The development of a commercial route toward the JAK1 inhibitor abrocitinib is described. The application of a late-stage Lossen rearrangement provided the desired cis-diaminocyclobutane, which was subsequently sulfonylated using a novel water-tolerable triazole sulfonylating reagent to provide the active pharmaceutical ingredient.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A scalable process for PF-06651600 (1) has been developed through successful enabling of the first generation syntheis. The synthesis highlights include the following: (1) replacement of costly PtO 2 with a less expensive 5% Rh/C catalyst for a pyridine hydrogenation, (2) identification of a diasteroemeric salt crystallization to isolate the enantiomerically pure cisisomer directly from a racemic mixture of cis/trans isomers, (3) a high yielding amidation via Schotten−Baumann conditions, and (4) critical development of a reproducible crystallization procedure for a stable crystalline salt (1•TsOH), which is suitable for long-term storage and tablet formulation. All chromatographic purifications, including two chiral SFC chromatographic separations, were eliminated. Combined with other improvements in each step of the synthesis, the overall yield was increased from 5% to 14%. Several multikilogram batches of the API have been delivered to support clinical studies.

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.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.