Piperidine → 4-((9aS)-3-(Ethoxycarbonyl)-5-oxo-2-{2-[4-(trifluoromethyl)phenyl]ethyl}-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizin-4-yl)benzoic acid

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Reaction Steps

Ethyl (2Z)-3-amino-5-[4-(trifluoromethyl)phenyl]-2-pentenoate (28.73 g, 100 mol), 4-carboxy-benzaldehyde (15.0 g, 100 mmol), tert-butyl (2S)-2-(3-ethoxy-3-oxopropanoyl)-1-pyrrolidinecarboxylate (28.52 g, 100 mmol), and piperidine (4.94 mL, 50 mmol) were added to 100 mL toluene and refluxed under Dean-Stark conditions for 18 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc and washed with pH 4.0 buffer (2×), brine and dried over Na2SO4. The organics were concentrated and used without further purification. The crude dihydropyridine (68.67 g, 100 nmol) was dissolved in 200 mL CH3CN and 200 mL H2O followed by the addition of ceric ammonium nitrate (109.64, 200 mmol). The reaction mixture was stirred for 45 min and then diluted with EtOAc. The organics were extracted and washed with H2O and brine and then dried (Na2SO4), filtered and concentrated to a reddish-brown residue. The residue was redissolved in 250 mL of 70% TFA in CH2Cl2. After 1.5 h of stirring at rt, the reaction mixture was concentrated and the residue redissolved in 300 mL of 10% triethylamine in CH2Cl2. After 20 h of stirring at rt the reaction was again concentrated and the resulting residue taken up in EtOAc and washed with pH 4.0 buffer (2×), brine and dried over Na2SO4. Filtration followed by concentration and chromatography on silica gel (90% EtOAc, 10% MeOH) eluted the title compound as a white solid (21.50 g, 39.92 mmol, 40%):

Provenance & Evidence