- Method for continuously synthesizing metoprolol and salts thereof
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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.
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Paragraph 0048; 0049
(2021/04/14)
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- Method for preparing metoprolol succinate
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The invention relates to a method for preparing high-purity metoprolol succinate, which adopts a single solvent system to prepare the metoprolol succinate in a reverse dropping mode. The method is simple and convenient to operate, stable in process, high in salifying yield and purity, low in process cost, and has good practical value. A single conventional solvent is adopted, so that post-treatment and solvent recovery are facilitated, and the method is environment-friendly.
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Paragraph 0036-0037; 0039-0040; 0042-0043; 0045-0046
(2020/09/16)
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- Synthesis method of metoprolol succinate isomer impurities
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The invention belongs to the technical field of medicinal chemistry, and particularly relates to a synthesis method of metoprolol succinate isomer impurities. According to the synthesis method, p-methoxyethyl phenol is used as a raw material, and the metoprolol succinate isomer impurity is prepared through five steps of reactions including a condensation reaction, a ring-opening reaction, an oxidation reaction, a reductive amination reaction and a hydrolysis reaction. The synthesis method provided by the invention comprises five steps of reactions, the raw materials are easy to obtain, the total yield is greater than 30%, and contribution is made to strict control of the impurity content of the metoprolol succinate isomer by adopting an external standard method; the synthesis method has the advantages of simple operation, mild reaction conditions and high product purity, is suitable for drug quality research, and provides a guarantee for improving the quality of metoprolol succinate bulk drugs.
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Paragraph 0011; 0039-0041; 0054-0056
(2020/08/27)
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- Preparation method of metoprolol
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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.
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Paragraph 0031; 0032; 0036; 0039
(2017/07/23)
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- Solvent-Directed Epoxide Opening with Primary Amines for the Synthesis of β-Amino Alcohols
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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.
- Lizza, Joseph R.,Moura-Letts, Gustavo
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supporting information
p. 1231 - 1242
(2017/03/11)
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- Kinetic resolution of (: RS)-1-chloro-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol: a metoprolol intermediate and its validation through homology model of Pseudomonas fluorescens lipase
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In the present study Pseudomonas fluorescens lipase (PFL) was screened as a time efficient biocatalyst for the kinetic resolution of a racemic intermediate [(RS)-1-chloro-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol] of metoprolol, an important selective β1-blocker drug. PFL selectively acylated the R-form of this racemic intermediate in a short duration of 3 h. Different reaction parameters were optimized to achieve maximum enantioselectivity. It was found that at 30 °C, enzyme activity of 400 units and substrate concentration of 10 mM gave a high enantioselectivity and conversion in an optimum time of 3 hours (C = 50.5%, eep = 97.2%, ees = 95.4%, E = 182). To validate these experimental results, the 3D structure of PFL was built using homology modelling. Validation of the model through Ramachandran plot (92.7% in favored region), Errat plot (overall quality factor, 79.27%), Verify-3D score (86.19) and ProSA-Z score (-6.24) depicted the overall good quality of the model. Molecular docking of the R- and S-enantiomers of the intermediate, which was performed on this model, demonstrated a strong H-bond interaction (1.6 ?) between the hydroxyl group of the R-enantiomer and Arg54, a key binding residue of the catalytic site of PFL, while no significant interaction with the S-enantiomer was observed. Thus, the outcome of this docking study was in agreement with the experimental data, clarifying that PFL preferentially catalysed the transesterification of the R-enantiomer into the corresponding ester, leaving the S-enantiomer intact.
- Soni, Surbhi-,Dwivedee, Bharat P.,Sharma, Vishnu K.,Banerjee, Uttam C.
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p. 36566 - 36574
(2017/08/02)
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- Continuous and convergent access to vicinyl amino alcohols
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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.
- Nobuta, Tomoya,Xiao, Guozhi,Ghislieri, Diego,Gilmore, Kerry,Seeberger, Peter H.
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supporting information
p. 15133 - 15136
(2015/10/12)
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- 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
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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.
