Hydrochloric Acid → 5-[4-(4-Ethoxy2,3-difluorophenoxymethyl)cyclohexyl]tetrahydropyran-2-one

HRID 605452Notes

Reaction equation

HRID 605452 reaction equation
C(O)C.C([BH3-])#N.[Na+].[CH2:8]([O:10][C:11]1[CH:34]=[CH:33][C:14]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([CH:23](C=O)[CH2:24][CH2:25][C:26]([O:28][CH2:29]C)=[O:27])[CH2:19][CH2:18]2)=[C:13]([F:35])[C:12]=1[F:36])[CH3:9].Cl>O>[CH2:8]([O:10][C:11]1[CH:34]=[CH:33][C:14]([O:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH:20]([CH:23]3[CH2:29][O:28][C:26](=[O:27])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[C:13]([F:35])[C:12]=1[F:36])[CH3:9]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 702EthanolHCID 5003444Sodium cyanoborohydrideHCID 86635748Ethyl 4-[4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexyl]5-oxopentanoate

Product 1

HCID 668767205-[4-(4-Ethoxy2,3-difluorophenoxymethyl)cyclohexyl]tetrahydropyran-2-oneYield 93.3%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

In a reactor under nitrogen atmosphere, 20 mL of ethanol and 0.4 g of sodium cyanoborohydride were added to 5.4 g of ethyl 4-[4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexyl]5-oxopentanoate obtained in the eleventh step, and pH of the mixture was adjusted to about 3 with hydrochloric acid (2M), followed by stirring at room temperature for 15 hours. 30 mL of water was added to the reaction solution, which was extracted three times with 20 mL of toluene. The mixture including the organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was placed in a flask equipped with a Dean-Stark apparatus, to which 100 mL of toluene and 0.1 g of p-toluenesulfonic acid monohydrate were added, and the mixture was refluxed for 1 hour while the solvent was distilled off with the Dean-Stark apparatus. The solution was cooled to room temperature, washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to provide 4.5 g of 5-[4-(4-ethoxy2,3-difluorophenoxymethyl)cyclohexyl]tetrahydropyran-2-one.

Workup

  1. customobtained in the eleventh step, and pH of the mixture
  2. extractionwas extracted three times with 20 mL of toluene
  3. washwas washed with water
  4. dry with materialdried over anhydrous magnesium sulfate
  5. distillationthe solvent was distilled off under reduced pressure
  6. customThe residue was placed in a flask
  7. customequipped with a Dean-Stark apparatus, to which 100 mL of toluene and 0.1 g of p-toluenesulfonic acid monohydrate
  8. additionwere added
  9. temperaturethe mixture was refluxed for 1 hour while the solvent
  10. distillationwas distilled off with the Dean-Stark apparatus
  11. temperatureThe solution was cooled to room temperature
  12. washwashed with water
  13. dry with materialdried over anhydrous magnesium sulfate
  14. distillationthe solvent was distilled off under reduced pressure
  15. customThe residue was purified by silica gel column chromatography

Sources & evidence

ORD record
ord-c2f53a64b8e04de69a09b4358c85e0c0
Source dataset
uspto-grants-2011_03
Patent number
US07914862B2

Reaction notes

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