3-(Trifluoromethyl)aniline → N'-hydroxy-4-[(2-methoxyethyl)amino]-N-[3-(trifluoromethyl)phenyl]-1,2,5-oxadiazole-3-carboximidamide

HRID 881164Notes

Reaction equation

HRID 881164 reaction equation
[OH:1][N:2]=[C:3](Cl)[C:4]1[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C(=O)(O)[O-].[Na+].C(OCC)(=O)C>O.[Cl-].[Na+].O>[OH:1][N:2]=[C:3]([C:4]1[C:8]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[N:7][O:6][N:5]=1)[NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([C:16]([F:15])([F:24])[F:25])[CH:18]=1

Participants

7

Reactant 4

HCID 73753-(Trifluoromethyl)anilineHCID 8857Ethyl AcetateHCID 516892Sodium BicarbonateHCID 136330165N-Hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidoyl chloride

Product 1

HCID 178495896N'-hydroxy-4-[(2-methoxyethyl)amino]-N-[3-(trifluoromethyl)phenyl]-1,2,5-oxadiazole-3-carboximidamideYield 81.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
60 °C

Procedure

N-Hydroxy-4-[(2-methoxyethyl)amino]-1,2,5-oxadiazole-3-carboximidoyl chloride (1.3 g, 5.0 mmol) [made according to Example 1, steps A through E] was stirred in water (10 mL) and warmed to 60° C. for 5 minutes. 3-(trifluoromethyl)aniline [Aldrich, product #A41801] (880 mg, 5.5 mmol) was added in one portion and the reaction stirred for 15 minutes. While remaining at 60° C., a solution of sodium bicarbonate (630 mg, 7.5 mmol) in water (10 mL) was added dropwise over 5 minutes. The reaction was stirred at 60° C. for an additional 50 minutes, and then allowed to cool to room temperature. Ethyl acetate (20 mL) and brine (30 mL) were added to the flask and the organic layer was collected. The aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organics were dried over sodium sulfate. The solvent was removed in vacuo to give the desired product as an orange solid (1.4 g, 80%). LCMS calculated for C13H15F3N5O3 (M+H)+: m/z=346.1. 1H NMR (400 MHz, CD3OD): δ 7.36 (t, J=8.2 Hz, 1H), 7.23 (d, J=7.6 Hz, 1H), 7.09 (s, 1H), 7.02 (d, J=8.2 Hz, 1H), 3.60 (t, J=5.2 Hz, 2H), 3.46 (t, J=5.2 Hz, 2H), 3.38 (s, 3H).

Workup

  1. customWhile remaining at 60° C.
  2. stirringThe reaction was stirred at 60° C. for an additional 50 minutes
  3. temperatureto cool to room temperature
  4. customthe organic layer was collected
  5. extractionThe aqueous layer was extracted with ethyl acetate (2×20 mL)
  6. dry with materialthe combined organics were dried over sodium sulfate
  7. customThe solvent was removed in vacuo

Sources & evidence

ORD record
ord-55eff646a13f49bb88fea2d86bcab2de
Source dataset
uspto-grants-2015_03
Patent number
US08993605B2

Reaction notes

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