18559-94-9

Basic information

• Product Name: Salbutamol
• Synonyms: LEVALBUTEROL HCL;LEVALBUTEROL;2-(tert-butylamino)-1-(4-hydroxy-3-hydroxymethylphenyl)ethanol;4-hydroxy-3-hydroxymethyl-alpha-((tert-butylamino)methyl)benzylalcohol;aerolin;ah3365;alpha’-diol,alpha’-((tert-butylamino)methyl)-4-hydroxy-m-xylene-alph;alpha-1-(((1,1-dimethylethyl)amino)methyl)-4-hydroxy-3-benzenedimethanol
• CAS NO: 18559-94-9
• Molecular Formula: C₁₃H₂₁NO₃
• Molecular Weight: 239.31
• EINECS: 242-424-0
• Product Categories: Steroids & Hormones - 13C & 2H;CELLCEPT
• Mol File: 18559-94-9.mol

Chemical Properties

• Melting Point: 157-160℃
• Boiling Point: 381.97°C (rough estimate)
• Flash Point: 159.5 °C
• Appearance: solid
• Density: 1.0700 (rough estimate)
• Vapor Pressure: 2.78E-08mmHg at 25°C
• Refractive Index: 1.4800 (estimate)
• Storage Temp.: ?20°C
• Solubility: Soluble in ethanol.
• PKA: pKa 9.07(H2O t = 25.0±0.05 I = 0.10) (Uncertain);10.37(H2O t = 25.0±0.05 I = 0.10) (Uncertain)
• Water Solubility: 17.95g/L(25 oC)
• Stability: Stable, but light sensitive. Incompatible with strong oxidizing agents.
• Merck: 13,215
• BRN: 6405698
• CAS DataBase Reference: Salbutamol(CAS DataBase Reference)
• NIST Chemistry Reference: Salbutamol(18559-94-9)
• EPA Substance Registry System: Salbutamol(18559-94-9)

Safety Data

• Hazard Codes: Xn,T,F
• Statements: 22-39/23/24/25-23/24/25-11
• Safety Statements: 36-45-36/37-16-7
• RIDADR: 3249
• WGK Germany: 3
• RTECS: ZE4400000
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 18559-94-9(Hazardous Substances Data)

Usage

Uses

Used in Respiratory Applications:
Salbutamol is used as a bronchodilator for severe and chronic bronchial asthma, chronic bronchitis, and other chronic bronchopulmonary disorders such as chronic obstructive pulmonary disorder (COPD). It relieves cough, wheezing, shortness of breath, and troubled breathing by increasing the flow of air through the bronchial tubes.
Used in Immune Suppression and Antineoplastic Applications:
Salbutamol is used as an immune suppressant and antineoplastic agent, potentially aiding in the treatment of certain cancers.
Used in Antiviral Applications:
Salbutamol is used as an antiviral agent, potentially helping to combat viral infections.
Used in Exercise-Induced Bronchospasm:
Salbutamol is used as a preventive measure for wheezing caused by exercise (exercise-induced bronchospasm).
Brand Names:
Salbutamol is marketed under various brand names, including Airomir, AirSalb, Asmasal Clickhaler, Asmavent, Easyhaler Salbutamol, Pulvinal Salbutamol, Salamol, Salbulin, and Ventolin.

