CN104557969A - Production technique of clopidogrel hydrogen sulfate - Google Patents

Production technique of clopidogrel hydrogen sulfate Download PDF

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Publication number
CN104557969A
CN104557969A CN201410700458.8A CN201410700458A CN104557969A CN 104557969 A CN104557969 A CN 104557969A CN 201410700458 A CN201410700458 A CN 201410700458A CN 104557969 A CN104557969 A CN 104557969A
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add
organic layer
clopidogrel
reactor
purified water
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周如国
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ANHUI YOUCARE KAIYUE PHARMACEUTICAL Co Ltd
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ANHUI YOUCARE KAIYUE PHARMACEUTICAL Co Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04Ortho-condensed systems

Abstract

The invention relates to a production technique of clopidogrel hydrogen sulfate, which comprises the following steps: (1) preparation of amide hydrochloride, (2) preparation of levo-camphorsulfonate, (3) preparation of clopidogrel hydrogen sulfate crude product and (4) preparation of I-type clopidogrel hydrogen sulfate. The technique is simple, reduces the synthesis steps, lowers the consumption of toxic solvents, enhances the drug safety, facilitates the recovery and treatment of the waste liquid and lowers the production cost. The purity of the clopidogrel hydrogen sulfate obtained by the method is high, and the yield is 6.5% higher than other methods.

