CN101100471A - Method for preparing (+)-(S-)-clopidogrel hydrosulfate high melting point crystal I - Google Patents
Method for preparing (+)-(S-)-clopidogrel hydrosulfate high melting point crystal I Download PDFInfo
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- CN101100471A CN101100471A CNA2007100699571A CN200710069957A CN101100471A CN 101100471 A CN101100471 A CN 101100471A CN A2007100699571 A CNA2007100699571 A CN A2007100699571A CN 200710069957 A CN200710069957 A CN 200710069957A CN 101100471 A CN101100471 A CN 101100471A
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Abstract
Preparation of (+)-(S)-chlorpyrroline hydrogen sulfate high-smelting point crystal Iis carried out by dissolving chlorpyrroline free alkali into ketone solvent, adding into concentrated sulfuric acid, eluting crystal out, adding into alcohol solvent, agitating while crystallizing, filtering, washing for filter cake by ketone solvent, pumping and vacuum drying to obtain final product. It's simple and efficient, has gentle reactive condition and can be used for industrial production.
Description
Technical field
The invention belongs to the chemical pharmaceutical technical field, relate to (+)-(S-)-clopidogrel hydrosulfate high melting point crystal I the preparation method of (formula one).
Formula one:
Background technology
Polymorphism extensively exists in organic drug, the medicine of same chemical structure, because crystallization condition, as differences such as solvent, temperature, speed of cooling, molecular arrangement is different with crystalline network when forming crystallization, thereby forms different crystal formations.The crystal formation difference causes the lattice energy difference, and the fusing point of medicine, dissolution rate, solubleness etc. are also different.
(+)-(S-)-SR-25990C is a kind of platelet aggregation inhibitor, and it is more effective than Asprin that scientific research finds that it suppresses platelet aggregation, and also very little to the side effect of enteron aisle.(+)-(S-)-SR-25990C is used in a large number at medical field.
European patent EP 281459 has been described SR-25990C the earliest, by racemic clopidogrel chiral is split, makes single dextrorotation clopidogrel, and then salify, makes SR-25990C.This piece patent does not relate to the problem of SR-25990C crystal formation.First piece of patent of describing the clopidogrel crystal formation is French Patent FR 2779726 A1, corresponding Chinese patent application 99807458.6, it has illustrated that there is polymorphic in SR-25990C, crystal formation I and crystal form II are arranged, and that point out to make by the method described in the EP281459 is SR-25990C crystal formation I, crystal is irregular sheet, and its fusing point is 184 ℃, and the specific rotation of surveying in the methyl alcohol of 1.891g/ml is+55.1 °.
Thereafter international monopoly WO2004020443, WO2005100364, WO2005003139 and Chinese patent open file CN1840533, CN1850827 disclose the preparation method of crystal formation I respectively, its fusing point is all at 180-186 ℃, though and patent US6767913, US6800759, US7074928, WO2004048385, WO2005063708 also disclose the preparation method of crystal formation I, the concrete fusing point data of crystal formation I openly.
International monopoly WO2005/012300 discloses the clopidogrel hydrosulfate high melting point crystal I preparation method, its preparation method is: (+)-(S-)-clopidogrel free alkali is dissolved in the ethyl acetate, add 2.5% (+)-(S-)-SR-25990C crystal formation I, room temperature drips the vitriol oil of 1: 1 amount, drips and finishes, reflux 1 hour, be cooled to stirring at room again 1 hour, and filtered, dry I type (+)-(S-)-SR-25990C, fusing point is 198～200 ℃, yield 88%.
The melting range that prior art publication technology makes all exists crystal formation I purity not high at 180-186 ℃ SR-25990C low melting point crystal formation I, and storage time is long to change defective such as crystalline substance easily; Though and international monopoly WO2005/012300 can make high-melting-point crystal formation I, yield is also higher, but its processing condition are comparatively harsh, existing needs the high-quality crystal seed of adding, salify, product oven dry under refluxad to need the high deficiency of long temperature of time, and we are according to our simulated experiment, and this technology obtains mixed crystal easily not adding crystal seed or crystal seed when second-rate, and repeatability is relatively poor, is not suitable for industrialization.
Summary of the invention
It is strong to the purpose of this invention is to provide a kind of process repeatability, processing condition require simple, with low cost, be more suitable for the method for preparation (+)-(the S-)-clopidogrel hydrosulfate high melting point crystal I of suitability for industrialized production, use (+)-(the S-)-clopidogrel hydrosulfate high melting point crystal I of the inventive method preparation to have the purity height, advantages such as easy storage.
