Hydrochloric Acid → [5-(4-Hydroxy-2-methyl-phenyl)-1H-indol-3-yl]-acetic acid methyl ester

HRID 250235Notes

Reaction equation

HRID 250235 reaction equation
[CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1B1OC(C)(C)C(C)(C)O1.[CH3:18][O:19][C:20](=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28](Br)[CH:29]=2)[NH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C.CN(C=O)C>[CH3:18][O:19][C:20](=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:7]3[CH:6]=[CH:5][C:4]([OH:17])=[CH:3][C:2]=3[CH3:1])[CH:29]=2)[NH:24][CH:23]=1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 49782545methyl 2-(5-bromo-1H-indol-3-yl)acetateHCID 574432723-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol

Product 1

HCID 57443276[5-(4-Hydroxy-2-methyl-phenyl)-1H-indol-3-yl]-acetic acid methyl esterYield 60%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 702EthanolSolventHCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (287 mg, 1.22 mmol), (5-bromo-1H-indol-3-yl)-acetic acid methyl ester (273 mg, 1.02 mmol), tetrakis(triphenylphosphine)palladium(0) (57 mg, 0.046 mmol), DMF (2.7 mL), ethanol (1.34 mL) and 2M aqueous potassium carbonate (1.34 mL) is heated to 100° C. for 16 hours. The reaction is cooled to room temperature and diluted with water and acidified with 1 N HCl. The resulting solution is extracted with ethyl acetate. The combined organic layers are dried over anhydrous magnesium sulfate and concentrated. The residue is dissolved in methanol (6 mL) and trimethylsilyldiazomethane (2.0 M solution in hexanes, approximately 4 mL) is added over approximately two minutes at room temperature. The yellow mixture is concentrated and the residue is purified via radial chromatography eluting with a gradient of 20 to 50% ethyl acetate/heptane and crystallized from CH2Cl2/heptane to give the title compound (180 mg, 60%). ES/MS m/e 296.1 (M+1).

Workup

  1. temperatureThe reaction is cooled to room temperature
  2. extractionThe resulting solution is extracted with ethyl acetate
  3. dry with materialThe combined organic layers are dried over anhydrous magnesium sulfate
  4. concentrationconcentrated
  5. dissolutionThe residue is dissolved in methanol (6 mL)
  6. additiontrimethylsilyldiazomethane (2.0 M solution in hexanes, approximately 4 mL) is added over approximately two minutes at room temperature
  7. concentrationThe yellow mixture is concentrated
  8. customthe residue is purified via radial chromatography
  9. washeluting with a gradient of 20 to 50% ethyl acetate/heptane
  10. customcrystallized from CH2Cl2/heptane

Sources & evidence

ORD record
ord-6c748b5b1e674c0b862ae067754ee53b
Source dataset
uspto-grants-2011_01
Patent number
US07863302B2

Reaction notes

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