An efficient, scalable, and chromatography-free six-step synthesis of the laxative drug bisacodyl (1) has been developed, starting from inexpensive 2-picolinic acid. This practical route achieves an overall yield of 46% and delivers the active pharmaceutical ingredient (API) in 99.88% HPLC purity. Key innovations include a crystallization-based workup for the key acid chloride intermediate, a highly selective Friedel–Crafts acylation/alkylation sequence, and a final acetylation employing a solvent-free system to suppress impurity formation. The process is distinguished by its operational simplicity, featuring direct filtration for the isolation of intermediates in five of the six steps and has been successfully demonstrated on a 500 g scale. This approach offers a robust, cost-effective, and environmentally friendly alternative to existing literature methods for the industrial manufacturing of bisacodyl.
Bian et al. (Fri,) studied this question.