Rhodium catalyzed hydroformylation of 1,1-bis( p-fluorophenyl)allyl or propargyl alcohol: a key step in the synthesis of Fluspirilen and Penfluridol

Abstract

Fluspirilen ( 1) and Penfluridol ( 2), two neuroleptic agents, belong to a wide class of pharmaceuticals that contain in their molecules a 4,4-bis( p-fluorophenyl)butyl group bound to a nitrogen atom of a pyrrolidine, piperidine or piperazine moiety. A key intermediate for the synthesis of compounds 1 and 2, 4,4-bis( p-fluorophenyl)butylbromide ( 15), has been prepared starting from commercially available 4,4′-difluorobenzophenone ( 7) following a preparative route involving the rhodium catalyzed hydroformylation in toluene or in the biphasic system toluene/water or cyclohexane/water of 1,1-bis( p-fluorophenyl)-2-propenol ( 8) and/or 1,1-bis( p-fluorophenyl)-2-propynol ( 12). Fluspirilen and Penfluridol were obtained in 70–80% yield by reaction of bromide 15 with 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one ( 16) and 4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol ( 17), respectively. The overall yields of the two pharmaceuticals 1 and 2, based on starting ketone 7, were about 35–40%.