Process Development and Manufacture of the Core Starting Material of Adagrasib (MRTX849)

beta-Ketoester 1 is one of the critical starting materials used in the second-generation synthesis of adagrasib. Disclosed within is a new, streamlined, operationally simple, and more environmentally friendly three-step telescoped protocol which was demonstrated on a >100 kg batch with an overall yield of 70%. Identification of the shortcomings and the quality issues of the initial route are discussed. The process development work overcoming these challenges and leading to the new route of synthesis is described.