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

HRID 2265736Notes

Reaction equation

HRID 2265736 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.C(N(CC)CC)C.Cl[C:40](OC1C=CC=CC=1)=[O:41].FC(F)(F)C(O)=O.[OH:56][CH2:57][CH:58]1[CH2:61][NH:60][CH2:59]1>O1CCCC1>[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:40]([N:60]2[CH2:61][CH:58]([CH2:57][OH:56])[CH2:59]2)=[O:41])[CH:7]=1

Participants

6

Reactant 4

HCID 8471Triethylamine2×HCID 15891Phenyl chloroformateHCID 59596906N-{4-[(2-Aminopyridin-4-yl)oxy]-3-fluorophenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideHCID 685001703-(Hydroxymethyl)azetidine trifluoroacetate

Product 1

HCID 59596982N-(3-Fluoro-4-{[2-({[3-(hydroxymethyl)azetidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 38.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

N-{4-[(2-Aminopyridin-4-yl)oxy]-3-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (297 mg) was dissolved in tetrahydrofuran (8.0 ml) under a nitrogen atmosphere, and triethylamine (0.293 ml) and phenyl chloroformate (0.193 ml) were added dropwise at room temperature in this order, followed by stirring for 1 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 residue was dissolved in N,N-dimethylformamide (8.0 ml). This solution was added to a mixture of a crude product of 3-(hydroxymethyl)azetidine trifluoroacetate (corresponds to 2.58 mmol) and triethylamine (2.0 ml), followed by stirring at room temperature for 11 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 removed, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:2, ethyl acetate, ethyl acetate:methanol=50:1, then 20:1). Fractions containing the target compound were concentrated. To the resultant residue (159.4 mg) was added diethyl ether:heptane=1:2 to suspend a solid. The solid was collected by filtration and washed with heptane. This was dried under aeration to provide the titled compound as white powder (143.2 mg, 38.1%).

Workup

  1. customThe reaction mixture was partitioned between ethyl acetate and water
  2. washThe organic layer was washed with a 1N aqueous solution of sodium hydroxide, water and brine in this order
  3. dry with materialdried over anhydrous sodium sulfate
  4. concentrationThe solvent was concentrated under reduced pressure
  5. dissolutionThe residue was dissolved in N,N-dimethylformamide (8.0 ml)
  6. stirringby stirring at room temperature for 11 hr
  7. customThe reaction mixture was partitioned between ethyl acetate and water
  8. washThe organic layer was washed with a 1N aqueous solution of sodium hydroxide, water and brine in this order
  9. dry with materialdried over anhydrous sodium sulfate
  10. customThe solvent was removed
  11. customthe residue was purified by silica gel column chromatography (eluent
  12. additionFractions containing the target compound
  13. concentrationwere concentrated
  14. additionTo the resultant residue (159.4 mg) was added diethyl ether
  15. filtrationThe solid was collected by filtration
  16. washwashed with heptane
  17. customThis was dried under aeration

Sources & evidence

ORD record
ord-dddcaeb258c946c2b9c2e1ff099877ba
Source dataset
uspto-grants-2010_12
Patent number
US07855290B2

Reaction notes

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