Isatoic Anhydride → HCID 67994656, compound

HRID 2361398Notes

Reaction equation

[NH2:1][C:2]1[C:3]([CH3:30])=[C:4]([C:8]2[C:20]3[C:19]4[C:14](=[CH:15][C:16]([O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:17][CH:18]=4)[NH:13][C:12]=3[C:11]([C:26]([NH2:28])=[O:27])=[N:10][C:9]=2[CH3:29])[CH:5]=[CH:6][CH:7]=1.[NH:31]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[C:34](=O)[O:33][C:32]1=O.COC(OC)OC.O.O.O.O.O.O.[N+]([O-])([O-])=O.[La+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>O1CCCC1.CCOC(C)=O.O.CO.CS(C)=O>[CH3:25][O:24][CH2:23][CH2:22][O:21][C:16]1[CH:15]=[C:14]2[C:19]([C:20]3[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([N:1]5[C:34](=[O:33])[C:35]6[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=6)[N:31]=[CH:32]5)[C:3]=4[CH3:30])=[C:9]([CH3:29])[N:10]=[C:11]([C:26]([NH2:28])=[O:27])[C:12]=3[NH:13]2)=[CH:18][CH:17]=1

Participants

Conditions

Temperature: 95 °C

Procedure

A sealed pressure tube containing 4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-3-methyl-9H-pyrido[3,4-b]indole-1-carboxamide (0.364 g, 0.9 mmol), 1H-benzo[d][1,3]oxazine-2,4-dione (0.367 g, 2.250 mmol), trimethoxymethane (0.887 ml, 8.10 mmol) and lanthanum nitrate hexahydrate (0.117 g, 0.270 mmol) in tetrahydrofuran (Volume: 4.50 ml) was heated at 95° C. overnight. The reaction was cooled to room temperature, diluted with EtOAc (100 mL) and water (30 mL); the insolubles were filtered, and the layers were separated. The organic layer was washed with water (30 mL) and brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography using an ISCO 40 g column eluting with 30-100% EtOAc/hexane (solid loading). Appropriate fractions were collected and concentrated in vacuo to give impure product It was diluted with MeOH (3 mL) and DMSO (0.1 mL) and subjected to autoprep HPLC. The appropriate fractions were collected; NaHCO3 (solid) was added, and the fractions were concentrated in vacuo not to dryness. It was extracted with CH2Cl2 (3×); the organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo to give 7-(2-methoxyethoxy)-3-methyl-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide (0.0372 g, 0.070 mmol, 7.75% yield) as a light tan solid, LC/MS (M+H)=534.18; 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for the major atropoisomer) δ ppm 11.44 (d, J=5.8 Hz, 1H), 8.46 (s, 1H), 8.24 (ddd, J=7.9, 3.3, 1.2 Hz, 1H), 8.12-8.17 (m, 1H), 7.85-7.93 (m 1H), 7.79 (dd, J=7.9, 2.6 Hz, 1H), 7.71 (br d, J=2.5 Hz, 1H), 7.51-7.68 (m, 2H), 7.46 (br ddd, J=7.1, 5.3, 1.4 Hz, 1H), 7.28 (d, J=2.2 Hz, 1H), 6.83 (d, J=8.9 Hz, 1 H), 6.59-6.70 (m, 2H), 4.10-4.16 (m, 2H), 3.69 (br q, J=4.7 Hz, 2H), 3.33 (s, 3H), 2.42 (s, 3H), 1.70 (s, 3H).

Workup

temperatureThe reaction was cooled to room temperature
filtrationthe insolubles were filtered
customthe layers were separated
washThe organic layer was washed with water (30 mL) and brine (30 mL)
dry with materialdried over MgSO4
filtrationfiltered
concentrationconcentrated in vacuo
customThe residue was purified by flash chromatography
washeluting with 30-100% EtOAc/hexane (solid loading)
customAppropriate fractions were collected
concentrationconcentrated in vacuo
customto give impure product It
customThe appropriate fractions were collected
additionNaHCO3 (solid) was added
concentrationthe fractions were concentrated in vacuo not to dryness
extractionIt was extracted with CH2Cl2 (3×)
dry with materialdried over Na2SO4
filtrationfiltered
concentrationconcentrated in vacuo

Sources & evidence

ORD record: ord-ac19f294f933479b9549711747e77d8a
Source dataset: uspto-grants-2014_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08685969B2

Reaction notes

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