Dimethylformamide → 4-Methyl-3-[({4-[(4-phenylquinazolin-2-yl)amino]phenyl}carbonyl)amino]benzoic acid

HRID 2402495Notes

Reaction equation

HRID 2402495 reaction equation
[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([NH:17][C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN([CH:33]([CH3:35])C)C(C)C.CN(C(ON1N=N[C:46]2[CH:47]=[CH:48][CH:49]=[N:50][C:45]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-:60].[Na+].CN(C)[CH:64]=[O:65]>ClCCl.CO.O1CCCC1>[CH3:33][C:35]1[CH:45]=[CH:46][C:47]([C:64]([OH:65])=[O:60])=[CH:48][C:49]=1[NH:50][C:22]([C:21]1[CH:25]=[CH:26][C:18]([NH:17][C:9]2[N:8]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:19][CH:20]=1)=[O:23]

Participants

9

Reactant 5

HCID 6228DimethylformamideHCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 7764484-[(4-Phenylquinazolin-2-yl)amino]benzoic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)

Product 1

HCID 250701624-Methyl-3-[({4-[(4-phenylquinazolin-2-yl)amino]phenyl}carbonyl)amino]benzoic acidYield 86%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To a stirred solution of 4-(4-phenylquinazolin-2-ylamino)benzoic acid (1.02 g, 2.99 mmol), prepared as described in Example 10, methyl-amino-4-methylbenzooate (496 mg, 3.01 mmol), and Hunig's base (1.57 mL, 9.01 mmol) in dimethylformamide (15 mL) was added HATU (1.14 g, 3.00 mmol). The stirred mixture was heated to 60° C. overnight, then cooled to rt. The reaction was diluted with dichloromethane and washed with 2 N aqueous sodium hydroxide. The organic layer was then dried over sodium sulfate and concentrated on a rotary evaporator. The residue was sonicated with acetonitrile and filtered to give a light yellow solid that was suspended in a mixture of methanol (22 mL) and tetrahydrofuran (11 mL). A 1 N aqueous solution of sodium hydroxide (11 mL) was added and the stirred mixture was heated to 70° C. for 3 h. The reaction mixture was cooled to rt, concentrated on a rotary evaporator and redissolved in water, which was then made acidic with 1 N aqueous hydrochloric acid until the pH of the solution reached 5. The precipitate that formed was collected and dried in vacuo to afford 4-methyl-3-[({4-[(4-phenylquinazolin-2-yl)amino]phenyl}carbonyl)amino]benzoic acid (1.23 g, 86%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.34 (s, 1H), 9.82 (s, 1H), 8.18 (d, 2H), 8.00 (d, 2H), 7.95 (s, 1H), 7.90-7.78 (m, 5H), 7.72 (dd, 1H), 7.66-7.64 (m, 3H), 7.42 (ddd, 1H), 7.36 (d, 1H), 2.31 (s, 3H). MS (EI) for C29H22N4O3: 475.3 (MH+).

Workup

  1. temperaturecooled to rt
  2. washwashed with 2 N aqueous sodium hydroxide
  3. dry with materialThe organic layer was then dried over sodium sulfate
  4. concentrationconcentrated on a rotary evaporator
  5. customThe residue was sonicated with acetonitrile
  6. filtrationfiltered
  7. customto give a light yellow solid
  8. temperaturethe stirred mixture was heated to 70° C. for 3 h
  9. temperatureThe reaction mixture was cooled to rt
  10. concentrationconcentrated on a rotary evaporator
  11. dissolutionredissolved in water
  12. customThe precipitate that formed
  13. customwas collected
  14. customdried in vacuo

Sources & evidence

ORD record
ord-7f8fe2d935b84e9789c14b1ab27b4bc4
Source dataset
uspto-grants-2014_08
Patent number
US08796294B2

Reaction notes

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