Phosgene → N-[4-fluoro-3-(trifluoromethyl)benzyl]-N'-(3-methyl-5-isoquinolinyl)urea

HRID 887280Notes

Reaction equation

HRID 887280 reaction equation
[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[C:14](Cl)(Cl)=[O:15].CCN(C(C)C)C(C)C.[NH2:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH:30]=[C:31]([CH3:38])[N:32]=[CH:33]2>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:14]([NH:27][C:28]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[CH:30]=[C:31]([CH3:38])[N:32]=[CH:33]3)=[O:15])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]

Participants

6

Reactant 4

HCID 6371PhosgeneHCID 81531DiisopropylethylamineHCID 522270[4-Fluoro-3-(trifluoromethyl)phenyl]methanamineHCID 122120553-Methylisoquinolin-5-amine

Product 1

HCID 22032629N-[4-fluoro-3-(trifluoromethyl)benzyl]-N'-(3-methyl-5-isoquinolinyl)urea

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent2×

Procedure

4-Fluoro-3-(trifluoromethyl)benzylamine (0.8 g, 4.15 mmol) in toluene (20 mL) was refluxed with 20% w/v phosgene solution in toluene (2.1 mL) overnight. The mixture was cooled to room temperature and concentrated in vacuo. The residue was again taken up in toluene (25 mL) and was stirred overnight at 80° C. with DIEA (2 mL, 11.5 mmol) and 5-amino-3-methylisoquinoline (500 mg, 3.16 mmol). The mixture was cooled to room temperature, concentrated in vacuo, and the residue was purified by silica gel chromatography (97:3 CH2Cl2:CH3OH, eluant) to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.72 (s, 1H), 8.16 (d, 1H, J=7.8 Hz), 7.70-7.77 (m, 4H), 7.48-7.54 (m, 3H), 7.14 (t, 1H, J=5.9 Hz), 4.42 (d, 2H, J=6.1 Hz), 2.64 (s, 3H); MS (ESI+) m/z 378 (M+H).

Workup

  1. concentrationconcentrated in vacuo
  2. temperatureThe mixture was cooled to room temperature
  3. concentrationconcentrated in vacuo
  4. customthe residue was purified by silica gel chromatography (97:3 CH2Cl2:CH3OH, eluant)

Sources & evidence

ORD record
ord-d91f034430704044967cb148c5eb9ae9
Source dataset
uspto-grants-2012_08
Patent number
US08247413B2

Reaction notes

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