CN101805354A - Preparation method of I type clopidogrel hydrogen sulfate - Google Patents
Preparation method of I type clopidogrel hydrogen sulfate Download PDFInfo
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- CN101805354A CN101805354A CN 201010154406 CN201010154406A CN101805354A CN 101805354 A CN101805354 A CN 101805354A CN 201010154406 CN201010154406 CN 201010154406 CN 201010154406 A CN201010154406 A CN 201010154406A CN 101805354 A CN101805354 A CN 101805354A
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- tetrahydrofuran
- hydrogen sulfate
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 229950010477 clopidogrel hydrogen sulphate Drugs 0.000 title abstract 5
- FDEODCTUSIWGLK-UHFFFAOYSA-N hydrogen sulfate;hydron;methyl 2-(2-chlorophenyl)-2-(6,7-dihydro-4h-thieno[3,2-c]pyridin-5-yl)acetate Chemical compound OS(O)(=O)=O.C1CC=2SC=CC=2CN1C(C(=O)OC)C1=CC=CC=C1Cl FDEODCTUSIWGLK-UHFFFAOYSA-N 0.000 title abstract 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 78
- GKTWGGQPFAXNFI-HNNXBMFYSA-N clopidogrel Chemical compound C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl GKTWGGQPFAXNFI-HNNXBMFYSA-N 0.000 claims abstract description 74
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 38
- 239000013078 crystal Substances 0.000 claims abstract description 31
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 claims abstract description 17
- 229960003009 clopidogrel Drugs 0.000 claims abstract description 17
- 238000001291 vacuum drying Methods 0.000 claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 12
- 238000005406 washing Methods 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims abstract description 6
- 239000003513 alkali Substances 0.000 claims description 15
- 238000002386 leaching Methods 0.000 claims description 4
- 238000000034 method Methods 0.000 abstract description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 10
- 239000012065 filter cake Substances 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 8
- 238000001914 filtration Methods 0.000 abstract description 7
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract description 3
- 239000012458 free base Substances 0.000 abstract 1
- 230000001376 precipitating effect Effects 0.000 abstract 1
- 238000002425 crystallisation Methods 0.000 description 14
- 230000008025 crystallization Effects 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 12
- 238000010792 warming Methods 0.000 description 8
- 238000005352 clarification Methods 0.000 description 6
- 239000000843 powder Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 208000005764 Peripheral Arterial Disease Diseases 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127217 antithrombotic drug Drugs 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 208000021090 palsy Diseases 0.000 description 1
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000000634 powder X-ray diffraction Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of I type clopidogrel hydrogen sulfate. The method comprises the following steps: (1) dissolving clopidogrel free base in tetrahydrofuran, and adding concentrated sulfuric acid at the temperature of minus 14-0 DEG C; (2) leading the mixture to react for 1-2 hours, then slowly increasing the reaction temperature to 20-40 DEG C, continuing the reaction for 10-12 hours, and fully precipitating crystals; and (3) filtering after obtaining the crystals, washing a filter cake with the tetrahydrofuran, draining, vacuum-drying and obtaining the I type clopidogrel hydrogen sulfate. The I type clopidogrel hydrogen sulfate prepared through the method is not doped with II type clopidogrel hydrogen sulfate and has high crystal phase purity, and the preparation process does not need the steps of nitrogen production and the like, thereby reducing the production cost, leading the operation method to be simple and easy, realizing high repeatability and being easy to realize mass production.
Description
Technical field
The present invention relates to the medical compounds preparation field, be specifically related to a kind of preparation method of I type SR-25990C.
Background technology
SR-25990C is a kind of antithrombotic drug, is used to prevent and treat the circulation disorder of the heart, brain and other arteries that cause because of the high state of aggregation of thrombocyte clinically.Clopidogrel is succeeded in developing in 1980 by French Sanofi company at first; on November 17th, 1997; U.S. food medicine Surveillance Authority approval SR-25990C (Bo Liwei) can be used for after heart stalk back, the palsy and the peripheral arterial disease of making a definite diagnosis, and SR-25990C calendar year 2001 enters treatment and the prevention that is mainly used in heart stalk patient after China.
The structural formula of SR-25990C molecule is as follows:
Existing result of study shows that this molecule exists six kinds of different crystal forms and a kind of unformed shape, and having only crystal formation I and crystal form II at present is medicinal crystal-form.Crystal formation I and crystal form II are having very big difference aspect physico-chemical property and the clinical effectiveness.Wherein I type SR-25990C is a metastable-state crystal, has higher solubleness and bioavailability.And II type SR-25990C has advantages of higher stability, but solubleness and bioavailability are poor than the I type.Usually in preparation I type SR-25990C process, metastable I type SR-25990C is easy to be converted into steady I I type SR-25990C in solution.What therefore usually obtain is the mixture of I type and II type SR-25990C, causes the crystal formation purity of I type SR-25990C not reach requirement, and then the drug effect of SR-25990C is exerted an influence.Because the stability of I type SR-25990C is not high, therefore the preparation of pure I type SR-25990C is very difficult.
