|Title:||Process for preparing 1-[2-(2,4-dimethylphenysulfanyl)-pheny]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 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.1, 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:||Aug 29, 2014|
|Claims:||1. A process for the preparation of ##STR00017## or a salt thereof, the process comprising reacting compound II ##STR00018## wherein R' represents hydrogen or a mono-valent metal ion, with compound III ##STR00019## wherein X.sub.1 represents Br and X.sub.2 represents I, and compound IV ##STR00020## wherein R represents hydrogen, 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 said solvent is an aprotic solvent.
5. 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.
6. The process according to claim 5, wherein the solvent is toluene.
7. The process according to claim 1, wherein the palladium source is selected from the group consisting of Pddba.sub.2, Pd(OAc).sub.2 and Pd.sub.2dba.sub.3.
8. The process according to claim 7, wherein said palladium source is Pddba.sub.2 or Pd.sub.2dba.sub.3.
9. 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.
10. The process according to claim 9, wherein said phosphine ligand is rac-BINAP.
11. The process according to claim 1, wherein said base is selected from the group consisting of NaO(t-Bu), KO(t-Bu), Cs.sub.2CO.sub.3, DBU and DABCO.
12. The process according to claim 11, wherein said base is NaO(t-Bu).
13. The process according to claim 1, wherein R' is hydrogen.
14. The process according to claim 1, wherein the temperature is between 80.degree. C. and 120.degree. C.
15. 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.
16. The process according to claim 1, further comprising an additional step of reacting aqueous HBr with the product ##STR00022## said product optionally being in a purified form, to obtain the hydrobromic acid salt of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine.
17. The process of claim 16, further comprises precipitating the hydrobromic acid salt after 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine is reacted with the aqueous HBr, wherein the hydrobromic acid salt is crystalline.