Water → 2-[4,6-difluoro-1-[3-(1H-pyrazol-4-yl)benzyl]indol-3-yl]sulfonyl-N-(5-methylisoxazol-3-yl)acetamide

HRID 1621268Notes

Reaction equation

HRID 1621268 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([F:16])[CH:11]=[C:12]([F:15])[CH:13]=2)[C:8]([S:17]([CH2:20][C:21]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[O:26][N:25]=2)=[O:22])(=[O:19])=[O:18])=[CH:7]1.C([N:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[N:41]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:40]1[CH:44]=[C:43]([C:2]2[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=2)[CH2:5][N:6]2[C:14]3[C:9](=[C:10]([F:16])[CH:11]=[C:12]([F:15])[CH:13]=3)[C:8]([S:17]([CH2:20][C:21]([NH:23][C:24]3[CH:28]=[C:27]([CH3:29])[O:26][N:25]=3)=[O:22])(=[O:18])=[O:19])=[CH:7]2)[CH:42]=[N:41]1

Participants

7

Reactant 4

HCID 962WaterHCID 10340Sodium CarbonateHCID 16217654tert-butyl 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylateHCID 444759462-[1-(3-bromobenzyl)-4,6-difluoro-indol-3-yl]sulfonyl-N-(5-methylisoxazol-3-yl)acetamide

Product 1

HCID 444759482-[4,6-difluoro-1-[3-(1H-pyrazol-4-yl)benzyl]indol-3-yl]sulfonyl-N-(5-methylisoxazol-3-yl)acetamideYield 21%

Reagents, catalysts & solvents 2

HCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

In a 5 mL microwave vial, 2-((1-(3-bromobenzyl)-4,6-difluoro-1H-indol-3-yl)sulfonyl)-N-(5-methyl-isoxazol-3-yl)acetamide (20 mg, 0.38 mmol), prepared in Example 1, was dissolved in DMF (2 mL). PdCl2(PPh3)2 (1.0 mg, 0.001 mmol), 1-Boc-pyrazole-4-boronic acid pinacol ester (20 mg, 0.68 mmol), and 2 N aqueous sodium carbonate (1 mL) were added and stirred at 80° C. overnight. The reaction was cooled to ambient temperature. Water (2 mL) was added and the mixture was extracted with ethyl acetate (2×3 mL). The organics were combined, dried over magnesium sulfate and concentrated in vacuo to give an oily residue which was purified on a Gilson Prep HPLC system (5-95% acetonitrile:water (0.1% TFA) over 6 min) to afford the title compound (4.0 mg, 0.008 mmol, 21% yield) as a white solid. LCMS>98% 220 nm, RT=0.79 min, m/z=512 (m+1). 1H NMR (400 MHz, DMSOD6) 12.97 (s, 1H), 11.33 (s, 1H), 8.38 (s, 1H), 8.16, (s, 1H), 7.91 (s, 1H), 7.61 (s, 1H), 7.49-7.55 (m, 2H), 7.28 (t, J=8.0 Hz, 1H), 7.18 (d, J=10.8 Hz, 1H), 7.00 (d, J=7.6 Hz, 1H), 6.48 (s, 1H), 5.52 (s, 2H), 4.48 (s, 2H), 2.35 (s, 3H).

Workup

  1. temperatureThe reaction was cooled to ambient temperature
  2. extractionthe mixture was extracted with ethyl acetate (2×3 mL)
  3. dry with materialdried over magnesium sulfate
  4. concentrationconcentrated in vacuo
  5. customto give an oily residue which
  6. customwas purified on a Gilson Prep HPLC system (5-95% acetonitrile:water (0.1% TFA) over 6 min)

Sources & evidence

ORD record
ord-901ca4adbe55484cadb4c180a587ac0a
Source dataset
uspto-grants-2014_07
Patent number
US08772509B2

Reaction notes

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