Sodium Hydroxide → (5'-(Difluoromethyl)-2-(2,2-dimethylcyclopentyl)-2'-fluoro-1,1'-biphenyl-4-yl)methanol

Participants

Reaction Conditions

Reaction Steps

To a cooled solution of 83.3C (0.86 g, 2.29 mmol) in dry THF (15 mL) at 0° C. was added LAH, 1.0M in THF (4.6 mL, 4.6 mmol) dropwise. Upon complete addition, the reaction was maintained at 0° C. and monitored by TLC and LCMS. After 45 minutes, 1N NaOH was added to quench the reaction (gas evolution occurred). The resulting solution was extracted three times with EtOAc. After drying over anhydrous magnesium sulfate, filtration, and concentration, the residue was purified by flash chromatography (SiO2 gel 60, eluted with 0%-100% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated to provide 83.3D as a colorless oil (0.62 g, 77%). MS ESI (pos.) m/e: 331.0 (M−H2O)+. Chiral separation of 83.3D was accomplished on Chiracel-OD (4% EPA in hexane) to provide 83.3E (peak 1) and 83.3F (peak 2). Both enantiomers were used to synthesize example compounds, and both enantiomers gave active compounds. The enantiomer corresponding to peak 2 provided the more active example compound.

Provenance & Evidence