Cesium carbonate → 2-[2-Chloro-5-(3-ethoxycarbonyl-pyrrolidin-1-yl)-phenyl]-5-methyl-benzoimidazole-1-carboxylic acid tert-butyl ester

HRID 77076Notes

Reaction equation

HRID 77076 reaction equation
[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]1[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:19]=1[Cl:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]([CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=[O:29].[C:35](=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]1[CH:23]=[C:22]([N:32]2[CH2:33][CH2:34][CH:30]([C:28]([O:27][CH2:26][CH3:35])=[O:29])[CH2:31]2)[CH:21]=[CH:20][C:19]=1[Cl:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 4114360Methyl Pyrrolidine-3-carboxylateHCID 669779132-(5-Bromo-2-chloro-phenyl)-5-methyl-benzoimidazole-1-carboxylic acid tert-butyl ester

Product 1

HCID 669779532-[2-Chloro-5-(3-ethoxycarbonyl-pyrrolidin-1-yl)-phenyl]-5-methyl-benzoimidazole-1-carboxylic acid tert-butyl esterYield 86%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

Method 5—Step a 2-(5-Bromo-2-chloro-phenyl)-5-methyl-benzoimidazole-1-carboxylic acid tert-butyl ester (obtained as described in general method 4, step c) (1.80 g, 4.28 mmol), pyrrolidine-3-carboxylic acid methyl ester (0.92 g, 5.56 mmol) and cesium carbonate (6.95 g, 21.38 mmol) were to a dry flask under nitrogen containing palladium acetate (0.19 g, 0.86 mmol) and BINAP (0.80 g, 1.28 mmol) in dry toluene (11 mL) and previously stirred for 20 minutes under nitrogen. The reaction mixture was heated at 80° C. overnight, cooled to room temperature, diluted with AcOEt (40 mL), salts were filtered off, the organic layer washed with water (1×30 mL) and brine (1×20 mL), dried over Na2SO4 and then concentrated under reduced pressure. To the crude a mixture of solvents cyclohexane:AcOEt/4:1 (15 mL) was added and filtered through a column with Na2SO4 to remove all the salts, washed with the mixture of solvents and the organic layer purified by flash chromatography (eluent: cyclohexane:AcOEt/4:1) to afford 1.71 g of the title compound (86%).

Workup

  1. temperaturecooled to room temperature
  2. filtrationwere filtered off
  3. washthe organic layer washed with water (1×30 mL) and brine (1×20 mL)
  4. dry with materialdried over Na2SO4
  5. concentrationconcentrated under reduced pressure
  6. additionTo the crude a mixture of solvents cyclohexane
  7. additionAcOEt/4:1 (15 mL) was added
  8. filtrationfiltered through a column with Na2SO4
  9. customto remove all the salts
  10. washwashed with the mixture of solvents
  11. customthe organic layer purified by flash chromatography (eluent: cyclohexane:AcOEt/4:1)

Sources & evidence

ORD record
ord-af700698cef243079340f439e6f58c02
Source dataset
uspto-grants-2014_09
Patent number
US08835648B2

Reaction notes

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