Methanol → 3-[4-(benzyloxy)-2-(trifluoromethyl)phenyl]4-methyl-5-(4-phenylbicyclo[2.2.2]oct-1-yl)4H-1,2,4-triazole

HRID 22849

Reaction equation

HRID 22849 reaction equation
FC(F)(F)C([O-])=O.[CH3:8][NH2:9].[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2O[C:26]([C:29]34[CH2:36][CH2:35][C:32]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)([CH2:33][CH2:34]3)[CH2:31][CH2:30]4)=[N:27][N:28]=2)=[C:20]([C:43]([F:46])([F:45])[F:44])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CO>>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:9]([CH3:8])[C:26]([C:29]34[CH2:36][CH2:35][C:32]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)([CH2:31][CH2:30]3)[CH2:33][CH2:34]4)=[N:27][N:28]=2)=[C:20]([C:43]([F:44])([F:45])[F:46])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1

Participants

5

Reactant 4

HCID 887MethanolHCID 6329Methylamine2×HCID 84468TrifluoroacetateHCID 225917222-[4-(Benzyloxy)-2-(trifluoromethyl)phenyl]-5-(4-phenylbicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole

Product 1

HCID 225916813-[4-(benzyloxy)-2-(trifluoromethyl)phenyl]4-methyl-5-(4-phenylbicyclo[2.2.2]oct-1-yl)4H-1,2,4-triazole

Conditions

Temperature
150 °C

Procedure

The trifluoroacetate salt of methylamine (380 mg, 2.61 mmol) and 2-[4-(benzyloxy)-2-(trifluoromethyl)phenyl]-5-(4-phenylbicyclo[2.2.2]oct-1-yl)-1,3,4-oxadiazole (8-D) were suspended in a 2 M solution of methylamine in methanol (1.3 mL, 2.61 mmol) and heated at 150° C. overnight. After being cooled to room temperature, the reaction mixture was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate (30 mL). The layers were separated and the aqueous layer extracted with twice with ethyl acetate (25 mL). The combined organic layers were washed with brine, dried (MgSO4), and solvent removed in vacuo. The residue was then dissolved in methanol (8 mL) and purified by reverse phase chromatography using gradient elution with 10% acetonitrile (0.1% TFA) /water (0.1% TFA) to 100% acetonitrile (0.1% TFA) over 10 min (20 mL/min). The fractions containing product were partitioned between saturated aqueous sodium bicarbonate (25 mL) and methylene chloride (15 mL). The layers were separated and the aqueous layer was extracted with methylene chloride (15 mL) three times, dried (MgSO4), and the solvent removed in vacuo to afford 3-[4-(benzyloxy)-2-(trifluoromethyl)phenyl]-4-methyl-5-(4-phenylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazole (8-E). MS: m/z 518 (M+1).

Workup

  1. temperatureAfter being cooled to room temperature
  2. customthe reaction mixture was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate (30 mL)
  3. customThe layers were separated
  4. extractionthe aqueous layer extracted with twice with ethyl acetate (25 mL)
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried (MgSO4), and solvent
  7. customremoved in vacuo
  8. dissolutionThe residue was then dissolved in methanol (8 mL)
  9. custompurified by reverse phase chromatography
  10. washelution with 10% acetonitrile (0.1% TFA) /water (0.1% TFA) to 100% acetonitrile (0.1% TFA) over 10 min (20 mL/min)
  11. additionThe fractions containing product
  12. customwere partitioned between saturated aqueous sodium bicarbonate (25 mL) and methylene chloride (15 mL)
  13. customThe layers were separated
  14. extractionthe aqueous layer was extracted with methylene chloride (15 mL) three times
  15. dry with materialdried (MgSO4)
  16. customthe solvent removed in vacuo

Sources & evidence

ORD record
ord-1f3649ba7d4448a79d0c5d86fd48c239
Source dataset
uspto-grants-2005_02
Patent number
US06849636B2

Linked notes

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