Acetic acid, azido-, ethyl ester → methyl 6-fluoro-4-methoxy-1H-indole-2-carboxylate

HRID 624377Notes

Reaction equation

HRID 624377 reaction equation
C[O-].[Na+].[N:4]([CH2:7][C:8]([O:10][CH2:11]C)=[O:9])=[N+]=[N-].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[C:16]([O:22][CH3:23])[CH:15]=1>CO>[CH3:11][O:10][C:8]([C:7]1[NH:4][C:20]2[C:17]([CH:18]=1)=[C:16]([O:22][CH3:23])[CH:15]=[C:14]([F:13])[CH:21]=2)=[O:9]

Participants

5

Reactant 3

HCID 69480Acetic acid, azido-, ethyl esterHCID 27745374-Fluoro-2-methoxybenzaldehydeHCID 10942334Sodium Methoxide2×

Product 1

HCID 67227532methyl 6-fluoro-4-methoxy-1H-indole-2-carboxylate

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
-20 °C

Procedure

Sodium methoxide solution (25% by weight in methanol, 22.25 mL) and methanol (52 mL) were added to a flask and cooled to −20° C. using an acetonitrile/dry ice bath. Ethyl 2-azidoacetate (25% by weight in ethanol, 50.3 g) and 4-fluoro-2-methoxybenzaldehyde (5.00 g, dissolved in ethyl 2-azidoacetate solution) were added drop-wise to the stirring sodium methoxide solution at −20° C. The solution was then stirred at −20° C. for 3.5 hours, then at 0° C. for one hour. The solution was poured over ice, vacuum filtered, and washed with water. The filtered solid was taken up in xylenes (100 mL), washed twice with brine, and dried using anhydrous sodium sulfate and filtered. In a separate flask xylenes (50 mL) was brought to reflux. The xylene solution containing the filtered material was added drop-wise to the refluxing xylenes. The solution was then refluxed for five hours, cooled, and placed in a freezer for 16 hours. The precipitate was filtered out. The volume of the filtrate was reduced on vacuum to generate a second crop of precipitate, which was washed with hexanes, then 5% ethyl acetate in hexanes and combined with material from the first filtration.

Workup

  1. waitat 0° C. for one hour
  2. additionThe solution was poured over ice, vacuum
  3. filtrationfiltered
  4. washwashed with water
  5. washwashed twice with brine
  6. customdried
  7. filtrationfiltered
  8. customIn a separate flask xylenes (50 mL) was brought
  9. temperatureto reflux
  10. additionThe xylene solution containing the filtered material
  11. additionwas added drop-wise to the refluxing xylenes
  12. temperatureThe solution was then refluxed for five hours
  13. temperaturecooled
  14. waitplaced in a freezer for 16 hours
  15. filtrationThe precipitate was filtered out
  16. washwas washed with hexanes
  17. filtration5% ethyl acetate in hexanes and combined with material from the first filtration

Sources & evidence

ORD record
ord-0918effe03294e48bfc3671e8c1a47be
Source dataset
uspto-grants-2016_04
Patent number
US09303025B2

Reaction notes

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