Described at acetone among the patent CN 10110047A, the method for preparing I type SR-25990C in butanone, the pimelinketone is dissolved in clopidogrel free alkali in the above-mentioned ketone solution 25 ± 2 ℃ of temperature controls, slowly dropping waits the vitriol oil of amount of substance, after having small amount of crystal to separate out, add a small amount of dehydrated alcohol, stirred crystallization is 12 hours under this temperature, after crystallization is finished, filter, drain, in 30 ℃ of following vacuum-drying filter cakes 2-4 hour.Obtain I type SR-25990C, yield 83%, fusing point 198-200 ℃.
The method for preparing I type SR-25990C in 2 pentanone, propione has been described among the patent CN 1903859A.Clopidogrel free alkali is dissolved in the pentanone solution, is cooled to 0-5 ℃, add I type SR-25990C crystal seed, dropping waits the vitriol oil of amount of substance then, and is warm at 0-5 ℃ in the control during dropping.Drip after the vitriol oil finishes, add I type SR-25990C crystal seed once more, and be warming up to 40-50 ℃ by 20 ℃ of speed per hour, and 40-50 ℃ of insulated and stirred 30 minutes.Decompress filter obtains product I type SR-25990C yield 85%.The product fusing point is 181 ℃, and its specific optical rotation is: 55.7 ° (c=1, methyl alcohol).
The preparation method of another I type SR-25990C has been described: under protection of inert gas and frozen water cooling conditions, in the organic solution of clopidogrel salt, drip yellow soda ash or solution of potassium carbonate, among the patent CN 1690060A to make clopidogrel free alkali.The clopidogrel free alkali that obtains is dissolved in ether or the ester is cooled to-20～5 ℃, drip the vitriol oil, dropwise the back and stir at-20～20 ℃ and obtained I type SR-25990C in 10 hours, its fusing point is 181～186 ℃, optically-active 52.0～55.0 (C=1/CH
3OH).
Patent CN 1850827A and patent CN 1840533A have write down the method for preparing I type SR-25990C in ethyl acetate, butylacetate, isobutyl acetate respectively; under nitrogen protection; in above-mentioned acetate esters solution, add clopidogrel free alkali; under 6～10 ℃ of conditions, add crystal seed; slowly the massfraction of amount of substance such as dropping is 10% sulfuric acid; add small amount of seeds after dropwising again; stir after ten minutes; be warming up to 60 ℃; reacted 30 minutes; filter, vacuum-drying gets I type SR-25990C.Find that all preparation method's circulation ratio is bad when utilizing above-mentioned 5 kinds of domestic patent of invention methods of having reported to prepare I type SR-25990C, obtain the mixture of I type and II type SR-25990C crystal formation sometimes.Therefore, above-mentioned 5 kinds of patented methods of having reported will be controlled I type SR-25990C crystal formation in actual production quality and purity are very difficult, and there is obvious defects in the patented method of having reported.Therefore, to produce I type SR-25990C for industrial scale significant for the preparation method who invents a kind of reliable and stable I type SR-25990C.In addition, patent CN 1903859A preparation method is owing to will use expensive five-carbon ketone and six-carbon ketone equal solvent, patent CN 1850827A and patent CN 1840533A prepare I type SR-25990C need lead to steps such as nitrogen, has defectives such as production cost is higher, complex operation.
Summary of the invention
The objective of the invention is at the production cost that exists among the preparation method who has I type SR-25990C now higher; complex operation; defectives such as preparation method's circulation ratio is bad; a kind of novel method that stably prepares high purity I type SR-25990C is provided; the maximum characteristics of this method are that each operation all can stably obtain I type SR-25990C; use cheap tetrahydrofuran solvent to replace expensive five-carbon ketone and the six-carbon ketone equal solvent that uses among the patent CN 1903859A simultaneously in the preparation process; and in preparation process, need not steps such as nitrogen protection; reduced production cost, working method is simple.
The object of the invention is achieved by the following technical programs:
A kind of preparation method of I type SR-25990C comprises the steps: that (1) is dissolved in clopidogrel free alkali in the tetrahydrofuran (THF), adds the vitriol oil down in-14～0 ℃ under well-beaten situation; (2) said mixture is reacted 1-2 hour after, abundant stirring reaction is continued in temperature of reaction to 20～40 ℃ of slowly raising, and crystal is separated out; (3) obtain crystal after, filter, use the tetrahydrofuran (THF) washing leaching cake, drain, vacuum-drying obtains I type SR-25990C.
