Toluene → (4-Benzyl-4-hydroxypiperidin-1-yl)(2-chloropyridin-3-yl)methanone

HRID 60610Notes

Reaction equation

HRID 60610 reaction equation
[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[C:11]1([CH3:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S(Cl)(Cl)=O.CO[CH2:24][CH2:25][O:26]C>>[CH2:17]([C:25]1([OH:26])[CH2:8][CH2:9][N:10]([C:4]([C:3]2[C:2]([Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=2)=[O:6])[CH2:2][CH2:24]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1

Participants

5

Reactant 4

HCID 1140TolueneHCID 80711,2-DimethoxyethaneHCID 24386Thionyl ChlorideHCID 762582-Chloronicotinic acid

Product 1

HCID 86680867(4-Benzyl-4-hydroxypiperidin-1-yl)(2-chloropyridin-3-yl)methanone

Conditions

Temperature
90 °C

Procedure

To a mixture of 2-chloronicotinic acid (1.0 g), toluene (15 mL) and DME (5 mL) was added thionyl chloride (0.51 mL), and the mixture was stirred at 90° C. for 4 hr under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in THF (15 mL), and triethylamine (0.97 mL) and 4-benzyl-4-hydroxypiperidine (1.1 g) were added thereto. The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere, saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.9 g).

Workup

  1. concentrationThe reaction mixture was concentrated under reduced pressure
  2. dissolutionthe residue was dissolved in THF (15 mL)
  3. additiontriethylamine (0.97 mL) and 4-benzyl-4-hydroxypiperidine (1.1 g) were added
  4. stirringThe reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere
  5. additionsaturated aqueous sodium hydrogen carbonate solution was added
  6. extractionthe mixture was extracted with ethyl acetate
  7. washThe extract was washed with saturated brine
  8. dry with materialdried over anhydrous sodium sulfate
  9. customThe solvent was evaporated under reduced pressure
  10. customThe residue was purified by silica gel column chromatography (ethyl acetate/hexane)

Sources & evidence

ORD record
ord-a23c0b140c0e461a932577296114f039
Source dataset
uspto-grants-2016_09
Patent number
US09440990B2

Reaction notes

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