CN102260213A - Method for preparing tolvaptan - Google Patents
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- CN102260213A CN102260213A CN2011101450026A CN201110145002A CN102260213A CN 102260213 A CN102260213 A CN 102260213A CN 2011101450026 A CN2011101450026 A CN 2011101450026A CN 201110145002 A CN201110145002 A CN 201110145002A CN 102260213 A CN102260213 A CN 102260213A
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Abstract
The invention discloses a method for preparing tolvaptan. In the method, 7-chloro-1,2,3,4,5-tetrahydro-1H-1-benzo-aza-5-one is taken as a raw material and is subjected to four steps, namely reduction, silylating agent protection, amino acylation and deprotection to form the target product of tolvaptan. Compared with the prior art, the method has the advantages of novel design, high yield, low cost and the like; moreover, the method is safe and easy to implement and has industrial prospect.
Description
Technical field
The invention belongs to field of medicine and chemical technology, specifically, relate to a kind of preparation method of tolvaptan.
Background technology
Tolvaptan is the novel arginine vasopressin V of the non-peptide class of a kind of oral selectivity by the exploitation of Japan big tomb company
2Receptor antagonist.FDA in 2009 approval listing is used for the treatment of the hyponatremia (blood sodium＜125mg/L, perhaps symptom is slight) of the normal or Hypervolemia of recycle system Q volume of blood, comprises the patient of heart failure, liver cirrhosis and syndrome of inapropriate ADH.Its chemistry N-[4-[(7-chloro-2,3,4 by name, 5-tetrahydrochysene-5-hydroxyl-1H-1-benzo-aza
-1-yl) carbonyl]-the 3-aminomethyl phenyl]-the 2-methyl benzamide, shown in structural formula 1:
Structural formula 1
At present, the preparation technology of tolvaptan has following several:
Kazumi Kondo etc. have reported a kind of preparation technology of tolvaptan at Bioorg Med Chem 1999 among the 7:1743-1754, it is with 7-chloro-1,2,3,4-tetrahydro benzo azepine
-5-ketone is starting raw material, through with 2-methyl-4-nitrobenzoyl chloride acidylate, nitroreduction, with 2-methyl benzoyl chloride acidylate, restore carbonyl and become hydroxyl to obtain target product.Route is as follows:
This route is too high with platinum dioxide catalytic reduction carbonyl cost, and multistep relates to column chromatography purification, is unsuitable for suitability for industrialized production.In addition, since starting raw material 7-chloro-1,2,3,4-tetrahydro benzo azepine
-5-ketone price is higher relatively, through the prepared in reaction end product of four step yields lower (30%～50%), causes the tolvaptan cost to increase itself and 2-methyl-4-nitrobenzoyl chloride condensation cheap and easy to get.
Alejandro Cordero-Vargas etc. are at Bioorg Med Chem, 2006,14 (18): the synthetic method that discloses another kind of tolvaptan among the 6165-6173, with 4-chloroacetophenone base xanthate is starting raw material, after elder generation and the addition of vinyl pivaloyl chloride, obtain 5-pivaloyl oxygen base-7-chloro-1,2 through cyclization, oximate, rearrangement, the reduction of two steps, 3,4-tetrahydro benzo azepine
Again through with 2-methyl-4-nitrobenzoyl chloride acidylate, reduction, obtain target product with 2-methyl benzoyl chloride acidylate, hydrolysis.Route is as follows:
This route starting raw material market supply is minimum, and technology is loaded down with trivial details, and the production cycle is long, and yield is low, is unsuitable for suitability for industrialized production.
Yasuhiro Torisawa etc. are at Bioorg Med Chem, and 2007,17 (23): reported the method for synthetic tolvaptan under palladium catalysis among the 6455-6458, route is as follows:
This route raw material is easy to get, step is short, though yield can reach 75%, but the palladium and the triphenylphosphine that relate in the reaction are difficult to remove, cause product to need column chromatography purification, and introduce carboxyl, though have feasibility in the operation with carbon monoxide, but performance difficulty is not adopted in the production usually.
