CN101284813B - Preparation method of ivabradine - Google Patents
Preparation method of ivabradine Download PDFInfo
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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); [{ [(7S)-3,4-dimethoxy dicyclo [4.2.0] hot-1,3 for chemical name 3-{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 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 to treat the symptomatic treatment with normal sinus rhythm, taboo maybe can not tolerate to beta-blockers chronic stable angina pectoris.
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, suppresses to be responsible for control sinus node spontaneous depolarization through selectivity and plays a role with the If passage of regulating heart rate.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 related patent U.S. Patent No. is US5296482, and this patent system Preparation Method is following, is raw material with compound V; 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 through column chromatography purification suitable suitability for industrialized production.
Shi Weiya company has applied for a kind of new preparing method's patent CN200510051779 again in China subsequently; Related patent U.S. Patent No. 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; Cost is high, thereby also is 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
-the 2-ketone compound II is a raw material; Obtain compound 3-(3-halopropyl)-7,8-dimethoxy-1,3 at suitable temperature, solvent and catalyst hydrogenation; 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 carried out more easily, and reaction conditions is gentle, yield high (about 80%).
The reaction formula III:
Wherein but R is halogen atom or similar leavings groups such as Cl, Br, I, like 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, nitriles such as acetonitrile or propionitrile; Ester classes such as ETHYLE ACETATE, propyl acetate or butylacetate, methylene dichloride, chloroform, 1, halogenated hydrocarbons such as 2-ethylene dichloride or chlorobenzene; Ethers such as isopropyl ether or THF, DMF, DMSO etc., preferred alcohols, ketone; More preferably alcohols, most preferably methyl alcohol, ethanol etc.
Temperature of reaction described in compound I synthetic be-10-100 ℃, and preferred room temperature to 60 ℃,
Reaction solvent described in compound I synthetic is ketones such as alcohols such as methyl alcohol, ethanol, acetone, butanone, pentanone, nitriles such as acetonitrile or propionitrile; Ester classes such as ETHYLE 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 THF; DMF, DMSO etc., preferred alcohols, ketone, nitrile, more preferably nitrile.
Reaction promotor described in compound I synthetic is a basic cpd, like 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 explaining 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 is filtered, and is 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, and [{ [(7S)-3,4-dimethoxy dicyclo [4.2.0] hot-1 for 3-{3-; 3,5-triolefin-7-yl]-methyl } (methyl) amino] propyl group-7,8-dimethoxy-1; 3; 4,5-tetrahydrochysene-2H-3-benzo-aza
-2-ketone (compound I, S 16257-2) synthetic:
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 filters, and concentrating under reduced pressure obtains yellow oil; Be that [{ [(7S)-3,4-dimethoxy dicyclo [4.2.0] hot-1,3 for 3-{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 with-CH2-), 6.5-6.70 (4H, fragrant hydrogen)
Embodiment three, and [{ [(7S)-3,4-dimethoxy dicyclo [4.2.0] hot-1 for 3-{3-; 3; 5-triolefin-7-yl]-methyl } (methyl) amino] propyl group-7,8-dimethoxy-1,3; 4, the preparation of 5-tetrahydrochysene-2H-3-benzo-aza
-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;) be dissolved in acetonitrile (40ml), be heated to 70 ℃ then, stir and feed exsiccant HCl gas down to the about 2-3 of reaction solution PH, add gac 1 gram; Refluxed filtered while hot, cooling 10 minutes; Filter, 60 ℃ of vacuum dryings obtain near-white powder 12.4g, mp: ℃; Yield 73.1% (in compound III), above-mentioned bullion 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 (15)
1. the preparation method of a S 16257-2; It is characterized in that this method is: with the 3-shown in the compound I I (3-substituted propyl)-7; 8-dimethoxy-1; 3-dihydro-2H-3-benzo-aza
-2-ketone is raw material; At ethanol is in the presence of solvent and the palladium-carbon catalyst; Obtain the 3-shown in the compound III (3-substituted propyl)-7,8-dimethoxy-1,3 60 ℃ of following catalytic hydrogenations; 4; 5-tetrahydrochysene-2H-3-benzo-aza
-2-ketone, then in solvent and reaction promotor with (1S)-4 shown in the compound IV, 5-dimethoxy-1-(methylamino methyl)-benzocyclobutane carries out alkylated reaction and obtains the S 16257-2 shown in the compound I:
Wherein, R is Cl, Br, I, phenylsulfonyloxy, tolysulfonyl oxygen base or mesyloxy.
2. the preparation method of S 16257-2 according to claim 1, wherein said R is selected from Cl, Br or I.
3. the preparation method of S 16257-2 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.
