4-Methylmorpholine → propyl [2-(4-diazo-3-oxobutyl)-1H-indol-3-yl]acetate

HRID 476225Notes

Reaction equation

HRID 476225 reaction equation
CN1CCOCC1.[O:8]=[C:9]([O:25][CH2:26][CH2:27][CH3:28])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]=1[CH2:20][CH2:21][C:22]([OH:24])=O.ClC(OCC)=O.[N+:35](=[CH2:37])=[N-:36]>C1COCC1>[N+:35](=[CH:37][C:22](=[O:24])[CH2:21][CH2:20][C:12]1[NH:13][C:14]2[C:19]([C:11]=1[CH2:10][C:9]([O:25][CH2:26][CH2:27][CH3:28])=[O:8])=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N-:36]

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 9550DiazomethaneHCID 10928Ethyl chloroformateHCID 673099093-[3-(2-oxo-2-propoxyethyl)-1H-indol-2-yl]propanoic acid

Product 1

HCID 86655415propyl [2-(4-diazo-3-oxobutyl)-1H-indol-3-yl]acetateYield 63%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

N-methylmorpholine (1.1 equiv.) was added dropwise over 1 h to a stirred, 0° C. mixture of 3-[3-(2-oxo-2-propoxyethyl)-1H-indol-2-yl]propanoic acid from Step 3 and ethyl chloroformate (1.11 equiv.) in THF (0.4 M). The reaction temperature was closely monitored during the addition and was not allowed to go over +2° C. The mixture was stirred at 0° C. an additional 30 min. A white precipitate formed rapidly. Diazomethane (0.3 M in Et2O, 1.8 equiv.) was added and the final mixture was stirred for 2 h at 0° C. The mixture was filtered and the supernatant was concentrated under vacuum (with AcOH put in the vacuum trap to quench excess diazomethane). The residue was purified by column chromatography on silica gel using automatized gradiant pump system CombiFlashRF (Teledyne ISCO) eluting with EtOAc/Hexane(10:90 to 60:40) to give the title compound (63%) as a yellow solid.

Workup

  1. additionThe reaction temperature was closely monitored during the addition
  2. customto go over +2° C
  3. customA white precipitate formed rapidly
  4. filtrationThe mixture was filtered
  5. concentrationthe supernatant was concentrated under vacuum (with AcOH
  6. customto quench excess diazomethane)
  7. customThe residue was purified by column chromatography on silica gel using automatized gradiant pump system CombiFlashRF (Teledyne ISCO)
  8. washeluting with EtOAc/Hexane(10:90 to 60:40)

Sources & evidence

ORD record
ord-e6a4458f48774111a65931c8c3a8e020
Source dataset
uspto-grants-2014_01
Patent number
US08637671B2

Reaction notes

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