Cesium carbonate → (S)-1-[3-(1-Methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidine-3-carboxylic acid ethyl ester

HRID 77066

Reaction equation

HRID 77066 reaction equation
Br[C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH3:13])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([O:20][C:21](=[O:28])[C@H:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1)[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH2:18]([O:20][C:21]([C@H:22]1[CH2:27][CH2:26][CH2:25][N:24]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[N:12]([CH3:13])[C:11]4[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=4[N:9]=3)[CH:3]=2)[CH2:23]1)=[O:28])[CH3:19]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 187784Ethyl (3S)-piperidine-3-carboxylateHCID 634876Binap, (A+-)-HCID 9624512-(3-bromophenyl)-1-methyl-1H-benzimidazole

Product 1

HCID 66977654(S)-1-[3-(1-Methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidine-3-carboxylic acid ethyl esterYield 70%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
80 °C

Procedure

Method 1—Step c 2-(3-Bromo-phenyl)-1-methyl-1H-benzoimidazole (0.85 g, 2.96 mmol), (S)-(+)-Nipecotic acid ethyl ester (0.60 g, 3.85 mmol) and cesium carbonate (4.82 g, 14.80 mmol) were placed into a dry Schlenk tube under nitrogen. At the same time palladium acetate (0.14 g, 0.60 mmol), and rac-2,2′bis(diphenylphosphino)-1,1′-binaphtyl (BINAP) (0.57 g, 0.90 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 0.75 g of the title compound (70%).

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-89a0edb05816463b8880ff3ddfc76274
Source dataset
uspto-grants-2014_09
Patent number
US08835648B2

Linked notes

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