References

[1] https://www.drugbank.ca [2] https://www.drugs.com

Originator

Ventolin ,Allen and Hanburys ,UK ,1969

Manufacturing Process

(a) α1-Benzyl-tert-butylaminomethyl-4-hydroxym-xylene-α1,α3-diol: 3.0 g of 5-(N-benzyl-N-tert-butylglycyl)-salicylic acid methyl ester hydrochloride in 40 ml of water was basified with sodium bicarbonate solution and extracted into ether. The ethereal solution was dried over MgSO4 and evaporated and the basic residue in 20 ml of dry tetrahydrofuran was added with stirring to 1.0 g of lithium aluminum hydride in 100 ml of dry tetrahydrofuran, over a period of 5 minutes. The light gelatinous precipitate that formed was stirred and refluxed for 8 hours after which time 7 ml of water was carefully added and the solvents were removed under reduced pressure. The residue was acidified with dilute hydrochloric acid and brought to pH 8 with sodium hydroxide and sodium bicarbonate. The mixture was filtered and the filtrate and orange solid were separately extracted with chloroform. The combined, dried, chloroform solutions were evaporated to give 22 g of the crude basic triol as an orange solid, when triturated with ether. A portion of the material was recrystallized from ether/light petroleum (BP 40-60°C) to give a white solid, MP 109-111°C. In an alternative process, sodium borohydride was used as the reducing agent, as follows: 36 g of 2-(benzyl-tert-butylamino)-4'-hydroxy-3'-hydroxymethyl acetophenone, hydrochloride was shaken with 100 ml of 10% sodium carbonate solution and 100 ml of ethyl acetate. The ethyl acetate layer was separated, washed with water, dried over anhydrous sodium sulfate and evaporated in vacuum. The residual gum was dissolved in 360 ml of ethanol and cooled to 15°C in an ice/water bath, 8 g of sodium borohydride was then added in portions over 30 minutes while maintaining the temperature at 15-20°C. After a further 30 minutes at 20°C the solution was stirred at room temperature for 2 hours. The solution was again cooled in ice and 250 ml of 2 N sulfuric acid were slowly added, then the solution was evaporated in vacuum until the ethanol had been removed. The clear aqueous solution was then treated with 250 ml of 10% sodium carbonate solution and the oil which precipitated was extracted into ethyl acetate. The ethyl acetate layer was washed with sodium carbonate solution, then with water, and was dried over anhydrous sodium sulfate and evaporated in vacuum, to a small volume. Petroleum ether (BP 40-60°C) was added, and after standing overnight a white solid was obtained. This was filtered off to give 23 g of the product, MP 110-114°C. (b) α1-tert-Butylaminomethyl-4-hydroxy-m-xylene-α1,α3-diol: 0.8 g of α1- benzyl-tert-butyl-aminomethyl-4-hydroxy-m-xylene-α1,α3-diol in 20 ml of ethanol and 2 ml of water was shaken with hydrogen in presence of 0.50 g of pre-reduced 10% palladium on charcoal catalyst. When uptake of hydrogen was complete, the solution was filtered and evaporated under reduced pressure to give 0,4 g of the base as a colorless oil which yielded a white solid, MP 144-145°C when triturated with ether/cyclohexane. Recrystallization from ethyl acetate-cyclohexane gave a white solid, MP 147-149°C.

Therapeutic Function

Bronchodilator

Biological Functions

Levalbuterol is the R-(–)-isomer of albuterol and is available only in solution to be administered via nebulizer. Because it is the active isomer, the dose is fourfold less than that of albuterol. Pirbuterol is the pyridine isostere of albuterol. It has pharmacokinetics similar to albuterol but is half as potent at the β2-receptor. Pirbuterol is only available as an inhaler, whereas albuterol comes in tablet, syrup, solution, and aerosol formulations.

Synthesis Reference(s)

Synthesis, p. 966, 1988 DOI: 10.1055/s-1988-27768

Biochem/physiol Actions

β2-adrenoceptor agonist

Clinical Use

Albuterol has the N-t-butyl and a salicyl alcohol phenyl ring, which gives it optimal β2-selectivity. It is resistant to COMT and slowly metabolized by MAO, giving it good oral bioavailability. Its onset by inhalation is within 5 minutes, with a duration of action between 4 and 8 hours. It currently is the drug of choice for relief of the acute bronchospasm of an asthmatic attack.

Side effects

Adverse effects of pirbuterol are nervousness, tremor, and headache, which is less than the profile for albuterol, which adds nausea, vomiting, dizziness, hypertension, insomnia, tachycardia, and palpitations.

