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

Abstract

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.

Preparation of the HIV Attachment Inhibitor BMS-663068. Part 8. Installation of the Phosphonoxymethyl Prodrug Moiety

“…With respect to the advantage of Et 4 NI versus potassium iodide under the K 2 CO 3 conditions, control experiments showed the conversion of 2 to diphosphate 8, via iodide 7, by 1 H NMR in the presence of KI and K 2 CO 3 in CH 3 CN at 35 °C (Figure 3). 9 On the other hand, switching to tetrabutylammonium iodide (Bu 4 NI, TBAI) led to significantly decreased formation of 8 10 and therefore enabled a reduction in the amount of 2 needed for the alkylation.…”

“…3 While this modified endgame enabled the production of >1000 kg of API, we more recently reported a proposed commercial route to BMS-663068 which led to a dramatic improvement in overall efficiency and a significant reduction in cost. 4 Two of the key features in this new route were the return to the use of alkylation agent 2 as the electrophile for installation of the phosphonoxymethyl prodrug moiety, 5 and modification of the parent BMS-626529 freebase starting material 5 to the corresponding BMS-626529-Li salt (1).…”

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.…”

A Journey through Hemetsberger–Knittel, Leimgruber–Batcho and Bartoli Reactions: Access to Several Hydroxy 5‐ and 6‐Azaindoles

“…This approach has been widely used for the preparation of indoles [41,42] and azaindoles. [43,44] Applied to the preparation of hydroxy azaindoles, this methodology should allow us to obtain 4-halogeno 5-azaindoles 13 (Scheme 4), suitable substrates for 4-hydroxy 5-azaindole formation, as outlined previously (Scheme 13). Our strategy is based on the preparation of intermediates 10a and 10b, from 2-chloro or 2-bromo picoline.…”