1,1'-Carbonyldiimidazole → Tert-butyl 4-[2-[2-(difluoromethyl)-4-methoxy-1h-benzimidazol-1-yl]-6-(4-morpholinyl)-8-oxo-7,8-dihydro-9h-purin-9-yl]-1-piperidinecarboxylate

HRID 1256573Notes

Reaction equation

HRID 1256573 reaction equation
[C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[F:13][CH:14]([F:55])[C:15]1[N:19]([C:20]2[N:25]=[C:24]([NH:26][CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[C:23]([N+:40]([O-])=O)=[C:22]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[N:21]=2)[C:18]2[CH:49]=[CH:50][CH:51]=[C:52]([O:53][CH3:54])[C:17]=2[N:16]=1>O1CCOCC1.O>[F:13][CH:14]([F:55])[C:15]1[N:19]([C:20]2[N:25]=[C:24]3[C:23]([NH:40][C:1](=[O:2])[N:26]3[CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]3)=[C:22]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[N:21]=2)[C:18]2[CH:49]=[CH:50][CH:51]=[C:52]([O:53][CH3:54])[C:17]=2[N:16]=1

Participants

5

Reactant 2

HCID 682631,1'-Carbonyldiimidazole2×HCID 66698145tert-butyl 4-{[2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-5-nitro-4-pyrimidinyl]amino}-1-piperidinecarboxylate

Product 1

HCID 67544210Tert-butyl 4-[2-[2-(difluoromethyl)-4-methoxy-1h-benzimidazol-1-yl]-6-(4-morpholinyl)-8-oxo-7,8-dihydro-9h-purin-9-yl]-1-piperidinecarboxylateYield 69%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

1,1′-Carbonyldiimidazole (689 mg, 4.25 mmol) was added to a solution of the above amine (244 mg, 0.425 mmol) in 1,4-dioxane (25 mL) and the mixture was refluxed under nitrogen for 4.5 hrs. Additional 1,1′-carbonyldiimidazole (689 mg, 4.25 mmol) was added, and the mixture refluxed for additional 17.5 hrs. The mixture was cooled to room temperature and diluted with water. The resulting precipitate was collected by filtration, washed with H2O, and dried. Chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 97:3), gave tert-butyl 4-[2-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-8-oxo-7,8-dihydro-9H-purin-9-yl]-1-piperidinecarboxylate (176 mg, 69%): mp (CH2Cl2/i-Pr2O) 269-272° C.; 1H NMR (CDCl3) δ 10.94 (br s, 1H), 7.73 (dd, J=8.3, 0.3 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 7.36 (t, JHF=53.6 Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 4.49 (tt, J=12.1, 4.1 Hz, 1H), 4.38 (br s, 2H), 4.06 (s, 3H), 3.89 (dd, J=5.6, 3.6 Hz, 4H), 3.82 (dd, J=5.6, 3.7 Hz, 4H), 2.85 (m, 2H), 2.56 (m, 2H), 1.83 (d, J=11.0 Hz, 2H), 1.48 (s, 9H); Anal. Calcd. for C28H34F2N8O5.0.1 i-Pr2O: C, 56.2; H, 5.8; N, 18.3. Found: C, 56.2; H, 5.90; N, 18.0%.

Workup

  1. temperaturethe mixture was refluxed under nitrogen for 4.5 hrs
  2. temperaturethe mixture refluxed for additional 17.5 hrs
  3. filtrationThe resulting precipitate was collected by filtration
  4. washwashed with H2O
  5. customdried
  6. washChromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 97:3)

Sources & evidence

ORD record
ord-509b6ced631547e69600cd55d5b74f87
Source dataset
uspto-grants-2013_06
Patent number
US08461158B2

Reaction notes

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