23031-25-6

Basic information

• Product Name: 5-(1-Hydroxy-2-tert-butylamino-ethyl)benzene-1,3-diol
• Synonyms: 5-(1-Hydroxy-2-tert-butylamino-ethyl)benzene-1,3-diol;Terbutaline;(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 NO: 23031-25-6
• Molecular Formula: C₁₂H₁₉NO₃
• Molecular Weight: 225.28
• EINECS: 245-385-8
• Mol File: 23031-25-6.mol

Chemical Properties

• Melting Point: 119-122°
• Boiling Point: 366.8°C (rough estimate)
• Flash Point: 165.3 °C
• Appearance: /
• Density: 1.0951 (rough estimate)
• Vapor Pressure: 3.42E-07mmHg at 25°C
• Refractive Index: 1.4596 (estimate)
• Storage Temp.: Refrigerator
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: pKa 8.70(H2O t = 25 I = 0.01) (Uncertain);10.09(H2O t = 25 I = 0.01) (Uncertain)
• CAS DataBase Reference: 5-(1-Hydroxy-2-tert-butylamino-ethyl)benzene-1,3-diol(CAS DataBase Reference)
• NIST Chemistry Reference: 5-(1-Hydroxy-2-tert-butylamino-ethyl)benzene-1,3-diol(23031-25-6)
• EPA Substance Registry System: 5-(1-Hydroxy-2-tert-butylamino-ethyl)benzene-1,3-diol(23031-25-6)

Safety Data

• Hazardous Substances Data: 23031-25-6(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
5-(1-Hydroxy-2-tert-butylamino-ethyl)benzene-1,3-diol is used as an active pharmaceutical ingredient for the development of bronchodilators and tocolytics due to its structural similarity with terbutaline, which is a known β2-adrenergic receptor agonist.
Used in Research and Development:
5-(1-Hydroxy-2-tert-butylamino-ethyl)benzene-1,3-diol is used as a research tool for studying the effects of β2-adrenergic receptor agonists on various physiological processes, including bronchodilation, tocolysis, and potential applications in treating certain neuromuscular disorders.
Used in Drug Delivery Systems:
Similar to terbutaline, 5-(1-Hydroxy-2-tert-butylamino-ethyl)benzene-1,3-diol may be utilized in the development of novel drug delivery systems to enhance its bioavailability and therapeutic outcomes in various medical applications.
Used in Asthma Treatment:
5-(1-Hydroxy-2-tert-butylamino-ethyl)benzene-1,3-diol is used as a bronchodilator for preventing and relieving bronchospasms in bronchial asthma, chronic bronchitis, pulmonary emphysema, and other broncho-pulmonary diseases, given its structural resemblance to terbutaline, which has been used in the treatment of asthma.
Used in Premature Labor Prevention:
5-(1-Hydroxy-2-tert-butylamino-ethyl)benzene-1,3-diol may be used for the prevention of premature labor, as it shares structural and functional similarities with terbutaline, which has been used for this purpose. However,

Originator

Bricanyl,Pharma-Stern,W. Germany,1971

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.

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.

InChI:InChI=1/C21H25N.ClH/c1-21(2,3)15-8-5-9-16-22(4)17-19-13-10-12-18-11-6-7-14-20(18)19;/h5-7,9-14H,16-17H2,1-4H3;1H/b9-5+;

Upstream product

• 51863-60-6 3,5-dihydroxyacetophenone 
• 62932-92-7 2-bromo-1-(3,5-dihydroxyphenyl)ethan-1-one 
• 75-64-9 tert-butylamine 
• 23031-32-5 terbutaline hemisulfate 
• 28924-21-2 3,5-dibenzyloxyacetophenone 
• 50841-49-1 3,5-dibenzyloxyphenylglyoxal 
• 28924-25-6 1-[3,5-bis(benzyloxy)phenyl]-2-(tert-butylamino)ethanol 
• 26153-38-8 3,5-dihydroxybenzaldehyde 
• 57179-37-0 3,5-diacetoxybenzaldehyde 
• 64339-43-1 5-iodoresorcinol 
• 106120-04-1 5-bromoresorcinol 
• 52780-23-1 chloro-3,5-dihydroxybenzene 
• 98-86-2 acetophenone 
• 14401-75-3 1-(3,5-dinitrophenyl)ethanone 

