Carbon Dioxide → 2-Difluoromethoxy-4-benzyloxypyridine

HRID 375056Notes

Reaction equation

HRID 375056 reaction equation
[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:17]([F:19])[F:18].C(=O)=O.Cl>O1CCOCC1.[OH-].[Na+].O>[F:18][CH:17]([F:19])[O:15][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:13][N:12]=1

Participants

8

Reactant 4

HCID 280Carbon DioxideHCID 313Hydrochloric AcidHCID 6372ChlorodifluoromethaneHCID 36077244-Benzyloxy-2(1H)-pyridone

Product 1

HCID 189941322-Difluoromethoxy-4-benzyloxypyridineYield 56.4%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 14798Sodium HydroxideSolventHCID 312751,4-DioxaneSolvent

Procedure

4-Benzyloxy-2-pyridone (311.4 g, 1.55 mol) was mechanically stirred under nitrogen in a mixture of dioxane (6.2 L) and 50% sodium hydroxide (2.48 L) while chlorodifluoromethane (1,332.4 g, 15.5 mol) was condensed into the 22 L flask over a 4 h period using a dry-ice condenser that was attached to one of the necks of the 4-neck flask. The temperature inside the flask was maintained below 35° C. by means of an ice-bath. The mixture was then stirred for 18 h maintaining the temperature of the mixture between 25° C. and 35° C. The dry-ice condenser was in place during the 18 h reaction time. The mixture was then diluted with water, acidified to pH 1 with conc. HCl and extracted three times with ethyl acetate. If emulsions formed the whole mixture was filtered through a bed of celite. The combined organic layers were dried (MgSO4), filtered through silica gel and concentrated in-vacuo. The crude oil was chromatographed on a Prep-500 HPLC to give 2-difluoromethoxy-4-benzyloxypyridine (219.75 g, 56% yield) as a yellow oil, nD =1.5274. Anal. Calcd. for C13H11NO2F2 : C,62.15; H,4.41; N,5.58 Found: C,62.18; H,4.40; N,5.52.

Workup

  1. customcondensed into the 22 L flask over a 4 h period
  2. temperatureThe temperature inside the flask was maintained below 35° C. by means of an ice-bath
  3. temperaturemaintaining the temperature of the mixture between 25° C. and 35° C
  4. extractionextracted three times with ethyl acetate
  5. customIf emulsions formed the whole mixture
  6. filtrationwas filtered through a bed of celite
  7. dry with materialThe combined organic layers were dried (MgSO4)
  8. filtrationfiltered through silica gel
  9. concentrationconcentrated in-vacuo
  10. customThe crude oil was chromatographed on a Prep-500 HPLC

Sources & evidence

ORD record
ord-fa692e6c642f4480bdb6b96cfa3028f5
Source dataset
uspto-grants-1996_01
Patent number
US05484761

Reaction notes

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