CN108997236B - Preparation method of anastrozole impurity - Google Patents
Preparation method of anastrozole impurity Download PDFInfo
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- CN108997236B CN108997236B CN201810855358.0A CN201810855358A CN108997236B CN 108997236 B CN108997236 B CN 108997236B CN 201810855358 A CN201810855358 A CN 201810855358A CN 108997236 B CN108997236 B CN 108997236B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
Abstract
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of anastrozole impurities. The invention takes 5-methyl-1, 3-benzene diacetonitrile as raw material, and obtains anastrozole impurity through methylation reaction, substitution reaction, N-halogenated succinimide free radical reaction and nucleophilic substitution reaction: the invention discloses a preparation method of 2, 3-bis (3- (1-cyano-1-methylethyl) -5- (1H-1,2, 4-triazole-1-methyl) phenyl) -2-methylpropanenitrile, and the preparation method has the characteristics of short synthetic route, simple and convenient operation, high purity of the obtained product, convenience for reference substance research and the like. The preparation method has great significance for researching the impurities of the anastrozole, and can be used for qualitative and quantitative analysis of the impurities in the anastrozole production, so that the quality standard of the anastrozole is improved, and important guiding significance is provided for safe medication.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of anastrozole impurities.
Background
Anastrozole, of the formula:
anastrozole, a potent selective non-steroidal aromatase inhibitor, is used primarily for first-line treatment of advanced breast cancer in postmenopausal women, and also in advanced breast cancer in postmenopausal women that remains uncontrollable by tamoxifen and other antiestrogen therapy, by significantly reducing the concentration of estradiol in the serum, which can reduce tumor volume or delay tumor growth.
The european pharmacopoeia reports an impurity of anastrozole, 2, 3-bis (3- (1-cyano-1-methylethyl) -5- (1H-1,2, 4-triazole-1-methyl) phenyl) -2-methylpropanenitrile, having the formula I:
the method has great significance for researching the impurities of the anastrozole, and can be used for qualitative and quantitative analysis of the impurities in the anastrozole production, so that the quality standard of the anastrozole is improved, and important guiding significance is provided for safe medication.
At present, no relevant report discloses a preparation method of 2, 3-bis (3- (1-cyano-1-methylethyl) -5- (1H-1,2, 4-triazole-1-methyl) phenyl) -2-methylpropanenitrile, and in order to better control the quality of anastrozole products and ensure the medication safety of anastrozole, a method for verifying the impurities of anastrozole south is needed, so that a synthesis process of the impurities needs to be deeply researched.
Disclosure of Invention
In view of the above, the invention aims to provide a preparation method of anastrozole impurities, which has the characteristics of short synthetic route, simple and convenient operation, high purity of the obtained product, convenience for reference substance research and the like, and has great significance for quality control and impurity research of anastrozole.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a process for the preparation of a compound of formula I, comprising the steps of:
1) reacting the compound of the formula II with a methyl substitution reagent in the presence of a solvent and a catalyst to obtain a compound of a formula III;
2) carrying out substitution reaction on a compound shown in a formula III and a compound shown in a formula IV in the presence of a solvent and a catalyst to obtain a compound shown in a formula V;
3) carrying out free radical substitution reaction on the compound of the formula V and N-halogenated succinimide in the presence of a solvent and a catalyst to obtain a compound of a formula VI;
4) nucleophilic substitution reaction is carried out on the compound in the formula VI and 1,2, 4-triazole sodium in the presence of a solvent to obtain the compound in the formula I.
The compound of the formula I prepared by the invention is 2, 3-bis (3- (1-cyano-1-methylethyl) -5- (1H-1,2, 4-triazole-1-methyl) phenyl) -2-methylpropanenitrile, one impurity of anastrozole is reported in European pharmacopoeia, the research significance on the impurity of anastrozole is quite important, and the compound can be used for qualitative and quantitative analysis of the impurity in anastrozole production, so that the quality standard of anastrozole is improved, and the important guiding significance is provided for safe medication. At present, no relevant report discloses a preparation method of the impurity, and the invention fills the blank.
