The Synthesis Of Rimonabant And Beckmann Rearrangement Catalyzed By Phosphorus Oxychloride

This paper was focused on the synthesis of rimonabant and Beckmann rearrangement catalyzed by phosphorus oxychlorideRimonabant was invented by Sanofi-Aventis and first to be launched to market in UK in 2006. It is the first selective CB1 receptor inverse agonist, which has recently been approved for the treatment of obesity and addiction.SR141716 was synthesized from 4-chloropropiophenone in four steps with an overall yield of 37.2%. The steps include the bromination of 4-chloropropiophenone to give 4-chlorophenyl 1-bromoethyl ketone; the reaction of diketene with 1-aminopiperidine hydrochloride to give N-(piperidin-1-yl)-3-oxobutanamide; the reaction of 4-chlorophenyl 1-bromoethyl ketone with N-(piperidin-1-yl)-3-oxobutanamide to give compound 16 and the key reaction of compound 16 with 2,4-dichlorobenzenediazonium chloride followed by heating at reflux in acetic acid to afford SR141716. At last, SR141716 is treated with hydrogen chloride to product rimonabant.The conversion of ketoxime into corresponding amide, known as the Beckmann rearrangement, is a common method used in organic chemistry and is also a topic of current interest. With the extensive applications of Beckmann rearrangement in organic synthesis, it is necessary to develop a simple, clean and no expensive catalyst system.Phosphorus oxychloride for Beckmann rearrangement was always used as solvent or dehydrating reagent. At present, P2O5, PC15 and bis(2-oxo-3-oxazolidinyl)phosphinic chloride as effective catalysts for Beckmann rearrangement have been reported and some new mechanisms have been proposed, we will show a protocol that uses phosphorus oxychloride as a catalyst for the Beckmann rearrangement. Initially, acetophenone oxime has been used as a substrate to establish the optimized reaction conditions, which are 5mol% phosphorus oxychloride in acetonitrile was heated under reflux for 10～20 min. Then, the Beckmann rearrangement of a series of ketoximes to the corresponding amides was also conducted at the optimized reaction conditions. At last, we prove that phosphorus oxychloride is an efficient catalyst for Beckmann rearrangement and propose its novel Beckmann rearrangement mechanism.The structure of all the intermediates and final product were identified by spectral data 1H-NMR and MS.