- Roy, Tamal,Barik, Sunirmal,Kumar, Manish,Kureshy, Rukhsana I.,Ganguly, Bishwajit,Khan, Noor-Ul H.,Abdi, Sayed H. R.,Bajaj, Hari C.
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p. 3899 - 3908
(2015/02/19)
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- 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
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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.
- Pujala, Brahmam,Rana, Shivani,Chakraborti, Asit K.
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experimental part
p. 8768 - 8780
(2011/12/04)
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- Lipase-mediated kinetic resolution of (RS)-1-bromo-3-[4-(2-methoxy-ethyl)- phenoxy]-propan-2-ol to (R)-1-bromo-3-(4-(2-methoxyethyl) phenoxy) propan-2-yl acetate
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A novel biocatalytic method for the enantioselective synthesis of (R)-bromo-3-[4-(2-methoxy-ethyl) phenoxy]-2-propanol [(R)-BMEPP], a precursor for the synthesis of (S)-metoprolol, an anti hypertensive drug is described. We have developed kinetic resolution of rac-BMEPP by transesterification using Candida rugosa lipase and vinyl acetate as the acyl donor affording the product with excellent conversion (49%) and ee (>99%). Various reaction parameters (source of enzyme, reaction media, and concentration of substrate and acylating agent) for the enzymatic kinetic resolution have been reported.
- Kaler, Abhishek,Meena, Vachan Singh,Singh, Manpreet,Pujala, Brahmam,Chakraborti, Asit K.,Banerjee, Uttam Chand
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experimental part
p. 5355 - 5358
(2011/10/19)
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- SYNTHESIS AND PREPARATIONS OF METOPROLOL AND ITS SALTS
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The invention relates to an improved process for preparing metoprolol and its salts.
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Page/Page column 3
(2009/10/06)
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- Chemoenzymatic synthesis of the potential antihypertensive agent (2R,2′S)-β-hydroxyhomometoprolol
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The kinetic resolution of 1-chloro-3-[4-(2-methoxyethyl)phenoxy]-2-propanol rac-4 with Novozym 435 and vinyl stearate, a key step in the gram-scale synthesis of (2S)-2-[[(2R)-2-hydroxy-3-[4-(2-methoxyethyl)phenoxy]propyl]amino]-1-butanol (R,S)-1 a potent antihypertensive agent currently under investigation, is reported here. Our approach differs from the previously reported synthesis, which involves a tedious and poorly effective fractional crystallization of (R,S)-1. This novel approach incorporates an enzymatic resolution for the efficient preparation of the oxirane precursor (R)-3. The two main advantages arising from this strategy are the high enantioselectivity of the enzymatic process and the facilitated recovery of the hydrophobic stearate intermediate (S)-5.
- Regla, Ignacio,Luviano-Jardon, Axel,Demare, Patricia,Hong, Enrique,Torres-Gavilan, Alejandro,Lopez-Munguia, Agustin,Castillo, Edmundo
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experimental part
p. 2439 - 2442
(2009/04/11)
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- Non-enzymatic kinetic resolution of β-amino alcohols using C-12 higher carbon sugar as a chiral auxiliary
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An efficient non-enzymatic kinetic resolution strategy capable of accessing optically active β-adrenergic antagonists intermediates is reported. The C-12 higher carbon sugar derived from naturally occurring sucrose was employed to probe the kinetic resolution. Excellent enantiomeric excesses (ee >99%) and high yields were obtained under very mild conditions. The chiral auxiliary could be recovered in a high reclaimed ratio (>95%) and reusable form without any decrease of the resolving ability.
- Zhang, Jing-Yu,Liu, Hong-Min,Xu, Hai-Wei,Shan, Li-Hong
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p. 512 - 517
(2008/09/19)
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- PROCESS FOR MANUFACTURE OF METOPROLOL AND SALTS THEREOF
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Metoprolol manufacturing process with optimized reaction temperatures and reactant molar ratios, to avoid the manufacture of excessive epoxide intermediates, thus avoiding the need for purification of epoxide intermediates, thus achieving higher yields and higher-purity product than that seen in the prior art teachings.
