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

HRID 2265739Notes

Reaction equation

HRID 2265739 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[O:22])[CH2:20][CH2:19]3)=[O:17])=[CH:11][C:10]=2[F:31])[CH:5]=[CH:4][N:3]=1.[CH2:32]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])C.ClC([O:42][C:43]1C=CC=C[CH:44]=1)=O.C(OCC)(=[O:51])C>O1CCCC1.O>[F:31][C:10]1[CH:11]=[C:12]([NH:15][C:16]([C:18]2([C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)=[O:22])[CH2:20][CH2:19]2)=[O:17])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:32]([N:34]2[CH2:37][CH2:38][CH:44]([CH2:43][OH:42])[CH2:36][CH2:35]2)=[O:51])[CH:7]=1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 8857Ethyl AcetateHCID 15891Phenyl chloroformateHCID 59596906N-{4-[(2-Aminopyridin-4-yl)oxy]-3-fluorophenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Product 1

HCID 59596969N-(3-Fluoro-4-{[2-({[4-(hydroxymethyl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 72%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

N-{4-[(2-Aminopyridin-4-yl)oxy]-3-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (150 mg) was dissolved in tetrahydrofuran (4.0 ml) under a nitrogen atmosphere, and triethylamine (0.148 ml) and phenyl chloroformate (0.098 ml) were added dropwise at room temperature in this order, followed by stirring for 10 min. The reaction mixture was stirred after addition of ethyl acetate and water. The organic layer was separated, washed with a 1N aqueous solution of sodium hydroxide, water and brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (4.0 ml). 4-Piperidinemethanol (163 mg) was added at room temperature, followed by stirring for 2 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a 1N aqueous solution of sodium hydroxide, water 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 (eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated. To the resultant residue was added tert-butyl methyl ether:heptane=1:2 to precipitate a solid. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (143.7 mg, 72%).

Workup

  1. stirringThe reaction mixture was stirred
  2. customThe organic layer was separated
  3. washwashed with a 1N aqueous solution of sodium hydroxide, water and brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. concentrationThe solvent was concentrated under reduced pressure
  6. dissolutionThe residue was dissolved in N,N-dimethylformamide (4.0 ml)
  7. addition4-Piperidinemethanol (163 mg) was added at room temperature
  8. stirringby stirring for 2 hr
  9. customThe reaction mixture was partitioned between ethyl acetate and water
  10. washThe organic layer was washed with a 1N aqueous solution of sodium hydroxide, water and brine in this order
  11. dry with materialdried over anhydrous sodium sulfate
  12. concentrationThe solvent was concentrated under reduced pressure
  13. customThe resultant residue was purified by silica gel column chromatography (eluent
  14. additionFractions containing the target compound
  15. concentrationwere concentrated
  16. additionTo the resultant residue was added tert-butyl methyl ether
  17. customheptane=1:2 to precipitate a solid
  18. filtrationThe solid was collected by filtration
  19. customdried under aeration

Sources & evidence

ORD record
ord-b0090e69b15743c79d90a52a0349e994
Source dataset
uspto-grants-2010_12
Patent number
US07855290B2

Reaction notes

Loading…