反应详情

1-(3,4,5,6,3′,6′-Hexahydro-2H,2′H-[1,4′]bipyridinyl-1′-yl)-ethanone. A flask equipped with a Dean-Stark trap and a reflux condenser was charged with 1-acetyl-piperdin-4-one (100 g, 0.71 mol) and toluene (1 L). Piperidine (63.4 g, 0.75 mol) and p-toluenesulfonic acid monohydrate (0.27 g, 1.4 mmol, 0.2 mol %) were added, and the resulting solution was heated at reflux for 8 h. The mixture was cooled to rt and concentrated to give a crude product which was used directly in the next reaction. Step B. 1-[5′-(4-Fluoro-benzoyl)-3,4,5,6,3′,6′-hexahydro-2H,2′H-[1,4′]bipyridinyl-1′-yl]-ethanone. A solution of crude 1-(3,4,5,6,3′,6′-hexahydro-2H,2′H-[1,4′]bipyridinyl-1′-yl)-ethanone in CH2Cl2 (1.5 L) was treated with Et3N (108 mL, 0.78 mol) and then cooled to 0° C. A solution of 4-fluorobenzoyl chloride (107 g, 0.68 mol) in CH2Cl2 (150 mL) was added over 1 h. The reaction mixture was stirred at rt for 2 h, then was concentrated to give a crude material which was directly used on next reaction. HPLC: RT=7.52 min. MS (ESI): exact mass calcd. for C19H23FN2O2, 330.17; m/z found, 331.0 [M+H]+. Step C. 1-[4-(4-Fluoro-phenyl)-2-isopropyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-ethanone. A solution of crude 1-[5′-(4-fluoro-benzoyl)-3,4,5,6,3′,6′-hexahydro-2H,2′H-[1,4′]bipyridinyl-1′-yl]-ethanone in t-amyl alcohol (1.5 L) was treated with Et3N (108 mL, 0.78 mol) and 2-methyl propanimidamide hydrochloride (82.6 g, 0.67 mol). The reaction mixture was heated at reflux for 16 h and then was cooled to rt. The mixture was concentrated, and the residue was diluted with water (2 L) and extracted with EtOAc (2×). The combined organic layers were dried (MgSO4) and concentrated to afford the crude title compound, which was used in next reaction without further purification. HPLC: RT=8.11 min. MS (ESI): exact mass calcd. for C18H20FN3O, 313.16; m/z found, 314.0 [M+H]+. 1H NMR (CDCl3; mixture of rotamers): 7.60-7.50 (m, 2H), 7.24-7.12 (m, 2H), 4.71 (s, 1.4H), 4.56 (s, 0.6H), 3.93 (t, J=6.2, 0.6H), 3.80 (t, J=6.2, 1.4H), 3.18 (sept, J=6.8, 1H), 3.07 (t, J=6.2, 1.4H), 3.02 (t, J=6.2, 0.6H), 2.15 (s, 2.1H), 2.00 (s, 0.9H), 1.34 (d, J=6.8, 6H). Step D. A mixture of crude 1-[4-(4-fluoro-phenyl)-2-isopropyl-7,8-dihydro-5H-pyrido[4,3-d]pyrimidin-6-yl]-ethanone in 10% aq. HCl (800 mL) was heated at reflux for 2 h and then cooled to rt. The aqueous solution was washed with EtOAc (400 mL) and then was basified with NaOH pellets (˜120 g) to pH>12. The basic solution was extracted with CH2Cl2 (2×500 mL). The combined organic layers were washed with 1 N NaOH (400 mL), dried (MgSO4), and concentrated to give the crude product (100 g), which was used in the next reaction without further purification. HPLC: RT=6.89 min. MS (ESI): exact mass calcd. for C16H18FN3, 271.15; m/z found, 271.9 [M+H]+.

1. customA flask equipped with a Dean-Stark trap and a reflux condenser
2. temperaturethe resulting solution was heated
3. temperatureat reflux for 8 h
4. concentrationconcentrated
5. customto give a crude product which
6. customwas used directly in the next reaction
7. temperaturecooled to 0° C
8. concentrationwas concentrated
9. customto give a crude material which
10. customwas directly used on next reaction
11. temperatureThe reaction mixture was heated
12. temperatureat reflux for 16 h
13. temperaturewas cooled to rt
14. concentrationThe mixture was concentrated
15. additionthe residue was diluted with water (2 L)
16. extractionextracted with EtOAc (2×)
17. dry with materialThe combined organic layers were dried (MgSO4)
18. concentrationconcentrated
19. customto afford the crude title compound, which
20. customwas used in next reaction without further purification
21. temperaturewas heated
22. temperatureat reflux for 2 h
23. temperaturecooled to rt
24. washThe aqueous solution was washed with EtOAc (400 mL)
25. extractionThe basic solution was extracted with CH2Cl2 (2×500 mL)
26. washThe combined organic layers were washed with 1 N NaOH (400 mL)
27. dry with materialdried (MgSO4)
28. concentrationconcentrated