Synthesis

Albuterol, 2-tert-butylamino-1-(4-hydroxy-3-hydroxymethylphenyl)ethanol (11.1.26), basically differs from all of the aforementioned sympathomimetics in that the hydroxyl group at C3 of the aromatic ring is replaced with a hydroxymethyl group. It is synthesized in two ways. According to the first, it is prepared from 4-hydroxyacetophenone, the chloromethylation of which gives 4-hydroxy-3-hydroxymethylacetophenone (11.1.20). This is acetylated into a diacetyl derivative (11.1.21), which is further brominated into the corresponding bromoacetophenone (11.1.22). Reacting this with N-benzylN-tert-butylamine gives a derivative of aminoacetophenone (11.1.23), the acetyl group of which is hydrolyzed by hydrochloric acid, and the resulting product (11.1.24) undergoes a reduction—first by sodium borohydride for transforming the keto group into a hydroxyl group to give 11.1.25, and then by hydrogenation over a palladium catalyst for removing the benzyl-protecting group, giving albuterol (11.1.26) [26–30].

Environmental Fate

Tachycardia occurs as a reflex to the drop in mean arterial pressure (MAP) or as a result of b-1 stimulus. b-Adrenergic receptors in the locus coeruleus also regulate norepinephrineinduced inhibitory effects, resulting in agitation, restlessness, and hand tremor. Stimulation of nonpulmonary b2 receptors may lead to an increase in heart rate, QTc interval prolongation, nonspecific T-wave changes, skeletal muscle tremor, and slight increases in blood glucose and nonesterified fatty acids. Hypokalemia is more pronounced in patients receiving intravenous albuterol. Hypotension is also known to occur mostly in overdose. The buildup of cyclic AMP in the liver 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 MAP.Myocardial ischemia and infarction have been associated with excessive tachycardia in elderly patients. The skin may be warm and pink with evidence of diaphoresis.

Toxicity evaluation

Albuterol’s production and use as a bronchodilator may result in its release to the environment through various waste streams.

InChI:InChI=1/C13H21NO3/c1-13(2,3)14-7-12(17)9-4-5-11(16)10(6-9)8-15/h4-6,12,14-17H,7-8H2,1-3H3

Upstream product

• 115787-52-5 5-(2-tert-Butylamino-acetyl)-2-hydroxy-benzaldehyde 
• 115787-57-0 2-Chloro-1-<3-<<(1,1-dimethylethyl)imino>methyl>-4-hydroxyphenyl>ethanone 
• 115787-56-9 2-Bromo-1-<3-<<(1,1-dimethylethyl)imino>methyl>-4-hydroxyphenyl>ethanone 
• 115787-53-6 5-<<(1,1-Dimethylethyl)amino>acetyl>-2-hydroxybenzaldehyde hydrochloride 
• 1239368-65-0 C₉H₁₀O₄ 
• 75-64-9 tert-butylamine 
• 89-55-4 5-bromosalicyclic acid 
• 96911-26-1 2-Brom-6-(hydroxy)benzylalkohol 
• 52113-69-6 6-bromo-2,2-dimethyl-4H-benzo[1,3]dioxine 
• 1426340-12-6 1-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2,2-methoxyethanone 
• 1426340-15-9 1-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)-2,2-dimethoxyethanol 
• 54208-72-9 2-(tert-butylamino)-1-(2,2-dimethyl-4H-benzo[d][1,3]dioxan-6-yl)ethanol 
• 27566-09-2 methyl 5-[2-[(1,1-dimethylethyl)amino]-1-hydroxyethyl]-2-hydroxybenzoate 
• 16475-90-4 estere metilico dell'acido 5-acetilsalicilico 

Downstream Products

• 62084-23-5 (+/-)-albuterol tri(trimethylsilyl)ether 
• 54208-72-9 2-(tert-butylamino)-1-(2,2-dimethyl-4H-benzo[d][1,3]dioxan-6-yl)ethanol 
• 864656-93-9 salbutamol cis-octadecenoate 
• 35459-13-3 (-)-(R)-salbutamol acetate 
• 348135-26-2 (R)-α1-[[(1,1-dimethylethyl)amino]methyl]-4-hydroxy-1,3-benzenedimethanol D-dibenzoyltartrate 
• 324000-05-7 salbutamol sulphate 
• 1033055-65-0 R-salbutamol*R-ibuprofen 
• 1033293-24-1 S-salbutamol*S-ibuprofen 
• 639007-19-5 2-(4-methoxybenzyloxy)-5-(2-(N-tert-butylamino)-1-(4-methoxybenzyloxy)ethyl)benzyl alcohol 
• 102015-18-9 4-[2-(tert-butylamino)-1-hydroxyethyl]-2-nitrophenol 
• 870076-72-5 N-(tert-butyl)-2-methoxy-2-(4-hydroxy-3-(hydroxymethyl)phen-1-yl)-ethanamine 
• 1356657-18-5 C₁₅H₂₅NO₂ 

