Phenyl chloroformate → 4-(4-Amino-2-fluorophenoxy)-2-{[4-(pyrrolidin-1-yl)piperidin-1-yl]carbonylamino}pyridine

HRID 492666Notes

Reaction equation

HRID 492666 reaction equation
[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.Cl[C:20](OC1C=CC=CC=1)=[O:21].[N:29]1([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:33][CH2:32][CH2:31][CH2:30]1.[H][H]>O1CCCC1.[C].[Pd].CO.CN(C)C=O.C(N(CC)CC)C>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:20]([N:37]3[CH2:38][CH2:39][CH:34]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH2:35][CH2:36]3)=[O:21])[CH:7]=2)=[C:10]([F:18])[CH:11]=1

Participants

10

Reactant 4

HCID 15891Phenyl chloroformateHCID 787034-(1-Pyrrolidinyl)piperidineHCID 231531982-Amino-4-(2-fluoro-4-nitrophenoxy)pyridineHCID 178418361HCID 178418361, compound

Product 1

HCID 231534244-(4-Amino-2-fluorophenoxy)-2-{[4-(pyrrolidin-1-yl)piperidin-1-yl]carbonylamino}pyridineYield 71%

Reagents, catalysts & solvents 5

HCID 178418390HCID 178418390, compoundCatalystHCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent2×HCID 8471TriethylamineSolvent

Procedure

2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (187 mg) was dissolved in tetrahydrofuran (4 ml) under a nitrogen atmosphere, and then triethylamine (0.21 ml) and phenyl chloroformate (0.188 ml) were added dropwise thereto while cooling in an ice bath, followed by stirring at room temperature for 20 min. To the reaction mixture were added N,N-dimethylformamide (2 ml) and 4-(pyrrolidin-1-yl)piperidine (609 mg) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, to which methanol (10 ml)-tetrahydrofuran (10 ml) was added to dissolve, and then 10% palladium carbon (200 mg) was added thereto under a nitrogen atmosphere, followed by replacing with hydrogen inside the system and stirring overnight. After replacing with nitrogen inside the system, the catalyst was filtered and washed with ethanol. The filtrate was concentrated under a reduced pressure to give a residue, which was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the titled compound (214 mg, 71%) as colorless crystals.

Workup

  1. temperaturewhile cooling in an ice bath
  2. stirringby stirring overnight
  3. customThe reaction mixture was partitioned between ethyl acetate and water
  4. washThe organic layer was washed with brine
  5. dry with materialdried over anhydrous sodium sulfate
  6. customThe solvent was evaporated under a reduced pressure
  7. customto give a residue
  8. dissolutionto dissolve
  9. stirringstirring overnight
  10. filtrationthe catalyst was filtered
  11. washwashed with ethanol
  12. concentrationThe filtrate was concentrated under a reduced pressure
  13. customto give a residue, which
  14. customwas purified by silica gel column chromatography (Fuji Silysia NH, eluent

Sources & evidence

ORD record
ord-ccc9f68a8e3b4145a9baf1c9209ea357
Source dataset
uspto-grants-2009_05
Patent number
US07531532B2

Reaction notes

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