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5-(1-Hydroxy-2-tert-butylamino-ethyl)benzene-1,3-diol

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5-(1-Hydroxy-2-tert-butylamino-ethyl)benzene-1,3-diol Basic information

Product Name:
5-(1-Hydroxy-2-tert-butylamino-ethyl)benzene-1,3-diol
Synonyms:
  • Bambuterol EP Impurity A
  • 5-(1-Hydroxy-2-tert-butylamino-ethyl)benzene-1,3-diol
  • (R)-α-[(tert-Butylamino)methyl]-3,5-dihydroxybenzyl alcohol
  • (S)-α-[(tert-Butylamino)methyl]-3,5-dihydroxybenzyl alcohol
  • 5-[(S)-1-Hydroxy-2-(tert-butylamino)ethyl]benzene-1,3-diol
  • rac-5-[(R*)-2-[(1,1-Dimethylethyl)amino]-1-hydroxyethyl]-1,3-benzenediol
  • C07129
  • Terbutaline & Terbutaline Sulfate
CAS:
23031-25-6
MF:
C12H19NO3
MW:
225.28
EINECS:
245-385-8
Mol File:
23031-25-6.mol
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5-(1-Hydroxy-2-tert-butylamino-ethyl)benzene-1,3-diol Chemical Properties

Melting point:
119-122°
Boiling point:
366.8°C (rough estimate)
Density 
1.0951 (rough estimate)
refractive index 
1.4596 (estimate)
pka
pKa 8.70(H2O t = 25 I = 0.01) (Uncertain);10.09(H2O t = 25 I = 0.01) (Uncertain)
CAS DataBase Reference
23031-25-6
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5-(1-Hydroxy-2-tert-butylamino-ethyl)benzene-1,3-diol Usage And Synthesis

Description

Terbutaline is a synthetic congener of adrenaline that acts at the β2-receptor causing bronchodilation and tocolytic effects. It was the first β2-selective adrenoreceptor agonist in general clinical use. In 2011, the Food and Drug Administration (FDA) placed a black-boxed warning on terbutaline stating that terbutaline injections should not be given to pregnant women nor should be used to prevent preterm labor or for long-term (greater than 48–72 h) treatment of preterm labor. Oral terbutaline should not be used at all due to its potential for cardiac toxicity and death. Terbutaline is on the World Anti- Doping Agency’s list of prohibited drugs for Olympic athletes (except when a Therapeutic Use Exemption has been granted in advance and when used by inhalation).

Description

Terbutaline is a short-acting β2-adrenergic receptor (β2-AR) agonist and an active metabolite of bambuterol (Item No. 17887). It binds to β1-, β2-, and β3-ARs (Ki = 31.3, 15.4, and 79.8 nM, respectively) and selectively increases adenylyl cyclase activity in CHO cell membranes expressing recombinant human β2- or β3- over β1-ARs at concentrations 100-fold greater than the respective Ki values. Terbutaline inhibits histamine release induced by ovalbumin in isolated guinea pig lung mast cells. It also inhibits airway obstruction induced by methacholine (acetyl-β-methylcholine; Item No. 23092) or leukotriene D4 (LTD4; Item No. 20310) in anesthetized guinea pigs. Formulations containing terbutaline have been used in the treatment of asthma.

Originator

Bricanyl,Pharma-Stern,W. Germany,1971

Uses

Terbutaline is used as a bronchodilator and for the prevention of premature labor. The FDA has added boxed warnings to terbutaline for its use as a tocolytic for the prevention of preterm labor. Unlabeled use includes treatment of hyperkalemia. Terbutaline is being studied for its use in treatment of certain neuromuscular disorders as well.

Uses

Terbutaline is a beta-adrenoceptor agonist used to treat asthma and premature labor.

Uses

Terbutaline is used for preventing and relieving bronchospasms in bronchial asthma, chronic bronchitis, pulmonary emphysema, and other broncho-pulmonary diseases.

Definition

ChEBI: A member of the class of phenylethanolamines that is catechol substuted at position 5 by a 2-(tert-butylamino)-1-hydroxyethyl group.

Indications

Terbutaline (Brethine, Bricanyl) is a relatively specific β2-adrenoceptor agonist. Terbutaline can prevent premature labor, especially in individuals who are more than 20 weeks into gestation and have no indication of ruptured fetal membranes or in whom labor is not far advanced. Its effectiveness in premature labor after 33 weeks of gestation is much less clear. Terbutaline can decrease the frequency, intensity, and duration of uterine contractions through its ability to directly stimulate β2-adrenoceptors. While it appears to be especially selective for β2-receptor activation, terbutaline does have some β1 activity as well.

