N-Methylbenzylamine → N-[2-{1-[benzyl(methyl)amino]-propyl}-5-(trifluoromethyl)benzyl]-N-[3,5-bis(trifluoromethyl)-benzyl]-2-methyl-2H-tetrazol-5-amine

HRID 390744Notes

Reaction equation

HRID 390744 reaction equation
[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:16]=1[CH:17]=O)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH3:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.N1[C:49]2C=CC=C[C:48]=2N=N1>C(O)C>[CH2:38]([N:37]([CH3:36])[CH:17]([C:16]1[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[CH:22][C:15]=1[CH2:14][N:7]([CH2:6][C:5]1[CH:4]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1)[CH2:48][CH3:49])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1

Participants

5

Reactant 3

HCID 7669N-MethylbenzylamineHCID 589665242-{[(3,5-bis-trifluoromethyl-benzyl)(2-methyl-2H-tetrazol-5-yl)amino]-methyl}-4-trifluoromethyl-benzaldehydeHCID 178418385HCID 178418385, compound

Product 1

HCID 58966437N-[2-{1-[benzyl(methyl)amino]-propyl}-5-(trifluoromethyl)benzyl]-N-[3,5-bis(trifluoromethyl)-benzyl]-2-methyl-2H-tetrazol-5-amineYield 96.3%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

To a solution of 2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzaldehyde (200.0 mg, 0.391 mmoles) in ethanol (3.0 mL) was added N-methyl benzylamine (61 μL, 0.469 mmol) and benzotriazole (56 mg, 0.469 mmoles) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated to remove ethanol and the residue was taken up in toluene (6.0 mL), cooled to 0° C. and ethyl magnesium chloride (0.78 mL, 1.564 mmoles of a 2M solution in ether) was added. The reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous NH4Cl. Ether was added and the mixture was stirred for 5 minutes, To the mixture was added 1N NaOH to achieve pH of 10. The aqueous layer was extracted with ether and the combined organic layer was dried over sodium sulfate and concentrated to give a yellow oil. The crude product was purified using silica gel chromatography on the ISCO Combiflash system (Teledyne ISCO, Lincoln, Nebr., USA) with a gradient of 1-3% methanol in dichloromethane to yield the title compound (242.7 mg, 96% yield) as light yellow oil. MS (ES+) Calc: 608.5, Found: 609.1 (M+1).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. customto remove ethanol
  3. temperaturecooled to 0° C.
  4. additionethyl magnesium chloride (0.78 mL, 1.564 mmoles of a 2M solution in ether) was added
  5. temperatureto warm to room temperature
  6. stirringstirred for 2 hours
  7. customThe reaction mixture was quenched with saturated aqueous NH4Cl
  8. additionEther was added
  9. stirringthe mixture was stirred for 5 minutes, To the mixture
  10. additionwas added 1N NaOH
  11. extractionThe aqueous layer was extracted with ether
  12. dry with materialthe combined organic layer was dried over sodium sulfate
  13. concentrationconcentrated
  14. customto give a yellow oil
  15. customThe crude product was purified

Sources & evidence

ORD record
ord-0689b503514f441aaf338d829e58ed14
Source dataset
uspto-grants-2013_02
Patent number
US08383660B2

Reaction notes

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