51384-51-1

Hazards Identification

Pictogram(s):

Signal:

Warning

GHS Hazard Statements:

H315 (100%): Causes skin irritation [Warning Skin corrosion/irritation]
H319 (100%): Causes serious eye irritation [Warning Serious eye damage/eye irritation]
H335 (100%): May cause respiratory irritation [Warning Specific target organ toxicity, single exposure; Respiratory tract irritation]

Precautionary Statement Codes:

P261, P264, P264+P265, P271, P280, P302+P352, P304+P340, P305+P351+P338, P319, P321, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501

Hazard Classes and Categories:

Skin Irrit. 2 (100%)
Eye Irrit. 2 (100%)
STOT SE 3 (100%)
Flam. Sol. 1 (50%)
Acute Tox. 4 (100%)
Eye Irrit. 2A (100%)
Acute Tox. 4 (50%)
Repr. 2 (50%)

Usage

Uses

Used in Pharmaceutical Industry:
Metoprolol is used as an anti-adrenergic agent for the treatment of a variety of cardiovascular disorders. It helps in reducing the heart rate, blood pressure, and the workload of the heart, thereby providing relief from conditions such as hypertension, angina, and heart failure.
Used in Cardiovascular Applications:
Metoprolol is used as a β1 selective aryloxypropanolamine andrenergic antagonist for the treatment of various cardiovascular disorders. It works by blocking the effects of adrenaline and noradrenaline on the heart and blood vessels, leading to a reduction in heart rate, blood pressure, and the workload of the heart. This makes it an effective treatment option for conditions like hypertension, angina, and heart failure.

Pharmacological action

Metoprolo has selective blocking effect on beta 1 receptor, and has no partial activity and no function of membrane stability. It can significantly reduce the blood pressure of the people with hypertension, and do not cause erect hypotension and electrolyte disorder. It can reduce the number of episodes of angina pectoris and increase exercise tolerance. Long term use can reduce the incidence of myocardial infarction. After myocardial infarction, medication can reduce the incidence of re infarction and reduce the mortality after myocardial infarction. It can block the stimulation of adrenergic receptor at the point of cardiac ectopic pacing. It is used for supraventricular tachyarrhythmias, ventricular arrhythmias, digitalis and catecholamine induced tachyarrhythmias. Metoprolo is more effective for tachyarrhythmia caused by hypertension, coronary heart disease and catecholamine increase. It can antagonize the effect of catecholamine, and it can be used to treat arrhythmia caused by hyperthyroidism. The effect of the treatment dose on the contractile bronchus and the peripheral blood vessels is not obvious. The resistance to the trachea will be increased after individual drug use, which can be corrected by extra taking beta 2 receptor agonist. Metoprolo is suitable for treatment of hypertension, angina pectoris, myocardial infarction, hypertrophic cardiomyopathy, aortic dissection, arrhythmia, hyperthyroidism, cardiac neurosis, etc.

Pharmacokinetics

Absorption of oral administration is rapid and peak time is generally at 1.5h. The maximum action time is 1 ~ 2h. The absorption rate is >90%, but the metabolic rate of liver is 95%.The effect of the first pass is 25% to 60%, so the bioavailability is only 40% ~ 75%. It is similar to propranolol and food can increase the oral absorption of this product.The plasma protein binding rate of this product is about 12% and it can penetrate the blood brain barrier and the placental barrier.It can also be secreted from milk. The decrease of blood pressure is not parallel to the concentration of blood, and the decrease of heart rate has a linear relationship with the concentration of blood.The metabolism of this product in the liver is influenced by genetic factors.The fast metabolic and slow metabolic half-life (t1/2) are 3 to 4h and 7.55h, respectively.It is excreted through the kidney and is mainly metabolites in the urine, only a small amount of (<5%) origin. It can not be discharged through dialysis.

Indication

Metoprolol belongs to class II antiarrhythmic drugs.It is used for the treatment of hypertension, angina pectoris, hypertrophic cardiomyopathy, aortic dissection, supraventricular arrhythmia, atrial fibrillation, ventricular rate, hyperthyroidism, pheochromocytoma and chronic heart failure.It can prevent and treat myocardial ischemia, rapid arrhythmia, and chest pain in acute myocardial infarction.

Adverse reaction

A few patients can have fatigue, gastrointestinal dysfunction and lethargy in the early stage of taking medicine, which can disappear after continuing to take the medicine.There were occasional nonspecific skin reactions and fear of cold in the limbs. Other adverse reactions include: Cardiovascular system: Slow heart rate, conduction block, lower blood pressure, aggravation of heart failure, cold limbs or unpalpable pulse caused by peripheral vasospasm and Reynolds phenomenon.Because of its fat solubility, this product is easily penetrated into the central nervous system, so there are more adverse reactions in the central nervous system. Fatigue and vertigo account for 10%, depression accounts for 5%, other adverse reactions include headache, dream, insomnia etc. With rare illusion. Digestive system: the ratio of people with symptoms of nausea, stomachache and constipation is <1%, and those with diarrhea account for 5%, but they are not serious and seldom affect the drug use. Other: such as shortness of breath, joint pain, pruritus, retroperitoneal fibrosis, deafness, eye pain, etc..

