Development of a Thiophosphorylation Process for the Synthesis of 2′F-Thio-Adenosine Monophosphate

• DOI: 10.1021/acs.oprd.3c00429
• Publication Date: 2024-02-05T17:29:10Z
• Authors: Jennifer V. Oblig...; Tao Wang; Thomas T. Kwok; Daniel Zewge; Ryan D. Cohen; Mikhail Reibarkh; Artis Klapars; Kerstin Zawatzky; Stephanus Axnanda; Zhu Liu; Zachary E. X. Dance; Joseph P. Smith; Wendy Zhong; Heather Wang; Cheol K. Chung; Nastaran Salehi M...; Zhijian Liu
• Keywords: Thio-

The process development for 2′F-thio-adenosine monophosphate, an intermediate MK-1454, immunooncology therapeutic, is described. Kinetic profiling, nuclear magnetic resonance monitoring, investigation of product decomposition pathways, and crystallization control identified important parameters efficient thiophosphorylation process. Among those are the use pivaloyl as protecting group nucleoside starting material well triethylphosphate a green reaction solvent, both which critical allowing homogeneous mixture key to success large-scale reaction. These insights enabled optimized process, delivered monophosphate in 77% overall yield at 2.5 kg scale.