Description

A kind of production technique of bisulfate clopidogrel
Technical field
The invention belongs to the field of chemical synthesis, be specifically related to a kind of production technique of bisulfate clopidogrel.
Background technology
Bisulfate clopidogrel is a kind of novel medicament for resisting platelet aggregation being similar to thiophene chloropyridine, research and develop successfully by French Sai Nuofei-Sheng Delabao company, being applicable to prevention and therapy because of thrombocyte height assembles the heart, brain and other arterial circulation disorder diseases that cause, as cerebral apoplexy, the myocardial infarction of showing effect in the recent period with make a definite diagnosis the patient of peripheral arterial disease.At present in the U.S., Europe and China in interior a lot of national widespread use.This product suppresses platelet activation by suppressing adenosine diphosphate (ADP) ester (ADP) approach, thus anticoagulant.Need a couple of days because bisulfate clopidogrel reaches effective blood drug concentration, therefore be not suitable for emergency treatment.This product of stopping using is after 7 ~ 10 days, and platelet function can return to standard state.The complex process during synthesis of present bisulfate clopidogrel, and in building-up process, solvent etc. is not easily separated, causes the cost of medicine to improve.
Summary of the invention
The object of this invention is to provide a kind of production technique of bisulfate clopidogrel, this technique is simple, decreases the step of synthesis, and reduces the usage quantity of noxious solvent, improve drug safety, the production cost also reduced.
The present invention is achieved through the following technical solutions:
A production technique for bisulfate clopidogrel, comprises the following steps:
(1), the preparation of aminate hydrochloride,
In reactor, add O-chlorobenzene glycine methyl ester tartrate 4kg, methylene dichloride 12L, purified water 4kg, lowering the temperature less than T=20 DEG C drips ammoniacal liquor and regulates PH=10, stirring at normal temperature half an hour; Extracting and demixing, water layer methylene dichloride 4L extracting twice, organic layer 16L purified water washs 1 time, 2.7kg anhydrous sodium sulfate drying 2h, suction filtration, and concentrating under reduced pressure obtains O-chlorobenzene glycine methyl ester 2.2kg;
Then in reactor, O-chlorobenzene glycine methyl ester 2.2kg, acetonitrile 12.3L, thiophene ethanol p-toluenesulfonic esters 3.8kg is added, sodium bicarbonate 2.95kg, stir, heat up, temperature control 50 DEG C reaction 15 hours, suction filtration when being cooled to 25 DEG C, filtrate concentrates, add 26L acetic acid ethyl dissolution completely after, add 50% salt solution 12.7L and wash; Layering, organic layer adds 8.7L purified water, stirs, and temperature control less than 10 DEG C drips the 25%HCL of 4L, and separate out the faint yellow or muddy retrogradation of off-white color solids liq, stirring at normal temperature 2 hours, suction filtration obtains aminate hydrochloride;
(2), the preparation of l-camphor sulfonic acid salt
Add aminate thing hydrochloride 2.95kg, 8.85kg formaldehyde solution to reactor, be warming up to 35 DEG C, react 2 hours, reacted rear cooling room temperature, added 23.9kg methylene dichloride, temperature control 20 DEG C drips ammoniacal liquor, regulate pH=10, layering, water layer 7.5kg dichloromethane extraction twice, merges organic layer, organic phase is washed once by 20kg purified water, release lower organic layer 3.9kg anhydrous sodium sulfate drying 2h, suction filtration, concentrating under reduced pressure obtains clopidogrel free alkali crude product; Then in the reactor of 50L, add clopidogrel free alkali crude product 2.7Kg and acetone 18L, stirring and dissolving, add l-camphor sulfonic acid 1.9Kg, dissolution of solid, about slowly separate out white solid half an hour, stir 1 hour; Then filter, obtain off-white color solid, pull an oar once with acetone, filter, use acetone drip washing, obtain white l-camphor sulfonic acid salt solid, 45-50 vacuum-drying 5h;
