Piperidine → 4-[(9As)-2-(4-fluorobenzyl)-5-oxo-7,8,9,9a-tetrahydro-5h-pyrido[2,3-a]pyrrolizin-4-yl]benzoic acid

A benzene (10 mL) solution of tert-Butyl (2S)-2-(3-ethoxy-3-oxopropanoyl)-1-pyrrolidinecarboxylate (1.93 g, 6.77 mmol), 4-carboxybenzaldehyde (1.01 g, 6.77 mmol) and piperidine (0.335 mL, 3.39 mmol) was refluxed with azeotropic removal of H2O for 1.5 h and then cooled to ambient temperature and concentrated. The residue was redissolved in EtOAc and washed with 1×1 N HC1, 2× H2O, 1× brine and the organics dried (Na2SO4), filtered and concentrated to an amorphous brown solid. The Knoevenagel product (2.83 g, 6.77 mmol) and allyl (2Z)-3-amino-4-(4-fluorophenyl)-2-butenoate (1.59 g, 6.77 mmol) were heated to 110° C. for 1.5 h and then cooled to ambient temperature. The dihydropyridine product (2.35 g, 3.71 mmol) was redissolved in CH3CN (10 mL) and to this was added morpholine (0.648 mL, 3.71 mmol) and Pd(PPh3)4 (0.215 g, 0.186 mmol). The reaction mixture was stirred at ambient temperature for 1.5 h and then filtered through Celite and concentrated. The residue was redissolved in toluene and heated to reflux for 6 h. The reaction was concentrated and redissolved in CH3CN (10 mL) and H2O (10 mL) followed by addition of ceric ammonium nitrate (4.06 g, 7.40 mmol). The reaction mixture stirred for 15 min at ambient temperature and then EtOAc 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 was subjected to TFA (4.5 mL in 1 mL CH2Cl2) for 1 h and then concentrated. The residue was redissolved in CH2Cl2 (5 mL) and treated with Et3N (3 mL). After 16 h the reaction mixture was concentrated to a brown foam. The residue was redissolved in EtOAc and washed 1× pH 4.5 buffer, 1×brine and the organics dried (Na2SO4), filtered and concentrated to yield 0.800 g (54% yield) of the title compound as a tan solid. 1H NMR (CDCl3, 400 MHz) δ 8.10 (d, J=8.0 Hz, 2H), 7.63 (d, J=8.3 Hz), 7.25 (t, J=7.3 Hz, 2H), 7.12 (s, 1H), 6.99 (t, J=8.6 Hz, 2H), 4.78–4.74 (m, 1H), 4.25 (s, 2H), 3.78–3.71 (m, 1H), 3.44–3.38 (m, 1H), 2.52–2.47 (m, 1H), 2.37–2.31 (m, 2H), 1.44–1.39 (m, 1H); ESMS m/z 403 (M+H)+, 401 (M−H)+.

1. concentrationconcentrated
2. dissolutionThe residue was redissolved in EtOAc
3. washwashed with 1×1 N HC1, 2× H2O, 1× brine
4. dry with materialthe organics dried (Na2SO4)
5. filtrationfiltered
6. concentrationconcentrated to an amorphous brown solid
7. temperaturecooled to ambient temperature
8. filtrationfiltered through Celite
9. concentrationconcentrated
10. dissolutionThe residue was redissolved in toluene
11. temperatureheated
12. temperatureto reflux for 6 h
13. concentrationThe reaction was concentrated
14. dissolutionredissolved in CH3CN (10 mL)
15. stirringThe reaction mixture stirred for 15 min at ambient temperature
16. extractionthe organics extracted
17. washwashed 1× H2O, 1× brine
18. dry with materialdried (Na2SO4)
19. filtrationfiltered
20. concentrationconcentrated to a dark tan solid
21. waitThe solid was subjected to TFA (4.5 mL in 1 mL CH2Cl2) for 1 h
22. concentrationconcentrated
23. dissolutionThe residue was redissolved in CH2Cl2 (5 mL)
24. additiontreated with Et3N (3 mL)
25. concentrationAfter 16 h the reaction mixture was concentrated to a brown foam
26. dissolutionThe residue was redissolved in EtOAc
27. washwashed 1× pH 4.5 buffer
28. dry with material1×brine and the organics dried (Na2SO4)
29. filtrationfiltered
30. concentrationconcentrated

ORD-Eintrag

ord-30f53ca9c1e74185be8485623ec08465

Quelldatensatz

uspto-grants-2007_03

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US07189851B2