Fenoterol

Originator

Berotec,Boehringer Ingelheim,W. Germany,1972

Uses

antiinflammatory

Definition

ChEBI: A member of the class resorcinols that is 5-(1-hydroxyethyl)benzene-1,3-diol in which one of the methyl hydrogens is replaced by a 1-(4-hydroxyphenyl)propan-2-amino group. A beta2-adrenergic agonist, it is used (as the ydrobromide salt) as a bronchodilator in the management of reversible airway obstruction.

Manufacturing Process

441 grams (1.4 mols) of 3,5-diacetoxy-α-bromo-acetophenone (MP 66°C), prepared by bromination of 3,5-diacetoxy-acetophenone, were added to a solution of 714 grams (2.8 mols) of 1-p-methoxyphenyl-2-benzylaminopropane in 1,000 cc of benzene, and the resulting solution mixture was refluxed for 1 hour. The molar excess of 1-p-methoxy-phenyl-2-benzylaminopropane precipitated out as its hydrobromide. After separation of the precipitated hydrobromide of the amino component, the hydrochloride of 1-pmethoxy- phenyl-2-(β-3',5'-diacetoxyphenyl-β-oxo)-ethyl-benzylamino-propane was precipitated from the reaction solution by addition of an ethanolic solution of hydrochloric acid. The precipitate was separated and, without further purification, was deacetylated by boiling it in a mixture of 2 liters of aqueous 10% hydrochloric acid and 1.5 liters of methanol.
The resulting solution was filtered through animal charcoal and, after addition of 2 liters of methanol, it was debenzylated by hydrogenation at 60°C over palladinized charcoal as a catalyst. After removal of the catalyst by filtration, the filtrate was concentrated by evaporation, whereupon the hydrochloride of 1-p-methoxyphenyl-2-(β-3',5'-dihydroxyphenyl-β-oxo)-ethylamino-propane (MP 244°C) crystallized out. For the purpose of demethylation, the 350 grams of the hydrochloride thus produced were refluxed for 2 hours with 3.5 liters of aqueous 48% hydrobromic acid. Upon cooling of the reaction solution, 320 grams of 1-p-hydroxyphenyl-2-(β-3',5'-dihydroxyphenyl-β-oxo)-ethylaminopropanehydrobromide (MP 220°C) crystallized out.
·220 grams of 1-p-hydroxyphenyl-2-(β-3',5'-dihydroxyphenyl-β-oxo)- ethylamino-propane hydrobromide were dissolved in 1 liter of methanol, the resulting solution was boiled with activated charcoal, the charcoal was filtered off and the filtrate was hydrogenated in the presence of Raney nickel at 60°C and 5 atmospheres gauge. Thereafter, the catalyst was filtered off, the methanolic solution was admixed with a small amount of concentrated hydrobromic acid, and the mixture was evaporated to dryness in vacuo. The residue was stirred with acetone, the mixture was vacuum filtered and the filter cake was recrystallized from a mixture of methanol and ether. The 1-phydroxyphenyl- 2-(β-3',5'-dihydroxyphenyl-β-hydroxy)-ethylamino-propane hydrobromide thus obtained had a melting point of 222° to 223°C.

brand name

Berotec [as hydrobromide](Boehringer Ingelheim);Dosberotec;Duovent;Fensol;Partusisten.

Therapeutic Function

Bronchodilator

World Health Organization (WHO)

Fenoterol, a beta 2-adrenoreceptor agonist with bronchodilator activity, was introduced in 1971 for the management of asthma. In the 1960's, the use of other sympathomimetics in pressurised aerosols had already been associated with an increase in mortality due to asthma. However, it was not clear whether patients died from the severity of the asthma attack or from its treatment.

Mechanism of action

Fenoterol is a selective stimulant of β2-adrenoreceptors. It dilates bronchi and blood vessels, has a pronounced tocolytic action, lowers contractile activity and reduces uterus tonicity. It is mainly used in premature births.

Clinical Use

Fenoterol is a selective β2-sympathomimetic agent that is in wide clinical use in Europe.

Synthesis

Fenoterol, 3,5-dihydroxy-|á[[(-p-hydroxy-|á-methylphenethyl)amino]methyl]- benzyl alcohol (23.3.16), is synthesized from 3,5-diacetoxyacetophenone, which is brominated to give 3,5-diacetoxybromacetophenone (23.3.12). This is reacted with 2-benzylamino-1-(4-methoxyphenyl)-propane, giving the corresponding tertiary amine 23.3.13. Hydrolysis of the acetyl group of this product and removal of the protective benzyl group by hydrogen reduction using a palladium on carbon catalyst gives a secondary amine 23.3.14. This is reacted with hydrobromic acid, which cleaves the ether bond in the benzene ring, producing phenol derivative 23.3.15. Finally, reduction of the carbonyl group with hydrogen gives the desired fenoterol (23.3.16).