【作者】 常宏宏；

【导师】 魏文珑；

【作者基本信息】 太原理工大学 ， 化学工艺， 2004， 硕士

【摘要】 本文介绍了抗高血压药物的应用现状及分类。钙拮抗剂因具有降压效果确切、对末梢血管选择性高、对各种代谢无副作用、禁忌症少和血管扩张作用等优点，而成为临床应用较广的心血管药物。尼伐地平属于第二代二氢吡啶类钙拮抗剂，其与Ca²⁺通道特异部位的结合力比硝苯地平强10倍，作用持续时间较之长2-3倍，血药浓度较为平稳，良好的降压作用能维持24小时以上。因此，尼伐地平是安全、高效的首选高血压治疗药物，其应用前景十分广阔，市场潜力十分巨大。 本文重点研究设计了尼伐地平的合成工艺路线，通过实验合成了尼伐地平及其五个中间体，并对其进行了分析表征。通过考察各步反应的影响因素，得到了最佳工艺条件，具体如下： （1）以50％乙醛酸水溶液和原甲酸三甲酯为主要原料，经浓硫酸催化，合成二甲氧基乙酸甲酯。在考察了合成工艺条件的基础上，通过正交实验设计对反应条件进行了优化，得到了最佳反应条件。二甲氧基乙酸甲酯的收率可达92.16％。太原理工大学硕士学位论文 （2）以二甲氧基乙酸甲酷和乙酸甲酷为主要原料，经甲醇钠催化制备二甲氧基乙酞乙酸甲醋。在考察了原料摩尔比、催化剂用量、加料温度、反应温度和反应时间等影响因素对反应收率影响的基础上，通过均匀实验设计优化了反应条件。在最佳合成条件下，二甲氧基乙酞乙酸甲酷的收率可达43.56%。 （3）以二甲氧基乙酞乙酸甲醋和间硝基苯甲醛为原料，呱咤和冰醋酸为催化剂，合成2一（3一硝基亚节基）一4，4一二甲基乙酞乙酸甲酷。通过考察原料配比、催化剂用量及加料方式、反应时间等因素对产率的影响，得到了最佳合成条件。粗产品产率可达112.30%。（粗产品不经提纯，直接用于下一步反应）。 （4）以2一（3一硝基亚节基）一4，4一二甲基乙酞乙酸甲醋和3一氨基巴豆酸异丙醋为主要原料，缩合脱水生成3一甲氧梭基一2，2一二甲氧基甲基一4一（3一硝基苯基）一6一甲基一1，4一二氢毗陡一5-梭基异丙酷。通过考察原料配比、反应温度和反应时间等因素对收率的影响，得到了最佳合成条件。3一甲氧梭基一2，2一二甲氧基甲基一4一（3一硝基苯基）一6一甲基一1，4一二氢毗陡一5一梭基异丙酷的收率可达83.52%。 （5）以3一甲氧梭基一2，2一二甲氧基甲基一4一（3一硝基苯基）一6一甲基一1，4一二氢毗吮一5一梭基异丙醋和6mol几盐酸为原料，丙 太原理工大学硕士学位论文酮作溶剂，缩合得到3一甲氧梭基一2一甲酞基一4一（3一硝基苯基）一6一甲基一1，4一二氢毗淀一5一梭酸异丙醋。通过考察配料比、反应温度及反应时间等因素的影响，得到了最佳合成条件。3一甲氧梭基一2一甲酞基一4一（3一硝基苯基）一6一甲基一1，4一二氢毗陡一5一梭酸异丙酉旨可达85.44%。 （6）以3一甲氧梭基一2一甲酞基一4一（3一硝基苯基）一6一甲基一1，4-二氢毗陡一5一竣酸异丙酷和盐酸经胺为原料，无水乙酸钠和乙酸配为脱水剂，合成尼伐地平。通过考察原料摩尔比、脱水剂用量、反应时间和反应温度等因素的影响，得到了最佳合成条件。尼伐地平的收率可达33.76%。 在上述最佳反应条件下，尼伐地平的总收率可达10.86%。在国内未见与本研究内容相同的报道。更多还原

【Abstract】 In this paper, the present situation of application and classfication of pharmaceutical for treatment of hypertesion were introduced. Calcium antagonists has been accepted for the treatment of cardiovascular diseases in clinical. It has many predominace such as the better for decreasing of blood pressure, high selectivity for distal blood vessel, and no side affection for all kinds of metabolism, small taboo symptom and affection for vascular expand etc.. Nilvadipine is the second generation of dihydropyridine calcium antagonists. Its cohesion with the special location of calcium ion is 10 times stronger than previous Nifeddipine and affect lasting 2 to 3 times longer than that. The blood pressure decreasing can be maintained well for 24 hours because of its steady pharmceutical concentrationin blood. So Nilvadipine is a safe, efficacious and first-selective pharmceutical in treatment of hypertension. Therefor it has a wild potential in the market.The synthesis process of Nilvadipine and its five intermediates were designed. The optimum reaction conditions were obtained as followry:(1) A new process has been developed to synthesize dimethoxyacetic acid methyl ester with the 50% solution of glyoxylic acid and methylorthoformate in the presence of concentrated sulfuric acid. The reaction conditions have been optimized by orthogonal experimental design. The yield of dimethoxyacetic acid methyl ester was to 92.16%.(2) A new process has been developed to synthesize dimethoxy methyl aceto acetate with dimethoxyacetic acid methyl ester and methyl acetate in the presence of sodium methanol. On the basis of investigating effects of the mole ratio of raw material, amount of catalyst, reaction temperature and time, the optimum reaction conditions were obtained by using uniform design, and the yield of dimethoxy methyl aceto acetate was to 43.56%.(3) A new process has been developed to synthesize mehtyl 2-(3-nitrobenzyliene)-4,4-dimethoxyacetoacetate with dimethoxy methyl aceto acetate and 3-nitrobenzal dehyde in the presence of piperidine and acetic acid ylacial. The effects of the mole ratio of raw material, the amount and feeding method of catalyst, reaction time on the yield were investigated. The optimum reaction conditions were obtained. The rate of production of methyl 2-(3-nitrobenzyliene)-4,4-dimethoxyacetoacetate was to 112.30%, which was used in the following reaction without purification.(4) A new process has been developed to synthesize 2,2-dimethoxyme-thyl-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methyl 5-(l-methylethyl) diester with methyl 2-(3-nitrobenzyliene) -4,4-dimethoxyacetoacetate and 3-aminocaotonic acid isproxycarbonyl ester. The optimum reaction conditions were obtained by investigating effects of the mole ratio of raw material, reaction temperature and time on the yield. The yield of 2,2-dimemoxymethyl-ls4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methyl 5-(l-methylethyl) diester was to83.52%.(5) A new process has been developed to synthesize 2-formyl-l,4- dihy-dro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-mehtylethyl diester with 2,2-dimethoxymethyl-l,4-dihydro-6-methyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylic acid 3-methyl 5-(l-methylethyl) diester and 6mol/L hydrochloric acid in the presence of acetone as solvent. The optimum reaction conditions were obtained by investigating the effects of mole ratio of raw material, reaction temperature and time on the yield. The yield of 2-formyl-l,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methylethyl diester was to 85.44%.(6) A new process has been developed to synthesize Nilvadipine with 2-formyl-l,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methylethyl diester and hydroxylamine hydrochloride in the presence of sodium acetate anhydrous as dehydrate. The optimum reaction conditions were obtained by investigating effects of the mole ratio of raw material, amount of dehydrate, re更多还原