As a kind of preferred version, in the aforesaid method, the massfraction of the vitriol oil is 98% described in the step (1).
As a kind of preferred version, in the aforesaid method, the mol ratio that adds the clopidogrel free alkali and the vitriol oil described in the step (1) is 1: 0.98～1: 1.20.
Because the crystal precipitation process is very slow, therefore as a kind of preferred version, in the aforesaid method, in the described step (2), behind elevated temperature to 20～40 ℃, the time of continuing reaction is more than 10 hours, to guarantee having time enough that crystal is separated out.
Because reaction initial period SR-25990C is thickness relatively, therefore as a kind of preferred version, in the aforesaid method, in described step (1) and (2), reaction must be carried out under well-beaten condition.
As a kind of preferred version, in the aforesaid method, the number of times with the tetrahydrofuran (THF) washing leaching cake described in the step (3) is 2～3 times.
As a kind of preferred version, in the aforesaid method, the vacuum drying time described in the step (3) is 3～4h.
Compared with prior art, the present invention has following beneficial effect:
The pure I type SR-25990C that can make by the inventive method; wherein can not mix II type SR-25990C; crystal formation purity height; use cheap tetrahydrofuran solvent in the preparation process; and need not steps such as nitrogen protection in the reaction process, reduced production cost, working method is simple; repeatable high, be easy to large-scale production.
Description of drawings
The infrared spectrogram of the I type SR-25990C that Fig. 1 makes for embodiment 1;
The X-ray powder diffraction figure of the I type SR-25990C that Fig. 2 makes for embodiment 1.
Embodiment
Further explain the present invention below in conjunction with embodiment, but embodiment does not do any type of qualification to the present invention.
Embodiment 1
In the 100ml flask, drop into clopidogrel free alkali 0.536 gram, 5 milliliters of tetrahydrofuran (THF)s, be stirred to the solution clarification under-14 ℃, slowly the dropping massfraction is 98% the vitriol oil 0.165 gram, reacts 1-2 hour down at-14 ℃, slowly is warming up to 20 ℃, under this temperature, continued stirred crystallization 10-12 hour, after-filtration is finished in crystallization, with the tetrahydrofuran (THF) washing, drains as far as possible.Vacuum-drying filter cake 3～4 hours gets white powder solid 0.538 gram, is I type SR-25990C, yield 77%, crystal formation purity 100% (Fig. 1～2 show that the SR-25990C that makes is pure I type).
Embodiment 2
In the 100ml flask, drop into clopidogrel free alkali 0.551 gram, 5 milliliters of tetrahydrofuran (THF)s, be stirred to the solution clarification under-12 ℃, slowly the dropping massfraction is 98% the vitriol oil 0.175 gram, reacts 1-2 hour down at-12 ℃, slowly is warming up to 20 ℃, under this temperature, continued stirred crystallization 10-12 hour, after-filtration is finished in crystallization, with the tetrahydrofuran (THF) washing, drains as far as possible.Vacuum-drying filter cake 3～4 hours gets white powder solid 0.521 gram, is I type SR-25990C, yield 73%, crystal formation purity 100%.
Embodiment 3
In the 100ml flask, drop into clopidogrel free alkali 0.502 gram, 5 milliliters of tetrahydrofuran (THF)s, be stirred to the solution clarification under 0 ℃, slowly the dropping massfraction is 98% the vitriol oil 0.166 gram, reacts 1-2 hour down at 0 ℃, slowly is warming up to 20 ℃, under this temperature, continued stirred crystallization 10-12 hour, after-filtration is finished in crystallization, with the tetrahydrofuran (THF) washing, drains as far as possible.Vacuum-drying filter cake 3～4 hours gets white powder solid 0.514 gram, is I type SR-25990C, yield 79%, crystal formation purity 100%.
Embodiment 4
In the 100ml flask, drop into clopidogrel free alkali 1.012 grams, 10 milliliters of tetrahydrofuran (THF)s, be stirred to the solution clarification under 0 ℃, slowly the dropping massfraction is 98% the vitriol oil 0.317 gram, reacts 1-2 hour down at 0 ℃, slowly is warming up to 20 ℃, under this temperature, continued stirred crystallization 10-12 hour, after-filtration is finished in crystallization, with the tetrahydrofuran (THF) washing, drains as far as possible.Vacuum-drying filter cake 3～4 hours gets white powder solid 1.045 grams, is I type SR-25990C, yield 79%, crystal formation purity 100%.
