反应 #657338

反应方程式

{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

收率 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

收率 36.0%

溶剂

dioxane

反应条件

后处理

1. 1
   其他The reaction mixture was sparged with argon
2. 2
   其他the reaction vessel sealed
3. 3
   其他(screw cap)
4. 4
   其他placed in 100° C.
5. 5
   其他partitioned between ethyl acetate and water (100 mL each)
6. 6
   其他The organic layer was separated
7. 7
   洗涤washed with saturated brine solution (100 mL)
8. 8
   干燥then dried (MgSO4)
9. 9
   过滤filtered
10. 10
    浓缩concentrated
11. 11
    其他The product was purified
12. 12
    洗涤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)

实验过程

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.

来源