycarbonyl or carboxybenzyl; and X is halogen.

10. The compound of claim 9 , wherein X is selected from: chlorine, bromine or iodine.

11. The compound of claim 10 , wherein X is bromine.

12. A method for synthesizing Vortioxetine represented by formula V, comprising: reacting the intermediate II with the compound III, wherein bis(2-diphenylphosphinophenyl)ether is used as a phosphine ligand,

wherein R is acetyl, 9-fluorenylmethoxycarbonyl, carboxybenzyl, or truflyoroacetyl; and X is a halogen.

13. The method of claim 12 , wherein the obtained compound IV is hydrolyzed directly without being separated to obtain Vortioxetine represented by compound V.

14. The method of claim 12 , wherein the molar ratio of bis(2-diphenylphosphinophenyl)ether to the intermediate II is 0.6 to 6.0%.

15. The method of claim 13 , wherein the molar ratio of bis(2-diphenylphosphinophenyl)ether to the intermediate II is 0.6 to 6.0%.

16. The method of claim 12 , wherein the molar ratio of bis(2-diphenylphosphinophenyl)ether to the intermediate II is 0.75 to 1.5%.

17. The method of claim 12 , wherein the molar ratio of bis(2-diphenylphosphinophenyl)ether to the intermediate II is 0.75 to 0.9%.

18. The method of claim 13 , wherein the molar ratio of bis(2-diphenylphosphinophenyl)ether to the intermediate II is 0.75 to 1.5%.

19. The method of claim 13 , wherein the molar ratio of bis(2-diphenylphosphinophenyl)ether to the intermediate II is 0.75 to 0.9%.

Assignees

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

Inventors

• Tang Caide
• Wang Gang
• Wang Boyu
• Huang Luning
• Gu Eric

Classifications

• C07D295/185

  from aliphatic carboxylic acids · CPC title

• C07D295/096 Primary

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

• C07D295/205

  Radicals derived from carbonic acid · CPC title