- AN IMPROVED PROCESS FOR THE SYNTHESIS OF IVABRADINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
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: 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.
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Page/Page column 20; 21
(2019/11/12)
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- Preparation method of high-purity ivabradine hydrochloride and intermediate thereof
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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.
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Paragraph 0056-0062
(2019/12/02)
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- A high-purity hydrochloric acid Ivabradine preparation method (by machine translation)
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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)
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Paragraph 0057; 0059-0062; 0063-0069
(2018/09/11)
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- (1 S) - 4, 5 - dimethoxy - 1 - [(methylamino) methyl] benzocyclobutane preparation of hydrochloride salts of method
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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.
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- A group of synthetic Ivabradine intermediate compound and use thereof
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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.
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- Exploiting the Biocatalytic Toolbox for the Asymmetric Synthesis of the Heart-Rate Reducing Agent Ivabradine
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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.).
- Pedragosa-Moreau, Sandrine,Le Flohic, Alexandre,Thienpondt, Vivien,Lefoulon, Fran?ois,Petit, Anne-Marie,Ríos-Lombardía, Nicolás,Morís, Francisco,González-Sabín, Javier
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supporting information
p. 485 - 493
(2017/02/10)
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- PROCESS FOR THE PREPARATION OF BENZAZEPINE-2-ONE DERIVATIVE
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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.
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Page/Page column 16
(2017/09/05)
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- Ivabradine and its hydrochloride preparation method
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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.
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- 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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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.
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- NEW METHOD FOR THE PREPARATION OF HIGHLY PURE IVABRADINE BASE AND SALTS THEREOF
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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.
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Page/Page column 16; 17
(2016/12/22)
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- PROCESS FOR THE ENZYMATIC SYNTHESIS OF (7S)-1-(3,4-DIMETHOXYBICYCLO[4.2.0]OCTA-1,3,5-TRIEN-7-YL) N-METHYL METHANAMINE, AND APPLICATION IN THE SYNTHESIS OF IVABRADINE AND SALTS THEREOF
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Synthesizing carbamate (IX) comprises performing an enantioselective enzymatic acylation of racemic form of (3,4-dimethoxy-7-bicyclo[4.2.0]octa-1,3,5-trienyl)methanamine (IV) with a lipase (EC 3.1.1.3 in the international classification of enzymes) by carbonate with 1-15 molar equivalents in organic solvents, aqueous solvents, a mixture of organic solvents and/or mixture of organic and aqueous solvents at a concentration of 5-500 g/l per liter of solvents and their mixtures, a E/S ratio of 10/1 to 1/100 and a temperature of 25-40[deg] C. Synthesizing carbamate of formula (IX) comprises performing an enantioselective enzymatic acylation of racemic form of (3,4-dimethoxy-7-bicyclo[4.2.0]octa-1,3,5-trienyl)methanamine of formula (IV) with a lipase (EC 3.1.1.3 in the international classification of enzymes) by carbonate of formula (R1O-(CO)-OR1) with 1-15 molar equivalents in organic solvents, aqueous solvents, a mixture of organic solvents and/or mixture of organic and aqueous solvents at a concentration of 5-500 g/l per liter of solvents and their mixtures, a E/S ratio of 10/1 to 1/100 and a temperature of 25-40[deg] C. R1 : linear or branched 1-6C-alkyl, allyl or benzyl. An independent claim is included for synthesis of (7S)-1-(3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-yl) N-methyl methanamine of formula (I) comprising performing enzymatic acylation of (IV) to obtain (IX), and performing reduction step using a reducing agent consisting of lithium tetrahydridoaluminate and sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) to obtain (I). ACTIVITY : Cardiant; Vasotropic; Antianginal; Antiarrhythmic. MECHANISM OF ACTION : None given.
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Paragraph 0106-0108
(2017/04/27)
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- A PROCESS FOR PREPARING IVABRADINE
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The invention refers to a process for preparing ivabradine, in particular a process for preparing an ivabradine salt.