(3), the preparation of bisulfate clopidogrel crude product
Above-mentioned obtained l-camphor sulfonic acid salt solid 3.8kg is added in reactor, add 28kg methylene dichloride and 15kg purified water again, lower the temperature less than 0 DEG C and drip saturated sodium carbonate solution, regulate pH value to be 9, layering, with 9kg dichloromethane extraction water layer twice, merge organic layer, purify with 20kg and wash organic layer, organic layer 4.6kg anhydrous sodium sulfate drying 3h after separatory, filter, less than 40 DEG C concentrating under reduced pressure obtain clopidogrel free alkali; In reactor, add above-mentioned clopidogrel free alkali 2.2kg and acetone 18kg, stirring and dissolving lowers the temperature less than 5 DEG C, drips vitriol oil 690g, dropwises naturally to be warmed up to about 25 DEG C afterwards, slowly separates out off-white color solid; Stir 3 hours ,filter, 45 DEG C of dry 2h obtain bisulfate clopidogrel crude product;
(4), the preparation of I type bisulfate clopidogrel
2.3kg bisulfate clopidogrel is added in reactor, add 16kg methylene dichloride and 11kg purified water again, lower the temperature less than 15 DEG C and drip saturated sodium carbonate solution, adjust ph is 10, stratification, then separatory extraction, water layer methylene dichloride 8kg*2 extracts 2 times, merges organic layer, organic layer 15kg purified water is washed once, then organic layer 1kg anhydrous magnesium sulfate drying 3h, filters, and filtrate concentrates to obtain refining clopidogrel free alkali; In the reactor of drying, add clopidogrel free alkali 1.6kg, ethyl acetate 48L, stirring and dissolving, regulation system temperature to 30 DEG C, mixing speed is adjusted to 25 revs/min, slowly drips vitriol oil 500g, within 2 hours, dropwises, be incubated at 55 DEG C, continues stirring 6 hours ,suction filtration, a small amount of ethyl acetate drip washing secondary of filter cake, then 50 DEG C, dry 12h under-0.095 Mpa, obtain I type hydrogen sulfate chlorine pyrrole lattice.
Beneficial effect of the present invention: technique of the present invention is simple, decrease the step of synthesis, and reduce the usage quantity of noxious solvent, improve drug safety, facilitate recovery and the process of waste liquid, also the production cost reduced, the bisulfate clopidogrel purity using present method to obtain is high, and productive rate also improves 6.5% than additive method.
Accompanying drawing explanation
Fig. 1 is present invention process schema.
Embodiment
The first step: the preparation of aminate hydrochloride
1.1 O-chlorobenzene glycine methyl ester preparations
Name of material Charging capacity Reagent specification Material effect
O-chlorobenzene glycine methyl ester tartrate 4kg Inner quality standard Starting material, obtains O-chlorobenzene glycine methyl ester after separating salt
Methylene dichloride 12L+4L*2=20L(26.5kg) Industry Reaction solvent, dissolves O-chlorobenzene glycine methyl ester
Ammoniacal liquor 4kg Industry Adjust ph, dissolves O-chlorobenzene glycine methyl ester under alkaline environment
Purified water 16L Self-control Dissolve O-chlorobenzene glycine methyl ester tartrate
Anhydrous sodium sulphate 2.7kg Industry Siccative
Table 1
The effect of the raw material that table 1 is prepared for O-chlorobenzene glycine methyl ester and raw material.
Technique describes:
Reaction: add O-chlorobenzene glycine methyl ester tartrate 4kg in 50L reactor, methylene dichloride 12L, purified water 4kg, lower the temperature T=20 DEG C below dropping ammoniacal liquor adjustment PH=10, and stirring at normal temperature half an hour, repetition measurement ph is constant.
Aftertreatment: extracting and demixing, water layer methylene dichloride 4L extracting twice, organic layer 16L purified water washs 1 time.2.7kg anhydrous sodium sulfate drying 2h.Suction filtration, concentrating under reduced pressure obtains O-chlorobenzene glycine methyl ester 2.2kg.
