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Paper | Special issue | Vol 88, No. 1, 2014, pp.287-295
Published online, 5th July, 2013
DOI: 10.3987/COM-13-S(S)15
New, Lithiation-Based Synthesis of Tofisopam, a 2,3-Benzodiazepine Type Anxiolytic Drug

Erika Molnárné Samu,* Gyula Lukács, Balázs Volk, and Gyula Simig

*Chemical Research Deivision, EGIS Pharmaceuticals PLC, 1106 Hungary, Budapest,
Keresztúri út 30-38, Hungary

Abstract

The classical, widely-used synthesis of the anxiolytic drug tofisopam applies chromium(VI) oxide reagent for the synthesis of the diketone key intermediate. The chromium salts formed in the course of the reaction are strongly toxic compounds. In order to reduce the reagents contributing to the pollution of the environment, an alternative manufacturing process has been elaborated at our laboratory. Starting compound (3,4-dimethoxyphenyl)acetone was transformed to the ethylene ketal of (2-bromo-4,5-dimethoxyphenyl)acetone. Bromine-lithium exchange and introduction of a 3,4-dimethoxybenzoyl moiety resulted in the new key intermediate. Removal of the ketal protecting group and ring closure with hydrazine was carried out in one pot affording drug substance tofisopam.