Downstream Products

• 37394-31-3 (-)-Terbutaline 
• 37394-31-3 (+)-Terbutaline 
• 1394837-92-3 C₁₂H₁₈⁽¹²⁵⁾INO₃ 
• 23031-32-5 terbutaline hemisulfate 
• 866343-17-1 C₄₂H₇₀O₃₅*C₁₂H₁₉NO₃ 

Relevant articles and documents

Enantioselective resolution of Rac-terbutaline and evaluation of optically pure R-terbutaline hydrochloride as an efficient anti-asthmatic drug

Terbutaline is a β2-adrenoceptor agonist for the treatment of asthma and chronic obstructive pulmonary disease (COPD). Among the two isomers of terbutaline (TBT 2), R-isomer was found to be the potent enantiomer in generating therapeutic effect, while S-isomer has been reported to show side effects. In this study, R-terbutaline hydrochloride (R-TBH 6) was synthesized through chiral resolution from the racemic terbutaline sulfate (rac-TBS 1) with 99.9% enantiomeric excess (ee) in good overall yield (53.6%). Further, R-TBH 6 nebulized solution was prepared in half dosage of Bricanyl, which is a marketed product of racemic terbutaline and evaluated in vitro aerosol performance and in vivo anti-asthmatic effect on guinea pigs via. pulmonary delivery. From the investigation, it is evident that R-TBH 6 nebulized solution of half dosage performed similar fine aerosol characteristics and anti-asthmatic effect with Bricanyl.

Preparation method of terra

The invention provides a preparation method of terra, and relates to the technical field of chemical synthesis. The preparation method comprises the following steps: (a) reacting compound 1 with halogenated oxirane through Suzuki to obtain compound 2. (b) Compound 2 was reacted with tert-butylamine to yield terbutaline. Suzuki Reaction is creatively applied to preparation of terbutaline, the reaction steps are greatly shortened, the processes of protecting groups and deprotection are avoided by using the bromination reaction, the reaction conditions are mild, the reaction process is easy to control, and the safety coefficient is high. Raw materials are simple and easy to obtain, and the industrial cost is saved. The product yield is high. The purity is high, and the process route of a product with higher quality can be industrially produced.

Method for synthesizing terbutaline

The invention discloses a method for synthesizing terbutaline. The method comprises the following steps: reacting a compound I with selenium dioxide to obtain a compound II; reacting the compound II with tert-butylamine to obtain a compound III; reacting the compound III with a reducing agent to obtain a compound IV; and reacting the compound IV with a catalyst to remove benzyloxy to obtain terbutaline. The synthesis method has the advantage that the generation of impurity alpha-bromo-3, 5-dibenzyloxyacetophenone is avoided.

Preparation method of terbutaline sulfate

The invention discloses a preparation method of terbutaline sulfate, wherein the method comprises the following steps: carrying out a bromination reaction on 3,5-dihydroxyacetophenone as a raw material by using a bromination reagent without hydroxyl protection, carrying out reduction and ring closing, carrying out a ring-opening reaction with tert-butylamine, and finally forming a salt with sulfuric acid to obtain terbutaline sulfate. According to the method, the defects of requirement of deprotection after hydroxyl protection, use of various high-risk highly toxic reagents, long reaction stepand low yield in the prior art are overcome.

Preparation method of terbutaline sulfate

The invention relates to the field of preparation of chemicals, in particular to a preparation method of terbutaline sulfate. The invention provides a preparation method of terbutaline sulfate. With simple and low-cost acetophenone as an initial raw material, the terbutaline is prepared through five-step reaction; then the terbutaline is subjected to salifying and purification to obtain terbutaline sulfate. According to the method disclosed by the invention, the total synthesis route of terbutaline is effectively shortened, so that the method is simple in intermediate purification, single in reaction solvent, simple in process, mild in reaction condition, easy to operate, high in total yield and more suitable for industrial production; the burden of workshop waste liquid treatment and purification is relieved, the three wastes and reaction energy consumption are reduced, the whole route is combined, research and control of raw material medicine impurities are better facilitated, and working hours are shortened technically and the three wastes and reaction energy consumption are reduced technically.

