Journal
ORGANIC PROCESS RESEARCH & DEVELOPMENT
Volume 26, Issue 10, Pages 2855-2863Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.oprd.2c00206
Keywords
vilazodone; impurity; process; detosylation; scalable
Categories
Funding
- State Key Laboratory of Anti-Infective Drug Development (Sunshine Lake Pharma Co., Ltd)
- Key-Area Research and Development Program of Guangdong Province
- [2015DQ780357]
- [2022B1111050003]
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A robust and scalable synthesis for vilazodone was developed to avoid the formation of impurities under alcoholic conditions. By adjusting the functionality transformations, the process successfully prevented the generation of harmful impurities and was validated at a kilogram scale.
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 center dot 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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