4-Fluoroaniline → N-{2,5-Difluoro-4-[(2-{([3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 388523Notes

Reaction equation

HRID 388523 reaction equation
O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.C(N(CC)CC)C.[F:27][C:28]1[CH:33]=[C:32]([O:34][C:35]2[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]([N:44]3[CH2:47][CH:46]([OH:48])[CH2:45]3)=[O:43])[CH:36]=2)[C:31]([F:49])=[CH:30][C:29]=1[NH:50][C:51]([C:53]1([C:56](O)=[O:57])[CH2:55][CH2:54]1)=[O:52].[F:59][C:60]1[CH:66]=[CH:65][C:63]([NH2:64])=[CH:62][CH:61]=1.C(=O)([O-])O.[Na+]>O1CCCC1>[F:27][C:28]1[CH:33]=[C:32]([O:34][C:35]2[CH:40]=[CH:39][N:38]=[C:37]([NH:41][C:42]([N:44]3[CH2:47][CH:46]([OH:48])[CH2:45]3)=[O:43])[CH:36]=2)[C:31]([F:49])=[CH:30][C:29]=1[NH:50][C:51]([C:53]1([C:56]([NH:64][C:63]2[CH:65]=[CH:66][C:60]([F:59])=[CH:61][CH:62]=2)=[O:57])[CH2:54][CH2:55]1)=[O:52]

Participants

6

Reactant 4

HCID 97314-FluoroanilineHCID 516892Sodium BicarbonateHCID 231494114-(4,6-Dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate2×HCID 247885641-[({2,5-Difluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}amino)carbonyl]cyclopropanecarboxylic acid triethylamine salt

Product 1

HCID 16116909N-{2,5-Difluoro-4-[(2-{([3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 92%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

4-(4,6-Dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (80.8 mg) was added to a mixture of 1-[({2,5-difluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}amino)carbonyl]cyclopropanecarboxylic acid triethylamine salt (75.3 mg), 4-fluoroaniline (0.026 ml) and tetrahydrofuran (1.0 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 5 hours. 4-(4,6-Dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (80.8 mg) was added again at room temperature, and the mixture was stirred for 87 hours. A saturated aqueous solution of sodium hydrogencarbonate (5 ml) was added to the reaction mixture and stirred, and the mixture was partitioned after the addition of ethyl acetate (20 ml) and water (20 ml). The organic layer was washed with brine (10 ml), and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, ethyl acetate:methanol=10:1). The fractions containing the target compound was concentrated under reduced pressure to give the title compound (68.1 mg, 92%) as a white solid.

Workup

  1. stirringthe mixture was stirred for 87 hours
  2. stirringstirred
  3. customthe mixture was partitioned
  4. additionafter the addition of ethyl acetate (20 ml) and water (20 ml)
  5. washThe organic layer was washed with brine (10 ml)
  6. dry with materialdried over anhydrous magnesium sulfate
  7. customThe desiccant was removed by filtration
  8. concentrationthe filtrate was concentrated under reduced pressure
  9. customThe resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, ethyl acetate:methanol=10:1)
  10. additionThe fractions containing the target compound
  11. concentrationwas concentrated under reduced pressure

Sources & evidence

ORD record
ord-6fee8ab9cebe494a8de86a82bb3a7fcc
Source dataset
uspto-grants-2013_02
Patent number
US08377938B2

Reaction notes

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