Hydrochloric Acid → 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-1H-indol-5-yl)benzoic acid

HRID 44018

Reaction equation

HRID 44018 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[C:5]2[C:18]([NH:20][CH3:21])=[O:19].B([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([OH:30])=[O:29])(O)O.C([O-])([O-])=O.[Cs+].[Cs+].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.CC#N.O1CCOCC1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:6]2[NH:7][C:8]3[C:4]([C:5]=2[C:18](=[O:19])[NH:20][CH3:21])=[CH:3][C:2]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28]([OH:30])=[O:29])=[CH:10][CH:9]=3)=[CH:12][CH:13]=1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 10796Cesium carbonateHCID 27339573-Carboxyphenylboronic acidHCID 592338075-bromo-2-(4-fluorophenyl)-N-methyl-1H-indole-3-carboxamide

Product 1

HCID 592338213-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-1H-indol-5-yl)benzoic acidYield 18%

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolvent2×HCID 6342AcetonitrileSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
90 °C

Procedure

In a 7 mL scintillation vial were combined 5-bromo-2-(4-fluorophenyl)-N-methyl-1H-indole-3-carboxamide (59 mg, 0.17 mmol), 3-boronobenzoic acid (47 mg, 0.28 mmol), Cs2CO3 (100 mg, 0.31 mmol), and Pd(PPh3)4 (17 mg, 0.015 mmol). 1,4-Dioxane (1.25 mL) and water (0.25 mL) were added, the vial was capped, and the reaction was heated in an oil bath to 90° C. After 7 h, the reaction was cooled to r.t. and diluted with water. 1 mL of 1N HCl was added and a ppt. formed. The suspension was extracted with EtOAc (+MeOH to aid dissolution), and the organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give a tan solid. This was purified by prep HPLC, and concentrated to give a white solid, (12 mg, 18% yield). 1H NMR (500 MHz, MeOD) δ ppm 8.34 (s, 1H) 8.06 (s, 1H) 7.97 (d, J=7.63 Hz, 1H) 7.92 (d, J=7.93 Hz, 1H) 7.65-7.74 (m, 2H) 7.54 (t, J=7.78 Hz, 1H) 7.51 (s, 2H) 7.23 (t, J=8.85 Hz, 2H) 2.89 (s, 3H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=5% CH3CN/95% H2O/10 mM NH4OAc, solvent B=95% CH3CN/5% H2O/10 mM NH4OAc, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=5 ml/min, column. XBridge C18 5 μm 4.6×50 mm; HPLC Rt=0.88, (ES+) m/z (MH+)=389.

Workup

  1. customthe vial was capped
  2. temperaturethe reaction was cooled to r.t.
  3. customformed
  4. extractionThe suspension was extracted with EtOAc (+MeOH to aid dissolution)
  5. washthe organic phase was washed with brine
  6. dry with materialdried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customto give a tan solid
  10. customThis was purified by prep HPLC
  11. concentrationconcentrated
  12. customto give a white solid, (12 mg, 18% yield)
  13. customB=100, gradient time=2 min
  14. customtime=3 min, flow rate=5 ml/min, column

Sources & evidence

ORD record
ord-3ed0416655d34b129f4276b0b0bdada2
Source dataset
uspto-grants-2013_09
Patent number
US08536338B2

Linked notes

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