Isatoic Anhydride → 7-(2-Methoxyethoxy)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamide

HRID 2361279Notes

Reaction equation

HRID 2361279 reaction equation
[NH2:1][C:2]1[C:3]([CH3:29])=[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][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:30]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33](=O)[O:32][C:31]1=O.COC(OC)OC.[N+](O[La](O[N+]([O-])=O)O[N+]([O-])=O)([O-])=O>O1CCCC1.C(OCC)(=O)C>[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:33](=[O:32])[C:34]6[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=6)[N:30]=[CH:31]5)[C:3]=4[CH3:29])=[CH:9][N:10]=[C:11]([C:26]([NH2:28])=[O:27])[C:12]=3[NH:13]2)=[CH:18][CH:17]=1

Participants

7

Reactant 4

HCID 8359Isatoic AnhydrideHCID 9005Trimethyl orthoformateHCID 679945404-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamideHCID 178526924HCID 178526924, compound

Product 1

HCID 706516047-(2-Methoxyethoxy)-4-(2-methyl-3-(4-oxoquinazolin-3(4H)-yl)phenyl)-9H-pyrido[3,4-b]indole-1-carboxamideYield 42.8%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
95 °C

Procedure

A mixture of 4-(3-amino-2-methylphenyl)-7-(2-methoxyethoxy)-9H-pyrido[3,4-b]indole-1-carboxamide (330 mg, 0.845 mmol), 1H-benzo[d][1,3]oxazine-2,4-dione (345 mg, 2.113 mmol), trimethoxymethane (0.926 mL, 8.45 mmol), and tris(nitrooxy)lanthanum, 6H2O (110 mg, 0.254 mmol) in tetrahydrofuran (Volume: 2 mL) was heated at 95° C. in a sealed vial for 20 hr. The mixture was diluted with ethyl acetate (100 mL), washed with water (30 mL), 1 N NaOH solution (30 mL), and brine (30 mL). The organic solution was dried over anhydrous MgSO4 and concentrated under vacuum. The residue was subjected to prep. reverse phase HPLC purification. The correct fractions were concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×35 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the desired product (188 mg, 0.362 mmol, 42.8% yield) as a yellow solid. The product is mixture of two atropisomers at rt. LCMS (M+H)+=520.29. 1H NMR (500 MHz, DMSO-d6) (recognizable peaks for the major atropisomer) δ: 11.68 (s, 1H), 8.44 (s, 1H), 8.21 (s, 1H), 7.36 (s, 1H), 7.25 (d, J=8.9 Hz), 4.17 (m, 2H), 3.73 (m, 2H), 3.35 (s, 3H), 1.81 (s, 3H).

Workup

  1. washwashed with water (30 mL), 1 N NaOH solution (30 mL), and brine (30 mL)
  2. dry with materialThe organic solution was dried over anhydrous MgSO4
  3. concentrationconcentrated under vacuum
  4. customphase HPLC purification
  5. concentrationThe correct fractions were concentrated under vacuum
  6. extractionextracted with ethyl acetate (3×35 mL)
  7. extractionThe combined extract
  8. washwas washed with brine (30 mL)
  9. dry with materialdried over anhydrous MgSO4
  10. customRemoval of solvent under vacuum

Sources & evidence

ORD record
ord-0d55febccf824e379f932f1a9d35bd72
Source dataset
uspto-grants-2014_04
Patent number
US08685969B2

Reaction notes

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