Wang Ting, Hua Yueting, Deng Fangbo, Wen Rui, Zhang Haoyu, Li Chunshi, Liu Yang, Cheng Maosheng
Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
Key Laboratory of Intelligent Drug Design and New Drug Discovery of Liaoning Province, Shenyang Pharmaceutical University, Shenyang 110016, China.
ACS Omega. 2024 Aug 23;9(36):37942-37952. doi: 10.1021/acsomega.4c04507. eCollection 2024 Sep 10.
A three-step method for the synthesis of methyl 5-(2,4-difluorophenyl)-4-methoxy-1-pyrrole-3-carboxylate , a key intermediate of fexuprazan, is reported in this paper. Using low-priced sodium -tolylsulfinate as the starting material, compound was obtained with a 96.8% yield in the first step by optimizing the experimental parameters with a Box-Behnken experimental design. Subsequently, isonitrile compound was obtained by dehydration. Finally, impurities and in the last step of the reaction were identified and converted into target product by a one-pot method, which significantly improves the utilization of atoms. Key intermediate was obtained via a three-step process with a yield of 68-70% and purity that exceeded 99%. In addition, the mechanism of the cyclization reaction was proposed. This method has potential for industrial production because the raw materials are inexpensive, the procedure is simple, and a high yield is obtained.
本文报道了一种合成非布司他关键中间体5-(2,4-二氟苯基)-4-甲氧基-1-吡咯-3-羧酸甲酯的三步方法。以低价的对甲苯亚磺酸钠为起始原料，通过Box-Behnken实验设计优化实验参数，第一步以96.8%的产率得到化合物。随后，通过脱水得到异腈化合物。最后，鉴定了反应最后一步中的杂质并通过一锅法将其转化为目标产物，这显著提高了原子利用率。关键中间体通过三步反应得到，产率为68-70%，纯度超过99%。此外，还提出了环化反应的机理。该方法具有工业生产潜力，因为原料廉价、操作简单且产率高。
