Heteronium

Originator

Hetrum bromide,Lilly

Uses

Anticholinergic.

Manufacturing Process

A solution of 5.0 g of 1-methyl-3-pyrrolidinol and 12.5 g of methyl phenyl-2- thienylglycolate in 200 ml of n-heptane is heated to reflux temperature, a trace of sodium methylate is added, and refluxing of the mixture is continued for 3 h. A Dean-Stark trap is incorporated in the reflux apparatus to separate and withdraw the methanol produced by the reaction. At the end of the reflux period, the reaction mixture is cooled and extracted two times with 100 ml portions of 2 N hydrochloric acid. The acid extracts are combined, basified with potassium carbonate, and extracted three times with 50 ml portions of benzene. The benzene extracts are combined, washed two times with 25 ml portions of water, and dried. The benzene is removed from the dried extract by evaporation at reduced pressure. The residue is 1-methyl-3- pyrrolidylphenyl-2-thienylglycolate in the form of a clear liquid.
1-Methyl-3-pyrrolidylphenyl-2-thienylglycolate is dissolved in ethyl acetate to a concentration of about 20% by weight. To the solution is added a small excess of an anhydrous ethanolic solution of hydrogen chloride, whereupon 1- methyl-3-pyrrolidylphenyl-2-thienylglycolate hydrochloride separates as a white crystalline solid and is removed by filtration.
5.0 g of 1-methyl-3-pyrrolidylphenyl-2-thienylglycolate hydrochloride are dissolved in 50 ml of water. The aqueous solution is basified by adding solid potassium carbonate with stirring, and the basified mixture is extracted three times with 25 ml portions of benzene. The benzene extracts are combined, dried with anhydrous magnesium sulfate, and evaporated to dryness. The residue is dissolved in methyl ethyl ketone. Into the resulting solution is bubbled an excess amount of methyl bromide, and the mixture is permitted to stand at room temperature, whereupon a white precipitate appears. The precipitate is removed by filtration, washed with methyl ethyl ketone, recrystallized from absolute ethanol, and dried. So the 1-methyl-3- pyrrolidylphenyl-2-thienylglycolate methobromide was obtained.
1-Methyl-3-pyrrolidylphenyl-2-thienylglycolate methobromide is readily separated into two diastereoisomeric fractions by fractional crystallization. The crude mixed 1-methyl-3-pyrrolidylphenyl-2-thienylglycolate methobromide is dissolved in the minimum quantity of methanol, decolorized with charcoal, diluted with 4 or 5 volumes of ethyl acetate, concentrated on a steam bath until crystals begin to appear, and cooled. The resulting crystals are the α- diastereoisomer of 1-methyl-3-pyrrolidylphenyl-2-thienylglycolate methobromide, melting point 210°-211°C.

Therapeutic Function

Anticholinergic

Raw materials

Preparation Products