Triethylamine → HCID 16117291, compound

HRID 2265752Notes

Reaction equation

HRID 2265752 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)[CH:5]=[CH:4][N:3]=1.C([N:35]([CH2:38]C)CC)C.ClC([O:43][C:44]1[CH:49]=CC=[CH:46][CH:45]=1)=O.C(=O)([O-])[OH:51].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:32][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:38]([N:35]3[CH2:46][CH2:45][C@@H:44]([OH:43])[CH2:49]3)=[O:51])[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])[CH2:21][CH2:20]1)=[O:18]

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 15891Phenyl chloroformateHCID 516892Sodium BicarbonateHCID 59596940N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Product 1

HCID 16117291HCID 16117291, compoundYield 61%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

N-{4-[(2-Aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (100.0 mg) was dissolved in tetrahydrofuran (2.0 ml) under a nitrogen atmosphere, triethylamine (0.0630 ml) and phenyl chloroformate (0.0624 ml) were added dropwise at 0° C., followed by stirring for 30 min. The reaction mixture was stirred after addition of ethyl acetate (5 ml) and saturated sodium hydrogencarbonate (5 ml). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and filtered it. The solvent was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (2.0 ml). (R)-(−)-3-Pyrrolidinol hydrochloride (112.0 mg) and triethylamine (0.315 ml) were added at room temperature under a nitrogen atmosphere, followed by stirring 22 hr and 15 min. The reaction mixture was partitioned between ethyl acetate (10 ml) and saturated 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 the resultant residue was added heptane:ethyl acetate=10:1 to suspend a solid. The solid was collected by filtration to provide the titled compound as white powder (76.4 mg, 61%).

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. filtrationfiltered it
  6. concentrationThe solvent was concentrated under reduced pressure
  7. dissolutionThe residue was dissolved in N,N-dimethylformamide (2.0 ml)
  8. addition(R)-(−)-3-Pyrrolidinol hydrochloride (112.0 mg) and triethylamine (0.315 ml) were added at room temperature under a nitrogen atmosphere
  9. stirringby stirring 22 hr and 15 min
  10. customThe reaction mixture was partitioned between ethyl acetate (10 ml) and saturated sodium hydrogencarbonate (5 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
  18. additionTo the resultant residue was added heptane
  19. filtrationThe solid was collected by filtration

Sources & evidence

ORD record
ord-de24afc7bab94f918e6ac8cae100180e
Source dataset
uspto-grants-2010_12
Patent number
US07855290B2

Reaction notes

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