Synthetic Process Development of BMS-599793 Including Azaindole Negishi Coupling on Kilogram Scale

Abstract

A new approach to the synthesis of 1 (DS003, BMS-599793), a small-molecule HIV entry inhibitor, is described. The initial medical chemistry route has been modified by rearranging the sequence of synthetic steps followed by replacement of the Suzuki coupling step by the Negishi conditions. Acylation of the resulting azaindole 7 under the Friedel–Crafts conditions is studied using monoesters of chlorooxalic acid in the presence of aluminum chloride. Polymorphism of 1 is also investigated to develop conditions suitable for preparation of the desired Form 1 of the target compound. The new route is further optimized and scaled up to establish a new process that is applied to the synthesis of kilogram quantites of the target active pharmaceutical ingredient.

Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals

“…This reagent has seen widespread use as coupling reagent for amide bond formation due to the mild reaction conditions and the usually high yields of amide product that it provides. It is also particularly efficient for sterically hindered couplings. , For these reasons, several process groups in pharmaceutical companies have reported HATU applications for the synthesis of drug candidates …”

Sulfur(IV)‐Mediated Unsymmetrical Heterocycle Cross‐Couplings

“…[5,6] As an example, a high loading of palladium (> 10 %) was required in the Negishi and Stille [7] couplings to access 7 (Figure 1), a key intermediate in the preparation of microbicide BMS-599793 (6), in both discovery [8] and process settings. [9] In light of the foregoing, development of an alternative and practical (and preferably transition-metal-free) method for crosscoupling, particularly one that is amendable for basic heterocyclic substrates remains desirable. Recently, the McNally group reported an elegant approach to access 2,2'-diazines through a phosphorous mediated cross-coupling.…”

“…Direct application of sulfinyl chloride 14 led to an increased yield of 77 % with only a trace amount of first homo-coupling (entry 4). Application of other alkyl sulfinyl chlorides (15)(16)(17)19) resulted in diminished yields (entries [5][6][7]9), while paramethylphenyl sulfinyl chloride 18 offered a slightly lower yield (entry 8). Furthermore, isopropylsulfinyl chloride 14 was proved to be a more general reagent than 18 after the side-by-side comparison reactions for selected substrates (see Supporting Information for additional details).…”

Sulfur(IV)‐Mediated Unsymmetrical Heterocycle Cross‐Couplings

“…Furthermore, a number of heteroaryl nucleophiles are known to have poor stability under cross‐coupling conditions; for example, boronic acids having azine nitrogen at the α‐position are prone to proto‐deborylation . As an example, a high loading of palladium (>10 %) was required in the Negishi and Stille couplings to access 7 (Figure ), a key intermediate in the preparation of microbicide BMS‐599793 ( 6 ), in both discovery and process settings . In light of the foregoing, development of an alternative and practical (and preferably transition‐metal‐free) method for cross‐coupling, particularly one that is amendable for basic heterocyclic substrates remains desirable.…”