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

HRID 2265737Notes

Reaction equation

HRID 2265737 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.[CH2:32]([N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])C.Cl[C:40](OC1C=CC=CC=1)=[O:41].[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:32]([N:34]3[CH2:37][CH2:38][CH:40]([OH:41])[CH2:36][CH2:35]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 16118938N-[2-Fluoro-4-[(2-{[(4-hydroxypiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideYield 87.3%

Procedure

N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (100 mg) was dissolved in tetrahydrofuran (1 ml) under a nitrogen atmosphere, and triethylamine (0.0658 ml) and phenyl chloroformate (0.0652 ml) were added while stirring and cooling in an ice water bath, followed by stirring at the same temperature for 1 hr. 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 (2.5 ml), and 4-hydroxypiperidine (95.5 mg) and triethylamine (0.132 ml) were added thereto, followed by stirring at room temperature overnight. 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 (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:5, ethyl acetate, then ethyl acetate:methanol=95:5). Crude fractions containing the target compound were concentrated 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 were added tert-butyl methyl ether (2 ml) and heptane (4 ml) to suspend a solid. The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (113.6 mg, 87.3%).

Workup

  1. temperaturecooling in an ice water bath
  2. stirringby stirring at the same temperature for 1 hr
  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 (2.5 ml), and 4-hydroxypiperidine (95.5 mg) and triethylamine (0.132 ml)
  8. additionwere added
  9. stirringby stirring at room temperature overnight
  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 (Fuji Silysia NH, eluent
  16. additionCrude fractions containing the target compound
  17. concentrationwere concentrated under reduced pressure
  18. customthe residue was purified by silica gel column chromatography (eluent
  19. additionFractions containing the target compound
  20. concentrationwere concentrated under reduced pressure
  21. additionto the residue were added tert-butyl methyl ether (2 ml) and heptane (4 ml)
  22. filtrationThe solid was collected by filtration
  23. customdried under aeration

Sources & evidence

ORD record
ord-136bac298e624ae99a2a61936885666b
Source dataset
uspto-grants-2010_12
Patent number
US07855290B2

Reaction notes

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