Phosphorus oxychloride → Ethyl 6-chloro-2-(2,4-difluorophenyl)pyridine-3-carboxylate

HRID 2390947Notes

Reaction equation

HRID 2390947 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=[CH:11][N+:10]=1[O-].P(Cl)(Cl)([Cl:23])=O>ClC(Cl)C>[Cl:23][C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[N:10]=1

Participants

4

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 582235643-Pyridinecarboxylic acid, 2-(2,4-difluorophenyl)-, ethyl ester, 1-oxide2×

Product 1

HCID 21062879Ethyl 6-chloro-2-(2,4-difluorophenyl)pyridine-3-carboxylate

Reagents, catalysts & solvents 1

HCID 63651,1-DichloroethaneSolvent

Conditions

Temperature
72.5 °C

Procedure

To a nitrogen purged 500 mL, 3-necked flask, fitted with a reflux condenser, heating mantle and a thermocouple was charged 2-(2,4-difluorophenyl)-3-(ethoxycarbonyl)pyridine 1-oxide, 4 (21 g, 75 mmoles, 1.0 eq), followed by 150 mL dichloroethane. Phosphorous oxychloride (75 mL) was added in one aliquate with stirring, causing an immediate rise in temperature from 21 to 23° C. followed by gradual warming. The solution was heated under nitrogen to 70-75° C. (completeness of reaction determined by HPLC). The reaction was then cooled to room temperature and concentrated under vacuum to remove most of the POCl3. The remainder was quenched by slowly pouring onto 450 g of ice. The mixture (after the ice melted) was then extracted into methylene chloride (2×200 mL). The combined organics were dried (MgSO4), filtered through silica, eluted with methylene chloride, and concentrated to give the title Compound, 5, as an orange solid. 1H NMR (500.0 MHz, CDCl3) d 8.15 (d, J=8.2 Hz, 1H), 7.54 (td, J=8.5, 5.0 Hz, 1H), 7.34 (d, J=8.2 Hz, 1H), 6.96-6.92 (m, 1H), 6.79-6.74 (m, 1H), 4.16 (q, J=7.2 Hz, 2H), 1.10 (t, J=7.1 Hz, H) ppm.

Workup

  1. customTo a nitrogen purged 500 mL, 3-necked flask
  2. customfitted with a reflux condenser
  3. temperatureheating mantle
  4. customfrom 21 to 23° C.
  5. custom(completeness of reaction determined by HPLC)
  6. temperatureThe reaction was then cooled to room temperature
  7. concentrationconcentrated under vacuum
  8. customto remove most of the POCl3
  9. customThe remainder was quenched
  10. additionby slowly pouring onto 450 g of ice
  11. extractionwas then extracted into methylene chloride (2×200 mL)
  12. dry with materialThe combined organics were dried (MgSO4)
  13. filtrationfiltered through silica
  14. washeluted with methylene chloride
  15. concentrationconcentrated

Sources & evidence

ORD record
ord-00a13e420eef435db479302d231960a1
Source dataset
uspto-grants-2012_09
Patent number
US08273896B2

Reaction notes

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