By repeatedly experiment, we have found the forming process of dystectic SR-25990C crystal formation I, wherein choice of Solvent is most important, adopt following method can make dystectic clopidogrel crystal formation I: to use ketones solvent, preferred lower alkyl ketone, more preferably butanone, separate out the back at crystal and add a small amount of alcoholic solvent, be generally 1～2% of reaction system cumulative volume, preferred lower alkyl alcohol, more preferably methyl alcohol is as solvent, gained clopidogrel crystal formation I like this, and fusing point is 198～200 ℃.
Technical scheme of the present invention:
Clopidogrel free alkali is dissolved in ketones solvent, preferred lower alkyl ketone, most preferably butanone; In 25 ℃ ± 2 ℃, in mixture, add the vitriol oil, massfraction is 98%, after crystal is separated out, promptly adds a small amount of alcoholic solvent, preferred lower alkyl alcohol, methyl alcohol most preferably, add-on is generally 1～2% of whole reaction system volume.The temperature of control reaction system is at 25 ℃ ± 2 ℃, and stirred crystallization is more than 12 hours, so that crystal is fully separated out; After crystallization is finished, filter, with a small amount of ketones solvent washing leaching cake, the preferred lower alkyl ketone of ketones solvent, butanone most preferably should be identical with the ketone of dissolving clopidogrel free alkali use, drains filter cake; In 30 ℃ of left and right sides vacuum-drying filter cakes, promptly get SR-25990C crystal formation I.In the reaction, the preferred lower alkyl ketone of ketones solvent, most preferably butanone can make free alkali fully dissolve, and reaction can fully be carried out, and the drying of filter cake also is easy to; Add alcoholic solvent, especially methyl alcohol, so just can make dystectic crystal formation I, it should be noted that in the crystalline process, the time of crystallization may be slower, so should keep the enough crystallization time, generally should be not less than 12 hours, crystal is fully separated out.In addition, for avoiding producing unnecessary impurity, the ketones solvent of washing leaching cake should be same with the solvent phase of last step dissolving clopidogrel free alkali.After filter cake was drained, the amount that should guarantee this residual solvent was less than 10%, and to avoid drying by the fire in the material process, it is brilliant that SR-25990C crystal formation I changes.Crystal formation detects with IR and XPRD.
Description of drawings
The opticmicroscope collection of illustrative plates of the SR-25990C crystal formation I that accompanying drawing 1: embodiment 1 makes.
The infrared spectra collection of illustrative plates of the SR-25990C crystal formation I that accompanying drawing 2: embodiment 1 makes.
The powder X ray diffracting spectrum of the SR-25990C crystal formation I that accompanying drawing 3: embodiment 1 makes.
Embodiment
In a 100ml there-necked flask, drop into clopidogrel free alkali 5g, butanone 35ml, stirring and dissolving clarification, 25 ± 2 ℃ of temperature controls, slowly drip the vitriol oil (massfraction is 98%) 1.5g, have small amount of crystal to separate out after, add methyl alcohol 0.5ml, stirred crystallization is 12 hours under this temperature, after crystallization is finished, filter, with a small amount of butanone washing, drain, the residual quantity of guaranteeing butanone in the filter cake is less than 10% as far as possible.In 30 ℃ of following vacuum-drying filter cakes 2-4 hour.Get white powder solid 5.6g, be SR-25990C crystal formation I, yield 86%.Fusing point: 198-200 ℃.
In a 100ml there-necked flask, drop into clopidogrel free alkali 5g, acetone 35ml, stirring and dissolving clarification, 25 ± 2 ℃ of temperature controls, slowly drip the vitriol oil (massfraction is 98%) 1.5g, have small amount of crystal to separate out after, add methyl alcohol 0.5ml, stirred crystallization is 12 hours under this temperature, after crystallization is finished, filter, wash with small amount of acetone, drain, the residual quantity of guaranteeing acetone in the filter cake is less than 8% as far as possible.In 30 ℃ of vacuum-drying filter cakes 2-4 hour.Get white powder solid 5.5g, be SR-25990C crystal formation I, this step yield 85%.Fusing point: 198-200 ℃.
In a 100ml there-necked flask, drop into clopidogrel free alkali 5g, butanone 35ml, stirring and dissolving clarification, 25 ± 2 ℃ of temperature controls, slowly drip the vitriol oil (massfraction is 98%) 1.5g, have small amount of crystal to separate out after, add dehydrated alcohol 0.5ml, stirred crystallization is 12 hours under this temperature, after crystallization is finished, filter, with a small amount of butanone washing, drain, the residual quantity of guaranteeing butanone in the filter cake is less than 10% as far as possible.In 30 ℃ of vacuum-drying filter cakes 2-4 hour.Get white powder solid 5.4g, be SR-25990C crystal formation I, this step yield 83%.Fusing point: 198-200 ℃.
