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

HRID 1712684Notes

Reaction equation

HRID 1712684 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[CH2:48][CH2:47][C@H:46]([OH:49])[CH2:45]3)=[O:43])[CH:36]=2)[C:31]([F:50])=[CH:30][C:29]=1[NH:51][C:52]([C:54]1([C:57](O)=[O:58])[CH2:56][CH2:55]1)=[O:53].[F:60][C:61]1[CH:67]=[CH:66][C:64]([NH2:65])=[CH:63][CH:62]=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[CH2:48][CH2:47][C@H:46]([OH:49])[CH2:45]3)=[O:43])[CH:36]=2)[C:31]([F:50])=[CH:30][C:29]=1[NH:51][C:52]([C:54]1([C:57]([NH:65][C:64]2[CH:66]=[CH:67][C:61]([F:60])=[CH:62][CH:63]=2)=[O:58])[CH2:56][CH2:55]1)=[O:53]

Participants

6

Reactant 4

HCID 97314-FluoroanilineHCID 516892Sodium BicarbonateHCID 231494114-(4,6-Dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrateHCID 247885011-[({2,5-Difluoro-4-[(2-{[((s)-3-hydroxypyrrolidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}amino)carbonyl]cyclopropanecarboxylic acid triethylamine salt

Product 1

HCID 16117165N-(2,5-Difluoro-4-{[2-({[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 75%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

4-(4,6-Dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (365 mg) was added to a mixture of 1-[({2,5-difluoro-4-[(2-{[((S)-3-hydroxypyrrolidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}amino)carbonyl]cyclopropanecarboxylic acid triethylamine salt (175 mg), 4-fluoroaniline (0.0587 ml) and tetrahydrofuran (4.0 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 68 hours and 30 minutes. A saturated aqueous solution of sodium hydrogencarbonate (10 ml) was added to the mixture and stirred, and the mixture was partitioned after the addition of ethyl acetate and tetrahydrofuran (1:1) (40 ml) and water (30 ml). The organic layer was washed with brine (20 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, then ethyl acetate:methanol=10:1). The fractions containing the target compound were concentrated under reduced pressure to give the title compound (128.5 mg, 75%) as a white solid.

Workup

  1. stirringstirred
  2. customthe mixture was partitioned
  3. additionafter the addition of ethyl acetate and tetrahydrofuran (1:1) (40 ml) and water (30 ml)
  4. washThe organic layer was washed with brine (20 ml)
  5. dry with materialdried over anhydrous magnesium sulfate
  6. customThe desiccant was removed by filtration
  7. concentrationthe filtrate was concentrated under reduced pressure
  8. customThe resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent
  9. additionThe fractions containing the target compound
  10. concentrationwere concentrated under reduced pressure

Sources & evidence

ORD record
ord-4e64a2c35d8a432c9a17aad241874811
Source dataset
uspto-grants-2010_09
Patent number
US07790885B2

Reaction notes

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