5051-22-9

Usage

Uses

Used in Cardiology:
R(+)-PROPRANOLOL HCL is used as an anti-arrhythmic agent for conditions such as ventricular tachycardia, arrhythmia caused by digitalis drug overdose, or as a result of thyrotoxosis or excess catecholamine activity. It is considered the first choice of drugs for these conditions, although other β-adrenoblockers and calcium blockers can be just as effective.
Used in Hypertension Treatment:
R(+)-PROPRANOLOL HCL is used as an antihypertensive agent for treating hypertension, angina pectoris, supraventricular arrhythmia, and migraines. It is also used following a myocardial infarction to help manage the postanginal phase and prevent further complications.
Used in Other Medical Applications:
R(+)-PROPRANOLOL HCL is used as a therapeutic agent for various conditions, including hypertrophic subaortic stenosis, pheochromocytosis, and extrasystole. Its versatile application in different medical fields highlights its importance in modern medicine.

Indications

Propranolol slows heart rate, increases the effective refractory period of atrioventricular ganglia, suppresses automatism of heart cells, and reduces excitability and contractibility of the myocardium. It is used for supraventricular and ventricular arrhythmias.

Synthesis Reference(s)

Tetrahedron Letters, 31, p. 2157, 1990 DOI: 10.1016/0040-4039(90)80097-6

Biological Activity

Less active enantiomer of the β -adrenoceptor antagonist propranolol ((RS)-1-[(1-Methylethyl)amino]-3-(1-naphthalenyloxy)-2-propanol hydrochloride ).

Mechanism of action

Propranolol is a nonselective β-adrenoblocker that affects both the mechanical and electrophysiological properties of the myocardium. It lowers myocardial contractibility, heart rate, blood pressure, and the myocardial need for oxygen. These properties make propranolol and other β-adrenoblockers useful antianginal drugs.

Clinical Use

Currently, R(+)-PROPRANOLOL HCL is approved for use inthe United States for hypertension, cardiac arrhythmias,angina pectoris, postmyocardial infarction, hypertrophiccardiomyopathy, pheochromocytoma, migraine prophylaxis,and essential tremor. In addition, because of its highlipophilicity (log P=3.10) and thus its ability to penetratethe CNS, propranolol has found use in treating anxiety andis under investigation for the treatment of a variety of otherconditions, including schizophrenia, alcohol withdrawalsyndrome, and aggressive behavior.

Side effects

The toxicity associated with propranolol is for the most part related to its primary pharmacological action, inhibition of the cardiac β-adrenoceptors. In addition, propranolol exerts direct cardiac depressant effects that become manifest when the drug is administered rapidly by the IV route.Glucagon immediately reverses all cardiac depressant effects of propranolol, and its use is associated with a minimum of side effects. The inotropic agents amrinone (Inocor) and milrinone (Primacor) provide alternative means of augmenting cardiac contractile function in the presence of β-adrenoceptor blockade. Propranolol may also stimulate bronchospasm in patients with asthma. Since propranolol crosses the placenta and enters the fetal circulation, fetal cardiac responses to the stresses of labor and delivery will be blocked. Additionally, propranolol crosses the blood-brain barrier and is associated with mood changes and depression. School difficulties are commonly associated with its use in children. Propranolol may also cause hypoglycemia in infants.

Synthesis

Propranolol, 1-(iso-propylamino)-3-(1-naphthyloxy)-2-propanol (12.1.2), is synthesized in two ways from the same initial substance. The first way consists of reacting 1-naphthol with epichlorohydrin. Opening of the epoxide ring gives 1-chloro-3- (1-naphthyloxy)-2-propanol (12.1.1), which is reacted further with iso-propylamine, giving propranolol (12.1.2). The second method uses the same reagents in the presence of a base and consists of initially making 3-(1-naphthyloxy)propylenoxide (12.1.3), the subsequent reaction with isopropylamine which results in epoxide ring opening leading to the formation of propranolol (12.1.2) [1–6].

