Water → N-[4-({2-[({4-[3-(Dimethylamino)azetidin-1-yl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)phenyl]-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 2066235Notes

Reaction equation

HRID 2066235 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:48]=[CH:47][C:20]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([N:28]([C:38]([O:40]C5C=CC=CC=5)=O)C(=O)OC5C=CC=CC=5)[CH:23]=4)=[CH:19][CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.Cl.Cl.Cl.[CH3:52][N:53]([CH3:64])[CH:54]1[CH2:57][N:56]([CH:58]2[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]2)[CH2:55]1.C(N(CC)CC)C.O>CN(C)C=O>[CH3:52][N:53]([CH3:64])[CH:54]1[CH2:55][N:56]([CH:58]2[CH2:63][CH2:62][N:61]([C:38]([NH:28][C:24]3[CH:23]=[C:22]([O:21][C:20]4[CH:19]=[CH:18][C:17]([NH:16][C:14]([C:11]5([C:9]([NH:8][C:5]6[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=6)=[O:10])[CH2:13][CH2:12]5)=[O:15])=[CH:48][CH:47]=4)[CH:27]=[CH:26][N:25]=3)=[O:40])[CH2:60][CH2:59]2)[CH2:57]1

Participants

6

Reactant 4

HCID 962WaterHCID 8471TriethylamineHCID 231534044-(3-Dimethylaminoazetidin-1-yl)piperidine trihydrochlorideHCID 59596935phenyl N-[4-(4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate

Product 1

HCID 59596941N-[4-({2-[({4-[3-(Dimethylamino)azetidin-1-yl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)phenyl]-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 24.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of phenyl N-[4-(4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (2.0 ml) were added N,N-dimethyl-N-[1-(piperidin-4-yl)azetidin-3-yl]amine trihydrochloride (90.5 mg), triethylamine (0.129 ml) and water (0.10 ml), followed by stirring at room temperature for 12 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 diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (11.8 mg, 24.8%).

Workup

  1. customThe reaction mixture was partitioned between ethyl acetate
  2. washThe organic layer was washed with brine
  3. dry with materialdried over anhydrous sodium sulfate
  4. customThe solvent was removed
  5. customthe residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate
  6. additionFractions containing the target compound
  7. concentrationwere concentrated
  8. additionTo the residue was added diethyl ether
  9. filtrationhexane=1:3, and the precipitate was collected by filtration
  10. washThis was washed with hexane
  11. customdried under aeration

Sources & evidence

ORD record
ord-1a78abd3c07f48048d4aa6d10402290c
Source dataset
uspto-grants-2012_10
Patent number
US08288538B2

Reaction notes

Loading…