Therefore, it is of crucial importance to develop a kind of novel process of tolvaptan of real adaptation suitability for industrialized production.
Summary of the invention
The invention provides a kind of new preparation process of tolvaptan, have simple to operate, advantage such as yield is high, product purity is high and cost is low, is a kind of industrialized production process that is suitable for.
The object of the present invention is to provide a kind of new preparation process of tolvaptan.
In embodiment provided by the invention, the invention provides a kind of novel method for preparing tolvaptan, comprise the steps:
A): with 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
-5-ketone reduces with reductive agent, gets 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
-5-alcohol;
B): with trimethyl silicone hydride protective material protection 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
-5-alcohol gets intermediate compound I;
C): with 4-(2-toluyl amino)-2-methyl-phenylformic acid and R-C (O)-R ' reaction, get intermediate II, wherein, R-C (O)-R ' is acyl chlorides or acid anhydrides, be that R ' is chlorine or R-C (O)-O-, and R is selected from the tertiary butyl, trifluoromethyl, 4-trifluoromethyl benzenesulfonyl, oxyethyl group, isopropoxy, isobutoxy, tert.-butoxy; R in the intermediate II is selected from the tertiary butyl, trifluoromethyl, 4-trifluoromethyl benzenesulfonyl, oxyethyl group, isopropoxy, isobutoxy, tert.-butoxy;
D): the intermediate II that intermediate compound I that step b) is obtained and step c) obtain is reacted under alkaline condition, intermediate III, wherein, the definition of R such as step c) in the intermediate II;
E):, get tolvaptan with the intermediate III hydrolysis.
In one embodiment of the present invention, the intermediate II that intermediate compound I that step b) obtains and step c) obtain does not need purifying, is directly used in step d).
In one embodiment of the present invention, the intermediate III that step d) obtains need not purifying, is directly used in step e).
In one embodiment of the present invention, preferably, the described reductive agent of step a) is selected from NaBH
4, KBH
4, LiBH
4Or LiAlH
4, reaction solvent is a methyl alcohol.
In one embodiment of the present invention, preferably, the described trimethyl silicone hydride protective material of step b) is selected from trimethylchlorosilane, hexamethyldisilazane, N, two (TMS) ethanamides of O-or N, two (TMS)-2,2 of N-, the 2-trifluoroacetamide; Described trimethyl silicone hydride protective material and 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
The mol ratio of-5-alcohol is 1: 1～5, preferably, is 1: 1～2.5, and temperature of reaction is-10～0 ℃.
In one embodiment of the present invention, preferably, the described R-C of step c) (O)-R ' is selected from isobutyryl chloride, pivaloyl chloride, trifluoroacetic anhydride, Vinyl chloroformate, isopropyl chlorocarbonate, isobutyl chlorocarbonate, the special pentyl ester of chloroformic acid or 4-trifluoromethylbenzene sulphonic acid anhydride, most preferably, be selected from pivaloyl chloride, trifluoroacetic anhydride; Temperature of reaction is-15～0 ℃, is preferably-10～-5 ℃.
In one embodiment of the present invention, preferably, the described alkaline condition of step d) is meant at triethylamine, pyridine, N, N-diisopropylethylamine, sodium methylate, potassium ethylate, potassium tert.-butoxide or 1,8-diaza-bicyclo [5.4.0] 11 carbon-7-alkene exists down, most preferably, under triethylamine or sodium methylate existence condition, react.
In one embodiment of the present invention, preferably, step e) is reacted under sulfuric acid, hydrochloric acid, nitric acid or phosphoric acid existence condition, and temperature of reaction is-5～0 ℃.
In one embodiment of the present invention, preferably, step b), c) or the reaction solvent of step d) be acetonitrile, methylene dichloride, chloroform, N, a kind of or wherein any two kinds mixture in the dinethylformamide.
