71970-91-7Relevant articles and documents
New disulfide route to 3-(1-piperazinyl)-1,2-benzisothiazole. Nucleus for atypical antipsychotic drugs
Walinsky, Stanley W.,Fox, Darrell E.,Lambert, John F.,Sinay, Terry G.
, p. 126 - 130 (1999)
A new, one-step commercial process for the preparation of 3-(1-piperazinyl)-l,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 °C for 3-24 h in the presence of small amounts of DMSO and 2-propanol formed 3-(l-piperazinyl)-l,2-benzisothiazole in 75-80% yields. The DMSO oxidized the liberated 2-mercaptobenzonitrile to regenerate bis(2-cyanophenyl) disulfide, thereby enabling the utilization of both halves of the symmetrical disulfide to generate product. The reaction mechanism for the conversion of the bis(2-cyanophenyl) disulfide to 3-amino-1,2-benzisothiazole involves the formation of ring-opened sulfenamide and benzamidine intermediates and then their subsequent ring closure to regenerate the 1,2-benzisothiazole nucleus. A safe, efficient, and robust process to prepare 3-(l-piperazinyl)-1,2-benzisothiazole under very concentrated reaction conditions was developed and successfully scaled up in the pilot plant to support the development of ziprasidone.
