2,3-Dichloro-5,6-dicyano-1,4-benzoquinone → Ethyl (9aS)-2-[2-(4-methoxyphenyl)ethyl]-5-oxo-4-(4-{[(2-pyridinylmethyl)amino]carbonyl}phenyl)-5,7,8,9,9a,10-hexahydropyrrolo[1,2-g][1,6]naphthyridine-3-carboxylate

Temperature

80 °C

Polymer-bound tert-butyl (3-oxopropanoyl)-1-pyrrolidinecarboxylate (1.0 g, 0.44 meq/g, 0.44 mmol) was suspended in 10 mL anhydrous DMF and 4-formylbenzoic acid (1.5 g, 9.8 mmol) was added followed by piperidine (0.1 mL), and trimethyl orthoformate (0.32 mL). After 5 h at 65° C., the resin was filtered and washed as above and resuspended in 6 mL fresh DMF. Ethyl (2Z)-3-amino-5-(4-methoxyphenyl)-2-pentenoate (1.2 g, 4.9 mmol) was added followed by trimethyl orthoformate (0.32 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 (10 mL) and DDQ (0.2 g, 0.98 mmol) was added. The brown suspension was shaken at room temperature for 10 min then filtered and washed as before. The resin was dried overnight at 30° C. under high vacuum. The resin was suspended in 5 mL DMF and 2 mL pyridine. Pentafluorophenyl trifluoracetate (1.4 g, 4.8 mmol, 0.84 mL) was added and the sealed reaction tube was shaken at room temperature for 45 min, filtered and washed as above and dried under high vacuum overnight. To 40 mg of (0.014 mmol, 0.35 meq/g) suspended in DCM (1 mL) was added DMAP (10 mg) and 2-aminomethylpyridine (0.015 mg, 0.14 mmol, 0.014 mL) and the reaction mixture was shaken at room temperature for 4 h. The resin was filtered and washed as before. The resin was suspended in 1 mL TFA:DCM:phenol:thioanisole (70:20:5:5) and shaken for 3 h, filtered and washed. The resin was shaken in 2 mL 5% TEA in DCM for 36 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 thin-layer chromatography (SiO2, 10% MeOH in EtOAc) to give the title compound as white solid (6.3 mg, 0.010 mmol, 74%): mp=>200° C. 1H NMR (300 MHz, CDCl3) δ 8.58 (d, J=4.5 Hz, 1H), 7.88 (m, 2H), 7.70 (m, 1H), 7.60 (m, 1H), 7.42 (d, J=7.4 Hz, 1H), 7.35 (d, J=8.1 Hz, 1H), 7.2 (m, 1H), 7.15 (d, J=8.4 Hz, 2H), 6.83 (d, J=8.4 Hz, 2H), 4.77 (d, J=4.7 Hz, 2H), 4.0–3.8 (m, 1H), 3.92 (q, J=7.4 Hz, 2H), 3.79 (s, 3H), 3.7–3.4 (m, 1H), 3.55 (dd, J=7.0, 24 Hz, 1H), 3.1–2.9 (m, 4H), 2.38 (m, 1H), 2.05 (m, 1H), 1.9–1.0 (m, 5H), 0.91 (t, J=7.1 Hz, 3H) ppm. ESMS m/z 605 (MH)+.

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. customthe sealed reaction tube
10. stirringwas shaken at room temperature for 45 min
11. filtrationfiltered
12. washwashed as above and
13. customdried under high vacuum overnight
14. stirringthe reaction mixture was shaken at room temperature for 4 h
15. filtrationThe resin was filtered
16. washwashed as before
17. stirringshaken for 3 h
18. filtrationfiltered
19. washwashed
20. stirringThe resin was shaken in 2 mL 5% TEA in DCM for 36 h
21. filtrationThe resin was filtered into a collection flask
22. washrinsed with additional DCM (3×)
23. concentrationThe filtrate was concentrated
24. customthe product was purified by preparative thin-layer chromatography (SiO2, 10% MeOH in EtOAc)

ORD record

ord-a5692405df33456bba8cb0f6d1af1af3

Source dataset

uspto-grants-2007_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07189851B2