Preparation method of terbutaline

The invention belongs to the field of pharmacy, and particularly relates to a preparation method of terbutaline. The method comprises: S1, adding a compound I and dichloromethane into a reaction kettle, stirring and dissolving, and then adding anhydride, S2, after the reaction is finished, adding dilute alkaline water into the system, fully stirring and washing, collecting a dichloromethane phase,and carrying out reduced pressure distillation to obtain a yellow oily matter, namely a compound II, S3, adding the compound II, ethyl acetate, tert-butylamine, sodium hydroxide and an oxidation protective agent into the reaction kettle, and S4, after the reaction in the step S3 is finished, adding purified water into the system to wash the reaction solution in the step S3, collecting an ethyl acetate phase, and carrying out reduced pressure distillation on the ethyl acetate phase to obtain terbutaline. According to the technical scheme provided by the invention, the post-reaction treatment difficulty is reduced, so that an intermediate compound is easily separated from a reaction system, meanwhile, side reactions such as epoxy bond hydrolysis are avoided, and the stability and yield of the final product terbutaline are improved.

Novel preparation method of terbutaline sulfate

The invention belongs to the field of organic synthesis of medicines, and concretely relates to a novel preparation method of a medicine terbutaline sulfate for treating bronchial spasm caused by bronchial asthma, chronic bronchitis, emphysema and other lung diseases. The synthesis route of the preparation method comprises the following steps: reacting 3,5-dihydroxybenzaldehyde with acetic anhydride to generate a compound I; reacting the compound I with trimethyloxosulfonium halide to generate a compound II; reacting the compound II with tert-butylamine to generate terbutaline; and salifying the terbutaline to generate the terbutaline sulfate. The method has the advantages of avoiding of dangerous chemical reagents, low price of adopted reagents, mild reaction conditions, and suitablenessfor industrial amplification.

Preparation method for terbutaline hemisulfate

The invention discloses a preparation method for terbutaline hemisulfate. The method comprises the following steps: by adopting 3, 5-resacetophenone as a raw material, performing bromination reaction by directly using a bromination reagent without protecting hydroxide radical, then reducing carbanyl group; condensing with tert-butylamine, finally, forming salt with sulfuric acid, thereby obtaining terbutaline hemisulfate. The method can overcome the defects of deprotection after hydroxide radical protection, usage of various high-risk toxic reagents, long reaction steps and low yield in the present technology.

Compositions and methods for inducing adipose tissue cell death

Pharmaceutical compositions, methods for increasing the rate of apoptosis in adipose tissue cells, and methods of reducing adipose tissue mass in a host, are described. One exemplary pharmaceutical composition, among others, includes at least one catecholamine in combination with a pharmaceutically acceptable carrier. The catecholamine is present in a dosage level effective to increase the rate of apoptosis in adipose tissue cells in a host.

Combined doses

The present invention discloses a method and a pharmaceutical dry powder combined dose for the prophylaxis or treatment of a respiratory disorder in a mammalian host by inhalation of a metered dry powder combined dose of finely divided dry medication powders. At least one dry powder medicament is selected from a first group of bronchodilating medicaments and at least one dry powder medicament from a second group of anti-inflammatory medicaments. A metered dry powder medicinal combined dose comprising separately metered deposits of medicinally suitable quantities of each of the selected medicaments is prepared, in which the sum of the metered deposits constitutes the metered quantities of powder of the combined dose and the medicinal combined dose is introduced into an adapted inhaler device for a generally simultaneous delivery of the medicinal combined dose during the course of a single inhalation by a user, such that the delivered medicinal combined dose is composed of a high proportion of mixed de-aggregated fine particles of the selected medicaments, whereby an desired therapeutic or treating effect to the user is achieved.