The preparation of 1.2 aminate hydrochlorides
Name of material Charging capacity Reagent specification Material effect
O-chlorobenzene glycine methyl ester 2.2kg Self-control Reaction major ingredient, with thiophene ethanol p-toluenesulfonic esters generation condensation reaction
Acetonitrile 12.3L(9.7kg) Industry Reaction solvent
Sodium bicarbonate 2.95kg AR Catalyzer
Thiophene ethanol p-toluenesulfonic esters 3.8kg -- Reaction major ingredient
25%HCL 4L Industry Reaction major ingredient, becomes aminate hydrochloride
Ethyl acetate 26L(23.4kg) Industry Reaction solvent
50% salt solution 12.7L Self-control Organic layer washed by salt, washes away inorganic salt impurities, produces salting-out effect, contributes to layering; Reduce emulsification
Acetone 10L Industry Wash and starch hydrochloride, removing impurity
Purified water 8.7L Self-control Washing organic layer, removing inorganic salt
Table 2
Table 2 is the raw material of the preparation of aminate hydrochloride and the effect of raw material.
Technique describes:
Reaction: add O-chlorobenzene glycine methyl ester 2.2kg, acetonitrile 12.3L, thiophene ethanol p-toluenesulfonic esters 3.8kg, sodium bicarbonate 2.95kg in 50 L reactors, stirs, and heats up, temperature control 50 DEG C reaction 15 hours.TLC detection reaction (sherwood oil: ethyl acetate=5:1), starts aftertreatment after completion of the reaction.
Aftertreatment: suction filtration when being cooled to 25 DEG C, filtrate concentrates.Add 26L acetic acid ethyl dissolution completely after, add 50% salt solution 12.7L and wash.Layering, organic layer adds 8.7L purified water, stirs, and temperature control less than 10 DEG C drips the 25%HCL of 4L, separates out the faint yellow or muddy retrogradation of off-white color solids liq, stirring at normal temperature 2 hours.Suction filtration, acetone making beating (mass volume ratio 1:2), suction filtration, uses acetone drip washing, 50 DEG C of drying under reduced pressure 5h, obtains aminate hydrochloride 2.95kg.
[0013second step: the preparation of l-camphor sulfonic acid salt
2.1 clopidogrel free alkali preparations
Reaction: add aminate thing hydrochloride 2.95kg to 50 L reactors, add 8.85kg formaldehyde solution, be warming up to 35 DEG C, react 2 hours, TLC detection reaction (sherwood oil: ethyl acetate=5:1), starts aftertreatment after completion of the reaction.
Aftertreatment: cooling room temperature, adds 23.9kg methylene dichloride, and temperature control 20 DEG C drips ammoniacal liquor (about 6.5L), regulates pH=10, layering, water layer 7.5kg dichloromethane extraction twice.Merge organic layer, wash organic phase once by 20kg purified water, release lower organic layer 3.9kg anhydrous sodium sulfate drying 2h, suction filtration, concentrating under reduced pressure obtains clopidogrel free alkali crude product 2.74Kg.
The preparation of 2.2 l-camphor sulfonic acid salt
Name of material Charging capacity Reagent specification Material effect
Clopidogrel free alkali crude product 2.7Kg Self-control Upper step product, this walks major ingredient
Acetone 21.8kg AR Reaction solvent
L-camphor sulfonic acid 1.9Kg Inner quality standard Reaction major ingredient, splits free alkali
Table 4
Table 4 is the raw materials of l-camphor sulfonic acid salt and the effect of raw material.
Technique describes:
Reaction: add clopidogrel free alkali crude product 2.7Kg and acetone 18L in the reactor of 50L, stirring and dissolving, add l-camphor sulfonic acid 1.9Kg, dissolution of solid, about slowly separate out white solid half an hour; Stir 1 hour.Aftertreatment: filter, obtain off-white color solid, pulls an oar once more than two hours (quantity of solvent 1:2) with acetone, filters, uses acetone drip washing, obtain white l-camphor sulfonic acid salt solid, 45-50 vacuum-drying 5h; Weigh: 3.4kg.
3rd step: the preparation of bisulfate clopidogrel crude product
3.1 clopidogrel free alkali preparations
Name of material Charging capacity Reagent specification Material effect
