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

Stanislaw Pikul,*,† Hua Cheng,‡ Allen Cheng,§ C. D. Huang,§ Alex Ke,§ LungHuang Kuo,§ Andrew Thompson,‡ and Susan Wilder⊥

†Princeton API Services, LLC, 42 Chase Road, Lumberton, New Jersey 08048, United States

‡J-Star Research, Inc., 3001 Hadley Road, Suites 1−4, South Plainfield, New Jersey 07080, United States

§ScinoPharm Taiwan, Ltd., No. 1, Nan-Ke eighth Road, Tainan Science-Based Industrial Park, Shan-Hua, Tainan County, 74144 Taiwan, Republic of China

⊥International Partnership for Microbicides, 8401 Colesville Road, Suite 200, Silver Spring, Maryland 20910, United States


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.


1 (DS003, BMS-599793) is a small-molecule entry inhibitor that interferes with HIV infection by binding to the gp120 protein.1 The International Partnership for Microbicides (IPM) licensed 1 from Bristol-Myers Squibb (BMS) with the goal to develop it as a topical microbicide for use in resource-poor countries. Microbicides are vaginal dosage forms of potent inhibitors of HIV that women can use to prevent sexual transmission of HIV from male partners. At the time of licensing, a synthesis developed by the BMS medicinal chemistry group was provided (Scheme 1). Milligram quantities of 1 were prepared at BMS during the course of the discovery program. This discovery route utilized a Stille coupling reaction in the last step of the synthesis, yielding 1 containing excessive levels of residual tin that proved difficult to remove. In addition, the Stille reaction2 required a pyrazine tributyltin reagent (6) that is toxic, expensive, unpleasant to use, and not readily available in larger quantities. Given these synthetic liabilities, the medicinal chemistry process was not suitable for scale-up and preparation of preclinical material. A new synthesis process was required to address these deficiencies.