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Page/Page column 6
(2008/06/13)
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- Conversion of epoxides to β-chlorohydrins with thionyl chloride and β-cyclodextrin in water
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Several epoxides are efficiently converted to the corresponding β-chlorohydrins in impressive yields with thionyl chloride in the presence of β-cyclodextrin using water as solvent at room temperature. Copyright Taylor & Francis, Inc.
- Surendra,Srilakshmi Krishnaveni,Nageswar,Rama Rao
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p. 2195 - 2201
(2007/10/03)
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- Design, synthesis and evaluation of racemic 1-(4-hydroxyphenyl)-2-[3- (substituted phenoxy)-2-hydroxy-1-propyl]amino-1-propanol hydrochlorides as novel uterine relaxants
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Novel 1-(4-hydroxyphenyl)-2-[3-(substituted phenoxy)-2-hydroxy-1-propyl] amino-1-propanol hydrochlorides were designed based on the pharmacophore for potent uterine relaxant activity and by utilizing the principles of structural hybridization. The designed molecules were synthesized as racemates by a novel route and were evaluated for uterine relaxant activity in vitro on isolated rat uterus and in vivo in pregnant rats. Their cAMP-releasing potential was studied using rat uterus tissue homogenates by the cAMP [3H] assay, and cardiac stimulant potential was evaluated on isolated guinea pig right atrium. All compounds exhibited potent uterine relaxant activity in vitro and produced a significant delay in the onset of labour in pregnant rats; their cAMP-releasing potential was slightly less, while their cardiac stimulant potential was insignificant as compared to isoxsuprine hydrochloride.
- Viswanathan,Kodgule,Chaudhari
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p. 3532 - 3535
(2007/10/03)
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- MERGED ION CHANNEL MODULATING COMPOUNDS AND USES THEREOF
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Merged compounds of ion channel modulating compounds, including, for example, merged compounds of the ion channel modulating compound of the following formula: (I) are described herein, as well as methods of making and using such merged compounds and pharmaceutical compositions containing such merged compounds.
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Page/Page column 75
(2008/06/13)
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- Metoprolol manufacturing process
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Metoprolol manufacturing process with optimized reaction temperatures and reactant molar ratios, to avoid the manufacture of excessive epoxide intermediates, thus avoiding the need for purification of epoxide intermediates, thus achieving higher yields and higher-purity product than that seen in the prior art teachings.
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Page/Page column 2
(2010/02/11)
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- Synthesis and cardiovascular activity of metoprolol analogues
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The synthesis of four novel analogues of metoprolol, a well-known β1-blocker used to reduce arterial blood pressure, is described. The preparation of (2S,2′S)-7, (2R,2′S)-7, (2R,2′R)-8, and (2S,2′R)-8 was based on the reaction of racemic 2-[4-(2′- methoxyethyl)-phenoxymethyl]-oxirane (4) with (R)- or (S)-2-amino-1-butanol. Salient characteristics of analogues 7 and 8 relative to metoprolol are the incorporation of an additional stereogenic center, as well as a methyl group and a hydroxyl function on the nitrogen-containing chain. These novel derivatives present significant hypotensive and bradycardiac activity, although no blocking action toward β1 and β2 adrenergic receptor.
- Melgar-Fernandez, Roberto,Demare, Patricia,Hong, Enrique,Rosas, Miguel Angel,Escalante, Jaime,Munoz-Muniz, Omar,Juaristi, Eusebio,Regla, Ignacio
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p. 191 - 194
(2007/10/03)
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- Efficient asymmetric hydrogenation of α-amino ketone derivatives. A highly enantioselective synthesis of phenylephrine, levamisole, carnitine and propranolol
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The complexes of pyrrolidine bisphosphine ligands (CPMs) with rhodium (I) were found to be efficient catalysts for asymmetric hydrogenation of α-amino ketone hydrochloride derivatives. Utilizing this methodology, we have developed efficient asymmetric syntheses of the optically active β-amino alcohols, phenylephrine, levamisole, carnitine and propranolol.
