Scalable Synthesis of Highly Pure ( R )‐3‐Fluoropyrrolidine From ( S )‐4‐Chloro‐3‐hydroxybutyronitrile

ABSTRACT ( S )‐Pyrrolidin‐3‐ol and ( R )‐3‐fluoropyrrolidine are key intermediates in Roche's drug candidates, Vicasinabin and Mosperafenib. Sourcing these compounds proved challenging, particularly for ( R )‐3‐fluoropyrrolidine, for which a quality of ≥ 99.8% purity and ≥ 99.95% chiral purity along with stringent impurity control was required. To address these challenges, a scalable process for the manufacturing of ( R )‐3‐fluoropyrrolidine hydrochloride salt using a stereoselective S N 2 reaction was developed based on prior work on ( S )‐pyrrolidin‐3‐ol synthesis. The process was successfully scaled up in the pilot plant, enabling the production of a total of 798 kg of high‐purity ( R )‐3‐fluoropyrrolidine hydrochloride salt to support the clinical development of Mosperafenib. Key steps included “pump‐hydrogenation” to improve the yield of ( S )‐pyrrolidin‐3‐ol from the cost‐effective starting material ( S )‐4‐chloro‐3‐hydroxybutyronitrile. This was followed by in situ Boc‐protection, and a two‐step stereospecific fluorination involving mesylation and nucleophilic substitution with potassium fluoride. Finally, Boc‐deprotection using HCl followed by recrystallization from n ‐BuOH and water, ensured efficient removal of impurities including the undesired enantiomer. This streamlined approach addressed supply challenges, ensured consistent quality, and established an efficient, robust manufacturing process for ( R )‐3‐fluoropyrrolidine hydrochloride.