Preparation of the HIV Attachment Inhibitor BMS-663068. Part 6. Friedel–Crafts Acylation/Hydrolysis and Amidation

The development of a process for appending the oxalyl amide side chain to the azaindole core of the HIV-attachment inhibitor BMS-663068 is described. A Friedel–Crafts acylation installed the oxalyl ester, which was subsequently hydrolyzed and amidated with a benzoyl piperazine. The development of the commercial route necessitated several key changes to the initial synthesis. For instance, in the original acylation process, nitromethane, a commonly used, but highly energetic cosolvent, was employed which was eventually replaced by catalytic tetra-n-butylammonium bisulfate to overcome gelling issues encountered during the reaction when nitromethane was omitted. It was further demonstrated that the amidation sequence could be relegated to a single-pot, homogeneous transformation through the use of the cost-effective coupling reagent diphenylphosphinic chloride. The above modifications have been utilized in multiple campaigns and reproducibly demonstrated on scales of up to 200 kg input.