Sodium hydride → (S)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

HRID 2075027Notes

Reaction equation

HRID 2075027 reaction equation
[F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[CH2:6][NH:7][C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].Br[CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[C@H:37]([CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[O:38][CH3:39]>CN(C=O)C>[F:18][C:17]([F:19])([F:20])[C:15]1[CH:14]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:16]=1)[CH2:6][N:7]([CH2:26][C:27]1[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[CH:29][C:28]=1[C@H:37]([CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[O:38][CH3:39])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 230732215-[N-(3',5'-Bistrifluoromethylbenzyl)amino]-2-methyltetrazoleHCID 58968737(S)-2-bromomethyl-1-(cyclohexyl-methoxy-methyl)-4-trifluoromethyl-benzene

Product 1

HCID 58968607(S)-(3,5-Bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amineYield 48.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of N-(3,5-bis(trifluoromethyl)benzyl)-2-methyl-2H-tetrazol-5-amine (26.7 mg, 0.082 mmol) in DMF (1 ml) at 0° C. under nitrogen was added sodium hydride (6 mg, 0.1 mmol, 60% dispersion in mineral oil). The reaction was stirred for 30 minutes while allowing it to warm to room temperature. The reaction mixture was then treated with (S)-2-bromomethyl-1-(cyclohexyl-methoxy-methyl)-4-trifluoromethyl-benzene (25 mg, 0.068 mmol) at 0° C. The ice bath was removed after the addition and the reaction was stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. Combined organic layers were washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on 12+S Biotage silica column, eluting with ethyl acetate in heptane 0-30% (10CV) and 30% (3CV) to yield the title compound (20 mg, 48%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.07 (m, 4H) 1.2 (m, 2H) 1.46 (m, 1H) 1.57 (m, 2H) 1.61(m, 1H) 1.90 (d, J=12.4, 1H) 3.06 (s, 3H) 4.08 (d, J=7.1, 1H) 4.2 (s, 3H) 4.70 (d, J=15.7, 1H) 4.89 (d, J=15.7, 1H) 7.35 (s, 1H) 7.50 (d, J=7.9, 1H) 7.55 (d, J=7.9, 1H) 7.65 (s, 2H) 7.77 (s, 1H). [α]D20=−26.6 deg (c=13 mg/mL, acetone).

Workup

  1. customThe ice bath was removed
  2. additionafter the addition
  3. stirringthe reaction was stirred at room temperature overnight
  4. additionWater was added
  5. extractionthe mixture was extracted with ethyl acetate
  6. washCombined organic layers were washed with water, brine
  7. dry with materialdried over sodium sulfate
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified by chromatography on 12+S Biotage silica column
  10. washeluting with ethyl acetate in heptane 0-30% (10CV) and 30% (3CV)

Sources & evidence

ORD record
ord-2dca5f0971734151ba043c7b3c1f9bea
Source dataset
uspto-grants-2011_04
Patent number
US07919506B2

Reaction notes

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