Hydrochloric Acid → 3-hydroxy-3-(5-hydroxy-3-methyl-1,2-benzisoxazol-6-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one

HRID 1965347Notes

Reaction equation

HRID 1965347 reaction equation
[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.C([Mg]Cl)(C)C.[CH3:17][O:18][C:19]1[CH:36]=[CH:35][C:22]([CH2:23][N:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26](=[O:33])[C:25]2=[O:34])=[CH:21][CH:20]=1.Cl>ClCCCl>[OH:33][C:26]1([C:9]2[C:8]([OH:11])=[CH:7][C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH:10]=2)[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:24]([CH2:23][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:36][CH:35]=2)[C:25]1=[O:34]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 20487021-(4-methoxybenzyl)-1H-indole-2,3-dioneHCID 226120343-Methylbenzo[d]isoxazol-5-olHCID 178418918HCID 178418918, compound

Product 1

HCID 686020023-hydroxy-3-(5-hydroxy-3-methyl-1,2-benzisoxazol-6-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-oneYield 10.6%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Conditions

Temperature
0 °C

Procedure

To a stirred solution of 3-methyl-1,2-benzisoxazol-5-ol (Lindemann, et al Justus Liebigs Annalen der Chemie 1927, 456:308) (3.10 g, 20.8 mmol) in 1,2-dichloroethane (200 mL) was added isopropylmagnesium chloride (10.4 mL, 2.0 M solution in tetrahydrofuran, 20.8 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h and then at ambient temperature for 2 h. 1-(4-methoxybenzyl)-1H-indole-2,3-dione (5.3 g, 19.8 mmol) was added and the reaction mixture was stirred at reflux for 120 h. The mixture was cooled to 0° C. and 5% w/v hydrochloric acid was added. The organic phase was separated, washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography eluted with ethyl acetate/hexanes (1/1) to afford 3-hydroxy-3-(5-hydroxy-3-methyl-1,2-benzisoxazol-6-yl)-1-(4-methoxybenzyl)-1,3-dihydro-2H-indol-2-one (0.87 g, 10%): 1H NMR (300 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.01 (s, 1H), 7.37-6.76 (m, 10H), 4.83 (ABq, 2H), 3.70 (s, 3H), 2.46 (s, 3H); MS (ES+) m/z 415.0 (M−1).

Workup

  1. waitat ambient temperature for 2 h
  2. stirringthe reaction mixture was stirred
  3. temperatureat reflux for 120 h
  4. temperatureThe mixture was cooled to 0° C.
  5. additionwas added
  6. customThe organic phase was separated
  7. washwashed with water and brine
  8. dry with materialdried over anhydrous sodium sulfate
  9. filtrationfiltered
  10. concentrationThe filtrate was concentrated in vacuo
  11. washeluted with ethyl acetate/hexanes (1/1)

Sources & evidence

ORD record
ord-ee316b75e6794764b604ff474faa9fb3
Source dataset
uspto-grants-2013_04
Patent number
US08415370B2

Reaction notes

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