A new approach to the synthesis of 1 (DS003, BMS-599793), a small-molecule HIV entry inhibitor, is described. The initial medical chemistry route has been modified by rearranging the sequence of synthetic steps followed by replacement of the Suzuki coupling step by the Negishi conditions. Acylation of the resulting azaindole 7 under the Friedel–Crafts conditions is studied using monoesters of chlorooxalic acid in the presence of aluminum chloride. Polymorphism of 1 is also investigated to develop conditions suitable for preparation of the desired Form 1 of the target compound. The new route is further optimized and scaled up to establish a new process that is applied to the synthesis of kilogram quantites of the target active pharmaceutical ingredient.
Pikul, S.; Hua Cheng; Cheng, A.; Huang, C.D.; Ke, A.; Kuo LungHuang; Thompson, A.; Wilder, S. Synthetic Process Development of BMS-599793 Including Azaindole Negishi Coupling on Kilogram Scale. Organic Process Research and Development (2013) 17 (6) 907-914. [DOI: 10.1021/op400012p]