1-[(6-Chloropyridin-3-yl)methyl]-4-methylpiperazine → 5-((4-Methylpiperazin-1-yl)methyl)pyridin-2-amine

HRID 402932Notes

Reaction equation

HRID 402932 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C[Si]([N-:45][Si](C)(C)C)(C)C.[Li+]>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].C1COCC1>[CH3:15][N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:5]2[CH:4]=[CH:3][C:2]([NH2:45])=[N:7][CH:6]=2)[CH2:10][CH2:11]1

Participants

6

Reactant 3

HCID 14735211-[(6-Chloropyridin-3-yl)methyl]-4-methylpiperazineHCID 2733832Lithium HexamethyldisilazideHCID 27342162-(Dicyclohexylphosphino)biphenyl

Product 1

HCID 592929015-((4-Methylpiperazin-1-yl)methyl)pyridin-2-amineYield 37%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
100 °C

Procedure

To 1-((6-chloropyridin-3-yl)methyl)-4-methylpiperazine (6.79 g, 30.1 mmol, Eq: 1.00), 2-(dicyclohexylphosphino)biphenyl (2.11 g, 6.02 mmol, Eq: 0.20) and tris(dibenzylideneacetone)dipalladium (0) (2.75 g, 3.01 mmol, Eq: 0.10) in a sealed tube was added THF (75 ml). The solution was placed under nitrogen. Lithium bis(trimethylsilyl)amide (75.2 ml, 75.2 mmol, Eq: 2.50) was added. The solution was degassed with argon and the tube was sealed and heated at 100° C. for 18 h. The solution was filtered through Celite™. The solvent was evaporated under reduced pressure. The residue was taken up in DCM. HCl (1N, 10 ml) was added slowly to adjust to pH=1 by adding 6 N HCl and water (as needed). The layers were separated. The organic layer was extracted once with water. The aqueous layers were combined and were brought to pH 10 by a slow addition of solid NaOH. Dichloromethane was added. The layers were separated. The aqueous layer was extracted three times with DCM. The organic layers were combined and dried over Na2SO4. The solvent was evaporated. The residue was triturated with Et2O. The solid was collected by filtration and dried to give 5-(4-methyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (2.3 g, 37%). LC/MS-ESI observed [M+H]+ 207.

Workup

  1. customThe solution was degassed with argon
  2. customthe tube was sealed
  3. filtrationThe solution was filtered through Celite™
  4. customThe solvent was evaporated under reduced pressure
  5. additionHCl (1N, 10 ml) was added slowly
  6. additionby adding 6 N HCl and water (as needed)
  7. customThe layers were separated
  8. extractionThe organic layer was extracted once with water
  9. additionwere brought to pH 10 by a slow addition of solid NaOH
  10. additionDichloromethane was added
  11. customThe layers were separated
  12. extractionThe aqueous layer was extracted three times with DCM
  13. dry with materialdried over Na2SO4
  14. customThe solvent was evaporated
  15. customThe residue was triturated with Et2O
  16. filtrationThe solid was collected by filtration
  17. customdried

Sources & evidence

ORD record
ord-36f20e1ecd0f4fb0bc7461cbd74de2dc
Source dataset
uspto-grants-2014_06
Patent number
US08742098B2

Reaction notes

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