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

HRID 2066243Notes

Reaction equation

HRID 2066243 reaction equation
C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:46])[NH:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:47])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10](OC2C=CC=CC=2)=[O:11])C=CC=CC=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>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:10]([NH:9][C:19]3[CH:24]=[C:23]([O:25][C:26]4[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]5([C:38]([NH:39][C:40]6[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=6)=[O:46])[CH2:36][CH2:37]5)=[O:34])=[C:28]([F:47])[CH:27]=4)[CH:22]=[CH:21][N:20]=3)=[O:11])[CH2:60][CH2:59]2)[CH2:57]1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 231534044-(3-Dimethylaminoazetidin-1-yl)piperidine trihydrochlorideHCID 59596979phenyl N-[4-(3-fluoro-4-{[1-(phenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate

Product 1

HCID 16118678N-[4-({2-[({4-[3-(Dimethylamino)azetidin-1-yl]piperidin-1-yl]carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N'-phenylcyclopropane-1,1-dicarboxamideYield 25.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of [4-(3-fluoro-4-{[1-(phenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (100 mg) in N,N-dimethylformamide (2.0 ml) were added 4-(3-dimethylaminoazetidin-1-yl)piperidine trihydrochloride (181 mg) and triethylamine (0.259 ml) at room temperature, followed by stirring for 5 days. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order, and dried over anhydrous sodium sulfate. The solvent 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=95:5). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of diethyl ether to the resultant residue. The solid was collected by filtration. The solid was dried under aeration to provide the titled compound as white powder (24.0 mg, 25%).

Workup

  1. customThe reaction mixture was partitioned between ethyl acetate and water
  2. washThe organic layer was washed with a saturated aqueous solution of ammonium chloride and brine in this order
  3. dry with materialdried over anhydrous sodium sulfate
  4. concentrationThe solvent was concentrated under reduced pressure
  5. customThe resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent
  6. additionFractions containing the target compound
  7. concentrationwere concentrated under reduced pressure
  8. customA solid was precipitated by addition of diethyl ether to the resultant residue
  9. filtrationThe solid was collected by filtration
  10. customThe solid was dried under aeration

Sources & evidence

ORD record
ord-4aeea78d7c6949768965bba9d66794a3
Source dataset
uspto-grants-2012_10
Patent number
US08288538B2

Reaction notes

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