Triethylamine → HCID 16117037, compound

HRID 2265746Notes

Reaction equation

HRID 2265746 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:33]([N:35]([CH2:38][CH3:39])[CH2:36]C)C.Cl[C:41](OC1C=CC=CC=1)=[O:42].C(OCC)(=[O:52])C>O1CCCC1.O>[F:32][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:36]([N:35]3[CH2:33][CH:39]([CH2:41][OH:42])[CH2:38]3)=[O:52])[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1([C:22]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)=[O:23])[CH2:21][CH2:20]1)=[O:18]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 8857Ethyl AcetateHCID 15891Phenyl chloroformateHCID 59596940N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Product 1

HCID 16117037HCID 16117037, compoundYield 28%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

N-{4-[(2-Aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (108.2 mg) was dissolved in tetrahydrofuran (2.5 ml) under a nitrogen atmosphere, and triethylamine (0.100 ml) and phenyl chloroformate (0.080 ml) were added dropwise at room temperature in this order, followed by stirring for 15 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, dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (2.5 ml). Triethylamine (0.256 ml) and 3-(hydroxymethyl)azetidine hydrochloride (182 mg) were added at room temperature, followed by stirring overnight. 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 under reduced pressure. 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 (38.1 mg, 28%).

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 (2.5 ml)
  7. additionTriethylamine (0.256 ml) and 3-(hydroxymethyl)azetidine hydrochloride (182 mg) were added at room temperature
  8. stirringby stirring overnight
  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 under reduced pressure
  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-ae35d503859740f49a5646bd4f5d4ccf
Source dataset
uspto-grants-2010_12
Patent number
US07855290B2

Reaction notes

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