Tetrahydrofuran → HCID 16118941, compound

HRID 2066313Notes

Reaction equation

HRID 2066313 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])=[C:11]([F:31])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C([N:34]([CH2:37]C)CC)C.ClC([O:42][C:43]1[CH:48]=CC=[CH:45][CH:44]=1)=O.[O:49]1CCCC1>>[F:31][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:37]([N:34]3[CH2:45][CH2:44][C@H:43]([OH:42])[CH2:48]3)=[O:49])[CH:7]=2)[CH:14]=[CH:13][C:12]=1[NH:15][C:16]([C:18]1([C:21]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)=[O:22])[CH2:20][CH2:19]1)=[O:17]

Participants

5

Reactant 4

HCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 15891Phenyl chloroformateHCID 59596943N-(4-(2-aminopyridin-4-yloxy)-2-fluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Product 1

HCID 16118941HCID 16118941, compoundYield 79.8%

Procedure

N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (150 mg) was dissolved in tetrahydrofuran (1.5 ml) under a nitrogen atmosphere, triethylamine (0.181 ml) and phenyl chloroformate (0.163 ml) were added while stirring and cooling in an ice water bath, followed by stirring at the same temperature for 15 min. The reaction mixture was partitioned between ethyl acetate (30 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The separated organic layer was washed with brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. To the residue was added N,N-dimethylformamide (1.5 ml), and (S)-3-pyrrolidinol (123 mg) was added, followed by stirring at room temperature for 3 hr. The reaction mixture was partitioned after addition of ethyl acetate (30 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The separated organic layer was washed with brine (30 ml), and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:5, ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure, and to the residue (169 mg) were added tert-butyl methyl ether (2 ml) and heptane (2 ml) to suspend a solid. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (151.9 mg, 79.8%).

Workup

  1. temperaturecooling in an ice water bath
  2. stirringby stirring at the same temperature for 15 min
  3. customThe reaction mixture was partitioned between ethyl acetate (30 ml)
  4. washThe separated organic layer was washed with brine (30 ml)
  5. dry with materialdried over anhydrous sodium sulfate
  6. customThe solvent was removed under reduced pressure
  7. additionTo the residue was added N,N-dimethylformamide (1.5 ml), and (S)-3-pyrrolidinol (123 mg)
  8. additionwas added
  9. stirringby stirring at room temperature for 3 hr
  10. customThe reaction mixture was partitioned
  11. additionafter addition of ethyl acetate (30 ml)
  12. washThe separated organic layer was washed with brine (30 ml)
  13. dry with materialdried over anhydrous sodium sulfate
  14. customThe solvent was removed under reduced pressure
  15. customthe residue was purified by silica gel column chromatography (eluent
  16. additionFractions containing the target compound
  17. concentrationwere concentrated under reduced pressure
  18. additionto the residue (169 mg) were added tert-butyl methyl ether (2 ml) and heptane (2 ml)
  19. filtrationThe solid was collected by filtration
  20. customdried under aeration

Sources & evidence

ORD record
ord-be903ff03006454d983d0dcdf818b7d0
Source dataset
uspto-grants-2012_10
Patent number
US08288538B2

Reaction notes

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