Synthesis of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine

Patent metadata

Field	Value
Publication number	US-10562872-B2
Application number	US-201716072596-A
Country	US
Kind code	B2
Filing date	Feb 6, 2017
Priority date	Feb 8, 2016
Publication date	Feb 18, 2020
Grant date	Feb 18, 2020

Abstract

The invention relates to a method for synthesis of 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]piperazine in the presence of a strong base.

First claim

The invention claimed is:

1. A method for preparing 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]piperazine, said method comprising the steps of
reacting a piperazine with an electrophile in an organic solvent in the presence of a base and in the absence of a transition metal catalyst, thereby obtaining
i. 1-[2-fluoro-phenyl]piperazine or 1-[2-chloro-phenyl]piperazine; or
ii. 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine,

wherein the electrophile is selected from the group consisting of 1, 2-di-fluorobenzene, 2-chloro-fluorobenzene, 1, 2-di-chlorobenzene, 2-(2,4-di-methyl-thiophenol-yl)-chlorobenzene, and 2-(2,4-di-methyl-thiophenol-yl)-fluorobenzene; the base has a pKa above 29 in DMSO or a pKa above 25 in THF; and the organic solvent only contains protons with a pKa above 32 in DMSO;
if 1-[2-fluoro-phenyl]piperazine or 1-[2-chloro-phenyl]piperazine is obtained, reacting said 1-[2-fluoro-phenyl]piperazine or 1-[2-chloro-phenyl]piperazine with 1-sulfanyl-2,4-dimethyl-benzene, thereby obtaining 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]piperazine; and
optionally purifying the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine.

2. The method according to claim 1 , wherein 2-(2,4-di-methyl-thiophenol-yl)-chlorobenzene or 2-(2,4-di-methyl-thiophenol-yl)-fluorobenzene has been obtained by reacting
i. 1, 2-di-fluorobenzene, 2-chloro-fluorobenzene, or 1, 2-di-chlorobenzene with
ii. 2,4-dimethyl-phenylsulfanyl.

3. The method according to claim 1 , wherein reacting the piperazine with the electrophile comprises the sub-steps of i) reacting the piperazine with said base and ii) reacting the product of step i) with said electrophile, and wherein sub-steps i) and ii) are performed in the indicated order.

4. The method according to claim 1 , wherein the solvent only contains protons with a pKa above 35.1 in DMSO.

5. The method according to claim 1 , wherein the solvent contains no carbonyl groups.

6. The method according to claim 1 , wherein the solvent contains no sulfoxide groups.

7. The method according to claim 1 , wherein the solvent is selected from the group consisting of ethers, alkanes, benzene and substituted benzene.

8. The method according to claim 7 , wherein the ether is selected from the group consisting of tetrahydrofuran (THF), dioxane, dimethoxyethane (DME), and 2-methyl-tetrahydrofuran (2-Me-THF).

9. The method according to claim 7 , wherein the alkane is a liquid at the reaction temperature.

10. The method according to claim 7 , wherein the alkane is methylcyclohexane.

11. The method according to claim 7 , wherein the substituted benzene is benzene substituted with one or more substituents selected from the group consisting of C1-3-alkyl and —Cl, wherein said benzene is substituted with at most 1 —Cl.

12. The method according to claim 7 , wherein the substituted benzene is selected from the group consisting of xylene, toluene and chlorobenzene.

13. The method according to claim 1 , wherein the base has a corresponding acid that has a pKa of less than 45 in THF.

14. The method according to claim 1 , wherein the base is selected from the group consisting of LiHMDS, NaHMDS, KHMDS, LiTMP, and BuLi.

15. The method according to claim 1 , wherein the base is selected from the group consisting of LiHMDS, NaHMDS, KHMDS and LiTMP.

16. The method according to claim 1 , wherein reacting the piperazine with the electrophile is performed at a temperature of at most 120° C.

17. The method according to claim 1 , wherein reacting the piperazine with the electrophile takes places for at most one week.

18. The method according to claim 1 , wherein reacting the piperazine with the electrophile takes places for 5 to 900 minutes.

19. The method according to claim 1 , wherein said 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine is obtained as a salt thereof.

20. The method of claim 1 , wherein reacting the piperazine with the electrophile is performed at a temperature of at most 110° C.

21. The method of claim 1 , wherein reacting the piperazine with the electrophile takes places for 5 to 720 minutes.

22. The method of claim 1 , wherein the solvent is selected from the group consisting of tetrahydrofuran (THF), dioxane, dimethoxyethane (DME), and 2-methyl-tetrahydrofuran (2-Me-THF), and the base is selected from the group consisting of LiHMDS, NaHMDS, KHMDS and LiTMP.

Assignees

• H Lundbeck As

Inventors

• Diness Frederik
• Meldal Morten
• Jacobsen Christian Borch

Classifications

• C07D295/073

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

• C07D333/70

  attached in position 2 · CPC title

• C07D413/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D217/02

  with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines · CPC title

• C07D295/033

  with the ring nitrogen atoms directly attached to carbocyclic rings · CPC title