- 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 0044-0055
(2019/12/02)
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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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Paragraph 0109; 0116; 0119; 0120
(2018/04/02)
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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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- 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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- New synthetic route to (1s)-4,5-dimethoxy-1-[(methylamino)methyl] benzocyclobutane, a key intermediate of ivabradine
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An efficient process for the preparation of (1S)-4,5-dimethoxy-1- [(methylamino)methyl] benzocyclobutane (S)-3 as ivabradine intermediate, which was obtained in 56% yield, is described. The salient feature of this process is the racemization of the undesired (1R)-4,5-dimethoxy-1,2- dihydrocyclobutabenzene-1-carboxylic acid (R)-12, and the overall yield of (S)-12 was improved to 70% by three resolutions of the racemized acid with R-(α)-phenylethanamine. The reduction of amide (S)-13 was achieved with NaBH4-I2 in refluxing tetrahydrofuran, giving the corresponding amine (S)-3 in 90% yield. The improved synthetic route described herein is cost-efficient, environmentally friendly and feasibile for scale-up production.
- Liu, Xin,Liu, Yu,He, Huili,Cai, Zhan,Yang, Yushe
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p. 451 - 456
(2014/01/23)
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- RESOLUTION OF 4,5-DIMETHOXY-1-(METHYLAMINOMETHYL)-BENZOCYCLOBUTANE
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A method of resolution of an important chemical intermediate, 4,5-dimethoxy- 1-(methylaminomethyl)-benzocyclobutane, comprises the following steps: reacting its two enantiomers of 4,5-dimethoxy-1-(methylaminomethyl)-benzocyclobutane with di-p-toluoyl-L-tartaric acid (L-DTTA) or di-p-toluoyl-D-tartaric acid (D-DTTA) in a solution of alcohol or alcohol in water to give its salts, and then resolving the salts. This gives high enantiomer excess value, high yield which is more than 80% in total with normal separation and reversed separation.
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Page/Page column 5
(2010/08/09)
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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 16
(2010/07/09)
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- PROCESS FOR THE SYNTHESIS OF (IS)-4,5-DIMETHOXY-1-(METHYLAMINOMETHYL)-BENZOCYCLOBUTANE AND ADDITION SALTS THEREOF, AND TO THE APPLICATION THEREOF 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 3
(2008/06/13)
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