Pyridine → HCID 178470035, compound

Temperature

5 °C

To dissolve 3-Amino-4,4,4-trifluorocrotonic acid ethyl ester (100 g/546 mmol) in dichloromethane (600 mL) was added pyridine (53 mL/660 mmol). 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. 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. Washed with 1M HCl(aq) (200 mL) then saturated NaHCO3(aq) (250 mL). Aqueous washings sequentially re-extracted with further dichloromethane (2×250 mL). Organics 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 (120 g) was dissolved in ethanol (300 mL) and placed under nitrogen. Potassium tert-butoxide (54 g/480 mmol) was added in several portions such that temperature did not exceed 60° C. resulting in a purple solution. Heated at 70° C. for 3 hrs. Added ethanol (100 mL) to reduce viscosity and heated at 80° C. for a further hour. Allowed to cool and concentrated in vacuo to a red solid. Dissolved in water (500 mL) and added citric acid (180 g) causing precipitation. Added ethyl acetate (600 mL). Poured into separating funnel and ran off aqueous. 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 methanol afforded 2,4-dihydroxy-6-trifluoromethyl-nicotinic acid ethyl ester (15.3 g) as a white solid.

1. customby suspending in an ice-bath
2. customdid not exceed 20° C
3. customResulting pale brown solution
4. temperatureto warm to room temperature overnight
5. customto give a dark green solution
6. washWashed with 1M HCl(aq) (200 mL)
7. extractionAqueous washings sequentially re-extracted with further dichloromethane (2×250 mL)
8. dry with materialdried over Na2SO4
9. filtrationfiltered
10. concentrationconcentrated to a dark green oil of crude 3-(2-Ethoxycarbonyl-acetylamino)-4,4,4-trifluoro-but-2-enoic acid ethyl ester (175 g)
11. dissolutionA portion of the crude (120 g) was dissolved in ethanol (300 mL)
12. customdid not exceed 60° C.
13. customresulting in a purple solution
14. temperatureHeated at 70° C. for 3 hrs
15. temperatureheated at 80° C. for a further hour
16. temperatureAllowed to cool
17. concentrationconcentrated in vacuo to a red solid
18. dissolutionDissolved in water (500 mL)
19. additionadded citric acid (180 g)
20. customprecipitation
21. additionPoured
22. custominto separating funnel
23. additionThe organic layer containing much undissolved solid
24. filtrationwas filtered

ORD record

ord-ddd4a83b12454702ba25f91000b8d966

Source dataset

uspto-grants-2013_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08372836B2