反应详情

温度

117 °C

A mixture of (R)-5-bromo-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole (Example 51, 0.792 g, 2.16 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) is weighed into a large Biotage microwave vial equipped with a magnetic stirbar. The vial is crimp capped with a septum. Pyridine (17.3 mL) is introduced via syringe. The reaction mixture is purged (vacuum/nitrogen) three times, then N1,N2-dimethylethane-1,2-diamine (0.065 mL, 0.605 mmol) is added via syringe and the reaction mixture is stirred with heating at 117° C. for 24 hours. The reaction mixture is allowed to cool to room temperature, then the vial is uncapped and the contents are transferred to a 100 mL round bottom flask (methanol rinse). Volatiles are removed under reduced pressure and the residue is partitioned between CHCl3 and aqueous ammonium hydroxide. The organic layer is washed with brine then dried (MgSO4) and filtered The filtrate is concentrated under reduced pressure to give a residue that is treated with toluene and returned to the rotary evaporator in an attempt to remove residual pyridine. This residue is purified by column chromatography on an Analogix IntelliFlash-280 (Analogix SF65-220 g, 100% CHCl3 to 97:3 CHCl3/methanol). Fractions containing product are combined and concentrated under reduced pressure to give a solid that is stirred with diethyl ether. The solid is collected by filtration and rinsed once with ethyl acetate and several times with hexane. This solid is crystallized from hot ethyl acetate. The first crystal batch is collected by filtration and dried in a vacuum oven at 84° C. for 5 hours. The filtrate is concentrated under reduced pressure and the solid residue is dissolved in hot ethyl acetate in a second crystallization attempt. The second crystal batch is collected by filtration and dried in the vacuum oven along with the first batch at 88° C. overnight. The two dried crystal batches combined give (R)-2-(2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazol-5-yl)pyridazin-3(2H)-one.

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