Ammonium Chloride → 3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one

HRID 1965335Notes

Reaction equation

HRID 1965335 reaction equation
[F:1][C:2]1([F:12])[O:6][C:5]2[CH:7]=[CH:8][C:9]([OH:11])=[CH:10][C:4]=2[O:3]1.C([Mg]Cl)(C)C.[F:18][C:19]([F:38])([F:37])[C:20]1[O:24][C:23]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:35])[C:27]2=[O:36])=[CH:22][CH:21]=1.[Cl-].[NH4+]>O1CCCC1>[F:12][C:2]1([F:1])[O:3][C:4]2[CH:10]=[C:9]([OH:11])[C:8]([C:28]3([OH:35])[C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:26]([CH2:25][C:23]4[O:24][C:20]([C:19]([F:38])([F:37])[F:18])=[CH:21][CH:22]=4)[C:27]3=[O:36])=[CH:7][C:5]=2[O:6]1

Participants

6

Reactant 4

HCID 25517Ammonium ChlorideHCID 673563422,2-Difluorobenzo[d][1,3]dioxol-5-olHCID 673564881-((5-(Trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dioneHCID 178418918HCID 178418918, compound

Product 1

HCID 673577963-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-oneYield 82%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 2,2-difluoro-1,3-benzodioxol-5-ol (Jacobus et al., WO 2004/4048320) (1.15 g, 6.60 mmol) in anhydrous tetrahydrofuran at 0° C. was added isopropylmagnesium chloride (2 M solution in tetrahydrofuran, 3.3 mL, 6.6 mmol). The reaction mixture was stirred at 0° C. for 0.5 h and 1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1H-indole-2,3-dione (1.95 g, 6.60 mmol) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 96 h. A saturated aqueous solution of ammonium chloride (30 mL) was added and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine (2×30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography eluted with a 0% to 35% gradient of ethyl acetate in hexanes afforded 3-(2,2-difluoro-6-hydroxy-1,3-benzodioxol-5-yl)-3-hydroxy-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one (2.54 g, 73%) as a pale orange solid: MS (ES+) 451.3 (M−17).

Workup

  1. temperatureto warm to ambient temperature
  2. stirringstirred for 96 h
  3. extractionthe mixture was extracted with ethyl acetate (3×30 mL)
  4. washThe combined organic extracts were washed with brine (2×30 mL)
  5. dry with materialdried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customPurification of the residue by column chromatography
  9. washeluted with a 0% to 35% gradient of ethyl acetate in hexanes

Sources & evidence

ORD record
ord-4e2f40148bf546ada12ab886532c7c59
Source dataset
uspto-grants-2013_04
Patent number
US08415370B2

Reaction notes

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