Relevant articles and documents

Preparation method of salbutamol sulfate

The invention provides a preparation method of salbutamol sulfate, and relates to the technical field of chemical synthesis. The preparation method of salbutamol sulfate comprises the following steps: (a) carrying out reaction on salicylic acid and a tert-butyl amino acetyl halogenating reagent under the action of a chlorinating agent to generate an intermediate 1; (b) reacting the intermediate 1 under the action of Lewis acid to generate an intermediate 2; (c) reacting the intermediate 2 under the action of an acid reagent to generate an intermediate 3; (d) reacting the intermediate 3 with a reducing agent under the action of a catalyst to generate salbutamol; and (e) reacting salbutamol with sulfuric acid to generate salbutamol sulfate. The raw materials are simple and easy to obtain, the reaction condition is mild, the reaction operation is simple, the reaction process is easier to control, and the safety coefficient is high; used raw materials, solvents and the like are environment-friendly; and the yield and purity of salbutamol sulfate are high, and a process route capable of industrially producing a product with higher quality is provided.

Preparation method of racemic salbutamol

The invention discloses a preparation method of racemic salbutamol. The method comprises the following steps: taking 5-bromosalicylaldehyde as a raw material, carrying out reduction reaction on the 5-bromosalicylaldehyde and sodium borohydride to obtain an intermediate I; carrying out alkylation reaction on the intermediate I, sodium hydride and benzyl halide to obtain an intermediate II; carryingout cross-coupling reaction on the intermediate II and vinyl potassium trifluoroborate to obtain an intermediate III; carrying out addition reaction on the intermediate III and N-bromo succinimide toobtain an intermediate IV; carrying out alkylation reaction on the intermediate IV and tert-butylamine to obtain an intermediate V; and carrying out deprotection reaction on the intermediate V in a hydrogen atmosphere to obtain the racemic salbutamol. The 5-bromosalicylaldehyde is used as a reaction raw material for the first time to reduce the production cost, and bromine atoms are introduced, so that functional groups can be directionally introduced to the 5th site by the reaction, and the selectivity and yield of the reaction are improved; no high-risk highly toxic reagent is involved; andthe Suzuki-Miyaura cross-coupling reaction is applied to synthesis of salbutamol for the first time, and a catalytic amount of palladium catalyst is used, so that efficient introduction of double bonds on an aromatic ring can be realized, and the cost is reduced while the reaction yield is increased.

A chromatography-free synthesis of racemic salbutamol hemisulfate

Our efforts to achieve an efficient synthesis of racemic salbutamol hemisulfate are described. The selected chemical route starts from commodity chemicals and allows the generation of salbutamol hemisulfate in 5 steps and 44% overall yield without any purification by column chromatography. The reaction sequence has been optimized to provide the title compound using robust procedures. Emphasis on reproducibility and experimental simplicity drove the work described herein.

Preparation method of salbutamol sulfate intermediate

The invention provides a preparation method of a salbutamol sulfate intermediate. Salbutamol is a beta receptor stimulant; a current preparation technology of the salbutamol mainly takes an original research technology as a main part; the original research technology takes p-hydroxyacetophenone as a starting material and the salbutamol is prepared through chloromethylation, esterification, bromination, amination, hydrolysis and reduction. An existing synthesis method of the salbutamol sulfate intermediate is used for synthesizing through a plurality of steps and is complicated to operate; theloss of products in a preparation process is great and the technological time is relatively long. The preparation method of the salbutamol sulfate intermediate, provided by the invention, comprises the following steps: reducing carbonyl of a compound I under the action of a reducing agent to obtain a compound II; then adding a debenzylation reagent and carrying out debenzylation reaction to obtainthe salbutamol sulfate intermediate III. According to the preparation method, the salbutamol sulfate intermediate III is prepared from the compound I by adopting a 'one-pot method'; operation steps are reduced, the reaction time is shortened and the reaction yield is improved.