Drug interaction

The combined use of Catecholamine depletion agent (such as reserpine) with this product can cause vertigo, or hypotension.? Its combined use with digitalis can cause the heart rate to be slow. It is forbidden to use with diltiazem for patients with heart failure. It is forbidden to combine with monoamine oxidase inhibitors for the cause of severe hypotension Its combined use of cimetidine or preuse of quinidine can increase the concentration of metoprolol in blood. It has similar side effects with calcium antagonists. When combined in use, they can cause serious slow arrhythmia, even cardiac arrest.

Precaution

Patients with the following circumstances can not be given immediate intravenous medication: The systolic pressure of supraventricular fast arrhythmia is lower than that of 110mmHg; ?acute myocardial infarction and unstable angina with heart rate less than 70 bpm, when the systolic pressure is lower than 110mmHg, or with the atrioventricular conduction block. The treatment of suspected or confirmed AMI should not be repeated if there is any aggravation of dyspnea or cold sweat. Patients with pheochromocytoma should use alpha receptor antagonist first. A moderate amount of beta 2 receptor agonist must be given to patienst with bronchial asthma or COPD. For patients undergoing general anesthesia, it must be stopped at least 48h before anesthesia. Careful use for patients with liver and kidney insufficiency, diabetes and hyperthyroidism.

InChI:InChI=1/C15H25NO3.C4H6O6/c1-12(2)16-10-14(17)11-19-15-6-4-13(5-7-15)8-9-18-3;5-1(3(7)8)2(6)4(9)10/h4-7,12,14,16-17H,8-11H2,1-3H3;1-2,5-6H,(H,7,8)(H,9,10)

Upstream product

• 75-31-0 isopropylamine 
• 56718-70-8 2-[4-(2'-methoxyethyl)phenoxymethyl]oxirane 
• 207983-04-8 metoprolol Succinate 
• 207983-04-8 metoprolol succinate 
• 56718-71-9 4-(2-methoxyethyl)phenol 
• 80448-05-1 3-[4-(2-methoxyethyl)phenoxy]propylene 

Downstream Products

• 20445-33-4 (R)-methoxytrifluoromethylphenylacetyl chloride 
• 112309-90-7 C₁₅H₂₄NO₄ 
• 81024-43-3 (2R)-metoprolol 
• 81024-42-2 S-(-)-metoprolol 
• 56392-16-6 alpha-Hydroxymetoprolol 
• 62572-94-5 (+/-)-O-Demethylmetoprolol 
• 138768-62-4 N-nitrosometoprolol 
• 207983-04-8 metoprolol Succinate 
• 56392-17-7 metoprolol tartrate 
• 1350626-99-1 N-(3-vinyloxycarbonylpropanoyl)metoprolol 
• 1350627-08-5 N-(5-vinyloxycarbonylpentanoyl)metoprolol 

Relevant academic research and scientific papers

Method for continuously synthesizing metoprolol and salts thereof

The invention discloses a method for continuously synthesizing metoram, which comprises the following steps: (1) carrying out vacuum rectification on a 1-(2, 3-epoxypropoxy)-4-(2-methoxyethyl)benzene raw material to obtain a pure product with the purity of more than 99%, and preparing the pure product into an ethanol solution; (2) uniformly mixing the ethanol solution obtained in the step (1) with isopropylamine, feeding the mixture into a pipeline reactor, and reacting to obtain a metoprolol reaction solution; and (3) depressurizing the reaction liquid, and recovering isopropylamine in a rectifying tower, wherein the tower bottom liquid contains high-purity metoprolol. The purity of the raw materials reaches 99% or above through the rectification step, and colored impurities are also removed; when metoprolol is synthesized, a rapid reaction method of large excess of isopropylamine in the pipeline reactor is adopted, so that secondary condensation side reactions are obviously reduced, and the purity of metoprolol reaches 98% or above; and after metoprolol is salified with succinic acid, a crude drug finished product with the purity larger than 99.5% can be obtained through crystallization. The method is high in yield, low in cost and easy to operate, and is an environment-friendly process route capable of realizing industrial production.

