Triethylamine → HCID 131730221, compound

HRID 388516Notes

Reaction equation

HRID 388516 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]([CH2:19][C:20]3([CH2:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[O:25])[CH2:22][CH2:21]3)=[O:18])=[C:11]([F:34])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C([N:37]([CH2:40]C)CC)C.ClC([O:45][C:46]1[CH:51]=CC=C[CH:47]=1)=O.C(=O)([O-])[OH:53].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:34][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:40]([N:37]3[CH2:47][CH:46]([OH:45])[CH2:51]3)=[O:53])[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([CH2:19][C:20]1([CH2:23][C:24]([NH:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)=[O:25])[CH2:22][CH2:21]1)=[O:18]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 15891Phenyl chloroformateHCID 516892Sodium BicarbonateHCID 131730222HCID 131730222, compound

Product 1

HCID 131730221HCID 131730221, compoundYield 58%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

After dissolving N-{4-[(2-aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxyamide (100.0 mg) in tetrahydrofuran (1 ml) under a nitrogen atmosphere, triethylamine (0.0630 ml) and phenyl chloroformate (0.0624 ml) were added dropwise in that order at 0° C. and the mixture was stirred for 30 minutes. Ethyl acetate (5 ml) and a saturated aqueous solution of sodium hydrogencarbonate (5 ml) were then added to the reaction mixture which was then stirred. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The residue was then dissolved in N,N-dimethylformamide (1.0 ml). After adding 3-hydroxyazetidine hydrochloride (99.0 mg) and triethylamine (0.315 ml) at room temperature, the mixture was stirred for 22 hours and 5 minutes. The reaction mixture was partitioned between ethyl acetate (10 ml) and a saturated aqueous solution of sodium hydrogencarbonate (5 ml). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. Ethyl acetate (1 ml) and heptane (1 ml) were then added to the obtained residue to precipitate a solid, and the solid was collected by filtration. The obtained solid was purified by silica gel column chromatography (Fuji Silysia NH, eluent: ethyl acetate, then ethyl acetate:methanol=10:1) and the fractions containing the target compound were concentrated under reduced pressure to give the title compound (71.1 mg, 58%) as white powder.

Workup

  1. stirringwas then stirred
  2. customThe organic layer was separated
  3. washwashed with brine
  4. dry with materialdried over anhydrous sodium sulfate
  5. concentrationThe solvent was concentrated under reduced pressure
  6. dissolutionThe residue was then dissolved in N,N-dimethylformamide (1.0 ml)
  7. additionAfter adding 3-hydroxyazetidine hydrochloride (99.0 mg) and triethylamine (0.315 ml) at room temperature
  8. stirringthe mixture was stirred for 22 hours and 5 minutes
  9. customThe reaction mixture was partitioned between ethyl acetate (10 ml)
  10. washThe organic layer was washed with brine
  11. dry with materialdried over anhydrous sodium sulfate
  12. concentrationThe solvent was concentrated under reduced pressure
  13. additionEthyl acetate (1 ml) and heptane (1 ml) were then added to the obtained residue
  14. customto precipitate a solid
  15. filtrationthe solid was collected by filtration
  16. customThe obtained solid was purified by silica gel column chromatography (Fuji Silysia NH, eluent
  17. additionethyl acetate, then ethyl acetate:methanol=10:1) and the fractions containing the target compound
  18. concentrationwere concentrated under reduced pressure

Sources & evidence

ORD record
ord-14a651cba0244dcca81c36297308983b
Source dataset
uspto-grants-2013_02
Patent number
US08377938B2

Reaction notes

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