CN109651402B - Preparation process of cefazedone sodium - Google Patents
Preparation process of cefazedone sodium Download PDFInfo
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- CN109651402B CN109651402B CN201811638227.3A CN201811638227A CN109651402B CN 109651402 B CN109651402 B CN 109651402B CN 201811638227 A CN201811638227 A CN 201811638227A CN 109651402 B CN109651402 B CN 109651402B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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Abstract
The invention belongs to the technical field of medicines, and discloses a preparation process of cefazedone sodium. 3, 5-dichloropyridone acetic acid and pivaloyl chloride are used as raw materials to synthesize mixed anhydride, and then the mixed anhydride reacts with an intermediate generated by 7-aminocephalosporanic acid and mercaptotetrazole to obtain cefazedone sodium through salification. The invention uses the mixed solvent in the 3-substitution, so that the reaction is more stable and softer, the generation of byproducts is reduced, the mixed anhydride is used in the acylation reaction, the activity is high, the 7-position acylation reaction is favorably carried out, and the obtained cefazedone sodium has higher yield and purity.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to a preparation process of cefazedone sodium.
Background
Cefazedone was developed by the laboratory of EMerck, Darmstadt, in the end of the 70's 20 th century and was the first cephalosporin antibiotic. The chemical name of cefazedone sodium is: (6R, 7R) -3- (5-methyl-1, 3, 4-thiadiazolyl-2-mercaptomethyl) -7(3, 5-dichloro-4-pyridone-1-acetylamino) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, sodium salt having the formula:
the synthesis method of cefazedone sodium mainly comprises the following steps
(1) A direct synthesis method. In patent CN101584671B, 7-aminocephalosporanic acid (7-ACA) is used as a raw material to perform amidation reaction with 3, 5-dichloropyridone acetic acid, and then the amidation reaction with 2-mercapto-5-methyl-1, 3, 4-thiadiazole (MMTD) is performed to synthesize cefazedone sodium. The synthetic route is shown as the following formula:
the route uses a condensing agent DCC with high price, and simultaneously needs anhydrous condition reaction, so the route is not suitable for industrial production. In addition, 7-ACA is adopted to react with MMTD firstly and then react with 3, 5-dichloropyridone acetic acid to synthesize cefazedone sodium, but carboxylic acid participates in competitive reaction to result in lower yield and easily generates byproducts.
In patent CN108084213A, 3, 5-dichloropyridone acetic acid ethyl ester is used for replacing 3, 5-dichloropyridone acetic acid, so that the problem of carboxyl participating in competitive reaction is solved, and the yield is improved, but the 3, 5-dichloropyridone acetic acid ethyl ester is not easy to obtain and expensive in price, and is not suitable for industrial production.
The patent CN106967092A takes deacetoxy 7-ACA as a raw material, firstly reacts with 3, 5-dichloropyridone acetic acid, then is substituted with N-bromosuccinimide, and finally reacts with MMTD to obtain cefazedone sodium, the selectivity problem of bromination reaction exists in the reaction, and the product purity cannot be guaranteed.
(2) An acid chloride method. CN104230958A uses 3, 5-dichloropyridone acetic acid as raw material, reacts with trichloroacetyl chloride to generate mixed anhydride, then reacts with 7-ACA to generate 7- (3, 5-dichloro-4-pyridone-1-2 acetamide) -cephalosporanic acid, and finally synthesizes cefazedone with 5-methyl-2-mercapto-1, 3, 4-thiadiazole. The synthetic route is shown as the following formula:
the route overcomes the defects of raw material sources and reaction conditions in the prior art, but the yield and the purity are still not ideal.
(3) An active ester method, patent CN105017285B, discloses a method for synthesizing active ester by using 3, 5-dichloropyridone acetic acid and 5-methyl-2-mercapto-1, 3, 4-thiadiazole, and then reacting the active ester with 7-ACA to generate cefazedone sodium. The synthetic route is shown as the following formula:
in patent CN105017286, GCLE is used as a raw material, and reacts with MMTD to obtain GTDE, then p-methoxybenzyl and phenylacetyl are removed to obtain 7-TDA, and the 7-TDA reacts with active ester to obtain cefazedone sodium. The active ester has high reaction activity, but poor stability, difficult storage, continuous reaction and difficult industrial production operation.
The invention content is as follows:
compared with the prior art, the synthesis method of cefazedone sodium provided by the invention has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, no need of special equipment, suitability for industrial production and higher yield and purity of the obtained product.