In the above reaction scheme, the compound of formula II is 5-methyl-1, 3-benzenediacetonitrile, the compound of formula III is 2- [3- (1-cyanoethyl) -5-methylphenyl ] -2-methylpropanenitrile, the compound of formula IV is 2- (3-bromomethyl-5-methylphenyl) -2-methylpropanenitrile, the compound of formula V is 2, 3-bis (3- (1-cyano-1-methylethyl) -5-methylphenyl) -2-methylpropanenitrile, and the compound of formula VI is 2, 3-bis (3- (1-cyano-1-methylethyl) -5- (bromomethyl) phenyl) -2-methylpropanenitrile.
The method takes 5-methyl-1, 3-benzene diacetonitrile as a raw material, obtains anastrozole impurities (the compound shown in the formula I) through methylation reaction, substitution reaction, N-halogenated succinimide free radical reaction and nucleophilic substitution reaction, and has the characteristics of short synthetic route, simple and convenient operation, high purity of the obtained product, convenience for reference substance research and the like.
Further, the methyl substitution reagent in the step 1) is one or more of methyl iodide, dimethyl sulfate, dimethyl carbonate and methyl bromide.
As a preference, the methyl-substitution reagent in step 1) is methyl iodide.
Further, the molar ratio of the compound II to the methyl substitution reagent in the step 1) is 1: 1.5-1: 4. A too high ratio tends to form tetrasubstituted methylated products VII.
Preferably, the molar ratio of compound II to methyl substitution reagent in step 1) is 1: 3.
Further, the molar ratio of the compound III to the compound IV in the step 2) is 1: 1-1: 1.5.
Preferably, the molar ratio of compound III to compound IV in step 2) is 1: 1.2.
Further, the solvent reacted in the step 1) and the step 2) is DMF, the catalyst is sodium hydride, and the reaction temperature is-10 ℃ to 25 ℃.
Preferably, the reaction temperature in the step 1) and the step 2) is 0 ℃ to 5 ℃.
Preferably, the purity of the intermediate III can be increased to 95% or more by column purification (n-hexane/ethyl acetate 15/1) after the reaction of step 1) and step 2) is completed.
Further, the N-halogenated succinimide in the step 3) is one or more of N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS) and N-iodosuccinimide (NIS); the molar ratio of the compound of formula V to the N-halogenated succinimide is 1:2 to 1: 2.4. A too high ratio tends to form tetrabrominated product.
As a preference, the N-halosuccinimide in step 3) is NBS.
Preferably, the molar ratio of the compound of formula V to NBS in step 3) is 1: 2.2.
Further, the solvent for the reaction in the step 3) is one or more of acetonitrile, carbon tetrachloride and chloroform.
As a preference, the solvent for the reaction in step 3) is acetonitrile.
Further, in the step 3), the reaction catalyst is one or more of azodiisobutyronitrile and benzoyl peroxide, and the reaction temperature is 50-81 ℃. The reaction is not easily initiated at too low a temperature.
Preferably, the reaction catalyst in step 3) is azobisisobutyronitrile.
As a preference, the reaction temperature in step 3) is 70 ℃.
Preferably, the purity of intermediate VI is increased by column chromatography (n-hexane/ethyl acetate 8/1) after the reaction of step 3).
Further, the molar ratio of the compound of formula VI in the step 4) to 1,2, 4-triazole sodium is 1: 1.2-1: 3.
Preferably, the molar ratio of the compound in the formula VI in the step 4) to the 1,2, 4-triazole sodium is 1:2.
Further, the solvent for the reaction in the step 4) is DMF, and the reaction temperature is-15 ℃ to 50 ℃.
Preferably, the reaction temperature is from 0 ℃ to 5 ℃.
Preferably, after the reaction of step 4) is completed, the compound of formula I is obtained by extraction, washing and column purification (first ethyl acetate and then ethyl acetate/methanol: 50/1) with a purity of 99% or more.
