Cesium carbonate → Vegfr-2-IN-9

HRID 1061713Notes

Reaction equation

HRID 1061713 reaction equation
Cl[C:2]1[C:11]([C:12]2[N:13](C(OC(C)(C)C)=O)[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([OH:21])=[CH:16][CH:15]=3)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl[CH2:30][CH2:31][N:32]([CH2:34][CH2:35][O:36][CH3:37])[CH3:33].C(=O)([O-])[O-:39].[Cs+].[Cs+]>CN(C)C=O.O.C(O)(=O)C>[CH3:37][O:36][CH2:35][CH2:34][N:32]([CH3:33])[CH2:31][CH2:30][O:21][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:11]1[C:2](=[O:39])[NH:3][C:4]3[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:20]2

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 13457831N-(2-chloroethyl)-2-methoxy-N-methylethanamineHCID 22285138HCID 22285138, compound

Product 1

HCID 5329372Vegfr-2-IN-9

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
70 °C

Procedure

A mixture of tert-butyl 2-(2-chloro-3-quinolinyl)-5-hydroxy-1H-indole-1-carboxylate (1-8, 1.50 g, 3.80 mmol, 1 equiv), 2-chloro-N-(2-methoxyethyl)-N-methylethanamine (720 mg, 4.75 mmol, 1.25 equiv), and cesium carbonate (3.09 g, 9.50 mmol, 2.50 equiv) in N, N-dimethylformamide (20 mL) was heated at 70° C. for 5 hours. The reaction mixture was concentrated, and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water then brine, dried over magnesium sulfate, and concentrated to give a brown gum. The gum was dissolved in a 1:1 mixture of water and acetic acid (60 mL), and the resulting solution was heated at 100° C. for 18 hours. The reaction mixture was concentrated, and the residue was partitioned between aqueous saturated sodium bicarbonate solution and ethyl acetate. The organic layer was washed with water then brine, dried over magnesium sulfate, and concentrated to give a yellow solid. Purification by flash column chromatography (5% ethanol saturated with ammonia/CH2Cl2, grading to 10% ethanol saturated with ammonia/CH2Cl2) provided 3-(5-{2-[(2-methoxyethyl)(methyl)amino]ethoxy}-1H-indol-2-yl)quinolin-2(1H)-one (1-9) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 11.10 (s, 1H), 9.72 (s, 1H), 8.32 (s, 1H), 7.68 (br d, 1H, J=7.8 Hz), 7.53 (br t, 1H, J=7.6 Hz), 7.35 (d, 1H, J=8.8 Hz), 7.29 (br t, 1H, J=7.8 Hz), 7.24 (br d, 1H, J=8.2 Hz), 7.09 (d, 1H, J=2.2 Hz), 6.97 (d, 1H, J=1.4 Hz), 6.89 (dd, 1H, J=8.6, 2.2 Hz), 4.16 (t, 2H, J=5.9 Hz), 3.54 (t, 2H, J=2.67 (t, 3H, J=5.7 Hz), 3.38 (s, 3H), 2.92 (t, 3H, J=6.0 Hz), 2.73 (t, 3H, J=5.8 Hz), 2.44 (s, 3H).

Workup

  1. concentrationThe reaction mixture was concentrated
  2. customthe residue was partitioned between water and ethyl acetate
  3. washThe organic layer was washed with water
  4. dry with materialbrine, dried over magnesium sulfate
  5. concentrationconcentrated
  6. customto give a brown gum
  7. temperaturethe resulting solution was heated at 100° C. for 18 hours
  8. concentrationThe reaction mixture was concentrated
  9. customthe residue was partitioned between aqueous saturated sodium bicarbonate solution and ethyl acetate
  10. washThe organic layer was washed with water
  11. dry with materialbrine, dried over magnesium sulfate
  12. concentrationconcentrated
  13. customto give a yellow solid
  14. customPurification by flash column chromatography (5% ethanol saturated with ammonia/CH2Cl2, grading to 10% ethanol saturated with ammonia/CH2Cl2)

Sources & evidence

ORD record
ord-49ca2d9347d34390acc11e34d9d7de6e
Source dataset
uspto-grants-2005_11
Patent number
US06960590B2

Reaction notes

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