Metabolism

Propranolol (Inderal) is suitable for both parental and oral administration. Absorption from the gastrointestinal tract is extensive. The peak therapeutic effect after oral administration occurs in 1 to 1.5 hours.The plasma half-life of propranolol is approximately 3 hours. The drug is concentrated in the lungs and to a lesser extent in the liver, brain, kidneys, and heart. Binding to plasma proteins is extensive (90%). The liver is the chief organ involved in the metabolism of propranolol, and the drug is subject to a significant degree of first-pass metabolism. At least eight metabolites have been recovered from the urine, the major excretory route.

Precautions

Propranolol is contraindicated for patients with depressed myocardial function and may be contraindicated in the presence of digitalis toxicity because of the possibility of producing complete A-V block and ventricular asystole. Patients receiving anesthetic agents that tend to depress myocardial contractility (ether, halothane) should not receive propranolol. Propranolol should be used with extreme caution in patients with asthma. Up-regulation of β-receptors follows long-term therapy, making abrupt withdrawal of β-blockers dangerous for patients with ischemic heart disease.

InChI:InChI=1/C16H21NO2/c1-12(2)17-10-14(18)11-19-16-9-5-7-13-6-3-4-8-15(13)16/h3-9,12,14,17-18H,10-11H2,1-2H3/t14-/m1/s1

Upstream product

• 90-15-3 α-naphthol 
• 61248-78-0 (R)-3-(1-naphthyloxy)-1,2-propanediol 
• 75-31-0 isopropylamine 
• 4290-58-8 (R)-O-acetyl propranolol hydrochloride 
• 525-66-6 propranolol 
• 129459-75-2 1-(isopropylamino)-3-(naphthalen-1-yloxy)propan-2-yl acetate 
• 111399-11-2 rac-2'-O-propionyl propranolol 
• 67-56-1 methanol 
• 108-05-4 vinyl acetate 
• 318-98-9 Inderal 
• 2461-42-9 3-(1-naphthyloxy)-1,2-epoxypropane 
• 20862-11-7 (S)-1-Amino-3-(naphthalen-1-yloxy)-propan-2-ol 
• 67-64-1 acetone 
• 111399-11-2 (R)-propranolol propionate 

Relevant academic research and scientific papers

Preparation of a novel hydroxypropyl-γ-cyclodextrin functionalized monolith for separation of chiral drugs in capillary electrochromatography

In this study, a novel hydroxypropyl-γ-cyclodextrin (HP-γ-CD) functionalized monolithic capillary column was prepared by one-pot sequential strategy and used for chiral separation in capillary electrochromatography for the first time. In one pot, GMA-HP-γ-CD as functional monomer was allowed to be formed via the ring opening reaction between HP-γ-CD and glycidyl methacrylate (GMA) catalyzed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and then copolymerized directly with ethylene dimethacrylate (EDMA) and 2-acrylamido-2-methyl propane sulfonic acid (AMPS) in the presence of porogenic solvents via thermally initiated free radical polymerization. The preparation conditions of monoliths were optimized. Enantiomer separations of six chiral drugs including pindolol, clorprenaline, tulobuterol, clenbuterol, propranolol, and tropicamide were achieved on the monolith. Among them, pindolol, clorprenaline, and tropicamide were baseline separated with resolution values of 1.62, 1.73, and 1.55, respectively. The mechanism of enantiomer separation was discussed by comparison of the HP-γ-CD and HP-β-CD functionalized monoliths.

