CN102050829A - Crystallizing method for obtaining I crystal form (+)-(S)-clopidogrel bisulfate - Google Patents
Crystallizing method for obtaining I crystal form (+)-(S)-clopidogrel bisulfate Download PDFInfo
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- CN102050829A CN102050829A CN2009102366596A CN200910236659A CN102050829A CN 102050829 A CN102050829 A CN 102050829A CN 2009102366596 A CN2009102366596 A CN 2009102366596A CN 200910236659 A CN200910236659 A CN 200910236659A CN 102050829 A CN102050829 A CN 102050829A
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Abstract
The invention discloses a crystallizing method for obtaining I crystal form (+)-(S)-clopidogrel bisulfate. The method disclosed by the invention comprises the following steps: dissolving (+)-(S)-clopidogrel free alkali in an alcohol solvent, and dropwise adding an alcohol solution of concentrated sulfuric acid, thereby obtaining the I crystal form (+)-(S)-clopidogrel bisulfate by controlling the dropwise adding temperature, mixing time and recrystallization temperature.
Description
Technical field
The present invention relates to a kind of crystallization method of antithrombotic (+)-(S)-bisulfate clopidogrel I crystal formation of following structure, i.e. (+)-(S)-2-(2-chloro-phenyl-)-2-(4,5,6,7-tetramethylene sulfide [3,2-c] and pyridine-5-yl) crystallization method of methyl acetate vitriol I crystal formation.
Background technology
Bisulfate clopidogrel is Xin-Dai anticoagulant of being succeeded in developing in 1986 by French Sanofi company, and commodity are called " Pohle dimension ".It belongs to the Thienopyridines medicine, is a kind of novel adenosine diphosphate (ADP) receptor antagonist, because have good security and suppress fast hematoblastic advantage, becomes one of antiplatelet drug of widespread use thereby replaced ticlopidine.
European patent EP 281459 points out that with U.S. Pat 6429210 there is different crystal forms in bisulfate clopidogrel, the method that obtains the I crystal formation is dissolving (+)-(S)-clopidogrel free alkali in ice-cooled acetone, add the vitriol oil until forming precipitation, the gained precipitation is separated after filtration, wash (+)-(S)-bisulfate clopidogrel white crystal, its fusing point is 184 ℃, optically-active+55.1 (C=1.89/CH
3OH).
According to patent EP281459 and the described method of CN200610062880.0, prepare I crystal formation clopidogrel with ice acetone as solvent, find that repeatability is relatively poor, the condition harshness, it adopts ketones solvent in patent CN200710069957.1, but in crystallisation process, added a small amount of alcoholic solvent, but from experiment effect, a small amount of alcoholic solvent there is not obvious improvement to crystallisation process.With reference to domestic patent CN200610051684.3 and CN200610023423.9, find that it mainly adopts low polar solvent such as methylene dichloride, ethers, the ester class is carried out the crystallization process, carry out repetition according to above patent, find low polar solvent when low temperature, drip the vitriol oil and can form white oily matter earlier, and the back of heating up is stirred also difficulty and is separated out solid, can't adapt to production requirement.
Therefore, we conceive raising crystallization polarity of solvent, adopt rudimentary liquid alcohol kind solvent or their mixture to be used as the crystallization solvent, because finished product is at methyl alcohol, solubleness is too high in the ethanol, therefore gets rid of this two solvent, and the vitriol oil that is dripped adopts identical alcoholic solvent dilution then, this method repeats through experiment, finds respond well.
Summary of the invention
It is strong to the purpose of this invention is to provide a kind of process repeatability, and the high yield of energy obtains the method for I crystal formation (+)-(the S)-bisulfate clopidogrel of high purity and good crystal formation flowability.
Technical scheme of the present invention:
In alcoholic solvent, add (+)-(S)-clopidogrel free alkali, the control solution temperature remains on-5 ℃～15 ℃, drip the alcoholic solution of the vitriol oil, dropwise back insulated and stirred 1h～12h, stir and finish after-filtration, a small amount of alcohol washing, drying under reduced pressure to constant weight gets I crystal formation (+)-(S)-bisulfate clopidogrel.
