CN101812071A - Method for processing mother liquor obtained by splitting clopidogrel hydrogen sulfate intermediate - Google Patents
Method for processing mother liquor obtained by splitting clopidogrel hydrogen sulfate intermediate Download PDFInfo
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- CN101812071A CN101812071A CN 201010165902 CN201010165902A CN101812071A CN 101812071 A CN101812071 A CN 101812071A CN 201010165902 CN201010165902 CN 201010165902 CN 201010165902 A CN201010165902 A CN 201010165902A CN 101812071 A CN101812071 A CN 101812071A
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Abstract
The invention discloses a method for processing mother liquor obtained by splitting a clopidogrel hydrogen sulfate intermediate, comprising: taking the mother liquor obtained by splitting the clopidogrel hydrogen sulfate intermediate as a reactant; evaporating to remove solvent; then, dissolving with dichloromethane and water; adjusting pH value to 7.0-10.0 with alkaline matter aqueous solution for dissociating; standing for layering, taking an organic layer, concentrating the organic layer, and adding an organic solvent; taking a strong-alkaline matter as a catalyst for racemization reaction; and after the reaction ends, processing to obtain the raceme of the clopidogrel hydrogen sulfate intermediate, wherein the ratio of sinistrogyration to dextrorotation of the raceme is basically 1:1. The raceme obtained by the method of the invention can prepare the final product of clopidogrel hydrogen sulphate by being repeatedly split into salt. The method can convert raceme in splitting mother liquor into the product, thus greatly improving the product yield, lowering the production cost, well solving the environmental protection problem when the splitting mother liquor is treated, and obtaining obvious economic benefit and social benefit.
Description
One, technical field
The present invention relates to a kind of bisulfate clopidogrel [(2S)-2-(2-chloro-phenyl-)-2-(4,5,6,7-tetramethylene sulfide [3,2-c] and pyridine-5-yl) the methyl acetate dithionate] mother liquor processing method after intermediate splits, its method is after the remaining chiral isomer in fractionations back is carried out the racemization processing, to split again again, obtain the finished product through after the reaction treatment, belong to pharmaceutical chemistry technical field.
Two, background technology
Bisulfate clopidogrel (commodity Plavix, Chinese commodity Bo Liwei by name, structure is as shown in Equation 1) by the exploitation of French Sanofi-Avetnis company, this product at first went on the market in the U.S. in March, 1998, enter multinational markets such as Europe, Canada, Australia, Singapore subsequently, and in August calendar year 2001 at Chinese official listing.
Clopidogrel is thienopyridine adenosine diphosphate (ADP) (ADP) receptor antagonist, belong to oral pharmaceutical, can suppress biologically active pdgf efficiently, be at present unique at arterial thrombotic disease, the antiplatelet drug that carries out broad research and application as every field such as myocardium infarct, cerebral apoplexy and peripheral arterial ischemic diseases.
Show according to data, clopidogrel when treatment TIA disease, have effective, distinguishing feature such as untoward reaction is few, clopidogrel compare with ticlopidine except the blood clotting situation slightly poor and ticlopidine, other are as all being better than ticlopidine to aspect untoward reactions such as white cell, blood platelet disorders.Clopidogrel is as the antiplatelet drug of a new generation, in liver, become active metabolite through the cytochrome P bio-transformation, selectivity is the adp receptor on blocking platelet film surface irreversibly, making therewith, the Fibrinogen binding site of the platelet glycoprotein acceptor of acceptor phase coupling connection can not expose, thereby suppressed combining of Fibrinogen and glycoprotein receptor indirectly, thrombocyte can not further be assembled mutually, thereby the performance antiplatelet effects cascade behind this medicine platelet activation also capable of blocking simultaneously amplifies reaction, the platelet aggregation that suppresses non-ADP agonist induction, extensive clinical trial is verified curative effect and security.
About the synthesis technique to bisulfate clopidogrel, at present bibliographical information is to be main by following two circuits basically, and EP0420706 (Sanofi-Aventis) has mainly set forth the basic synthesis technique of clopidogrel, basically based on following synthetic route:
Synthetic line 1
This route is to be main raw material with the o-chlorobenzene glycine, through over-churning, fractionation, condensation, cyclization and salify, obtain bisulfate clopidogrel at last, this line cost is lower, reaction temperature and, shortcoming is that entire reaction period is very long, general facilities and the energy consumption employed are more, in addition, because the chiral purity that the tartrate fractionation obtains is lower, the mass ratio of final product is difficult to control.
