Nitromethane → 2-(4-Fluoro-phenoxymethyl)-5-(2-nitro-ethyl)-pyridine

HRID 77995Notes

Reaction equation

HRID 77995 reaction equation
[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][C:8]2[N:13]=[CH:12][C:11]([CH:14]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N+:18]([CH3:21])([O-:20])=[O:19].C([O-])(=O)C.[NH4+].[BH4-].[Na+]>O.C(O)(=O)C.CS(C)=O.C(OCC)(=O)C>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:21][N+:18]([O-:20])=[O:19])=[CH:12][N:13]=2)=[CH:4][CH:3]=1

Participants

9

Reactant 4

HCID 6375NitromethaneHCID 517165Ammonium AcetateHCID 4311764Sodium borohydrideHCID 592553676-(4-Fluorophenoxymethyl)-pyridine-3-carbaldehyde

Product 1

HCID 592551902-(4-Fluoro-phenoxymethyl)-5-(2-nitro-ethyl)-pyridineYield 13.9%

Reagents, catalysts & solvents 4

HCID 176Acetic AcidSolvent2×HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
105 °C

Procedure

To an acetic acid (5.00 mL) solution of 6-(4-fluoro-phenoxymethyl)-pyridine-3-carbaldehyde (500 mg, 1.30 mmol) described in Manufacturing Example 72-1-2 were added nitromethane (923 mg, 15.1 mmol) and ammonium acetate (333 mg, 4.32 mmol) under nitrogen atmosphere, which was stirred for 2 hours at 105° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated from the filtrate under a reduced pressure. Dimethyl sulfoxide (10.0 mL) and acetic acid (600 μL) were added to the residue, and sodium borohydride (131 mg, 3.46 mmol) was then added at room temperature while cooling appropriately. Following 20 minutes of stirring, water was added dropwise at room temperature while cooling appropriately. The reaction mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1) to obtain the title compound (50 mg, 8.38%).

Workup

  1. extractionthe organic layer was extracted with ethyl acetate
  2. washThe organic layer was washed with water and saturated aqueous sodium chloride
  3. dry with materialdried over anhydrous magnesium sulfate
  4. filtrationfiltered
  5. customThe solvent was evaporated from the filtrate under a reduced pressure
  6. additionwas then added at room temperature
  7. temperaturewhile cooling appropriately
  8. waitFollowing 20 minutes
  9. stirringof stirring
  10. temperaturewhile cooling appropriately
  11. extractionThe reaction mixture was extracted with ethyl acetate
  12. washthe organic layer was washed with water and saturated aqueous sodium chloride
  13. dry with materialdried over anhydrous magnesium sulfate
  14. filtrationfiltered
  15. concentrationThe filtrate was concentrated under a reduced pressure
  16. customthe residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1)

Sources & evidence

ORD record
ord-e125256955334b39a78bc9f6aadf2587
Source dataset
uspto-grants-2014_09
Patent number
US08841327B2

Reaction notes

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