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

HRID 455263Notes

Reaction equation

HRID 455263 reaction equation
C(N(C(C)C)CC)(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH2:18])=[CH:13][CH:12]=1.[C:19](=[O:30])([O:25][C:26](Cl)(Cl)Cl)OC(Cl)(Cl)Cl.O[C@H]1[CH2:51][N:35]2[C:36](=[O:50])[N:37]([C:39]3[CH:44]=[CH:43][C:42]([O:45][C:46]([F:49])([F:48])[F:47])=[CH:41][CH:40]=3)[CH2:38][C@@H:34]2[CH2:33]1>ClCCl.O>[O:50]=[C:36]1[N:35]2[CH2:51][C@H:26]([O:25][C:19](=[O:30])[NH:18][CH2:17][C:14]3[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=3)[CH2:33][C@H:34]2[CH2:38][N:37]1[C:39]1[CH:40]=[CH:41][C:42]([O:45][C:46]([F:49])([F:47])[F:48])=[CH:43][CH:44]=1

Participants

7

Reactant 4

HCID 673264-FluorobenzylamineHCID 81531DiisopropylethylamineHCID 94429TriphosgeneHCID 70976331(6R,7aS)-6-Hydroxy-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-3-one

Product 1

HCID 71003238(4-Fluoro-benzyl)-carbamic acid (6R,7aS)-3-oxo-2-(4-trifluoromethoxy-phenyl)-hexahydro-pyrrolo[1,2-c]imidazol-6-yl esterYield 33.4%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent

Procedure

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]+.

Workup

  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)

Sources & evidence

ORD record
ord-6bd68ded53da410fbc08effc31b5530c
Source dataset
uspto-grants-2013_07
Patent number
US08497288B2

Reaction notes

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