4-Methylmorpholine → [(S)-1-(7-chloro-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester

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Reaction Steps

A mixture of 3-chloro-4-fluoro-N2-phenylbenzene-1,2-diamine (300 mg, 1.26 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (264 mg, 1.39 mmol), HOAt (190 mg, 1.39 mmol), 4-methylmorpholine (0.31 mL, 2.79 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (270 mg, 1.39 mmol) in DCM (5 mL) was stirred at RT for 18 h. The reaction mixture was diluted with a saturated aqueous solution of NaHCO3 and extracted with DCM (×3). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was dissolved in AcOH (5 mL) and the solution heated at 70° C. for 36 h. The volatiles were removed in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-100% EtOAc in cyclohexane) to afford impure [(S)-1-(7-chloro-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester. The product thus obtained was dissolved in 4N HCl in dioxane (7 mL) and heated at 70° C. for 2 h. The volatiles were removed in vacuo to afford (S)-1-(7-chloro-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride as an off-white foam (368 mg, 80% over three steps). LCMS (Method C): RT 2.28 min [M+H]+ 290.2.

Provenance & Evidence