Hydrochloric Acid → 3-{5-[3,3-Bis-(4-hydroxy-3,5-dimethyl-phenyl)-2-oxo-2,3-dihydro-indol-1-ylmethyl]-[1,2,4]oxadiazol-3-yl}-benzoic acid methyl ester

HRID 1297799Notes

Reaction equation

HRID 1297799 reaction equation
[OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2([C:22]3[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[C:24]([CH3:30])[CH:23]=3)[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:18][C:19]#[N:20])[C:10]2=[O:21])=[CH:4][C:3]=1[CH3:31].[CH3:32][O:33][C:34](=[O:45])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41](Cl)=[N:42][OH:43])[CH:36]=1.C(N(CC)CC)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C(OCC)C.C1COCC1.O.C(OCC)(=O)C>[CH3:32][O:33][C:34](=[O:45])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[N:20]=[C:19]([CH2:18][N:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:9]([C:5]4[CH:4]=[C:3]([CH3:31])[C:2]([OH:1])=[C:7]([CH3:8])[CH:6]=4)([C:22]4[CH:27]=[C:26]([CH3:28])[C:25]([OH:29])=[C:24]([CH3:30])[CH:23]=4)[C:10]3=[O:21])[O:43][N:42]=2)[CH:36]=1

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 2724141Tetrabutylammonium FluorideHCID 85867392Methyl 3-[chloro(hydroxyimino)methyl]benzoateHCID 86597007[3,3-Bis-(4-hydroxy-3,5-dimethyl-phenyl)-2-oxo-2,3-dihydro-indol-1-yl]-acetonitrile

Product 1

HCID 589147003-{5-[3,3-Bis-(4-hydroxy-3,5-dimethyl-phenyl)-2-oxo-2,3-dihydro-indol-1-ylmethyl]-[1,2,4]oxadiazol-3-yl}-benzoic acid methyl esterYield 8%

Reagents, catalysts & solvents 4

HCID 962WaterSolvent2×HCID 3283Diethyl EtherSolvent2×HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent2×

Procedure

Under an N2 atmosphere combine [3,3-Bis-(4-hydroxy-3,5-dimethyl-phenyl)-2-oxo-2,3-dihydro-indol-1-yl]-acetonitrile (0.501 g, 0.782 mmol), 3-[chloro(hydroxyimino)methyl]-benzoic acid methyl ester (1.17 g, 5.47 mmol), and diethyl ether (20 mL). Add a solution of triethylamine (0.84 mL, 6.02 mmol) in diethyl ether (10 mL) over 30 minutes. Stir the reaction at room temperature overnight. Dilute the reaction with ethyl acetate (200 mL) and water (200 mL). Separate the layers, and dry the organic layer with sodium sulfate. Concentrate in vacuo. Chromatograph on silica gel eluting with 20% ethyl acetate in hexanes and concentrate. Dissolve the resulting compound (0.124 g, 0.152 mmol) in THF (1 mL). Add a solution of tetrabutylammonium fluoride (1.0 M) in THF (0.38 mL) and stir the reaction at room temperature for 30 minutes. Add 1N aqueous HCl(10 mL), ethyl acetate (50 mL), and water (40 mL). Separate the layers and wash the organic layer with brine (50 mL). Dry the ethyl acetate with sodium sulfate, and concentrate in vacuo. Chromatograph on silica gel eluting with a gradient from 25% to 50% ethyl acetate in hexanes to give 0.037 g of the title compound: mass spectrum (ion spray): m/z=590(M+1); 1H NMR(DMSO-d6): δ8.24 (s, 2H), 8.10-8.03 (m, 4H), 7.29-7.25 (m, 2H), 7.17 (d, 1H), 7.09 (t, 1H) 6.71 (s, 1H), 5.48 (s, 2H), 3.87 (s, 3H), 2.04 (s, 12H).

Workup

  1. customthe reaction at room temperature overnight
  2. additionDilute
  3. customSeparate the layers
  4. dry with materialdry the organic layer with sodium sulfate
  5. concentrationConcentrate in vacuo
  6. concentrationChromatograph on silica gel eluting with 20% ethyl acetate in hexanes and concentrate
  7. stirringstir
  8. customthe reaction at room temperature for 30 minutes
  9. customSeparate the layers
  10. washwash the organic layer with brine (50 mL)
  11. dry with materialDry the ethyl acetate with sodium sulfate
  12. concentrationconcentrate in vacuo

Sources & evidence

ORD record
ord-550bbb5ca2724e47a8c45a9a168eb65a
Source dataset
uspto-grants-2007_07
Patent number
US07250442B2

Reaction notes

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