Dimethylformamide → 3-{[[(2-Cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-5-trifluoromethyl-benzonitrile

HRID 2075073Notes

Reaction equation

HRID 2075073 reaction equation
C1(C(OC)[C:8]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:9]=2[CH2:10][NH:11][C:12]2[N:13]=[N:14][N:15]([CH3:17])[N:16]=2)CCCCC1.[H-].[Na+].Br[CH2:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:35]#[N:36].CN([CH:47]=[O:48])C>>[CH2:8]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:9]1[CH:10]([CH:10]([N:11]([CH2:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[C:35]#[N:36])[C:12]1[N:13]=[N:14][N:15]([CH3:17])[N:16]=1)[C:9]1[CH:18]=[C:19]([C:22]([F:23])([F:25])[F:24])[CH:20]=[CH:21][CH:8]=1)[O:48][CH3:47]

Participants

5

Reactant 4

HCID 6228DimethylformamideHCID 24758Sodium hydrideHCID 116013693-(Bromomethyl)-5-(trifluoromethyl)benzonitrileHCID 58968679[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

Product 1

HCID 866150533-{[[(2-Cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-5-trifluoromethyl-benzonitrileYield 49%

Procedure

To a solution of [2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine (28 mg, 0.073 mmol) in DMF (2 mL) at 0° C. under nitrogen was added sodium hydride (4.4 mg, 0.11 mmol, 60% dispersion in mineral oil). The reaction was stirred for 30 minutes, allowing it to warm to room temperature. The reaction mixture was then treated with 3-(bromomethyl)-5-(trifluoromethyl)benzonitrile (19.3 mg, 0.073 mmol) at room temperature and stirred for overnight. Solvent was removed in vacuo. The residue was diluted with ethyl acetate and washed with satd. sodium bicarbonate solution, water and brine, dried over anhydrous magnesium sulphate and concentrated in vacuo. The product was purified on Biotage column (12+S), eluting with 2% ethyl acetate in heptane (1CV), 2-20% (10CV), 20% (2CV) to yield the title compound (21 mg, 49%) as a colorless oil, 1H NMR (400 MHz, CDCl3) δ ppm 1.07 (m, 4H) 1.2 (m, 3H) 1.65(m, 3H) 1.73 (m, 1H) 3.18 (s, 3H) 4.06 (s, 3H) 4.2 (m, 1H) 4.67-5.04 (m, 2H) 5.4 (m, 1H) 7.39 (s, 1H) 7.50 (m, 3H) 7.5 (m, 2H). MS (ES+) Calc: 566.2, Found: 567.5 (M+1). According to the procedures described in Examples 42-45 and using the appropriate amine, Examples 46-50 were prepared.

Workup

  1. stirringstirred for overnight
  2. customSolvent was removed in vacuo
  3. additionThe residue was diluted with ethyl acetate
  4. washwashed with satd
  5. dry with materialsodium bicarbonate solution, water and brine, dried over anhydrous magnesium sulphate
  6. concentrationconcentrated in vacuo
  7. customThe product was purified on Biotage column (12+S)
  8. washeluting with 2% ethyl acetate in heptane (1CV), 2-20% (10CV), 20% (2CV)

Sources & evidence

ORD record
ord-c22af0ee1fc54a07879ff266d5c8be4f
Source dataset
uspto-grants-2011_04
Patent number
US07919506B2

Reaction notes

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