Tetrahydrofuran → HCID 16118808, compound

HRID 2265733Notes

Reaction equation

HRID 2265733 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=C[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[CH2:44][CH: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 16118808HCID 16118808, compound

Procedure

N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (250 mg) was dissolved in tetrahydrofuran (6.0 ml) under a nitrogen atmosphere, and triethylamine (0.247 ml) and phenyl chloroformate (0.163 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 (6.0 ml). This solution was added to a mixture of 3-hydroxyazetidine hydrochloride (259 mg) and triethylamine (0.822 ml), followed by stirring at room temperature for 14.25 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 (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:2, ethyl acetate, ethyl acetate:methanol=30:1, then 10:1). Fractions containing the target compound were concentrated. To the resultant residue 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 white powder (198 mg). This was suspended in 2-propanol (2 ml). Insoluble matter was removed by filtration and washed with 2-propanol. This was dried under aeration to provide white powder (178 mg). This was again suspended in 2-propanol (2 ml). This was collected by filtration, washed with 2-propanol, and dried under aeration to provide the titled compound as white powder (144.2 mg, 46.7%).

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 (6.0 ml)
  6. additionThis solution was added to a mixture of 3-hydroxyazetidine hydrochloride (259 mg) and triethylamine (0.822 ml)
  7. stirringby stirring at room temperature for 14.25 hr
  8. customThe reaction mixture was partitioned between ethyl acetate and water
  9. washThe organic layer was washed with a 1N aqueous solution of sodium hydroxide, water and brine in this order
  10. dry with materialdried over anhydrous sodium sulfate
  11. customThe solvent was removed
  12. customthe residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent
  13. additionFractions containing the target compound
  14. concentrationwere concentrated
  15. additionTo the resultant residue was added diethyl ether
  16. filtrationThe solid was collected by filtration
  17. washwashed with heptane
  18. customThis was dried under aeration

Sources & evidence

ORD record
ord-b1e5f678cc7b42bf95092d85d9494350
Source dataset
uspto-grants-2010_12
Patent number
US07855290B2

Reaction notes

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