Lithium Hydroxide → 4-(6-(4-butylphenyl)-7-fluoro-1H-indol-2-yl)benzoic acid

HRID 1160786Notes

Reaction equation

HRID 1160786 reaction equation
C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[C:14](Cl)[C:13]=3[F:20])=[CH:6][CH:5]=1.[CH2:22]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)[CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].[Li+].[OH-]>O1CCOCC1.[Pd].C(OCC)(=O)C>[CH2:22]([C:26]1[CH:31]=[CH:30][C:29]([C:14]2[C:13]([F:20])=[C:12]3[C:17]([CH:18]=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:21])=[CH:5][CH:6]=4)[NH:11]3)=[CH:16][CH:15]=2)=[CH:28][CH:27]=1)[CH2:23][CH2:24][CH3:25]

Participants

8

Reactant 4

HCID 3939Lithium HydroxideHCID 10796Cesium carbonateHCID 41008604-Butylphenylboronic acidHCID 595180194-(6-chloro-7-fluoro-1H-indol-2-yl)-benzoic acid methyl ester

Product 1

HCID 159515144-(6-(4-butylphenyl)-7-fluoro-1H-indol-2-yl)benzoic acid

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 8857Ethyl AcetateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

Steps 2 and 3: To a mixture of 4-(6-chloro-7-fluoro-1H-indol-2-yl)-benzoic acid methyl ester (37 mg, 0.122 mmol) from the previous step, 4-n-butylphenyl-boronic acid (43 mg, 0.244 mmol), and cesium carbonate (159 mg, 0.487 mmol) in dioxane (4 mL), is added CombiPhos-Pd6 palladium catalyst (Combiphos Catalysts Inc., 3 mg). The mixture is purged with N2 for 5 minutes and heated at 120° C. for 7 hours in a sealed tube. After cooling to room temperature, the reaction is diluted with ethyl acetate and sequentially washed with 1 N HCl, H2O, and saturated aqueous NaCl. The organics are then dried over Na2SO4, filtered, and concentrated. The resulting residue is treated with ethanol/H2O (2 mL/1 mL) followed by LiOH (26 mg, 0.609 mmol). This mixture is heated at 50° C. for 1 hour. After cooling to room temperature, the reaction is diluted with ethyl acetate and washed with 1 N aqueous HCl. The organic layer is dried over Na2SO4 and filtered. After concentration, the crude product is purified by preparative RP LC-MS to give 4-[6-(4-Butyl-phenyl)-7-fluoro-1H-indol-2-yl]-benzoic acid as a white solid: 1H NMR (400 MHz, Acetone-d6) δ 11.13 (bs, 1H), 8.10-8.05 (m, 4H), 7.59 (d, 2H), 7.52 (d, 1H), 7.32 (d, 2H), 7.18-7.12 (m, 2H), 2.71 (t, 2H), 1.70-1.63 (m, 2H), 1.49-1.40 (m, 2H), 0.98 (t, 3H); ESMS m/z 388.2 (M+H+).

Workup

  1. customThe mixture is purged with N2 for 5 minutes
  2. temperatureAfter cooling to room temperature
  3. additionthe reaction is diluted with ethyl acetate
  4. washsequentially washed with 1 N HCl, H2O, and saturated aqueous NaCl
  5. dry with materialThe organics are then dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. additionThe resulting residue is treated with ethanol/H2O (2 mL/1 mL)
  9. temperatureThis mixture is heated at 50° C. for 1 hour
  10. temperatureAfter cooling to room temperature
  11. washwashed with 1 N aqueous HCl
  12. dry with materialThe organic layer is dried over Na2SO4
  13. filtrationfiltered
  14. concentrationAfter concentration
  15. customthe crude product is purified by preparative RP LC-MS

Sources & evidence

ORD record
ord-6ea85e8c9048409cb9989e4cf6bc3df1
Source dataset
uspto-grants-2010_10
Patent number
US07816542B2

Reaction notes

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