Morpholine → N-[3,5-Bis(trifluoromethyl)benzyl]-2-methyl-N-[2-(1-morpholin-4-yl-propyl)-5-(trifluoromethyl)benzyl]-2H-tetrazol-5-amine

HRID 390741Notes

Reaction equation

HRID 390741 reaction equation
N1[C:5]2C=CC=[CH:9][C:4]=2N=N1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.FC(F)(F)[C:18]1[CH:19]=[C:20]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:21][N:22]([CH2:29][C:30]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:31]=1C=O)[C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1>C(O)C>[F:48][C:45]([F:47])([F:46])[C:43]1[CH:42]=[C:20]([CH:19]=[C:18]([C:38]([F:41])([F:40])[F:39])[CH:44]=1)[CH2:21][N:22]([CH2:29][C:30]1[CH:37]=[C:36]([C:38]([F:40])([F:39])[F:41])[CH:35]=[CH:34][C:31]=1[CH:5]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH2:4][CH3:9])[C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1

Participants

5

Reactant 3

HCID 8083MorpholineHCID 589665242-{[(3,5-bis-trifluoromethyl-benzyl)(2-methyl-2H-tetrazol-5-yl)amino]-methyl}-4-trifluoromethyl-benzaldehydeHCID 178418385HCID 178418385, compound

Product 1

HCID 23642337N-[3,5-Bis(trifluoromethyl)benzyl]-2-methyl-N-[2-(1-morpholin-4-yl-propyl)-5-(trifluoromethyl)benzyl]-2H-tetrazol-5-amine

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Procedure

To a solution of benzotriazole (25.6 mg, 0.215 mmoles) in ethanol (2 mL) was added morpholine (18.7 mg, 0.215 mmoles) and the reaction mixture was stirred for 10 minutes at room temperature. A solution of 2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzaldehyde (100 mg, 0.195 mmoles) in ethanol (2 mL) was added and the reaction mixture was further stirred for 16 hours. MS indicated formation of the imine intermediate MH+=581.4. The ethanol was evaporated and the residue was dissolved in toluene (3 mL). Ethyl magnesium bromide (0.19 mL, 0.586 mmoles of a 3M solution in ether) was added and the reaction mixture was heated at 50° C. for 2 h. LC-MS indicated formation of the desired product. The reaction mixture was diluted with ethyl acetate then washed with saturated aqueous NH4Cl solution followed by 1N NaOH solution. The organic layer was concentrated. The residue was purified by flash chromatography (silica gel, 40 g) (eluted over a gradient 5-30-50% ethyl acetate and hexane) to give the title compound as clear oil, 91 mg (76%). 1H NMR (CDCl3) δ 7.79 (1H, s), 7.65 (2H,s), 7.46(2H,m), 7.25(1H, s), 4.85(2H,m), 4.68(2H,s), 4.20(3H,s), 3.60(2H,m), 3.55(2H,m), 2.98(1H,m), 2.50(2H,m), 2.25(2H,m), 1.80(2H,m), 0.85(3H, t). MS (ES+) Calc: 610.5, Found: 611.2 (M+1).

Workup

  1. stirringthe reaction mixture was further stirred for 16 hours
  2. customThe ethanol was evaporated
  3. dissolutionthe residue was dissolved in toluene (3 mL)
  4. additionEthyl magnesium bromide (0.19 mL, 0.586 mmoles of a 3M solution in ether) was added
  5. temperaturethe reaction mixture was heated at 50° C. for 2 h
  6. additionThe reaction mixture was diluted with ethyl acetate
  7. washthen washed with saturated aqueous NH4Cl solution
  8. concentrationThe organic layer was concentrated
  9. customThe residue was purified by flash chromatography (silica gel, 40 g) (
  10. washeluted over a gradient 5-30-50% ethyl acetate and hexane)

Sources & evidence

ORD record
ord-8207f810c0664be7ace09a701d0ca1c0
Source dataset
uspto-grants-2013_02
Patent number
US08383660B2

Reaction notes

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