4-(Azetidin-1-ylmethyl)piperidine dihydrochloride → N-(4-{[2-({[4-(Azetidin-1-ylmethyl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

HRID 2265660Notes

Reaction equation

HRID 2265660 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(OC2C=CC=CC=2)=O)[C:13](=O)[O:14]C2C=CC=CC=2)[CH:7]=1.Cl.Cl.[N:52]1([CH2:56][CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[CH2:55][CH2:54][CH2:53]1>CN(C)C=O>[N:52]1([CH2:56][CH:57]2[CH2:62][CH2:61][N:60]([C:13]([NH:12][C:8]3[CH:7]=[C:6]([O:5][C:4]4[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]5([C:40]([NH:41][C:42]6[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=6)=[O:49])[CH2:39][CH2:38]5)=[O:36])=[C:2]([F:1])[CH:3]=4)[CH:11]=[CH:10][N:9]=3)=[O:14])[CH2:59][CH2:58]2)[CH2:55][CH2:54][CH2:53]1

Participants

4

Reactant 2

HCID 231533864-(Azetidin-1-ylmethyl)piperidine dihydrochlorideHCID 59597026[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester

Product 1

HCID 16118533N-(4-{[2-({[4-(Azetidin-1-ylmethyl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 48.3%

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 (2.0 ml) was added 4-(azetidin-1-ylmethyl)piperidine dihydrochloride (85.2 mg), followed by stirring at room temperature for 16 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 (21.9 mg, 48.3%).

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-81110da5bb0c480d81c557807fc63ebf
Source dataset
uspto-grants-2010_12
Patent number
US07855290B2

Reaction notes

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