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-{[(2
S,3
S,4
S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide
(PF-06650833).
Org. Process Res. Dev. 2018;
22: 1835-1845
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.