Preparation and evaluation of a triazole-bridged bis(β-cyclodextrin)–bonded chiral stationary phase for HPLC

A triazole-bridged bis(β-cyclodextrin) was synthesized via a high-yield Click Chemistry reaction between 6-azido-β-cyclodextrin and 6-propynylamino-β-cyclodextrin, and then it was bonded onto ordered silica gel SBA-15 to obtain a novel triazole-bridged bis (β-cyclodextrin)–bonded chiral stationary phase (TBCDP). The structures of the bridged cyclodextrin and TBCDP were characterized by the infrared spectroscopy, mass spectrometry, elemental analysis, and thermogravimetric analysis. The chiral performance of TBCDP was evaluated by using chiral pesticides and drugs as probes including triazoles, flavanones, dansyl amino acids and β-blockers. Some effects of the composition in mobile phase and pH value on the enantioseparations were investigated in different modes. The nine triazoles, eight flavanones, and eight dansyl amino acids were successfully resolved on TBCDP under the reversed phase with the resolutions of hexaconazole, 2′-hydroxyflavanone, and dansyl-DL-tyrosine, which were 2.49, 5.40, and 3.25 within 30 minutes, respectively. The ten β-blockers were also separated under the polar organic mode with the resolution of arotinolol reached 1.71. Some related separation mechanisms were discussed preliminary. Compared with the native cyclodextrin stationary phase (CDSP), TBCDP has higher enantioselectivity to separate more analytes, which benefited from the synergistic inclusion ability of the two adjacent cavities and bridging linker of TBCDP, thereby enabling it a promising prospect in chiral drugs and food analysis.

Enantioseparation of mandelic acid on vancomycin column: Experimental and docking study

So far, no detailed view has been expressed regarding the interactions between vancomycin and racemic compounds including mandelic acid. In the current study, a chiral stationary phase was prepared by using 3-aminopropyltriethoxysilane and succinic anhydride to graft carboxylated silica microspheres and subsequently by activating the carboxylic acid group for vancomycin immobilization. Characterization by elemental analysis, Fourier transform infrared spectroscopy, solid-state nuclear magnetic resonance, and thermogravimetric analysis demonstrated effective functionalization of the silica surface. R and S enantiomers of mandelic acid were separated by the synthetic vancomycin column. Finally, the interaction between vancomycin and R/S mandelic acid enantiomers was simulated by Auto-dock Vina. The binding energies of interactions between R and S enantiomers and vancomycin chiral stationary phase were different. In the most probable interaction, the difference in mandelic acid binding energy was approximately 0.2 kcal/mol. In addition, circular dichroism spectra of vancomycin interacting with R and S enantiomers showed different patterns. Therefore, R and S mandelic acid enantiomers may occupy various binding pockets and interact with different vancomycin functions. These observations emphasized the different retention of R and S mandelic acid enantiomers in vancomycin chiral column.

Preparation of polar group derivative β-cyclodextrin bonded hydride silica chiral stationary phases and their chromatography separation performances

Three novel β-cyclodextrin compounds derived with piperidine which is flexible, L-proline containing a chiral center, ionic liquid with 3,5-diamino-1,2,4-triazole as the cation were designed and synthesized as chiral selectors for enantiomer separation, whose name were (mono-6-deoxy-6-(piperidine)-β-cyclodextrin, mono-6-deoxy-6-(L-proline)-β-cyclodextrin, mono-6-deoxy-6-(3,5-diamino-1,2,4-triazole)-β-cyclodextrin, multi-substituted 3,5-diamino-1,2,4- triazole-(p-toluenesulfonic)-β-cyclodextrin), respectively. In addition, to enhance the polarity of chiral stationary phases, hydrosilylation and silylation reactions were implemented to derive ordinary silica, the common used selector carrier, to hydride silica, whose surface is covered with proton. 31 pyrrolidine compounds and some chiral drugs were tested in both polar organic mobile phase mode and normal mobile phase mode. 6-Deoxy-6-L-proline-β-cyclodextrin-CSP showed satisfactory separations in polar organic mobile phase mode and exihibited a strong separation capability in different pH values; multi-substituted 3,5-diamino-1,2,4-triazole-(p-toluenesulfonic)-β-cyclodextrin-CSP can separate pyrrolidine compounds in both mobile phase modes with high resolutions and separation efficiency compared to commercially available CSPs, making it to be the most valuable object to study. The composition of mobile phase, type of stationary phase as well as the peak problem of chromatograms was discussed deeply.

