Sodium hydride → 2-[1-(3-bromobenzyl)-4,6-difluoro-indol-3-yl]sulfonyl-N-(5-methylisoxazol-3-yl)acetamide

HRID 1621267Notes

Reaction equation

HRID 1621267 reaction equation
[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([S:12]([CH2:15][C:16]([NH:18][C:19]1[CH:23]=[C:22]([CH3:24])[O:21][N:20]=1)=[O:17])(=[O:14])=[O:13])=[CH:5][NH:6]2.[H-].[Na+].[Br:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br>CN(C=O)C>[Br:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][N:6]1[C:7]2[C:3](=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH:8]=2)[C:4]([S:12]([CH2:15][C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[O:17])(=[O:14])=[O:13])=[CH:5]1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 699793-Bromobenzyl bromideHCID 680040782-((4,6-difluoro-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide

Product 1

HCID 444759462-[1-(3-bromobenzyl)-4,6-difluoro-indol-3-yl]sulfonyl-N-(5-methylisoxazol-3-yl)acetamideYield 51.7%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
0 °C

Procedure

In a 5 mL microwave vial, 2-((4,6-difluoro-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide (62.0 mg, 0.174 mmol) from Step C was dissolved in DMF (3 mL) and cooled to 0° C. Sodium hydride (60% by weight, 8.0 mg, 0.35 mmol) was then added in one portion and the reaction mixture was vigorously stirred at 0° C. for 15 minutes. 3-bromo-benzylbromide (44.0 mg, 0.174 mmol) was added in one portion and the reaction mixture was stirred while being allowed to warm to ambient temperature over 3 hours. The reaction mixture was quenched with water (2 mL) and the solution was extracted with ethyl acetate (3×4 mL). The organics were combined, dried over magnesium sulfate, and concentrated in vacuo to give an oily residue which was purified on a silica gel column (0-50% ethyl acetate:hexanes over 19 min) to yield the title compound (45 mg, 0.09 mmol, 50% yield). LCMS>98% 220 nm, RT=0.84 min, m/z=524 ([79Br]m+1), 526 ([81Br]m+1). 1H NMR (400 MHz, DMSOD6) 11.32 (s, 1H), 8.39 (s, 1H), 7.59 (s, 1H), 7.52 (m, 2H), 7.29 (t, J=7.6 Hz, 1H), 7.17-7.24 (m, 2H), 6.52 (s, 1H), 5.53 (s, 2H), 4.47 (s, 2H), 2.36 (s, 3H).

Workup

  1. stirringthe reaction mixture was stirred
  2. temperatureto warm to ambient temperature over 3 hours
  3. customThe reaction mixture was quenched with water (2 mL)
  4. extractionthe solution was extracted with ethyl acetate (3×4 mL)
  5. dry with materialdried over magnesium sulfate
  6. concentrationconcentrated in vacuo
  7. customto give an oily residue which
  8. customwas purified on a silica gel column (0-50% ethyl acetate:hexanes over 19 min)

Sources & evidence

ORD record
ord-ca37c9f73a1747ccafbe3b0c45defbec
Source dataset
uspto-grants-2014_07
Patent number
US08772509B2

Reaction notes

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