Acetic Acid → Methyl 1-{[2-[(tert-butoxycarbonyl)amino]-2-(3,5-difluorophenyl)propyl]amino}cyclopentanecarboxylate

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Reaction Steps

To tert-butyl[1-(3,5-difluorophenyl)-1-methyl-2-oxoethyl]carbamate (28.9 g, 101 mmol) were added methyl 1-aminocyclopentanecarboxylate (43.4 g, 303 mmol) followed by titanium(IV) isopropoxide (44.5 mL, 152 mmol) and the reaction mixture was stirred at ambient temperature for 90 min, diluted with MeOH (130 mL), and cooled in an ice-water bath. To this stirred mixture were added AcOH (29 mL, 507 mmol) followed by NaCNBH3 (7.64 g, 122 mmol), portionwise, over 5 min. Stirring was continued for 5 min, then the ice-water bath was removed, and stirring was continued for 30 min. The reaction mixture was quenched with saturated aqueous NaHCO3 (1 L) and extracted with EtOAc (3×1.5 L). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with hexane:EtOAc—100:0 to 50:50, to give a mixture of the title compound and the corresponding isopropyl ester. MS: m/z=413 (M+1).

Provenance & Evidence