反应详情

温度

130 °C

6′-Bromo-5″-methyl-3′H-dispiro[cyclopropane-1,2′-indene-1′,2″-imidazol]-4″-amine (Example 77, 0.10 g, 0.33 mmol), 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (Intermediate 35, 0.121 g, 0.46 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.048 g, 0.07 mmol), 2 M aq. K2CO3 (0.493 mL, 0.99 mmol) and THF (1 mL) were added to microwave vial. The mixture was degassed by bubbling N2 (g) through it. The vial was sealed and heated in a microwave reactor at 130° C. for 30 min. [1,1′-Bis(diphenylphosphino)-ferrocene]palladium(II) chloride (0.048 g, 0.07 mmol) was added and the mixture was degassed by bubbling N2 (g) through it. The vial was sealed and heated in a microwave reactor at 130° C. for 30 min. The residue was dissolved in EtOAc and the mixture was extracted with 1.0 M HCl (2×10 mL). The organic layer was discarded while the aq phase was basified to pH 12 by addition of 1 M NaOH (aq). The basic water phase was extracted with DCM (2×20 mL). The organic phase was dried through a phase separator and concentrated in vacuo. The crude product was purified by flash chromatography (0-10% 0.1 M NH3 in McOH, in DCM, 25 g SiO2 column). The product was purified by a second flash chromatography (0-100% EtOAc in heptane, 25 g SiO2 column) followed by preparative chromatography. The fractions containing pure product were combined and concentrated. DCM was added and the organic phase was collected and dried through a phase separator and concentrated in vacuo, yielding the title compound (10 mg, 0.028 mmol, 8% yield): 1H NMR (500 MHz, CD3OD) δ ppm 0.14-0.23 (m, 1H), 0.50-0.58 (m, 1H), 0.62-0.70 (m, 1H), 0.80 (ddd, 1H), 2.30 (s, 3H), 2.96 (d, 1H), 3.49 (d, 1H), 7.02-7.08 (m, 1H), 7.47 (d, 1H), 7.59 (dd, 1H), 7.73 (s, 1H), 7.88 (s, 2H); MS (MM-ES+APCI)+ m/z 361 [M+H]+.

1. customThe mixture was degassed
2. customby bubbling N2 (g) through it
3. customThe vial was sealed
4. additionwas added
5. customthe mixture was degassed
6. customby bubbling N2 (g) through it
7. customThe vial was sealed
8. dissolutionThe residue was dissolved in EtOAc
9. extractionthe mixture was extracted with 1.0 M HCl (2×10 mL)
10. additionwas basified to pH 12 by addition of 1 M NaOH (aq)
11. extractionThe basic water phase was extracted with DCM (2×20 mL)
12. customThe organic phase was dried through a phase separator
13. concentrationconcentrated in vacuo
14. customThe crude product was purified by flash chromatography (0-10% 0.1 M NH3 in McOH, in DCM, 25 g SiO2 column)
15. customThe product was purified by a second flash chromatography (0-100% EtOAc in heptane, 25 g SiO2 column)
16. additionThe fractions containing pure product
17. concentrationconcentrated
18. additionDCM was added
19. customthe organic phase was collected
20. customdried through a phase separator
21. concentrationconcentrated in vacuo