Sodium hydride → 4-(2-cyclopropylethoxy)-2,5-difluoro-N-(methylsulfonyl)benzamide

HRID 1427799Notes

Reaction equation

HRID 1427799 reaction equation
[CH:1]1([CH2:4][CH2:5][OH:6])[CH2:3][CH2:2]1.[H-].[Na+].[F:9][C:10]1[CH:22]=[C:21](F)[C:20]([F:24])=[CH:19][C:11]=1[C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[O:13]>CN(C)C=O>[CH:1]1([CH2:4][CH2:5][O:6][C:21]2[C:20]([F:24])=[CH:19][C:11]([C:12]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[O:13])=[C:10]([F:9])[CH:22]=2)[CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 1376422-Cyclopropylethan-1-olHCID 580424352,4,5-trifluoro-N-(methylsulfonyl)benzamide

Product 1

HCID 725454204-(2-cyclopropylethoxy)-2,5-difluoro-N-(methylsulfonyl)benzamideYield 19%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
45 °C

Procedure

To a mixture of 2-cyclopropylethanol (0.172 g, 2.0 mmol) in anhydrous N,N-dimethylformamide (20 mL) was added sodium hydride (60% in mineral oil, 0.20 g, 5.0 mmol) at room temperature. The resulting mixture was stirred at 45° C. for 30 min and then cooled to room temperature. 2,4,5-Trifluoro-N-(methylsulfonyl)benzamide (WO 2012007883 A1) (0.51 g, 2.2 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The mixture was cooled to 0° C. and quenched with hydrochloride acid (1N, 30 mL) followed by extraction with ethyl acetate (100 mL). The organic layer was washed with water (30 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo, the crude product was purified by silica gel column chromatography using 10-60% ethyl acetate (containing 2% acetic acid) in hexanes as an eluent to afford the title compound as a white solid (0.12 g, 19%): 1H NMR (300 MHz, DMSO-d6) δ 12.06 (brs, 1H), 7.58 (dd, J=6.9 Hz & 11.4 Hz, 1H), 7.30 (dd, J=6.9 Hz & 12.1 Hz, 1H), 4.19 (t, J=6.6 Hz, 2H), 3.35 (s, 3H), 1.69-1.62 (m, 2H), 0.88-0.74 (m, 1H), 0.47-0.41 (m, 2H), 0.16-0.11 (m, 2H); MS (ES−) m/z 318.1 (M−1).

Workup

  1. temperaturecooled to room temperature
  2. stirringthe reaction mixture was stirred at room temperature for 16 h
  3. temperatureThe mixture was cooled to 0° C.
  4. customquenched with hydrochloride acid (1N, 30 mL)
  5. extractionfollowed by extraction with ethyl acetate (100 mL)
  6. washThe organic layer was washed with water (30 mL)
  7. dry with materialdried over anhydrous sodium sulfate
  8. filtrationfiltered
  9. concentrationThe filtrate was concentrated in vacuo
  10. customthe crude product was purified by silica gel column chromatography

Sources & evidence

ORD record
ord-fde3c68ed60149d29e7e588b3c2120bf
Source dataset
uspto-grants-2015_01
Patent number
US08933236B2

Reaction notes

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