Preparation of the HIV Attachment Inhibitor BMS-663068. Part 1. Evolution of Enabling Strategies

Autor:	Schultz Mitchell J, Payack Joseph Francis, Thomas E. La Cruz, Deniz Erdemir, Peng Geng, Sévrine Broxer, Ivy Sabrina E, Chung-Pin H. Chen, David A. Conlon, Zhongmin Xu, Saravanababu Murugesan, Fanfair Dayne Dustan, Fritz Alan W, Ryan Cullen, Tripp Jonathan Clive, Boguslaw Mudryk, Wendel W. Doubleday, Richard J. Fox
Rok vydání:	2017
Předmět:	Active ingredient 010405 organic chemistry Chemistry Organic Chemistry Human immunodeficiency virus (HIV) medicine Physical and Theoretical Chemistry 010402 general chemistry medicine.disease_cause 01 natural sciences Combinatorial chemistry 0104 chemical sciences
Zdroj:	Organic Process Research & Development. 21:1095-1109
ISSN:	1520-586X 1083-6160
DOI:	10.1021/acs.oprd.7b00134
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::0c87b27b11fba74bca85d3614705da09 https://doi.org/10.1021/acs.oprd.7b00134 Zobrazit plný text záznamu