CN102432625A - Crystallization method for preparing high-purity I-type clopidogrel hydrogen sulfate - Google Patents
Crystallization method for preparing high-purity I-type clopidogrel hydrogen sulfate Download PDFInfo
- Publication number
- CN102432625A CN102432625A CN2011103455927A CN201110345592A CN102432625A CN 102432625 A CN102432625 A CN 102432625A CN 2011103455927 A CN2011103455927 A CN 2011103455927A CN 201110345592 A CN201110345592 A CN 201110345592A CN 102432625 A CN102432625 A CN 102432625A
- Authority
- CN
- China
- Prior art keywords
- clopidogrel
- type
- solution
- free alkali
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for preparing high-purity I-type clopidogrel hydrogen sulfate, belonging to the technical field of finding and preparing of drug crystal forms. The method comprises the following four steps of: (A) transforming a clopidogrel salt into free alkali thereof at a lower temperature; (B) dropwise adding sulfuric acid into aqueous alkali at 20 to 25 DEG C, reacting and crystallizing; (C) growing crystals for 1 to 2 hours at the same temperature; and (D) washing an obtained solid by using ethyl acetate, and performing vacuum drying. An I-type clopidogrel hydrogen sulfate crystal prepared by using the method is determined to be the high crystal form purity I-type clopidogrel hydrogen sulfate after being subjected to X-ray powder diffraction, infrared spectrum and thermal analysis. An appropriate amount of seed crystal is added during crystallization, the crystallization speed is obviously increased, and the crystallization can be completed within about 5 hours.
Description
Technical field
The present invention relates to a kind of preparation method of I type SR-25990C of high crystal formation purity, in particular, the present invention relates to the clopidogrel salt is the method for feedstock production I type SR-25990C, belongs to the medicine crystal formation and finds and preparing technical field.
Background technology
SR-25990C (clopidogrel hydrogen sulfate, structural formula is shown below), chemistry (+) by name-(
S)-α-(2-chloro-phenyl-)-6,7-dihydro-thiophene also [3,2-
c] pyridyl-5 (4
H)-methyl acetate hydrosulfate is a kind of new and effective medicament for resisting platelet aggregation.This medicine has continued 1998 first since U.S.'s listing, successively in the listing of states such as Europe, Canada, Australia, Singapore, in calendar year 2001 entering Chinese market by the at first research and development in 1987 of French Sanofi-Aventis company.This medicine better tolerance, untoward reaction are few, clinical treatment atherosclerosis, the acute coronary syndrome etc. of being widely used in.
SR-25990C has multiple crystal formation, and that the SR-25990C crystalline structure of existing method preparation comprises is amorphous, I type, II type and solvolyte thereof.The various crystal formations of SR-25990C are having than big-difference aspect physico-chemical property and the clinical effectiveness, and for example, the II type is compared with I, and good stability be prone to preparation, but its solubleness and bioavailability is poor than the I type.But in most of documents, the synthetic SR-25990C is often mostly to be II types, even the I type, its crystal formation purity is not high, and being prone to during storage change crystalline substance is the II type.
Patent EP281459 has described the preparation of SR-25990C the earliest, but does not relate to the crystal formation problem.Patent WO99/65915 (US6429210) discloses two kinds of crystal formations of SR-25990C, i.e. I type and II type, and this is first patent of describing the SR-25990C crystal formation.Patent EP281459 and WO99/65915 disclose with acetone and have done the method that solvent prepares the I type, but through our experimental verification, make solvent with acetone, and mostly the crystal product of acquisition is the mixture of II type or I type and II type.Patent WO2003/051362 discloses other crystal formation of SR-25990C first; Like III, IV, V, VI and amorphous; This patent adopts the Fatty Alcohol(C12-C14 and C12-C18) of C1-C4 to make solvent, but in the preparation process, can produce the very high oil phase of viscosity, can't be used for industrial production.Patent WO2004/020443 and US7772398B2 adopt with the brothers tertiary alcohol of C1-C5 respectively or are solvent by it with the sour synthetic ester of C1-C4, Virahol, isopropyl ether, 2-butanone etc., prepare I type SR-25990C, but crystal formation purity are not high.It is that solvent prepares I type SR-25990C that patent US6429210B1, WO2005/012300 and CN101100471A adopt ETHYLE ACETATE, and crystallization time is all longer.Patent WO2005/012300 then adopts high-temperature solvent to reflux and cooling crystallization method prepares I type SR-25990C, about reaction times 2 h, shortened crystallization time greatly, but process is complicated, wayward, is difficult to suitability for industrialized production and uses.
