- Synthetic method of ivabradine
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The invention provides a synthetic method of ivabradine. The synthetic method of ivabradine comprises following steps: 1, a compound II and bromo chloropropane are subjected to alkylation reaction under the catalytic effect of a first alkali so as to obtain a compound III; 2, the compound III is subjected to hydrogenation reaction in a palladium on carbon and ammonium formate system so as to obtain a compound IV; 3, the compound IV and an iodination reagent are subjected to iodization reaction so as to obtain a compound V; 4, the compound V and the compound VI are subjected to condensation reaction under the catalytic effect of a second alkali so as to obtain a compound I. Operation is simple; reaction conditions are mild; the raw materials are commercially available; the synthetic methodis simple; cost is low; and the ivabradine synthesis difficulty is reduced greatly.
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- NEW SALT OF IVABRADINE AND USES THEREOF
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The present invention relates to novel salts and physical forms of ivabradine, methods for their formation, and uses thereof, such as in the treatment of myocardial ischemia and the like.
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Page/Page column 16
(2018/07/22)
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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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- Ivabradine and preparation method of a pharmaceutically acceptable salt thereof
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The invention discloses a preparation method for ivabradine. The method includes: in the presence of a noble metal catalyst and a hydrogen transfer reagent, subjecting 3-3{-[{[(7S)-3, 4-dimethoxy benzocyclobutene-7-]methyl}(methyl)amino-propyl]- 7, 8-dimethoxy-1, 3-dihydro-2-hydro-3-benzoazepine-2-one to hydrogen transfer reaction, and after complete reaction, conducting aftertreatment to obtain the ivabradine. The method provided by the invention avoids strict requirements for equipment in hydrogenation reaction, also effectively reduces side effect, and increases the reaction yield.
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Paragraph 0011; 0026-0027
(2017/08/25)
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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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Paragraph 0055; 0056
(2017/10/06)
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- Ivabradine and its intermediate preparation method
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The invention provides a preparation method for ivabradine and an intermediate thereof dehydrogenated ivabradine. The preparation method of the dehydrogenated ivabradine comprises: step a1, enabling a compound shown as a formula II and a compound shown as a formula III 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 dehydrogenated ivabradine; and step b1, performing separation and purification on dehydrogenated 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 1-10:1, and X in the formula II 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, improving product purity, avoiding a column chromatography process and reducing production cost.
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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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- A kind of ivabradine method for the preparation of
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The invention relates to a preparation method of ivabradine. An isomer mixture (II) of ivabradine is resolved by a resolving agent so that the desired S-configuration ivabradine (I) is obtained. The preparation method utilizes chiral tartaric acid subjected to benzoyl or substituted benzoyl double-acylation as the resolving agent, utilizes a process of salt-forming crystallization resolving of the isomer mixture in an alcohol solvent or an alcohol solvent aqueous solution and can produce ivabradine (I) at a high yield. The resolved product has optical purity of more than 99%. The resolving method provided by the invention can be used for chiral drug ivabradine preparation and ivabradine optical purity control.
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Paragraph 0031-0032
(2017/02/09)
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- IVABRADINE HYDROCHLORIDE AND THE PROCESSES FOR PREPARATION THEREOF
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The present disclosure relates to a process of preparing Ivabradine Hydrochloride, which is devoid of product related impurities. More specifically, the present disclosure provides a process to obtain a new polymorph of Ivabradine Hydrochloride, wherein said polymorph is pure and devoid of impurities at particular RRTs. The disclosure further relates to the removal of specific impurities of Formula 8 and/or Formula 9 during the preparation of said Ivabradine Hydrochloride. The disclosure also specifically provides the said polymorphic form of Ivabradine Hydrochloride.
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- PROCESS FOR PREPARATION OF IVABRADINE
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A process for the preparation of ivabradine pharmaceutically acceptable salts is disclosed. An amorphous form of ivabradine hydrochloride and a process for the preparation of it are also provided.
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- PROCESS FOR MAKING IVABRADINE
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The invention relates to an improved process for making ivabradine of formula (I) or an acid addition salt thereof, by hydrogenation of dehydroivabradine of formula (II) as well as to an improved process for making said dehydroivabradine of formula (II) or an acid addition salt thereof.
