Bambuterol is a new once-daily, oral bronchodilator especially useful in the chronic
treatment of nocturnal asthma. It is a prodrug slowly converted by hydrolysis in the
lung tissue to terbutaline, generating long-acting bronchodilation with comparable
side effects.
ChEBI: A carbamate ester that is terbutaline in which both of the phenolic hydroxy groups have been protected as the corresponding N,N-dimethylcarbamates. A long acting beta-adrenoceptor agonist used in the treatment of asthm
, it is a prodrug for terbutaline.
Preparation of 1-[bis-(3',5'-N,N-dimethylcarbamoyloxy)phenyl]-2-N-tbutylaminoethanol
hydrochloride:
A solution of 78 g of bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-(N-benzyl-tbutyl)
aminoacetophenone in 300 ml of ethanol was hydrogenated in a Parr
equipment in the presence of 25 ml of benzyl chloride and 3.5 g of 10% Pd/C.
The hydrogenation time was 24 hrs at a pressure of 345 KPa (50 psig) and a
temperature of 50°C. The catalyst was filtered off, and the filtrate was
evaporated to dryness. The residue was dissolved in isopropanol, filtered, and
to the filtrate was added diethylether to precipitate the title compound. The
identity of the title product obtained was confirmed with NMR. Yield: 46.5 g.
The bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-(N-benzyl-tbutyl)
aminoacetophenone which was used as starting material was prepared
as follows:
(1a). Bis-3,5-(N-N-dimethylcarbamoyloxy)acetophenone:
To a solution of 152 g of 3,5-dihydroxyacetophenone in 700 ml dry pyridine
was added 280 ml of N,N-dimethylcarbamoyl chloride. The mixture was stirred
for 18 hrs at 60°-70°C. After evaporation in vacuum the residue was treated
with a mixture of diethylether and water. The water phase was extracted with
diethylether, whereafter the combined diethylether phases were washed with
water, and dried over MgSO4. After evaporation, the residue was recrystallized
from isopropylalcohol-petroleum ether b.p. 40°-60°C. The identity of the
product was confirmed with NMR. Yield: 180.4 g.
(1b). Bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-bromoacetophenone:
To a solution of 180 g of bis-3,5-(N,N-dimethylcarbamoyloxy)acetophenone
obtained in step 1a in 700 ml of dioxane was added dropwise a solution of 31
ml of bromine in 200 ml of dioxane. The mixture was stirred at 35°C for 1 hr.
The residue obtained after evaporation in vacuum was recrystallized from
isopropylalcohol-petroleum ether b.p. 40°-60°C. The identity of the product
(1c). Bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-(N-benzyl-tbutyl)
aminoacetophenone:
To a solution of 5.6 g of the bromoacetophenone obtained in step 1b in 75 ml
of acetone was added a solution of 4.9 g of N-benzyl-t-butylamine in 30 ml of
acetone. The mixture was refluxed under stirring for 18 hrs, filtered, and
evaporated in vacuum. The residue was dissolved in diethyl ether, petroleum
ether b.p. 61°-70°C was added, and the yellow precipitate formed filtered off.
After washing with water followed by a 1:1 mixture of isopropylalcoholpetroleum
ether white crystals were obtained. The identity of the product was
confirmed with NMR. Yield: 4.6 g.
was confirmed with NMR. Yield: 174 g.
