Sodium hydride → (3-Chloro-2,5,6-trifluoro-pyridin-4-yl)-acetic acid benzyl ester

HRID 426223Notes

Reaction equation

HRID 426223 reaction equation
[Cl:1][C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1F.C(OCC1C=CC=CC=1)(=O)[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C.CS(C)=O.O>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][C:7]1[C:6]([F:9])=[C:5]([F:10])[N:4]=[C:3]([F:11])[C:2]=1[Cl:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1

Participants

8

Reactant 4

HCID 24758Sodium hydrideHCID 25517Ammonium ChlorideHCID 84754Dibenzyl malonateHCID 1371833-Chloro-2,4,5,6-tetrafluoropyridine

Product 1

HCID 59184738(3-Chloro-2,5,6-trifluoro-pyridin-4-yl)-acetic acid benzyl esterYield 74.6%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 962WaterSolvent2×HCID 6228DimethylformamideSolvent

Procedure

3-Chloro-2,4,5,6-tetrafluoropyridine (33.1 g, 178 mmol) and dibenzyl malonate (44.5 ml, 178 mmol) were dissolved in anhydrous DMF (360 ml) under nitrogen atmosphere. The mixture (142) was then cooled in an ice bath. To a stirred mixture, was portionwise added 60% sodium hydride (15.68 g, 392 mmol) during 2.5 hr. The mixture was then stirred in a water bath for ca. 15 hr. The mixture was neutralized with aqueous saturated ammonium chloride solution and the mixture was partitioned between ether and water. Ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a crude product as an yellow oil. The crude product was then dissolved in DMSO (200 ml) and stirred with water (3.2 ml) in an oil bath (130˜140° C.) for 3 hr. After cooling to room temperature, water was added to the mixture and the product was extracted with ether. The ether layer was washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a light brown oil. The crude product was purified by silica gel column chromatography (eluent, ether:hexane (1:9)) to afford 41.9 g (74% for two steps) of (3-chloro-2,5,6-trifluoro-pyridin-4-yl)-acetic acid benzyl ester as a white solid. m.p. 87-92° C.; 1H NMR (200 MHz, CDCl3) δδ 3.96 (2H, d, J=1.6 Hz), 5.19 (2H, s), 7.30-7.39 (5H, m).

Workup

  1. customduring 2.5 hr
  2. customthe mixture was partitioned between ether and water
  3. washwashed with water twice
  4. dry with materialdried with anhydrous magnesium sulfate
  5. filtrationfiltered
  6. customevaporated in vacuo
  7. customto give a crude product as an yellow oil
  8. extractionthe product was extracted with ether
  9. washThe ether layer was washed with water twice
  10. dry with materialdried with anhydrous magnesium sulfate
  11. filtrationfiltered
  12. customevaporated in vacuo
  13. customto give a light brown oil
  14. customThe crude product was purified by silica gel column chromatography (eluent, ether:hexane (1:9))

Sources & evidence

ORD record
ord-5d4ef20e241c49c5823c1ad92780bf48
Source dataset
uspto-grants-2012_01
Patent number
US08106064B2

Reaction notes

Loading…