Methanol → Methyl 4-(2-(4-morpholinophenylamino)-5-methylpyrimidin-4-yl)-2-methoxybenzoate

HRID 591127Notes

Reaction equation

HRID 591127 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([O:18][CH3:19])[CH:9]=2)[C:5]([CH3:20])=[CH:4][N:3]=1.[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>O1CCOCC1>[O:21]1[CH2:22][CH2:23][N:24]([C:27]2[CH:28]=[CH:29][C:30]([NH:31][C:2]3[N:7]=[C:6]([C:8]4[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([O:18][CH3:19])[CH:9]=4)[C:5]([CH3:20])=[CH:4][N:3]=3)=[CH:32][CH:33]=2)[CH2:25][CH2:26]1

Participants

6

Reactant 4

HCID 887MethanolHCID 75655Benzenamine, 4-(4-morpholinyl)-HCID 521998p-Toluenesulfonic acid monohydrateHCID 86643815Methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-2-methoxybenzoate

Product 1

HCID 68425754Methyl 4-(2-(4-morpholinophenylamino)-5-methylpyrimidin-4-yl)-2-methoxybenzoateYield 32.8%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

To a solution of methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-2-methoxybenzoate (165 mg, 0.56 mmol) in 1,4-dioxane (5 mL) was added 4-morpholinoaniline (96 mg, 0.54 mmol) and p-toluenesulfonic acid monohydrate (97 mg, 0.51 mmol). The reaction was heated at reflux for 40 h, cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted twice more with ethyl acetate and the combined organic fractions were washed twice with 5% aqueous citric acid, water, brine then dried (sodium sulfate) filtered and concentrated to afford the crude product. Trituration with methanol provided methyl 4-(2-(4-morpholinophenylamino)-5-methylpyrimidin-4-yl)-2-methoxybenzoate as a yellow solid (77 mg, 32%); 1H NMR (300 MHz, d6-DMSO) δ 9.36 (s, 1H), 8.38 (s, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.62 (d, J=9.0 Hz, 2H), 7.38 (s, 1H), 7.27 (d, J=8.1 Hz, 1H), 6.88 (d, J=9.0 Hz, 2H), 3.89 (s, 3H), 3.82 (s, 3H), 3.72 (m, 4H), 3.01 (m, 4H), 2.12 (s, 3H); LC-ESI-MS (method B): rt 6.7 min.; m/z 435.3 [M+H]+.

Workup

  1. temperatureThe reaction was heated
  2. temperatureat reflux for 40 h
  3. custompartitioned between ethyl acetate and saturated aqueous sodium bicarbonate
  4. extractionThe aqueous layer was extracted twice more with ethyl acetate
  5. washthe combined organic fractions were washed twice with 5% aqueous citric acid, water, brine
  6. dry with materialthen dried (sodium sulfate)
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto afford the crude product

Sources & evidence

ORD record
ord-c1b9b12154ea46bf86cf9a1a103c4d22
Source dataset
uspto-grants-2016_01
Patent number
US09238628B2

Reaction notes

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