Summary of the invention
Main purpose of the present invention is to overcome problems such as existing I type SR-25990C preparation process is complicated, product crystal formation purity is not high, period of storage is short, and a kind of preparation method of I type SR-25990C of 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), under dry air or the protection of inert gas; Clopidogrel salt is mixed with an amount of organic solvent; Add an amount of water, clopidogrel Yan ︰ You machine Rong Ji ︰ water is counted 4～7 ︰, 50 ︰ 50 with g/mL/mL, and in solution, adds an amount of salt of wormwood (or yellow soda ash, sodium hydrogencarbonate, the saleratus) aqueous solution; 0 ~ 5 ℃ of control reaction temperature is reacted pH value to 7 ~ 8 to the solution water;
(2), when the pH value of step (1) reaction solution water 7 ~ 8 the time, standing demix is collected organic phase and water respectively;
(3), step (2) gained water with organic solvent extraction once, merge organic phase, the evaporate to dryness organic solvent obtains liquid clopidogrel free alkali;
(4), in the clopidogrel free alkali of step (3) gained, add proper amount of diluting, stir and make the clopidogrel free alkali dissolving fully, filter and obtain settled solution;
Said thinner is an ETHYLE ACETATE.
(5), the temperature of constant step (4) gained settled solution, add an amount of crystal seed, and drip diluted sulphuric acid soln;
(6), after sulphuric acid soln dropwises, growing the grain 1 ~ 2 h under the same temperature;
(7), ETHYLE ACETATE washing step (6) gained solid 2 times, and vacuum-drying (vacuum tightness 50 mbar, 50 ~ 55 ℃, 24 h) obtains I type SR-25990C product.
Above-mentioned clopidogrel salt comprises clopidogrel camphorsulfonate, clopidogrel hydrochloride, clopidogrel hydrobromate or clopidogrel sulfate.
Above-mentioned organic solvent comprises methylene dichloride, ethylene dichloride or ether.
The add-on of above-mentioned thinner is counted 27 ︰ 1 with the ratio of clopidogrel free alkali with mL/g.
Above-mentioned reactive crystallization steady temperature is 20 ~ 25 ℃.
Above-mentioned crystal seed is an I type SR-25990C, and its add-on is controlled to be 1% of theoretical yield.
Above-mentioned sulphuric acid soln is meant 98% the vitriol oil is diluted to the sulfuric acid ethyl acetate solution of mass concentration 10% with ETHYLE ACETATE that the mol ratio of sulfuric acid dripping quantity and clopidogrel free alkali is 1:1.
Beneficial effect of the present invention: the present invention adopts seed technology and suitable reactive crystallization temperature and solvent, can effectively avoid the generation of the oil phase of high viscosity in the reaction crystallization process.Compared with prior art, the present invention has following characteristics: be easy to suitability for industrialized production, product crystal formation purity height, efficient.
Description of drawings
The I type SR-25990C X-ray powder diffraction that Fig. 1 the inventive method instance 1 obtains.
The I type SR-25990C DSC figure that Fig. 2 the inventive method instance 1 obtains.
The I type SR-25990C IR collection of illustrative plates that Fig. 3 the inventive method instance 1 obtains.
Fig. 4 II type SR-25990C X-ray powder diffraction.
Fig. 5 II type SR-25990C DSC figure.
Fig. 6 II type SR-25990C IR collection of illustrative plates.
