Early Process Development of Two Vanin-1 Inhibitors: Solid Form Challenges and Control of Ambident Reactivity

Discovery chemistry efforts within Pfizer identified a new vanin-1 inhibitor, (S)-1, bearing a chiral methyl substituent, which exhibited an excellent profile as a potential drug-candidate selection except for the propensity to exist as an amorphous solid. Based on an improved solid form proposition, the project team chose to prioritize 2, the corresponding des-methyl compound. Both compounds were scaled to supply toxicology studies in preclinical species, and kilograms of compound 2 were manufactured to support the preclinical development work. The development of our synthetic chemistry and solid form work on this program are described in the paper. Included are computational studies to rationalize both an expected TBD-mediated epimerization as well as the control of ambident reactivity of activated 2-chloro-pyrimidine-5-carboxylic acid.