Ethyl Acetate → 2-Tert-butoxycarbonylamino-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester

HRID 230325Notes

Reaction equation

HRID 230325 reaction equation
[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5](CC=C)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].I[C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:31])[C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:20][CH:19]=1.[C:32](=O)([O-])[O-].[K+].[K+].C(O[CH2:42][CH3:43])(=O)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][O:2][C:3](=[O:16])[CH:4]([NH:5][C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])[CH2:32][CH:42]=[CH:43][C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:31])[C:25]2[N:30]=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:20][CH:19]=1

Participants

8

Reactant 4

HCID 8857Ethyl AcetateHCID 11430Potassium CarbonateHCID 22243128N-Boc-allylglycine methyl esterHCID 46184395N-(4-iodophenyl)-N-methylpyrimidin-2-amine

Product 1

HCID 669119472-Tert-butoxycarbonylamino-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester

Reagents, catalysts & solvents 3

HCID 80271Tri-o-tolylphosphineCatalystHCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

Under an argon atmosphere, palladium acetate (54 mg) and tris(2-methylphenyl)phosphine (70 mg) were added to a suspension of N-Boc-allylglycine methyl ester (1.03 g), N-(4-iodophenyl)-N-methylpyrimidin-2-amine (1.40 g) and potassium carbonate (933 mg) in DMF (15 ml), and the resulting mixture was stirred at 80° C. overnight. The reaction solution was allowed to cool to room temperature and ethyl acetate was added thereto. The solution was washed 3 times with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate=20/1-4/1). The obtained solid was recrystallized from hexane/ethyl acetate mixed solvent to obtain 2-tert-butoxycarbonylamino-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (976 mg). (4) Trifluoroacetic acid (2 ml) was added to a solution of 2-tert-butoxycarbonylamino-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (976 mg) in dichloromethane (20 ml), and the resulting mixture was stirred at room temperature for 4.5 hours. Water was added to the reaction solution, and sodium hydrogen carbonate was added thereto in small portions to neutralize it, followed by extracting the resulting solution twice with chloroform. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to dryness to obtain 2-amino-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (599 mg). NMR (HL, CDCl3): δ 2.58-2.64 (2H, brm), 3.48-3.58 (1H, brm), 3.52 (3H, s), 3.75 (3H, s), 6.07-6.14 (1H, m), 6.49 (1H, d, J=5.6 Hz), 6.57 (1H, t, J=4.6 Hz), 7.26 (2H, d, J=8.1 Hz), 7.38 (2H, d, J=8.3 Hz), 8.34 (2H, d, J=4.6 Hz)

Workup

  1. temperatureto cool to room temperature
  2. washThe solution was washed 3 times with water
  3. dry with materialonce with saturated brine, and dried over anhydrous sodium sulfate
  4. customAfter removing anhydrous sodium sulfate
  5. filtrationby filtration
  6. concentrationthe filtrate was concentrated
  7. customThe residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate=20/1-4/1)
  8. customThe obtained solid was recrystallized from hexane/ethyl acetate mixed solvent

Sources & evidence

ORD record
ord-f8888528eefc476bb7eb0808cb82a4d2
Source dataset
uspto-grants-2009_07
Patent number
US07566724B2

Reaction notes

Loading…