医用胶中间体氰基乙酸正丁酯的合成工艺改进

Improved synthesis of n-butyl cyanoacetate

目的改进医用胶中间体氰基乙酸正丁酯的合成工艺,避免原料氰基乙酸乙酿反应不完全导致终产品合成中产生副产物α-氰基丙烯酸乙酯,有效降低终产品的细胞毒性。方法以氰基乙酸乙酯和正丁醇为起始原料(原料物质的量比为1:3),反应程序升温,反应时间为8h,经酯交换反应得到医用胶中间体氰基乙酸正丁酯,其结构经1H-NMR谱确证。采用CCK-8法,测定以此中间体制备的终产品氰基丙烯酸正丁酯对人包皮成纤维细胞Hs27的增殖抑制活性。结果与结论对氰基乙酸正丁酯的合成工艺进行了优化,总收率为86.5%(以氰乙酸乙酯计),HPLC测定纯度达99.98%。该合成路线原料容易获得、操作简便、无需额外纯化步骤、收率较高,有利于实验室和工业化生产。以此中间体制备的α-氰基丙烯酸正丁酯医用胶单体,不含有副产物α-氰基丙烯酸乙酯,可以有效避免副产物带来的细胞毒性。

n-Butyl cyanoacetate is the important intermediate in the synthesis ofα-butyl cyanoacrylate which is a common composition of medical adhesive.Synthesis of n-butyl cyanoacetate with a high purity is a key factor in the whole reaction for production of theα-butyl cyanoacrylate.Synthesis of n-butyl cyanoacetate via transesterification is an effective method.However,the purity of h-butyl cyanoacetate was always insufficient which finally led to the cytotoxicity ofα-butyl cyanoacrylate.In this paper,an optimal process for improved synthesis of n-butyl cyanoacetate was developed:the molar ratio was b 3,the reaction time was 8 h,and a gradient temperature raise.The total yield of n-butyl cyanoacetate was 86.5%(calculated from ethyl cyanoacetate).The structure was identified by 1H-NMR,and the purity was 99.98%determined by HPLC.The improved process is facile with convenient operation procedures and suitable for industrial production,α-butyl cyanoacrylate synthesized from n-butyl cyanoacetate by the optimal process could effectively avoid the cytotoxicity generated by the by-product ethylα-cyanoacrylate.