Reacción #657338

Ecuación de reacción

{3-chloro-6-[2-(3-fluoro-phenyl)-ethyl]-benzo[1,4]oxazin-2-ylidenemethyl}-dimethyl-amine

[3-(4-ureido-piperidin-1-yl)-propyl]-carbamic acid tert-butyl ester

cesium carbonate

→

title compound

Rendimiento 36.0%

{3-[4-(3-{2-Dimethylaminomethylene-6-[2-(3-fluoro-phenyl)-ethyl]-2H-benzo[1,4]oxazin-3-yl}-ureido)-piperidin-1-yl]-propyl}-carbamic acid tert-butyl ester

Rendimiento 36.0%

Disolventes

dioxane

Condiciones de reacción

Tratamiento posterior

1. 1
   OtroThe reaction mixture was sparged with argon
2. 2
   Otrothe reaction vessel sealed
3. 3
   Otro(screw cap)
4. 4
   Otroplaced in 100° C.
5. 5
   Otropartitioned between ethyl acetate and water (100 mL each)
6. 6
   OtroThe organic layer was separated
7. 7
   Lavadowashed with saturated brine solution (100 mL)
8. 8
   Secadothen dried (MgSO4)
9. 9
   Filtraciónfiltered
10. 10
    Concentraciónconcentrated
11. 11
    OtroThe product was purified
12. 12
    Lavadothen eluted with 2 M ammonia in methanol in dichloromethane (0-8% 2 M ammonia in methanol linear gradient over 18 column volumes at a flow rate of 60 mL/min)

Procedimiento

To a solution of {3-chloro-6-[2-(3-fluoro-phenyl)-ethyl]-benzo[1,4]oxazin-2-ylidenemethyl}-dimethyl-amine (500 mg, 1.45 mmol, 1 equiv) and [3-(4-ureido-piperidin-1-yl)-propyl]-carbamic acid tert-butyl ester (435 mg, 1.45 mmol, 1 equiv) in dioxane (15 mL) was added palladium(II) acetate (3.2 mg, 0.0145 mmol, 0.01 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos, 17 mg, 0.029 mmol, 0.02 equiv) and cesium carbonate (709 mg, 2.18 mmol, 1.5 equiv). The reaction mixture was sparged with argon then the reaction vessel sealed (screw cap) and placed in 100° C. oil bath. After 14 h at 100° C. the reaction was cooled to 23° C., and then partitioned between ethyl acetate and water (100 mL each). The organic layer was separated and washed with saturated brine solution (100 mL) then dried (MgSO4), filtered and concentrated. The product was purified using an Isco CombiFlash automated chromatography system. The residue was loaded onto an 80 g silica gel column as a solution in dichloromethane (5 mL) then eluted with 2 M ammonia in methanol in dichloromethane (0-8% 2 M ammonia in methanol linear gradient over 18 column volumes at a flow rate of 60 mL/min) to give 313 mg (0.515 mmol, 36%) of the title compound as a yellow/brown solid.

Fuente