The invention has the beneficial effects that:
1) the preparation method of the known anastrozole impurities provided by the invention uses 5-methyl-1, 3-benzene diacetonitrile as a raw material, and obtains anastrozole impurities (a compound shown in a formula I) through methylation reaction, substitution reaction, N-halogenated succinimide free radical reaction and nucleophilic substitution reaction.
2) The invention discloses an impurity for preparing anastrozole for the first time: the method for preparing the compound of the formula I, namely the 2, 3-bis (3- (1-cyano-1-methylethyl) -5- (1H-1,2, 4-triazole-1-methyl) phenyl) -2-methylpropanenitrile, has great significance for researching impurities of anastrozole, and can be used for qualitative and quantitative analysis of the impurities in anastrozole production, so that the quality standard of anastrozole is improved, and important guiding significance is provided for safe medication.
Detailed Description
Hereinafter, preferred embodiments of the present invention will be described in detail. The experimental methods of the preferred embodiments, which do not indicate specific conditions, are generally performed according to conventional conditions, and the examples are given for better illustration of the present invention, but the present invention is not limited to the examples. Therefore, those skilled in the art should make insubstantial modifications and adaptations to the embodiments of the present invention in light of the above teachings and remain within the scope of the invention.
Example 1
The method comprises the following steps: preparation of 2- [3- (1-cyanoethyl) -5-methylphenyl ] -2-methylpropanenitrile (formula III)
To N2Adding 26.0g of 5-methyl-1, 3-benzene diacetonitrile and 260ml of DMF into a protected reaction flask, stirring, adding 65.0g of methyl iodide, and cooling to 0-5 ℃ in an ice water bath. Controlling the temperature to be 0-5 ℃, adding 14.6g of sodium hydride in batches, and keeping the temperature to be 0-5 ℃ after the addition is finished, and reacting for 0.5 h. Pouring the reaction solution into 800ml of water, extracting the reaction solution once by using 400ml of dichloromethane and extracting the reaction solution by using 200ml of dichloromethaneTaking once, combining organic phases, washing with drinking water 400ml multiplied by 3 times, evaporating the organic phases under reduced pressure, purifying by a column, and eluting: n-hexane/ethyl acetate 15/1, and the relatively pure eluent was collected and evaporated to dryness under reduced pressure to obtain an off-white solid 10.0g with a yield of 31.0%.
Step two: preparation of 2, 3-bis (3- (1-cyano-1-methylethyl) -5-methylphenyl) -2-methylpropanenitrile (formula V)
To N2To the protected reaction flask was added 7.5g of 2- [3- (1-cyanoethyl) -5-methylphenyl]And (3) -2-methyl propionitrile (formula III) and 150ml of DMF (dimethyl formamide), stirring, cooling to 0-5 ℃ in an ice water bath, adding 1.7g of sodium hydride, keeping the temperature at 0-5 ℃ for reaction for 15min after the addition is finished, adding 10.7g of the compound 2- (3-bromomethyl-5-methylphenyl) -2-methyl propionitrile of the formula IV into the system, and keeping the temperature at 0-5 ℃ for reaction until the reaction is finished. The reaction mixture was poured into 600ml of water and extracted with 600ml × 3 times of dichloromethane, the organic phases were combined, washed with 400ml × 3 times of saturated sodium chloride, evaporated to dryness under reduced pressure, purified by column chromatography (n-hexane/ethyl acetate ═ 5/1), the purer eluate was collected and evaporated to dryness under reduced pressure to give 10.8g of an off-white solid with a yield of 79.7%.
