Diisopropylethylamine → (1-(2-Bromo-5-fluoro-3-nitropyridin-4-yl)piperidin-4-yl)(4-methylpiperazin-1-yl)methanone

HRID 869130Notes

Reaction equation

HRID 869130 reaction equation
Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[Br:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[C:32](Br)[C:31]([F:38])=[CH:30][N:29]=1>CN1C(=O)CCC1.CCOC(C)=O>[Br:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[C:32]([N:15]2[CH2:16][CH2:17][CH:12]([C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH3:3])[CH2:9][CH2:8]3)=[O:11])[CH2:13][CH2:14]2)[C:31]([F:38])=[CH:30][N:29]=1

Participants

6

Reactant 3

HCID 81531Diisopropylethylamine2×HCID 223090822,4-Dibromo-5-fluoro-3-nitropyridineHCID 45036889(4-Methylpiperazin-1-yl)piperidin-4-yl-methanone dihydrochloride2×

Product 1

HCID 86720939(1-(2-Bromo-5-fluoro-3-nitropyridin-4-yl)piperidin-4-yl)(4-methylpiperazin-1-yl)methanoneYield 81.3%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Procedure

A round-bottomed flask was charged with (4-methylpiperazin-1-yl)-(4-piperidyl)methanone dihydrochloride (16.45 g, 57.89 mmol) and DIPEA (23.20 g, 31.27 mL, 179.5 mmol) in NMP (160 mL). 2,4-Dibromo-5-fluoro-3-nitro-pyridine (17.36 g, 57.89 mmol) was added and the reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. Additional (4-methylpiperazin-1-yl)-(4-piperidyl)methanone dihydrochloride (1.65 g, 0.1 eq) and DIPEA (1 mL, 0.1 eq) was added and stirred at room temperature for a further 3 h. The mixture diluted with EtOAc, washed with water (3×). The aqueous layer was extracted with EtOAc (3×) and the combined organic extracts were combined, washed with brine, dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was purified by chromatography (330 g SiO2, 0 to 5% MeOH (containing 10% ammonium hydroxide)/DCM) to afford product as a yellow solid (20.24 g, 81%). MS (ES+) 432.0.

Workup

  1. stirringstirred at room temperature for a further 3 h
  2. washwashed with water (3×)
  3. extractionThe aqueous layer was extracted with EtOAc (3×)
  4. washwashed with brine
  5. dry with materialdried (sodium sulfate)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe crude product was purified by chromatography (330 g SiO2, 0 to 5% MeOH (containing 10% ammonium hydroxide)/DCM)

Sources & evidence

ORD record
ord-e09ee3df05324a88b515a77babf2dc58
Source dataset
uspto-grants-2015_03
Patent number
US08969360B2

Reaction notes

Loading…