CN102050784B - Novel method for preparing amorphous Ivabradine hydrochloride - Google Patents
Novel method for preparing amorphous Ivabradine hydrochloride Download PDFInfo
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- CN102050784B CN102050784B CN200910210042.7A CN200910210042A CN102050784B CN 102050784 B CN102050784 B CN 102050784B CN 200910210042 A CN200910210042 A CN 200910210042A CN 102050784 B CN102050784 B CN 102050784B
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- ivabradine hydrochloride
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Abstract
The invention provides a novel method for preparing amorphous Ivabradine hydrochloride, which comprises the following steps: firstly, Ivabradine hydrochloride is dissolved in a solvent to form a solution, and secondly, the solution is added into a non-solvent, a mixed solution is obtained through stirring, and amorphous Ivabradine hydrochloride is obtained after cooling. The method has the advantage that the traditional two-step amorphous preparation method (crystal type high-quality product is produced at first and then amorphous is prepared through a concentration method) is integrated into one step, so as to achieve high yield and greatly improve the production efficiency.
Description
Technical field
The present invention relates to the synthetic technical field of medicine, particularly, the present invention relates to a kind of preparation method of unformed hydrochloric acid Ivabradine.
Background technology
Hydrochloric acid Ivabradine, its chemistry 3-[3-[[(8S by name)-3,4-dimethoxy-8-dicyclo [4.2.0] pungent-1,3,5-triolefin] methyl-methylamino-] propyl group]-7,8-dimethoxy-2,5-dihydro-1H-3-benzazepine-4-keto hydrochloride, structural formula is as follows
Hydrochloric acid Ivabradine is If inhibitor, is used for the treatment of the chronic stable angina symptom to beta-blockers taboo or not tolerant regular sinus rhythm patient.
Many patents disclose hydrochloric acid Ivabradine, and preparation method thereof with the preparation of key intermediate.These patents comprise: EP534859, US5296482, FR19910011894, CN1699331A, CN1683342A, CN1683343A, CN1683341A.
In addition, many patents disclose polymorphous method of hydrochloric acid Ivabradine.Comprise: CN1683341A, CN1827599, CN1827600, CN1827601, CN1827602, CN1948292, CN1948293.
Document (Konno T., Chem.Pharm.Bull., 1990; 38:2003-2007), reported compared with crystallized form, the amorphism form in many medicines demonstrates dissolution characteristics, and demonstrates different biological utilisation patterns in some situation.For some treatment card, certain biological utilisation pattern may be more favourable than another kind.Therefore, preferably there is the method that crystallinity medicine is changed into non-crystalline state form.
The unformed patent of published preparation (as CN101463008) adopts method of enrichment, the method need previously prepared go out up-to-standard crystal type hydrochloric acid Ivabradine, be then dissolved in solvent, be concentrated into dryly, production efficiency is low.
Summary of the invention
The object of the invention is, for the low problem of production efficiency existing in unformed S 16257-2 preparation method, provides a kind of novel method of preparing unformed hydrochloric acid Ivabradine.
Comprise the steps:
(a) thus hydrochloric acid Ivabradine is dissolved in and in solvent, forms a kind of solution; With
(b) this solution is joined in non-solvent, stir and form mixed solution, cooling, obtain unformed hydrochloric acid Ivabradine.
Unformed hydrochloric acid Ivabradine is by wherein the solution of hydrochloric acid Ivabradine being joined in non-solvent to such an extent that the method for mixed solution precipitates to form with a kind of.The solution that is applicable to dissolve hydrochloric acid Ivabradine comprises for example hydrochloric acid Ivabradine soluble organic solvent therein, and the non-solvent that is applicable to the inventive method comprises ether, paraffinic hydrocarbons, naphthenic hydrocarbon.
Said solvent and non-solvent are also preferably volatile, have 150 DEG C or lower boiling point.In addition, this solvent also has the toxicity at the relative end and can from unformed hydrochloric acid Ivabradine, be gone out to pharmacopeia acceptable level.Hydrochloric acid Ivabradine preferably has the solubleness of at least 1% (weight ratio) in dissolution solvent, and the more preferably solubleness of at least 5% (weight ratio).Preferred solvent comprises, for example methyl alcohol, ethanol, 1-propyl alcohol, 2-propyl alcohol, butanols, acetone, methylethylketone, methylene dichloride, trichloromethane, tetracol phenixin.
