Details for Patent: 9,101,626

Title:	Process for preparing 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or pharmaceutically acceptable salt thereof
Abstract:	This disclosure relates to a process for the preparation of 1-[2-(2,4-dimethylphenylsulfanyl) -phenyl]piperazine or a pharmaceutically acceptable salt thereof. The process includes reacting compound II with compound III and compound IV ##STR00001## in the presence of a solvent, a base and a palladium catalyst. R, R', X.sub.i, and X.sub.2 in the formulas above are defined in the Specification.
Inventor(s):	Faldt; Andre (Ishoj, DK), Ringgaard; Lone Munch (Copenhagen, DK), Mealy; Michael J. (Lejre, DK), Rock; Michael Harold (Hvidovre, DK), Brodersen; Jorgen (Holbaek, DK), Jorgensen; Morten (Bagsvaerd, DK)
Assignee:	H. Lundbeck A/S (Copenhagen-Valby, DK)
Filing Date:	Apr 29, 2014
Application Number:	14/264,373
Claims:	1. A process for the preparation of ##STR00017## or a pharmaceutically salt thereof, the process comprising reacting compound II ##STR00018## wherein R' represent hydrogen or a mono-valent metal ion, with a compound of formula III ##STR00019## wherein X.sub.1 and X.sub.2 independently represent halogen, and a compound ##STR00020## wherein R represent hydrogen or a protecting group, in the presence of a solvent, a base and a palladium catalyst consisting of a palladium source and a phosphine ligand at a temperature between 60.degree. C. and 130.degree. C. 2. The process according to claim 1, wherein compound II and compound III are reacted in a first reaction, and wherein the reaction product ##STR00021## for said first reaction is optionally isolated and purified, followed by a subsequent reaction with the compound IV. 3. The process according to claim 1, wherein compound II, compound III and compound IV are mixed together at the start of the process. 4. The process according to claim 1 wherein X.sub.1 and X.sub.2 independently represent Br or I. 5. The process according to claim 4, wherein X.sub.1 represents Br and X.sub.2 represents I. 6. The process according to claim 1, wherein said solvent is an aprotic solvent. 7. The process according to claim 1, wherein the solvent is selected from the group consisting of toluene, xylene, triethyl amine, tributyl amine, dioxin and N-methylpyrrolidone. 8. The process according to claim 7, wherein the solvent is toluene. 9. The process according to claim 1, wherein the palladium source is selected from Pddba.sub.2, Pd(OAc).sub.2 and Pd.sub.2 dba.sub.3. 10. The process according to claim 9, wherein said palladium source is Pddba.sub.2 or Pd.sub.2 dba.sub.3. 11. The process according to claim 1, wherein said phosphine ligand is selected from the group consisting of 2,2'-bis-diphenylphosphanyl-[1,1']binaphtalenyl(rac-BINAP), 1,1'-bis(diphenylphosphino)ferrocene (DPPF), bis-(2-diphenylphosphinophenyl)ether (DPEphos), tri-t-butyl phosphine (Fu's salt), biphenyl-2-yl-di-t-butyl-phosphine, biphenyl-2-yl-dicyclohexyl-phosphine, (2'-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine, [2'-(di-t-butyl-phosphanyl)-biphenyl-2-yl]-dimethyl-amine, and dicyclohexyl-(2',4',6'-tri-propyl-biphenyl-2-yl)-phosphane. 12. The process according to claim 11, wherein said phosphine ligand is rac-BINAP. 13. The process according to claim 1, wherein said base is selected from NaO(t-Bu), KO(t-Bu), Cs.sub.2CO.sub.3, DBU and DABCO. 14. The process according to claim 13, wherein said base is NaO(t-Bu). 15. The process according to claim 1, wherein R represents hydrogen. 16. The process according to claim 1, wherein R represents a protecting group selected from Boc, Bn, Cbz, C(.dbd.O)OEt and Me. 17. The process according to claim 1, wherein the R' is hydrogen. 