Trifluoroacetic acid → 5-{(9aS)-3-(ethoxycarbonyl)-2-[2-(4-fluorophenyl)ethyl]-5-oxo-7,8,9,9a-tetrahydro-5H-pyrido[2,3-a]pyrrolizin-4-yl}-3-thiophenecarboxylic acid

A DMF (10 mL) solution of tert-Butyl (2S)-2-(3-ethoxy-3-oxopropanoyl)-1-pyrrolidinecarboxylate (2.85 g, 9.99 mmol), 5-formyl-3-thiophene carboxylic acid (1.56 g, 9.99 mmol) and piperidine (0.494 mL, 5.00 mmol) was heatd to 80° C. for 45 min and then cooled to ambient temperature. The reaction mixture was diluted with Et2O and washed 1 N HCl, 2×H2O, 1×brine and the organics dried (Na2SO4), filtered and concentrated to a brown residue. The Knoevenagel product (4.23 g, 9.99 mmol) and ethyl (2Z)-3-amino-5-(4-fluorophenyl)-2-pentenoate (2.37 g, 9.99 mmol) were heated to 110° C. for 1.5 h and then cooled to ambient temperature. The glassy solid was redissolved in CH3CN (20 mL) and H2O (20 mL) followed by addition of ceric ammonium nitrate (10.95 g, 19.98 mmol). The reaction mixture stirred for 45 min at ambient temperature and then Et2O was added and the organics extracted and washed 1×H2O, 1×brine, and then dried (Na2SO4), filtered and concentrated to a dark tan solid. The solid from the previous reaction was subjected to TFA (15 mL in 4 mL CH2Cl2) for 1 h and then concentrated. The residue was redissolved in CH2Cl2 (20 mL) and treated with Et3N (12 mL). After 16 h the reaction mixture was concentrated to a brown foam. The residue was redissolved in CHCl3 and washed 1×pH 4.5 buffer, 1×brine and the organics dried (Na2SO4), filtered and concentrated. Chromatography on silica gel using (4:1 EtOAc:Hexanes with 1% AcOH) eluted the desired compound as a tan solid (1.98 g, 4.00 mmol) 40% yield: 1H NMR (CDCl3, 400 MHz) δ 8.33 (s, 1H), 7.60 (s, 1H), 7.17 (dd, J=8.6, 5.5 Hz, 2H), 6.97 (t, J=8.6, 2H), 4.73 (dd, J=10.4, 6.2 Hz, 1H), 4.17 (dd, J=14.3, 7.0 Hz, 2H), 3.82–3.74 (m, 1H), 3.46–3.40 (m, 1H), 3.19–3.04 (m, 4H), 2.52–2.48 (m, 1H), 2.41–2.31 (m, 2H), 1.48–1.38 (m, 1H), 1.11 (t, J=7.0 Hz, 3H) ESMS m/z 495 (M+H)+, 493 (M−H)+

1. washwashed 1 N HCl, 2×H2O, 1×brine
2. dry with materialthe organics dried (Na2SO4)
3. filtrationfiltered
4. concentrationconcentrated to a brown residue
5. temperaturecooled to ambient temperature
6. extractionthe organics extracted
7. washwashed 1×H2O, 1×brine
8. dry with materialdried (Na2SO4)
9. filtrationfiltered
10. concentrationconcentrated to a dark tan solid
11. customThe solid from the previous reaction
12. concentrationconcentrated
13. dissolutionThe residue was redissolved in CH2Cl2 (20 mL)
14. additiontreated with Et3N (12 mL)
15. concentrationAfter 16 h the reaction mixture was concentrated to a brown foam
16. dissolutionThe residue was redissolved in CHCl3
17. washwashed 1×pH 4.5 buffer
18. dry with material1×brine and the organics dried (Na2SO4)
19. filtrationfiltered
20. concentrationconcentrated

ORD record

ord-99c35c340bdc427e8ee9147877dbd91f

Source dataset

uspto-grants-2007_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07189851B2