In a kind of preferred embodiment of the present invention, the invention provides a kind of novel method for preparing tolvaptan, comprise the steps:
A): with 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
-5-ketone gets 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza through sodium borohydride reduction
-5-alcohol;
B): with trimethylchlorosilane or hexamethyldisilazane protection 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
-5-alcohol gets intermediate compound I;
C): under-10～-5 ℃ of conditions, with 4-(2-toluyl amino)-2-methyl-phenylformic acid and pivaloyl chloride or trifluoroacetic acid anhydride reactant, get intermediate II, R is the tertiary butyl or trifluoromethyl in the intermediate II here;
D): with the intermediate II of the intermediate compound I of step b) gained and step c) gained under triethylamine or sodium methylate catalysis, react intermediate III, here, R is defined as the tertiary butyl or trifluoromethyl in the intermediate II;
E):, get tolvaptan with intermediate III hydrolysis in the presence of hydrochloric acid or sulfuric acid.
In a kind of embodiment preferred of the present invention, the intermediate II that intermediate compound I that step b) obtains and step c) obtain need not purifying, is directly used in step d).
In a kind of embodiment preferred of the present invention, the intermediate III that step d) obtains need not purifying, is directly used in step e).
Compared with prior art, the present invention has following beneficial effect: 1. yield height: the preparation technology of tolvaptan provided by the invention, and with starting raw material 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
-5-ketone meter, yield can reach 78%, improves a lot than prior art; 2. product purity height: after the silylating reagent protection, effectively avoided 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
The direct acidylate of-5-alcohol causes the generation of acylated hydroxy product, and the purity of gained tolvaptan finished product can reach more than 99.5%;
3. cost is low: starting raw material is after quantitative reduction, and each goes on foot intermediate and all need not purifying and can be directly used in the next step, makes the production cycle shorten greatly, production cost than commercially available product low～40%.
Embodiment
Specifically describe embodiment of the present invention by following examples, but the present invention is not limited by the following examples:
Embodiment 1:
In the dry reaction bottle, add 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
-5-ketone (providing) 195g by Jintan City dawn beautiful jade medical material company limited, methyl alcohol 1000ml.Stir molten clearly, add sodium borohydride 14g in 20 ℃, stirring reaction 30min, concentrating under reduced pressure is done.Add methylene dichloride 500ml, wash with water (2 * 200ml), anhydrous sodium sulfate drying, filter, concentrate 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
-5-alcohol crude product 189.6g.Yield 96%, purity＞98% directly carries out next step.
1HNMR(CDCl
3，400MHz)：δ1.76-2.05(m，4H)，2.97-3.09(m，3H)，3.60(s，1H)，4.71-4.72(s，1H)，6.65-6.67(d，J＝8.0Hz，1H)，7.02-7.04(d，J＝8.0Hz，1H)，7.26-7.29(s，1H)。
Silicon etherificate: in the dry reaction bottle, add 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
-5-alcohol 43g, methylene dichloride 200ml, potassium tert.-butoxide 25g.Stir also and cool to-5 ℃, drip the dichloromethane solution 100ml of trimethylchlorosilane 46g, in 0 ℃ of stirring reaction 3 hours.Add washing (2 * 50ml).After drying, filtration, concentrating under reduced pressure get 7-chloro-1-(trimethyl silicon based)-5-(trimethylsiloxy group)-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
Crude product 69.2g, yield 93% directly carries out next step.
Mix the preparation of acid anhydride: in the dry reaction bottle, add 4-(2-toluyl amino)-2-methyl-phenylformic acid 65g, methylene dichloride 350ml, N, dinethylformamide 10ml, pyridine 1ml.Stirring also is cooled to-10 ℃, drips the dichloromethane solution 50ml of pivaloyl chloride 35.3g.In-10 ℃ of reactions 2 hours, obtain the dichloromethane solution of 4-(2-toluyl amino)-2-tolyl acid trimethylacetic acid acid anhydride, low temperature (5 ℃) is preserved stand-by.