18. The process according to claim 1, wherein the temperature is between 80.degree. C. and 120.degree. C. 19. The process according to claim 3, comprising the steps of a. Dissolving or dispersing 1-1.5 equivalents of compounds II, III, and IV in toluene to obtain mixture A; b. Adding 1-2 mole-% of Pddba.sub.2 and 1-2 mole-% of rac-BINAP together with 2-3 equivalents of NaO(t-Bu) to mixture A to obtain mixture B, which is heated to around 100.degree. C. until compound II and III are fully converted; c. Increasing the temperature of the mixture obtained in step b to around 120.degree. C. until compound IV is fully converted; and d. Optionally removing the protecting group by the addition of aqueous acid if compound IV is a protected piperazine. 20. The process according to claim 3, wherein 1-1.5 equivalents of 2,4-dimethylthiolphenol, piperazine, and one of 1-bromo-2-iodo-benzene and 1,2-dibromo-benzene are dispersed in toluene followed by the addition of 2-5 equivalents NaO(t-Bu) and 1-2 mole-% Pd.sub.2dba.sub.3 and rac-BINAP dispersed in toluene to obtain a mixture which is heated to 100-130.degree. C. for 2-10 hours to obtain the product 1-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine. 21. The process according to claim 20, wherein said mixture is heated to reflux for 3-5 hours, and which process is followed by a subsequent step in which the obtained product is further reacted with aqueous HBr to obtain the corresponding hydrobromic acid addition salt. 22. The process according to claim 3, wherein 2-5 equivalents of NaO(t-Bu), 2-5 equivalents piperazine, 0.2-0.6 mole-% Pddba.sub.2, and 0.6-1 mole-% rac-BINAP are dispersed in toluene to obtain mixture A', to which mixture approximately 1 equivalent 2-bromo-iodobenzene is added to obtain mixture B', to which mixture 1 equivalent 2,4-dimethylthiophenol is added and the resulting mixture is heated to reflux for 3-7 hours to obtain 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine. 23. The process according to claim 22, wherein said resulting mixture is heated to reflux for 4-6 hours, and which process is followed by a subsequent step in which the obtained product is further reacted with aqueous HBr to obtain the corresponding hydrobromic acid addition salt. 24. The process according to claim 1 with the additional step of adding aqueous HBr to the product ##STR00022## said product optionally being in a purified form, to obtain the corresponding hydrobromic acid salt. 25. A process for the manufacturing of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromic acid addition salt in which process 1-1.5 equivalents of 2,4-dimethylthiolphenol, piperazine, and one of 1-bromo-2-iodo -benzene and 1,2-dibromo-benzene are dispersed in toluene followed by the addition of 2-5 equivalents NaO(t-Bu) and 1-2 mole-% Pd.sub.2dba.sub.3 and rac-BINAP dispersed in toluene to obtain a mixture which is heated to reflux 3-5 hours to obtain the product 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine, which is further reacted with aqueous hydrobromic acid. 26. A process for the manufacturing of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromic acid addition salt in which process 2-5 equivalents of NaO (t-Bu), 2-5 equivalents piperazine, 0.2-0.6 mole-% Pddba.sub.2, and 0.6-1 mole-% rac-BINAP are dispersed in toluene to obtain mixture A', to which mixture approximately 1 equivalent 2-bromo-iodobenzene is added to obtain mixture B', to which mixture 1 equivalent 2,4-dimethylthiophenol is added and the resulting mixture is heated to reflux for 4-6 hours to obtain 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine, which is further reacted with aqueous hydrobromic acid. 27. The process of claim 25, wherein the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromic acid addition salt is crystalline and the process further comprises precipitating the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromic acid addition salt after 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine is reacted with aqueous hydrobromic acid. 28. The process of claim 26, wherein the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromic acid addition salt is crystalline and the process further comprises precipitating the 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromic acid addition salt after 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]piperazine is reacted with aqueous hydrobromic acid.