阿折地平的合成及其结晶的研究

Synthesis of Azelnidipine and Its Crystallization

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。

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 （ⅠI ） 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.