Download PDF
Synfacts 2019; 15(03): 0215
DOI: 10.1055/s-0037-1611188
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of PF-06650833

Contributor(s):
Philip Kocienski
Wright SW. * Li B, Peng Z, Wei L, McInturff E, Place D, Damon DB, Singer RA. Pfizer Worldwide Research & Development, Groton, USA
Improvements to Enable the Large Scale Synthesis of 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833).

Org. Process Res. Dev. 2018;
22: 1835-1845
CrossrefSearch in Google Scholar
Further Information

Publication History

Publication Date:
15 February 2019 (online)

 
 PDF Download Permissions and Reprints

Key words

PF-06650833 - IRAK-4 inhibitor - enolate oxidation - lithium tert-butylperoxide - α-fluorination

Significance

PF-06650833 is an interleukin-4 receptor associated kinase (IRAK-4) inhibitor that is of interest for the treatment of inflammatory disorders such as rheumatoid arthritis. A significant challenge in the large-scale synthesis of PF-06650833 was the construction of lactam I with its three contiguous stereogenic centers.


#

Comment

The preparation of lactam I from E was achieved by the highly diastereoselective oxidation of enolate E to F with lithium tert-butylperoxide in a flow process (Org. Process Res. Dev. 2018, 22, 707, see also Synfacts 2019, 15, 328, this issue). Thereafter activation of F by reaction with nonafluorobutanesulfonyl fluoride allowed SN2 displacement by fluoride ion in a single step, without need for the isolation of the intermediate sulfonate ester G. This route provided PF-06650833 in batches of greater than 30 kg at a time.


#
#


   Permissions and Reprints