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

Participants

Reaction Conditions

Reaction Steps

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.

Provenance & Evidence