Preparation method of free racemic albuterol

The invention discloses a preparation method of free racemic albuterol. The preparation method comprises the following steps: with methyl salicylate as a raw material, successively carrying out Friedel-Crafts acylation and oxidation, carrying out condensation and borate reduction in pure water with a 'one-pot' method, carrying out ester group reduction and acetonylidene protection of crude albuterol with a 'one-pot' method, and carrying out deprotection and purification to obtain the free racemic albuterol. The preparation method has the advantages of high labor efficiency, low reaction reagent cost and high yield.

Method for preparing salbutamol

The invention provides a preparation method of an intermediate salbutamol of salbutamol sulfate. The method comprises the following steps: (1) preparing acidified gel type strongly acidic cation exchange resin or macroporous type strongly acidic cation exchange resin through hydrochloric acid elution; (2) carrying out propylidene protection group removal on a compound shown as a formula I by utilizing the acidified acidic cation exchange resin; then filtering to remove the acidic cation exchange resin, so as to obtain filtrate containing a compound salbutamol shown as a formula II; (3) regulating the pH (Potential of Hydrogen) value of the filtrate to be 9 to 10 and filtering to separate out a solid, so as to obtain the salbutamol. According to the preparation method provided by the invention, the propylidene protection group removal is carried out on the strongly acidic cation exchange resin; the method is simple to operate, short in reaction time and high in yield; strong acid is notused so that corrosion, caused by the strong acid, to equipment is avoided and harms, caused by the strong acid, to health of operators are reduced. Furthermore, the acidic cation exchange resin canbe repeatedly utilized and the production cost can be greatly reduced.

A Combined High-Throughput Screening and Reaction Profiling Approach toward Development of a Tandem Catalytic Hydrogenation for the Synthesis of Salbutamol

A combined high-throughput screening and reaction profiling approach to the telescoping of two reductions in the synthesis of Salbutamol is described. Optimization studies revealed the beneficial effect of mildly acidic conditions, and the use of water as a cosolvent. Persistent formation of deoxygenated impurities using a Pd/C catalyst led to the initiation of reaction profiling studies, which revealed that the ketone intermediate formed after rapid debenzylation is the sole source of deoxygenated impurities, indicating that more rapid ketone hydrogenation should minimize this deoxygenation. A dual catalyst approach based on these insights has been developed, with both Pd/Pt and Ru/Pt catalyst systems as more selective than Pd-only systems. Based on reaction profiles that indicate the deoxygenation side reaction is first-order in the concentration of debenzylated ketone intermediate, Pt catalysts for rapid and selective ketone hydrogenation were paired with Pd and Ru catalysts known to perform selective debenzylation. Optimization of these dual catalyst processes led to conditions that were demonstrated on 20 g scale to prepare Salbutamol in 49% isolated yield after recrystallization.

Efficient preparation of α-ketoacetals

The Weinreb amides 2a,b were prepared from the a,a-dimethoxyacetic acids 1c,d. A number of representative nucleophilic additions (RMgX and RLi) on 2 afforded a-ketoacetals 3a-j in 70-99% yield. These compounds represent a versatile arrangement of functional groups of significant synthetic value, as demonstrated in the synthesis of (±)-salbutamol.

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.

Administration of medicinal dry powders

A method as well as a therapeutic metered combined dose are disclosed for a combined administration of medicinal dry powders. A metered medicinal dry powder combined dosage comprising at least two medicaments of separate dry powder formulations is prepared, whereby the metered powder quantity per medicament is deposited in a dose forming step creating the medicinal combined dose. The deposits of the at least two medicaments are suitably kept separated from each other, such that the medicaments cannot detrimentally interact after forming of the combined dose, and the medicinal combined dose is introduced into an inhaler device for a delivery of the powder dose during the course of a single inhalation. The therapeutic metered medicinal, combined dosage of finely divided dry medication powders disclosed comprises metered quantities of at least two medicaments, separately deposited and the medicinal combined dosage is adapted for a user initiated delivery of the dosage during a single inhalation through an inhaler device. The at least two medicaments of the medicinal combined dosage will generally be aerosolized simultaneously or sequentially during the inhalation such that a large proportion of each medicament will settle in the intended target area of the airways and lungs of a user.