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

HRID 390742Notes

Reaction equation

HRID 390742 reaction equation
N1C2C=CC=C[C:4]=2N=N1.[NH:10]1[CH2:15][CH2:14][O:13][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:48][C:45]([F:47])([F:46])[C:43]1[CH:42]=[C:20]([CH:19]=[C:18]([C:17]([F:49])([F:50])[F:16])[CH:44]=1)[CH2:21][N:22]([CH2:29][C:30]1[CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:35]=[CH:34][C:31]=1[CH:32]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH3:4])[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 58966509N-[3,5-Bis(trifluoromethyl)benzyl]-2-methyl-N-[2-(1-morpholin-4-ylethyl)-5-(trifluoromethyl)benzyl]-2H-tetrazol-5-amineYield 28%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Procedure

To a solution of benzotriazole (12.8 mg, 0.1075 mmoles) in ethanol (2 mL) was added morpholine (9.4 mg, 0.1075 mmoles) and the reaction was stirred for 10 minutes. A solution of 2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzaldehyde (50 mg, 0.0977 mmoles) in ethanol (1 mL) was added to the reaction mixture and it was further stirred for 16 hours. The imine fragment was observed MH+=581.4. Parent ion for the intermediate was not found. The ethanol was evaporated and the crude product was taken to the next step. Half of the crude was dissolved in toluene and methyl magnesium bromide (97 □L, 0.2916 mmoles of a 3M solution in ether) was added. The reaction mixture was heated at reflux for 2 hours. LC-MS indicated formation of product. The solvent was evaporated from the reaction mixture. 1N NaOH solution was added and the aqueous layer was extracted with dichloromethane. 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 8.2 mg (28%) of the title compound as clear oil. MS (ES+) Calc: 596.4, Found: 597.2 (M+1).

Workup

  1. stirringwas further stirred for 16 hours
  2. customThe ethanol was evaporated
  3. dissolutionHalf of the crude was dissolved in toluene
  4. additionmethyl magnesium bromide (97 □L, 0.2916 mmoles of a 3M solution in ether) was added
  5. temperatureThe reaction mixture was heated
  6. temperatureat reflux for 2 hours
  7. customThe solvent was evaporated from the reaction mixture
  8. addition1N NaOH solution was added
  9. extractionthe aqueous layer was extracted with dichloromethane
  10. concentrationThe organic layer was concentrated
  11. dissolutionthe residue was dissolved in DMSO
  12. custompurified on prepHPLC (Shimadzu, 30×50 C18, Basic, 30-95%, 0.1% NaOH, 8 min gradient, 220 UV)

Sources & evidence

ORD record
ord-4be07b88af3a4ed19241713e1ea64f70
Source dataset
uspto-grants-2013_02
Patent number
US08383660B2

Reaction notes

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