Cesium carbonate → 2-Chloro-5-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-benzoic acid ethyl ester

HRID 2047363Notes

Reaction equation

HRID 2047363 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:13])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].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-])[O-].[Cs+].[Cs+].[CH3:66][N:67]([CH3:76])[CH2:68][CH2:69][N:70]1[CH2:75][CH2:74][NH:73][CH2:72][CH2:71]1>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH2:10]([O:9][C:7](=[O:8])[C:6]1[CH:12]=[C:2]([N:73]2[CH2:74][CH2:75][N:70]([CH2:69][CH2:68][N:67]([CH3:76])[CH3:66])[CH2:71][CH2:72]2)[CH:3]=[CH:4][C:5]=1[Cl:13])[CH3:11]

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 144749Ethyl 5-bromo-2-chlorobenzoateHCID 634876Binap, (A+-)-HCID 27362291-(2-(Dimethylamino)ethyl)piperazine

Product 1

HCID 686703542-Chloro-5-[4-(2-dimethylamino-ethyl)-piperazin-1-yl]-benzoic acid ethyl esterYield 30%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

Ethyl 5-bromo-2-chlorobenzoate (0.80 g, 3.04 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (0.19 g, 0.30 mmol), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3) (0.28 g, 0.30 mmol) and cesium carbonate (Cs2CO3) (1.39 g, 4.26 mmol) were placed in a Schlenk tube and purged by repeated nitrogen/vacuum cycles for 30 minutes. Dry toluene (6 mL) and 1-(2-dimethylaminoethyl)piperazine (0.55 mL, 3.65 mmol) were then added. The reaction mixture was stirred for 10 min at room temperature, heated at 85° C. overnight and then cooled to room temperature. The solution was diluted with EtOAc (30 mL), the insoluble material was filtered off and the filtrate was washed with saturated brine (15 mL). The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue that was purified by flash chromatography (eluent gradient: EtOAc, EtOAc:MeOH/1:1, EtOAc:MeOH:NH3 in MeOH (2M)/1:1:0.2) to afford 0.30 g of the title compound (30%). 1H-NMR (400 MHz, DMSO): δ 1.28 (3H, t), 2.12 (6H, s), 2.32-2.42 (4H, m), 2.47-2.51 (4H, m), 3.11-3.14 (4H, m), 4.27 (2H, q), 7.06-7.09 (1H, m), 7.18-7.19 (1H, m), 7.30-7.32 (1H, m).

Workup

  1. custompurged by repeated nitrogen/vacuum cycles for 30 minutes
  2. temperatureheated at 85° C. overnight
  3. temperaturecooled to room temperature
  4. filtrationthe insoluble material was filtered off
  5. washthe filtrate was washed with saturated brine (15 mL)
  6. dry with materialThe organic phase was dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customto obtain a residue that
  10. customwas purified by flash chromatography (eluent gradient: EtOAc, EtOAc:MeOH/1:1, EtOAc:MeOH:NH3 in MeOH (2M)/1:1:0.2)

Sources & evidence

ORD record
ord-b03ceb2d8869452abc77ac9d5ee47d83
Source dataset
uspto-grants-2013_11
Patent number
US08592463B2

Reaction notes

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