Formaldehyde → 5-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one

HRID 425542Notes

Reaction equation

HRID 425542 reaction equation
[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1)[C:6](=[O:21])[CH:5]2[C:22]1[C:30]([OH:31])=[CH:29][C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=1.[CH2:32]=[O:33].O.[OH-].[Li+]>O1CCCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[O:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=1)[C:6](=[O:21])[C:5]2([C:22]1[C:30]([OH:31])=[CH:29][C:25]2[O:26][CH2:27][O:28][C:24]=2[CH:23]=1)[CH2:32][OH:33]

Participants

6

Reactant 3

HCID 712FormaldehydeHCID 168937Lithium hydroxide, monohydrateHCID 588725305-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one

Product 1

HCID 588724935-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-oneYield 59%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A mixture of 5-fluoro-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-{[5-(trifluoromethyl)-2-furyl]methyl}-1,3-dihydro-2H-indol-2-one (3.64 g, 8.41 mmol), para-formaldehyde (2.52 g, 84.1 mmol) and lithium hydroxide monohydrate (1.06 g, 25.2 mmol) in tetrahydrofuran (84.0 mL) and water (10.0 mL) was stirred at 0° C. for 4 h. After the solvent was removed in vacuo, the residue was dissolved in ethyl acetate (100 mL), washed with 10% aqueous HCl (3×25.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography eluting with ethyl acetate/hexanes (50%) to give the title compound (0.65 g, 59%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.12 (d, 1H), 6.99-6.87 (m, 3H), 6.80 (dd, 1H), 6.48 (d, 1H), 6.23 (s, 1H), 5.89 (d, 2H), 5.09 (br, 1H), 4.97 (ABq, 2H), 4.01(ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ 176.1, 160.5; MS (ES+) m/z 466.2 (M+1), 448.2 (M−17).

Workup

  1. customAfter the solvent was removed in vacuo
  2. dissolutionthe residue was dissolved in ethyl acetate (100 mL)
  3. washwashed with 10% aqueous HCl (3×25.0 mL)
  4. dry with materialdried over anhydrous sodium sulfate
  5. filtrationfiltered
  6. concentrationThe filtrate was concentrated in vacuo to dryness
  7. washeluting with ethyl acetate/hexanes (50%)

Sources & evidence

ORD record
ord-bebc48cdb9e84917b7c8665438d53788
Source dataset
uspto-grants-2012_01
Patent number
US08106087B2

Reaction notes

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