Enantioseparation of chiral pharmaceuticals by vancomycin-bonded stationary phase and analysis of chiral recognition mechanism

The drug chirality is attracting increasing attention because of different biological activities, metabolic pathways, and toxicities of chiral enantiomers. The chiral separation has been a great challenge. Optimized high-performance liquid chromatography (HPLC) methods based on vancomycin chiral stationary phase (CSP) were developed for the enantioseparation of propranolol, atenolol, metoprolol, venlafaxine, fluoxetine, and amlodipine. The retention and enantioseparation properties of these analytes were investigated in the variety of mobile phase additives, flow rate, and column temperature. As a result, the optimal chromatographic condition was achieved using methanol as a main mobile phase with triethylamine (TEA) and glacial acetic acid (HOAc) added as modifiers in a volume ratio of 0.01% at a flow rate of 0.3?mL/minute and at a column temperature of 5°C. The thermodynamic parameters (eg, ΔH, ΔΔH, and ΔΔS) from linear van 't Hoff plots revealed that the retention of investigated pharmaceuticals on vancomycin CSP was an exothermic process. The nonlinear behavior of lnk′ against 1/T for propranolol, atenolol, and metoprolol suggested the presence of multiple binding mechanisms for these analytes on CSP with variation of temperature. The simulated interaction processes between vancomycin and pharmaceutical enantiomers using molecular docking technique and binding energy calculations indicated that the calculated magnitudes of steady combination energy (ΔG) coincided with experimental elution order for most of these enantiomers.

HPLC with cellulose Tris (3,5-DimethylPhenylcarbamate) chiral stationary phase: Influence of coating times and coating amount on chiral discrimination

Coating cellulose tris (3,5-dimethylphenylcarbamate) (CDMPC) on silica gels with large pores have been demonstrated as an efficient way for the preparation of chiral stationary phase (CSP) for high-performance liquid chromatography (HPLC). During the process, a number of parameters, including the type of coating solvent, amount of coating, and the method for subsequent solvent removing, have been proved to affect the performance of the resultant CSPs. Coating times and the concentration of coating solution, however, also makes a difference to CSPs' performance by changing the arrangement of cellulose derivatives while remaining the coating amount constant, have much less been studied before, and thereby, were systematically investigated in this work. Results showed that CSPs with more coating times exhibited higher chiral recognition and column efficiency, suggesting that resolution was determined by column efficiency herein. Afterwards, we also investigated the effect of coating amount on the performance of CSPs, and it was shown that the ability of enantio-recognition did not increase all the time as the coating amount; and four of seven racemates achieved best resolution when the coating amount reached to 18.37%. At the end, the reproducibility of CDMPC-coated CSPs were further confirmed by two methods, ie, reprepared the CSP-0.15-3 and reevaluated the effect of coating times.

Effect of vitamin C template on morphology and structure of alumina: emerging application in enantiomer separation

Mesoporous nano-aluminas were prepared using aluminium isopropoxide, vitamin C (VC as a chiral template and a co-structural directing agent with molar ratios of 50:50 and 90:10) and water. These compositions when dried at 120?°C and calcined at 250, 350 and 500?°C for 8?h under air atmosphere transformed to boehmite and γ-alumina depending on the concentration of VC. The influence of vitamin C and its degradation products on the morphology and texture of alumina was investigated by the means of XRD, FT-IR, SEM, EDX, TEM, TGA, DSC, BET and N2 adsorption–desorption isotherm. Mesoporous aluminas possess excellent characteristics such as large surface area (ca. 394?m2/g), 0.4?cm3/g pore volume and narrow pore size distributions that can be synthesized through a facile and green procedure. In addition, the enantiomers of propranolol hydrochloride were successfully resolved from its racemate using Al50VC50T350 (AlMolar ratio of the Aluminium isopropoxide, VCMolar ratio of the Vitamin C,TTemperature) (Rs = 2.5) as chiral stationary phase. The synthesis of chiral stationary phase was accomplished in a green, facile and inexpensive procedure that is of paramount importance in food and pharmaceutical industries.