Embodiment
Further present invention is described through specific embodiment: under dry air or protection of inert gas; Clopidogrel salt (can be clopidogrel camphorsulfonate, clopidogrel hydrochloride, clopidogrel hydrobromate or clopidogrel sulfate) is mixed with certain amount of organic solvent (methylene dichloride, ethylene dichloride or ether etc.); Add suitable quantity of water; And in solution, add yellow soda ash, salt of wormwood, sodium hydrogencarbonate or potassium bicarbonate aqueous solution, stirring reaction.When the pH of solution water value to 7 ~ 8, standing demix is told organic phase, and water with organic solvent extraction once merge organic phase, and the evaporate to dryness organic solvent obtains clopidogrel free alkali.In clopidogrel free alkali, add ethyl acetate solvent (add-on is counted 27 ︰ 1 with the ratio of free alkali with mL/g), stir and make the clopidogrel free alkali dissolving fully, filter and obtain settled solution.The control solution temperature is 20 ~ 25 ℃, adds an amount of crystal seed, and the ratio according to the mol ratio 1:1 of sulfuric acid and clopidogrel free alkali drips the sulphuric acid soln that dilutes through ETHYLE ACETATE in solution immediately, and control reaction temperature is at 20 ~ 25 ℃ when dripping said sulphuric acid soln.After dropwising, growing the grain 1 ~ 2 h.Filter and washing, product obtains I type SR-25990C at 50 ~ 55 ℃ of following vacuum-drying 24 h.
Embodiment 1:
Under nitrogen protection, 5 gram II type SR-25990Cs, 50 milliliters of methylene dichloride and 50 ml waters join in 250 milliliters of there-necked flasks, stir, are cooled to 0 ~ 5 ℃, drip 30 milliliter of 10% aqueous sodium carbonate.React pH value to 7 ~ 8 to the solution water, standing demix is told organic phase, and water with 50 milliliters of extractions of methylene dichloride once.Merge organic phase, and the evaporate to dryness methylene dichloride, 3.5 gram clopidogrel free alkalis obtained.In free alkali, add 94.5 milliliters of (ρ=0.9 g/cm of ETHYLE ACETATE
3), stir and make the free alkali dissolving fully, filter and obtain settled solution.The control solution temperature is in 23 ℃; In solution, add 0.05 gram I type SR-25990C; Mix; And beginning to drip 10.5 milliliter 10% sulfuric acid ethyl acetate solution (control sulfuric acid dripping quantity is 1:1 with the mol ratio of clopidogrel free alkali), solution temperature is at 23 ~ 25 ℃ during the control dropping.After dropwising, growing the grain 1 ~ 2 h.Filter and wash with ETHYLE ACETATE, product obtains 4 gram I type SR-25990Cs at 50 ~ 55 ℃, 50 mbar vacuum-dryings, 24 h, and yield is 80%.It is 182.5 ℃ that DSC measures first fusing point, and PXRD and IR detect its I type crystal formation purity>95%.
Embodiment 2:
Under nitrogen protection, 6.5 gram clopidogrel camphorsulfonates, 50 milliliters of methylene dichloride and 50 ml waters join in 250 milliliters of there-necked flasks, stir, are cooled to 0 ~ 5 ℃, drip 30 milliliter of 10% aqueous sodium carbonate.React pH value to 7 ~ 8 to the solution water, standing demix is told organic phase, and water with 50 milliliters of extractions of methylene dichloride once.Merge organic phase, and the evaporate to dryness methylene dichloride, 3.6 gram clopidogrel free alkalis obtained.In free alkali, add 97.2 milliliters of (ρ=0.9g/cm of ETHYLE ACETATE
3), stir and make the free alkali dissolving fully, filter and obtain settled solution.The control solution temperature adds 0.05 gram I type SR-25990C in 23 ℃ in solution, mix, and begin to drip 10.8 milliliter 10% sulfuric acid ethyl acetate solution, and solution temperature was at 23 ~ 25 ℃ when control dripped.After dropwising, growing the grain 1 ~ 2 h.Filter and wash with ETHYLE ACETATE, product obtains 4.2 gram I type SR-25990Cs at 50 ~ 55 ℃, 50 mbar vacuum-dryings, 24 h, and yield is 84%.It is 182.5 ℃ that DSC measures first fusing point, and PXRD and IR detect its I type crystal formation purity>95%.