Linked reaction and deprotection: in the dry reaction bottle, add 7-chloro-1-(trimethyl silicon based)-5-(trimethylsiloxy group)-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
68.4g, methylene dichloride 50ml, triethylamine 30g.Stirring also is cooled to-5 ℃, and step resulting 4-(2-toluyl amino)-2-methyl-phenylformic acid trimethylacetic acid acid anhydride dichloromethane solution 400ml dripped complete stirring reaction 4 hours in the dropping.(2 * 200ml), back anhydrous sodium sulfate drying filters, and concentrates and obtains N-(4-(7-chloro-5-(trimethyl silicane alcoxyl base)-2,3,4,5-tetrahydrochysene-1H-benzo-aza to add washing
-1-carbonyl)-the 3-aminomethyl phenyl)-2-methyl benzamide crude product.Add the making beating of methyl alcohol 300ml heated and stirred, the cooling room temperature is filtered.Oven dry obtains N-(4-(7-chloro-5-(trimethyl silicane alcoxyl base)-2,3,4,5-tetrahydrochysene-1H-benzo-aza
-1-carbonyl)-the 3-aminomethyl phenyl)-2-methyl benzamide solid 83.5g, be directly used in the next step.
In the dry reaction bottle, add N-(4-(7-chloro-5-(trimethyl silicane alcoxyl base)-2,3,4,5-tetrahydrochysene-1H-benzo-aza
-1-carbonyl)-the 3-aminomethyl phenyl)-2-methyl benzamide solid 52.5g ,-5～0 ℃ of hydrochloric acid 500ml that adds 0.2N down is warming up to 40 ℃ and stirred 2 hours, filters, and obtains the tolvaptan crude product.Use methyl alcohol: the mixed solution recrystallization of water=4: 1 obtains tolvaptan 40g, yield 89%, purity 99.9%.mp：219.5-221.5℃(lit：220-221℃)。
1H?NMR(DMSO-d6)δ1.35-3.20(4H，m)，2.36(6H，m)，4.46-5.04(2H，m)，5.55-5.78(1H，m)，6.55-7.85(10H，m)，10.12-10.45(1H，m)；MS(ES)m/z?448.2。
The condition determination and the method for tolvaptan are as follows:
Chromatographic condition and system suitability: with octadecylsilane chemically bonded silica is weighting agent, (the 0.03mol potassium primary phosphate is dissolved in the 1000ml water with the 0.03Mol/L phosphate buffer salt, phosphoric acid adjust pH to 4.0)-acetonitrile (50: 50) is a moving phase, the detection wavelength is 230nm, flow velocity is 1.0ml/min, and main peak and the peak-to-peak resolution of adjacent impurity meet the requirements.
Assay method: get the about 25mg of this product, accurate claim surely, put in the 50ml measuring bottle, add that acetonitrile 5ml is ultrasonic to make dissolving, make the solution that contains 0.5mg among every 1ml approximately with the moving phase dilution, as need testing solution; Precision is measured need testing solution 20 μ l, injects liquid chromatograph, and the record color atlas is to 2.5 times of principal constituent peak retention time; Calculate main peak purity by area normalization method.
Embodiment 2:
In the dry reaction bottle, add 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
-5-ketone 195g, methyl alcohol 1000ml.Stir molten clearly, add sodium borohydride 18g in 20 ℃, stirring reaction 30min, concentrating under reduced pressure is done.Add methylene dichloride 500ml, washing (2 * 200ml), anhydrous sodium sulfate drying, filter, concentrate 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
-5-alcohol crude product 190.2g.Yield 96.3%, purity 98.6% is directly carried out next step.
Silicon etherificate: in the dry reaction bottle, add 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
-5-alcohol 43g, methylene dichloride 200ml, potassium tert.-butoxide 25g.Stir also and cool to-5 ℃, drip the dichloromethane solution 100ml of hexamethyldisilazane 32g, in 0 ℃ of stirring reaction 3 hours.Add washing (2 * 50ml).After drying, filtration, concentrating under reduced pressure get 7-chloro-1-(trimethyl silicon based)-5-(trimethylsiloxy group)-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
Crude product 70g, yield 94% directly carries out next step.
