Study On The Synthesis Of Rimonabant

Rimonabant was synthesized from 4-chloropropiophenone via 6 steps. Bromination of 4-chloropropiophenone with Br₂ in AcOH gives a-bromo-4-chloropropiophenone in 98% yield.Reaction of a-bromo-4-chloropropiophenone with ethyl acetoaetate in THF in the presence of Nail gave ethyl 2-acetyl-3-(4-chlorophenylformyl) butanoate in 75% yield. Cyclization of ethyl 2-acetyl-3-(4-chlorophenylformyl) butanoate with 2,4-dichlorophenyl diazonium chloride in EtOH in the presence of NaOH ,followed by base catalyzed hydrolysis, gave 5-(4-chlorophenyl)-l-(2,4-dichloroph-enyl) -4-methyl-lH-pyrazole-3- carboxylic acid ethyl ester in 56% yield. The final product Rimonbant was then obtained in 64% yield via chlorination of the acid with oxalyl chloride followed by treatment of the resultant acyl chloride with 1-aminoperidine.The structure of the product and intermediates was determined by NMR and IR.The reaction parameters such as reaction temperature,reaction time,solvents used and reactant amount used were optimized.The overall of the process reached 25% yield under optimized,compared with the literature value of 12%.The mechanism of reactions were discussed according to experimental results.