Synthesis Process Improvement Of Sibutramine Hydrochloride

Obesity is a chronic disease that body wrongly control body fat and energy metabolism balance leading to excessive accumulation and abnormal distribution of body fat. It is caused by both genetic and environmental factors. Obesity has been clearly identified by World Health Organization as the world's largest adult chronic disease, and is listed as one of the world's four major medical community problems.China has more than 7000 million people obese patients (not including childhood obesity),5.4% of the total population. With the reform and opening up and improvement of people's material living conditions, obese patients are growing year by year, especially in cities with high incidence, accounting for 17% of the urban population. In Beijing, Shanghai and other major cities, nearly one-third of adults are overweight, a high incidence of obesity. The past decade, child obesity were an average annual growth rate of 9%, which means that after ten years the number of obese children in China than they are now twice as many. Obesity is now considered a chronic disease that is difficult to cure, and with amazing speed. Therefore, obesity research and treatment of drug development is extremely urgent.Sibutramine bydrochloride is a new appetite suppression weight control agent, it does not have the potential addiction of amphetamine. Its active metabolite Ml and a secondary amine M2 could inhibite 5-Serotonin and norepinephrine in the body. It suppressed appetite by increasing the sense of fullness and enhanced energy consumption by inducing heat production. Using the drug, Weight loss effect is obvious, and well tolerated, and don't cause any addiction. As a drug having great potential market, its development could bring enormous economic and social benefit.There are two routes in the synthesis of sibutramine hydrochloride.The Route 1 has eiight-step synthetic reaction with the overall yield of 12.1%(counted by chlorophenyl acetonitrile). The technology having relatively long route and hard conditions cause the disadvantages with greater difficultes in the working up, high cost and unstable quality of the product.Route 2 made the improvements on the basis of Route 1, the reaction route was shortened and the yield reached 36.3%. There are also some problems in this route, such as the process being unstable, hard conditions and environmental problems etal.Based on the second method and other papers, the syntheses of sibutramine hydrochloride were improved and optimized in this dissertation. We use the following synthetic route considering the safety, environmental protection, energy conservation and lower production costs. Chlorobenzyl chloride reacted with sodium cyanide in ethanol to replace to get 4-chlorophenyl acetonitrile(1), via replacement reaction. 1-(4-chlorophenyl) cyclobtanecarbonitrle (2) was obtained by the reaction of 4 chlorophenyl acetonitrile with 1,3-dibromo propane hydrocarbons in the presence of the catalyst KF/Al2O3. 1-(4-chlorophenyl) cyclobtanecarbonitrle reacted with isobutyl magnesium bromide to get (1-[1-(4-chlorophenyl) cyclobutyl]-3-methyl) magnesium enamine (3) via Grignard reagent reaction. N-(1-[1-(4-chlorophenyl) ring butyl]-3-methyl butyl])-N, N-dimethyl amine (7) was obtained by the reduction of 3 using the reduction system of potassium borohydride and formaldehyde.The target compound 1 (4-chlorophenyl)-N, N-dimethyl-a-(2-methyl propyl) cyclobutane-methanamine hydrochloride salt M was obtained by the acidification of 7 reacting with HCl.The improved and optimized synthesis of Sibutramine hydrochloride is more suitable for industrial production with the mild reaction conditions, stable process and simple operation. Under the optimized conditions, Sibutramine hydrochloride was obtained in the yield of 57.8%, which reduce the cost of the production. Inensuring production safety, product quality and running stability of the process, reduce production costs and improve the market competitiveness of products, while maximizing energy savings, reduced emissions, truly social and economic maximize the benefits.