Enantiospecific Synthesis of (3R,4R)-1-Benzyl-4-fluoropyrrolidin-3-amine Utilizing a Burgess-Type Transformation

Abstract

Manufacture of an EGFR inhibitor required the asymmetric synthesis of a key 3,4-trans-substituted pyrrolidine suitable for pilot-plant scale. The initial synthetic route utilized reagents and intermediates that posed safety concerns due to their energetic potential and then required supercritical fluid chromatography to access the desired single enantiomer. Burgesstype reagents provide tremendous utility in organic synthesis but see limited use on large scales because of their high cost and instability. Nevertheless, extensive process development led to a scale-friendly process where in situ formation of a Boc-Burgess reagent enabled access to a chiral cyclic sulfamate from inexpensive materials. ReactIR monitoring was used to study intermediate stability and enabled processing on a multikilogram scale. The sulfamate was converted to trans-3-fluoro-4aminopyrrolidine 1 with complete stereospecificity. Intermediate crystallinity offered purity control points where byproducts and impurities were rejected, avoiding the need for chromatography.

Synthesis of Nirmatrelvir: Design and Optimization of an Efficient Telescoped Amidation–Dehydration Sequence

“…While some Burgess-type reagents successfully produced 1 (compounds 12 – 16 , Scheme c) in Step 4, 3.0 equivalents (equiv) were required even when reagents were generated in situ . This strategy did not represent a significant improvement and was abandoned for more atom-economical approaches.…”