反应详情

温度

80 °C

Polymer-bound tert-butyl (3-oxopropanoyl)-1-pyrrolidinecarboxylate (2.5 g, 1.1 mmol, 0.44 meq/g) was suspended in 25 mL anhydrous DMF and 4-nitrobenzoic acid (1.7 g, 11 mmol) was added followed by piperidine (0.22 mL), and trimethyl orthoformiate (0.72 mL). After 18 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-(trifluoromethyl)phenyl]-2-pentenoate (3.2 g, 11 mmol) was added followed by trimethyl orthoformate (0.72 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 (0.62 g, 2.75 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 DMF (20 mL) and 10 mL of a 2.0 M aqueous solution of SnCl22H2O was added and the mixture was shaken at room temperature for 16 h. The resin was filtered and washed with water (5×) then organic solvents as before then taken up in 70% TFA in DCM and shaken for 16 h. Filtration and washing was followed by treatment of the resin with 5% TEA in DCM (25 mL) for 72 h. Filtration, rinsing the resin with DCM provided the aniline as a reddish oil (0.227 g, 0.44 mmol, 100%): ESMS m/z 510 (M+H)+. Treatment of 0.071 g (0.139 mmol) of aniline in 1 mL CHCl3 with phenylisocyanate (0.020 g, 0.167 mmol) for 0.75 h, concentration and purification by thin-layer chromatography (SiO2, 2000 μm; EtOAc:MeOH 3:1) provided the title compound (35 mg) which was recrystallized from EtOAc/i-Pr2O and dried at 45° C. under high vac. to provide a white solid (24 mg, 0.038 mmol, 27% for final step): mp=137–139° C. 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J=8.1 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.4–7.1 (m, 8H), 7.00 (m, 1H), 4.82 (m, 1H), 4.00 (m, 2H), 3.75 (m, 1H), 3.46 (m, 1H), 3.22 (m, 2H), 3.2–3.1 (m, 2H), 2.59 (m, 1H), 2.40 (m, 2H), 1.8–1.4 (bs, NH, H2O); 1.4 (m, 1H), 0.92 (t, J=7.0 Hz, 3H) ppm. ESMS m/z 629 (M+H)+. Anal. calcd. for 35H31F3N4O4.½H2O: C, 65.93; H, 5.06; N, 8.79, found: C, 65.90; H, 5.04; N, 8.69.

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. addition10 mL of a 2.0 M aqueous solution of SnCl22H2O was added
10. stirringthe mixture was shaken at room temperature for 16 h
11. filtrationThe resin was filtered
12. washwashed with water (5×)
13. stirringshaken for 16 h
14. filtrationFiltration
15. washwashing
16. waitwas followed by treatment of the resin with 5% TEA in DCM (25 mL) for 72 h
17. filtrationFiltration
18. washrinsing the resin with DCM