Described alcoholic solvent is selected from propyl alcohol, Virahol, butanols, sec-butyl alcohol, isopropylcarbinol, 1-amylalcohol, 2-amylalcohol, 3-amylalcohol, 2-methyl-1-butene alcohol, 2-methyl-2-butanols, 3-methyl isophthalic acid-butanols, the mixed solvent of one or more in 3-methyl-2-butanols.
Advantage of the present invention and positively effect: by the prepared finished product of the present invention, infrared through the powder X-ray diffraction, methods such as DSC are confirmed as I crystal formation (+)-(S)-bisulfate clopidogrel.Crystallisation process of the present invention is simple and easy to control, and used alcoholic solvent makes the product yield height, and the crystalline form good fluidity especially is fit to suitability for industrialized production.
Description of drawings
The powder x diffracting spectrum of I crystal formation (+)-(S)-bisulfate clopidogrel that accompanying drawing 1: embodiment 1 makes
The infared spectrum of I crystal formation (+)-(S)-bisulfate clopidogrel that accompanying drawing 2: embodiment 1 makes
The DSC collection of illustrative plates of I crystal formation (+)-(S)-bisulfate clopidogrel that accompanying drawing 3: embodiment 1 makes
Embodiment:
Below with specific embodiment technical scheme of the present invention is described, but protection scope of the present invention is not limited thereto:
In the 100ml there-necked flask, add (+)-(S)-clopidogrel free alkali 5.00g, propyl alcohol 25ml, stirring and dissolving, ice bath controlled temperature and the slow 25ml propanol solution that drips the 1.5g vitriol oil (mass concentration is 98%), after dropwising, insulated and stirred 10h gets a large amount of white solids, filter, decompression is dried to constant weight, gets 4.75g I crystal formation (+)-(S)-bisulfate clopidogrel, yield 73%.
Embodiment 2
In the 100ml there-necked flask, add (+)-(S)-clopidogrel free alkali 5.00g, butanols 25ml, stirring and dissolving, ice bath controlled temperature and the slow 25ml butanol solution that drips the 1.5g vitriol oil (mass concentration is 98%), after dropwising, insulated and stirred 10h gets a large amount of white solids, filter, decompression is dried to constant weight, gets 5.01g I crystal formation (+)-(S)-bisulfate clopidogrel, yield 77%.
Embodiment 3
In the 100ml there-necked flask, add (+)-(S)-clopidogrel free alkali 5.00g, butanols 100ml, stirring and dissolving, ice bath controlled temperature and the slow 100ml butanol solution that drips the 1.5g vitriol oil (mass concentration is 98%), after dropwising, insulated and stirred 12h gets white solid, filter, decompression is dried to constant weight, gets 2.73g I crystal formation (+)-(S)-bisulfate clopidogrel, yield 41.96%.
In the 100ml there-necked flask, add (+)-(S)-clopidogrel free alkali 5.00g, butanols 12.5ml, stirring and dissolving, ice bath controlled temperature and the slow 12.5ml propanol solution that drips the 1.5g vitriol oil (mass concentration is 98%), after dropwising, insulated and stirred 10h gets a large amount of white solids, filter, decompression is dried to constant weight, gets 5.14g I crystal formation (+)-(S)-bisulfate clopidogrel, yield 79%.
Claims (5)
1. crystallization method that obtains I crystal formation (+)-(S)-bisulfate clopidogrel is characterized in that may further comprise the steps:
1. a certain amount of vitriol oil is splashed in a certain amount of alcoholic solvent and mix, and (+)-(S)-clopidogrel free alkali also is dissolved in certain alcoholic solvent stirs, keep this solution to drip the alcoholic solution of the vitriol oil at a certain temperature then, and keep certain rate of addition to dropwising.
2. after dropwising, insulated and stirred for some time filters and washes with a small amount of alcohol to obtaining a large amount of white solids, and drying under reduced pressure gets single I crystal formation (+)-(S)-clopidogrel bisulfate solid to constant weight then.
