反应详情

A dry flask containing 3.00 g (7.93 mmol) of 2-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid ethyl ester (prepared essentially as described in Example 7.1 Step A), 4.76 g (39.7 mmol) of anhydrous MgSO4, and a magnetic stirring bar was fitted with a septum and needle adapter leading to a Firestone valve. The flask was thoroughly purged with N2, and the mixture was cooled in an ice-MeOH bath at -10° to -5° C. and stirred vigorously as a solution of 1.32 g (8.88 mmol) of 4-(pyridin-3-yl)butyraldehyde in 15 ml of dry CDCl3 was added gradually by syringe over 10-15 minutes. The resulting mixture was stirred under N2 at -10° to -5° C. for 40-45 minutes. Then the septum was removed just long enough to add 390 mg (10.3 mmol) of sodium borohydride. The mixture was stirred under N2 at -10° to -5° C. as 10 ml of dry MeOH was added dropwise by syringe over several minutes. After 30 minutes, the mixture was removed from the cooling bath and partitioned between 90 ml of EtOAc and 90 ml of H2 O. The organic layer was washed with 2×30 ml of brine, then dried over anhydrous Na2SO4. The filtered solution was concentrated in vacuo, and the residue was flash chromatographed of silica gel (gradient elution with 0-10% MeOH in CH2Cl2). Fractions containing product and a small amount of unreacted starting material were combined and concentrated to give 3.00 g of light beige, stiff foam, used directly in the next step without further purification or characterization.

1. customprepared essentially
2. customwas fitted with a septum and needle adapter
3. customThe flask was thoroughly purged with N2
4. temperaturethe mixture was cooled in an ice-MeOH bath at -10° to -5° C.
5. additionwas added gradually by syringe over 10-15 minutes
6. customThen the septum was removed just long enough
7. additionwas added dropwise by syringe over several minutes
8. waitAfter 30 minutes
9. customthe mixture was removed from the cooling bath
10. custompartitioned between 90 ml of EtOAc and 90 ml of H2 O
11. washThe organic layer was washed with 2×30 ml of brine
12. dry with materialdried over anhydrous Na2SO4
13. concentrationThe filtered solution was concentrated in vacuo
14. customchromatographed of silica gel (gradient elution with 0-10% MeOH in CH2Cl2)
15. additionFractions containing product
16. concentrationconcentrated
17. customto give 3.00 g of light beige
18. customstiff foam, used directly in the next step without further purification or characterization