Reaction #87472

Reaction equation

acetic acid 2-bromo-ethyl ester

(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

potassium carbonate

Water

acetic acid 2-bromo-ethyl ester

→

Acetic acid 2-{4-[2-chloro-5-((1S,2S,3S,4R,5S)-2,3,4-trihydroxy-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]oct-5-yl)-benzyl]-phenoxy}-ethyl ester

Yield 22.0%

Solvents

acetonitrile

ethyl acetate

Conditions

Workup

1. 1
   Temperaturethe resulting mixture was heated to 50 degrees Celsius for 72 hours
2. 2
   Temperaturethe mixture was heated at 50 degrees Celsius for an additional 24 hours
3. 3
   Otherthe two phases separated
4. 4
   Extractionthe aqueous phase was extracted 3 times with ethyl acetate (20 mL)
5. 5
   WashThe combined organic layers were washed with brine
6. 6
   Dryingdried over sodium sulfate
7. 7
   Filtrationfiltered
8. 8
   Concentrationconcentrated under reduced pressure
9. 9
   OtherThe crude material was purified by flash chromatography over silica gel using the ISCO automated chromatography unit (4 g silica gel column)
10. 10
    Washeluting with a gradient of 0 to 30% methanol in dichloromethane
11. 11
    workup.ADDITION10 mg (22% yield) of a ˜2:1 mixture of the desired product
12. 12
    Otherwas obtained

Procedure

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).

Source