Tetrahydrofuran → HCID 16117161, compound

HRID 2265748Notes

Reaction equation

HRID 2265748 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)[N: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].[O:50]1CCCC1>>[F:32][C:11]1[CH:10]=[C:9]([O:8][C:6]2[N: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:50])[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])[CH2:20][CH2:21]1)=[O:18]

Participants

5

Reactant 4

HCID 8028TetrahydrofuranHCID 8471TriethylamineHCID 15891Phenyl chloroformateHCID 59597015HCID 59597015, compound

Product 1

HCID 16117161HCID 16117161, compoundYield 12%

Procedure

N-{4-[(4-Aminopyrimidin-6-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (100 mg) was dissolved in tetrahydrofuran (7.5 ml) under a nitrogen atmosphere, triethylamine (0.180 ml) and phenyl chloroformate (0.150 ml) were added dropwise at room temperature, followed by stirring for 50 min. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with a 1N aqueous solution of sodium hydroxide 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). To the solution were added triethylamine (0.400 ml) and 3-(hydroxymethyl)azetidine hydrochloride (280 mg) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with a 1N aqueous solution of sodium hydroxide and brine, 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), and 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 (15.6 mg, 12%).

Workup

  1. customThe reaction mixture was partitioned between ethyl acetate and water
  2. customThe organic layer was separated
  3. washwashed with a 1N aqueous solution of sodium hydroxide 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. additionTo the solution were added triethylamine (0.400 ml) and 3-(hydroxymethyl)azetidine hydrochloride (280 mg) at room temperature
  8. stirringby stirring overnight
  9. customThe reaction mixture was partitioned between ethyl acetate and water
  10. customThe organic layer was separated
  11. washwashed with a 1N aqueous solution of sodium hydroxide and brine
  12. dry with materialdried over anhydrous sodium sulfate
  13. concentrationThe solvent was concentrated under reduced pressure
  14. customThe resultant residue was purified by silica gel column chromatography (eluent
  15. additionethyl acetate, then ethyl acetate:methanol=95:5), and fractions containing the target compound
  16. concentrationwere concentrated under reduced pressure
  17. additionTo the resultant residue was added tert-butyl methyl ether
  18. customheptane=1:2 to precipitate a solid
  19. filtrationThe solid was collected by filtration
  20. customdried under aeration

Sources & evidence

ORD record
ord-5828d0529f41406999cb0f2b5566bcc2
Source dataset
uspto-grants-2010_12
Patent number
US07855290B2

Reaction notes

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