56718-70-8Relevant articles and documents
Method for continuously synthesizing metoprolol and salts thereof
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Paragraph 0048; 0049, (2021/04/14)
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.
Method for preparing metoprolol succinate
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Paragraph 0036-0037; 0039-0040; 0042-0043; 0045-0046, (2020/09/16)
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.
Synthesis method of metoprolol succinate isomer impurities
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Paragraph 0011; 0039-0041; 0054-0056, (2020/08/27)
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.
Preparation method of metoprolol
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Paragraph 0031; 0032; 0036; 0039, (2017/07/23)
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.
Solvent-Directed Epoxide Opening with Primary Amines for the Synthesis of β-Amino Alcohols
Lizza, Joseph R.,Moura-Letts, Gustavo
supporting information, p. 1231 - 1242 (2017/03/11)
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.
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
Soni, Surbhi-,Dwivedee, Bharat P.,Sharma, Vishnu K.,Banerjee, Uttam C.
, p. 36566 - 36574 (2017/08/02)
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.
Continuous and convergent access to vicinyl amino alcohols
Nobuta, Tomoya,Xiao, Guozhi,Ghislieri, Diego,Gilmore, Kerry,Seeberger, Peter H.
supporting information, p. 15133 - 15136 (2015/10/12)
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
Roy, Tamal,Barik, Sunirmal,Kumar, Manish,Kureshy, Rukhsana I.,Ganguly, Bishwajit,Khan, Noor-Ul H.,Abdi, Sayed H. R.,Bajaj, Hari C.
, p. 3899 - 3908 (2015/02/19)
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.
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
Pujala, Brahmam,Rana, Shivani,Chakraborti, Asit K.
experimental part, p. 8768 - 8780 (2011/12/04)
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.
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
Kaler, Abhishek,Meena, Vachan Singh,Singh, Manpreet,Pujala, Brahmam,Chakraborti, Asit K.,Banerjee, Uttam Chand
experimental part, p. 5355 - 5358 (2011/10/19)
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.
