posted on 2024-02-05, 17:37authored byJennifer V. Obligacion, 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 Marzijarani, Zhijian Liu
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′F-thio-adenosine monophosphate in
77% overall yield at a 2.5 kg scale.