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- POLYMORPHIC FORMS OF IVABRADINE HYDROCHLORIDE
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Stable crystalline Form II and stable crystalline Form III of ivabradine hydrochloride and processes for their preparation are disclosed.
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Paragraph 0104
(2014/11/11)
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- IVABRADINE HYDROCHLORIDE FORM IV
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Ivabradine hydrochloride Form IV, its pharmaceutical composition, process for its preparation, and its use as therapeutically active ingredient.
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Page/Page column 17
(2013/05/22)
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- Ivabradine hydrochloride Form IV
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Ivabradine hydrochloride Form IV, its pharmaceutical composition, process for its preparation,and its use as therapeutically active ingredient.
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Paragraph 0099
(2013/05/22)
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- A PROCESS FOR MAKING CRYSTALLINE DELTA-FORM OF IVABRADINE HYDROCHLORIDE
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The present invention relates to an improved process for making the pharmaceutically advantageous crystalline delta-form of ivabradine hydrochloride.
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Page/Page column 11-12
(2013/05/22)
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- POLYMORPHIC FORMS OF IVABRADINE HYDROCHLORIDE
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Stable crystalline Form II and stable crystalline Form III of ivabradine hydrochloride and processes for their preparation are disclosed.
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Page/Page column 16-17
(2013/07/19)
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- Process for preparation of ivabradine hydrochloride
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The present invention relates to crystalline Ivabradine hydrochloride Form-I and a process for its preparation.
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- An improved process for the preparation of highly pure ivabradine hydrochloride
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The present invention encompasses a process for the preparation of highly pure Ivabradine hydrochloride by treating crude Ivabradine with derivatizing agent which derivatize impurities adhered with the crude Ivabradine.
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Page/Page column 8
(2012/09/21)
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- PROCESS FOR THE SYNTHESIS OF IVABRADINE AND ADDITION SALTS THEREOF WITH A PHARMACEUTICALLY ACCEPTABLE ACID
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Process for the synthesis of ivabradine of formula (I): and addition salts thereof with a pharmaceutically acceptable acid.
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- POLYMORPHIC FORM OF IVABRADINE HYDROCHLORIDE AND PROCESS FOR PREPARATION THEREOF
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The present invention discloses Crystalline Form Zeta ζ of ivabradine hydrochloride and process for its preparation..
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Page/Page column 14
(2012/03/26)
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- INDUSTRIAL PROCESS FOR THE SYNTHESIS OF IVABRADINE SALTS
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Process for the synthesis of Ivabradine salts of formula (I) the chemical name of which is: 3-{3-[((S)-3,4-dimethoxy-bicyclo[4.2.0]octa-1,3,5-triene- 7-ylmethyl)-methyl-amino]-propyl}-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2-one salts (HQ=HCl, HBr, HI, HNO3, HClO4, (COOH)2), and new intermediates thereof. Certain crystalline forms of the acid addition salts of Ivabradine (I) with nitric acid (I, HQ=HNO3), hydrobromic acid (I, HQ=HBr), hydroiodic acid (I, HQ=HI), oxalic acid (I, HQ= (COOH)2) and perchloric acid (I, HQ=HClO4)).
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- PROCESS FOR THE PREPARATION OF IVABRADINE HYDROCHLORIDE AND POLYMORPH THEREOF
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The present invention encompasses a process for the preparation of highly pure ivabradine hydrochloride by treating ivabradine with alcoholic hydrogen chloride. The invention further encompasses amorphous ivabradine hydrochloride and process for its preparation using suitable acid addition salts of ivabradine.
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Page/Page column 13-16
(2009/01/20)
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- Process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid
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Process for the synthesis of ivabradine of formula (I): addition salts with a pharmaceutically acceptable acid and hydrates thereof. α crystalline form of ivabradine hydrochloride. Medicinal products containing the a crystalline form of ivabradine hydrochloride, which are useful as bradycardics.
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Page/Page column 3-4
(2010/02/14)
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