反应详情

温度

120 °C

5-Bromo-2,4-dimethoxy-pyrimidine (89 mg, 0.41 mmol), X-Phos (46 mg, 0.09 mmol) bis(dibenzylideneacetone)palladium(0) (29 mg, 0.03 mmol), cesium carbonate (203 mg, 0.62 mmol) were combined and flushed 10 min with Argon. To this mixture was added (S)-3-(5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (intermediate 7) (100 mg, 0.31 mmol) in dioxane (4 mL), the vial was capped and the reaction mixture was stirred at 120° C. for 4.5 h. The mixture was allowed to cool to rt and filtered through a celite pad. The filtrate was diluted with EtOAc (20 mL) and washed with sat. NaHCO3(aq) (10 mL), brine (10 mL), dried (Na2SO4) and concentrated in vacuo. Dissolved in dioxane (4 mL) and added to a glass vial containing 5-bromo-2,4-dimethoxy-pyrimidine (89 mg, 0.41 mmol), X-Phos (46 mg, 0.09 mmol) tris(dibenzylideneacetone)dipalladium(0) (29 mg, 0.03 mmol), cesium carbonate (203 mg, 0.62 mmol). The vial was capped and the reaction mixture was stirred at 120° C. for 4.5 h. The mixture was allowed to cool to rt and filtered through a celite pad. The filtrate was diluted with EtOAc (20 mL) and washed with sat. NaHCO3(aq) (10 mL) then brine (10 mL), dried (Na2SO4) and concentrated in vacuo to give (S)-3-(6-(2,4-dimethoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester which was used without further purification. (S)-3-(6-(2,4-dimethoxy-pyrimidin-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yloxy)pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in CH2Cl2 (2.0 mL) and TFA added (1 mL). The resulting mixture was stirred for 30 min. at room temperature. The reaction mixture was concentrated in vacuo. Purification by preparative reverse phase Gilson HPLC and subsequent neutralization of the combined fractions by PL-HCO3 cartridge & lyophilisation gave 6-(2,4-dimethoxy-pyrimidin-5-yl)-4-((S)-pyrrolidin-3-yloxy)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidine as a yellow powder (11 mg, 10% yield over 2 steps). LCMS: [M+H]+=359.1, Rt(2)=0.79 min

1. customflushed 10 min with Argon
2. customthe vial was capped
3. temperatureto cool to rt
4. filtrationfiltered through a celite pad
5. additionThe filtrate was diluted with EtOAc (20 mL)
6. washwashed with sat. NaHCO3(aq) (10 mL), brine (10 mL)
7. dry with materialdried (Na2SO4)
8. concentrationconcentrated in vacuo
9. dissolutionDissolved in dioxane (4 mL)
10. additionadded to a glass vial
11. customThe vial was capped
12. stirringthe reaction mixture was stirred at 120° C. for 4.5 h
13. temperatureto cool to rt
14. filtrationfiltered through a celite pad
15. additionThe filtrate was diluted with EtOAc (20 mL)
16. washwashed with sat. NaHCO3(aq) (10 mL)
17. dry with materialbrine (10 mL), dried (Na2SO4)
18. concentrationconcentrated in vacuo