Large-Scale Practical Synthesis of Boc-Protected 4-Fluoro-l-Proline

Abstract

A large-scale synthesis process of N-Boc-4-fluoro-l-proline (1) from N-Boc-4-hydroxy-l-proline methyl ester (2) using nosyl fluoride (13) as a deoxyfluorinating agent has been developed. An eco-friendly and large-scale feasible process using a single solvent was developed to afford moderate yields of products with excellent purity >99% by high-performance liquid chromatography. The key feature of the optimization involving chromatography-free purification and isolation on a kilogram-scale at a pilot plant scale is described.