Development of a Practical and Scalable Synthesis of (R)- and (S)‑3-Amino-2-[(benzyloxy)methyl]propan-1-ol Monohydrochloride: A Useful C‑4 Chiral Building Block

The development of a practical and scalable synthesis of a C-4 chiral amine building block ( R )-1·HCl and ( S )-1·HCl is described. This important chiral intermediate ( R )-1·HCl is efficiently synthesized from the commercially available, inexpensive, and simple 2-(hydroxymethyl)-1,3-propanediol (31) using lipase-catalyzed enantioselective hydrolysis as a key reaction. Development resulted in a telescoped process that was operated successfully and reproducibly in a pilot-plant-scale synthesis, and 22 kg of chiral amine ( R )-1·HCl was prepared in the first scale-up synthesis. This synthetic method is also useful for preparation of the important chiral building block ( S )-1·HCl, which is the enantiomer of ( R )-1·HCl.