Acetic Acid → tert-butyl (1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)carbamate

HRID 2064433Notes

Reaction equation

HRID 2064433 reaction equation
[CH3:1][N:2]1[CH:6]=[C:5]([C:7]([NH:9][NH:10][C:11]2[N:20]=[CH:19][CH:18]=[C:17]3[C:12]=2[CH:13]=[C:14]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:15]([C:21]2[CH:26]=[CH:25][C:24]([C:27]4([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=2)=[N:16]3)=O)[N:4]=[CH:3]1.C(O)(=O)C.O1CCOCC1>C(OCC)(=O)C>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:20]3[C:11]([C:12]4[CH:13]=[C:14]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C:15]([C:21]5[CH:22]=[CH:23][C:24]([C:27]6([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:35])[CH3:36])[CH2:28][CH2:29][CH2:30]6)=[CH:25][CH:26]=5)=[N:16][C:17]=4[CH:18]=[CH:19]3)=[N:10][N:9]=2)[N:4]=[CH:3]1

Participants

5

Reactant 3

HCID 176Acetic AcidHCID 312751,4-DioxaneHCID 57805467HCID 57805467, compound

Product 1

HCID 57805469tert-butyl (1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)carbamate

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
80 °C

Procedure

To a round bottom flask was added tert-butyl {1-[4-(5-{2-[(1-methyl-1H-imidazol-4-yl)carbonyl]hydrazino}-3-phenyl-1,6-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (1-7) (2.73 g, 4.63 mmol), acetic acid (5.30 mL, 93 mmol), and 1,4-dioxane (20 mL). The reaction mixture was heated to 80° C. while stirring open to the atmosphere (capped) in a hot oil bath. After 3 hours the reaction mixture was permitted to cool to room temperature, suspended in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography 1-15% IPA/DCM. The appropriate fractions were combined and the solvent was removed in vacuo. The resulting residue was repurified by reverse phase column chromatography (Sunfire C18) eluting with 5 to 95% acetonitrile/(0.1% TFA/water) gradient. The appropriate fractions were free based by suspending in ethyl acetate, washed with a saturated solution of sodium bicarbonate, followed by water, brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give tert-butyl (1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)carbamate (1-8) as an off-white solid. MS (M+H)+: observed=572.3, calculated=572.7.

Workup

  1. temperatureto cool to room temperature
  2. washwashed with a saturated solution of sodium bicarbonate
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe resulting residue was purified by silica gel chromatography 1-15% IPA/DCM
  7. customthe solvent was removed in vacuo
  8. customThe resulting residue was repurified by reverse phase column chromatography (Sunfire C18)
  9. washeluting with 5 to 95% acetonitrile/(0.1% TFA/water) gradient
  10. washwashed with a saturated solution of sodium bicarbonate
  11. dry with materialdried over sodium sulfate
  12. filtrationfiltered
  13. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-51b96605bf5c417e9d2c224331c79578
Source dataset
uspto-grants-2012_10
Patent number
US08288407B2

Reaction notes

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