N,5-Dimethyl-3-phenyl-4-isoxazolecarboxamide → 5-Methyl-6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one

HRID 8308Notes

Reaction equation

HRID 8308 reaction equation
[CH3:1][NH:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=[O:4].C([Li])CCC.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30]2[CH:37]=[CH:36][C:33]([C:34]#N)=[CH:32][CH:31]=2)[CH2:25][CH2:24]1>O1CCCC1>[CH3:1][N:2]1[C:34]([C:33]2[CH:32]=[CH:31][C:30]([CH2:29][N:26]3[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]3)=[CH:37][CH:36]=2)=[CH:10][C:9]2[O:8][N:7]=[C:6]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]=2[C:3]1=[O:4]

Participants

5

Reactant 3

HCID 4104650N,5-Dimethyl-3-phenyl-4-isoxazolecarboxamideHCID 75376124-((4-Methylpiperazin-1-yl)methyl)benzonitrileHCID 178418339Butyllithium

Product 1

HCID 112237295-Methyl-6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-oneYield 41.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-10 °C

Procedure

In a 500 ml flask, 10.0 g (46.3 mmol) of 5-methyl-3-phenyl-isoxazole-4-carboxylic acid methylamide is suspended in 150 ml of tetrahydrofuran (THF) under argon. At −70° C. a solution of butyl lithium (63 ml, 1.6M in hexane, 101 mmol, 2.2 eq.) is slowly added. After 1 h at this temperature, the solution is warmed to −10° C. and a solution of 11.9 g (55.5 mmol, 1.2 eq.) of 4-(4-methyl-piperazin-1-ylmethyl)-benzonitrile in 80 ml of THF is slowly added. Under warming to room temperature, the red solution is stirred for another hour, then quenched with 2 ml of water and concentrated. The yellow residue is then taken up in 75 ml of dioxane and kept at 5° C. Then, 230 ml of a 4M solution of HCl in dioxane is carefully added and the suspension stirred for 20 h at room temperature. Then, the solvent is removed and the residue dissolved in ethyl acetate and carefully neutralised with sat. NaHCO3-solution. The phases are separated and the organic phases washed with brine, dried over Na2SO4 and concentrated. Chromatographic purification (CH2Cl2/MeOH 95:5 to 90:10) yields 7.9 g (41%) of 5-methyl-6-[4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3-phenyl-5H-isoxazolo[4,5-c]pyridin-4-one as a white solid. Mass spectrum: m/z (M+H)+: 415.0

Workup

  1. temperatureUnder warming to room temperature
  2. customquenched with 2 ml of water
  3. concentrationconcentrated
  4. customkept at 5° C
  5. additionThen, 230 ml of a 4M solution of HCl in dioxane is carefully added
  6. stirringthe suspension stirred for 20 h at room temperature
  7. customThen, the solvent is removed
  8. dissolutionthe residue dissolved in ethyl acetate
  9. customThe phases are separated
  10. washthe organic phases washed with brine
  11. dry with materialdried over Na2SO4
  12. concentrationconcentrated
  13. customChromatographic purification (CH2Cl2/MeOH 95:5 to 90:10)

Sources & evidence

ORD record
ord-433f21c4ffa94d9ab075303661c50861
Source dataset
uspto-grants-2006_08
Patent number
US07087756B2

Reaction notes

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