Embodiment 4
In a 100ml there-necked flask, drop into clopidogrel free alkali 5g, acetone 35ml, stirring and dissolving clarification, 25 ± 2 ℃ of temperature controls, slowly drip the vitriol oil (massfraction is 98%) 1.5g, have small amount of crystal to separate out after, add Virahol 0.5ml, stirred crystallization is 12 hours under this temperature, after crystallization is finished, filter, wash with small amount of acetone, drain, the residual quantity of guaranteeing acetone in the filter cake is less than 10% as far as possible.In 30 ℃ of vacuum-drying filter cakes 2-4 hour.Get white powder solid 5.5g, be SR-25990C crystal formation I, this step yield 85%.Fusing point: 198-200 ℃.
Embodiment 5
In a 100ml there-necked flask, drop into clopidogrel free alkali 5g, pimelinketone 35ml, stirring and dissolving clarification, 25 ± 2 ℃ of temperature controls, slowly drip the vitriol oil (massfraction is 98%) 1.5g, have small amount of crystal to separate out after, add methyl alcohol 0.5ml, stirred crystallization is 12 hours under this temperature, after crystallization is finished, filter, with a small amount of pimelinketone washing, drain, the residual quantity of guaranteeing pimelinketone in the filter cake is less than 10% as far as possible.In 30 ℃ of vacuum-drying filter cakes 2-4 hour.Get white powder solid 5.4g, be SR-25990C crystal formation I, this step yield 83%.Fusing point: 198-200 ℃.
Claims (8)
1. the preparation method of one kind (+)-(S-)-clopidogrel hydrosulfate high melting point crystal I is characterized in that:
Clopidogrel free alkali is dissolved in ketones solvent; In above-mentioned solvent system mixture, add the vitriol oil, have crystal to separate out after, add alcoholic solvent, stirred crystallization; Filter, with a small amount of ketones solvent washing leaching cake, drain, vacuum-drying promptly gets (+)-(S-)-SR-25990C crystal formation I.
2. according to the method for claim 1, the ketones solvent of described dissolving clopidogrel free alkali is a lower alkyl ketone.
3. lower alkyl ketone according to claim 2 is a butanone.
4. according to the method for claim 1, described alcoholic solvent is a lower alkyl alcohol.
5. lower alkyl alcohol according to claim 4 is a methyl alcohol.
6. according to the method for claim 1, the volume of described alcoholic solvent accounts for 1～2% of whole solvent system volume.
7. according to the method for claim 1, the filter cake after the washing will be drained as far as possible, guarantees that solvent residual amount is less than 10%.
8. according to the method for claim 1, the ketones solvent of washing leaching cake is identical with the employed ketones solvent of dissolving clopidogrel free alkali.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101805354A (en) * | 2010-04-16 | 2010-08-18 | 中山大学 | Preparation method of I type clopidogrel hydrogen sulfate |
| CN102875568A (en) * | 2012-09-06 | 2013-01-16 | 苏州晶云药物科技有限公司 | Method for preparing (+)-(S)-clopidogrel hydrogen sulfate pure crystal type I |
| CN103360406A (en) * | 2012-03-26 | 2013-10-23 | 黑龙江福和华星制药集团股份有限公司 | Method for preparing I-type clopidogrel hydrogen sulfate |
| CN104045653A (en) * | 2014-07-15 | 2014-09-17 | 苏州天马精细化学品股份有限公司 | Method for purifying hydrosulfate clopidogrel |
| CN113735877A (en) * | 2021-09-10 | 2021-12-03 | 天方药业有限公司 | Refining method of clopidogrel hydrogen sulfate |
-
2007
- 2007-07-09 CN CN 200710069957 patent/CN100584845C/en active Active
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101805354A (en) * | 2010-04-16 | 2010-08-18 | 中山大学 | Preparation method of I type clopidogrel hydrogen sulfate |
| CN103360406A (en) * | 2012-03-26 | 2013-10-23 | 黑龙江福和华星制药集团股份有限公司 | Method for preparing I-type clopidogrel hydrogen sulfate |
| CN102875568A (en) * | 2012-09-06 | 2013-01-16 | 苏州晶云药物科技有限公司 | Method for preparing (+)-(S)-clopidogrel hydrogen sulfate pure crystal type I |
| CN104045653A (en) * | 2014-07-15 | 2014-09-17 | 苏州天马精细化学品股份有限公司 | Method for purifying hydrosulfate clopidogrel |
| CN113735877A (en) * | 2021-09-10 | 2021-12-03 | 天方药业有限公司 | Refining method of clopidogrel hydrogen sulfate |
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