【摘要】 对阿折地平的合成工艺进行了研究,设计了一条适合于工业化生产的合成路线。以(1-二苯甲基-3-吖丁啶醇)脒基乙酸酯乙酸盐(Ⅲ)和2-(3-硝基苄叉)乙酰乙酸异丙酯(Ⅳ)为原料通过麦克加成得产品阿折地平(Ⅴ),产物收率86%,产品纯度大于99.5%。其中原料(Ⅲ)和(Ⅳ)可通过其它原料的合成得到,由乙酰乙酸异丙酯和间硝基苯甲醛可得原料(Ⅳ),产物收率76%;由3-氯-1,2-环氧丙烷和二苯甲胺制备1-二苯甲基-3-吖丁啶醇(Ⅰ),产物收率58%,化合物(Ⅰ)与氰基乙酸酯化得(1-二苯甲基-3-吖丁啶醇)氰基乙酸酯(Ⅱ),产物收率90%,化合物(Ⅱ)醇解胺化得原料(Ⅲ),产物收率85%。合成路线总收率达到30%,高于目前文献报道合成路线的收率。阿折地平粗品用苯-正己烷重结晶得α型阿折地平产品,用单一溶剂氯苯结晶得β型阿折地平产品。所有中间体和产品均采用HPLC和1H-NMR进行了定性及定量分析。更多还原

【Abstract】 The synthesizing route of Azelnidipine was studied and an appropriate synthesizing process was designed for industrialization.Azelnidipine was synthesized by Michael Reaction of(1-benzhydryl-3-azetidinyl)3,3-diaminoacrylate(Ⅲ) and isopropyl 2-(3-nitrobenzylidene) acetoacetate(Ⅳ).The yield of Azelnidipine was 86%,with purity of 99.5% by HPLC.Compound(Ⅳ) was synthesized by 3-Nitrobenzaldehyde and isopropyl acetoacetate,the yield was 76%.1-Benzhydryl-3-azetidinol(Ⅰ) was synthesized by benzhydrylamine and epichlorohydrin,the yield was 58%.(1-Benzhydryl-3-azetidinyl) cyanoacetate(Ⅱ) was synthesized by esterification of compound(Ⅰ) with cyanoacetic acid,the yield was 90%.Next,compound(Ⅲ) was prepared by alcoholysis and ammonolysis of compound(Ⅱ),the yield was 85%.The total yield of this route was 30%,higher than those of other synthesis routes reported.Azelnidipine was recrystallized from benzene and n-hexane to α-crystal form,and from chlorobenzene to β-crystal form.The intermediates and final products were characterized by HPLC and(()~1HNMR.)更多还原