Process Development and Scale-Up of a Protease Inhibitor for the Treatment of HIV Featuring the Preparation of a Neopentyl Grignard Reagent and Development of a One-Pot Curtius Reaction

Compound 1 is a densely functionalized iminohydantoin that possesses a quaternary stereocenter and is under development as an HIV protease inhibitor. Key challenges that are discussed include the preparation of a neopentyl Grignard reagent via magnesium insertion, development of a one-pot Curtius reaction that generated a volatile isocyanate and was trapped with an alcohol, and removal of a CBz protecting group to isolate a succinate salt. This study describes process development efforts that enabled the first scale-up of 1.