2,3-Dichloro-5,6-dicyano-1,4-benzoquinone → Ethyl (9as)-4-(4-{[(2-furylmethyl)amino]sulfonyl}phenyl)-5-oxo-2-{2-[4-(trifluoromethyl)phenyl]ethyl}-7,8,9,9a-tetrahydro-5h-pyrido[2,3-a]pyrrolizine-3-carboxylate

Temperature

80 °C

Polymer-bound tert-butyl (3-oxopropanoyl)-1-pyrrolidinecarboxylate (0.70 g, 0.31 meq/g, 0.44 mmol) was suspended in 5 mL anhydrous DMF and 4-formyl-N-(2-furylmethyl)benzenesulfonamide (0.82 g, 3.1 mmol) was added followed by piperidine (0.06 mL), and trimethyl orthoformate (0.2 mL) and AcOH (0.04 mL). After 14 h at 65° C., the resin was filtered and washed as above and resuspended in 5 mL fresh DMF. Ethyl (2Z)-3-amino-5-[4-(trifluoromethyl)phenyl]-2-pentenoate (0.89 g, 3.1 mmol) was added followed by trimethyl orthoformate (0.2 mL) and the sealed reaction mixture was heated at 80° C. for 16 h. The resin was filtered and washed as before. The resin was suspended in DCM (8 mL) and DDQ (0.17 g, 0.77 mmol) was added. The brown suspension was shaken at room temperature for 30 min then filtered and washed as before. The resin was dried overnight at 30° C. under high vacuum. The resin was suspended in 1 mL TFA:DCM:phenol:thioanisole (70:20:5:5) and shaken for 0.5 h, filtered and washed. The resin was shaken in 2 mL 5% TEA in DCM for 24 h. The resin was filtered into a collection flask and rinsed with additional DCM (3×). The filtrate was concentrated and the product was purified by preparative column chromatography (SiO2, hexanes:EtOAc 2:3) then triturated in ether to provide the title compound as white solid (21 mg, 0.032 mmol, 100%): mp=181–182° C. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.30 (m, 1H), 6.24 (m, 1H), 6.16 (m, 1H), 4.84 (t, J=6.0 Hz, 1H), 4.74 (dd, J=10.2, 6.4 Hz, 1H), 4.24 (d, J=6.0 Hz, 2H), 4.01 (q, J=7.0 Hz, 2H), 3.71 (m, 1H), 3.40 (m, 1H), 3.3–3.1 (m, 4H), 2.49 (m, 1H), 2.37 (m, 2H), 1.5–1.3 (m, 1H), 0.92 (t, J=7.0 Hz, 3H) ppm. ESMS m/z 654 (M+H)+. Anal. calcd. For C33H30F3N3O6S: C, 60.64; H, 4.63; N, 6.43; S, 4.91; found: C, 60.41; H, 4.63; N, 6.43; S, 4.99.

1. filtrationthe resin was filtered
2. washwashed as above and
3. customthe sealed reaction mixture
4. filtrationThe resin was filtered
5. washwashed as before
6. filtrationthen filtered
7. washwashed as before
8. customThe resin was dried overnight at 30° C. under high vacuum
9. stirringshaken for 0.5 h
10. filtrationfiltered
11. washwashed
12. stirringThe resin was shaken in 2 mL 5% TEA in DCM for 24 h
13. filtrationThe resin was filtered into a collection flask
14. washrinsed with additional DCM (3×)
15. concentrationThe filtrate was concentrated
16. customthe product was purified by preparative column chromatography (SiO2, hexanes:EtOAc 2:3)
17. customthen triturated in ether

ORD record

ord-51e0d7ad63764be1941645138bc5063c

Source dataset

uspto-grants-2007_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07189851B2