Embodiment 3:
Under nitrogen protection, 4.8 gram clopidogrel hydrobromates, 50 milliliters of methylene dichloride and 50 ml waters join in 250 milliliters of there-necked flasks, stir, are cooled to 0 ~ 5 ° of C, drip 30 milliliter of 10% aqueous sodium carbonate.React pH value to 7 ~ 8 to the solution water, standing demix is told organic phase, and water with 50 milliliters of extractions of methylene dichloride once.Merge organic phase, and the evaporate to dryness methylene dichloride, 3.4 gram clopidogrel free alkalis obtained.In free alkali, add 91.8 milliliters of (ρ=0.9 g/cm of ETHYLE ACETATE
3), stir and make the free alkali dissolving fully, filter and obtain settled solution.The control solution temperature adds 0.05 gram I type SR-25990C in 23 ℃ in solution, mix, and begin to drip 10.2 milliliter 10% sulfuric acid ethyl acetate solution, and solution temperature was at 23 ~ 25 ℃ when control dripped.After dropwising, growing the grain 1 ~ 2 h.Filter and wash with ETHYLE ACETATE, product obtains 3.9 gram I type SR-25990Cs at 50 ~ 55 ℃, 50 mbar vacuum-dryings, 24 h, and yield is 78%.It is 182.5 ℃ that DSC measures first fusing point, and PXRD and IR detect its I type crystal formation purity>95%.
Embodiment 4:
Under nitrogen protection, add 270 milliliters of (ρ=0.9g/cm of ETHYLE ACETATE in the clopidogrel free alkali after 10 gram decolourings
3), stir and make the free alkali dissolving fully, filter and obtain settled solution.The control solution temperature adds 0.5 gram I type SR-25990C in 23 ℃ in solution, mix, and begin to drip 30 milliliter 10% sulfuric acid ethyl acetate solution, and solution temperature was at 23 ~ 25 ℃ when control dripped.After dropwising, growing the grain 1 ~ 2 h.Filter and wash with ETHYLE ACETATE, product obtains 10.02 gram I type SR-25990Cs at 50 ~ 55 ℃, 50 mbar vacuum-dryings, 24 h, and yield is 78%.It is 181.5 ℃ that DSC measures first fusing point, and PXRD and IR detect its I type crystal formation purity>95%.
Embodiment 5:
Under nitrogen protection, 500 gram II type SR-25990Cs, 5 liters of methylene dichloride and 5 premium on currency join in 20 liters of reaction kettles, stir, are cooled to 0 ~ 5 ° of C, drip 3 liter of 10% aqueous sodium carbonate.React pH value to 7 ~ 8 to the solution water, standing demix is told organic phase, and water with 5 liters of extractions of methylene dichloride once.Merge organic phase, and the evaporate to dryness methylene dichloride, 368 gram clopidogrel free alkalis obtained.In free alkali, add 9.9 liters of (ρ=0.9 g/cm of ETHYLE ACETATE
3), stir and make the free alkali dissolving fully, filter and obtain settled solution.The control solution temperature adds 5 gram I type SR-25990Cs in 23 ℃ in solution, mix, and begin to drip 1.1 liter 10% sulfuric acid ethyl acetate solution, and solution temperature was at 23 ~ 25 ℃ when control dripped.After dropwising, growing the grain 1 ~ 2 h.Filter and wash with ETHYLE ACETATE, product obtains 386 gram I type SR-25990Cs at 50 ~ 55 ℃, 50 mbar vacuum-dryings, 24 h, and yield is 77.2%.It is 181.8 ℃ that DSC measures first fusing point, and PXRD and IR detect its I type crystal formation purity>95%.