4. the preparation method of S 16257-2 according to claim 3, the mol ratio of wherein said compound III and compound IV is 1.05: 1 to 1.1: 1.
5. the preparation method of S 16257-2 according to claim 1 is characterized in that in the preparation of compound III, and described palladium-carbon catalyst is 5% palladium carbon or 10% palladium carbon, and the per-cent of the amount of used catalyzer and substrate formula II compound is 1%-30%.
6. the preparation method of S 16257-2 according to claim 5 is characterized in that described palladium-carbon catalyst is 5% palladium carbon.
7. the preparation method of S 16257-2 according to claim 5 is characterized in that the amount of described catalyzer and the per-cent of substrate formula II compound are 5%-10%.
8. the preparation method of S 16257-2 according to claim 1 is characterized in that in the preparation of compound III, and the hydrogen pressure of hydrogenation is 1-150atm.
9. the preparation method of S 16257-2 according to claim 8, the hydrogen pressure of wherein said hydrogenation is 1-80atm.
10. the preparation method of S 16257-2 according to claim 9, the hydrogen pressure of wherein said hydrogenation is 1-40atm.
11. the preparation method of S 16257-2 according to claim 1; It is characterized in that the solvent described in the alkylated reaction is methyl alcohol, ethanol, acetone, butanone, pentanone, acetonitrile, propionitrile, ETHYLE ACETATE, propyl acetate, butylacetate, methylene dichloride, chloroform, 1,2-ethylene dichloride, chlorobenzene, ether, isopropyl ether, THF, DMF or DMSO.
12. the preparation method of S 16257-2 according to claim 1 is characterized in that described reaction promotor is NaOH, KOH, K
2CO
3, Na
2CO
3, diethylamine, triethylamine, pyridine, potassium tert.-butoxide or sodium methylate.
13. the preparation method of S 16257-2 according to claim 12 is characterized in that described reaction promotor is diethylamine, triethylamine or NaOH.
14. the preparation method of S 16257-2 according to claim 12 is characterized in that the consumption of described reaction promotor and compound IV mol ratio are 1: 1 to 5: 1.
15. the preparation method of S 16257-2 according to claim 14 is characterized in that the consumption of described reaction promotor and compound IV mol ratio are 1: 1 to 2.5: 1.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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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Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101723897B (en) * | 2008-10-31 | 2011-11-16 | 齐鲁制药有限公司 | Method for synthesizing Ivabradine |
| 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 |
| CN101768116B (en) * | 2008-12-29 | 2014-06-18 | 北京德众万全药物技术开发有限公司 | Preparation method for Ivabradine |
| ME00987B (en) * | 2009-03-31 | 2012-06-20 | Servier Lab | New process for synthesiis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid |
| FR2956401B1 (en) * | 2010-02-17 | 2012-02-03 | Servier Lab | NOVEL PROCESS FOR THE SYNTHESIS OF IVABRADINE AND ITS SALTS OF ADDITION TO A PHARMACEUTICALLY ACCEPTABLE ACID |
| CN102827080B (en) * | 2012-09-12 | 2014-03-19 | 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 |
| CN103848789B (en) * | 2012-11-29 | 2016-05-18 | 江苏恒瑞医药股份有限公司 | A kind of preparation method of Ivabradine |
| FR3002542B1 (en) * | 2013-02-28 | 2016-01-22 | Servier Lab | PROCESS FOR THE ENZYMATIC SYNTHESIS OF (7S) 3,4-DIMETHOXYBICYCLO [4.2.0] OCTA-1,3,5-TRIENE 7-CARBOXYLIC ACID AND APPLICATION TO THE SYNTHESIS OF IVABRADINE AND ITS SALTS |
| CN104447554B (en) * | 2013-09-22 | 2017-02-15 | 广东众生药业股份有限公司 | Preparation method for ivabradine and hydrochloride thereof |
| CN103864690B (en) * | 2014-01-06 | 2016-09-14 | 北京莱瑞森医药科技有限公司 | S crystal formation, its preparation method and the pharmaceutical composition of Ivabradine hydrochloride |
| CN103880748B (en) * | 2014-04-03 | 2015-09-16 | 南京正大天晴制药有限公司 | A kind of hydrochloric acid Ivabradine analog and its preparation method and application |
| CN108003102A (en) * | 2017-08-30 | 2018-05-08 | 嘉实（湖南）医药科技有限公司 | A kind of synthetic method of Ivabradine |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5296482A (en) * | 1991-09-27 | 1994-03-22 | Adir Et Compagnie | (Benzocycloalkyl) alkylamines |
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2007
- 2007-04-12 CN CN2007100394183A patent/CN101284813B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5296482A (en) * | 1991-09-27 | 1994-03-22 | Adir Et Compagnie | (Benzocycloalkyl) alkylamines |
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