Originator
Berotec,Boehringer Ingelheim,W. Germany,1972
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.
Clinical Use
Fenoterol is an investigational drug in the United States that has been in use in Europe since
1970. It is the p-hydroxyphenyl derivative of metaproteronol, and the combination of the
resorcinol ring and the bulky p-hydroxyphenyl isopropyl group on the nitrogen gives fenoterol
significant β2-receptor selectivity. It has approximately half the affinity for the β2-receptor as
compared to albuterol. The resorcinol ring is resistant to COMT metabolism, and the bulky
nitrogen substituent greatly retards MOA metabolism as well giving fenoterol a reasonable oral
bioavailability with pharmacokinetics similar to albuterol (i.e., rapid onset and a 4- to 6-hour
duration of action after oral inhalation).
