Streamlined Atom-Economical Synthesis of Escitalopram: Kilogram-Scale Process Optimization and Industrial-Scale Implementation

A straightforward, efficient, atom-economical, and scalable commercial manufacturing process was developed for the treatment of depression via commercial available starting materials. Citalopram, a selective serotonin reuptake inhibitor introduced in 1989, is a racemic mixture whose entire inhibitory activity resides in the S-(+)-enantiomer, also known as escitalopram. While the original six-step route suffered from sub-30% overall yield, inefficient diol resolution (<40%), nonrecyclable solvents, and problematic reaction byproduct management, our redesigned process achieves three critical advancements: (1) controlled impurity profiles, enhanced reaction efficiency (over 90% yield per step), streamlined postprocessing and recyclable solvents for preparation of racemic diol; (2) effective stereoinvertive cyclization strategy for converting R-diol byproducts into escitalopram via S_N²; (3) closed-loop resolution agent recovery and valorization of escitalopram enantiomeric byproduct. Safety-optimized scale-up enabled production of 446 kg batches with exceptional purity (>99.7%), enantiomeric excess (>99.8% ee), and 81.6% overall yield─representing 3.9-fold process intensification versus legacy methods. This sustainable platform demonstrates unprecedented atom utilization efficiency (>90%) while eliminating stereochemical waste, establishing new benchmarks for escitalopram manufacturing.