CN101284813A - Preparation method of ivabradine - Google Patents
Preparation method of ivabradine Download PDFInfo
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- CN101284813A CN101284813A CNA2007100394183A CN200710039418A CN101284813A CN 101284813 A CN101284813 A CN 101284813A CN A2007100394183 A CNA2007100394183 A CN A2007100394183A CN 200710039418 A CN200710039418 A CN 200710039418A CN 101284813 A CN101284813 A CN 101284813A
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Abstract
The invention relates to a novel method for preparing angina pectoris medicine Ivabradine (compound I and salt thereof). The method takes a formula II compound as the raw material to obtain a compound III through catalytic hydrogenation, the compound III is made an alkylation reaction with a formula IV compound to produce the compound I. The method is simple and convenient, is easy to obtain raw materials, and is suitable for industrialized production.
Description
Technical field:
The present invention relates to pharmaceutical chemistry, be specifically related to a kind of novel painful medicine S 16257-2 (Compound I) of heart strand and the preparation method of salt thereof.
Background technology:
S 16257-2 (Ivabradine), chemical name 3-{3-[{[(7S)-3,4-dimethoxy dicyclo [4.2.0] suffering-1,3,5-triolefin-7-yl]-methyl } (methyl) amino] propyl group-7,8-dimethoxy-1,3,4,5-tetrahydrochysene-2H-3-benzo-aza
-2-ketone and pharmaceutically-acceptable acid addition thereof and hydrate thereof, following formula: compound I:
S 16257-2 (Ivabradine), obtain approval 27 country's listings of European medical evaluation office (EMEA) in Europe on November 3rd, 2005, name of product Procoralan is used for the treatment of the symptomatic treatment of the chronic stable angina pectoris that maybe can not tolerate with normal sinus rhythm, to beta-blockers taboo.
Procoralan is by Shi Weiya company research and development, and one of the most important progress that the cardiovascular treatment field is obtained in 20 years that becomes history.Procoralan is that the 1st pure heart rate lowers medicine, and the If passage that suppresses to be responsible for control sinus node spontaneous depolarization and to regulate heart rate by selectivity plays a role.The Procoralan selectively acting is in sinus node, to the not influence of intracardiac conduction, myocardial contraction or ventricular bipolarization.Different with anginal medicine beta-blocker commonly used, Procoralan do not cause sexual dysfunction, because of air flue shrinks and spasm causes respiratory system untoward reaction and bradyrhythmia or rebound phenomenon.
The patent of this compound of the relevant preparation of report the earliest has EP05348059, its relevant patent is US5296482, this patent system Preparation Method is as follows, with compound V is raw material, obtain iodo thing (compound VI) with the NaI back flow reaction, with compound IV the N-alkylated reaction taking place, obtains compound VI I, obtains target compound S 16257-2 (reaction formula I) through catalytic hydrogenation more at last:
Reaction formula I:
This method yield is lower, this step of catalytic hydrogenation particularly, and yield only 40%, total recovery is 18%, and product needs be not suitable for suitability for industrialized production through column chromatography purification.
Shi Weiya company has applied for a kind of new preparation method's patent CN200510051779 again in China subsequently, relevant patent has US20050228177, this method is raw material with the compound VIII, obtain Compound I X through catalytic hydrogenation, obtain target compound S 16257-2 (reaction formula II) through reductive amination process again:
Reaction formula II:
This method yield of bibliographical information is 85%, but the two-step reaction of this method all will be used expensive metal catalyst, and large usage quantity, cost is extremely expensive, and starting compound VIII is not easy to obtain, and its preparation process is comparatively complicated, the cost height, thereby also be not suitable for suitability for industrialized production.
Summary of the invention:
Technical problem to be solved by this invention is to overcome above-mentioned weak point, and research and design is suitable for the method for preparing S 16257-2 of suitability for industrialized production.
The invention provides the preparation method of a kind of S 16257-2 (Compound I) and salt thereof, this method is with 3-(3-halopropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzo-aza
-2-ketone compound II is a raw material, obtain compound 3-(3-halopropyl)-7 at suitable temperature, solvent and catalyst hydrogenation, 8-dimethoxy-1,3,4,5-tetrahydrochysene-2H-3-benzazepine-2-ketone compound II I, then in suitable temperature, solvent and reaction promotor with (1S)-4,5-dimethoxy-1-(methylamino methyl)-benzocyclobutane compounds IV carries out alkylated reaction and obtains the S 16257-2 Compound I, see the reaction formula III, this method is easier carries out, and the reaction conditions gentleness, yield height (about 80%).
The reaction formula III:
Wherein but R is halogen atom or similar leavings groups such as Cl, Br, I, as phenylsulfonyloxy, tolysulfonyl oxygen base, mesyloxy etc., and halogen atoms such as preferred Cl, Br, I.
