反应详情

Add Ti(iPrO)4 (1.70 g, 6.00 mmol) to a suspension of 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 805 mg, 3.00 mmol), 2-(3-methylphenyl)ethylamine (446 mg, 3.30 mmol) and THF (20 ml) and stir for six hours under a nitrogen atmosphere at ambient temperature. After cooling in an ice/water bath, treat the reaction mixture with a solution of TiCl4 (1.0M/DCM, 6.00 ml, 6.00 mmol) and stir at 0-5° C. for two hours before adding NaBH3CN (377 mg, 6.00 mmol) dissolved in MeOH (5 ml). Allow the reaction mixture to warm to ambient temperature as the cold bath warms and stir overnight. Quench the reaction with 2N aq. NaOH, making the suspension basic. Stir the suspension for one hour and filter through a filter aid to remove solids, washing them with EtOAc. Separate layers in the filtrate/wash and wash the organic layer with brine before drying (MgSO4) and concentrating. Purify on silica gel (5% (1N NH3/MeOH)/45% EtOAc/DCM) to obtain 849 mg of the title compound as a light yellow solid. Mass spectrum (ion spray): m/z=388 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.15 (d, 1H), 7.30 (d, 1H), 7.19 (t, 1H), 7.05-7.01 (m, 3H), 6.98 (s, 1H), 6.93 (d, 2H), 5.96 (br. s, 2H), 4.26 (t, 1H), 3.02-2.94 (m, 3H), 2.86-2.76 (m, 3H), 2.44 (m, 1H), 2.33 (s, 3H), 1.84 (m, 1H).

1. temperatureAfter cooling in an ice/water bath
2. stirringstir at 0-5° C. for two hours
3. temperatureto warm to ambient temperature as the cold bath warms
4. stirringstir overnight
5. customQuench
6. customthe reaction with 2N aq. NaOH
7. stirringStir the suspension for one hour
8. filtrationfilter through a filter aid
9. customto remove solids
10. washwashing them with EtOAc
11. washSeparate layers in the filtrate/wash
12. washwash the organic layer with brine
13. dry with materialbefore drying (MgSO4)
14. concentrationconcentrating
15. customPurify on silica gel (5% (1N NH3/MeOH)/45% EtOAc/DCM)