Step three: preparation of 2, 3-bis (3- (1-cyano-1-methylethyl) -5- (bromomethyl) phenyl) -2-methylpropanenitrile (formula VI)
To N26.0g of 2, 3-bis (3- (1-cyano-1-methylethyl) -5-methylphenyl) -2-methylpropionitrile (formula V), 120mg of azobisisobutyronitrile and 100ml of acetonitrile are added into a protected reaction flask, stirred and heated to 50-55 ℃, 1.5g of NBS is added, heated to 70 ℃, 4.5g of NBS is added, and the reaction is carried out at 70 ℃ with heat preservation till the end. Cooling to room temperature after the reaction is finished, adding 120ml of water and 120ml of dichloromethane, stirring, separating liquid, extracting the water phase once by using 120ml of dichloromethane, combining the organic phases, washing once by using 120ml of 10% sodium bisulfite, washing once by using 120ml of saturated sodium bicarbonate solution, washing once by using 120ml of water finally, evaporating the organic phase under reduced pressure, purifying by a column, and eluting by using an eluent: the pure product eluent was collected at 8/1 with n-hexane/ethyl acetate and evaporated to dryness under reduced pressure to give 5.6g of an off-white solid with a yield of 66.1%.
Step four: preparation of 2, 3-bis (3- (1-cyano-1-methylethyl) -5- (1H-1,2, 4-triazole-1-methyl) phenyl) -2-methylpropanenitrile (formula I)
To N2Adding 3.6g of 2, 3-bis (3- (1-cyano-1-methylethyl) -5- (bromomethyl) phenyl) -2-methylpropanenitrile (formula VI) and 54ml of DMF into a protected reaction bottle, stirring, cooling to 0-5 ℃ in an ice water bath, adding 1.2g of 1,2, 4-triazole sodium, and keeping the temperature at 0-5 ℃ after the addition is finished until the reaction is finished. Pouring the reaction solution into 300ml of water, extracting with 300ml of toluene for 3 times, combining organic phases, washing with 180ml of drinking water for 3 times, evaporating the organic phases under reduced pressure, purifying the organic phases by a column, eluting the eluent with ethyl acetate to remove impurities, eluting the product with ethyl acetate/methanol (50/1), collecting the eluent of the purer product, and evaporating the eluent under reduced pressure to dryness to obtain 1.6g of brown solid with the yield of 46.5% and the purity of 99.2% by HPLC detection.
MS(ESI):[M+H]+＝518.3,[M+Na]+＝540.1,[M+K]+＝556.3。
IR：3122，2962～2874，2237，1607～1461，1392～1349，1274～1017，880～680。
Example 2
The method comprises the following steps: preparation of 2- [3- (1-cyanoethyl) -5-methylphenyl ] -2-methylpropanenitrile (formula III)
To N226.0g of 5-methyl-1, 3-benzene diacetonitrile and 260ml of DMF are added into a protected reaction bottle, stirred, added with 57.8g of dimethyl sulfate, and cooled to 0-5 ℃ in an ice water bath. Controlling the temperature to be 0-5 ℃, adding 14.6g of sodium hydride in batches, and keeping the temperature to be 0-5 ℃ after the addition is finished, and reacting for 0.5 h. Pouring the reaction liquid into 800ml water, extracting once with 400ml dichloromethane and once with 200ml, combining organic phases, washing with 400ml drinking water multiplied by 3 times, evaporating the organic phases under reduced pressure, purifying by a column, eluting: n-hexane/ethyl acetate 15/1, and the relatively pure eluent was collected and evaporated to dryness under reduced pressure to give an off-white solid 9.7g with a yield of 30.0%.
Step two: preparation of 2, 3-bis (3- (1-cyano-1-methylethyl) -5-methylphenyl) -2-methylpropanenitrile (formula V)
To N2To the protected reaction flask was added 7.5g of 2- [3- (1-cyanoethyl) -5-methylphenyl]Stirring (formula III) 2-methyl propionitrile and 150ml of DMF, cooling to 0-5 ℃ in an ice water bath, adding 1.7g of sodium hydride, keeping the temperature at 0-5 ℃ for reaction for 15min after the addition is finished, and adding the mixture into the systemAdding 10.7g of a compound 2- (3-bromomethyl-5-methylphenyl) -2-methylpropanenitrile shown in the formula IV, and carrying out heat preservation reaction at 0-5 ℃ until the reaction is finished. The reaction mixture was poured into 600ml of water and extracted with 600ml × 3 times of dichloromethane, the organic phases were combined, washed with 400ml × 3 times of saturated sodium chloride, evaporated to dryness under reduced pressure, purified by column chromatography (n-hexane/ethyl acetate: 5/1), the purer eluate was collected and evaporated to dryness under reduced pressure to give 10.7g of an off-white solid with a yield of 79.0%.