And then obtain pharmaceutically-acceptable acid addition with corresponding acid-respons as required.
In above-mentioned reaction formula III synthetic route, hydrogenation catalyst system therefor at the compound that is used for formula (III), can be but be not limited to palladium, platinum, nickel, ruthenium, rhodium and their compound, the particularly form of load or oxide form are used for the preferred palladium carbon of hydrogenation catalyst system therefor of the compound of formula (III).The hydrogenation catalyst system therefor that is used for the compound of formula (III) is 5% palladium carbon or 10% palladium carbon, more preferably 5% palladium carbon.Being used for the amount of the used catalyzer of the catalytic hydrogenation of compound of formula (III) and the per-cent of substrate (formula II) is 1%-30%, more preferably 5-10%.
In the compound III described in Compound I synthetic and the mol ratio of compound IV is 1: 1 to 1.5: 1, more preferably 1.05: 1 to 1.1: 1.
The preferred room temperature to 120 of temperature ℃ of hydrogenation that is used for the compound of formula (III), more preferably 30-100 ℃, preferred 40-80 ℃ especially.
The hydrogen pressure 1-150atm of hydrogenation that is used for the compound of formula (III), preferred 1-80atm, preferred especially 1-40atm.
The solvent of hydrogenation that is used for the compound of formula (III) is alcohols such as methyl alcohol, ethanol, ketones such as acetone, butanone, pentanone N-Methyl pyrrolidone, nitrile such as acetonitrile or propionitrile, ester classes such as ethyl acetate, propyl acetate or butylacetate, methylene dichloride, chloroform, 1, halogenated hydrocarbons such as 2-ethylene dichloride or chlorobenzene, ethers such as isopropyl ether or tetrahydrofuran (THF), DMF, DMSO etc., preferred alcohols, ketone, more preferably alcohols, most preferably methyl alcohol, ethanol etc.
In the temperature of reaction described in Compound I synthetic be-10-100 ℃, preferred room temperature to 60 ℃,
At the reaction solvent described in Compound I synthetic is alcohols such as methyl alcohol, ethanol, ketones such as acetone, butanone, pentanone, nitrile such as acetonitrile or propionitrile, ester classes such as ethyl acetate, propyl acetate or butylacetate, methylene dichloride, chloroform, 1, halogenated hydrocarbons such as 2-ethylene dichloride or chlorobenzene, ethers such as ether, isopropyl ether or tetrahydrofuran (THF), DMF, DMSO etc., preferred alcohols, ketone, nitrile, more preferably nitrile.
At the reaction promotor described in Compound I synthetic is basic cpd, as mineral alkalis such as NaOH, KOH, K2CO3, Na2CO3, or organic basess such as diethylamine, triethylamine, pyridine, potassium tert.-butoxide, sodium methylate, preferred diethylamine, triethylamine.Consumption and compound IV mol ratio at the reaction promotor basic cpd described in Compound I synthetic are 1: 1 to 5: 1, are preferably 1: 1 to 2.5: 1.Consumption and compound IV mol ratio at the reaction promotor basic cpd described in Compound I synthetic are 1: 1 to 5: 1, are preferably 1: 1 to 2.5: 1.
The inventive method is easy, and raw material is easy to get, and is suitable for suitability for industrialized production, and bigger using value is arranged.
Embodiment:
Following examples are to be used for illustrating the present invention, rather than restriction the present invention.
Embodiment one, 7,8-dimethoxy-3-(3-chloropropyl)-1,3,4, and 5-tetrahydrochysene-2H-3-benzazepine-2-ketone synthetic:
With 7,8-dimethoxy-3-(3-chloropropyl)-1,3-dihydro-2H-3-benzo-aza
-2-ketone (15.0g, 50.8mmol), ethanol (80ml) and 5%Pd/C (0.8g) add autoclave, under 5-10 crust hydrogen pressure, 60 ℃ down reaction to not inhaling hydrogen, termination reaction, cooling, filter, be evaporated to about 30ml, cold filtration obtains 7,8-dimethoxy-3-(3-chloropropyl)-1,3,4,5-tetrahydrochysene-2H-3-benzo-aza
-2-ketone, white solid 13.9g, mp:93-95 ℃, yield 92.1%
MS：297(M+)，299(M+2)，262(M-Cl)
1HNMR (CDCl3): δ 2.06 (2H, m), 3.07 (2H, t), 3.56 (2H, M), 3.76 (2H, t), 3.81 (2H, t), 3.84 (3H, s), 3.85 (3H, s), 6.58-6.60 (2H, fragrant hydrogen)
Embodiment two, 3-{3-[{[(7S)-3, and 4-dimethoxy dicyclo [4.2.0] suffering-1,3,5-triolefin-7-yl]-methyl } (methyl) amino] propyl group-7,8-dimethoxy-1,3,4,5-tetrahydrochysene-2H-3-benzo-aza
Synthesizing of-2-ketone (Compound I, S 16257-2):
With 7,8-dimethoxy-3-(3-chloropropyl)-1,3,4,5-tetrahydrochysene-2H-3-benzo-aza
-2-ketone (10.0g.33.7mmol), (1S)-4,5-dimethoxy-1-(methylamino methyl)-benzocyclobutane (compound IV, 7.0g, 33.8mmol), triethylamine (10ml) and acetonitrile (50ml) add there-necked flask, then in stirring at room reaction 20h, be evaporated to then, add 200ml water then, with ethyl acetate extraction (150ml*3), anhydrous magnesium sulfate drying, filter, concentrating under reduced pressure obtains yellow oil, i.e. 3-{3-[{[(7S)-3,4-dimethoxy dicyclo [4.2.0] hot-1,3,5-triolefin-7-yl]-methyl } (methyl) amino] propyl group-7,8-dimethoxy-1,3,4,5-tetrahydrochysene-2H-3-benzo-aza
-2-ketone, about 13.5g.
