反应详情

To a solution of (1S,2S,3S,4R,5S)-5-[4-chloro-3-(4-hydroxy-benzyl)-phenyl]-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol (38 mg, 0.093 mmol) in acetonitrile (0.9 mL) was added potassium carbonate (40 mg, 0.28 mmol) followed by the addition of acetic acid 2-bromo-ethyl ester (0.012 mL, 0.112 mmol) and the resulting mixture was heated to 50 degrees Celsius for 72 hours. The reaction showed some product formation but the majority of starting material remained. An additional 2 equivalents of acetic acid 2-bromo-ethyl ester was added and the mixture was heated at 50 degrees Celsius for an additional 24 hours. Water (20 mL) and ethyl acetate were added, the two phases separated and the aqueous phase was extracted 3 times with ethyl acetate (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash chromatography over silica gel using the ISCO automated chromatography unit (4 g silica gel column) and eluting with a gradient of 0 to 30% methanol in dichloromethane. 10 mg (22% yield) of a ˜2:1 mixture of the desired product contaminated with some unidentified compound was obtained. LCMS 539 M+HCOO−, negative mode). The compound was purified by HPLC on a Phenomenex Lux Cellulose-2 5u column eluting with a flow rate of 28 mL/min. and a mobile phases A: heptane and B: ethanol. The product was eluted using a gradient of 5% ethanol for 2 minutes and increased to 100% ethanol at time 10.0 minutes to give 1.1 mg of the desired product.

1. temperaturethe resulting mixture was heated to 50 degrees Celsius for 72 hours
2. temperaturethe mixture was heated at 50 degrees Celsius for an additional 24 hours
3. customthe two phases separated
4. extractionthe aqueous phase was extracted 3 times with ethyl acetate (20 mL)
5. washThe combined organic layers were washed with brine
6. dry with materialdried over sodium sulfate
7. filtrationfiltered
8. concentrationconcentrated under reduced pressure
9. customThe crude material was purified by flash chromatography over silica gel using the ISCO automated chromatography unit (4 g silica gel column)
10. washeluting with a gradient of 0 to 30% methanol in dichloromethane
11. addition10 mg (22% yield) of a ˜2:1 mixture of the desired product
12. customwas obtained
13. customThe compound was purified by HPLC on a Phenomenex Lux Cellulose-2 5u column
14. washeluting with a flow rate of 28 mL/min.
15. washThe product was eluted
16. customfor 2 minutes
17. temperatureincreased to 100% ethanol at time 10.0 minutes