Development and Scale-Up of an Improved Manufacturing Route to the ATR Inhibitor Ceralasertib

Abstract

Ceralasertib is currently being evaluated in multiple phase I/II clinical trials for the treatment of cancer. Its structure, comprising a pyrimidine core decorated with a chiral morpholine, a cyclopropyl sulfoximine and an azaindole, makes it a challenging molecule to synthesize on a large scale. Several features of the medicinal chemistry and early development route make it unsuitable for the long-term commercial manufacture of the active pharmaceutical ingredient. We describe the investigation and development of a new and improved route which introduces the cyclopropyl moiety in a novel process from methyl 2,4-dibromobutyrate. Following construction of the pyrimidine ring, large-scale chlorination with phosphoryl chloride was performed with a safe and robust work-up. An SNAr reaction required an innovative work-up to remove the unwanted regio-isomer, and then a Baeyer–Villiger monooxygenase enzyme was used to enable asymmetric sulfur oxidation to a sulfoxide. A safe and scalable metal-free sulfoximine formation was developed, and then optimization of a Suzuki reaction enabled the manufacture of high-quality ceralasertib with excellent control of impurities and an overall yield of 16%.