Abstract
Methods for the preparation of (3S )-3-(4-fluorobenzyl)piperidine (2 ) and its mandelate salt (9 ) are described. The first generation synthesis started from 3-benzylpiperidone, and required Boc protection of the nitrogen for efficient separation of the enantiomers using chromatography on a chiral stationary phase. Subsequently, a resolution method using (R )-mandelic acid, produced high %ee salt 9 after recrystallization and eliminated the need for Boc protection. The third generation route, starting from pyridine-3-carboxaldehyde, led to a streamlined synthesis of racemate 2 and was optimized for producing multi-hundred gram quantities of the chiral salt.
Key words
piperidines - chiral resolution - enantiomeric resolution - medicinal chemistry
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