148849-67-6Relevant articles and documents
AN IMPROVED PROCESS FOR THE SYNTHESIS OF IVABRADINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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Page/Page column 20; 21, (2019/11/12)
: Disclosed herein is an improved process for the preparation of Ivabradine and pharmaceutically acceptable salts thereof. The invention more particularly disclosesthe synthesis of key intermediates viz.,(S)-N-[(4,5-dimethoxybenzocydobut-l-yl)-methyl]-N- (methyl)amine hydrochloride of Formula-II and 3-(3-Iodopropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzapin-2-one of Formula-III, and its use in industrial synthesis of Ivabradine and pharmaceutically acceptable salts thereof.
Preparation method of high-purity ivabradine hydrochloride and intermediate thereof
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Paragraph 0056-0062, (2019/12/02)
The invention discloses a preparation method of high-purity ivabradine hydrochloride and an intermediate thereof. According to the invention, a specific refining method is adopted; by-products generated in the preparation process are effectively removed, wherein the byproducts refer to an impurity shown in a formula I and an impurity shown in a formula II. Results confirm that the purity of the ivabradine intermediate shown in the formula IV is remarkably improved, and the contents of the impurity compound shown in the formula I and the impurity shown in the formula II in the ivabradine intermediate shown in the formula IV are controlled within the range of less than 0.1%, so that the purity of the subsequently prepared ivabradine hydrochloride can be improved. And in the process of preparing ivabradine hydrochloride by using the prepared ivabradine intermediate shown in the formula IV, impurities shown in the formula II are further removed by re-utilizing a recrystallization mode of amixed solution of acetyl chloride, acetone and ethanol. The impurity shown in the formula I and the impurity shown in the formula II obtained by separation can be used as impurity reference substances for quality control of an ivabradine raw material and a preparation thereof.
(1 S) - 4, 5 - dimethoxy - 1 - [(methylamino) methyl] benzocyclobutane preparation of hydrochloride salts of method
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Paragraph 0137; 0138; 0139, (2018/04/02)
The invention provides a preparation method of (1S)-4,5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane hydrochloride, which specially comprises the following step: carrying out reduction and salting-out on 4,5-dimethoxybenzocyclobutyl-1-methyl formamide in an inert solvent to finally obtain the (1S)-4,5-dimethoxy-1-[(methylamino)methyl]benzocyclobutane hydrochloride (I). The reaction is simple to operate, has the advantages of mild reaction conditions, clean and accessible raw/auxiliary materials, low overall cost, high chemical and enantiomer purity and the like, and therefore, is suitable for industrial production.
A high-purity hydrochloric acid Ivabradine preparation method (by machine translation)
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Paragraph 0057; 0059-0062; 0063-0069, (2018/09/11)
The invention discloses a high-purity hydrochloric acid Ivabradine preparation method, the method after the nucleophilic substitution, catalytic hydrogenation, into the hydrochloric acid salt of three-step reaction, the preparation of the hydrochloride of ivabradine, wherein the use of bicarbonate solution to wash the dehydrogenation Ivabradine solution to remove most of the un-reacted compound II, to avoid a column chromatography operation, the operation is simple; at the same time, the way using atmospheric pressure of hydrogenation, does not need to use high-pressure hydrogenation cauldron, also non-blocking condenser risk, safe operation; the resulting salts are acid Ivabradine purity to be 99.8%, most large [...]0.10%, does not need to re-refining can achieve the standard of the raw material, the reaction route is as follows. (by machine translation)
A group of synthetic Ivabradine intermediate compound and use thereof
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Paragraph 0057; 0058, (2017/10/06)
The invention provides a set of intermediate compounds used for synthesis of Ivabradine and a preparation method thereof, and also provides a method used for synthesizing Ivabradine from the intermediate compounds. According to the method, the set of intermediate compounds are subjected to a plurality of N alkylation or N acylation so as to obtain a compound IV; and Ivabradine is directly synthesized from the compound IV. The method is short in synthesis route; raw materials are simple and easily available; reaction sequence is reasonable; operation is simple and high in efficiency; the method is green and friendly to the environment; synthesis difficulty of Ivabradine is reduced greatly; cost is low; product yield is high; and the method is suitable for industrialization production.
Ivabradine and its hydrochloride preparation method
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Paragraph 0107; 0108; 0116; 0117, (2017/09/23)
The invention provides a preparation method for ivabradine and hydrochloride thereof. The preparation method for ivabradine comprises: step a1, enabling a compound shown as a formula III and a compound shown as a formula IV to have a nucleophilic substitution reaction in a polar aprotic solvent in the presence of an acid binding agent and a composite phase-transfer catalyst to generate ivabradine; and step b1, performing separation and purification on ivabradine obtained in the step a1. The composite phase-transfer catalyst is composed of a quaternary ammonium salt phase-transfer catalyst and a polyether phase-transfer catalyst with the mass ratio of 1-8:1, and X in the formula III is selected from Cl, Br, I, sulfonyloxy, methane sulfonyloxy, benzene sulfonyloxy, p-methylbenzene sulfonyloxy, o-methylbenzene sulfonyloxy or m-methylbenzene sulfonyloxy. The method is capable of substantially shortening the time of nucleophilic substitution reaction, reducing reaction temperature, improving product purity and reducing production cost.
PROCESS FOR THE PREPARATION OF BENZAZEPINE-2-ONE DERIVATIVE
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Page/Page column 16, (2017/09/05)
The present, invention relates to a cost effective, environment friendly industrially viable process for the preparation of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-one, an intermediate used in the preparation of ivabradine, without using acid chloride intermediate and condensing agent.
Exploiting the Biocatalytic Toolbox for the Asymmetric Synthesis of the Heart-Rate Reducing Agent Ivabradine
Pedragosa-Moreau, Sandrine,Le Flohic, Alexandre,Thienpondt, Vivien,Lefoulon, Fran?ois,Petit, Anne-Marie,Ríos-Lombardía, Nicolás,Morís, Francisco,González-Sabín, Javier
supporting information, p. 485 - 493 (2017/02/10)
Several chemoenzymatic routes have been evaluated for the production of the heart-rate reducing agent ivabradine. Lipases and ω-transaminases have been identified as useful biocatalysts for the preparation of key enantiopure precursors. The lipase-catalysed kinetic resolution by alkoxycarbonylation of a racemic primary amine and subsequent chemical reduction of the resulting carbamate provided an N-methylated (S)-amine, one step away from ivabradine. Alternatively, the dynamic kinetic resolution by asymmetric bioamination of an aldehyde precursor enabled, in a four-step sequence, the preparative scale synthesis of enantiopure ivabradine in 50% overall yield. (Figure presented.).
Process for the enzymatic synthesis of (7S)-3,4-dimethoxybicyclo[4.2.0]OCTA-1,3,5-triene-7-carboxylic acid and application in the synthesis of ivabradine and salts thereof
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, (2016/11/14)
Process for the enzymatic synthesis of the compound of formula (I): comprising enantioselective enzymatic hydrolysis of the nitrile of formula (IV): using the nitrilase of Rhodococcus rhodochrous of EMBL accession number EF467367.1, and the application of such a process in the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid.
NEW METHOD FOR THE PREPARATION OF HIGHLY PURE IVABRADINE BASE AND SALTS THEREOF
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Page/Page column 16; 17, (2016/12/22)
A method for the preparation of purified ivabradine and salts thereof, a method for the purification of ivabradine and salts thereof, a new reactant used in said methods and the use of said reactant for the preparation of ivabradine.
