Sodium hydride → HCID 66729451, compound

HRID 516642Notes

Reaction equation

HRID 516642 reaction equation
[Br:1][C:2]1[C:3]([C:7]2[C:8]([F:28])=[C:9]([N:13]([CH2:25][O:26][CH3:27])[S:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:4][NH:5][CH:6]=1.[H-].[Na+].Br[CH2:32][CH2:33][O:34][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([C:7]2[C:8]([F:28])=[C:9]([N:13]([CH2:25][O:26][CH3:27])[S:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=3[F:24])(=[O:16])=[O:15])[CH:10]=[CH:11][CH:12]=2)=[N:4][N:5]([CH2:32][CH2:33][O:34][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][O:36]2)[CH:6]=1

Participants

6

Reactant 3

HCID 24758Sodium hydrideHCID 866212-(2-Bromoethoxy)tetrahydro-2H-pyranHCID 178496782HCID 178496782, compound

Product 1

HCID 66729451HCID 66729451, compoundYield 55.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

A solution of N-[3-(4-Bromo-1H-pyrazol-3-yl)-2-fluoro-phenyl]-2,5-difluoro-N-methoxymethyl-benzenesulfonamide (346 mg, 0.726 mmol)(prepared as described in Preparation 1) in anhydrous DMF (4 mL) was cooled to 0° C. under an argon atmosphere and sodium hydride (60% in mineral oil, 87 mg, 2.179 mmol, 3 eq) was added. The mixture was stirred at 0° C. for 30 minutes, then 2-(2-bromo-ethoxy)-tetrahydro-pyran (0.165 mL, 1.089 mmol, 1.5 eq) was added dropwise and the mixture was stirred at 0° C. for 1 hour. The reaction mixture was then diluted with AcOEt and washed with water and brine. The organic layer was dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography on silica gel (cyclohexane/AcOEt 55:45) affording 243 mg (55%) of the desired regioisomer N-(3-{4-Bromo-1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-1H-pyrazol-3-yl}-2-fluoro-phenyl)-2,5-difluoro-N-methoxymethyl-benzenesulfonamide. HPLC (254 nm): Rt: 7.21 min; 1H NMR (DMSO-d6) Shift (selected signals): 8.07 (s, 1H), 7.55-7.69 (m, 2H), 7.47-7.53 (m, 2H), 7.39-7.45 (m, 1H), 7.30-7.35 (m, 1H), 5.09 (s, 2H), 4.51-4.57 (m, 1H), 4.29-4.35 (m, 2H), 3.89-3.97 (m, 1H), 3.70-3.78 (m, 1H), 3.42-3.51 (m, 1H), 3.38 (s, 3H), 1.29-1.69 (3 m, 6H); HRMS (ESI) calcd for C24H26BrF3N3O5S [M+H]+ 604.0723. found 604.0693.

Workup

  1. stirringthe mixture was stirred at 0° C. for 1 hour
  2. washwashed with water and brine
  3. dry with materialThe organic layer was dried over Na2SO4
  4. customevaporated to dryness
  5. customThe crude product was purified by flash chromatography on silica gel (cyclohexane/AcOEt 55:45)

Sources & evidence

ORD record
ord-c6c85b89bda342de9a7e2564d038ae9e
Source dataset
uspto-grants-2015_08
Patent number
US09114137B2

Reaction notes

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