4-Methylmorpholine → 4-{2-[(1R,2R)-1-Amino-2-methoxypropyl]-6-fluoro-1H-benzimidazol-5-yl}benzonitrile

Participants

Reaction Conditions

Reaction Steps

Isobutylchloroformate (0.17 g, 0.125 mmol) was added to a cooled mixture of N-(tert-butoxycarbonyl)-O-methyl-L-threonine (Preparation 51, 0.28 g, 0.12 mmol) and NMM (0.137 g, 0.135 mmol) in THF (10 mL) at −78° C. The reaction was stirred at this temperature for 1 hour and then added dropwise to a cooled solution of 4′,5′-diamino-2′-fluorobiphenyl-4-carbonitrile (Preparation 76, 0.28 g, 0.12 mmol) at −78° C. and stirred at this temperature for 3 hours. The reaction was partitioned between EtOAc (70 mL) and saturated aqueous NaHCO3 solution (30 mL), the organic layer was collected and concentrated in vacuo to afford a brown residue that was dissolved in AcOH (5 mL) and heated to 40° C. for 2 days followed by 50° C. for 1 day. The reaction was concentrated in vacuo and purified using silica gel column chromatography to afford a beige solid that was dissolved in TFA/DCM (0.2 mL/3 mL) and stirred at room temperature for 5 hours. The reaction was partitioned between saturated aqueous Na2CO3 solution (10 mL) and EtOAc (30 mL). The organic layer was collected and concentrated in vacuo. The residue was purified using reverse phase column chromatography eluting with a gradient of acetonitrile in 0.5% formic acid in water followed by elution through an SCX cartridge to afford the title compound that contains some of the other diastereomer.

Provenance & Evidence