Embodiment 6:
Under nitrogen protection, 800 gram II type SR-25990Cs, 8 liters of methylene dichloride and 8 premium on currency join in 25 liters of reaction kettles, stir, are cooled to 0 ~ 5 ° of C, drip 4.8 liter of 10% aqueous sodium carbonate.React pH value to 7 ~ 8 to the solution water, standing demix is told organic phase, and water is with 8 liters of extracted twice of methylene dichloride.Merge organic phase, and the evaporate to dryness methylene dichloride, 600 gram clopidogrel free alkalis obtained.In free alkali, add 16.2 liters of (ρ=0.9 g/cm of ETHYLE ACETATE
3), stir and make the free alkali dissolving fully, filter and obtain settled solution.The control solution temperature adds 8 gram I type SR-25990Cs in 23 ℃ in solution, mix, and begin to drip 1.8 liter 10% sulfuric acid ethyl acetate solution, and solution temperature was at 23 ~ 25 ℃ when control dripped.After dropwising, growing the grain 1 ~ 2 h.Filter and wash with ETHYLE ACETATE, product obtains 640 gram I type SR-25990Cs at 50 ~ 55 ℃, 50 mbar vacuum-dryings, 24 h, and yield is 80%.It is 182.5 ℃ that DSC measures first fusing point, and PXRD and IR detect its I type crystal formation purity>95%.
The above content is merely the basic explanation of the present invention under conceiving, and according to any equivalent transformation that technical scheme of the present invention is done, all should belong to protection scope of the present invention.
Claims (4)
1. the preparation method of a high purity I type SR-25990C is characterized in that this method comprises the following steps:
(1), under dry air or the protection of inert gas; Clopidogrel salt is mixed with an amount of organic solvent; Add an amount of water, clopidogrel Yan ︰ You machine Rong Ji ︰ water is counted 4～7 ︰, 50 ︰ 50 with g/mL/mL, and in solution, adds an amount of salt of wormwood, yellow soda ash, sodium hydrogencarbonate or potassium bicarbonate aqueous solution; 0 ~ 5 ℃ of control reaction temperature is reacted pH value to 7 ~ 8 to the solution water;
Said organic solvent is selected methylene dichloride, ethylene dichloride or ether for use;
(2), when the pH value of step (1) reaction solution water 7 ~ 8 the time, standing demix is collected organic phase and water respectively;
(3), step (2) gained water with organic solvent extraction once, merge organic phase, the evaporate to dryness organic solvent obtains liquid clopidogrel free alkali;
(4), in the clopidogrel free alkali of step (3) gained, add proper amount of diluting, stir and make the clopidogrel free alkali dissolving fully, filter and obtain settled solution;
Said thinner is an ETHYLE ACETATE;
(5), the temperature of constant step (4) gained settled solution, add an amount of crystal seed, and drip diluted sulphuric acid soln;
(6), after sulphuric acid soln dropwises, growing the grain 1 ~ 2 h under the same temperature;
(7), ETHYLE ACETATE washing step (6) gained solid 2 times, and vacuum-drying 24 h under vacuum tightness 50 mbar, 50 ~ 55 ℃ of conditions obtain I type SR-25990C product.
2. the preparation method of high purity I type SR-25990C according to claim 1; When it is characterized in that wherein said step (1), said clopidogrel salt is selected clopidogrel camphorsulfonate, clopidogrel hydrochloride, clopidogrel hydrobromate or clopidogrel sulfate for use.
3. the preparation method of high purity I type SR-25990C according to claim 1, when it is characterized in that wherein said step (4), the add-on of said thinner is counted 27 ︰ 1 with the ratio of clopidogrel free alkali with mL/g.
