Methanol → methyl 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylate

HRID 272862Notes

Reaction equation

HRID 272862 reaction equation
[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH3:29]O>C(OCC)(=O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]([O:24][CH3:29])=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 887MethanolHCID 24386Thionyl ChlorideHCID 598374194-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylic acid

Product 1

HCID 68575572methyl 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylate

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-2.5 °C

Procedure

A suspension of 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylic acid (23.5 g, 0.0636 mol) in methanol (235 ml, 10 vol) was stirred and cooled to 0 to −5° C. under nitrogen. Thionyl chloride (9.3 ml, 0.1272 mol, 0.40 vol) was charged dropwise over 20 minutes, maintaining the temperature at −5 to +5° C. The resulting slurry was then heated and stirred at reflux under nitrogen for 16 h after which time LC analysis showed 1.4% by area of acid remaining. The solution was evaporated to dryness in vacuo at 40° C. to give a brown sludge. The sludge was dissolved in ethyl acetate (118 ml, 5 vol) and water (235 ml, 10 vol) and the layers separated. The aqueous layer was washed with ethyl acetate (118 ml, 5 vol) and basified to pH 11 with saturated aqueous potassium carbonate (118 ml, 5 vol). The product was extracted into dichloromethane (3×118 ml, 3×5 vol) and the combined extracts dried over magnesium sulfate (23 g) and concentrated in vacuo at 40° C. to yield methyl 4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylate (21.7 g, 98% from the nitrile) as a cream solid.

Workup

  1. temperaturemaintaining the temperature at −5 to +5° C
  2. temperatureThe resulting slurry was then heated
  3. stirringstirred
  4. temperatureat reflux under nitrogen for 16 h after which time LC analysis
  5. customThe solution was evaporated to dryness in vacuo at 40° C.
  6. customto give a brown sludge
  7. customwater (235 ml, 10 vol) and the layers separated
  8. washThe aqueous layer was washed with ethyl acetate (118 ml, 5 vol)
  9. extractionThe product was extracted into dichloromethane (3×118 ml, 3×5 vol)
  10. dry with materialthe combined extracts dried over magnesium sulfate (23 g)
  11. concentrationconcentrated in vacuo at 40° C.

Sources & evidence

ORD record
ord-1ac366c6ccac4e8a8dedfe0398765766
Source dataset
uspto-grants-2008_11
Patent number
US07456164B2

Reaction notes

Loading…