Biphenyl → 5-[(4-Ethyl-1-piperazinyl)methyl]-2-pyridinamine

HRID 2264360Notes

Reaction equation

HRID 2264360 reaction equation
C[Si](C)(C)[NH:3][Si](C)(C)C.[Li].Br[C:12]1[N:17]=[CH:16][C:15]([CH2:18][N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH3:26])[CH2:21][CH2:20]2)=[CH:14][CH:13]=1.C1(C2C=CC=CC=2)C=CC=CC=1.C1COCC1>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].O>[CH2:25]([N:22]1[CH2:23][CH2:24][N:19]([CH2:18][C:15]2[CH:14]=[CH:13][C:12]([NH2:3])=[N:17][CH:16]=2)[CH2:20][CH2:21]1)[CH3:26]

Participants

7

Reactant 4

HCID 7095BiphenylHCID 8028TetrahydrofuranHCID 57426343Lithium bis(trimethylsilyl)amideHCID 86642886Piperazine, 1-[(6-broMo-3-pyridinyl)Methyl]-4-ethyl-

Product 1

HCID 454899105-[(4-Ethyl-1-piperazinyl)methyl]-2-pyridinamine

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolvent

Conditions

Temperature
65 °C

Procedure

Add lithium 1,1,1,3,3,3-hexamethyl-disilazane (1055 mL) slowly to a degassed mixture of 1-(6-bromo-pyridin-3-ylmethyl)-4-ethyl-piperazine (250 g), dicyclohexylphosphino)biphenyl (18.50 g), tris(dibenzylideneacetone)dipalladium (24.17 g) and THF (250 mL) at 50° C. Heat the mixture at 65° C. overnight. Cool to 37° C. and add water (500 mL). Remove half of the solvent under vacuum and add DCM (2.5 L). Filter over a celite pad and remove part of the solvent. Add methanol (300 mL) and methyl tert-butyl ether (MtBE, 600 mL) to the mixture and cool in an ice bath. Then, add hydrochloric acid 2 M in ethyl ether (800 mL) and a 32% aqueous solution of hydrochloric acid (100 mL). Remove the organic layer, and add an aqueous solution of sodium hydroxide 2 M (2500 mL). Extract the aqueous phase three times with DCM and remove the solvent under vacuum. Solve in 90 mL of toluene at 50° C. until complete dissolution and then add 80 mL of MtBE. Stir overnight at RT. Add additional MtBE (100 mL) for complete precipitation. Filter the solid and dry to afford 108.24 g of the title compound. MS (ES+): m/z=221 (M+H)+.

Workup

  1. temperatureCool to 37° C.
  2. customRemove half of the solvent under vacuum
  3. additionadd DCM (2.5 L)
  4. filtrationFilter over a celite pad
  5. customremove part of the solvent
  6. temperatureAdd methanol (300 mL) and methyl tert-butyl ether (MtBE, 600 mL) to the mixture and cool in an ice bath
  7. additionThen, add hydrochloric acid 2 M in ethyl ether (800 mL)
  8. customRemove the organic layer
  9. additionadd an aqueous solution of sodium hydroxide 2 M (2500 mL)
  10. extractionExtract the aqueous phase three times with DCM
  11. customremove the solvent under vacuum
  12. dissolutionSolve in 90 mL of toluene at 50° C. until complete dissolution
  13. additionadd 80 mL of MtBE
  14. additionAdd additional MtBE (100 mL)
  15. customfor complete precipitation
  16. filtrationFilter the solid
  17. customdry

Sources & evidence

ORD record
ord-8d23c4ac855d4951adc80a58a40ea6db
Source dataset
uspto-grants-2010_12
Patent number
US07855211B2

Reaction notes

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