Isatoic Anhydride → HCID 67994899, compound

HRID 2361381Notes

Reaction equation

HRID 2361381 reaction equation
[NH2:1][C:2]1[C:3]([CH3:29])=[C:4]([C:8]2[C:20]3[C:19]4[CH:18]=[CH:17][C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:15][C:14]=4[NH:13][C:12]=3[C:11]([C:26]([NH2:28])=[O:27])=[N:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.COC(OC)OC.[NH:37]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[C:40](=O)[O:39][C:38]1=O.O.O.O.O.O.O.[N+]([O-])([O-])=O.[La+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>O1CCCC1.CS(C)=O.CCOC(C)=O>[CH3:25][O:24][CH2:23][CH2:22][O:21][C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([N:1]5[C:40](=[O:39])[C:41]6[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=6)[N:37]=[CH:38]5)[C:3]=4[CH3:29])=[N:9][N:10]=[C:11]([C:26]([NH2:28])=[O:27])[C:12]=3[NH:13][C:14]=2[CH:15]=1

Participants

8

Reactant 4

HCID 8359Isatoic AnhydrideHCID 9005Trimethyl orthoformateHCID 16211478Lanthanum nitrate hexahydrateHCID 67994970HCID 67994970, compound

Product 1

HCID 67994899HCID 67994899, compoundYield 4.4%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
95 °C

Procedure

A sealed pressure tube containing 1-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-5H-pyridazino[4,5-b]indole-4-carboxamide (0.2785 g, 0.712 mmol), trimethoxymethane (0.701 mL, 6.40 mmol), 1H-benzo[d][1,3]oxazine-2,4-dione (0.232 g, 1.423 mmol), and lanthanum nitrate hexahydrate (0.092 g, 0.213 mmol) in tetrahydrofuran (3.56 mL) was heated at 95° C. for 6 hr and cooled to room temperature. EtOAc (100 mL) was added, and the resulting mixture was washed with water (20 mL), 1N aq. NaOH (20 mL), water (20 mL) and brine (20 mL) successively. It was then dried over MgSO4 and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 24 g column eluting with 1-10% MeOH/CH2Cl2 to give crude product. This crude was dissolved in DMSO (0.2 mL) and MeOH (0.6 mL) and purified by reverse phase HPLC. The appropriate fractions were collected, basified with NaHCO3 (solid), and concentrated in vacuo. The residue was extracted with CH2Cl2 (3×). The combined extract was dried over Na2SO4 and concentrated in vacuo to give (0.0163 g, 0.031 mmol, 4.4% yield) as a light yellow solid. LC/MS (M+H)=521.18; 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for the major atropoisomer) δ ppm 12.24 (s, 1H), 8.76 (br. S, 1H), 8.71 (br. S, 1H), 8.53 (s, 1H), 8.48 (s, 1H), 8.26 (t, J=6.9 Hz, 1H), 8.00 (br. S, 1H), 7.89-7.94 (m, 1H), 7.80 (s, 1H), 7.74 (d, J=5.6 Hz, 1H), 7.60-7.70 (m, 2H), 7.41 (d, J=2.2 Hz, 1H), 6.88 (d, J=8.9 Hz, 1H), 4.15-4.21 (m, 2H), 3.72 (t, J=4.3 Hz, 2 H), 3.33 (s, 3H), 1.81 (s, 3H).

Workup

  1. temperaturecooled to room temperature
  2. washthe resulting mixture was washed with water (20 mL), 1N aq. NaOH (20 mL), water (20 mL) and brine (20 mL) successively
  3. dry with materialIt was then dried over MgSO4
  4. concentrationconcentrated in vacuo
  5. customto give a residue which
  6. customwas purified by flash chromatography
  7. washeluting with 1-10% MeOH/CH2Cl2
  8. customto give crude product
  9. customMeOH (0.6 mL) and purified by reverse phase HPLC
  10. customThe appropriate fractions were collected
  11. concentrationconcentrated in vacuo
  12. extractionThe residue was extracted with CH2Cl2 (3×)
  13. extractionThe combined extract
  14. dry with materialwas dried over Na2SO4
  15. concentrationconcentrated in vacuo
  16. customto give (0.0163 g, 0.031 mmol, 4.4% yield) as a light yellow solid

Sources & evidence

ORD record
ord-9a60c99059b2455b8e01b076c72b929c
Source dataset
uspto-grants-2014_04
Patent number
US08685969B2

Reaction notes

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