In addition, US6495691 provides an other synthesis technique, is main raw material with thiophene pyridine hydrochloride and methyl alpha-bromo-2-chlorophenylacetate, through condensation and fractionation, obtains the finished product behind the salify.This circuit synthesis technique is simple, stable yield, and the good product quality that obtains, but cost is high slightly.The synthetic line See Figure:
Synthetic line 2
But, no matter be to adopt that circuit, all must be through splitting, according to present state of the art, about the multipotency to 30% (molar yield) of general resolution yield (chiral separation yield about 60%), mother liquor after the fractionation, except solvent recuperation was utilized, remaining DL thing can only be worked as waste product and be gone to burn.Caused production cost high like this, in addition, the processing of DL thing does not have better way except burning, and in today that environment protection more and more comes into one's own, we need find a kind of better treatment process to reduce the harm to environment.
Three, summary of the invention
The technical problem to be solved in the present invention is to provide a kind of clopidogrel intermediate to split the post-treating method of back mother liquor, the DL thing that is about to after bisulfate clopidogrel splits carries out the racemization processing, again the ratio of revolving is essentially 1: 1 DL thing about obtaining, and obtains the final product bisulfate clopidogrel then after repeating to split salify.Adopt this method, the DL thing that splits in the mother liquor can be converted into product, increased the yield of product greatly, reduce production costs, and solving the environmental issue that splits in the mother liquor processing well, economic benefit and social benefit are very obvious.
For solving the problems of the technologies described above, the present invention adopts following technical scheme:
The treatment process of a kind of bisulfate clopidogrel intermediate racemization, described method comprises: the mother liquor after splitting with the bisulfate clopidogrel intermediate is a reaction substrate, steam earlier and desolventize, after using methylene dichloride and water dissolution again, dissociate between aqueous solution adjusting pH to 7.0～10.0 with alkaline matter, get organic layer behind the standing demix, organic layer concentrates, add organic solvent then, with the strong alkaline substance is that catalyzer carries out racemization reaction, reaction finish after aftertreatment obtain about the ratio of revolving be essentially the racemic modification of 1: 1 bisulfate clopidogrel intermediate; It is one of following that described strong alkaline substance is selected from: sodium hydroxide, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium hydroxide, potassium methylate, potassium ethylate, potassium tert.-butoxide; Described organic solvent is selected from following alcohols a kind of or several combinations: C1～C4 arbitrarily, the ketone of C1～C4, the ester class of C1～C6.
Reaction substrate of the present invention can be the mother liquor after splitting through L-(+) tartrate suc as formula the O-chlorobenzene glycine methyl ester shown in (II) according to the structure that said synthesis route 1 makes, also can be that the structure that makes according to said synthesis route 2 is suc as formula the 2-shown in (III) (2-chloro-phenyl-)-2-(4,5,6,7-tetramethylene sulfide [3,2-c] and pyridine-5-yl) mother liquor after methyl acetate splits through l-camphor sulfonic acid;
The present invention's ratio of revolving about obtaining is reacted according to said synthesis route 1 or synthetic route 2, again with preparation the finished product bisulfate clopidogrel after being essentially 1: 1 the racemic modification of bisulfate clopidogrel intermediate.Technical scheme of the present invention recycles, and by repeatedly racemization processing, can improve the yield of the finished product greatly.
The present invention is 0.5～3: 1 in order to the methylene dichloride of solubilizing reaction substrate and the volume ratio of water preferably.
Among the present invention, free used alkaline matter is the alkaline matter commonly used in order to regulator solution pH value, as sodium hydroxide, potassium hydroxide, ammoniacal liquor, sodium bicarbonate, yellow soda ash etc.; The preferably free used alkaline matter of the present invention is sodium bicarbonate or yellow soda ash, more preferably yellow soda ash.
The present invention dissociates under the temperature condition below 10 ℃, is preferably 0～5 ℃.
