Studies On Synthesis Of Rimonabant

Angiocardiopathy is closely related to many diseases and unhealthy life style, such as obesity, smoking, hyperlipoidemia, hypertension, type II diabetes and so on. Angiocardiopathy is the long-term superposed consequence of above many risk factors. The correlation is present between obesity, smoking type II diabetes and some cancers, such as breast and colorectal cancer. Increasing in body weight leads to changing in blood lipid and cholesterol levels, predisposing to atherosclerosis. Recent years Studies had shown that obesity could lead to changes in cardiac structure and function.The dramatic rise in the incidence of type II diabetes is due largely to the increased prevalence of obesity. In the past years, the research has clearly showed that endocannabinoid system was related to the risk factors of cardiovascular disease.The Endocannabinoid System (EC System) is a physiological system of cannabinoid receptors and corresponding chemical messengers that is believed to play an important role in regulating body weight and glucose and lipid metabolism. The EC System is also related with tobacco dependence.The new drug Rimonabant developed by Sanofi-Aventis in France is the first selective CB1 endocannabinoid receptor s antagonist. Rimonabant had effect on reducing appetite and abstaining from smoking by selectively blocking endogenous cannabinoid CB1 receptors. Rimonabant was used to treat obesity, smoking, type II diabetes and hyperlipoidemia simultaneously. The results showed that Rimonabant had clearly effect on such diseases. Meanwhile, side-effect and toxicity was very low. The characteristic of Rimonabant was that it not only aimed at just one of cardiovascular risk factors, but controlled all the cardiovascular risk factors. So it provided a brand-new research direction for the discovery of new drug. It was likely to be a new treatment for cardiovascular disease.Objective:①to synthesize N-(Piperidin1yl)-5-(4-chlo-rophenyl)-1-(2,4-dichlorophenyl)-4-methyl-pyrazole-3-carbox-amide hydrochloric acid salt, and to characterize its struct-ure by spectrum.②to improve the synthetic procedures,and synthesi-ze enough Rimonabant for formulating quality standard and the pharmaco-test.Methods:①Rimonabant was obtained via seven step-s. Firstly, the starting material 4-chloropropiophenone reac-ted with chorotrimethylsilane to form the trimethylsilylenolether of 4-chloropropiophenone, which reacted with ethyl oxalyl chloride to form the Ethyl 2,4-dioxo-3-methyl-4-(4-chlorophenyl)-butanoate(II). And then condensation of (II) with the2,4-dichlorophenylhydrazine hydrochloride salt, cyclized and hydrolyzed to produce the 5-(4-Chloro-phen yl)-1-(2,4-dichlr-ophenyl)-4-methyl-pyrazole-3-carboxylicacid(III). Finally,(III) was reacted to form 5-(4-Chlorophenyl)-1-(2,4-dihl-orophenyl)-4-methyl-pyrazole-3-carboxylic acid chloride, which reacted with 1-aminopiperidine to produceN-(Piperidin1yl)-5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-pyazole-3-carboxamide(Ⅳ).(Ⅳ) was finally treated with hydrochloric acid to form Rimonabant.②There is two Synthesis methods of 2,4-dioxo-3-methyl-4-(4-chlorophenyl)-butanoate(II)according to the documents.After analysis, we choosed to the second method to prepare(II): 4-chloro-propiophenone reacted with chorotrim-ethylsilane to form silyl enol ether, which reacted with ethyloxalyl chloride to synthesize the Ethyl 2,4-dioxo-3-methyl-butanoate(II). We set up the optimal condition to synthesize (II).③The structure of the product was characterized byinfrared spectroscopy, 1HNMR spectroscopy, mass spectra and element analysis. Its physicochemical property was studied.④The purity of the production was checked up by TCL and HPLC.Result:①N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4-methyl-pyrazole-3-carboxamide(Ⅳ), was synthesized. mp. 221.3~223.5℃. Rf=0.48 [Stationary Phase: GF254 for thin-layer chromatography; Mobile Phase:methylene chloride:acetic ether=1.5:1(v/v); detected at UVL254 nm]. The structure was characterized by 1HNMR, MS, IR,UV and EA.②Set up the optimal conditions to synthesize 2,4- dioxo-3-methyl-4-(4-chlorophenyl)-butanoate (II).③Purify product by recrystallization for three times instead of column chromotagraphy, so ispropyl ether was used as solvent to recrystallize(Ⅳ), yield 65.1%.Conclusion:①Rimonabant was synthesized. And thesynthetic route was an ideal one, which had common starting materials, simple operation,short reaction time, andsimple post-proceessing.②The synthesis of 2, 4-dioxo-3-methyl-4-(4-chloroph-enyl)-butanoate(II) was the key step, We set up theoptimal conditions to synthesize (II), and the determinationmethod of (II).③to synthesize enough Rimonabant for formulating quality standard and the pharmaco-test.