A Novel and Practical Synthesis of Rimonabant Hydrochloride

摘要

Rimonabant hydrochloride (8) is the first drug in a new class of selective cannabinoid type 1 (CB1) receptor antagonists, which also shows to play a significant role in clinical trials for the treatment of obesity and related metabolic risk factors, as well as tobacco dependence. Over the past few years, several synthetic strategies for the preparation of 8 have been reported. Potentially the most useful route for the large scale synthesis of 8 is illustrated in Scheme 1. Its initial stages involve treatment of 4-chloropropiophenone (1), to afford l-(4-chlorophenyl) -1-trimethylsiloxylpropene (2) in the presence of chlorotrimethylsi-lane and upon addition of ethyl chlorooxoacetate produced ethyl 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutanoate (3).An alternate approach to 3 entails the acylation of the enolate of 1 (from LiHMDS) to yield the lithium salt of 3.Co~(II)densation of 3 with 2,4-chlorophenylhydrazine to give phenylhydrazone intermediate 4 which was cyclized to ethy1-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-1Hyrazole-3-carboxylate(5); hydrolysis of 5 gave 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl-1Hyrazole-3-carboxylic acid (6) which was subsequently converted to 8 (cheme 1).