Ethanol → Methyl 3-[3-(2-{[2-methyl-4-(4-piperidinyloxy)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzoate

HRID 419316Notes

Reaction equation

HRID 419316 reaction equation
C([C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:17]=2[C:18]2[CH:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH:32]4[CH2:37][CH2:36][N:35](C(OCC5C=CC=CC=5)=O)[CH2:34][CH2:33]4)=[CH:27][C:26]=3[CH3:48])[N:19]=2)[CH:6]=[CH:7][CH:8]=1)#N.[OH-].[Na+].S(=O)(=O)(O)O.[C:56]([O-:59])(O)=[O:57].[Na+].[CH3:61]CO>C(Cl)Cl.C(OCC)C.O.C1COCC1>[CH3:48][C:26]1[CH:27]=[C:28]([O:31][CH:32]2[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]2)[CH:29]=[CH:30][C:25]=1[NH:24][C:20]1[N:19]=[C:18]([C:17]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:56]([O:59][CH3:61])=[O:57])[CH:23]=[CH:22][N:21]=1

Participants

10

Reactant 5

HCID 702EthanolHCID 1118Sulfuric AcidHCID 14798Sodium Hydroxide2×HCID 516892Sodium BicarbonateHCID 66649613Phenylmethyl 4-([4-({4-[2-(3-cyanophenyl)imidazo[1,2-a]pyridin-3-yl]-2-pyrimidinyl}amino)-3-methylphenyl]oxy}-1-piperidinecarboxylate

Product 1

HCID 59452874Methyl 3-[3-(2-{[2-methyl-4-(4-piperidinyloxy)phenyl]amino}-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]benzoateYield 88%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
80 °C

Procedure

Phenylmethyl 4-{[4-({4-[2-(3-cyanophenyl)imidazo[1,2-a]pyridin-3-yl]-2-pyrimidinyl}amino)-3-methylphenyl]oxy}-1-piperidinecarboxylate (0.699 g, 1.10 mmol) was dissolved in 20 mL of EtOH with stirring. To the solution was added 20 mL of 2N NaOH solution. The reaction was placed in a 60° C. oil bath, and 20 mL of THF was added. The reaction was stirred at 60° C. overnight. Solid NaOH (1.6 g, 40 mmol) was added and the heat was increased to 80° C. Stirring was continued for 2.5 days, and the reaction was cooled to rt. The mixture was poured into H2O and diethyl ether, and the layers were separated. The organic layer was washed with 1N NaOH solution. The combined aqueous layers were acidified with concentrated HCl. The aqueous layer was concentrated in vacuo. The residue was dissolved in 25 mL of MeOH with stirring. Sulfuric acid (0.29 mL, 5.4 mmol) was added, and the reaction was heated to 65° C. The reaction was stirred overnight and cooled to rt. The mixture was poured into half-saturated NaHCO3 solution and DCM. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford 0.518 g (88%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 9.24 (br. s., 1H), 8.87 (s, 1H), 8.21 (s, 1H), 8.17 (d, J=5.1 Hz, 1H), 8.01-7.96 (m, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.69 (d, J=9.0 Hz, 1H), 7.58 (t, J=7.8 Hz, 1H), 7.46-7.38 (m, 1H), 7.22 (d, J=8.6 Hz, 1H), 6.85 (s, 2H), 6.77 (dd, J=8.5, 2.7 Hz, 1H), 6.41 (d, J=5.3 Hz, 1H), 4.39-4.28 (m, 1H), 3.84 (s, 3H), 2.97-2.87 (m, 2H), 2.49-2.59 (m, 2H), 2.17 (s, 3H), 1.93-1.83 (m, 2H), 1.48-1.35 (m, 2H).

Workup

  1. customwas placed in a 60° C.
  2. stirringThe reaction was stirred at 60° C. overnight
  3. stirringStirring
  4. temperaturethe reaction was cooled to rt
  5. customthe layers were separated
  6. washThe organic layer was washed with 1N NaOH solution
  7. concentrationThe aqueous layer was concentrated in vacuo
  8. dissolutionThe residue was dissolved in 25 mL of MeOH
  9. stirringwith stirring
  10. temperaturethe reaction was heated to 65° C
  11. stirringThe reaction was stirred overnight
  12. temperaturecooled to rt
  13. customThe layers were separated
  14. washthe organic layer was washed with brine
  15. extractionThe combined aqueous layers were extracted with EtOAc (2×)
  16. dry with materialThe combined organic layers were dried over MgSO4
  17. filtrationfiltered
  18. concentrationconcentrated in vacuo
  19. customThe residue was purified by flash chromatography

Sources & evidence

ORD record
ord-b5f1132109654a9597922592a2833594
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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