Umpolung Flow Chemistry for the Synthesis of a 3-Oxo-3 H -spiro[benzofuran-2,4'-piperidine] Building Block.

An efficient and scalable route to tert -butyl 3-oxo-3 H -spiro[benzofuran-2,4'-piperidine]-1'-carboxylate, a central prochiral intermediate in the synthesis of SHP2 inhibitor GDC-1971 ( migoprotafib ), was achieved. Preparation of the title compound from readily available 2-fluorobenzaldehyde included formation of a modified Katritzky benzotriazole hemiaminal, which, upon deprotonation by n -butyllithium, participated in umpolung reactivity via 1,2-addition to tert -butyl 4-oxopiperidine-1-carboxylate ( N -Boc-4-piperidone). Most notably, this reaction was developed as a robust plug-flow process that could be executed on multiple kilograms without the need for pilot-scale reaction vessels operating at low cryogenic temperatures. Treatment of the resulting tetrahedral intermediate with oxalic acid resulted in collapse to the corresponding 4-(2-fluorobenzoyl)-4-hydroxypiperidine, which was isolated as a solid via crystallization. The synthesis concluded with an optimized intramolecular S N Ar reaction and final crystallization to generate tert -butyl 3-oxo-3 H -spiro[benzofuran-2,4'-piperidine]-1'-carboxylate as a stable, high-quality intermediate suitable for further functionalization toward GDC-1971 .