反应详情

温度

135 °C

A suspension of methyl 2-amino-1-cyclopropyl-4,5,6,7-tetrahydro-1H-indole-3-carboxylate (2.29 g, 9.77 mmol) in Toluene (46 mL) was treated with ethyl 3-ethoxybut-2-enoate (3.09 g, 19.55 mmol) and pTsOH (0.093 g, 0.489 mmol), and then heated to reflux (135° C.) for 2.5 hours using Dean-Stark. The mixture was cooled to rt, slowly treated with sodium ethoxide (21 wt % in EtOH) (4.38 mL, 11.73 mmol), and refluxed at 135° C. with Dean-Stark for 4 hours. The reaction was cooled to rt and concentrated. The brown residue was diluted with water and 1N HCl until neutral (pH ˜6), extracted with EtOAc, washed with brine, dried with Na2SO4, filtered, and concentrated to give 2.9568 g crude product. Water layer still contained some product. It was acidified with 1N HCl. extracted with EtOAc, washed with brine, dried with Na2SO4, filtered, and concentrated to give 203 mg crude product. Both products were combined and purified with column chromatography (0-50% EtOAc/Hexane) to give ethyl 9-cyclopropyl-4-hydroxy-2-methyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]indole-3-carboxylate (1.3474 g, 4.29 mmol, 43.8% yield) as white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 12.48 (s, 1 H), 4.43 (q, J=7.1 Hz, 2 H), 3.06 (quin, J=5.4 Hz, 1 H), 2.94-2.85 (m, 2 H), 2.85-2.70 (m, 5 H), 1.96-1.75 (m, 4 H), 1.45 (t, J=7.1 Hz, 3 H), 1.11 (d, 4 H); LCMS (m/z) ES+=315 (M+1).

1. temperatureheated
2. temperatureThe mixture was cooled to rt
3. temperaturerefluxed at 135° C. with Dean-Stark for 4 hours
4. temperatureThe reaction was cooled to rt
5. concentrationconcentrated
6. additionThe brown residue was diluted with water and 1N HCl until neutral (pH ˜6)
7. extractionextracted with EtOAc
8. washwashed with brine
9. dry with materialdried with Na2SO4
10. filtrationfiltered
11. concentrationconcentrated
12. customto give 2.9568 g crude product
13. extractionextracted with EtOAc
14. washwashed with brine
15. dry with materialdried with Na2SO4
16. filtrationfiltered
17. concentrationconcentrated
18. customto give 203 mg crude product
19. custompurified with column chromatography (0-50% EtOAc/Hexane)