The present invention can carry out some conventional processing to organic layer earlier, as required as drying, activated carbon decolorizing etc. before concentrating after free, separation obtain organic layer.
The used organic solvent of racemization of the present invention can be selected from following a kind of or several mixing arbitrarily: methyl alcohol, ethanol, propyl alcohol, ethyl acetate, methyl acetate, butylacetate, acetone, butanone are preferably methyl alcohol, ethyl acetate or acetone.
Strong alkaline substance particular methanol sodium of the present invention, sodium ethylate, potassium methylate or potassium ethylate, more preferably sodium methylate or potassium methylate.
Among the present invention, the bisulfate clopidogrel intermediate that contains in the described reaction substrate and the molar ratio of strong alkaline substance be recommended as 1: 0.3～and 2.0, preferred 1: 0.5～1.The form of the salt that the bisulfate clopidogrel intermediate forms with itself and resolving agent in the described reaction substrate exists, and the present invention calculates with the bisulfate clopidogrel intermediate when calculating feed ratio.
The temperature of racemization reaction of the present invention is that room temperature is to reflux temperature.The present invention can monitor reaction process by HPLC, when the dextral ratio in a left side reaches 1: 1 substantially, and stopped reaction.
Aftertreatment of the present invention can be adopted conventional post-processing step, as carrying out aftertreatment: gained reaction solution concentrating under reduced pressure solvent is extremely done according to following steps, the adding volume ratio is 0.5～3: 1 methylene dichloride and water dissolution, regulate pH value to 7.0～8.0 with dilute hydrochloric acid, layering, get the organic layer anhydrous sodium sulfate drying, underpressure distillation, the ratio of revolving is essentially the racemic modification of 1: 1 bisulfate clopidogrel intermediate about obtaining.
Compared to general process modification and environmental protection treatment, the DL thing that treatment process of the present invention will split in the mother liquor is converted into product, increased the yield of product greatly, the real realization turned waste into wealth, disposable processing can reduce the technology cost more than 25%, through repeatedly recycling, basically can reach the technological balance of racemization, total cost can reduce more than 50%, and, can thoroughly solve the environmental issue of handling about the fractionation mother liquor on the technology, remarkable economic efficiency and social benefit are arranged.
Four, specific embodiment
Following Example is to understand content of the present invention for better, but does not limit protection scope of the present invention with this.
Embodiment 1
Get fractionation mother liquor 100ml by synthetic line 1 preparation (contain O-chlorobenzene glycine methyl ester tartrate 25 grams, 0.067mol), 60 ℃ of evaporated under reduced pressure solvents, vacuum tightness≤-0.09mpa, get yellow oily liquid, the 60ml that adds methylene chloride, deionized water 30ml, ice-water bath is cooled to 0～5 ℃, drip saturated sodium bicarbonate solution to pH7.5～8.0, insulated and stirred 30 minutes, layering, collected organic layer, water layer 30ml dichloromethane extraction, water layer is used the 30ml dichloromethane extraction again, merges organic layer, add dry 1 hour of anhydrous magnesium sulfate 10 grams, the elimination anhydrous magnesium sulfate, the 15ml dichloromethane, filtrate adds 1 gram gac, stirred 2 hours under the room temperature, the elimination gac, 15ml dichloromethane, 60 ℃ of outer warm evaporated under reduced pressure solvents, vacuum tightness≤-0.09mpa, get little yellow oily liquid.Add anhydrous methanol 60ml, be warming up to backflow, add sodium methylate 1.73 gram (0.032mol) in another reaction flask, the dissolving of 10ml anhydrous methanol fully, the solution dropping funnel of packing into, splash into above-mentioned reaction solution, 10 minutes dropping time, insulated and stirred 8 hours, HPLC detection reaction terminal point, after reacting completely, concentrated solvent, room temperature during cooling adds the water of 50ml and the methylene dichloride of 100ml, be that 10% hydrochloric acid is regulated pH to 7.0～8.0 with mass concentration then, the dichloromethane extraction of 50ml is used in layering, water layer again, merges organic layer, anhydrous sodium sulfate drying, remove by filter siccative, concentrated filtrate obtains faint yellow oily thing and is racemization product 23.5g, about the ratio of revolving be that 47.7: 51.1 these products are operated according to normal process flow, finally obtain bisulfate clopidogrel.