L-camphor sulfonic acid salt 3.8kg Self-control Upper step product, this walks major ingredient
Methylene dichloride 28kg+9kg*2=46kg Industry Reaction solvent, dissolves clopidogrel free alkali
Purified water 35kg Self-control Dissolve camsilate, washing organic phase, removing inorganic salt
Anhydrous sodium sulphate 4.6kg Industry Siccative
Table 5
Table 5 is the effect of clopidogrel free alkali raw materials and raw material.
Technique describes:
Reaction: add refining l-camphor sulfonic acid salt solid 3.8kg in the reactor of 50L, add 28kg methylene dichloride and 15kg purified water, lower the temperature less than 0 DEG C and drip saturated sodium carbonate solution, regulates pH value to be 9.
Aftertreatment: layering, with 9kg dichloromethane extraction water layer twice, merges organic layer, and purify with 20kg and wash organic layer, organic layer 4.6kg anhydrous sodium sulfate drying 3h after separatory, filter, less than 40 DEG C concentrating under reduced pressure obtain clopidogrel free alkali 2.0kg.
The preparation of 3.2 bisulfate clopidogrel crude products
Name of material Charging capacity Reagent specification Material effect
Clopidogrel free alkali 2.2kg Self-control Reaction major ingredient
Acetone 18kg Industry Reaction solvent
The vitriol oil 690g AR Reaction major ingredient, becomes hydrosulfate
Table 6
Table 6 is the raw materials of bisulfate clopidogrel crude product and the effect of raw material.
Technique describes:
Reaction: add above-mentioned clopidogrel free alkali 2.2kg and acetone 18kg in the reactor of 50L, stirring and dissolving lowers the temperature less than 5 DEG C, drips vitriol oil 690g, dropwises naturally to be warmed up to about 25 DEG C afterwards, slowly separates out off-white color solid; Stir 3 hours.
Aftertreatment: filter, 45 DEG C of dry 2h obtain bisulfate clopidogrel 2.6kg
4th step: the preparation (turning brilliant) of I type bisulfate clopidogrel
4.1 bisulfate clopidogrel solution salt
Name of material Charging capacity Reagent specification Material effect
Bisulfate clopidogrel 2.3kg Self-control Upper step product, this walks major ingredient
Methylene dichloride 16kg+8kg*2=32kg Industry Reaction solvent, dissolves clopidogrel free alkali
Purified water 20L Self-control Separate salt, dissolve bisulfate clopidogrel; Washing organic phase, removing inorganic salt
Anhydrous magnesium sulfate 1kg Industry Siccative
Table 7
Table 7 is the raw material of bisulfate clopidogrel solution salt.
Technique describes:
Reaction: add in the reactor of 50L by 2.3kg bisulfate clopidogrel, add 16kg methylene dichloride and 11kg purified water, lower the temperature less than 15 DEG C and drip saturated sodium carbonate solution, adjust ph is 10, stratification.
Aftertreatment: separatory extracts, and water layer methylene dichloride 8kg*2 extracts 2 times, merges organic layer.Organic layer 15kg purified water is washed once, and organic layer 1kg anhydrous magnesium sulfate drying 3h filters, and filtrate is concentrated to obtain refining clopidogrel free alkali 1.76kg.
The preparation (turning brilliant) of 4.2 I type bisulfate clopidogrels
Name of material Charging capacity Reagent specification Material effect
Clopidogrel free alkali 1.6kg Self-control Reaction major ingredient
The vitriol oil 500g AR Reaction major ingredient, becomes hydrosulfate
Ethyl acetate 48L(43.3kg) Industry Reaction solvent
Table 8
Table 8 is the raw material of the preparation of I type bisulfate clopidogrel.
Technique describes:
Reaction: add clopidogrel free alkali 1.6kg, ethyl acetate 48L, stirring and dissolving in 100 L reactors of drying.System temperature to 30 DEG C, mixing speed is adjusted to 25 revs/min, slowly drips vitriol oil 500g, within 2 hours, dropwises, be incubated at 55 DEG C, continues stirring 6 hours (vitriol oil dropwises latter 6 hours and rotating speed is adjusted to 40 revs/min).
Aftertreatment: suction filtration or dry reaction solution with whizzer, a small amount of ethyl acetate drip washing secondary of filter cake.50 DEG C, dry 12h under-0.095 Mpa, obtains I type bisulfate clopidogrel 2.0kg.

