富马酸沃诺拉赞关键中间体的中试研究

Pilot Study on the Key Intermediate of Vonoprazan Fumarate

富马酸沃诺拉赞是一种治疗胃酸相关性疾病的新型钾离子竞争性酸阻滞剂,5-(2-氟苯基)-1H-吡咯-3-甲醛是其制备过程中的关键中间体。目的:开发一套反应步骤少、收率高、安全环保可控的中间体中试工艺。方法:以吡咯-3-甲醛为起始原料,在无水三氯化铝催化下与邻二氟苯进行傅克烷基化反应。结果:当无水三氯化铝用量为0.04 eq,滴加温度为0℃~5℃,保温温度为15℃~20℃,反应时间为12 h时反应效果最佳,产品外观为类白色,熔点为126.6℃~127.5℃,摩尔收率为62.75%。结论:中试过程产生的废物较少,无突出安全环保隐患,可为规模化量产提供一定的借鉴。

Voronazan fumarate is a novel potassium ion competitive acid blocker for gastric acid-related diseases,and 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde is a key intermediate in its preparation.Objective:Develop a intermediate pilot process with few reaction steps,high yield,safe and environmental controllability.Method:Using pyrrole-3-carbaldehyde as the starting material,it undergoes a Friedel-Crafts alkylation with o-difluorobenzene under the catalysis of anhydrous aluminum trichloride.Results:When the amount of anhydrous aluminum trichloride was 0.04 eq,the dropping temperature was 0℃~5℃,the holding temperature was 15℃~20℃,the reaction time was 12 h,the reaction effect was the best.The appearance of the product was similar to white,the melting point was 126.6℃~127.5℃,the molar yield was 62.75%.Conclusion:During the pilot test,less waste is produced,and there are no obvious safety and environmental hazards,which can provide some reference for large-scale production.