Sodium hydride → tert-Butyl 4-(5-cyanopyridin-2-yloxy)piperidine-1-carboxylate

HRID 459920Notes

Reaction equation

HRID 459920 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 643502Tert-butyl 4-hydroxypiperidine-1-carboxylateHCID 51520946-Chloro-3-pyridinecarbonitrile

Product 1

HCID 57027834tert-Butyl 4-(5-cyanopyridin-2-yloxy)piperidine-1-carboxylateYield 94.9%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Procedure

Add dropwise a solution of 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1210 mg, 6.01 mmol) in DMF (1.8 mL) to a suspension of NaH (360 mg, 9.02 mmol) in DMF (7.2 mL). Stir at room temperature for 45 min then at 50° C. for additional 40 min. Add a solution of 6-chloro-nicotinonitrile (1000 mg, 7.22 mmol) in DMF (3.6 mL) dropwise and stir overnight at 60° C. Cool down the reaction mixture and evaporate the solvent. Wash the residue with water (10) and extract with EtOAc/hex (2/1, 15 mL). Combine the organic layers and dry over sodium sulfate. Filter and concentrate. Purify the resulting residue through an SCX column. Further purified by chromatography [CH2Cl2/NH3 (2.0M in methanol) 20/1] to provide the title compound (1.73 g, 94%).

Workup

  1. waitat 50° C. for additional 40 min
  2. stirringstir overnight at 60° C
  3. temperatureCool down the reaction mixture
  4. customevaporate the solvent
  5. washWash the residue with water (10)
  6. extractionextract with EtOAc/hex (2/1, 15 mL)
  7. dry with materialCombine the organic layers and dry over sodium sulfate
  8. filtrationFilter
  9. concentrationconcentrate
  10. customPurify the resulting residue through an SCX column
  11. customFurther purified by chromatography [CH2Cl2/NH3 (2.0M in methanol) 20/1]

Sources & evidence

ORD record
ord-b74b9b5696c94d7ea8fc626135e924de
Source dataset
uspto-grants-2007_03
Patent number
US07196100B2

Reaction notes

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