- Sukuraba,Takahashi,Takeda,Achiwa
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p. 738 - 747
(2007/10/02)
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- DIHYDROPYRIDIN-3,5-DICARBOXYLATES INCORPORATING ARYLOXYPROPANOLAMINE MOIETIES
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A series of compounds useful in treating cardiovascular disorders due to the combined expression of both β-block and calcium-block activity by these agents. This useful combination of actions is effected by a novel combination of structural subunits forming these compounds. Essentially, β-blocking aryloxypropanolamine moieties are attached via their aryl ring or amino nitrogen at one of the carboxylate groups of calcium-blocking 4-aryl-1,4-dihydropyridine-3,5-dicarboxylates. These compounds are prepared from new 4-aryl-1,4-dihydropyridine intermediate compounds.
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- A New Route to (+/-) Metoprolol
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Synthesis of 4-(2-methoxyethyl)phenol (5) from phenol is described.The derived aryloxyallyl ether (6) is converted into (+/-)-metoprolol (10) by involving dihydroxylation reaction with OsO4 and NMO.
- Gurjar, M.K.,Joshi, Shreerang V,Sastry, B.S.,Rao, A V Rama
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p. 3489 - 3496
(2007/10/02)
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- Design and synthesis of a series of combined vasodilator/β-adrenoceptor antagonists based on 6-arylpyridazinones
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A series of new 6-[4-[[(aryloxy)acyl]amino]phenyl]-4,5-dihydropyridazinones have been synthesized and evaluated as combined vasodilator/β-adrenoceptor antagonists and potential antihypertensive agents. Many of the early compounds displayed an unacceptably high level of intrinsic sympathomimetic activity (ISA) and a relatively short duration of action. Disubstitution in the 2,3-positions or in the 4-position of the aryloxy ring gave compounds with low ISA levels and, in some instances, improved duration of action. All of the compounds were vasodilators, but the 5-methylpyridazinone derivatives showed consistently greater antihypertensive activity than their 5-H lower homologues. Further detailed pharmacological investigations led to the selection of 6-[4-[3-[[2-hydroxy-3-[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]propyl]amino ]propionamido]phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone (4t) (SK&F 95018) as a development candidate.
- Slater,Howson,Swayne,Taylor,Reavill
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p. 345 - 351
(2007/10/02)
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- DERIVATIVES OF 3-AMINOPROPANE-1,2-DIOL
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Derivatives of 3-aminopropane-1,2-diol of the formula STR1 in which Ar represents optionally substituted aryl,n represents the number 0 or 1, andalk represents alkylene having 2 to 5 carbon atoms, the nitrogen atom and the oxygen atom, or, if n is zero, the phenyl radical, being separated from one another by at least two carbon atoms, andR 1 and R. sub.2, independently of one another, each represents hydrogen or lower alkyl, or together they represent lower alkylene, oxa-lower alkylene, thia-lower alkylene, aza-lower alkylene or N-lower alkyl-aza-lower alkylene,and salts of such compounds, processes for their manufacture, medicaments containing the new compounds and their use for the treatment of Angina pectoris and cardiac arrhythmia, and as blood pressure-reducing agents, as well as for the treatment of reactive or endogenic states of depression.
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- Derivatives of 3-aminopropane-1,2-diol
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Derivatives of 3-aminopropane-1,2-diol of the formula STR1 in which Ar represents optionally substituted aryl, n represents the number 0 or 1, and alk represents alkylene having 2 to 5 carbon atoms, the nitrogen atom and the oxygen atom, or, if n is zero, the phenyl radical, being separated from one another by at least two carbon atoms, and R1 and R2, independently of one another, each represents hydrogen or lower alkyl, or together they represent lower alkylene, oxa-lower alkylene, thia-lower alkylene, aza-lower alkylene or N-lower alkyl-aza-lower alkylene, and salts of such compounds, processes for their manufacture, medicaments containing the new compounds and their use for the treatment of Angina pectoris and cardiac arrhythmia, and as blood pressure-reducing agents, as well as for the treatment of reactive or endogenic states of depression.
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