Lithium Hydroxide → 4-(6-(4-butylphenyl)-3-ethyl-7-fluoro-1H-indol-2-yl)-2-hydroxybenzoic acid

HRID 1160796Notes

Reaction equation

HRID 1160796 reaction equation
C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH2:19][CH3:20])=[CH:16][CH:15]=[C:14](Cl)[C:13]=3[F:22])=[CH:6][C:5]=1[OH:23].[CH2:25]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)[CH2:26][CH2:27][CH3:28].[F-].[Cs+].[Li+].[OH-]>O1CCOCC1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Pd]>[CH2:25]([C:29]1[CH:34]=[CH:33][C:32]([C:14]2[C:13]([F:22])=[C:12]3[C:17]([C:18]([CH2:19][CH3:20])=[C:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:24])=[C:5]([OH:23])[CH:6]=4)[NH:11]3)=[CH:16][CH:15]=2)=[CH:31][CH:30]=1)[CH2:26][CH2:27][CH3:28]

Participants

7

Reactant 4

HCID 3939Lithium HydroxideHCID 25953Cesium fluorideHCID 41008604-Butylphenylboronic acidHCID 595180204-(6-chloro-3-ethyl-7-fluoro-1H-indol-2-yl)-2-hydroxy-benzoic acid methyl ester

Product 1

HCID 160621674-(6-(4-butylphenyl)-3-ethyl-7-fluoro-1H-indol-2-yl)-2-hydroxybenzoic acid

Reagents, catalysts & solvents 2

HCID 2734558Bis(tri-tert-butylphosphine)palladium(0)CatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

Steps 8 and 9: To a mixture of 4-(6-chloro-3-ethyl-7-fluoro-1H-indol-2-yl)-2-hydroxy-benzoic acid methyl ester (50 mg, 0.14 mmol), 4-n-butyl-phenylboronic acid (50 mg, 0.28 mmol), and cesium fluoride (78 mg, 0.52 mmol) in dioxane (3 mL, anhydrous) is added palladium bis(tri-tert-butyl-phosphine) (6 mg, 10 mol %). This mixture is purged with N2 for 3 minutes and then heated in a sealed tube at 120° C. for 4 hours. The mixture is cooled to room temperature, filtered, and the filtrate is concentrated. The resulting residue is dissolved in ethanol/H2O (1 mL/0.1 mL) and transferred to a microwave tube. LiOH (12 mg, 0.54 mmol) is added and the mixture is heated at 120° C. for 6 minutes under microwave irradiation. The crude product mixture is filtered. After concentration of the filtrate, the crude product is purified by preparative RP LC-MS to give 4-[6-(4-butyl-phenyl)-3-ethyl-7-fluoro-1H-indol-2-yl]-2-hydroxy-benzoic acid as a yellow solid: 1H NMR (400 MHz, CD3OD) δ 7.96 (d, 1H, J=8.8 Hz), 7.50 (d, 2H, J=8 Hz), 7.42 (d, 1H, J=8.4 Hz), 7.24 (d, 2H, J=8 Hz), 7.21-7.20 (m, 2H), 7.10 (dd, 1H, J=8, 8 Hz), 2.95 (q, 2H, J=7.6 Hz), 2.66 (t, 2H, J=8 Hz), 1.65 (m, 2H), 1.40 (m, 2H), 1.34 (t, 3H, J=7.6 Hz), 0.97 (t, 3H, J=7.6 Hz); ESMS m/z 432.2 (M+H+).

Workup

  1. customThis mixture is purged with N2 for 3 minutes
  2. temperatureThe mixture is cooled to room temperature
  3. filtrationfiltered
  4. concentrationthe filtrate is concentrated
  5. dissolutionThe resulting residue is dissolved in ethanol/H2O (1 mL/0.1 mL)
  6. customtransferred to a microwave tube
  7. temperaturethe mixture is heated at 120° C. for 6 minutes under microwave irradiation
  8. filtrationThe crude product mixture is filtered
  9. customAfter concentration of the filtrate, the crude product is purified by preparative RP LC-MS

Sources & evidence

ORD record
ord-bf7c65260ae54cb599b4d851cd7f5cb3
Source dataset
uspto-grants-2010_10
Patent number
US07816542B2

Reaction notes

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