1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine dihydrochloride

1-{[2-(4-Chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazine Dihydrochloride is an intermediate used in the preparation of Venetoclax (A112430), which is a potent and selective BCL-2 inhibitor with potent antitumour activity while sparing platelets. Venetoclax is used to treat chronic lymphocytic leukaemic cells and estrogen receptor-positive breast cancer.

To a solution of tert-butyl 4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1 -enyl)methyl)piperazine-1 - carboxylate 6 (30 g, 0.072 mol) in MeOH (20 mL) was added conc.HCI (50 mL). The reaction was stirred for 24 hours and then concentrated under reduced pressure. A saturated solution of NazCCh was added to adjust the pH to 8-9, and the mixture was extracted with dichloromethane (2x200 mL). The combined extracts were washed with brine, dried (NazSC ), filtered, and concentrated under reduced pressure. The oil product was treated with MeOH/HCI (g) (3.0 M, 500 mL) and stirred for 1 hour, then concentrated under reduced pressure to get the product 1-((4'-chloro-5,5-dimethyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazine dihydrochloride (23 g, 83%).