Manufacturing Process

To a solution of 32 g of benzyl-t-butylamine in 300 ml of absolute ethanol at reflux temperature was added 32 g of 3,5-dibenzyloxy-?-bromoacetophenone in 10 ml of dry benzene. The mixture was refluxed for 20 hours and then evaporated. When absolute ether was added to the residue, benzyl-tbutylamine hydrobromide was precipitated. The precipitated compound was filtered off and to the filtrate was added an excess of 2 N sulfuric acid. This caused precipitation of the hydrogen sulfate of 3,5-dibenzyloxy-?-(benzyl-tbutylamino)- acetophenone which was recrystallized from acetone/ether. If the product is crystallized from different organic solvents, the melting point will vary with the type and amount of solvent of crystallization, but the product can be used directly for hydrogenation.
15 g of 3,5-dibenzyloxy-?-(benzyl-t-butylamino)-acetophenone hydrogen sulfate in 200 ml of glacial acetic acid were hydrogenated in a Parr pressure reaction apparatus in the presence of 1.5 g of 10% palladium charcoal at 50°C and 5 atmospheres pressure. The reaction time was 5 hours. The catalyst was filtered off, the filtrate was evaporated to dryness and the hydrogen sulfate of 1-(3',5'-dihydroxyphenyl)-2-(t-butylamino)-ethanol was received. This compound is hygroscopic, but it can be transformed into a nonhygroscopic sulfate in the following manner.
The hydrogen sulfate was dissolved in water and the pH of the solution was adjusted to 5.6 (pH-meter) with 0.1 N sodium hydroxide solution. The water solution was evaporated to dryness and the residue dried with absolute ethanol/benzene and once more evaporated to dryness. The remaining crystal mixture was extracted in a Soxhlet extraction apparatus with absolute methanol. From the methanol phase the sulfate of 1-(3',5'-dihydroxyphenyl)- 2-(t-butylamino)-ethanol crystallized. Melting point 246°C to 248°C.

Therapeutic Function

Bronchodilator

Mechanism of action

Terbutaline is a synthetic sympathomimetic amine. It is one of the most selective direct–acting stimulants of β2-adrenoreceptors. It stimulates smooth muscle β2-adrenoreceptors in the bronchi, relaxing them and relatively minutely acting on the β1—receptors of the heart.

Clinical Use

Terbutaline should be initially used only in an appropriate hospital setting where any obstetric complications can be readily addressed. After initial administration, it can be used in the outpatient setting. Concomitant use of β2-adrenergic agonists and corticosteroids have additional diabetic effects and may rarely lead to pulmonary edema.The combination of β2- adrenergic agonists and magnesium sulfate can cause cardiac disturbances, while coadministration of terbutaline with other sympathomimetics can lead to the potentiation of the actions of the latter drugs.

Side effects

Terbutaline is frequently used in the management of premature labor, although it has not been marketed for such use. Its effectiveness, side effects, precautions, and contraindications are similar to those of all β2-adrenergic agonists. Terbutaline can cause tachycardia, hypotension, hyperglycemia, and hypokalemia. It can be given orally in addition to subcutaneous or intravenous administration.

Chemical Synthesis

Terbutaline, α-[(tert-butylamino)methyl]-3,5-dihydroxybenzylic alcohol (11.1.14), differs from the examined compounds mainly in the location of hydroxyl groups in the benzene ring, and is synthesized by brominating 3,5-dibenzyloxyαcetophenone into the appropriate 3,5-dibenzyloxybromoacetophenone (11.1.12), which is reacted with N-benzyl-N-tert-butylamine, giving the aminoketone (11.1.13). Reduction of this product by hydrogen over a palladium catalyst leads to terbutaline (11.1.14) [16–18].

Environmental Fate

Terbutaline is administered as the sulfate. It is a white to graywhite, crystalline powder; nearly odorless or with the faint odor of acetic acid. Terbutaline has a slightly bitter taste. It has a melting point of 247°C. Terbutaline sulfate is soluble at 1 g per 1.5 ml water or 250 ml of ethanol. It is soluble in 0.1 N hydrochloric acid, slightly soluble in methanol, and insoluble in chloroform. While terbutaline is stable under normal conditions as a solid, it is unstable in light. Terbutaline is degraded through oxidative processes; this is enhanced in the presence of trace levels of metals and in the presence of oxygen.
No information is currently available on breakdown in soil, groundwater, or surface water.

Toxicity evaluation

The primary mechanism of terbutaline is the stimulation of adenyl cyclase, which catalyzes cyclic adenosine monophosphate (AMP) from adenosine triphosphate (ATP). In the liver, buildup of cyclic AMP stimulates glycogenolysis and an increase in serum glucose. In skeletal muscle, this process results in increased lactate production. Direct stimulus of sodium/potassium ATPase in skeletal muscle produces a shift of potassium from the extracellular space to the intracellular space. Relaxation of smooth muscle produces a dilation of the vasculature supplying skeletal muscle, which results in a drop in diastolic and mean arterial pressure (MAP). Terbutaline has greater b2 selectivity, but overdose will have both β1 and β2 activity. Tachycardia occurs as a reflex to the drop in MAP or as a result of β1 stimulus. β1-Adrenergic receptors in the locus ceruleus also regulate norepinephrine-induced inhibitory effects, resulting in agitation, restlessness, and tremor.

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