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- PROCESS FOR THE SYNTHESIS OF 7,8-DIMETHOXY-1,3-DIHYDRO-2H-3-BENZAZEPIN-2-ONE COMPOUNDS, AND APPLICATION IN THE SYNTHESIS OF IVABRADINE
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Process for the synthesis of the compound of formula (I): wherein R represents a para-methoxybenzyl (PMB) group or the following group: Application in the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid.
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Paragraph 0130; 0131; 0132
(2014/10/16)
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- PROCESS FOR THE SYNTHESIS OF 3-(2-BROMO-4,5-DIMETHOXYPHENYL)PROPANENITRILE, AND APPLICATION IN THE SYNTHESIS OF IVABRADINE AND ADDITION SALTS THEREOF WITH A PHARMACEUTICALLY ACCEPTABLE ACID
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Process for the synthesis of the compound of formula (I): Application in the synthesis of ivabradine, addition salts thereof with a pharmaceutically acceptable acid and hydrates thereof.
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Paragraph 0068-0071
(2014/05/07)
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- PROCESS FOR THE SYNTHESIS OF (2E)-3-(3,4-DIMETHOXYPHENYL)PROP-2-ENENITRILE, AND APPLICATION IN THE SYNTHESIS OF IVABRADINE AND ADDITION SALTS THEREOF WITH A PHARMACEUTICALLY ACCEPTABLE ACID
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Process for the synthesis of the compound of formula (I): Application in the synthesis of ivabradine, addition salts thereof with a pharmaceutically acceptable acid and hydrates thereof.
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Paragraph 0060-0064
(2014/05/20)
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- PROCESS FOR THE SYNTHESIS OF 3-(2-BROMO-4,5-DIMETHOXYPHENYL)PROPANENITRILE, AND APPLICATION IN THE SYNTHESIS OF IVABRADINE AND ADDITION SALTS THEREOF WITH A PHARMACEUTICALLY ACCEPTABLE ACID
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Process for the synthesis of the compound of formula (I): Application in the synthesis of ivabradine, addition salts thereof with a pharmaceutically acceptable acid and hydrates thereof.
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Paragraph 0058-0062
(2014/06/24)
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- Process for the synthesis of 3,4-dimethoxybicyclo[4.2.0]OCTA-1,3,5-triene-7-carbonitrile, and application in the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid
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Process for the synthesis of the compound of formula (I): Application in the synthesis of ivabradine, addition salts thereof with a pharmaceutically acceptable acid and hydrates thereof.
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Page/Page column 8
(2014/10/29)
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- IVABRADINE HYDROCHLORIDE SOLID DISPERSION
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The present invention provides a compound of 7,8-dimethoxy-3-[3-[[(1S)-(4,5-dimethoxybenzocyclobutan-1-yl)methyl]methylamino]propyl]-1,3-de-hydro-7,8-dimethoxy-2H-3-benzazepin-2-one oxalate (de-hydro ivabradine oxalate salt) and process for its preparation. The present invention also provides a process for the purification of de-hydro ivabradine oxalate salt. The present invention further provides a novel process for the preparation of ivabradine using novel intermediate. The present invention further provides a novel amorphous solid dispersion of ivabradine hydrochloride in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
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Page/Page column 12; 13
(2013/10/22)
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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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- 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 thereof with a pharmaceutically acceptable acid, and hydrates thereof.
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Page/Page column 9; 10
(2013/08/28)
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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 thereof with a pharmaceutically acceptable acid, and hydrates thereof.
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Paragraph 0026; 0027; 0028; 0029
(2013/06/28)
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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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Page/Page column 3
(2012/07/14)
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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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- 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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Page/Page column 3
(2011/09/14)
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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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Page/Page column 5
(2010/10/19)
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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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Page/Page column 5
(2010/07/04)
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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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Page/Page column 3
(2010/10/19)
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- PROCESS FOR PREPARATION OF IVABRADINE
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The present invention describes a new process for optical resolution of [N-[[3,4- dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl]-N-methylamine] which is an intermediate in the preparation of ivabradine.
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Page/Page column 21
(2010/07/09)
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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 13-14
(2009/01/20)
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