Reacción #9930

Ecuación de reacción

1-methyl piperidine

3-(3-ethoxy-4-methoxyphenyl)-3-(1-oxoisoindolinyl)propanoic acid

ether

→

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

Rendimiento 67.0%

Disolventes

methylene chloride

Condiciones de reacción

Tratamiento posterior

1. 1
   workup.STIRRINGThe mixture was stirred at room temperature for 2 hours
2. 2
   Temperaturawas heated
3. 3
   Temperaturato reflux for 14 hours
4. 4
   OtroThe cooled reaction mixture
5. 5
   Lavadowas washed with hydrochloric acid (1N, 25 mL), saturated sodium bicarbonate (25 mL), brine (25 mL)
6. 6
   Secadodried over sodium carbonate and sodium sulfate
7. 7
   OtroRemoval of solvent in vacuo
8. 8
   Otrogave a solid which
9. 9
   FiltraciónThis suspension was filtered
10. 10
    Lavadothe solid was washed with ether (2×10 mL)

Procedimiento

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.

Fuente