CN102358743A - Simple method for preparing amorphous clopidogrel hydrosulphate - Google Patents
Simple method for preparing amorphous clopidogrel hydrosulphate Download PDFInfo
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- CN102358743A CN102358743A CN2011103455931A CN201110345593A CN102358743A CN 102358743 A CN102358743 A CN 102358743A CN 2011103455931 A CN2011103455931 A CN 2011103455931A CN 201110345593 A CN201110345593 A CN 201110345593A CN 102358743 A CN102358743 A CN 102358743A
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Abstract
The invention discloses a simple method for preparing amorphous clopidogrel hydrosulphate from II type clopidogrel hydrosulphate directly. The method includes three steps: A, dissolving the II type clopidogrel hydrosulphate in an appropriate solvent at the temperature of 20 to 25 DEG C to obtain high concentration clopidogrel hydrosulphate solution; B, flash evaporating and crystallizing the obtained clopidogrel hydrosulphate solution; and C, washing obtained solid with ethyl acetate, drying and storing the solid in vacuum. The clopidogrel hydrosulphate solid product prepared in the method is determined as high-purity crystal form amorphous clopidogrel hydrosulphate without other crystal forms through X-ray powder diffraction, infrared spectrum and thermal analysis.
Description
Technical field
A kind of short-cut method for preparing amorphous SR-25990C, specifically, the present invention relates to by II type SR-25990C is the short-cut method of the amorphous SR-25990C of feedstock production high purity.Belonging to the medicine crystal formation finds and preparing technical field.
Background technology
SR-25990C (clopidogrel hydrogen sulphate; Structural formula is formula as follows); Chemistry (S)-α by name-(2-chloro-phenyl-)-6, the 7-dihydro-thiophene is [3,2-c] pyridines-5 (4H)-methyl acetate hydrosulfate also; It is anti-platelet aggregation agent of new generation; Can suppress ADP inductive platelet aggregation, spinoff is little, clinical treatment arteriosclerosis, acute coronary syndrome, the interior restenosis of prevention intracoronary stent implantation after poppet and the thrombotic complications etc. of being mainly used in.This medicine in 1987 by the development of French Sanofi-Aventis company, went on the market in the Britain and the U.S. in 1998, go on the market in China August calendar year 2001.
SR-25990C has multiple crystal formation, comprises amorphous, I type, II type and solvolyte thereof.Patent P355814 discloses with the mixed solvent of MTBE and Virahol, has prepared unbodied method down at 0 ~ 5 ℃.This method preparation temperature is lower, and about 5 hours consuming time.CN02828204.3 discloses the method that adopts different solvents and anti-solvent to prepare amorphous SR-25990C.First method is that SR-25990C is dissolved in methyl alcohol or ethanol earlier, steams partial solvent after the dissolving, and adds anti-solvents such as MTBE or ether, within several hours with the throw out vacuum filtration.Contain a large amount of I types or II type crystal formation in this method process complicacy, the product.Second method is that SR-25990C is dissolved in the methyl alcohol, and this drips of solution is added in the ebullient toluene, refluxes 20 minutes, is cooled to room temperature, stirs 16 hours.This method operation is strict, length consuming time.The third method is that SR-25990C is dissolved in acetone, refluxes several hours in dissolving back, is cooled to room temperature and stirred for several hour again.This method empirical tests, the solubleness of this salt in acetone is little, and preparation efficiency is lower.In addition, patent US 2010/0216996 A1 discloses amorphous in I type transforming process, is accompanied by the I type to the more transformation of steady I I type.Therefore, for the polymorphous preparation of SR-25990C faster of crystal conversion speed, its key issue is to control the conversion rates between each crystal formation.
Summary of the invention
Main purpose of the present invention is to overcome existing complicated preparation technology and causes problems such as SR-25990C product crystal formation purity is not high, period of storage is short, and the method for the amorphous SR-25990C for preparing high crystal formation purity is provided.
