| 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 asolution of 714 grams (2.8 mols) of 1-p-methoxyphenyl-2-benzylaminopropanein 1,000 cc of benzene, and the resulting solution mixture wasrefluxed for 1 hour. The molar excess of 1-p-methoxy-phenyl-2-benzylaminopropaneprecipitated out as its hydrobromide. After separation of theprecipitated hydrobromide of the amino component, the hydrochloride of 1-pmethoxy-phenyl-2-(β-3',5'-diacetoxyphenyl-β-oxo)-ethyl-benzylamino-propanewas precipitated from the reaction solution by addition of an ethanolic solutionof hydrochloric acid. The precipitate was separated and, without furtherpurification, was deacetylated by boiling it in a mixture of 2 liters of aqueous10% hydrochloric acid and 1.5 liters of methanol.
The resulting solution was filtered through animal charcoal and, after additionof 2 liters of methanol, it was debenzylated by hydrogenation at 60°C overpalladinized charcoal as a catalyst. After removal of the catalyst by filtration,the filtrate was concentrated by evaporation, whereupon the hydrochloride of1-p-methoxyphenyl-2-(β-3',5'-dihydroxyphenyl-β-oxo)-ethylamino-propane(MP 244°C) crystallized out. For the purpose of demethylation, the 350 gramsof the hydrochloride thus produced were refluxed for 2 hours with 3.5 liters ofaqueous 48% hydrobromic acid. Upon cooling of the reaction solution, 320grams 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, theresulting solution was boiled with activated charcoal, the charcoal was filteredoff and the filtrate was hydrogenated in the presence of Raney nickel at 60°Cand 5 atmospheres gauge. Thereafter, the catalyst was filtered off, themethanolic solution was admixed with a small amount of concentratedhydrobromic acid, and the mixture was evaporated to dryness in vacuo. Theresidue was stirred with acetone, the mixture was vacuum filtered and thefilter cake was recrystallized from a mixture of methanol and ether. The 1-phydroxyphenyl-2-(β-3',5'-dihydroxyphenyl-β-hydroxy)-ethylamino-propanehydrobromide 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 bronchodilatoractivity, was introduced in 1971 for the management of asthma. In the 1960's, theuse of other sympathomimetics in pressurised aerosols had already beenassociated with an increase in mortality due to asthma. However, it was not clearwhether 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 uterustonicity. It is mainly used in premature births. |
| Clinical Use | Fenoterol is a selective β2-sympathomimeticagent 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 brominatedto give 3,5-diacetoxybromacetophenone (23.3.12). This is reacted with2-benzylamino-1-(4-methoxyphenyl)-propane, giving the corresponding tertiary amine23.3.13. Hydrolysis of the acetyl group of this product and removal of the protective benzylgroup by hydrogen reduction using a palladium on carbon catalyst gives a secondaryamine 23.3.14. This is reacted with hydrobromic acid, which cleaves the ether bond in thebenzene ring, producing phenol derivative 23.3.15. Finally, reduction of the carbonyl groupwith hydrogen gives the desired fenoterol (23.3.16). |
