反应详情

A 1.899 g (3.99 mmol) sample of 75 in CH2Cl2 (20 ml) was treated with anhydrous TFA (5 ml) then stirred at room temperature under N2 for 1 hour and evaporated to dryness. The residue was repeatedly concentrated from CH2Cl2 (3×) then dried under vacuum. The resulting residue was dissolved in CH2Cl2 (20 ml), cooled to 0° C., then treated with DIEA (5.6 ml, 8 eq, 32.1 mmol), 4-amino-3-chloro-benzoic acid (0.910 g, 5.3 mmol), HOBT (0.824 g, 6.1 mmol), and EDC (1.197 g, 6.23 mmol). The resulting mixture was warmed to room temperature and stirred for 18 hours. The solvent was removed in vacuo and the residue dissolved in EtOAc then washed with distilled water (3×), 0.5N NaHSO4 (2×), saturated NaHCO3 (2×) and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a residue that was purified by flash chromatography using CH2Cl2/MeOH (99/1 to 97/3%). The title compound was obtained as a white solid (1.221 g, 58% yield). 1H-NMR (500 MHz, CD3OD) δ 1.15 (d, 0.25H), 1.29-1.60 (m, 2.75H), 2.41-2.54 (m, 0.5H), 2.55-2.70 (m, 0.5H), 2.77 (dd, 0.5H), 3.03 (ddd, 0.5H), 3.59-3.75 (m, 1H), 3.75-3.98 (m, 1H), 4.26-5.01 (m, 5H), 5.41-5.57 (m, 1H), 5.60-5.76 (m, 0.5H), 6.70-6.92 (m, 0.5H), 7.15-7.48 (m, 5H), 7.48-7.68 (m, 1H), 7.68-7.88 (m, 1H), 8.15-8.34 (m, 1H). Analytical HPLC (cyano column) (mixture of 2 diastereomers) 14.44, 14.89 min. LC-MS (ES+) m/e=529.3 (M+H).

1. customevaporated to dryness
2. concentrationThe residue was repeatedly concentrated from CH2Cl2 (3×)
3. customthen dried under vacuum
4. dissolutionThe resulting residue was dissolved in CH2Cl2 (20 ml)
5. temperaturecooled to 0° C.
6. temperatureThe resulting mixture was warmed to room temperature
7. stirringstirred for 18 hours
8. customThe solvent was removed in vacuo
9. dissolutionthe residue dissolved in EtOAc
10. washthen washed with distilled water (3×), 0.5N NaHSO4 (2×), saturated NaHCO3 (2×) and brine
11. dry with materialThe organic layer was dried over Na2SO4
12. filtrationfiltered
13. customevaporated
14. customto give a residue that
15. customwas purified by flash chromatography