Chemical Properties
The hydrochloride is a white to off-white crystalline powder with a melting point of 184-186°C. It is freely soluble in DMF, pyridine, and methanol, poorly soluble in ethanol and water, and practically insoluble in chloroform. It is odorless and tastes bitter.
Originator
Dobutrex,Lilly,UK,1977
Uses
Dobutamine is predominantly a β1-agonist, with some activity at β2-
receptors. Its primary effect is an increase in cardiac output as a consequence
of increased contractility and HR and decreased afterload. Systolic arterial
pressure may therefore increase, but peripheral resistance is reduced or
unchanged. It is primarily used as an inotrope (inodilator) in low CO states.
D obutamine increases SA node automaticity and conduction velocity in the
atria, ventricles and AV node, with tachyarrhythmias occurring at higher
doses. Dobutamine is administered as an i.v. infusion at a dose range of 0.5–
40 μg kg–1 min–1.
Definition
ChEBI: A catecholamine that is 4-(3-aminobutyl)phenol in which one of the hydrogens attached to the nitrogen is substituted by a 2-(3,4-dihydroxyphenyl)ethyl group. A beta1-adrenergic receptor agonist that has cardiac stimulan
action without evoking vasoconstriction or tachycardia, it is used as the hydrochloride to increase the contractility of the heart in the management of acute heart failure.
Manufacturing Process
In a stainless steel hydrogenation bottle were placed 17.6 g (0.1 mol) of 4-(pmethoxyphenyl)-3-buten-2-one, 80 ml of ethyl acetate, and 1 g of Raney
nickel catalyst. The hydrogenation bottle was attached to a Paar low-pressure
hydrogenation apparatus and the solution was hydrogenated under an initial
hydrogen pressure of 50 psi. The hydrogenation was carried out at room
temperature and after about 12 hours one equivalent of hydrogen had been
absorbed. The catalyst was filtered from the reduction mixture and 18.1 g
(0.1 mol) of homoveratrylamine were added to the reduction mixture.
To the reduction mixture was then added 3.5 g of 5% palladium on carbon
catalyst and the mixture was hydrogenated under a hydrogen pressure of 50
psi at room temperature for 12 hours. The catalyst was removed by filtration
and the filtrate was evaporated to a small volume. The concentrated filtrate
was dissolved in diethyl ether and the ethereal solution was saturated with
anhydrous hydrogen chloride. The reduction product, 3,4-dimethoxy-N-[3-(4-
methoxyphenyl)-1-methyl-n-propyl]phenethylamine was precipitated as the
hydrochloride salt. The salt was filtered and recrystallized from ethanolmelting at about 147°C to 149°C.
To a solution of 101.2 g of the trimethoxy secondary amine, obtained as
described above, in 3,060 ml of glacial acetic acid was added 1,225 ml of
48% hydrobromic acid and the reaction mixture heated at the reflux
temperature for 4 hours. The reaction mixture was then cooled and
evaporated to a small volume. The crystalline residue which formed was
filtered and dried in vacuo. The dried crystalline residue was then triturated
with ethyl acetate and redried to yield 97.3 g of crude crystalline material.
The crude product was dissolved in 970 ml of warm water to obtain a yellow
solution. To the solution was added successively by dropwise addition 75 ml of
1 N and 75 ml of 2 N hydrochloric acid. Following the dropwise addition, the
solution was allowed to stir with ice cooling. The impurities which precipitated
were removed by filtration through a gauze filter. Concentrated hydrochloric
acid was then added dropwise. When approximately 50 to 75 ml of the
concentrated acid had been added with ice bath cooling a pale yellow oil
precipitated along with a while solid precipitate. With continued stirring of the
cold solution, the pale yellow oil crystallized.
The cold solution was then allowed to stand overnight and all crystalline
material filtered through a sintered glass filter. The filtrate was treated with an
additional 300 ml of concentrated hydrochloric acid to yield a heavy white
precipitate. The precipitate was filtered, dried and combined with the initial
precipitate obtained as described above. The combined precipitated product,
3,4-dihydroxy-N-[3-(4-hydroxyphenyl)-1-methyl-n-propyl-β-phenethylamine
hydrochloride, had a melting point of about 184°C to 186°C after
recrystallization from boiling 4 N hydrochloric acid.
Brand name
Dobutrex (Lilly）.
Therapeutic Function
Cardiotonic
Drug interactions
Potentially hazardous interactions with other drugs
Anaesthetics: risk of ventricular arrhythmias with
isoflurane - avoid.
Antidepressants: risk of hypertensive crisis with
MAOIs and moclobemide.
Beta-blockers: possibly severe hypertension and
bradycardia with non-cardioselective beta-blockers.
Dopaminergics: effects possibly enhanced by
entacapone; avoid with rasagiline.
Metabolism
Dobutamine is metabolised in the liver and other
tissues by catechol-o-methyltransferase to an inactive
compound, 3-0-methydobutamine and by conjugation
with glucuronic acid.
Conjugates of dobutamine and 3-0-methyldobutamine
are excreted mainly in urine and to a minor extent in
faeces.
