Practical Synthesis of Chiral 3-(Hydroxyiminomethyl)adipic Acid, a Key Intermediate of the ROR-γ Inhibitor JTE-151, via Crystallization-Induced Dynamic Resolution

A practical six-step process for the production of chiral 3-(hydroxyiminomethyl)adipic acid 4 featuring highly efficient crystallization-induced dynamic resolution (CIDR) as the key step is reported. This compound was converted to isoxazole 23, an API starting material candidate of the ROR-γ inhibitor JTE-151, via isoxazole core construction by 1,3-dipolar cycloaddition and subsequent Ag2O-catalyzed decarboxylation of the tentatively introduced carboxyl group on the isoxazole core.