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

HRID 77069

Reaction equation

HRID 77069 reaction equation
[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:22]=[C:21](Br)[CH:20]=[CH:19][C:18]=1[Cl:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25]([O:27][C:28](=[O:35])[C@@H:29]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]1)[CH3:26].C(=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>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[CH:22]=[C:21]([N:31]2[CH2:32][CH2:33][CH2:34][C@@H:29]([C:28]([O:27][CH2:25][CH3:26])=[O:35])[CH2:30]2)[CH:20]=[CH:19][C:18]=1[Cl:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 185582ethyl (3R)-piperidine-3-carboxylateHCID 634876Binap, (A+-)-HCID 66977869Tert-butyl 2-(5-bromo-2-chlorophenyl)-1H-benzimidazole-1-carboxylate

Product 1

HCID 669775292-[2-Chloro-5-((R)-3-ethoxycarbonyl-piperidin-1-yl)-phenyl]-benzoimidazole-1-carboxylic acid tert-butyl esterYield 74.5%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

Method 2—Step c 2-(5-bromo-2-chloro-phenyl)-benzoimidazole-1-carboxylic acid tert-butyl ester (1.50 g, 3.69 mmol), (R)-(−)-Nipecotic acid ethyl ester (0.75 g, 4.79 mmol) and cesium carbonate (6.00 g, 18.43 mmol) were placed into a dry Schlenk tube under nitrogen. At the same time palladium acetate (0.17 g, 0.74 mmol), and BINAP (0.71 g, 1.11 mmol) were placed into a dry 7 mL vial under nitrogen. Then dry toluene (5 mL) was added and the mixture was stirred 20 minutes under nitrogen before being added to the first flask. The reaction mixture was heated at 80° C. overnight, cooled to room temperature, filtered off, and the insoluble material was washed with EtOAC (3×10 mL). The organic solution was concentrated under reduced pressure and crude was purified by flash chromatography (eluent: cyclohexane:AcOEt gradient from 100% of cyclohexane to cyclohexane 4: AcOEt 1) to afford 1.33 g of the title compound (74%).

Workup

  1. additionbefore being added to the first flask
  2. temperaturecooled to room temperature
  3. filtrationfiltered off
  4. washthe insoluble material was washed with EtOAC (3×10 mL)
  5. concentrationThe organic solution was concentrated under reduced pressure and crude
  6. customwas purified by flash chromatography (eluent: cyclohexane:AcOEt gradient from 100% of cyclohexane to cyclohexane 4: AcOEt 1)

Sources & evidence

ORD record
ord-569f983af67a45679f4a10b98a5d8aa5
Source dataset
uspto-grants-2014_09
Patent number
US08835648B2

Linked notes

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