The route selection and process research and development of a practical synthesis for JAK2 inhibitor LY2784544 is described. The first-generation synthesis route, similar to that used in discovery for derivatization of a benzylic amine moiety, was 14 overall steps and possessed several steps that required extensive development for large-scale production. Route selection considerations led to a modified synthesis that utilized a novel vanadium-catalyzed carbon–carbon bond-forming arylation reaction for incorporation of the key benzylic morpholine moiety. A protecting group used to mask an amino pyrazole unit was modified from PMB to tert-butyl, resulting in a dramatic reduction in the overall length of the route. These two major changes resulted in an eight-step synthesis, which was six steps shorter than the first-generation synthesis. In the pilot plant, the new synthesis was scaled to produce >100 kg of LY2784544 in high yield and purity under GMP conditions. The overall development including the vanadium-catalyzed C–C bond-forming methodology, a ketone reductive deoxygenation, and a palladium-catalyzed amination is described.

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The palladium-catalyzed decarboxylative cross-coupling of aminothiophene carboxylate and 1-bromo-4-chlorobenzene to produce 3-amino-2-(4-chlorophenyl)thiophene (2) is described. The cross-coupling proceeds under relatively mild conditions using catalytic Pd(0) and TBAB. Through use of a mixed-solvent system of DMF and NMP, it was possible to operate the cross-coupling system at 80 °C. An assessment of carbon dioxide liberation, which provides insight into the reaction operating parameters, is also discussed.

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