1-Methylpiperazine → 5-Bromo-4-(4-methylpiperazin-1-yl)pyridin-3-amine

HRID 524896Notes

Reaction equation

HRID 524896 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([N+:16]([O-])=O)[C:14]=1Cl.CCN(C(C)C)C(C)C.C(Cl)Cl.CCOC(C)=O>C(Cl)Cl.C(O)(=O)C.[Fe]>[Br:8][C:9]1[C:14]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[C:13]([NH2:16])[CH:12]=[N:11][CH:10]=1

Participants

8

Reactant 4

HCID 531671-MethylpiperazineHCID 81531DiisopropylethylamineHCID 125100523-Bromo-4-chloro-5-nitropyridineHCID 21226138Dichloromethane ethylacetate

Product 1

HCID 867209525-Bromo-4-(4-methylpiperazin-1-yl)pyridin-3-amine

Reagents, catalysts & solvents 3

HCID 23925IronCatalystHCID 176Acetic AcidSolventHCID 6344DichloromethaneSolvent2×

Procedure

1-methylpiperazine (2.109 g, 21.06 mmol) in DCM (62.50 mL) was added to a stirred solution of 3-bromo-4-chloro-5-nitro-pyridine (5000 mg, 21.06 mmol) and DIPEA (3.266 g, 4.402 mL, 25.27 mmol) in DCM (62.50 mL) at RT. The reaction was allowed to stir at ambient temperature for 2 h, then was concentrated in vacuo. The residue was partitioned between a saturated aqueous solution of NaHCO3 and DCM. Combined organic extract was dried and concentrated in vacuo. The orange solid was suspended in Acetic acid (60.00 mL) before iron (7.059 g, 126.4 mmol) was added. The mixture was warmed at 50° C. and stirred for 15 min. The mixture was allowed to cool to RT and DCM:EtOAc (4:1) (400 mL) was added to the reaction. The resulting brown suspension was filtered using a prewetted Celite cartridge (25 g), washing with more DCM:MeOH (4:1) (200 mL). Combined filtrate was concentrated in vacuo to afford a red/brown gum which was purified by chromatography on silica (Rf companion, 80 g cartridge), eluting with DCM-DCM:MeOH:NE3(90:10:1) a gradient of 100-0 to 20:80. Fractions containing clean product were collected and concentrated in vacuo to afford 5-bromo-4-(4-methylpiperazin-1-yl)pyridin-3-amine as a viscous, clear light yellow oil that solidifies on standing. MS (ES+) 273.1.

Workup

  1. concentrationwas concentrated in vacuo
  2. customThe residue was partitioned between a saturated aqueous solution of NaHCO3 and DCM
  3. extractionCombined organic extract
  4. customwas dried
  5. concentrationconcentrated in vacuo
  6. additionwas added
  7. temperatureThe mixture was warmed at 50° C.
  8. stirringstirred for 15 min
  9. temperatureto cool to RT
  10. filtrationThe resulting brown suspension was filtered
  11. washwashing with more DCM:MeOH (4:1) (200 mL)
  12. concentrationCombined filtrate was concentrated in vacuo
  13. customto afford a red/brown gum which
  14. customwas purified by chromatography on silica (Rf companion, 80 g cartridge)
  15. washeluting with DCM-DCM
  16. additionFractions containing clean product
  17. customwere collected
  18. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-3aaceb4b58e645b28af3ce01bb1f15bf
Source dataset
uspto-grants-2016_05
Patent number
US09340546B2

Reaction notes

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