Development of a Scaleable Process for the Synthesis of a Next-Generation Statin

This manuscript details the process research and development of a convergent and safe approach to 1 on a multikilo scale. Specific highlights of the process development efforts will be described, including the development of a dehydrogenation method for dihydropyrimidines and a thermochemically safe synthesis of a 1,2,4-aminotriazole fragment. A key feature of the synthesis is the use and optimization of a modified Julia−Kocienski olefination reaction. Specifically, we report an unprecedented dependence of the product olefin geometry on reaction temperature, where an E:Z ratio as high as 200:1 can be obtained. Initial insights into the mechanistic rationale for this observation are also provided. Finally, a purity upgrade sequence via an intermediate crystalline form is highlighted as a method of controlling the final API quality.