Enantiomeric separation of β-blockers and tryptophan using heparin as stationary and pseudostationary phases in capillary electrophoresis

The separation methods of the enantiomers of two β-blockers and tryptophan were studied using capillary electrochromatography with heparin covalently as well as non-covalently, bonded onto the capillary inner wall as stationary phase and electrokinetic chromatography with heparin as pseudostationary phase. In the case of heparin, used as a stationary phase, the method was unable to resolve enantiomers in both cases β-blockers and tryptophan. On the other hand, when heparin was used as a pseudostationary phase, the resolution of the enantiomers was obtained only with 3-aminopropyltriethoxysilane which were immobilised onto the inner phase of the capillary. The results of this study let us infer that the electrostatic, hydrophobic, and steric interactions were involved in the separation mechanisms. The separation was achieved in less than 10?minutes under the optimized conditions: 30?mM phosphate buffer (pH?2.5) with the adding of 15?mg/mL of heparin at 15°C and 10?kV. The usefulness of heparin as a chiral selector both in electrokinetic chromatography using 3-aminopropyltriethoxysilane attached to the capillary was demonstrated for the first time. The developed method was powerful, sensitive, and fast, and it could be considered an important alternative to conventional methods used for chiral separation.

Cellulose type chiral stationary phase based on reduced graphene oxide@silica gel for the enantiomer separation of chiral compounds

The graphene oxide (GO) was covalently coupled to the surfaces of silica gel (SiO2) microspheres by amide bond to get the graphene oxide@silica gel (GO@SiO2). Then, the GO@SiO2 was reduced with hydrazine to the reduced graphene oxide@silica gel (rGO@SiO2), and the cellulose derivatives were physically coated on the surfaces of rGO@SiO2 to prepare a chiral stationary phase (CSP) for high performance liquid chromatography. Under the optimum experimental conditions, eight benzene-enriched enantiomers were separated completely, and the resolution of trans-stilbene oxide perfectly reached 4.83. Compared with the blank column of non-bonded rGO, the separation performance is better on the new CSP, which is due to the existence of rGO to produce special retention interaction with analytes, such as π-π stacking, hydrophobic effect, π-π electron-donor–acceptor interaction, and hydrogen bonding. Therefore, the obtained CSP shows special selectivity for benzene-enriched enantiomers, improves separation selectivity and efficiency, and rGO plays a synergistic effect with cellulose derivatives on enantioseparation.

Evaluation of the Edman degradation product of vancomycin bonded to core-shell particles as a new HPLC chiral stationary phase

A modified macrocyclic glycopeptide-based chiral stationary phase (CSP), prepared via Edman degradation of vancomycin, was evaluated as a chiral selector for the first time. Its applicability was compared with other macrocyclic glycopeptide-based CSPs: TeicoShell and VancoShell. In addition, another modified macrocyclic glycopeptide-based CSP, NicoShell, was further examined. Initial evaluation was focused on the complementary behavior with these glycopeptides. A screening procedure was used based on previous work for the enantiomeric separation of 50 chiral compounds including amino acids, pesticides, stimulants, and a variety of pharmaceuticals. Fast and efficient chiral separations resulted by using superficially porous (core-shell) particle supports. Overall, the vancomycin Edman degradation product (EDP) resembled TeicoShell with high enantioselectivity for acidic compounds in the polar ionic mode. The simultaneous enantiomeric separation of 5 racemic profens using liquid chromatography-mass spectrometry with EDP was performed in approximately 3?minutes. Other highlights include simultaneous liquid chromatography separations of rac-amphetamine and rac-methamphetamine with VancoShell, rac-pseudoephedrine and rac-ephedrine with NicoShell, and rac-dichlorprop and rac-haloxyfop with TeicoShell.