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 °C for 3−24 h in...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Organic process research & development 1999-03, Vol.3 (2), p.126-130
Hauptverfasser: Walinsky, Stanley W, Fox, Darrell E, Lambert, John F, Sinay, Terry G
Format: Artikel
Sprache:eng
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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 °C for 3−24 h in the presence of small amounts of DMSO and 2-propanol formed 3-(1-piperazinyl)-1,2-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-(1-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.
ISSN:1083-6160
1520-586X
DOI:10.1021/op980210k