2. crystallization method according to claim 1 is characterized in that employed alcoholic solvent is selected from propyl alcohol, Virahol, butanols, sec-butyl alcohol, isopropylcarbinol, the 1-amylalcohol, the 2-amylalcohol, 3-amylalcohol, 2-methyl-1-butene alcohol, 2-methyl-2-butanols, 3-methyl isophthalic acid-butanols, the mixed solvent of one or more in 3-methyl-2-butanols, wherein optimum is a butanols.
3. crystallization method according to claim 1, it is characterized in that required vitriol oil concentration is 95%～98%, with the mol ratio of (+)-(S)-clopidogrel free alkali be (0.9～1.1): 1, the mass concentration that (+)-(S)-clopidogrel free alkali is dissolved in behind the alcoholic solvent is 50g/L～400g/L, its optimum is 200g/L, the volume ratio of the dilution vitriol oil and dissolving (+)-(S)-required alcohol of clopidogrel free alkali is (0.5～2): 1, and optimum is 1: 1.
4. crystallization method according to claim 1, when it is characterized in that dripping the alcoholic solution of the vitriol oil, the temperature of (+)-(S)-clopidogrel solution should remain on-5 ℃～15 ℃, and optimum is 0 ℃～5 ℃.
5. crystallization method according to claim 1, after it is characterized in that dropwising, solution temperature should continue to remain on-5 ℃～15 ℃, and optimum is 0 ℃～5 ℃ and continues to stir 10h～12h.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102432625A (en) * | 2011-11-05 | 2012-05-02 | 江南大学 | Crystallization method for preparing high-purity I-type clopidogrel hydrogen sulfate |
| CN102796114A (en) * | 2011-05-25 | 2012-11-28 | 浙江京新药业股份有限公司 | Method for preparing (+)-(S-)-clopidogrel hydrogen sulfate 1 crystal form |
| WO2016011783A1 (en) * | 2014-12-31 | 2016-01-28 | 天津大学 | Method for preparing spherical clopidogrel hydrogen sulfate polymorph i |
| KR101616928B1 (en) | 2010-01-07 | 2016-05-02 | 동화약품주식회사 | Method for manufacturing crystalline form (I) of Clopidogrel hydrogen sulphate |
| CN105748419A (en) * | 2015-07-17 | 2016-07-13 | 深圳信立泰药业股份有限公司 | Pharmaceutical composition containing spherical I-type crystal form of clopidogrel hydrogen sulfate and preparation method thereof |
-
2009
- 2009-11-04 CN CN2009102366596A patent/CN102050829A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101616928B1 (en) | 2010-01-07 | 2016-05-02 | 동화약품주식회사 | Method for manufacturing crystalline form (I) of Clopidogrel hydrogen sulphate |
| CN102796114A (en) * | 2011-05-25 | 2012-11-28 | 浙江京新药业股份有限公司 | Method for preparing (+)-(S-)-clopidogrel hydrogen sulfate 1 crystal form |
| CN102432625A (en) * | 2011-11-05 | 2012-05-02 | 江南大学 | Crystallization method for preparing high-purity I-type clopidogrel hydrogen sulfate |
| WO2016011783A1 (en) * | 2014-12-31 | 2016-01-28 | 天津大学 | Method for preparing spherical clopidogrel hydrogen sulfate polymorph i |
| US9815848B2 (en) | 2014-12-31 | 2017-11-14 | Tianjin University | Method for preparing spherical Clopidogrel Hydrogen Sulfate polymorph I |
| CN105748419A (en) * | 2015-07-17 | 2016-07-13 | 深圳信立泰药业股份有限公司 | Pharmaceutical composition containing spherical I-type crystal form of clopidogrel hydrogen sulfate and preparation method thereof |
| CN105748419B (en) * | 2015-07-17 | 2018-09-14 | 深圳信立泰药业股份有限公司 | A kind of pharmaceutical composition and preparation method thereof containing spherical bisulfate clopidogrel I crystal |
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Application publication date: 20110511 |