N1C=CC=CC=1.C(O[C:10](=[O:18])/[CH:11]=[C:12](\[NH2:17])/[C:13]([F:16])([F:15])[F:14])C.C([CH:21]([C:25](Cl)=[O:26])[C:22](Cl)=[O:23])C.[CH3:28][C:29](C)([O-:31])C.[K+]>C(Cl)Cl.CCO>[CH2:29]([O:31][C:25](=[O:26])[C:21]1[C:10]([OH:18])=[CH:11][C:12]([C:13]([F:14])([F:15])[F:16])=[N:17][C:22]=1[OH:23])[CH3:28]
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.
불러오는 중…
