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

• Published in: Organic process research & development 2017-08, Vol.21 (8), p.1145-1155
• Main Authors: Zheng, Bin, Silverman, Steven M, Steinhardt, Sarah E, Kolotuchin, Sergei, Iyer, Vidya, Fan, Junying, Skliar, Dimitri, McLeod, Douglas D, Bultman, Michael, Tripp, Jonathan C, Murugesan, Saravanababu, La Cruz, Thomas E, Sweeney, Jason T, Eastgate, Martin D, Conlon, David A
• Format: Article
• Language: English
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.7b00133

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.