Potassium Carbonate → 1-methyl-3-(1-methylethyl)-5-(6-methyl-3-pyridinyl)-1H-indole-7-carboxylic acid

HRID 1616806Notes

Reaction equation

HRID 1616806 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[N:7]([CH3:14])[CH:6]=[C:5]2[CH:15]([CH3:17])[CH3:16].[CH3:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:14][N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:22]3[CH:23]=[N:24][C:19]([CH3:18])=[CH:20][CH:21]=3)=[CH:10][C:9]=2[C:11]([OH:13])=[O:12])[C:5]([CH:15]([CH3:17])[CH3:16])=[CH:6]1

Participants

8

Reactant 3

HCID 11430Potassium CarbonateHCID 27630812-Methylpyridine-5-boronic acidHCID 678162465-bromo-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxylic acid

Product 1

HCID 678173771-methyl-3-(1-methylethyl)-5-(6-methyl-3-pyridinyl)-1H-indole-7-carboxylic acidYield 66.7%

Reagents, catalysts & solvents 4

HCID 178418807HCID 178418807, compoundCatalystHCID 962WaterSolvent2×HCID 80711,2-DimethoxyethaneSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
100 °C

Procedure

To a 40 mL vial was added 5-bromo-1-methyl-3-(1-methylethyl)-1H-indole-7-carboxylic acid (0.850 g, 2.87 mmol), (6-methyl-3-pyridinyl)boronic acid (0.432 g, 3.16 mmol), K2CO3 (1.190 g, 8.61 mmol) and PdCl2(dppf)-CH2Cl2 adduct (0.234 g, 0.287 mmol). The reagents were diluted with 1,2-dimethoxyethane (21.5 mL) and water (7.2 mL). The reaction was heated to 100° C. with stirring for 30 minutes, then filtered and concentrated under vacuum to give a thick brown residue. The residue was diluted with saturated NaHCO3 (15 mL) and water (10 mL) and aqueous solution washed with EtOAc (3×40 mL). The aqueous solution was then slowly added to a rapidly stirred, cooled (0° C.) solution of 1 N HCl. The mixture was stirred for 20 min and the solids collected by vacuum filtration. LCMS showed the solids contained only a small amount of desired product. The solids were discarded. The acidic aqueous solution was extracted with EtOAc (3×250 mL). LCMS showed the desired product in both layers. Thus, both the organic and aqueous layers were concentrated. The residue was purified by reverse phase HPLC (Gemini 50×100 mm column, acetonitrile and 0.1% formic acid/water) to give 1-methyl-3-(1-methylethyl)-5-(6-methyl-3-pyridinyl)-1H-indole-7-carboxylic acid (590 mg, 66.6% yield) as light tan solid. MS (ES) [M+H]+ 309.5.

Workup

  1. filtrationfiltered
  2. concentrationconcentrated under vacuum
  3. customto give a thick brown residue
  4. washwashed with EtOAc (3×40 mL)
  5. additionThe aqueous solution was then slowly added to
  6. stirringa rapidly stirred
  7. temperaturecooled (0° C.) solution of 1 N HCl
  8. stirringThe mixture was stirred for 20 min
  9. filtrationthe solids collected by vacuum filtration
  10. extractionThe acidic aqueous solution was extracted with EtOAc (3×250 mL)
  11. concentrationThus, both the organic and aqueous layers were concentrated
  12. customThe residue was purified by reverse phase HPLC (Gemini 50×100 mm column, acetonitrile and 0.1% formic acid/water)

Sources & evidence

ORD record
ord-d2a3f0b232be42da9bde056f0278fc67
Source dataset
uspto-grants-2014_07
Patent number
US08765792B2

Reaction notes

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