| Bisoprolol fumarate, is a novel and specific ?1 receptor blocking agent by the German MERK company to the market in 1958. It has been one of the choice for the treatment of hypertension, angina, arrhythmias, and heart failure and so on.Bisoprolol fumarate, having water-lipid double dissolubility, compares with other drugs for treat hypertension has many advantages, such as rapid absorption, long half-life, low first pass effect, the liver and kidney metabolism in balance, as well as small individual differences in pharmacokinetics. Thus to explore a route with a high purity and high yield is of great significance. In this paper, based on analysis of existing synthetic route and several experiments, we adopted a synthetic process which use 4-hydroxybenzaldehyde as a starting material, by the reduction, etherified alcohol hydroxyl, etherified phenolic hydroxyl group, amine solution and salt formation to obtain bisoprolol fumarate, and we optimized and improved the process to suitable for industrial production.Reduction reaction used sodium borohydride as the reducing agent, avoiding the security risks caused by going to hydrogen in pressure. To prevent the waste of sodium borohydride, water as a reaction solvent. We determined the molar ratio of the 4-hydroxybenzaldehyde and sodium borohydride is 1: 0.4 by a single variable method and the reaction temperature is 15 ~ 20 ?, the total yield of the technology is 95.6%.In the alcoholic hydroxyl esterification reaction, concentrated sulfuric acid as a catalyst, instead of the organic acids and acidic ion exchange resins, simplified the operation process route. Using dichloromethane as a reaction solvent, the amount of 2-isopropoxy-ethanol was reduced from 15 times to 4 times and reduced the production costs. Raw material dropped to the reaction mixture about 6 hours in 20~30?, effectively controlling the generation of impurities, after the treatment process used sodium hydroxide neutralize acidic catalyst and ethyl acetate instead of toluene to ensure the health of laboratory personnel, the total yield of the technology is 90%.Phenolic hydroxyl etherification used Williamson ether synthesis, using water as a solvent to avoid the formation of impurities and sodium hydroxide as catalyst to promote the conversion reaction, we determined the molar ratio of 4-isopropoxy-ethoxy-methylphenol and epichlorohydrin is 1:3 by orthogonal experiments. The reaction time is 1 h, the reaction temperature is 65~70?, This process yield up to 84.2% by 65.7%.Aminolysis reaction used methanol as a solvent, the reaction temperature and the reaction rate can be increased, we determined the molar ratio of 2-((4-((2-isopropoxy-ethoxy) methyl) phenoxy) methyl) oxirane and isopropylamine is 1:3, the reaction time is 6h, the reaction temperature is 40~45?, in the after treatment, we converted isopropylamine into isopropylamine hydrochloride was removed by water, optimum pH8.5 ~ 9, This process is more stable and controllable and the overall yield is 79.1%, a 1.9% increased in yield compared to the original process.In salt-forming reaction, crystallization used ethyl acetate solvent instead of acetone, and recrystallization used isopropanol solvent, the total yield of the technology is raised to 80.2% by 77.4%. The structure and purity of these substances were confirmed by 1HNMR and HPLC.The process route in this paper had made development in the process, 4-hydroxybenzaldehyde is unexpensive and easily available, reduced the amount of isopropoxy ethanol, isopropyl amine and epichlorohydrin and optimumed reaction temperature, reaction time, improved process route, the product yield and purity, and the environmental protection. |
PDF Full Text Request