C(O[C:4](=[O:12])/[CH:5]=[C:6](\[NH2:11])/[C:7]([F:10])([F:9])[F:8])C.N1C=CC=CC=1.C([CH:21]([C:25](Cl)=[O:26])[C:22](Cl)=[O:23])C.[CH3:28][C:29](C)([O-:31])C.[K+]>ClCCl.C(O)C>[CH2:29]([O:31][C:25](=[O:26])[C:21]1[C:4]([OH:12])=[CH:5][C:6]([C:7]([F:8])([F:9])[F:10])=[N:11][C:22]=1[OH:23])[CH3:28]
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.
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