Mix the preparation of acid anhydride: in the dry reaction bottle, add 4-(2-toluyl amino)-2-methyl-phenylformic acid 65g, methylene dichloride 350ml, N, dinethylformamide 10ml, pyridine 1ml.Stirring also is cooled to-10 ℃, drips the dichloromethane solution 50ml of trifluoroacetic anhydride 35.3g.In-10 ℃ of reactions 2 hours, obtain the dichloromethane solution of 4-(2-toluyl amino)-2-tolyl acid trifluoroacetic anhydride, low temperature (5 ℃) is preserved stand-by.
Linked reaction and deprotection: in the dry reaction bottle, add 7-chloro-1-(trimethyl silicon based)-5-(trimethylsiloxy group)-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
68.4g, methylene dichloride 50ml, triethylamine 30g.Stirring also is cooled to-5 ℃, and step resulting 4-(2-toluyl amino)-2-tolyl acid trifluoroacetic anhydride dichloromethane solution 400ml dripped complete stirring reaction 4 hours in the dropping.(2 * 200ml), back anhydrous sodium sulfate drying filters, and concentrates and obtains N-(4-(7-chloro-5-(trimethyl silicane alcoxyl base)-2,3,4,5-tetrahydrochysene-1H-benzo-aza to add washing
-1-carbonyl)-the 3-aminomethyl phenyl)-2-methyl benzamide crude product.Add the making beating of methyl alcohol 300ml heated and stirred, the cooling room temperature is filtered.Oven dry obtains N-(4-(7-chloro-5-(trimethyl silicane alcoxyl base)-2,3,4,5-tetrahydrochysene-1H-benzo-aza
-1-carbonyl)-the 3-tolyl)-2-methylbenzene acid amides solid 83.5g, be directly used in the next step.
In the dry reaction bottle, add N-(4-(7-chloro-5-(trimethyl silicane alcoxyl base)-2,3,4,5-tetrahydrochysene-1H-benzo-aza
-1-carbonyl)-the 3-aminomethyl phenyl)-2-methyl benzamide solid 52.5g ,-5～0 ℃ of hydrochloric acid 500ml that adds 0.2N down is warming up to 40 ℃ and stirred 2 hours, filters, and obtains the tolvaptan crude product.Use methyl alcohol: the mixed solution recrystallization of water=4: 1 obtains tolvaptan 41g, yield 91.2%, purity 99.6%.(method for detecting purity and condition such as embodiment 1).
Claims (10)
1. a method for preparing tolvaptan comprises the steps:
A): with 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
-5-ketone reduces with reductive agent, gets 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
-5-alcohol;
B): with trimethyl silicone hydride protective material protection 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
-5-alcohol gets intermediate compound I;
C): with 4-(2-toluyl amino)-2-methyl-phenylformic acid and R-C (O)-R ' reaction, get intermediate II, wherein, R-C (O)-R ' is acyl chlorides or acid anhydrides, be that R ' is chlorine or R-C (O)-O-, and R is selected from the tertiary butyl, trifluoromethyl, 4-trifluoromethyl benzenesulfonyl, oxyethyl group, isopropoxy, isobutoxy, tert.-butoxy; R in the intermediate II is selected from the tertiary butyl, trifluoromethyl, 4-trifluoromethyl benzenesulfonyl, oxyethyl group, isopropoxy, isobutoxy, tert.-butoxy;
D): the intermediate II that intermediate compound I that step b) is obtained and step c) obtain is reacted under alkaline condition, intermediate III, wherein, the definition of R such as step c) in the intermediate II;
E):, get tolvaptan with the intermediate III hydrolysis.
2. method according to claim 1, wherein, the described reductive agent of step a) is selected from NaBH
4, KBH
4, LiBH
4Or LiAlH
4, reaction solvent is a methyl alcohol.