Embodiment 2
The fractionation mother liquor 100ml that gets by synthetic line 1 preparation (contains O-chlorobenzene glycine methyl ester tartrate 25 grams, 0.067mol), 60 ℃ of evaporated under reduced pressure solvents, vacuum tightness≤-0.09mpa, get yellow oily liquid, the 60ml that adds methylene chloride, deionized water 30ml, ice-water bath are cooled to 0～5 ℃, drip saturated sodium carbonate solution to pH7.5～8.0, insulated and stirred 30 minutes, layering, collected organic layer, water layer is used the 30ml dichloromethane extraction again, merge organic layer, add dry 1 hour of anhydrous magnesium sulfate 10 grams, the elimination anhydrous magnesium sulfate, the 15ml dichloromethane, filtrate adds 1 gram gac, stirs 2 hours the elimination gac under the room temperature, the 15ml dichloromethane, 60 ℃ of outer warm evaporated under reduced pressure solvents, vacuum tightness≤-0.09mpa, get little yellow oily liquid.Add anhydrous methanol 60ml, be warming up to backflow, add potassium methylate 4.2 grams (0.06mol) in another reaction flask, the dissolving of 10ml anhydrous methanol fully, the solution dropping funnel of packing into, splash into above-mentioned reaction solution, 10 minutes dropping time, insulated and stirred 3 hours, HPLC detection reaction terminal point, after reacting completely, concentrated solvent, room temperature during cooling, add the water of 50ml and the methylene dichloride of 100ml, regulate pH to 7.0～8.0 with 10% hydrochloric acid then, layering, water layer is used the dichloromethane extraction of 50ml again, merge organic layer, anhydrous sodium sulfate drying removes by filter siccative, concentrated filtrate, obtain faint yellow oily thing and be racemization product 24g, about revolved ratio 49.6: 49.8, this product is operated according to normal process flow, finally obtains bisulfate clopidogrel.
Embodiment 3
Get fractionation mother liquor 100ml by synthetic line 2 preparation (contain camphorsulfonic acid clopidogrel 17.5 grams, 0.032mol, about the ratio of revolving be about 2: 8), 60 ℃ of evaporated under reduced pressure solvents, vacuum tightness≤-0.09mpa, get yellow oily liquid, 60ml adds methylene chloride, deionized water 50ml, ice-water bath are cooled to 0-5 ℃, drip saturated sodium bicarbonate solution to pH7.5-8.0, insulated and stirred 30 minutes, layering, collected organic layer, water layer 30ml dichloromethane extraction, water layer is used the 30ml dichloromethane extraction again, merge organic layer, add dry 1 hour of anhydrous magnesium sulfate 10 grams, the elimination anhydrous magnesium sulfate, the 15ml dichloromethane, filtrate adds 1 gram gac, stirs 2 hours the elimination gac under the room temperature, the 15ml dichloromethane, 60 ℃ of outer warm evaporated under reduced pressure solvents, vacuum tightness≤-0.09mpa, get little yellow oily liquid.Add methyl alcohol 60ml, stirring at room adds 2 gram sodium hydroxide (0.05mol) in another reaction flask, the 20ml dissolve with methanol is complete, the solution dropping funnel of packing into splashes into above-mentioned reaction solution, 10 minutes dropping time, stirred 10 hours, HPLC detection reaction process, 60 ℃ of outer warm evaporated under reduced pressure solvents, the water of add methylene chloride 100ml and 50ml, dissolving fully, salt acid for adjusting pH value to 7.0～8.0 with 10%, layering, water layer is used the 50ml dichloromethane extraction again, merge organic layer, add dry 1 hour of anhydrous magnesium sulfate 5 grams, elimination anhydrous magnesium sulfate, 15ml dichloromethane, 60 ℃ of outer warm evaporated under reduced pressure solvents, vacuum tightness≤-0.09mpa, get little yellow oily liquid 13.7g, be the racemization product, about the ratio of revolving be about 49.3: 49.8, this product splits with l-camphor sulfonic acid again, obtain the finished product behind the sulfuric acid salify.
