Sodium hydride → 5-Chloro-2-fluoro-N-(methylsulfonyl)-4-((2,2,3,3-tetramethyl-cyclopropyl)methoxy)benzamide

HRID 1849496Notes

Reaction equation

HRID 1849496 reaction equation
[CH3:1][C:2]1([CH3:9])[C:4]([CH3:6])([CH3:5])[CH:3]1[CH2:7][OH:8].[H-].[Na+].[Cl:12][C:13]1[C:14](F)=[CH:15][C:16]([F:26])=[C:17]([CH:25]=1)[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[O:19]>CN(C=O)C.O.CCOC(C)=O>[Cl:12][C:13]1[C:14]([O:8][CH2:7][CH:3]2[C:4]([CH3:6])([CH3:5])[C:2]2([CH3:9])[CH3:1])=[CH:15][C:16]([F:26])=[C:17]([CH:25]=1)[C:18]([NH:20][S:21]([CH3:24])(=[O:22])=[O:23])=[O:19]

Participants

7

Reactant 3

HCID 24758Sodium hydrideHCID 5441792,2,3,3-TetramethylcyclopropanemethanolHCID 580424175-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide

Product 1

HCID 867028415-Chloro-2-fluoro-N-(methylsulfonyl)-4-((2,2,3,3-tetramethyl-cyclopropyl)methoxy)benzamideYield 25.2%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a stirred solution of (2,2,3,3-tetramethylcyclopropyl)methanol (80 mg, 0.62 mmol) in dry DMF (10 mL) at 0° C. was added NaH (25 mg, 0.62 mmol). After being stirred for 30 min, 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide (54 mg, 0.21 mmol) was added. After being stirred at room temperature for 18 h, the mixture was diluted with water (10 mL) and EtOAc (20 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (20 ml×2). The combined organic layers was dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford 5-chloro-2-fluoro-N-(methylsulfonyl)-4-((2,2,3,3-tetramethylcyclopropyl)-methoxy)benzamide (20 mg, 25% yield) as a white solid. LCMS (ESI) Method A: RT=5.11 min, m/z: 268 [M-109]+. 1H NMR (500 MHz, DMSO-d6): δ 7.35 (d, J=9.0 Hz 1H), 7.03 (d, J=7.0 Hz, 1H), 6.04 (brs, 1H), 3.99 (d, J=7.5 Hz, 2H), 2.80 (s, 3H), 1.06 (s, 6H), 0.99 (s, 6H), 0.65 (t, J=7.5 Hz, 1H); 13C NMR (125 MHz, MeOH-d4): δ 159.4 (d, J=3.5 Hz), 133.9 (d, J=2.1 Hz), 114.1, 104.2, 103.9, 71.4, 41.7, 32.5, 24.2, 23.7, 17.4.

Workup

  1. stirringAfter being stirred at room temperature for 18 h
  2. customThe organic layer was separated
  3. extractionthe aqueous layer was extracted with EtOAc (20 ml×2)
  4. dry with materialThe combined organic layers was dried over Na2SO4
  5. concentrationconcentrated
  6. customThe residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min)

Sources & evidence

ORD record
ord-64ebbabfc3804cdbb344d12fde62cfe3
Source dataset
uspto-grants-2015_02
Patent number
US08952169B2

Reaction notes

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