In order to solve the problems of the technologies described above, the present invention realizes through following technical scheme:
(1), dry air or protection of inert gas, under 20 ~ 25 ℃, II type SR-25990C is dissolved in solvent; Solvent is selected one or more the mixture in water, methyl alcohol or the ethanol for use; Control II type clopidogrel sulfuric acid hydrogen salt ︰ solvent is counted 1 ︰ 5 with g/mL;
(2), filtration step (1) gained solution, remove solid impurity, obtain clear filtrate;
(3), step (2) gained filtrating is introduced in the flash evaporation crystallizer, carry out flash crystallization;
(4), ETHYLE ACETATE washing step (3) gained solid 2 times, and under vacuum tightness 50 mbar, 50 ~ 55 ℃ of conditions of temperature dry 24 h, obtain amorphous SR-25990C product.
Above-mentioned solvent is included as one or more the mixture in the lower boiling alkyl low-carbon (LC) alcohols such as water, methyl alcohol or ethanol.
Above-mentioned solution allocation temperature is 20 ~ 25 ℃.
Above-mentioned crystallization method adopts flash crystallization, and vacuum tightness is 100 mbar in the mold, and temperature is 20 ~ 25 ℃.
Beneficial effect of the present invention: the present invention adopts the method for flash crystallization, through selecting suitable solvent and vaporator rate thereof for use, prepares the amorphous SR-25990C of high crystal formation purity.Compared with prior art, the present invention has following characteristics: technology is simply efficient, energy-conservation, environmental friendliness; Do not need to set up in addition fully, simple to operate, controllability is strong; Can on the large-scale industrial production device, implement immediately, crystal formation purity is high, has tangible economic benefit.
Description of drawings
The X-ray powder diffraction spectrogram of the amorphous SR-25990C that Fig. 1 the inventive method embodiment 1 obtains.
The DSC figure of the amorphous SR-25990C that Fig. 2 the inventive method embodiment 1 obtains.
The IR spectrogram of the amorphous SR-25990C that Fig. 3 the inventive method embodiment 1 obtains.
The X-ray powder diffraction spectrogram of Fig. 4 I type SR-25990C.
The X-ray powder diffraction spectrogram of Fig. 5 II type SR-25990C.
Embodiment
Further present invention is described through specific embodiment: under exsiccant air or controlled atmosphere; II type SR-25990C is dissolved in low-carbon alcohol kind solvent or the water, filters and obtain settled solution, this solution is introduced flash evaporation crystallizer; ETHYLE ACETATE washing gained solid 2 times and vacuum-drying (vacuum tightness 50 mbar; 50 ~ 55 ℃, 24 h), obtain amorphous SR-25990C product.
Embodiment 1:
Under nitrogen protection, 20 ~ 25 ℃, 1.0 gram II type SR-25990Cs dissolvings are distributed in 5 milliliters of ethanol, filter; Filtrating is introduced flash evaporation crystallizer (vacuum tightness 100 mbar, 20 ~ 25 ℃ of temperature), ETHYLE ACETATE wash solids 2 times and vacuum-drying (vacuum tightness 50 mbar; 50 ~ 55 ℃; 24 h), obtain the amorphous SR-25990C product of 0.87 gram, yield 87%.No fusing point detects other crystal formations of nothing through PXRD.
Embodiment 2:
Under nitrogen protection, 20 ~ 25 ℃, 2.0 gram II type SR-25990Cs dissolvings are distributed in 10 ml waters, filter; Filtrating is introduced flash evaporation crystallizer (vacuum tightness 100 mbar, 20 ~ 25 ℃ of temperature), washing and vacuum-drying (vacuum tightness 50 mbar; 50 ~ 55 ℃; 24 h), obtain the amorphous SR-25990C product of 1.8 grams, yield 90%.No fusing point detects other crystal formations of nothing through PXRD.
Embodiment 3:
Under nitrogen protection, 20 ~ 25 ℃, 3.0 gram II type SR-25990Cs dissolvings are distributed in 15 ml methanol, filter; Filtrating is introduced flash evaporation crystallizer (vacuum tightness 100 mbar, 20 ~ 25 ℃ of temperature), washing and vacuum-drying (vacuum tightness 50 mbar; 50 ~ 55 ℃; 24 h), obtain the amorphous SR-25990C product of 2.8 grams, yield 93%.No fusing point detects other crystal formations of nothing through PXRD.
