Abstract: Mitiglinide acid and its isomer by-product acid were prepared by the reaction of cis-hexahydroisoindoline with acid anhydride which was prepared firstly from (S)-2-benzylsuccinic acid via dehydration. Isomer by-product acid was separated and isomerizated to mitiglinide acid,with which mitiglinide calcium was obtained by salification reaction. The effects of process conditions were studied. It has been shown that the yield of acid anhydride could reach 90.49% with 0.03mol (S)-2-benzyl succinic acid as raw material,10mL toluene as solvent,5mL acetic anhydride as dehydrating agent,and reaction temperature 110℃,reaction time 1h,while the yield of the reaction of acid anhydride with cis-hexahydroisoindoline can reach 97.60%. The HPLC contents of mitiglinide acid and its isomer were both higher than 98% after separated with ethyl acetate. The isomerization conversion rate can reach 57.65% using toluene as solvent and refluxed for 3h. The overall yield of product mitiglinide calcium was up to 67.49% with a HPLC content of 99.25%. The structure of the intermediates and products were characterized by ¹H NMR.

Key words: pharmaceuticals, mitiglinide calcium, synthesis, isomer, separation

摘要： (S)-2-苄基丁二酸脱水生成酸酐后与顺式全氢异吲哚反应生成米格列奈酸及其异构体副产物酸。将副产物酸分离出并异构化为米格列奈酸；米格列奈酸经成盐得产品米格列奈钙。考察了工艺条件对反应的影响，结果表明：以10mL甲苯为溶剂，5mL乙酸酐为脱水剂，0.03mol (S)-2-苄基丁二酸在110℃下脱水反应1h，酸酐收率可达90.49%；酸酐与顺式全氢异吲哚反应产物收率可达97.60%；用乙酸乙酯对产物米格列奈酸及其异构体副产物酸进行分离后，二者HPLC含量均高于98%；以甲苯为溶剂，回流反应3h，异构体副产物酸异构化为米格列奈酸，转化率达到57.65%；产品米格列奈钙总收率可达67.49%，HPLC含量高达99.25%。中间体和产物结构用¹H NMR进行表征确认。

关键词: 药物, 米格列奈钙, 合成, 异构体, 分离