Hydrochloric Acid → methyl (S)-1-((S)-2-(5-(4-bromo-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate

(S)-tert-Butyl 2-(5-(4-bromo-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (400 mg, 0.873 mmol) was dissolved in DCM (10 mL) and treated with HCl (4.0 M in dioxane, 2 mL). The reaction mixture was stirred at RT for 50 min, then concentrated under reduced pressure. The crude residue was treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (168 mg, 0.960 mmol), HATU (365 mg, 0.960 mmol) and DMF (4 mL) then cooled to 0° C. DIPEA (0.760 mL, 4.37 mmol) was added dropwise and the reaction mixture was stirred for 30 min. After warming to RT, the mixture was diluted with EtOAc and the organic solution was washed with saturated aqueous NaHCO3, and brine then dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (0% to 33% MeOH/EtOAc) to afford methyl (S)-1-((S)-2-(5-(4-bromo-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (333 mg, 74%).

1. concentrationconcentrated under reduced pressure
2. temperaturethen cooled to 0° C
3. stirringthe reaction mixture was stirred for 30 min
4. temperatureAfter warming to RT
5. washthe organic solution was washed with saturated aqueous NaHCO3, and brine
6. dry with materialthen dried over MgSO4
7. filtrationfiltered
8. concentrationconcentrated under reduced pressure
9. customThe crude residue was purified by silica column chromatography (0% to 33% MeOH/EtOAc)

ORD record

ord-2c9acf1307ae491c875349260927a24c

Source dataset

uspto-grants-2015_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09156823B2