The solid-state structure of the β-blocker metoprolol: a combined experimental and in silico investigation

Metoprolol {systematic name: (RS)-1-isopropylamino-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol}, C15H25NO3, is a cardioselective β1-adrenergic blocking agent that shares part of its molecular skeleton with a large number of other β-blockers. Results from its solid-state characterization by single-crystal and variable-temperature powder X-ray diffraction and differential scanning calorimetry are presented. Its molecular and crystal arrangements have been further investigated by molecular modelling, by a Cambridge Structural Database (CSD) survey and by Hirshfeld surface analysis. In the crystal, the side arm bearing the isopropyl group, which is common to other β-blockers, adopts an all-trans conformation, which is the most stable arrangement from modelling data. The crystal packing of metoprolol is dominated by an O—H…N/N…H—O pair of hydrogen bonds (as also confirmed by a Hirshfeld surface analysis), which gives rise to chains containing alternating R and S metoprolol molecules extending along the b axis, supplemented by a weaker O…H—N/N—H…O pair of interactions. In addition, within the same stack of molecules, a C—H…O contact, partially oriented along the b and c axes, links homochiral molecules. Amongst the solid-state structures of molecules structurally related to metoprolol deposited in the CSD, the β-blocker drug betaxolol shows the closest analogy in terms of three-dimensional arrangement and interactions. Notwithstanding their close similarity, the crystal lattices of the two drugs respond differently on increasing temperature: metoprolol expands anisotropically, while for betaxolol, an isotropic thermal expansion is observed.

Solvent-Directed Epoxide Opening with Primary Amines for the Synthesis of β-Amino Alcohols

An efficient synthesis of β-amino alcohols from a variety of epoxides and primary unbranched amines in the absence of any catalyst in high yields and regioselectivities is reported. A variety of polar mixed solvent systems allow for the selective formation of secondary amino alcohols over tertiary amino alcohols. The reaction scope extends to a wide variety of aromatic and aliphatic substituted epoxides and primary amines bearing complex functionality.

Preparation method of metoprolol

The invention discloses a preparation method of metoprolol. The method comprises the following steps: firstly, preparing p-hydroxyphenylethyl methyl ether and sodium hydroxide solution into an alkalescence solution, heating the alkalescence solution, mixing with heated epoxy chloropropane, and introducing into an extracting tower type reactor for reaction; meanwhile, introducing methylbenzene into the extracting tower type reactor for extraction, pumping reaction liquid into a rectifying tower after the reaction liquid enters a receiving groove, enabling the methylbenzene steamed out of the upper part of the rectifying tower and a small quantity of the epoxy chloropropane to enter the extracting tower type reactor from the bottom for continuous reaction, thus obtaining an intermediate (II) at the bottom of the rectifying tower, and then carrying out ammonolysis reaction on the intermediate (II) and isopropylamine, thus obtaining the metoprolol. The method provided by the invention is simple and environment-friendly in operation, the dosage of alkali is accurately controlled by adjusting a pH value, and thus the open-loop side reaction on the epoxy chloropropane and the intermediate is reduced. In addition, by adopting the tower-type continuous reaction, the time is shortened by a large margin, and the dosage of the epoxy chloropropane is reduced, so that the open-loop side reaction is correspondingly reduced, and the quality and yield of a product are improved.

Continuous and convergent access to vicinyl amino alcohols

Five active pharmaceutical ingredients (APIs) containing the vicinyl amino alcohol moiety were synthesized using a convergent chemical assembly system. The continuous system is composed of four flow reaction modules: biphasic oxidation, Corey-Chaykovsky epoxidation, phenol alkylation, and epoxide aminolysis. Judicious choice of reagents and module order allowed for two classes of β-amino alcohols, aryl and aryloxy, to be synthesized in good (27-69%) overall yields.

Asymmetric hydrolytic kinetic resolution with recyclable polymeric Co(iii)-salen complexes: A practical strategy in the preparation of (S)-metoprolol, (S)-toliprolol and (S)-alprenolol: Computational rationale for enantioselectivity

A series of chiral polymeric Co(iii)-salen complexes based on a number of achiral and chiral linkers were synthesized and their catalytic performances were assessed in the asymmetric hydrolytic kinetic resolution of terminal epoxides. The effects of the linker were judiciously studied and it was found that in the case of the chiral BINOL-based polymeric salen complex 1, there was an enrichment in catalyst reactivity and enantioselectivity of the unreacted epoxide, particularly in the case of short as well as long chain aliphatic epoxides. Good isolated yields of the unreacted epoxide (up to 46% compared to 50% theoretical yield) along with high enantioselectivity (up to 99%) were obtained in most cases using catalyst 1. Further studies showed that catalyst 1 could retain its catalytic activity for six cycles under the present reaction conditions without any significant loss in activity or enantioselectivity. To show the practical applicability of the above synthesized catalyst we have synthesised some potent chiral β-blockers in moderate yield and high enantioselectivity using complex 1. The DFT (M06-L/6-31+G??//ONIOM(B3LYP/6-31G?:STO-3G)) calculations revealed that the chiral BINOL linker influences the enantioselectivity achieved with Co(iii)-salen complexes. Further, the transition state calculations show that the R-BINOL linker with the (S,S)-Co(iii)-salen complex is energetically preferred over the corresponding S-BINOL linker with the (S,S)-Co(iii)-salen complex for the HKR of 1,2-epoxyhexane. The role of non-covalent C-H?π interactions and steric effects has been discussed to control the HKR reaction of 1,2-epoxyhexane.