Embodiment 4
Get fractionation mother liquor 100ml by synthetic line 2 preparation (contain camphorsulfonic acid clopidogrel 17.5 grams, 0.032mol, about the ratio of revolving be about 2: 8), 60 ℃ of evaporated under reduced pressure solvents, vacuum tightness≤-0.09mpa, get yellow oily liquid, 60ml adds methylene chloride, deionized water 50ml, ice-water bath are cooled to 0-5 ℃, drip saturated sodium bicarbonate solution to pH7.5-8.0, insulated and stirred 30 minutes, layering, collected organic layer, water layer 30ml dichloromethane extraction, water layer is used the 30ml dichloromethane extraction again, merge organic layer, add dry 1 hour of anhydrous magnesium sulfate 10 grams, the elimination anhydrous magnesium sulfate, the 15ml dichloromethane, filtrate adds 1 gram gac, stirs 2 hours the elimination gac under the room temperature, the 15ml dichloromethane, 60 ℃ of outer warm evaporated under reduced pressure solvents, vacuum tightness≤-0.09mpa, get little yellow oily liquid.Add methyl alcohol 60ml, stirring at room adds 2.3 gram potassium hydroxide (0.032mol) in another reaction flask, the 20ml dissolve with methanol is complete, the solution dropping funnel of packing into splashes into above-mentioned reaction solution, 10 minutes dropping time, stir HPLC detection after 3 hours, after the reaction substantially fully, 60 ℃ of outer warm evaporated under reduced pressure solvents, the water of add methylene chloride 100ml and 50ml, dissolving fully, salt acid for adjusting pH value to 7.0～8.0 with 10%, layering, water layer is used the 50ml dichloromethane extraction again, merge organic layer, add dry 1 hour of anhydrous magnesium sulfate 5 grams, elimination anhydrous magnesium sulfate, 15ml dichloromethane, 60 ℃ of outer warm evaporated under reduced pressure solvents, vacuum tightness≤-0.09mpa, get little yellow oily liquid 13.5g, be the racemization product, about the ratio of revolving be about 49.5: 49.8, this product splits with l-camphor sulfonic acid again, obtain the finished product behind the sulfuric acid salify.
Claims (10)
1. the mother liquor processing method after a bisulfate clopidogrel intermediate splits, described method comprises: the mother liquor after splitting with the bisulfate clopidogrel intermediate is a reaction substrate, steam earlier and desolventize, use methylene dichloride and water dissolution again, dissociate between aqueous solution adjusting pH to 7.0～10.0 with alkaline matter, standing demix is got organic layer, concentrate organic layer, add organic solvent then, with the strong alkaline substance is that catalyzer carries out racemization reaction, reaction finish after aftertreatment obtain about the ratio of revolving be essentially the racemic modification of 1: 1 bisulfate clopidogrel intermediate; It is one of following that described strong alkaline substance is selected from: sodium hydroxide, sodium methylate, sodium ethylate, sodium tert-butoxide, potassium hydroxide, potassium methylate, potassium ethylate, potassium tert.-butoxide; Described organic solvent is selected from following alcohols a kind of or several combinations: C1～C4 arbitrarily, the ketone of C1～C4, the ester class of C1～C6.
2. the mother liquor processing method after bisulfate clopidogrel intermediate as claimed in claim 1 splits, mother liquor after it is characterized in that described reaction substrate to be structure suc as formula the O-chlorobenzene glycine methyl ester shown in (II) splitting through L-(+) tartrate or structure are suc as formula the 2-shown in (III) (2-chloro-phenyl-)-2-(4,5,6,7-tetramethylene sulfide [3,2-c] and pyridine-5-yl) mother liquor after methyl acetate splits through l-camphor sulfonic acid;
3. as the mother liquor processing method after claims 1 or the 2 described bisulfate clopidogrel intermediates fractionations, it is characterized in that described organic solvent is selected from following a kind of or several combination arbitrarily: methyl alcohol, ethanol, propyl alcohol, ethyl acetate, methyl acetate, butylacetate, acetone, butanone.
4. the mother liquor processing method after bisulfate clopidogrel intermediate as claimed in claim 1 or 2 splits is characterized in that free used alkaline matter is sodium hydroxide, potassium hydroxide, ammoniacal liquor, sodium bicarbonate or yellow soda ash.
