Acetic Acid → 3-(3-Ethoxy-4-methoxy-phenyl)-3-(4-isobutylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionitrile

To a mixture of dimethyl-3-aminophthalic ester (0.75 g, 3.6 mmol), 3-methyl-butyraldehyde (0.36 mL, 4.0 mmol), acetic acid (1.3 mL, 23 mmol) in 1,2-dichloroethane (30 mL), was added sodium triacetoxyborohydride (1.5 g, 7.2 mmol) at room temperature. After 30 minutes, the mixture was extracted with methylene chloride (30 mL) and water (30 mL). The organic layer was washed with sodium hydrogen carbonate (sat. 30 mL). The solvent was removed in vacuo to give a yellow oil. To the oil in methanol (5 mL), was added sodium hydroxide (10 N, 1.5 mL), and kept at room temperature overnight. To the mixture, was added HCl (12 N, 1.3 mL). The solvent was removed in vacuo to give a solid. The solid was dissolved in pyridine (10 mL), and 3-amino-3-(3-ethoxy-4-methoxy-phenyl)-propionitrile (1.0 g, 3.6 mmol) was added to the solution. The solution was heated to reflux for 2 days. The solvent was removed in vacuo to give an oil. The oil was extracted with ethyl acetate (100 mL) and water (100 mL). The organic layer was washed with water (50 mL), HCl (1N, 2×50 mL), water (50 mL), sodium hydrogen carbonate (sat, 2×50 mL), and brine (50 mL), and dried over MgSO4. Filtration and removal of solvent in vacuo gave an oil. The oil was purified by column chromatography (Silca Gel, 1:3 EtOAc:hexanes) to give 3-(3-ethoxy-4-methoxy-phenyl)-3-(4-isobutylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propionitrile as a yellow solid (700 mg, 46% yield): mp, 12-123° C.; 1H NMR (CDCl3) δ 1.01 (d, J=7 Hz, 6H, 2CH3), 1.45 (t, J=7 Hz, 3H, CH3), 1.88-1.99 (m, 1H, CH), 3.07 (t, J=6 Hz, 2H, CH2), 3.27 (dd, J=7, 17 Hz, 1H, CHH), 3.76 (dd, J=10, 17 Hz, 1H, CHH), 3.84 (s, 3H, CH3), 4.09 (q, J=7 Hz, 2H, CH2), 5.55 (dd, J=7, 10 Hz, 1H, NCH), 6.37 (t, J=6 Hz, 1H, Ar), 6.81-6.86 (m, 2H, Ar), 7.01-7.06 (m, 3H, Ar), 7.44 (t, J=8 Hz, 1H, Ar); 13C NMR (CDCl3) δ 14.69, 20.26, 21.29, 28.27, 50.31, 50.63, 55.95, 64.49, 109.63, 111.10, 111.42, 112.22, 116.58, 117.09, 119.96, 129.55, 132.33, 135.93, 147.14, 148.53, 149.66, 168.18. Analy. Calculated for C24H27N3O4: C, 68.39; H, 6.46; N, 9.97. Found: C, 68.32; H, 6.39; N, 9.95.

1. extractionthe mixture was extracted with methylene chloride (30 mL) and water (30 mL)
2. washThe organic layer was washed with sodium hydrogen carbonate (sat. 30 mL)
3. customThe solvent was removed in vacuo
4. customto give a yellow oil
5. waitkept at room temperature overnight
6. customThe solvent was removed in vacuo
7. customto give a solid
8. temperatureThe solution was heated
9. temperatureto reflux for 2 days
10. customThe solvent was removed in vacuo
11. customto give an oil
12. extractionThe oil was extracted with ethyl acetate (100 mL) and water (100 mL)
13. washThe organic layer was washed with water (50 mL), HCl (1N, 2×50 mL), water (50 mL), sodium hydrogen carbonate (sat, 2×50 mL), and brine (50 mL)
14. dry with materialdried over MgSO4
15. filtrationFiltration and removal of solvent in vacuo
16. customgave an oil
17. customThe oil was purified by column chromatography (Silca Gel, 1:3 EtOAc:hexanes)

ORD record

ord-273143a2d6d34e80942fee0edb8930ea

Source dataset

uspto-grants-2011_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08026269B2