Obtain sample for analysis through silica gel column chromatography, light yellow oil, the low temperature curable obtains yellow solid.
MS：468(M+)，469(M+1)，353(468-CH3)，305(M-163)，262(M-206)，
1HNMR (CDCl3): δ 1.79 (2H, m), 2.33 (3H, s), 2.44 (2H, t), 2.44 (2H, t), 2.5 (1H, M), 2.74 (2H, dd), 3.04 (2H, t), 3.25 (1H, dd), 3.5 ((3H, m), 3.7 (2H, t), 3.8-3.9 (14H, 4-OCH3 and-CH2-), 6.5-6.70 (4H, fragrant hydrogen)
Embodiment three, 3-{3-[{[(7S)-3, and 4-dimethoxy dicyclo [4.2.0] suffering-1,3,5-triolefin-7-yl]-methyl } (methyl) amino] propyl group-7,8-dimethoxy-1,3,4,5-tetrahydrochysene-2H-3-benzo-aza
The preparation of-2-keto hydrochloride:
With compound 3-{3-[{[(7S)-3,4-dimethoxy dicyclo [4.2.0] suffering-1,3,5-triolefin-7-yl]-methyl } (methyl) amino] propyl group-7,8-dimethoxy-1,3,4,5-tetrahydrochysene-2H-3-benzo-aza
-2-ketone (S 16257-2) (13.5g) is dissolved in acetonitrile (40ml), is heated to 70 ℃ then, stir and feed exsiccant HCl gas down, add gac 1 gram, refluxed 10 minutes to the about 2-3 of reaction solution PH, filtered while hot, cooling is filtered, 60 ℃ of vacuum dryings obtain near-white powder 12.4g, mp: ℃, yield 73.1% (in compound III), above-mentioned crude product obtains white powder 10.6g with the acetonitrile recrystallization, yield 85.5%, HPLC＞99.0%, [α] 7.2 (DMSO, 1%)
MS：468(M+)，469(M+1)，453(M-CH3)，305(M-163)，262(M-206)。
Claims (10)
1, a kind of preparation method of S 16257-2 is characterized in that this method is: with 3-(3-halopropyl)-7,8-dimethoxy-1,3-dihydro-2H-3-benzo-aza
-2-ketone compound II is a raw material, and in the presence of solvent and catalyzer, catalytic hydrogenation obtains 3-(3-halopropyl)-7,8-dimethoxy-1,3,4,5-tetrahydrochysene-2H-3-benzo-aza
-2-ketone compound II I, then in solvent and reaction promotor with (1S)-4,5-dimethoxy-1-(methylamino methyl)-benzocyclobutane compounds IV carries out alkylated reaction and obtains the S 16257-2 Compound I:
Wherein R is Cl, Br or I halogen atom or phenylsulfonyloxy, tolysulfonyl oxygen base or mesyloxy; Preferred Cl, Br or I halogen atom.
2, a kind of S 16257-2 preparation method according to claim 1 is characterized in that in the compound III described in Compound I synthetic and the mol ratio of compound IV be 1: 1 to 1.5: 1, more preferably 1.05: 1 to 1.1: 1.
3, a kind of S 16257-2 preparation method according to claim 1 is characterized in that in the preparation of compound III, and the used catalyzer of catalytic hydrogenation is palladium, platinum, nickel, ruthenium or rhodium or their compound, preferred palladium carbon; Described catalyzer is 5% palladium carbon or 10% palladium carbon, preferred 5% palladium carbon; The per-cent of the amount of used catalyzer and substrate formula II is 1%-30%, is preferably 5-10%.
