Methyl iodide → 1-cyclopropyl-5,6-difluoro-2-[5-(2-methoxypropan-2-yl)pyridin-3-yl]-1H-benzimidazole

HRID 1048957Notes

Reaction equation

HRID 1048957 reaction equation
[CH:1]1([N:4]2[C:8]3[CH:9]=[C:10]([F:14])[C:11]([F:13])=[CH:12][C:7]=3[N:6]=[C:5]2[C:15]2[CH:16]=[C:17]([C:21]([OH:24])([CH3:23])[CH3:22])[CH:18]=[N:19][CH:20]=2)[CH2:3][CH2:2]1.[H-].[Na+].I[CH3:28]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([N:4]2[C:8]3[CH:9]=[C:10]([F:14])[C:11]([F:13])=[CH:12][C:7]=3[N:6]=[C:5]2[C:15]2[CH:20]=[N:19][CH:18]=[C:17]([C:21]([O:24][CH3:28])([CH3:22])[CH3:23])[CH:16]=2)[CH2:3][CH2:2]1

Participants

6

Reactant 3

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 566455682-[5-(1-Cyclopropyl-5,6-difluoro-1H-benzimidazol-2-yl)pyridin-3-yl]propan-2-ol

Product 1

HCID 666847641-cyclopropyl-5,6-difluoro-2-[5-(2-methoxypropan-2-yl)pyridin-3-yl]-1H-benzimidazole

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a cooled (0° C.) solution of 2-[5-(1-Cyclopropyl-5,6-difluoro-1H-benzimidazol-2-yl)pyridin-3-yl]propan-2-ol (from Example 38 Step E) (0.086 g, 0.26 mmol) in tetrahydrofuran (1.3 mL) was added sodium hydride (60% dispersion in mineral oil, 0.026 g, 0.65 mmol). After 1 hour, iodomethane (0.024 mL, 0.389 mmol) was added. The reaction was then warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica gel (30-60% ethyl acetate in hexanes) provided the title compound: LCMS m/z 344.03 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 9.09 (d, J=1.9 H, 1 H), 8.79 (d, J=2.0 Hz, 1 H), 8.29 (t, J=2.0, 2.0 Hz, 1 H), 7.58 (dd, J=10.3, 7.3 Hz, 1 H), 7.40 (dd, J=9.7, 7.1 Hz, 1 H), 3.59-3.57 (m, 1 H), 3.16 (s, 3 H), 1.63 (s, 3 H), 1.60 (s, 3 H), 1.20-1.17 (m, 2 H), 0.79-0.76 (m, 2 H).

Workup

  1. washwashed with water and brine
  2. dry with materialdried over magnesium sulfate
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customPurification by flash chromatography on silica gel (30-60% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-aeaec93be35f41a6b4795fe06c1338ec
Source dataset
uspto-grants-2016_07
Patent number
US09382226B2

Reaction notes

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