反应详情

温度

117 °C

A mixture of (R)-6-bromo-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole (Example 14, 0.792 g, 2.162 mmol), pyridazin-3(2H)-one (0.415 g, 4.32 mmol), copper powder (0.137 g, 2.16 mmol), copper(I) iodide (57.6 mg, 0.303 mmol), and potassium carbonate (0.896 g, 6.49 mmol) were combined into a large Biotage microwave vial equipped with a magnetic stirbar. The vial was crimp capped with a septum. Pyridine (17.3 mL) was introduced via syringe. The reaction mixture was purged (vacuum/nitrogen) three times, then N1,N2-dimethylethane-1,2-diamine (0.065 mL, 0.605 mmol) was added via syringe and the reaction mixture was stirred with heating at 117° C. for 24 hours. The reaction mixture was allowed to cool to room temperature then the vial was uncapped and the contents were transferred to a 100 mL round bottom flask (methanol rinse). Volatiles were removed under reduced pressure and the residue was partitioned between CHCl3 and aqueous ammonium hydroxide. The organic layer was washed with brine then dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a solid that was treated with toluene and returned to the rotary evaporator in an attempt to remove residual pyridine. A solid was obtained. This was purified by column chromatography on an Analogix IntelliFlash-280 (Analogix SF65-220g, 100% CHCl3 to 97:3 CHCl3/methanol). Fractions containing product were combined and concentrated under reduced pressure to give a solid that was stirred with diethyl ether. The solid was collected by filtration and rinsed once with ethyl acetate and several times with hexane. This solid was crystallized from hot ethyl acetate. The first crystal batch was collected by filtration and dried in a vacuum oven at 84° C. for 5 hours. The filtrate was concentrated under reduced pressure and the solid residue was dissolved in hot ethyl acetate in a second crystallization attempt. The second crystal batch was collected by filtration and dried in the vacuum oven along with the first batch at 88° C. overnight. The two dried crystal batches combined gave (R)-2-(2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-6-yl)pyridazin-3(2H)-one. 1H NMR (300 MHz, CD3OD) δ ppm 1.51-1.59 (m, 2H), 1.70 (pentet, J=6 Hz, 4H), 1.99-2.15 (m, 1H), 2.36-2.47 (m, 1H), 2.56-2.77 (m, 4H), 3.17-3.31 (m, 1H), 3.47 (t, J=9 Hz, 1H), 3.53-3.64 (m, 1H), 3.73-3.82 (m, 1H), 3.87-3.96 (m, 1H), 7.09 (dd, J=2, 9 Hz, 1H), 7.45-7.51 (m, 1H), 7.57 (d, J=9 Hz, 1H), 7.89 (d, J=2 Hz, 1H), 8.04 (dd, J=2, 4 Hz, 1H); MS (DCI/NH3) m/z 382 (M+H)+.

1. customvial equipped with a magnetic stirbar
2. customThe vial was crimp capped with a septum
3. customThe reaction mixture was purged (vacuum/nitrogen) three times
4. temperatureto cool to room temperature
5. customthe contents were transferred to a 100 mL round bottom flask
6. wash(methanol rinse)
7. customVolatiles were removed under reduced pressure
8. customthe residue was partitioned between CHCl3 and aqueous ammonium hydroxide
9. washThe organic layer was washed with brine
10. dry with materialthen dried (MgSO4)
11. filtrationfiltered
12. concentrationThe filtrate was concentrated under reduced pressure
13. customto give a solid
14. customreturned to the rotary evaporator in an attempt
15. customto remove residual pyridine
16. customA solid was obtained
17. customThis was purified by column chromatography on an Analogix IntelliFlash-280 (Analogix SF65-220g, 100% CHCl3 to 97:3 CHCl3/methanol)
18. additionFractions containing product
19. concentrationconcentrated under reduced pressure
20. customto give a solid
21. filtrationThe solid was collected by filtration
22. washrinsed once with ethyl acetate and several times with hexane
23. customThis solid was crystallized from hot ethyl acetate
24. filtrationThe first crystal batch was collected by filtration
25. customdried in a vacuum oven at 84° C. for 5 hours
26. concentrationThe filtrate was concentrated under reduced pressure
27. dissolutionthe solid residue was dissolved in hot ethyl acetate in a second crystallization attempt
28. filtrationThe second crystal batch was collected by filtration
29. customdried in the vacuum oven along with the first batch at 88° C. overnight