Diethyl Ether → 3-(3-ethoxy-4-methoxyphenyl)-N-methoxy-3-(1-oxoisoindolinyl)-propionamide

HRID 9834

Reaction equation

HRID 9834 reaction equation
[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14]([OH:16])=O)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C[N:28]1CCCCC1.CC[O:36][CH2:37]C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][C:14]([NH:28][O:36][CH3:37])=[O:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]

Participants

5

Reactant 3

HCID 3283Diethyl EtherHCID 12291N-MethylpiperidineHCID 183492403-(3-Ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid

Product 1

HCID 99299653-(3-ethoxy-4-methoxyphenyl)-N-methoxy-3-(1-oxoisoindolinyl)-propionamideYield 67%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A mixture of 3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid (500 mg, 1.41 mmol) and N,N′-carbonyldiimidazole (250 mg, 1.54 mmol) in methylene chloride (30 mL) under nitrogen was stirred at room temperature for 30 minutes. To the solution was added 0-methyl hydroxylamine hydrochloride (175 mg, 2.09 mmol) followed by the addition of 1-methyl piperidine (0.26 mL, 2.14 mmol). The mixture was stirred at room temperature for 2 hours and then was heated to reflux for 14 hours. The cooled reaction mixture was washed with hydrochloric acid (1N, 25 mL), saturated sodium bicarbonate (25 mL), brine (25 mL), and then dried over sodium carbonate and sodium sulfate. Removal of solvent in vacuo gave a solid which was stirred with ether (10 mL) for 30 minutes. This suspension was filtered and the solid was washed with ether (2×10 mL) to give 3-(3-ethoxy-4-methoxyphenyl)-N-methoxy-3-(1-oxoisoindolinyl)-propionamide as a white solid (360 mg, 67% yield): mp, 138.0–139.5° C.; 1H NMR (CDCl3) δ 1.41 (t, J=6.9 Hz, 3H, CH3), 2.95 (dd, J=4.6, 14.5 Hz, 1H, CHH), 3.53 (dd, J=11.2, 14.5 Hz, 1H, CHH), 3.62 (s, 3H, CH3), 3.84 (s, 3H, CH3), 4.02 (q, J=6.9 Hz, 2H, CH2), 4.23 (d, J=17.1 Hz, 1H, NCHH), 4.46 (d, J=17 Hz, 1H, NCHH), 5.49 (dd, J=4.4, 10.3 Hz, 1H, NCH), 6.78–6.99 (m, 3H, Ar,), 7.27–7.51 (m, 3H, Ar), 7.78 (dd, J=7.4 Hz, 1H, Ar), 10.08 (br s, 1H, NH); 13C NMR (CDCl3) δ 14.66, 37.52, 49.48, 54.94, 5.91, 64.01, 64.41, 111.37, 112.12, 119.26, 122.75, 123.54, 128.04, 131.38, 131.68, 132.58, 141.44, 148.56, 149.15, 167.81, 169.47. Anal. Calcd for C21H24N2O5: C, 65.61; H, 6.29; N, 7.29. Found: C, 65.23; H, 6.52; N, 6.88.

Workup

  1. stirringThe mixture was stirred at room temperature for 2 hours
  2. temperaturewas heated
  3. temperatureto reflux for 14 hours
  4. customThe cooled reaction mixture
  5. washwas washed with hydrochloric acid (1N, 25 mL), saturated sodium bicarbonate (25 mL), brine (25 mL)
  6. dry with materialdried over sodium carbonate and sodium sulfate
  7. customRemoval of solvent in vacuo
  8. customgave a solid which
  9. filtrationThis suspension was filtered
  10. washthe solid was washed with ether (2×10 mL)

Sources & evidence

ORD record
ord-3ed65af14c334ce9a46a8ca839a30133
Source dataset
uspto-grants-2006_08
Patent number
US07091356B2

Linked notes

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