Claims (1)

1. a production technique for bisulfate clopidogrel, is characterized in that, comprises the following steps:
(1), the preparation of aminate hydrochloride,
In reactor, add O-chlorobenzene glycine methyl ester tartrate 4kg, methylene dichloride 12L, purified water 4kg, lowering the temperature less than T=20 DEG C drips ammoniacal liquor and regulates PH=10, stirring at normal temperature half an hour; Extracting and demixing, water layer methylene dichloride 4L extracting twice, organic layer 16L purified water washs 1 time, 2.7kg anhydrous sodium sulfate drying 2h, suction filtration, and concentrating under reduced pressure obtains O-chlorobenzene glycine methyl ester 2.2kg;
Then in reactor, O-chlorobenzene glycine methyl ester 2.2kg, acetonitrile 12.3L, thiophene ethanol p-toluenesulfonic esters 3.8kg is added, sodium bicarbonate 2.95kg, stir, heat up, temperature control 50 DEG C reaction 15 hours, suction filtration when being cooled to 25 DEG C, filtrate concentrates, add 26L acetic acid ethyl dissolution completely after, add 50% salt solution 12.7L and wash; Layering, organic layer adds 8.7L purified water, stirs, and temperature control less than 10 DEG C drips the 25%HCL of 4L, and separate out the faint yellow or muddy retrogradation of off-white color solids liq, stirring at normal temperature 2 hours, suction filtration obtains aminate hydrochloride;
(2), the preparation of l-camphor sulfonic acid salt
Add aminate thing hydrochloride 2.95kg, 8.85kg formaldehyde solution to reactor, be warming up to 35 DEG C, react 2 hours, reacted rear cooling room temperature, added 23.9kg methylene dichloride, temperature control 20 DEG C drips ammoniacal liquor, regulate pH=10, layering, water layer 7.5kg dichloromethane extraction twice, merges organic layer, organic phase is washed once by 20kg purified water, release lower organic layer 3.9kg anhydrous sodium sulfate drying 2h, suction filtration, concentrating under reduced pressure obtains clopidogrel free alkali crude product; Then in the reactor of 50L, add clopidogrel free alkali crude product 2.7Kg and acetone 18L, stirring and dissolving, add l-camphor sulfonic acid 1.9Kg, dissolution of solid, about slowly separate out white solid half an hour, stir 1 hour; Then filter, obtain off-white color solid, pull an oar once with acetone, filter, use acetone drip washing, obtain white l-camphor sulfonic acid salt solid, 45-50 vacuum-drying 5h;
(3), the preparation of bisulfate clopidogrel crude product
Above-mentioned obtained l-camphor sulfonic acid salt solid 3.8kg is added in reactor, add 28kg methylene dichloride and 15kg purified water again, lower the temperature less than 0 DEG C and drip saturated sodium carbonate solution, regulate pH value to be 9, layering, with 9kg dichloromethane extraction water layer twice, merge organic layer, purify with 20kg and wash organic layer, organic layer 4.6kg anhydrous sodium sulfate drying 3h after separatory, filter, less than 40 DEG C concentrating under reduced pressure obtain clopidogrel free alkali; In reactor, add above-mentioned clopidogrel free alkali 2.2kg and acetone 18kg, stirring and dissolving lowers the temperature less than 5 DEG C, drips vitriol oil 690g, dropwises naturally to be warmed up to about 25 DEG C afterwards, slowly separates out off-white color solid; Stir 3 hours ,filter, 45 DEG C of dry 2h obtain bisulfate clopidogrel crude product;
(4), the preparation of I type bisulfate clopidogrel
2.3kg bisulfate clopidogrel is added in reactor, add 16kg methylene dichloride and 11kg purified water again, lower the temperature less than 15 DEG C and drip saturated sodium carbonate solution, adjust ph is 10, stratification, then separatory extraction, water layer methylene dichloride 8kg*2 extracts 2 times, merges organic layer, organic layer 15kg purified water is washed once, then organic layer 1kg anhydrous magnesium sulfate drying 3h, filters, and filtrate concentrates to obtain refining clopidogrel free alkali; In the reactor of drying, add clopidogrel free alkali 1.6kg, ethyl acetate 48L, stirring and dissolving, regulation system temperature to 30 DEG C, mixing speed is adjusted to 25 revs/min, slowly drips vitriol oil 500g, within 2 hours, dropwises, be incubated at 55 DEG C, continues stirring 6 hours ,suction filtration, a small amount of ethyl acetate drip washing secondary of filter cake, then 50 DEG C, dry 12h under-0.095 Mpa, obtain I type hydrogen sulfate chlorine pyrrole lattice.
CN201410700458.8A 2014-11-28 2014-11-28 Production technique of clopidogrel hydrogen sulfate Pending CN104557969A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109867684A (en) * 2017-12-01 2019-06-11 武汉武药制药有限公司 A kind of preparation method of II type bisulfate clopidogrel
CN109867685A (en) * 2017-12-01 2019-06-11 武汉武药制药有限公司 A kind of preparation method of bisulfate clopidogrel II type
CN110590805A (en) * 2019-09-11 2019-12-20 天方药业有限公司 Preparation method of high-purity II crystal form clopidogrel hydrogen sulfate
CN110776519A (en) * 2020-01-02 2020-02-11 湖南迪诺制药股份有限公司 Preparation method of clopidogrel hydrogen sulfate crystal form II

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1840533A (en) * 2006-01-18 2006-10-04 上海应用技术学院 Process for synthesizing I-clopidogrel hydrogen sulfate
CN1951940A (en) * 2005-10-21 2007-04-25 浙江华海药业股份有限公司 Plavix raceme resolution method
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

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1951940A (en) * 2005-10-21 2007-04-25 浙江华海药业股份有限公司 Plavix raceme resolution method
CN1840533A (en) * 2006-01-18 2006-10-04 上海应用技术学院 Process for synthesizing I-clopidogrel hydrogen sulfate
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

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109867684A (en) * 2017-12-01 2019-06-11 武汉武药制药有限公司 A kind of preparation method of II type bisulfate clopidogrel
CN109867685A (en) * 2017-12-01 2019-06-11 武汉武药制药有限公司 A kind of preparation method of bisulfate clopidogrel II type
CN110590805A (en) * 2019-09-11 2019-12-20 天方药业有限公司 Preparation method of high-purity II crystal form clopidogrel hydrogen sulfate
CN110776519A (en) * 2020-01-02 2020-02-11 湖南迪诺制药股份有限公司 Preparation method of clopidogrel hydrogen sulfate crystal form II

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Application publication date: 20150429