Embodiment 4:
Under nitrogen protection, 20 ~ 25 ℃, 2.0 gram II type SR-25990Cs dissolvings are distributed in 10 milliliters of mixed solvents (methyl alcohol and alcoholic acid volume ratio are 1 ︰ 1) filtration; Filtrating is introduced flash evaporation crystallizer (vacuum tightness 100 mbar, 20 ~ 25 ℃ of temperature), washing and vacuum-drying (vacuum tightness 50 mbar; 50 ~ 55 ℃; 24 h), obtain the amorphous SR-25990C product of 1.8 grams, yield 90%.No fusing point detects other crystal formations of nothing through PXRD.
The above content is merely the basic explanation of the present invention under conceiving, and according to any equivalent transformation that technological line of the present invention is done, all should belong to protection scope of the present invention.
Claims (2)
1. a short-cut method for preparing amorphous SR-25990C is characterized in that with II type SR-25990C be raw material, comprises the following steps:
(1), dry air or protection of inert gas, under 20 ~ 25 ℃, II type SR-25990C is dissolved in solvent; Solvent is selected one or more the mixture in water, methyl alcohol or the ethanol for use; Control II type clopidogrel sulfuric acid hydrogen salt ︰ solvent is counted 1 ︰ 5 with g/mL;
(2), filtration step (1) gained solution, remove solid impurity, obtain clear filtrate;
(3), step (2) gained filtrating is introduced in the flash evaporation crystallizer, carry out flash crystallization;
(4), ETHYLE ACETATE washing step (3) gained solid 2 times, and under vacuum tightness 50 mbar, 50 ~ 55 ℃ of conditions of temperature dry 24 h, obtain amorphous SR-25990C product.
2. the short-cut method of the amorphous SR-25990C of preparation according to claim 1 when it is characterized in that wherein said step (3), adopts the flash crystallization method, and vacuum tightness is 100 mbar in the mold, and temperature is 20 ~ 25 ℃.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004026879A1 (en) * | 2002-09-19 | 2004-04-01 | Cipla Limited | Clopidogrel |
| WO2004081015A1 (en) * | 2003-03-10 | 2004-09-23 | Hetero Drugs Limited | Amorphous clopidogrel hydrogen sulfate |
| WO2004081016A1 (en) * | 2003-03-12 | 2004-09-23 | Cadila Healthcare Limited | Polymorphs and amorphous form of (s) - (+) -clopidogrel bisulfate |
| WO2005016931A2 (en) * | 2003-08-13 | 2005-02-24 | Krka, Torvarna Zdravil, D.D., Novo Mesto | Crystallisation of solid forms of clopidogrel addition salts |
| CN1620293A (en) * | 2001-12-18 | 2005-05-25 | 特瓦制药工业有限公司 | Polymorphs of clopidogrel hydrogensulfate |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1620293A (en) * | 2001-12-18 | 2005-05-25 | 特瓦制药工业有限公司 | Polymorphs of clopidogrel hydrogensulfate |
| WO2004026879A1 (en) * | 2002-09-19 | 2004-04-01 | Cipla Limited | Clopidogrel |
| WO2004081015A1 (en) * | 2003-03-10 | 2004-09-23 | Hetero Drugs Limited | Amorphous clopidogrel hydrogen sulfate |
| WO2004081016A1 (en) * | 2003-03-12 | 2004-09-23 | Cadila Healthcare Limited | Polymorphs and amorphous form of (s) - (+) -clopidogrel bisulfate |
| US7872019B2 (en) * | 2003-03-12 | 2011-01-18 | Cadila Healthcare Limited | Polymorphs and amorphous form of (S)-(+)-clopidogrel bisulfate |
| WO2005016931A2 (en) * | 2003-08-13 | 2005-02-24 | Krka, Torvarna Zdravil, D.D., Novo Mesto | Crystallisation of solid forms of clopidogrel addition salts |
Non-Patent Citations (1)
| Title |
|---|
| 潘仙华，等: "Ⅰ型氯吡格雷硫酸氢盐的合成及晶型转换", 《精细化工》, vol. 23, no. 12, 31 December 2006 (2006-12-31), pages 1221 - 1226 * |
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Application publication date: 20120222 |