In the inventive method, non-solvent used is that hydrochloric acid Ivabradine is not allowed or sl. sol. solvent only therein, and preferred non-solvent comprises, for example ether, tetrahydrofuran (THF), hexane, heptane, hexanaphthene.Can be 1 gram of about 10ml of hydrochloric acid Ivabradine to about 100ml non-solvent for the non-strength of solution of said intermediate processing, preferred non-strength of solution can be 1 gram of hydrochloric acid Ivabradine and is about 40ml.
Preferably approximately 1 hour to 4 hours mix and blend time.
Be approximately-20 DEG C-20 DEG C, approximately 1 hour to 4 hours cooling time for the cooling temperature that makes unformed hydrochloric acid Ivabradine precipitation.
The advantage of present method is: the method for being prepared by traditional two steps to unformed (first make crystal type fine work, then it being unformed to adopt method of enrichment to prepare) is combined into a step, and yield is high, has greatly improved production efficiency.
The hydrochloric acid Ivabradine that adopts above-mentioned technique to prepare, content is high, and yield is high, can be used for producing corresponding preparation.
Below in conjunction with specific examples, the invention will be further described.
embodiment
Embodiment mono-
100g hydrochloric acid Ivabradine is joined in 1000ml ethanol, be stirred to dissolve.Gained solution is joined in 4000ml ether and obtains mixed solution, at 15 DEG C-30 DEG C, it is carried out to high-speed stirring.The slurry of gained is stirred 1 hour.This slurry is cooled to approximately 0 DEG C, stirs 2 hours, filter, dry, collect to obtain the unformed hydrochloric acid Ivabradine of 81g, yield 81.0%.
The powder X-ray diffracting spectrum of unformed hydrochloric acid Ivabradine is shown in accompanying drawing one.
Embodiment bis-
100g hydrochloric acid Ivabradine is joined in 1000ml acetone, be stirred to dissolve.Gained solution is joined in 3000ml hexanaphthene and obtains mixed solution, at 15 DEG C-30 DEG C, it is carried out to high-speed stirring.The slurry of gained is stirred 1 hour.This slurry is cooled to approximately 0 DEG C, stirs 2 hours, filter, dry, collect to obtain the unformed hydrochloric acid Ivabradine of 83g, yield 83.0%.
Claims (5)
1. a preparation method for unformed hydrochloric acid Ivabradine, it comprises:
(a) thus hydrochloric acid Ivabradine is dissolved in and in solvent, forms a kind of solution; With
(b) this solution is joined in non-solvent, stir and form mixed solution, cooling, obtain unformed hydrochloric acid Ivabradine; Wherein in step (a), said solvent is ethanol or acetone, and in step (b), said non-solvent is ether or hexanaphthene.
2. the method for claim 1, wherein the concentration of said non-solvent is that 1 gram of hydrochloric acid Ivabradine needs 10ml to 100ml non-solvent.
3. the method for claim 1, wherein the concentration of said non-solvent is that 1 gram of hydrochloric acid Ivabradine needs 40ml non-solvent.
4. the method for claim 1, wherein in step (b), churning time 1 hour to 4 hours.
5. the method for claim 1, wherein, in step (b), cooling temperature is-20 DEG C-20 DEG C, 1 hour to 4 hours cooling time.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910210042.7A CN102050784B (en) | 2009-11-04 | 2009-11-04 | Novel method for preparing amorphous Ivabradine hydrochloride |
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| CN200910210042.7A CN102050784B (en) | 2009-11-04 | 2009-11-04 | Novel method for preparing amorphous Ivabradine hydrochloride |
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| Publication Number | Publication Date |
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| CN102050784A CN102050784A (en) | 2011-05-11 |
| CN102050784B true CN102050784B (en) | 2014-07-09 |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2589594A1 (en) | 2011-11-04 | 2013-05-08 | Urquima S.A. | Ivabradine hydrochloride Form IV |
| CN104230808B (en) * | 2014-08-22 | 2016-05-18 | 苏州亚宝药物研发有限公司 | Amorphous ivabradine hydrochloride and preparation method thereof and application |
| CN104829530A (en) * | 2015-04-23 | 2015-08-12 | 扬子江药业集团北京海燕药业有限公司 | Amorphous ivabradine hydrochloride and preparation method thereof |
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