364046-14-0Relevant articles and documents
Preparation of the HIV Attachment Inhibitor BMS-663068. Part 1. Evolution of Enabling Strategies
Fox, Richard J.,Tripp, Jonathan C.,Schultz, Mitchell J.,Payack, Joseph F.,Fanfair, Dayne D.,Mudryk, Boguslaw M.,Murugesan, Saravanababu,Chen, Chung-Pin H.,La Cruz, Thomas E.,Ivy, Sabrina E.,Broxer, Sévrine,Cullen, Ryan,Erdemir, Deniz,Geng, Peng,Xu, Zhongmin,Fritz, Alan,Doubleday, Wendel W.,Conlon, David A.
, p. 1095 - 1109 (2017/08/23)
The development of two enabling routes that led to the production of >1000 kg of BMS-663068 (3) is described. The route identified for the initial 100 kg delivery to support development activities and initial clinical trials involved the conversion of 2-amino-4-picoline to the parent active pharmaceutical ingredient (API), followed by pro-drug installation and deprotection. To eliminate the problematic isolation of the parent API and synthesis of di-t-butyl(chloromethyl)phosphate, a second-generation pro-drug installation route was developed which involved the conversion of a late-stage common intermediate to an N(1)-thioether derivative followed by chloromethylation, displacement with di-t-butylpotassium phosphate, and deprotection. This second strategy resulted in the multikilogram scale preparation of the API in 14 linear steps and ~7% overall yield.