吉非替尼合成方法改进

Improved Synthesis of Gefitinib

本文报道一条简单有效的合成吉非替尼的工艺路线。以3-羟基-4-甲氧基苯甲醛为起始原料,将其醛基转化为氰基后再与N-(3-氯丙基)吗啉缩合,然后依次经硝化、水解、还原、环合等操作得到重要的中间体7,最后经氯化后与3-氯-4-氟苯胺缩合以总收率48%得到吉非替尼。其中对如下过程进行优化:硝化反应后处理改用NaOH中和酸,然后过滤纯化;硝基还原反应改用甲酸铵、Pd/C的催化的条件;环合反应后处理采用蒸馏的方法除去甲酸,这些改进显著提高了反应总收率。

A convenient procedure for the synthesis of gefitinib is described.Important intermediate 7 was obtained from 3-hydroxy-4-methoxybenzaldehyde via conversion of aldehyde to nitrile,followed by alkylation with N-（3-chloropropy1）morpholine,nitration,hydrolization,reduction,cyclization and finally subjected to chlorination and condensation with 3-chloro-4-fluoroaniline.The procedure was improved and the overall yield was raised to 48% by optimizing the following procedures： NaOH was employed for neutralization in the post-processing of nitration reaction and then purified by filtration;ammonium formate was used as the hydrogen donor in the Pd/C catalyzed reduction and finally in the post-processing of cyclyzation,formic acid was removed by distillation.