Diethyl Ether → 4,4-Difluoro-1-[6-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-cyclohexanecarbonitrile

HRID 512159Notes

Reaction equation

HRID 512159 reaction equation
[C:1]([C:4]1[N:9]=[CH:8][C:7]([C:10]2([C:18]#[N:19])[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:20][Mg]Br.CCOCC>C1COCC1>[F:17][C:13]1([F:16])[CH2:12][CH2:11][C:10]([C:7]2[CH:8]=[N:9][C:4]([C:1]([OH:3])([CH3:20])[CH3:2])=[CH:5][CH:6]=2)([C:18]#[N:19])[CH2:15][CH2:14]1

Participants

5

Reactant 3

HCID 3283Diethyl EtherHCID 867161801-(6-Acetyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrileHCID 178418573HCID 178418573, compound

Product 1

HCID 867161824,4-Difluoro-1-[6-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-cyclohexanecarbonitrileYield 48%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
-50 °C

Procedure

A solution of 1-(6-acetyl-pyridin-3-yl)-4,4-difluoro-cyclohexanecarbonitrile (17 mg, 0.064 mmol) in THF (1.2 mL) was cooled at −50° C. and treated with a 3.0 M solution of methylmagnesium bromide in ether (110 μL, 0.32 mmol). After stirring at −50° C. for 3 hours, the reaction was quenched by adding saturated aqueous ammonium chloride (5 mL) and stirred at room temperature for a few minutes. AcOEt (5 mL) was added and the biphasic mixture was stirred vigorously for a few seconds. The layers were separated and the aqueous layer was extracted again with AcOEt (5 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was then purified by preparative TLC, eluting with 60% AcOEt in hexanes to afford 4,4-difluoro-1-[6-(1-hydroxy-1-methyl-ethyl)-pyridin-3-yl]-cyclohexanecarbonitrile as a colorless oil (8.7 mg, 48%). LC-MS (m/z) 280.0 (MH+); tR=1.11.

Workup

  1. customthe reaction was quenched
  2. additionby adding saturated aqueous ammonium chloride (5 mL)
  3. stirringstirred at room temperature for a few minutes
  4. additionAcOEt (5 mL) was added
  5. stirringthe biphasic mixture was stirred vigorously for a few seconds
  6. customThe layers were separated
  7. extractionthe aqueous layer was extracted again with AcOEt (5 mL)
  8. dry with materialThe combined organic layers were dried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customThe residue was then purified by preparative TLC
  12. washeluting with 60% AcOEt in hexanes

Sources & evidence

ORD record
ord-63eae451ce874ba694a323e9005689db
Source dataset
uspto-grants-2015_08
Patent number
US09102591B2

Reaction notes

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