反应详情

温度

5 °C

Pyridine (53 mls/660 mmols) was added to dissolve 3-Amino-4,4,4-trifluorocrotonic acid ethyl ester (100 g/546 mmols) in DCM(6000 mls). The mixture was then placed under nitrogen and cooled to 5° C. by suspending in an ice-bath. Ethyl malonyl chloride was added dropwise over approx 1 hr such that temperature did not exceed 20° C. The resulting pale brown solution was stirred at 5° C. for 3 hrs then allowed to warm to room temperature overnight to give a dark green solution. The mixture was then washed with 1M HCl(aq) (200 mls) then sat.NaHCO3(aq) (250 mls). Aqueous washings were sequentially re-extracted with further DCM (2×250 mls). The Organic layers were combined, dried over Na2SO4, filtered and concentrated to a dark green oil of crude 3-(2-Ethoxycarbonyl-acetylamino)-4,4,4-trifluoro-but-2-enoic acid ethyl ester (175 g). A portion of the crude material (120 g) was dissolved in EtOH (300 mls) and placed under nitrogen. Potassium tert-butoxide (54 g/480 mmols) was then added in several portions such that temperature did not exceed 60° C. resulting in a purple solution. The mixture was then heated at 70° C. for 3 hrs. EtOH (100 mls) was then added to reduce viscosity and heated at 80° C. for a further hour. The mixture was then allowed to cool and then concentrated in vacuo to a red solid. The mixture was dissolved in water (500 mls) and citric acid (180 g) then added, causing precipitation. EtOAc (600 mls) was then added and the mixture poured into a separating funnel and the aqueous layer run off. The organic layer containing much undissolved solid was filtered to give the title compound (46.5 g) as a white solid. Concentration of the organic filtrate and trituration with MeOH afforded further title compound (15.3 g) as a white solid.

1. customby suspending in an ice-bath
2. customdid not exceed 20° C
3. temperatureto warm to room temperature overnight
4. customto give a dark green solution
5. washThe mixture was then washed with 1M HCl(aq) (200 mls)
6. extractionAqueous washings were sequentially re-extracted with further DCM (2×250 mls)
7. dry with materialdried over Na2SO4
8. filtrationfiltered
9. concentrationconcentrated to a dark green oil of crude 3-(2-Ethoxycarbonyl-acetylamino)-4,4,4-trifluoro-but-2-enoic acid ethyl ester (175 g)
10. dissolutionA portion of the crude material (120 g) was dissolved in EtOH (300 mls)
11. customdid not exceed 60° C.
12. customresulting in a purple solution
13. temperatureThe mixture was then heated at 70° C. for 3 hrs
14. temperatureheated at 80° C. for a further hour
15. temperatureto cool
16. concentrationconcentrated in vacuo to a red solid
17. dissolutionThe mixture was dissolved in water (500 mls)
18. additioncitric acid (180 g) then added
19. customprecipitation
20. additionEtOAc (600 mls) was then added
21. additionthe mixture poured into a separating funnel
22. additionThe organic layer containing much undissolved solid
23. filtrationwas filtered