Development of a Cost-Efficient Process Toward a Key Synthetic Intermediate of the EZH2 Inhibitor PF-06821497

A cost-efficient approach for the synthesis of a key intermediate of the EZH2 inhibitor PF-06821497 was identified after performing process chemistry development. A wide route scouting effort was initially deployed to finally identify a successful oxidative decyanation approach. Widely available raw materials were utilized to access a desired oxetanyl-ketone as a precursor for a KRED process to generate the enantioenriched alcohol in 99% ee. Subsequent methylation followed by a carboxylation led to our targeted building block in seven steps with an overall yield of 28%. This process was demonstrated on a large scale to produce up to 50 kg of our key intermediate in the synthesis of PF-06821497.