反应详情

A mixture of 3-bromo-4-fluoro-N2-phenylbenzene-1,2-diamine (500 mg, 1.79 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (370 mg, 1.95 mmol), HOAt (266 mg, 1.95 mmol), 4-methylmorpholine (0.43 mL, 3.91 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (376 mg, 1.95 mmol) in DCM (5 mL) was stirred at RT for 2 h. The reaction mixture was diluted with water 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 dioxane (10 mL) and HCl (12N, 1.5 mL) added. The reaction mixture was stirred at RT for 18 h then made basic by addition of 1N NaOH. The aqueous phase was extracted with EtOAc (×3) and the combined organic fractions washed with brine, dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford (S)-1-(7-bromo-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine (102 mg, 17%). LCMS (Method C): RT 2.28 min [M+H]+ 334.1/336.1. Chromatography purification afforded also (S)-2-amino-N-(3-bromo-4-fluoro-2-phenylaminophenyl)propionamide (384 mg) which was dissolved in 4N HCl in dioxane (10 mL) and heated at 70° C. for 3 h. The volatiles were removed in vacuo to afford (S)-1-(7-bromo-6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine dihydrochloride salt (434 mg, 60%). 1H NMR (DMSO-d6, 400 MHz): δ 8.84 (2H, s), 7.83 (1H, dd, J=8.80, 4.57 Hz), 7.71-7.58 (5H, m), 7.38 (1H, dd, J=9.65, 8.80 Hz), 4.17-4.07 (1H, m), 3.56 (2H, s), 1.42 (3H, d, J=6.80 Hz)

1. extractionextracted with DCM (×3)
2. washThe combined organic fractions were washed with brine
3. dry with materialdried (MgSO4)
4. concentrationconcentrated in vacuo
5. dissolutionThe resulting residue was dissolved in dioxane (10 mL)
6. additionHCl (12N, 1.5 mL) added
7. stirringThe reaction mixture was stirred at RT for 18 h
8. additionthen made basic by addition of 1N NaOH
9. extractionThe aqueous phase was extracted with EtOAc (×3)
10. washthe combined organic fractions washed with brine
11. dry with materialdried (MgSO4)
12. concentrationconcentrated under reduced pressure
13. customThe resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM)