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

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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Bibliographic Details
Published in:Organic process research & development Vol. 28; no. 6; pp. 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: Journal Article
Language:English
Published: American Chemical Society 21-06-2024
Subjects:
Process Chemistry
API
Biocatalysis
Oxetane
Scale-up
EZH2
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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