反应详情

温度

85 °C

To a round bottom flask was added the methane sulfonic acid salt of methyl 1-amino-4-bromo-1H-pyrrole-2-carboxylate (140 g, 0.444 mol), isopropanol (700 mL) and 3,3-diethoxypropionitrile (128 g, 0.888 mol). The reaction mixture was slowly brought to 85° C. over 1 hour and then stirred at 85° C. for 2 hours. At this time, the ethanol that was generated and the isopropanol was removed under vacuum. The resulting residue was dissolved in CH2Cl2 and washed with water and brine solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The resulting residue was transferred into a 2 L round bottom flask and dichloroethane (900 mL) and DBU (210 gm, 1.36 mol) were successively added to the reaction mixture. The resulting mixture was then stirred at 85° C. for 5 hours then cooled to rt and diluted with CH2Cl2 followed by washing with water then brine solution. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by flash silica gel column chromatography to yield 58 g of title compound as the crude product containing residual DBU. This material was used as is in the next transformation. LCMS (condition A) m/z=236.0−ve. 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.76 (1H, br.s), 7.62 (1H, s), 7.39 (1H, d, 2.0 Hz), 6.43 (1H, d, 2.0 Hz). The product is contaminated with DBU and was used directly as such without further purification in the next step.

1. customthe isopropanol was removed under vacuum
2. dissolutionThe resulting residue was dissolved in CH2Cl2
3. washwashed with water and brine solution
4. customThe organic layer was separated
5. dry with materialdried over Na2SO4
6. filtrationfiltered
7. concentrationconcentrated
8. customThe resulting residue was transferred into a 2 L round bottom flask
9. stirringThe resulting mixture was then stirred at 85° C. for 5 hours
10. temperaturethen cooled to rt
11. washby washing with water
12. customThe organic layer was separated
13. dry with materialdried over Na2SO4
14. filtrationfiltered
15. concentrationconcentrated
16. customThe resulting residue was purified by flash silica gel column chromatography