Carbon Dioxide → 2-(1-Benzyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide

HRID 2370430Notes

Reaction equation

HRID 2370430 reaction equation
[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:12])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([OH:25])(=O)[CH2:20]C(O)=O.[N:26]1[CH:31]=CC=C[CH:27]=1.C(=O)=O.C(N(CC)CC)C.CN(C)C(Cl)=O>C(OCC)(=O)C>[CH2:1]([N:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11]([CH2:20][C:19]([N:26]([CH3:31])[CH3:27])=[O:25])([OH:12])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

8

Reactant 6

HCID 280Carbon Dioxide2×HCID 867Malonic AcidHCID 1049PyridineHCID 6598Dimethylcarbamoyl ChlorideHCID 8471TriethylamineHCID 2647341-Benzylisatin

Product 1

HCID 104039792-(1-Benzyl-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)-N,N-dimethyl-acetamide

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

A 500 mL flask is charged with N-benzyl isatin (55 g, 0.231 mol), malonic acid (28.95 g, 0.278 mol), and pyridine (73.4 g, 0.927 mol). To the formed red suspension, ethyl acetate (50 mL) is added, and the stirred mixture is heated to 80° C. After about 30 minutes a solution has formed which is kept stirring at 80° C. until no further formation of carbon dioxide is observed (about 2.5 h). Then triethyl amine (35.2 g, 0.347 mol) is added, and the mixture is stirred for another 10 minutes at 80° C. To the dark red solution, then dropwise (exothermicl) dimethyl carbamoyl chloride (32.4 g, 0.301 mol) is added during 10 minutes. When the evolution of carbon dioxide ceases, the mixture is kept stirring at 80° C. for another two hours, and then the solvent is removed from the brown suspension on the rotavapor. To the residue, HCl (4N, 0.2 L) is added, and the formed suspension is stirred for one hour at 80° C. After cooling and standing in the refrigerator over night, the crystals are filtered off, washed twice with water (about 150 mL each wash) and dried in vacuo to give light brown crystals. Yield of the title compound: 66.7 g (88.7% based on N-benzyl isatin). 1H-NMR (CDCl3, 300 MHz) δ 2.69, 3.03 (AB, 2H, 2J=16.1 Hz, CH2CONMe2); 2.91, 2.99 (2 s, 3 each, N(CH3)2); 4.87, 4.89 (AB, 2H, 2J=15.8 Hz, CH2Ph); 6.70 (d, 1H, J=7.7 Hz, H-7); 7.01 (dtr, J=7.7 Hz, J=1.1 Hz, H-5); 7.17 (dtr, 1H, J=7.7 Hz, J=11 Hz, H-6); 7.21-7.34 (m, 5H, Ph); 7.49 (dd, J=7.3 Hz, J=1.8 Hz, H-4). 13C-NMR (CDCl3, 75 MHz) δ 35.64, 37.66 N(CH3)2; 38.21 (CH2CONMe2); 44.02 (CH2Ph); 74.61 (C-3); 109.70 (C-7); 123.38 (C-5); 124.63 (C-4); 127.51, 127.90, 129.03 (Ph ortho-C, para-C, meta-C); 129.82 (C-6), 131.15 (C-9); 135.77 (Ph ipso-C); 142.47 (C-8); 171.18 (CONMe2); 176.51 (C-2).

Workup

  1. customAfter about 30 minutes a solution has formed which
  2. custom(about 2.5 h)
  3. customthe solvent is removed from the brown suspension on the rotavapor
  4. additionTo the residue, HCl (4N, 0.2 L) is added
  5. stirringthe formed suspension is stirred for one hour at 80° C
  6. temperatureAfter cooling
  7. waitstanding in the refrigerator over night
  8. filtrationthe crystals are filtered off
  9. washwashed twice with water (about 150 mL each wash)
  10. customdried in vacuo
  11. customto give light brown crystals

Sources & evidence

ORD record
ord-1e00f5282b3e4b3bbc1f3c38b381f626
Source dataset
uspto-grants-2014_04
Patent number
US08710093B2

Reaction notes

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