4. the preparation method of high purity I type SR-25990C according to claim 1, when it is characterized in that wherein said step (5), said steady temperature is 20 ~ 25 ℃; Said an amount of crystal seed is meant that I type crystal seed add-on is controlled to be 1% of I type SR-25990C theoretical yield; Said sulphuric acid soln is meant that the vitriol oil with 98% is diluted to 10% sulfuric acid ethyl acetate solution with ETHYLE ACETATE, and the mol ratio of sulfuric acid dripping quantity and clopidogrel free alkali is 1:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011103455927A CN102432625A (en) | 2011-11-05 | 2011-11-05 | Crystallization method for preparing high-purity I-type clopidogrel hydrogen sulfate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2011103455927A CN102432625A (en) | 2011-11-05 | 2011-11-05 | Crystallization method for preparing high-purity I-type clopidogrel hydrogen sulfate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102432625A true CN102432625A (en) | 2012-05-02 |
Family
ID=45981012
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2011103455927A Pending CN102432625A (en) | 2011-11-05 | 2011-11-05 | Crystallization method for preparing high-purity I-type clopidogrel hydrogen sulfate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102432625A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044444A (en) * | 2013-01-21 | 2013-04-17 | 上海现代哈森（商丘）药业有限公司 | Synthesis method of high-purity I-type (+)-(S)-clopidogrel hydrogen sulfate |
| CN103833770A (en) * | 2014-04-02 | 2014-06-04 | 南京工业大学 | Method for preparing I-type clopidogrel hydrogen sulfate |
| CN104610274A (en) * | 2013-11-05 | 2015-05-13 | 亚宝药业集团股份有限公司 | Type I clopidogrel hydrogen sulfate salt preparation method |
| CN113735877A (en) * | 2021-09-10 | 2021-12-03 | 天方药业有限公司 | Refining method of clopidogrel hydrogen sulfate |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005016931A2 (en) * | 2003-08-13 | 2005-02-24 | Krka, Torvarna Zdravil, D.D., Novo Mesto | Crystallisation of solid forms of clopidogrel addition salts |
| WO2009080469A1 (en) * | 2007-12-24 | 2009-07-02 | Sandoz Ag | Process for the preparation of clopidogrel bisulphate form i |
| CN102014899A (en) * | 2006-04-27 | 2011-04-13 | 因-斯韦特实验室有限公司 | Process for the preparation of polymorphic forms of clopidogrel hydrogen sulfate |
| CN102050829A (en) * | 2009-11-04 | 2011-05-11 | 北京华禧联合科技发展有限公司 | Crystallizing method for obtaining I crystal form (+)-(S)-clopidogrel bisulfate |
| CN102070648A (en) * | 2010-12-07 | 2011-05-25 | 天津红日药业股份有限公司 | Preparation method of clopidogrel hydrogen sulfate I |
| CN102083837A (en) * | 2008-06-24 | 2011-06-01 | Zach系统股份公司 | Process for the preparation of clopidogrel hydrogen sulfate crystalline form i |
| WO2011125069A1 (en) * | 2010-03-22 | 2011-10-13 | Rpg Life Sciences Limited | A process for preparation of crystalline form i of clopidogrel bisulfate |
-
2011
- 2011-11-05 CN CN2011103455927A patent/CN102432625A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005016931A2 (en) * | 2003-08-13 | 2005-02-24 | Krka, Torvarna Zdravil, D.D., Novo Mesto | Crystallisation of solid forms of clopidogrel addition salts |
| CN102014899A (en) * | 2006-04-27 | 2011-04-13 | 因-斯韦特实验室有限公司 | Process for the preparation of polymorphic forms of clopidogrel hydrogen sulfate |
| WO2009080469A1 (en) * | 2007-12-24 | 2009-07-02 | Sandoz Ag | Process for the preparation of clopidogrel bisulphate form i |
| CN102083837A (en) * | 2008-06-24 | 2011-06-01 | Zach系统股份公司 | Process for the preparation of clopidogrel hydrogen sulfate crystalline form i |
