Efficient Method for Synthesis of 2-Acetylbenzo(b)thiophene and Its Derivatives, the Key Synthons for 5-Lipoxygenase Inhibitors

Abstract

An efficient method was developed for synthesis of 2-acetylbenzo(b)thiophene (2a), the key intermediate for zileuton (1). Synthesis involves treatment of 2-chlorobenzaldehyde (5a) with tert-butylmercaptan (6) to form 2-(tert-butylthio)benzaldehyde (7a), which upon treatment with HBr in water gave the disulfide derivative 2,2′-disulfanediyldibenzaldehyde (8a) in 97% yield. Finally, the reaction of 8a with acetylacetone (9) and 1-chloroacetone (10) gave 2-acetylbenzo(b)thiophene (2a) in 94% yield. The methodology is general and suitable for the preparation of its derivatives, 2b–d.

Keywords:

• 2-Acetylbenzo(b)thiophene
• 5-lipoxygenease inhibitors
• synthesis

ACKNOWLEDGMENTS

We thank Dr. Martin Babcock, director of API products, Abbott, for support and Dr. Hua-Hai Gong, Abbott, for HRMS assistance.