Methyl iodide → (3,5-Bis-trifluoromethyl-benzyl)-[2-(1-cyclohexyl-1-methoxy-ethyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amine

HRID 2075090Notes

Reaction equation

HRID 2075090 reaction equation
[F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)([OH:27])[CH3:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[H-].[Na+].I[CH3:46]>O1CCCC1>[F:40][C:37]([F:38])([F:39])[C:35]1[CH:34]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:36]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)([O:27][CH3:46])[CH3:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1

Participants

5

Reactant 3

HCID 6328Methyl iodide3×HCID 24758Sodium hydride3×HCID 589686081-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-1-cyclohexylethanol

Product 1

HCID 24853421(3,5-Bis-trifluoromethyl-benzyl)-[2-(1-cyclohexyl-1-methoxy-ethyl)-5-trifluoromethyl-benzyl]-(2-methyl-2H-tetrazol-5-yl)-amineYield 71%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 1-(2-(((3,5-bis(trifluoromethyl)benzyl)(2-methyl-2H-tetrazol-5-yl)amino)methyl)-4-(trifluoromethyl)phenyl)-1-cyclohexylethanol (26 mg; 0.043 mmol) in tetrahydrofuran (0.7 mL) was added sodium hydride (11 mg; 0.275 mmol; 60% dispersion in mineral oil). After stirring for 30 minutes at room temperature, iodomethane (30 uL; 0.485 mmol) was added. The reaction was stirred for 16 hours. More sodium hydride (12 mg; 0.3 mmol; 60% dispersion in mineral oil) and iodomethane (30 uL; 0.485 mmol) were added. After 1 hour more sodium hydride (12 mg; 0.3 mmol; 60% dispersion in mineral oil) was added. After 30 minutes, iodomethane (30 uL; 0.485 mmol) was added. The reaction was stirred for 2 hours. The reaction was quenched with aqueous 2N hydrochloric acid (6 drops). The mixture was diluted with ethyl acetate and filtered over sodium sulfate/silica plug. Then the solution was concentrated. The residue was purified by 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-25% ethyl acetate in heptane) to give 19 mg (71% yield) of a colorless gum. MS (ES+): Calc: 623.5, Found: 592.5 (M-OCH3). 1H NMR (400 MHz, CDCl3) δ ppm 7.78 (s, 1H), 7.73 (s, 2H), 7.46 (s, 1H), 7.45 (d, J=7.47 Hz, 1H), 7.27 (d, J=8.30 Hz, 1H), 5.25 (d, J=17.43 Hz, 1H), 5.07 (d, J=17.43 Hz, 1H), 4.79 (q, J=16.60, 16.18 Hz, 2H), 4.19 (s, 3H), 3.02 (s, 3H), 2.01 (d, J=11.2 Hz, 1H), 1.78-1.67 (m, 2H), 1.66-1.55 (m, 2H), 1.53 (s, 3H), 1.11-0.83 (m, 6H).

Workup

  1. stirringThe reaction was stirred for 16 hours
  2. waitAfter 30 minutes
  3. stirringThe reaction was stirred for 2 hours
  4. customThe reaction was quenched with aqueous 2N hydrochloric acid (6 drops)
  5. additionThe mixture was diluted with ethyl acetate
  6. filtrationfiltered over sodium sulfate/silica plug
  7. concentrationThen the solution was concentrated
  8. customThe residue was purified by 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-25% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-675aacbc18c7408a928e9b0a20b458f7
Source dataset
uspto-grants-2011_04
Patent number
US07919506B2

Reaction notes

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