R. Vaid, Sathish K. Boini, Jeremy T. Spitler
Apr 16, 2013
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Synthesis
Abstract
An efficient eight-step synthesis of the title compound, starting from oxoacetic acid monohydrate, was developed. Condensation of oxoacetic acid monohydrate with N , N -dimethylethanamine followed by reductive amination and protection gave N -( tert -butoxycarbonyl)- N -[2-(dimethylamino)ethyl]glycine. Activation of this intermediate with 1,1′-carbonylbis-1 H -imidazole followed by treatment with (methoxyamino)methane gave tert -butyl [2-(dimethylamino)ethyl]{2-[methoxy(methyl)amino]-2-oxoethyl}carbamate, which upon reaction with [4-fluoro-3-(trifluoromethyl)phenyl]magnesium bromide, generated in situ, and subsequent deprotection gave 2-{[2-(dimethylamino)ethyl]amino}-1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone dihydrochloride. Coupling of this diamine with an activated carboxylic acid gave tert -butyl 4-{1-[2-(dimethylamino)ethyl]-4-[4-fluoro-3-(trifluoromethyl)phenyl]-1 H -imidazol-2-yl}piperidine-1-carboxylate, which on treatment with sodium acetate in ethanol followed by deprotection in situ and neutralization gave the title compound in good yield.