1-[2-(2,4-Dimethylphenylsulfanyl)-Phenyl]Piperazine As A Compound With Combined Serotonin Reuptake, 5-HT3 And 5-HT1a Activity For The Treatment Of Cognitive Impairment
AssigneeH. Lundbeck A/S
InventorsAndre Faldt, Lone Munch Ringgaard, Michael J. Mealy, Michael Harold Rock, Jorgen Brodersen, Morten Jorgensen
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Abstract
This disclosure relates to a process for the preparation of 1-[2-(2,4-dimethylphenylsulfanyl)-phenyl]piperazine or a salt thereof.
Claims30
A process for the preparation of
- or a salt thereof, the process comprising reacting compound II
- wherein R′ represent hydrogen or a mono-valent metal ion,
- with a compound of formula III
- wherein X1 and X2 independently represent halogen, and a compound of formula IV
- 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° C. and 130° C.
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-dimethyl-thiol, 1-bromo-1-iodo-benzene or 1,2-dibromo-benzene, and piperazine are dispersed in toluene followed by the addition of 2-5 equivalents NaO(t-Bu) and 1-2 mole-% Pd2dba3 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.
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-% Pddba2, 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.
Dependencies are inferred from the claim text.