3. method according to claim 1, wherein, the described trimethyl silicone hydride protective material of step b) is selected from trimethylchlorosilane, hexamethyldisilazane, N, two (TMS) ethanamides of O-or N, two (TMS)-2,2 of N-, the 2-trifluoroacetamide; Described trimethyl silicone hydride protective material and 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
The mol ratio of-5-alcohol is 1: 1～5, and temperature of reaction is-10～0 ℃.
4. method according to claim 3, wherein, described trimethyl silicone hydride protective material of step b) and 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
The mol ratio of-5-alcohol is 1: 1～2.5.
5. method according to claim 1, wherein, the described R-C of step c) (O)-R ' is selected from isobutyryl chloride, pivaloyl chloride, trifluoroacetic anhydride, Vinyl chloroformate, isopropyl chlorocarbonate, isobutyl chlorocarbonate, the special pentyl ester of chloroformic acid or 4-trifluoromethylbenzene sulphonic acid anhydride; Temperature of reaction is-15～0 ℃.
6. method according to claim 5, wherein, the described R-C of step c) (O)-R ' is selected from pivaloyl chloride or trifluoroacetic anhydride; Temperature of reaction is-10～-5 ℃.
7. method according to claim 1, wherein, the described alkaline condition of step d) is meant at triethylamine, pyridine, N, N-diisopropylethylamine, sodium methylate, potassium ethylate, potassium tert.-butoxide or 1,8-diaza-bicyclo [5.4.0] 11 carbon-7-alkene exists down, most preferably, under triethylamine or sodium methylate existence condition, react.
8. method according to claim 1, wherein, step e) is reacted under sulfuric acid, hydrochloric acid, nitric acid or phosphoric acid existence condition, and temperature of reaction is-5～0 ℃.
9. method according to claim 1, wherein, step b), c) or the reaction of step d) in organic solvent, carry out, described organic solvent is acetonitrile, methylene dichloride, chloroform, N, a kind of or wherein any two kinds mixture in the dinethylformamide.
10. a novel method for preparing tolvaptan comprises the steps:
A): with 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
-5-ketone gets 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza through sodium borohydride reduction
-5-alcohol;
B): with trimethylchlorosilane or hexamethyldisilazane protection 7-chloro-2,3,4,5-tetrahydrochysene-1H-1-benzo-aza
-5-alcohol gets intermediate compound I;
C): under-10～-5 ℃ of conditions, with 4-(2-toluyl amino)-2-methyl-phenylformic acid and pivaloyl chloride or trifluoroacetic acid anhydride reactant, get intermediate II, R is the tertiary butyl or trifluoromethyl in the intermediate II here;
D): with the intermediate II of the intermediate compound I of step b) gained and step c) gained under triethylamine or sodium methylate catalysis, react intermediate III;
E):, get tolvaptan with intermediate III hydrolysis in the presence of hydrochloric acid or sulfuric acid
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| CN113277980A (en) * | 2021-04-27 | 2021-08-20 | 南京海纳医药科技股份有限公司 | Tolvaptan impurity and preparation method thereof |
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| CN104418803A (en) * | 2013-08-21 | 2015-03-18 | 上海天慈生物谷生物工程有限公司 | Preparation method of tolvaptan |
| CN110274966A (en) * | 2019-03-08 | 2019-09-24 | 常州市阳光药业有限公司 | Method in relation to substance in high effective liquid chromatography for measuring tolvaptan bulk pharmaceutical chemicals |
| CN110274966B (en) * | 2019-03-08 | 2022-01-18 | 常州市阳光药业有限公司 | Method for determining related substances in tolvaptan bulk drug by high performance liquid chromatography |
| CN113277980A (en) * | 2021-04-27 | 2021-08-20 | 南京海纳医药科技股份有限公司 | Tolvaptan impurity and preparation method thereof |
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| CN102260213B (en) | 2013-05-15 |
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