反应详情

To a solution of [3-cyclopropyl-3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 99a (0.9 g, 3.76 mmol) and (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-fluoro-phenyl)-acrylonitrile (1.16 g, 3.76 mmol) prepared in Example 52a in dichloromethane (100 mL) were added triethylamine (0.76 g, 7.5 mmol) and AgF (0.47 g, 3.76 mmol), in one portion. The mixture was stirred at room temperature for overnight. The mixture was then quenched with sat. NH4Cl and extracted with CH2Cl2. The organic phase was separated, filtered through celite and dried over Na2SO4, and concentrated. The residue was dissolved into methanol (40 mL), and DBU (3 mL) was added. The mixture was heated at 100° C. for 5 h, then cooled to room temperature, and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer were separated, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:5, 1:3) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2-cyclopropyl-2-methyl-propyl)-pyrrolidine-2-carboxylic acid methyl ester as a white foam (0.95 g, 50%).

1. customThe mixture was then quenched with sat. NH4Cl
2. extractionextracted with CH2Cl2
3. customThe organic phase was separated
4. filtrationfiltered through celite
5. dry with materialdried over Na2SO4
6. concentrationconcentrated
7. dissolutionThe residue was dissolved into methanol (40 mL), and DBU (3 mL)
8. additionwas added
9. temperatureThe mixture was heated at 100° C. for 5 h
10. temperaturecooled to room temperature
11. concentrationconcentrated
12. customThe residue was partitioned between ethyl acetate and water
13. customThe organic layer were separated
14. dry with materialdried over MgSO4
15. concentrationconcentrated
16. customThe residue was purified by chromatography (EtOAc:hexanes=1:5, 1:3)