Development of a Scalable Enantioselective Synthesis of JAK Inhibitor Upadacitinib

Abstract

Process development of a six-stage synthesis of upadacitinib, a JAK1 inhibitor, is described. It is highlighted by an enantioselective and diastereoselective hydrogenation of a tetrasubstituted olefin to set the two pyrrolidine stereocenters. Preparation of the main fragments and strategies to link them together, optimization of the imidazole cyclization, and in-depth understanding of the formation of the urea moiety at the final stage are discussed.

Investigation of Mechanochemical Sonogashira Couplings─From Batch Solution to Continuous Reactive Extrusion through Ball-Milling Optimization

“…The solid extrudate obtained from these experiments is amenable to straightforward workup using the procedure outlined in the previous section: extraction with a solvent such as EtOAc, carbon treatment, and filtration. This would reduce the number of workup operations and volume of the solvent used in a typical, large-scale workup …”

“…The launch point for our reaction conditions was adapted from solution-based Sonogashira reactions 24 and, to our delight, provided good conversion after 4 h of milling (Table 1, Entry 1). These results were encouraging; however, the large loadings of liquid reagents caused the reaction mixture to be a Reactions were performed on a 0.25 g scale of heteroarene and performed in a 15 mL stainless-steel milling jar with three (3) 3/16th″ stainlesssteel balls.…”

“…Assay yields were comparable to standard solution-based methods for the reaction, and reaction times and workup efficiency were superior. Additionally, the solvent used was reduced in reactions using 1a from 9 V of tetrahydrofuran (THF) in the solution process to 6 V of EtOAc and a 63% reduction when compared to work by Rozema and co-workers (from 16 to 6 V) . Finally, reactions could be conducted without rigorous exclusion of air at <1 mol % Pd loading in the extruder. , …”

Enantioselective Synthesis of the Chiral Pyrrolidine Fragment of Upadacitinib via Chiral Auxiliary Directed Diastereoselective 1,3-Dipolar Cycloaddition

“…1,3-Dipolar cycloaddition between ethyl pent-2-ynoate and 4 was carried out in the presence of catalytic TFA. Unfortunately, the reaction afforded an intractable mixture of products and the desired 2,5-dihydro-1 H -pyrrole 10 could be isolated in merely 57% yield and 71% high-performance liquid chromatography (HPLC) purity only after careful column chromatography . Hydrogenation of 10 in the presence of Raney nickel did afford rac -5 albeit with 71% purity once again after column chromatography (Scheme ).…”

“…(3R,4S)-1-((Benzyloxy)carbonyl)-4-ethylpyrrolidine-3-carboxylic Acid (8). To a solution of 22a [92.5 g (purity corrected based on HPLC), 0.3960 moles] in methanol (2.6 L) was charged 20% Pd(OH) 2 on carbon (16.72 g) at room temperature.…”