Triethylamine → HCID 59596916, compound

HRID 2265749Notes

Reaction equation

HRID 2265749 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])[C:10]=2[F:32])[CH:5]=[CH:4][N:3]=1.C([N:35]([CH2:38]C)CC)C.ClC([O:43][C:44]1[CH:49]=CC=C[CH:45]=1)=O.C(=O)([O-])[OH:51].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:31][C:11]1[C:10]([F:32])=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:38]([N:35]3[CH2:45][CH:44]([OH:43])[CH2:49]3)=[O:51])[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:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[O:22])[CH2:19][CH2:20]1)=[O:17]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 15891Phenyl chloroformateHCID 516892Sodium BicarbonateHCID 59596915HCID 59596915, compound

Product 1

HCID 59596916HCID 59596916, compoundYield 78%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

N-{4-[(2-Aminopyridin-4-yl)oxy]-2,3-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (84.0 mg) was dissolved in tetrahydrofuran (1 ml) under a nitrogen atmosphere, triethylamine (0.0530 ml) and phenyl chloroformate (0.0524 ml) were added dropwise at 0° C., followed by stirring for 20 min. The reaction mixture was stirred after addition of ethyl acetate (5 ml) and a saturated aqueous solution of sodium hydrogencarbonate (5 ml). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and filtrated. The solvent was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (2.0 ml). 3-hydroxyazetidine hydrochloride (83.3 mg) and triethylamine (0.265 ml) were added at room temperature under a nitrogen atmosphere, followed by stirring for 12 hr and 25 min. The reaction mixture was partitioned between ethyl acetate (10 ml) and a saturated aqueous solution of sodium hydrogencarbonate (5 ml). The organic layer was separated, washed with twice in water (10 ml) 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 (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1), and fractions containing the target compound were concentrated under reduced pressure to provide the titled compound as white powder (80.3 mg, 78%).

Workup

  1. stirringThe reaction mixture was stirred
  2. customThe organic layer was separated
  3. washwashed with brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. filtrationfiltrated
  6. concentrationThe solvent was concentrated under reduced pressure
  7. dissolutionThe residue was dissolved in N,N-dimethylformamide (2.0 ml)
  8. addition3-hydroxyazetidine hydrochloride (83.3 mg) and triethylamine (0.265 ml) were added at room temperature under a nitrogen atmosphere
  9. stirringby stirring for 12 hr and 25 min
  10. customThe reaction mixture was partitioned between ethyl acetate (10 ml)
  11. customThe organic layer was separated
  12. washwashed with twice in water (10 ml) and brine in this order
  13. dry with materialdried over anhydrous sodium sulfate
  14. concentrationThe solvent was concentrated under reduced pressure
  15. customThe resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent
  16. additionethyl acetate, then ethyl acetate:methanol=10:1), and fractions containing the target compound
  17. concentrationwere concentrated under reduced pressure

Sources & evidence

ORD record
ord-1e4a3dd7928e4fda91c8289e3c7262bf
Source dataset
uspto-grants-2010_12
Patent number
US07855290B2

Reaction notes

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