Development of a Scalable Process for an IL-17A Inhibitor LY3509754. Part II: Synthesis of the α-Bromoketone Intermediate Leveraging Concomitant Decarboxylation Following Enzymatic Ester Hydrolysis

Abstract

A route to the key α-bromoketone intermediate for the synthesis of an imidazo[1,2-b]pyridazine IL-17A inhibitor via Horner–Wadsworth–Emmons condensation of commercially available 4,4-difluorocyclohexan-1-one (8) and methyl 2-(((benzyloxy)carbonyl)amino)-2-(dimethoxyphosphoryl)acetate (7) was developed and scaled up to support the production of drug substance for toxicology and clinical studies. The α,β-didehydroamino acid ester product 13 from Horner–Wadsworth–Emmons condensation was hydrolyzed under basic conditions to afford the corresponding N-protected α,β-didehydroamino acid 14, which was asymmetrically hydrogenated in the presence of the Ru-S-Xyl-Segphos dimer to afford the desired chiral amino acid 15. After activation with carbonyl diimidazole, the resulting acyl imidazole was reacted with the magnesium ethyl malonate complex to afford a β-oxo ester 17, which was brominated followed by concomitant decarboxylation after enzymatic ester hydrolysis with Lipozyme TL IM to afford the desired α-bromoketone intermediate 5. Stress tests and range-finding studies were carried out for all steps to support production. The optimized process was successfully scaled up to deliver 110 kg of α-bromoketone intermediate 5 to support the production of an IL-17A inhibitor. The overall yield of the optimized process was significantly improved to 46.5% from the 19.1% of the preclinical supplies process.