Embodiment 5
In the 100ml flask, drop into clopidogrel free alkali 1.04 grams, 10 milliliters of tetrahydrofuran (THF)s, be stirred to the solution clarification under 0 ℃, add 10 milligrams of crystal seeds, slow dropping massfraction is 98% the vitriol oil 0.312 gram in solution, reacted 1-2 hour down at 0 ℃, slowly be warming up to 35 ℃, continued stirred crystallization 10-12 hour under this temperature, after-filtration is finished in crystallization, with the tetrahydrofuran (THF) washing, drain as far as possible.Vacuum-drying filter cake 3～4 hours gets white powder solid 1.08 grams, is I type SR-25990C, yield 80%, crystal formation purity 100%.
Embodiment 6
In the 500ml flask, drop into clopidogrel free alkali 40 grams, 250 milliliters of tetrahydrofuran (THF)s, be stirred to the solution clarification under 0 ℃, add 0.4 gram crystal seed, slow dropping massfraction is 98% the vitriol oil 12 grams in solution, reacted 1-2 hour down at 0 ℃, slowly be warming up to 35 ℃, continued stirred crystallization 10-12 hour under this temperature, after-filtration is finished in crystallization, with the tetrahydrofuran (THF) washing, drain as far as possible.Vacuum-drying filter cake 3～4 hours gets white powder solid 41.7 grams, is I type SR-25990C, yield 80%, crystal formation purity 100%.
Claims (6)
1. the preparation method of an I type SR-25990C is characterized in that comprising the steps: that (1) is dissolved in clopidogrel free alkali in the tetrahydrofuran (THF), adds the vitriol oil down at-14～0 ℃; (2) with after the said mixture reaction 1～2 hour, reaction is continued in temperature of reaction to 20～40 ℃ of slowly raising, and crystal is fully separated out; (3) obtain crystal after, filter, use the tetrahydrofuran (THF) washing leaching cake, drain, vacuum-drying obtains I type SR-25990C.
2. according to the preparation method of the described I type of claim 1 SR-25990C, the massfraction that it is characterized in that the vitriol oil described in the step (1) is 98%.
3. according to the preparation method of the described I type of claim 1 SR-25990C, it is characterized in that the mol ratio of the adding clopidogrel free alkali described in the step (1) and the vitriol oil is 1: 0.98～1: 1.20.
4. according to the preparation method of the described I type of claim 1 SR-25990C, it is characterized in that in the described step (2) that behind elevated temperature to 20～40 ℃, the time of continuing reaction is more than 10 hours.
5. according to the preparation method of the described I type of claim 1 SR-25990C, it is characterized in that the number of times with the tetrahydrofuran (THF) washing leaching cake is 2～3 times described in the step (3).
6. according to the preparation method of the described I type of claim 1 SR-25990C, it is characterized in that the vacuum drying time is 3～4h described in the step (3).
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN102924474A (en) * | 2012-11-08 | 2013-02-13 | 浙江海翔药业股份有限公司 | Preparation method of crystal form I of clopidogrel hydrogen sulfate |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030114479A1 (en) * | 2001-12-18 | 2003-06-19 | Revital Lifshitz-Liron | Novel crystal forms III, IV, V, and novel amorphous form of clopidogrel hydrogensulfate, processes for their preparation, processes for the preparation of form I, compositions containing the new forms and methods of administering the new forms |
| CN101100471A (en) * | 2007-07-09 | 2008-01-09 | 浙江九洲药业股份有限公司 | Method for preparing (+)-(S-)-clopidogrel hydrosulfate high melting point crystal I |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030114479A1 (en) * | 2001-12-18 | 2003-06-19 | Revital Lifshitz-Liron | Novel crystal forms III, IV, V, and novel amorphous form of clopidogrel hydrogensulfate, processes for their preparation, processes for the preparation of form I, compositions containing the new forms and methods of administering the new forms |
| CN101100471A (en) * | 2007-07-09 | 2008-01-09 | 浙江九洲药业股份有限公司 | Method for preparing (+)-(S-)-clopidogrel hydrosulfate high melting point crystal I |
Non-Patent Citations (1)
| Title |
|---|
| 《精细化工》 20061231 潘仙华等 Ⅰ型氯吡格雷硫酸氢盐的合成及晶型转换 1221-1226 1-6 第23卷, 第12期 2 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN102924474A (en) * | 2012-11-08 | 2013-02-13 | 浙江海翔药业股份有限公司 | Preparation method of crystal form I of clopidogrel hydrogen sulfate |
| CN102924474B (en) * | 2012-11-08 | 2015-04-01 | 浙江海翔药业股份有限公司 | Preparation method of crystal form I of clopidogrel hydrogen sulfate |
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| CN101805354B (en) | 2012-05-30 |
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