Preparation of the HIV Attachment Inhibitor BMS-663068. Part 2. Strategic Selections in the Transition from an Enabling Route to a Commercial Synthesis

Abstract

During the process of developing a synthesis to a complex molecule, multiple decisions are made regarding the strategies and tactics used to prepare key bonds. In this article, we preface a series of papers describing the development of the commercial synthesis of BMS-663068 (a potential new treatment for HIV), with an in-depth discussion of the important strategic decisions made during the process of designing and demonstrating the proposed commercial synthesis of this complex clinical candidate. We discuss the key strategic disconnections and the key experimental data used to drive our tactical decisions during development. In the remaining articles in this series, we outline the development of these enabling chemical processes into scalable procedures ready to support commercialization of this promising new medicine.

Evolving Green Chemistry Metrics into Predictive Tools for Decision Making and Benchmarking Analytics

“…To expand upon this concept and to demonstrate this approach on fundamentally different synthetic approaches, we explored PMI prediction in the different strategies considered for the end-game of the synthesis of BMS-663068 ( 8), a potential new treatment for HIV. 33,34 Here, we present some of the strategic options considered by the team working on this molecule starting from the 7-bromo-6-azaindole 1 to the penultimate 8 (Scheme 2). 35 In order to demonstrate the importance of holistic comparisons, we compared several different scenarios.…”

Thermal Stability Assessment of Peptide Coupling Reagents Commonly Used in Pharmaceutical Manufacturing

“…Entries 5–13 contain coupling reagents that facilitate amidations via mixed anhydride formation. Both T3P (entry 5) and CDI (entry 6) are commonly used for the scale-up of APIs in the pharmaceutical industry. CDI is inexpensive, readily available in bulk quantities, and soluble in a number of common organic solvents.…”

Synthetic Approaches to the New Drugs Approved During 2020

“…Cabotegravir was approved in Canada and Europe for the treatment of HIV-1 infection in adults to replace the current antiretroviral therapy in patients who are virologically stable and suppressed . The initial approval of the drug was for codosing of cabotegravir with rilpivirine, which was approved in 2011 for the treatment of HIV-1 infection in treatment-naïve adult patients as a fixed-dose combination with emtricitabine and tenofovir disoproxil .…”