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...

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Published in:Organic process research & development 2024-06, Vol.28 (6), p.2260-2268
Main Authors: Ashcroft, Christopher P., Berne, Alexander M., Blasberg, Florian, Catlin, Kelly, Collins, Michael R., Critcher, Doug J., Desrosiers, Jean-Nicolas, Goetz, Adam, Hayward, Cheryl, Jones, Ricky A., Karmilowicz, Michael J., Keene, Nandell, Martinez, Carlos A., Monfette, Sebastien, Pattavina, Sebastian David, Perfect, Hahdi H., Ragan, John A., Rauschenberger, Blake, Sach, Neal W., Scotney, Gemma, Sutton, Scott C., Talicska, Courtney, Twiddle, Steven J.R., Haitsma, Jared Van, Wisdom, Richard
Format: Article
Language:English
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Summary: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.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.3c00477