反应详情

A suspension of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate K8 (483 mg, 1.08 mmol), 1-(3-ethynylphenyl)cyclopropanecarboxamide A60 (200 mg, 1.08 mmol), PPh3 (14 mg, 0.054 mmol) and CuI (10 mg, 0.054 mmol) in Et3N (1 mL) and DMF (4 mL) was sonicated for 10 minutes, PdCl2(PPh3)2 (38 mg, 0.054 mmol) was added and the reaction mixture was irradiated in the microwave at 120° C. for 40 minutes. The mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give a yellow oil. Further purification by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% MeOH in EtOAc) gave a yellow oil which was taken up in EtOAc (20 mL) and DMF (2 mL). Pd/C 10% (100 mg) was added to this solution and the mixture was stirred overnight under an atmosphere of hydrogen at room temperature. The mixture was filtered through Celite and the filter cake was washed with EtOAc (50 mL). The washings were combined and the volatiles were removed in vacuo to give a yellow oil that was adsorbed onto silica gel and purified by silica gel column chromatography (Biotope Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. then 0-20% MeOH in EtOAc). Further purification by silica column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. then 0-20% MeOH in EtOAc) gave a crude material that was dissolved in DCM (20 mL). TFA (1 mL) was added to this solution and the mixture was stirred at room temperature overnight. The volatiles were removed in vacuo and the resulting solid was sonicated for 10 minutes in sat. Na2CO3 (aq.) (25 mL). The precipitate was collected by filtration and washed with water (25 mL), toluene (50 mL) and air dried to give the title compound 53 as a yellow solid (15 mg, 32%). LCMS-A: rt 4.784 min; m/z 500.3 [M+H]+.

1. customwas sonicated for 10 minutes
2. customthe reaction mixture was irradiated in the microwave at 120° C. for 40 minutes
3. custompurified by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.)
4. customto give a yellow oil
5. customFurther purification by column chromatography (Biotage Isolera, 40 g SiO2 cartridge, 0-100% MeOH in EtOAc)
6. customgave a yellow oil which
7. filtrationThe mixture was filtered through Celite
8. washthe filter cake was washed with EtOAc (50 mL)
9. customthe volatiles were removed in vacuo
10. customto give a yellow oil that
11. custompurified by silica gel column chromatography (Biotope Isolera, 40 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.
12. customFurther purification by silica column chromatography (Biotage Isolera, 25 g SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.
13. custom0-20% MeOH in EtOAc) gave a crude material that
14. stirringthe mixture was stirred at room temperature overnight
15. customThe volatiles were removed in vacuo
16. customthe resulting solid was sonicated for 10 minutes in sat. Na2CO3 (aq.) (25 mL)
17. filtrationThe precipitate was collected by filtration
18. washwashed with water (25 mL), toluene (50 mL) and air
19. customdried