化学
产量(工程)
烷基化
烷基
吲哚试验
酰化
弗里德尔-克拉夫茨反应
杂质
组合化学
有机化学
催化作用
材料科学
冶金
作者
Zihong Zhou,Yahui Feng,Yongbo Xu,S. X. Wu,Jingping Kou,Yanqing Hu,Meng Zhang,Wei-Jian Ling,Lei Zhang,Zhongqing Wang
标识
DOI:10.1021/acs.oprd.2c00206
摘要
A robust and scalable synthesis for vilazodone was developed to avoid the formation of impurities derived from N-detosylation reactions under alcoholic conditions. During our research, these impurities, potentially genotoxic alkyl tosylate and out-of-specification indole N-alkylated vilazodones, were identified as process impurities that have never been reported. Through adjusting the functionality transformations, this process successfully prevented the tosyl group from encountering any alkoxides, which would inevitably lead to the generation of alkyl tosylate and indole N-alkylated vilazodone byproducts. In addition, this manufacturing process has also been demonstrated on a kilogram scale, delivering 1.05 kg of vilazodone hydrochloride with an overall yield of 71% (calculated from ethyl 5-(piperazin-1-yl)benzofuran-2-carboxylate hydrochloride 7·HCl). HPLC purity of the product was detected >99.5%, with any single impurity <0.1% HPLC area percentage. Indole N-alkylated vilazodones were not detected, and the yield was 10% higher than the previous Friedel–Crafts acylation route.
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