Water → N-[4-({2-[({4-[(Dimethylamino)methyl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 2066207Notes

Reaction equation

HRID 2066207 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12]([C:22](OC2C=CC=CC=2)=[O:23])C(=O)OC2C=CC=CC=2)[CH:7]=1.Cl.Cl.[CH3:52][N:53]([CH2:55][CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1)[CH3:54].C(N(CC)CC)C.O>CN(C)C=O>[CH3:52][N:53]([CH2:55][CH:56]1[CH2:61][CH2:60][N:59]([C:22]([NH:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]4([C:40]([NH:41][C:42]5[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=5)=[O:49])[CH2:38][CH2:39]4)=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)=[O:23])[CH2:58][CH2:57]1)[CH3:54]

Participants

6

Reactant 4

HCID 962Water2×HCID 8471Triethylamine2×HCID 23153381N,N-Dimethyl-1-(piperidin-4-yl)methanamine dihydrochlorideHCID 59597026[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester

Product 1

HCID 15965411N-[4-({2-[({4-[(Dimethylamino)methyl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 50.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (1.0 ml) were added 4-(dimethylaminomethyl)piperidine dihydrochloride (67.0 mg), triethylamine (0.0523 ml) and water (0.050 ml), followed by stirring at room temperature for 10 hr. To the reaction mixture were added triethylamine (0.0523 ml) and water (0.050 ml), followed by further stirring at room temperature for 24 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added hexane, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (22.4 mg, 50.4%).

Workup

  1. stirringby further stirring at room temperature for 24 hr
  2. customThe reaction mixture was partitioned between ethyl acetate
  3. washThe organic layer was washed with brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. customThe solvent was removed
  6. customthe residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate
  7. additionFractions containing the target compound
  8. concentrationwere concentrated
  9. additionTo the residue was added hexane
  10. filtrationthe precipitate was collected by filtration
  11. washThis was washed with hexane
  12. customdried under aeration

Sources & evidence

ORD record
ord-94968d1a49014a15928d49b140122381
Source dataset
uspto-grants-2012_10
Patent number
US08288538B2

Reaction notes

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