Step three: preparation of 2, 3-bis (3- (1-cyano-1-methylethyl) -5- (bromomethyl) phenyl) -2-methylpropanenitrile (formula VI)
To N26.0g of 2, 3-bis (3- (1-cyano-1-methylethyl) -5-methylphenyl) -2-methylpropanenitrile (formula V), 120mg of benzoyl peroxide and 100ml of carbon tetrachloride are added into a protected reaction flask, stirred and heated to 50-55 ℃, 1.1g of NCS is added, the temperature is heated to 70 ℃, 3.3g of NCS is added, and the reaction is carried out at 70 ℃ for heat preservation till the reaction is finished. Cooling to room temperature after the reaction is finished, adding 120ml of water and 120ml of dichloromethane, stirring, separating liquid, extracting the water phase once by using 120ml of dichloromethane, combining the organic phases, washing once by using 120ml of 10% sodium bisulfite, washing once by using 120ml of saturated sodium bicarbonate solution, washing once by using 120ml of water finally, evaporating the organic phase under reduced pressure, purifying by a column, and eluting by using an eluent: the pure product eluent was collected at 8/1 with n-hexane/ethyl acetate, and evaporated to dryness under reduced pressure to give 5.3g of an off-white solid with a yield of 62.6%.
Step four: preparation of 2, 3-bis (3- (1-cyano-1-methylethyl) -5- (1H-1,2, 4-triazole-1-methyl) phenyl) -2-methylpropanenitrile (formula I)
To N2Adding 3.6g of 2, 3-bis (3- (1-cyano-1-methylethyl) -5- (bromomethyl) phenyl) -2-methylpropanenitrile (formula VI) and 54ml of DMF into a protected reaction bottle, stirring, cooling to 0-5 ℃ in an ice water bath, adding 1.2g of 1,2, 4-triazole sodium, and keeping the temperature at 0-5 ℃ after the addition is finished until the reaction is finished. Pouring the reaction solution into 300ml of water, extracting with 300ml of toluene for 3 times, combining organic phases, washing with 180ml of drinking water for 3 times, evaporating the organic phases under reduced pressure, purifying the organic phases by a column, eluting the eluent with ethyl acetate to remove impurities, eluting the product with ethyl acetate/methanol (50/1), collecting the eluent of the purer product, evaporating the eluent under reduced pressure to dryness to obtain 1.6g of brown solid with the yield of 46.5% and 99.1% purity by HPLC.
Finally, the above embodiments are only for illustrating the technical solutions of the present invention and not for limiting, although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions may be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all of them should be covered in the claims of the present invention.
Claims (8)
1. A process for the preparation of a compound of formula I, comprising the steps of:
1) reacting the compound of the formula II with a methyl substitution reagent in the presence of a solvent and a catalyst to obtain a compound of a formula III; the molar ratio of the compound II to the methyl substitution reagent is 1: 1.5-1: 4;
2) carrying out substitution reaction on a compound of a formula III and a compound of a formula IV in the presence of a solvent and a catalyst, wherein the molar ratio of the compound III to the compound IV is 1: 1-1: 1.5, so as to obtain a compound of a formula V;
3) carrying out free radical substitution reaction on the compound of the formula V and N-halogenated succinimide in the presence of a solvent and a catalyst to obtain a compound of a formula VI;
4) nucleophilic substitution reaction is carried out on the compound in the formula VI and 1,2, 4-triazole sodium in the presence of a solvent to obtain the compound in the formula I.
2. The method of claim 1, wherein the methyl-substitution reagent in step 1) is one or more of methyl iodide, dimethyl sulfate, dimethyl carbonate, and methyl bromide.