| CN102050829A (en) * | 2009-11-04 | 2011-05-11 | 北京华禧联合科技发展有限公司 | Crystallizing method for obtaining I crystal form (+)-(S)-clopidogrel bisulfate |
| WO2011125069A1 (en) * | 2010-03-22 | 2011-10-13 | Rpg Life Sciences Limited | A process for preparation of crystalline form i of clopidogrel bisulfate |
| CN102070648A (en) * | 2010-12-07 | 2011-05-25 | 天津红日药业股份有限公司 | Preparation method of clopidogrel hydrogen sulfate I |
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 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103044444A (en) * | 2013-01-21 | 2013-04-17 | 上海现代哈森（商丘）药业有限公司 | Synthesis method of high-purity I-type (+)-(S)-clopidogrel hydrogen sulfate |
| CN103044444B (en) * | 2013-01-21 | 2015-04-15 | 上海现代哈森（商丘）药业有限公司 | Synthesis method of high-purity I-type (+)-(S)-clopidogrel hydrogen sulfate |
| CN104610274A (en) * | 2013-11-05 | 2015-05-13 | 亚宝药业集团股份有限公司 | Type I clopidogrel hydrogen sulfate salt preparation method |
| CN104610274B (en) * | 2013-11-05 | 2017-04-19 | 亚宝药业集团股份有限公司 | Type I clopidogrel hydrogen sulfate salt preparation method |
| CN103833770A (en) * | 2014-04-02 | 2014-06-04 | 南京工业大学 | Method for preparing I-type clopidogrel hydrogen sulfate |
| CN113735877A (en) * | 2021-09-10 | 2021-12-03 | 天方药业有限公司 | Refining method of clopidogrel hydrogen sulfate |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102558182B (en) | Ertapenem sodium crystal form E and preparation method thereof | |
| CN101863784B (en) | Methods for preparing and extracting betaine and betaine hydrochloride | |
| CN102432625A (en) | Crystallization method for preparing high-purity I-type clopidogrel hydrogen sulfate | |
| CN101570543B (en) | Preparation method of mezlocillin sodium solvent crystal | |
| CN110041261A (en) | A kind of preparation method of naphcon | |
| CN102267957A (en) | Method for preparing Febuxostat crystal A | |
| CN100503615C (en) | Method of preparing chloropy gra hydrogen sulphate type I | |
| CN102964396B (en) | A kind of method of trichloro-cane-6-ethyl ester recrystallization | |
| CN103483231B (en) | Method for synthesizing alliin with optical activity and reaction device thereof | |
| CN102731508A (en) | Crystal ertapenem intermediate as well as preparation method and application thereof | |
| CN112707829B (en) | Toxolol crystal form and preparation method thereof | |
| CN104628743A (en) | New crystal form of cefathiamidine compounds and crystallized preparation method thereof | |
| CN103030599B (en) | Gefitinib intermediate and preparation method thereof | |
| CN103539733B (en) | A kind of preparation method of isoniazid para-aminosalicylate | |
| CN102875568B (en) | The method of the pure crystal formation I of preparation (+)-(S)-SR-25990C | |
| CN112645945A (en) | Preparation method of Wumei ammonium bromide intermediate | |
| CN104447273B (en) | A kind of recovery method of Zopiclone resolving agent D-(+)-oxysuccinic acid | |
| CN104447724A (en) | Refining method of raltitrexed | |
| CN103012267B (en) | Novel crystalline object of benazepril hydrochloride and preparation method of crystalline object | |
| CN102351775A (en) | Preparation method of levo-5-hydroxytryptophan | |
| CN103450097A (en) | Preparation method of high-purity crystal-form-A erlotinib hydrochloride | |
| CN102633775B (en) | Method for preparing alpha-crystal-form imatinib mesylate | |
| CN102321083B (en) | Preparation method of new anhydrous moxifloxacin hydrochloride crystal F | |
| CN102391156B (en) | Preparation method of guanidine derivative creatine hydrochloride | |
| CN102070461A (en) | Synthesis method of N-methyl isopropylamine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20120502 |