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 1 from ethyl 2-(4-hydrazinophenyl)-2-methylpropionate), 4.76 g (39.7 mmol) of anhydrous magnesium sulfate, and a magnetic stirring bar was fitted with a septum and needle adapter leading to a Firestone valve. The flask was thoroughly purged with nitrogen, and the mixture was cooled in an ice-methanol 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 nitrogen 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 nitrogen at -10° to -5° C. as 10 mL of dry methanol 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 ethyl acetate and 90 mL of water. The organic layer was washed with 2×30 mL of brine, then dried over anhydrous sodium sulfate. The filtered solution was concentrated in vacuo, and the residue was flash chromatographed of silica gel (gradient elution with 0-10% methanol in methylene chloride). 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 nitrogen
4. temperaturethe mixture was cooled in an ice-methanol 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 ethyl acetate and 90 mL of water
11. washThe organic layer was washed with 2×30 mL of brine
12. dry with materialdried over anhydrous sodium sulfate
13. concentrationThe filtered solution was concentrated in vacuo
14. customchromatographed of silica gel (gradient elution with 0-10% methanol in methylene chloride)
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