Sodium hydride → 2-chloro-6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-9-tetrahydro-2H-pyran-2-yl-9H-purine

HRID 450197Notes

Reaction equation

HRID 450197 reaction equation
[H-].[Na+].[F:3][CH:4]([F:16])[C:5]1[NH:9][C:8]2[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:7]=2[N:6]=1.[Cl:17][C:18]1[N:26]=[C:25]2[C:21]([N:22]=[CH:23][N:24]2[CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)=[C:20](Cl)[N:19]=1>CN(C=O)C>[Cl:17][C:18]1[N:26]=[C:25]2[C:21]([N:22]=[CH:23][N:24]2[CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)=[C:20]([N:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:7]=3[N:6]=[C:5]2[CH:4]([F:3])[F:16])[N:19]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 2702652,6-Dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purineHCID 534881012-(Difluoromethyl)-4-methoxy-1H-benzimidazole

Product 1

HCID 866497832-chloro-6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-9-tetrahydro-2H-pyran-2-yl-9H-purineYield 51%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

NaH (148 mg, 6.17 mmol) was added to a solution of 2-difluoromethyl-4-methoxy-1H-benzimidazole (Example 2) (638 mg, 3.22 mmol) in DMF (10 mL) at 0° C., and the mixture was warmed to room temperature and stirred for 45 min. 2,6-Dichloro-9-tetrahydro-2H-pyran-2-yl-9H-purine (800 mg, 2.93 mmol) was then added and the resulting mixture was stirred at room temperature for 5 days, quenched with H2O, and extracted with EtOAc (2×). The combined organic extracts were washed with H2O (3×), dried (Na2SO4) and the solvent was removed under vacuum. Chromatography on silica, eluting with hexanes/EtOAc (100:0 to 60:40), gave 2-chloro-6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-9-tetrahydro-2H-pyran-2-yl-9H-purine (645 mg, 51%): 1H NMR (CDCl3) δ 8.38 (s, 1H), 7.52 (t, JHF=54.2 Hz, 1H), 7.37-7.31 (m, 2H), 6.84 (m, 1H), 5.86 (dd, J=10.7, 2.5 Hz, 1H), 4.23 (ddd, J=10.0, 3.8, 1.8 Hz, 1H), 4.07 (s, 3H), 3.83 (dt, J=11.7, 2.8 Hz, 1H), 2.26 (m, 1H), 2.14 (m, 1H), 2.03 (m, 1H), 1.91-1.69 (m, 3H).

Workup

  1. stirringthe resulting mixture was stirred at room temperature for 5 days
  2. customquenched with H2O
  3. extractionextracted with EtOAc (2×)
  4. washThe combined organic extracts were washed with H2O (3×)
  5. dry with materialdried (Na2SO4)
  6. customthe solvent was removed under vacuum
  7. washChromatography on silica, eluting with hexanes/EtOAc (100:0 to 60:40)

Sources & evidence

ORD record
ord-01d85969d3d74352922f665a8fc2b2de
Source dataset
uspto-grants-2013_07
Patent number
US08486939B2

Reaction notes

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