4-Fluorobenzylamine → (4-Fluoro-benzyl)-carbamic acid (6R,7aS)-3-oxo-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-6-yl ester

Diisopropylethylamine (800 mg, 6.2 mmol) and (4-fluorophenyl)methanamine (400 mg, 3.2 mmol) was dropped into a solution of bis(trichloromethyl) carbonate (300 mg, 1 mmol) in anhydrous dichloromethane (30 mL) at −78° C., the mixture was stirred for 2 hours at room temperature. Then (6R,7aS)-6-Hydroxy-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one (example 1, step e) (50 mg, 0.165 mmol) was added into the mixture, the mixture was refluxed for 2 days. The mixture was cooled and poured into water (50 mL), extracted with ethyl acetate (3×30 mL), the organic layers was combined washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5:1) to yield 25 mg (33%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.60 (d, 2H, J=9.3 Hz), 7.29-7.24 (m, 2H), 7.19 (d, 2H, J=8.4 Hz), 7.03 (t, 2H, J=8.7 Hz), 5.38 (t, 1H, J=5.7 Hz), 5.04 (s, 1H), 4.34 (d, 2H, J=5.7 Hz), 4.15 (dd, 1H, J1=13.5 Hz, J2=6.0 Hz), 4.05-4.00 (m, 1H), 3.74 (d, 1H, J=6.9 Hz), 3.2 (d, 1H, J=13.5 Hz), 2.27-2.21 (m, 1H), 1.78-1.63 (m, 1H); LC-MS: 454.1 [M+1]+.

1. temperaturethe mixture was refluxed for 2 days
2. temperatureThe mixture was cooled
3. extractionextracted with ethyl acetate (3×30 mL)
4. washthe organic layers was combined washed with brine (30 mL)
5. dry with materialdried over anhydrous sodium sulfate
6. filtrationfiltered
7. concentrationconcentrated
8. customThe residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=5:1)

ORD record

ord-6bd68ded53da410fbc08effc31b5530c

Source dataset

uspto-grants-2013_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08497288B2