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

Abstract

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