Piperidine → N-[3,5-Bis(trifluoromethyl)benzyl]-2-methyl-N-[2-(1-piperidin-1-ylpropyl)-5-(trifluoromethyl)benzyl]-2H-tetrazol-5-amine

HRID 390743Notes

Reaction equation

HRID 390743 reaction equation
[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9]C=2N=N1.N1CCC[CH2:12][CH2:11]1.[F:16][C:17]([F:50])([F:49])[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]=1[CH:32]=O)[C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1>C(O)C>[F:50][C:17]([F:49])([F:16])[C:18]1[CH:19]=[C:20]([CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1)[CH2:21][N:22]([CH2:29][C:30]1[CH:37]=[C:36]([C:38]([F:39])([F:41])[F:40])[CH:35]=[CH:34][C:31]=1[CH:32]([N:1]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)[CH2:11][CH3:12])[C:23]1[N:24]=[N:25][N:26]([CH3:28])[N:27]=1

Participants

5

Reactant 3

HCID 8082PiperidineHCID 589665242-{[(3,5-bis-trifluoromethyl-benzyl)(2-methyl-2H-tetrazol-5-yl)amino]-methyl}-4-trifluoromethyl-benzaldehydeHCID 178418385HCID 178418385, compound

Product 1

HCID 24757851N-[3,5-Bis(trifluoromethyl)benzyl]-2-methyl-N-[2-(1-piperidin-1-ylpropyl)-5-(trifluoromethyl)benzyl]-2H-tetrazol-5-amineYield 23.2%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Conditions

Temperature
50 °C

Procedure

To a solution of benzotriazole (12.8 mg, 0.1075 mmoles) in ethanol (2.5 mL) was added piperidine (9.2 mg, 0.1075 mmoles) and the reaction was stirred for 10 minutes. 2-{[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzaldehyde (50 mg, 0.0977 mmoles) was added to the reaction mixture and it was further stirred for 16 hours. The imine fragment was observed MH+=579.4. Parent ion for the intermediate was not found. Ethanol was evaporated and the crude product was taken to the next step. To the crude product in toluene (2 mL) was added ethyl magnesium bromide (97 □L, 0.2916 mmoles of a 3M solution in ether). The reaction mixture was heated at 50° C. for 2 hours. LC-MS indicated formation of product. The reaction mixture was diluted with ethyl acetate (2 mL). The organic layer was washed with saturated aqueous NH4Cl solution followed by 1N NaOH solution. The organic layer was concentrated and the residue was dissolved in DMSO and purified on prepHPLC (Shimadzu, 30×50 C18, Basic, 30-95%, 0.1% NaOH, 8 min gradient, 220 UV) to yield the title compound as clear oil 13.8 mg (23%). MS (ES+) Calc: 608.5, Found: 609.1 (M+1).

Workup

  1. stirringwas further stirred for 16 hours
  2. customEthanol was evaporated
  3. additionTo the crude product in toluene (2 mL) was added ethyl magnesium bromide (97 □L, 0.2916 mmoles of a 3M solution in ether)
  4. additionThe reaction mixture was diluted with ethyl acetate (2 mL)
  5. washThe organic layer was washed with saturated aqueous NH4Cl solution
  6. concentrationThe organic layer was concentrated
  7. dissolutionthe residue was dissolved in DMSO
  8. custompurified on prepHPLC (Shimadzu, 30×50 C18, Basic, 30-95%, 0.1% NaOH, 8 min gradient, 220 UV)

Sources & evidence

ORD record
ord-94c18f327a9540d1b9bc07417ea5d3de
Source dataset
uspto-grants-2013_02
Patent number
US08383660B2

Reaction notes

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