反应详情

温度

23 °C

To a solution of the acid structural unit S27 (1.5 g) in dichloromethane (5 ml/mmol) there was added at 0° C. diisopropylethylamine (2.5 eq.), followed by N-hydroxybenzotriazole (HOBt) (1 eq.) and N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) (1.5 eq.). The resulting reaction mixture was stirred for 15 min. at 23° C. It was then cooled to 0° C., and 6-bromo-1,2,3,4-tetrahydroisoquinoline (1.2 eq., dissolved in dichloromethane) was added dropwise. The reaction mixture was stirred for 16 h at 25° C. until the reaction was complete. The mixture was diluted with dichloromethane (100 ml) and extracted with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium hydrogen carbonate solution and again with saturated sodium chloride solution. The organic phase was dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography (5% ethyl acetate in dichloromethane). Yield: 80% Step (ii): Cesium carbonate (2.5 eq.) was added to a solution of N-methylpiperazine (3.6 mmol) and 1-(6-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-2-((1-(4-methoxy-2,6-dimethyl-phenylsulfonyl)piperidin-2-yl)methoxy)ethanone (3 mmol) in dioxane (20 ml), and the resulting solution was degassed for 30 min. with argon. Xanthphos (2 mmol), followed by palladium tris(dibenzylideneacetone)dipalladium (0.15 mmol) were then added, under argon, and the mixture was heated for 16 h at 120° C. The progress of the reaction was monitored by thin-layer chromatography. The reaction mixture was filtered and washed with ethyl acetate, and the filtrate was concentrated in vacuo. The crude product was taken up in dichloromethane and washed with water and saturated sodium chloride solution. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. The product was purified by column chromatography (4% methanol in dichloromethane). Yield: 10%; MS, m/z 585.3 (MH+).

1. customThe resulting reaction mixture
2. temperatureIt was then cooled to 0° C.
3. stirringThe reaction mixture was stirred for 16 h at 25° C. until the reaction
4. extractionextracted with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium hydrogen carbonate solution and again with saturated sodium chloride solution
5. dry with materialThe organic phase was dried (Na2SO4)
6. concentrationconcentrated in vacuo
7. customThe crude product was purified by column chromatography (5% ethyl acetate in dichloromethane)
8. customthe resulting solution was degassed for 30 min. with argon
9. additionwere then added, under argon
10. temperaturethe mixture was heated for 16 h at 120° C
11. filtrationThe reaction mixture was filtered
12. washwashed with ethyl acetate
13. concentrationthe filtrate was concentrated in vacuo
14. washwashed with water and saturated sodium chloride solution
15. dry with materialThe organic phase was dried (Na2SO4)
16. filtrationfiltered
17. concentrationconcentrated in vacuo
18. customThe product was purified by column chromatography (4% methanol in dichloromethane)