New disulfide route to 3-(1-piperazinyl)-1,2-benzisothiazole. Nucleus for atypical antipsychotic drugs

A new, one-step commercial process for the preparation of 3-(1-piperazinyl) -1,2-benzisothiazole hydrochloride, a key intermediate for the syntheses of some new "atypical antipsychotic" drugs, was developed. Reaction of bis(2- cyanophenyl) disulfide with excess piperazine at 120-140 degrees C for 3-24 h in the presence of small amounts of DMSO and 2-propanol formed 3-(1-pipe razinyl)-1,2-benzisothiazole in 75-80% yields. The DMSO oxidized the libera ted 2-mercaptobenzonitrile to regenerate bis(2-cyanophenyl) disulfide, ther eby enabling the utilization of both halves of the symmetrical disulfide to generate product. The reaction mechanism for the conversion of the bis(2-c yanophenyl) disulfide to 3-amino-1,2-benzisothiazole involves the formation of ring opened sulfenamide and benzamidine intermediates and then their su bsequent ring closure to regenerate the 1,2-benzisothiazole nucleus. A safe , efficient, and robust process to prepare 3-(1-piperazinyl)-1,2-benzisothi azole under very concentrated reaction conditions was developed and success fully scaled up in the pilot plant to support the development of ziprasidon e.