Development of a Scalable Process for an IL-17A Inhibitor LY3509754: Part I: Synthesis of the Pyridazinyl Imidazolidinone Intermediate Enabled by Biocatalysis and CSTR Technologies

Process development and scale-up of the synthesis of a pyridazinyl imidazolidinone intermediate for the production of an imidazo[1,2-b]pyridazine IL-17A inhibitor are described. A transamination process was developed for the preparation of (S)-3,3,3-trifluoropropane-1,2-diamine, eliminating an unstable enamine intermediate that significantly limited the scalability of the original asymmetric hydrogenation route. A CSTR continuous flow process was developed for the carbonylation of N-(6-chloropyridazin-3-yl)pivalamide under cryogenic conditions that successfully suppressed product decomposition, improving the isolated yield to ∼60% from the ∼40% yield of the batch mode process. A robust KRED process was developed for the reduction of N-(6-chloro-5-(2-methoxyacetyl)pyridazin-3-yl)pivalamide to the corresponding chiral alcohol, which was further derivatized as its triflate for the SN2 reaction with (S)-3,3,3-trifluoropropane-1,2-diamine and treated with carbonyl diimidazole to assemble the target pyridazinyl imidazolidinone intermediate. The developed process was successfully scaled up to deliver 157 kg of the pyridazinyl imidazolidinone intermediate to support the production of the final drug substance, demonstrating the robustness of the optimized process.