3. The preparation method according to claim 1, wherein the solvent for the reaction in the steps 1) and 2) is DMF, the catalyst is sodium hydride, and the reaction temperature is-10 ℃ to 25 ℃.
4. The preparation method according to claim 1, wherein the N-halogenated succinimide in step 3) is one or more of N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), N-iodosuccinimide (NIS); the molar ratio of the compound of formula V to the N-halogenated succinimide is 1:2 to 1: 2.4.
5. The preparation method according to claim 1, wherein the solvent for the reaction in step 3) is one or more of acetonitrile, carbon tetrachloride and chloroform.
6. The preparation method according to claim 1, wherein the reaction catalyst in step 3) is one or more of azobisisobutyronitrile and benzoyl peroxide, and the reaction temperature is 50 ℃ to 81 ℃.
7. The preparation method according to claim 1, wherein the molar ratio of the compound of formula VI to the 1,2, 4-triazole sodium in the step 4) is 1: 1.2-1: 3.
8. The method according to claim 1, wherein the solvent used in the reaction in step 4) is DMF, and the reaction temperature is-15 ℃ to 50 ℃.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101074215A (en) * | 2006-05-17 | 2007-11-21 | 常州市第四制药厂有限公司 | Production of 1-[3,5-2(2,2-dimethyl) ethylcyano] benzyl triazole |
| CN101233100A (en) * | 2005-06-27 | 2008-07-30 | 西科尔公司 | An impurity of anastrozole intermediate, and uses thereof |
| CN101973911A (en) * | 2010-10-11 | 2011-02-16 | 中国科学技术大学 | Method for synthesizing anastrozole intermediate-2,2'-(5-methyl-1,3-phenylene)-bis-(2-methyl propionitrile) |
| CN102050775A (en) * | 2009-11-11 | 2011-05-11 | 常州市第四制药厂有限公司 | Anastrozole impurity alpha, alpha, alpha', alpha'-tetramethyl-5-(succinimide-1-methyl)-1,3-phenyl diacetonitrile and preparation method thereof |
| CN102050796A (en) * | 2009-11-11 | 2011-05-11 | 常州市第四制药厂有限公司 | Method for preparing alpha,alpha,alpha',alpha'-tetramethyl-5-(1H-1,3,4-triazole-1-ylmethyl)-1,3-phenylenediacetonitrile |
-
2018
- 2018-07-31 CN CN201810855358.0A patent/CN108997236B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101233100A (en) * | 2005-06-27 | 2008-07-30 | 西科尔公司 | An impurity of anastrozole intermediate, and uses thereof |
| CN101074215A (en) * | 2006-05-17 | 2007-11-21 | 常州市第四制药厂有限公司 | Production of 1-[3,5-2(2,2-dimethyl) ethylcyano] benzyl triazole |
| CN102050775A (en) * | 2009-11-11 | 2011-05-11 | 常州市第四制药厂有限公司 | Anastrozole impurity alpha, alpha, alpha', alpha'-tetramethyl-5-(succinimide-1-methyl)-1,3-phenyl diacetonitrile and preparation method thereof |
| CN102050796A (en) * | 2009-11-11 | 2011-05-11 | 常州市第四制药厂有限公司 | Method for preparing alpha,alpha,alpha',alpha'-tetramethyl-5-(1H-1,3,4-triazole-1-ylmethyl)-1,3-phenylenediacetonitrile |
| CN101973911A (en) * | 2010-10-11 | 2011-02-16 | 中国科学技术大学 | Method for synthesizing anastrozole intermediate-2,2'-(5-methyl-1,3-phenylene)-bis-(2-methyl propionitrile) |
Non-Patent Citations (1)
| Title |
|---|
| "N-Heterocyclic Carbene Catalysed Oxygen-to-Carbon Carboxyl Transfer of Indolyl and Benzofuranyl Carbonates";Jennifer E. Thomson等;《 SYNTHESIS》;20080806(第17期);第2805-2818页 * |
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Inventor after: Deng Qingjun Inventor after: Wang Xianhui Inventor before: Deng Qingjun Inventor before: Wang Xianhui |