98485-43-9Relevant articles and documents
Development and Scale-Up of an Improved Manufacturing Route to the ATR Inhibitor Ceralasertib
Graham, Mark A.,Askey, Hannah,Campbell, Andrew D.,Chan, Lai,Cooper, Katie G.,Cui, Zhaoshan,Dalgleish, Andrew,Dave, David,Ensor, Gareth,Galan Espinosa, Maria Rita,Hamilton, Peter,Heffernan, Claire,Jackson, Lucinda V.,Jing, Dajiang,Jones, Martin F.,Liu, Pengpeng,Mulholland, Keith R.,Pervez, Mohammed,Popadynec, Michael,Randles, Emma,Tomasi, Simone,Wang, Shenghua
, p. 43 - 56 (2021/01/09)
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%.