Regioselective synthesis of amphiphilic metoprolol-saccharide conjugates by enzymatic strategy in organic media

An efficient protocol to prepare metoprolol-saccharide conjugates by a selective enzymatic synthesis method was developed. Firstly, the transesterification of metoprolol with three divinyl dicarboxylates (divinyl succinate, divinyl adipate and divinyl sebacate) was performed. The influences of organic solvents, sources of enzymes and acylating reagents on the synthesis of N-(vinyloxycarbonyl)metoprolol were investigated. A series of lipophilic metoprolol derivatives with vinyl group were obtained by using a lipase from porcine pancreas (PPL) in anhydrous tetrachloromethane at 50 °C. Subsequently, alkaline protease from Bacillus subtilis catalyzed highly regioselective acylation of three monosaccharides (glucose, mannose and galactose) and two disaccharides (maltose and sucrose) with N-(5- vinyloxycarbonylpentanoyl)metoprolol in anhydrous pyridine at 50 °C to give metoprolol-saccharide conjugates in good yields. The partition coefficients of the products were investigated. The results indicated that the aqueous solubility of metoprolol-monosaccharide and metoprolol-disaccharide conjugates was improved markedly compared with the parent drug of metoprolol, and the aqueous solubility of metoprolol-disaccharide conjugates was much better than that of metoprolol-monosaccharide conjugates.

Zinc tetrafluoroborate hydrate as a mild catalyst for epoxide ring opening with amines: Scope and limitations of metal tetrafluoroborates and applications in the synthesis of antihypertensive drugs (RS)/(R)/(S)-metoprolols

The scope and limitations of metal tetrafluoroborates have been studied for epoxide ring-opening reaction with amines, and Zn(BF4) 2?xH2O has been found to be a mild and efficient catalyst affording high yields under solvent-free conditions at rt with excellent chemo-, regio-, and stereoselectivities. The catalytic efficiency followed the order Zn(BF4)2?xH2O ? Cu(BF4)2?xH2O > Co(BF4) 2?6H2O ? Fe(BF4)2? 6H2O > LiBF4 for reactions with cyclohexene oxide and Zn(BF4)2?xH2O ? Co(BF4) 2?6H2O ? Fe(BF4)2? 6H2O > Cu(BF4)2?xH2O for stilbene oxide, but AgBF4 was ineffective. For reaction of styrene oxide with aniline, the metal tetrafluoroborates exhibited comparable regioselectivity (1:99-7:93) with preferential reaction at the benzylic carbon of the epoxide ring. A reversal of regioselectivity (91:1-69:31) in favor of the reaction at the terminal carbon of the epoxide ring was observed for reaction with morpholine. The regioselectivity was dependent on the electronic and steric factors of the epoxide and the pKa of the amine and independent of amine nucleophilicity. The role of the metal tetrafluoroborates is envisaged as "electrophile nucleophile dual activation" through cooperativity of coordination, charge-charge interaction, and hydrogen-bond formation that rationalizes the catalytic efficiency, substrate reactivity, and regioselectivity. The methodology was used for synthesis of cardiovascular drug metoprolol as racemic and enriched enantiomeric forms.

CONTINUOUS FLOW SYNTHESIS OF AMINO ALCOHOLS USING MICROREACTORS

The present invention provides various methods for the synthesis of chemical species in a microreactor environment. In some cases, reaction products of the present invention may be valuable as intermediates and/or products in pharmaceutical and polymer research. For example, the method may involve the synthesis of amino alcohols within a microchannel. Embodiment described herein may allow for reactions with significantly shorter reaction times and increased efficiency.

Aminolysis of epoxides in a microreactor system: A continuous flow approach to β-Amino alcohols

The use of a continuous flow microreactor for β-amino alcohol formation by epoxide aminolysis is evaluated. Comparison to microwave batch reactions reveals that conditions obtainable in the microreactor can match or improve yields in many cases. By increasing the pressure of the system, maximum temperatures can also exceed those accessible using a microwave unit. The use of a microreactor for epoxide aminolysis reactions in the synthesis of two pharmaceutical relevant compounds is described.