4, a kind of S 16257-2 preparation method according to claim 1 is characterized in that in the preparation of compound III, and hydrogenation is to carry out under the temperature of room temperature to 120 ℃, preferred 30-100 ℃, and preferred 40-80 ℃ especially.
5, a kind of S 16257-2 preparation method according to claim 1 is characterized in that in the preparation of compound III, and the hydrogen pressure of hydrogenation is 1-150atm, preferred 1-80atm, preferred especially 1-40atm.
6, a kind of S 16257-2 preparation method according to claim 1 is characterized in that in the preparation of compound III, and the solvent of its hydrogenation is methyl alcohol or ethanol; Acetone, butanone, pentanone or N-Methyl pyrrolidone; Acetonitrile or propionitrile; Ethyl acetate, propyl acetate or butylacetate; Methylene dichloride, chloroform, 1,2-ethylene dichloride or chlorobenzene; Isopropyl ether or tetrahydrofuran (THF) or DMF or DMSO; Preferred alcohols, ketone; More preferably pure; Special particular methanol or ethanol.
7, S 16257-2 preparation method according to claim 1 is characterized in that the alkylated reaction solvent is methyl alcohol or ethanol; Acetone, butanone or pentanone; Acetonitrile or propionitrile; Ethyl acetate, propyl acetate or butylacetate; Methylene dichloride, chloroform, 1,2-ethylene dichloride or chlorobenzene; Ether, isopropyl ether or tetrahydrofuran (THF); DMF or DMSO; Preferred alcohols, ketone or nitrile, more preferably nitrile.
8, S 16257-2 preparation method according to claim 1 is characterized in that described reaction promotor is a basic cpd, and it is NaOH, KOH, K
2CO
3Or Na
2CO
3Mineral alkali; Or diethylamine, triethylamine, pyridine, potassium tert.-butoxide or sodium methylate organic bases; Preferred diethylamine, triethylamine or NaOH.
9, reaction promotor according to claim 8 is characterized in that the consumption of described reaction promotor basic cpd and compound IV mol ratio are 1: 1 to 5: 1, is preferably 1: 1 to 2.5: 1.
10, S 16257-2 preparation method according to claim 1 is characterized in that described temperature of reaction is-10～100 ℃, is preferably from room temperature to 60 ℃.
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| CN2007100394183A CN101284813B (en) | 2007-04-12 | 2007-04-12 | Preparation method of ivabradine |
| PCT/CN2008/000699 WO2008125006A1 (en) | 2007-04-12 | 2008-04-07 | Preparation processes for ivabradine hydrochloride and its stable crystalline form |
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| CN2007100394183A CN101284813B (en) | 2007-04-12 | 2007-04-12 | Preparation method of ivabradine |
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| CN101768116A (en) * | 2008-12-29 | 2010-07-07 | 北京德众万全药物技术开发有限公司 | Preparation method for Ivabradine |
| CN101851205A (en) * | 2009-03-31 | 2010-10-06 | 瑟维尔实验室 | S 16257-2 and with the novel synthesis of the additive salt of pharmaceutically acceptable acid |
| CN101723897B (en) * | 2008-10-31 | 2011-11-16 | 齐鲁制药有限公司 | Method for synthesizing Ivabradine |
| CN102827080A (en) * | 2012-09-12 | 2012-12-19 | 江苏宇田生物医药科技有限公司 | Novel synthetic method of ivabradine and novel intermediate product of ivabradine |
| TWI395738B (en) * | 2010-02-17 | 2013-05-11 | Servier Lab | New process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid |
| CN101768117B (en) * | 2008-12-29 | 2014-05-07 | 北京德众万全药物技术开发有限公司 | New crystalline form of hydrochloric acid Ivabradine and preparation method thereof |
| CN103848789A (en) * | 2012-11-29 | 2014-06-11 | 江苏恒瑞医药股份有限公司 | Preparation method of ivabradine |
| CN103864690A (en) * | 2014-01-06 | 2014-06-18 | 北京莱瑞森医药科技有限公司 | S crystal form of ivabradine hydrochloride, and preparation method and pharmaceutical composition thereof |
| CN103880748A (en) * | 2014-04-03 | 2014-06-25 | 南京正大天晴制药有限公司 | Ivabradine hydrochloride structure analogue and preparation method and application thereof |
| CN104447554A (en) * | 2013-09-22 | 2015-03-25 | 广东众生药业股份有限公司 | Preparation method for ivabradine and hydrochloride thereof |
| EA023883B1 (en) * | 2013-02-28 | 2016-07-29 | Ле Лаборатуар Сервье | Process for 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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Family Cites Families (1)
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| FR2681862B1 (en) * | 1991-09-27 | 1993-11-12 | Adir Cie | NOVELS (BENZOCYCLOALKYL) ALKYLAMINES, THEIR PREPARATION PROCESS, AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
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