5. the mother liquor processing method after bisulfate clopidogrel intermediate as claimed in claim 1 or 2 splits is characterized in that described strong alkaline substance is selected from sodium methylate, sodium ethylate, potassium methylate or potassium ethylate.
6. the mother liquor processing method after bisulfate clopidogrel intermediate as claimed in claim 1 or 2 splits is characterized in that the bisulfate clopidogrel intermediate that contains in the described reaction substrate and the molar ratio of strong alkaline substance are 1: 0.3～2.0.
7. the mother liquor processing method after bisulfate clopidogrel intermediate as claimed in claim 1 or 2 splits, the volume ratio that it is characterized in that being used for dissolved methylene dichloride and water is 0.5～3: 1.
8. the mother liquor processing method after bisulfate clopidogrel intermediate as claimed in claim 1 or 2 splits is characterized in that carrying out under the described temperature condition that is free in below 10 ℃.
9. the mother liquor processing method after bisulfate clopidogrel intermediate as claimed in claim 1 or 2 splits, the temperature that it is characterized in that described racemization reaction is that room temperature is to reflux temperature.
10. the mother liquor processing method after bisulfate clopidogrel intermediate as claimed in claim 1 or 2 splits, it is characterized in that described aftertreatment employing following steps: gained reaction solution concentrating under reduced pressure solvent is extremely done, adding volume ratio and be 0.5～3: 1 methylene dichloride and water dissolves, regulate pH value to 7.0～8.0 with dilute hydrochloric acid, layering, the organic layer anhydrous sodium sulfate drying, underpressure distillation, the ratio of revolving is essentially the racemic modification of 1: 1 bisulfate clopidogrel intermediate about obtaining.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108069855A (en) * | 2016-11-18 | 2018-05-25 | 鲁南制药集团股份有限公司 | A kind of recoverying and utilizing method of S- o-chloromandelic acids |
| CN110627808A (en) * | 2018-06-21 | 2019-12-31 | 江苏同禾药业有限公司 | Recovery treatment process of clopidogrel hydrogen sulfate splitting mother liquor |
| CN113593718A (en) * | 2021-07-29 | 2021-11-02 | 复旦大学附属中山医院 | Model for predicting clopidogrel antiplatelet effect and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0099802A1 (en) * | 1982-07-13 | 1984-02-01 | Elf Sanofi | Thieno(3,2-c) pyridine derivatives, process for their preparation and their therapeutical use |
| CN1487943A (en) * | 2001-01-24 | 2004-04-07 | Process for preparing clopidogrel | |
| CN100999525A (en) * | 2006-10-18 | 2007-07-18 | 深圳信立泰药业有限公司 | Preparation process of clopidogre and its salt |
-
2010
- 2010-05-10 CN CN 201010165902 patent/CN101812071A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0099802A1 (en) * | 1982-07-13 | 1984-02-01 | Elf Sanofi | Thieno(3,2-c) pyridine derivatives, process for their preparation and their therapeutical use |
| CN1487943A (en) * | 2001-01-24 | 2004-04-07 | Process for preparing clopidogrel | |
| CN100999525A (en) * | 2006-10-18 | 2007-07-18 | 深圳信立泰药业有限公司 | Preparation process of clopidogre and its salt |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108069855A (en) * | 2016-11-18 | 2018-05-25 | 鲁南制药集团股份有限公司 | A kind of recoverying and utilizing method of S- o-chloromandelic acids |
| CN108069855B (en) * | 2016-11-18 | 2021-02-02 | 鲁南制药集团股份有限公司 | Method for recycling S-o-chloromandelic acid |
| CN110627808A (en) * | 2018-06-21 | 2019-12-31 | 江苏同禾药业有限公司 | Recovery treatment process of clopidogrel hydrogen sulfate splitting mother liquor |
| CN110627808B (en) * | 2018-06-21 | 2022-04-01 | 江苏同禾药业有限公司 | Recovery treatment process of clopidogrel hydrogen sulfate splitting mother liquor |
| CN113593718A (en) * | 2021-07-29 | 2021-11-02 | 复旦大学附属中山医院 | Model for predicting clopidogrel antiplatelet effect and application thereof |
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Open date: 20100825 |