37350-58-6

Basic information

• Product Name: Metoprolol
• Synonyms: 1-(Isopropylamino)-3-[4-(2-methoxyethyl)phenoxy]-2-propanol;1-(Isopropylamino)-3-[p-(2-methoxyethyl)phenoxy]-2-propanol;2-Propanol, 1-[4-(2-methoxyethyl)phenoxy]-3-[(1-methylethyl)amino]-;2-Propanol, 1-[4-(2-methoxyethyl)phenoxy]-3-[(1-methylethyl)amino]-, (±2-Propanol, 1-[4-(2-methoxyethyl)phenoxy]-3-[(1-methylethyl)amino]-, (.+/-.)-;CGP 2175;cgp2175;H-23/96
• CAS NO: 37350-58-6
• Molecular Formula: C15H25NO3
• Molecular Weight: 267.36
• EINECS: 253-483-7
• Product Categories: Cardiovascular
• Mol File: 37350-58-6.mol
• Article Data: 45

Chemical Properties

• Boiling Point: 410.55°C (rough estimate)
• Flash Point: 194.9 °C
• Appearance: powder
• Density: 1.0281 (rough estimate)
• Vapor Pressure: 1.02E-17mmHg at 25°C
• Refractive Index: 1.5000 (estimate)
• CAS DataBase Reference: Metoprolol(CAS DataBase Reference)
• NIST Chemistry Reference: Metoprolol(37350-58-6)
• EPA Substance Registry System: Metoprolol(37350-58-6)

Safety Data

• Hazardous Substances Data: 37350-58-6(Hazardous Substances Data)

Usage

Originator

Betaloc,Astra,UK,1975

Uses

Different sources of media describe the Uses of 37350-58-6 differently. You can refer to the following data:
1. Metoprolol is used in moderate hypertension, serious conditions of myocardial infarction, for preventing death of cardiovascular tissue, in angina, tachycardia, extrasystole, and for secondary prophylaxis after a heart attack.
2. Antiadrenergic (β-receptor).
3. Metoprolol is a β-adrenergic blocking antihypertensive and antianginal agent; to treat raised blood pressure; to prevent attacks of angina (pain from an inadequate oxygen supply to the heart); after a heart attack to prevent further damage to the heart muscle; treatment of some disturbances of heart rhythm; used to help prevent attacks of migraine; in ophthalmic preparations; treatment of myocardial infarcts.

Manufacturing Process

The starting material 1,2-epoxy-3-[p-(β-methoxyethyl)phenoxy]-propane was obtained from p-(β-methoxyethyl)-phenol which was reacted with epichlorohydrin whereafter the reaction product was distilled at 118°C to 128°C at a pressure of 0.35mm Hg.1,2-Epoxy-3-[p-(β-methoxyethyl)-phenoxy]-propane (16.7g) was dissolved in 50 ml isopropanol and mixed with 20 ml isopropylamine. The mixture was heated in an autoclave on boiling water-bath overnight, whereafter it was evaporated and the remainder dissolved in 2 N HCI. The solution was extracted first with ether and thereafter with methylene chloride. After evaporating the methylene chloride phase, the hydrochloride of 1- isopropylamino-3-[p(β-methoxyethyl)-phenoxy] -propanol-2 was obtained which, after recrystallization from ethyl acetate, weighed 10.4 g. Melting point 83°C. Equivalent weight: found 304.0, calculated 303.8.The hydrochloride is then converted to the tartrate.

Brand name

Lopressor (Novartis).

Therapeutic Function

Beta-adrenergic blocker

Mechanism of action

Unlike propranolol, which blocks both β1 and β2-adrenoreceptors, metroprolol exhibits cardioselective action, i.e. in therapeutic doses, it blocks β1-adrenoreceptors with insignificant effects on β2-adrenoreceptors.

Synthesis

Metoprolol, 1-(iso-propylamino)-3-[4′(2-methoxyethyl)phenoxy]-2- propanol (12.1.5), is synthesized by reacting 4-(2-methoxyethyl)phenol with epichlorhydride in the presence of a base, isolating 1,2-epoxy-3-[4′(2-methoxyethyl)phenoxy] propane (12.1.4), the subsequent reaction of which, analogous to that described before, with iso-propylamine, gives an opening of the epoxide ring and leads to the formation of metoprolol (12.1.5) [7,8].

Metabolism

The pharmacokinetic profile of metoprolol (Lopressor) is similar to that of propranolol. Metoprolol is readily and rapidly absorbed after oral administration and is subject to a significant amount of first-pass metabolism by the liver. Curiously, the duration of metoprolol’s action is longer than one would predict from its plasma half-life, which ranges from 0.5 to 2.5 hours. The degree of binding of metoprolol to plasma proteins is modest (10%). The extensive distribution of metoprolol to the lungs and kidney is typical of a moderately lipophilic drug. Metoprolol undergoes considerable metabolism;only 3 to 10% of an administered dose is recovered as unchanged drug.The metabolites are essentially inactive as -receptor blocking agents and are eliminated primarily by renal excretion. Small amounts of the drug are present in the feces.

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 
• 105780-38-9 (2S)-2-{[4-(2-Methoxyethyl)phenoxy]methyl}oxirane 
• 114218-34-7 (R)-1-O-methanesulfonyl-3-O-p-(2-methoxyethyl)phenylglyserol 
• 207983-04-8 metoprolol Succinate 
• 80448-05-1 3-[4-(2-methoxyethyl)phenoxy]propylene 
• 56718-71-9 4-(2-methoxyethyl)phenol 
• 133397-54-3 (R)-2-{[4-(2-methoxyethyl)phenoxy]methyl}oxirane 
• 104450-90-0 2,2'-O-methylenebis<(R)-1-O-methanesulfonyl-3-O-p-(2-methoxyethyl)phenylglycerol> 
• 114218-32-5 1,6-bis-O-p-(2-methoxyethyl)phenyl-3,4-O-methoxymethylene-2,5-O-methylene-D-mannitol 
• 104450-88-6 2,2'-O-methylenebis<3-O-p-(2-methoxyethyl)phenyl-(R)-glyceraldehyde> 
• 104450-87-5 1,6-bis-O-p-(2-methoxyethyl)phenyl-2,5-O-methylene-D-mannitol 
• 104450-89-7 2,2'-O-methylenebis<(S)-1-O-p-(2-methoxyethyl)phenylglycerol> 
• 104857-48-9 1-[4-(2-hydroxyethyl)phenoxy]-2,3-epoxypropane 

Downstream Products

• 110458-46-3 (1'S,2R)-3-<4-(1-hydroxy-2-methyloxyethyl)phenoxy>-1-(isopropylamino)-2-propanol 
• 110458-52-1 (1'R,2R)-3-<4-(1-hydroxy-2-methyloxyethyl)phenoxy>-1-(isopropylamino)-2-propanol 
• 110458-47-4 (1'S,2S)-3-<4-(1-hydroxy-2-methyloxyethyl)phenoxy>-1-(isopropylamino)-2-propanol 
• 110458-48-5 (1'R,2S)-3-<4-(1-hydroxy-2-methyloxyethyl)phenoxy>-1-(isopropylamino)-2-propanol 
• 62572-94-5 (+)-O-Demethylmetoprolol 

Relevant articles and documents

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.

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.

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.