The preparation process of cefazedone sodium provided by the invention comprises the following steps:
(1) adding MMTD and 7-ACA into a dimethyl carbonate solvent, adding another solvent, slowly adding a catalyst, controlling the temperature to be 20-30 ℃ for reaction, dropwise adding an alkali after the reaction is finished to adjust the pH, and cooling and crystallizing to obtain 7-TD A;
(2) the compound 3, 5-dichloropyridone acetic acid and pivaloyl chloride generate mixed anhydride reaction liquid under the action of a catalyst;
(3) adding 7-TDA into the mixed anhydride reaction liquid in three batches, adjusting the pH value with an acid-binding agent after each batch is added, adding a catalyst, controlling the temperature to be-10-0 ℃ for reaction, adding a sodium bicarbonate solution for salification after the reaction is finished, heating to room temperature for extraction, and adding acetone for crystallization to obtain cefazedone sodium;
the reaction route is as follows:
in the step (1), the other solvent is one or more of citric acid, tartaric acid, 2-malic acid, acetic acid and benzoic acid, and the molar ratio of the solvent to the 7-ACA is 1-3: 1;
in the step (1), the catalyst is boron trifluoride-dimethyl carbonate complex, and the molar ratio of the boron trifluoride-dimethyl carbonate complex to the 7-ACA is 6-8: 1;
the alkali used in the step (1) is one of strong ammonia water, triethylamine and sodium hydroxide, and the pH value is adjusted to 3.0-4.5;
in the step (2), the catalyst is one of N, N-dimethylformamide, N-dimethylacetamide and N, N-diisopropylethylamine;
in the step (3), the acid-binding agent is one of strong ammonia water, triethylamine and sodium hydroxide, and the pH is adjusted for three times to 6.0-7.0, 5.5-6.5 and 4.5-5.0 respectively;
in the step (3), the catalyst is one of 2, 6-lutidine, 4-dimethylaminopyridine and N-methylcyclohexylamine.
The preparation process of cefazedone sodium provided by the invention has the following beneficial effects:
(1) in the 7-TDA synthesis process, another solvent and dimethyl carbonate are added to form a mixed solvent, so that on one hand, the polarity of the solution can be adjusted, the proton concentration is changed, the solubility of the 7-ACA and the MMTD is increased, and a homogeneous reaction is formed, on the other hand, the reaction is properly inhibited, the reaction is more stable and softer, the generation of byproducts is reduced, and the product yield and purity are both improved; the boron trifluoride dimethyl carbonate with high concentration is used as a catalyst, so that the 3-position substitution reaction activity is improved, and the reaction time is shortened.
(2) When the pivaloyl chloride and the pyridone acetic acid are used for preparing the mixed anhydride, the mixed anhydride has lower activation energy and high activity, is beneficial to the 7-bit acylation reaction, can inhibit the side reaction of parent nucleus carboxyl, and improves the reaction purity.
(3) In the synthesis process of cefazedone sodium, 7-TDA is directly added into the reaction liquid of the mixed anhydride, and the operation is simple; the PH is adjusted back by an acid-binding agent three times (mixed anhydride reacts with amino to generate a part of carboxylic acid, the generated carboxylic acid reacts with the acid-binding agent to generate carboxylate), compared with the one-time PH adjustment, the acid-binding agent in a reaction system can not be accumulated, the mixed anhydride is prevented from being gradually decomposed into raw materials along with the time to lose the reactivity, the reaction rate is increased, the reaction is not too violent, the reaction is more thorough, the generation of impurities is reduced, and the product yield and the purity are improved.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention.
Example 1
(1) Adding 60mL of dimethyl carbonate and 7.06g of citric acid into a 500mL three-necked flask, adding 4.85g of MMTD while stirring, adding 7-ACA10.00g, slowly adding 34.82g of boron trifluoride-dimethyl carbonate complex, controlling the temperature to 20-30 ℃ for reaction, after 1h, monitoring the reaction by HPLC, adding 1.28g of sodium hydrosulfite, stirring for 10min, transferring to water, adding 80mL of isopropanol, slowly adding concentrated ammonia water to adjust the pH value to 3.0, controlling the adding time to 30-60 min, cooling to 0-10 ℃ and crystallizing for 1 h. Suction filtering, vacuum drying to obtain 7-TDA 11.60g, yield 91.7%, HPLC detection purity 99.4%, maximum single impurity 0.08%.
(2) 150mL of dichloromethane is added into a 500mL three-necked bottle, 10.00g of 3, 5-dichloropyridone acetic acid is added, the temperature is reduced to-10-0 ℃, 5.85g of N, N-diisopropylethylamine is slowly dripped, and 10.86g of pivaloyl chloride is slowly added. Controlling the temperature to be-10-0 ℃ for reaction, and after 30min, monitoring the reaction by HPLC to finish to obtain a mixed anhydride reaction solution with the purity of 99.7% by HPLC detection.
(3) Cooling the mixed anhydride reaction liquid obtained in the step (2) to-5 ℃, adding 4.00g of 7-TDA obtained in the step (1), adding triethylamine to adjust the pH value to 6.0, adding 4.00g of 7-TDA, adding triethylamine to adjust the pH value to 5.5, adding 2.32g of 7-TDA, adding triethylamine to adjust the pH value to 4.5, adding 0.37g of 4-dimethylaminopyridine, controlling the temperature to be-10-0 ℃ for reaction, monitoring the reaction by HPLC, adding 10% sodium bicarbonate solution to adjust the pH value to 7.0-8.0, raising the temperature to room temperature, adding 60mL of acetone for crystallization for 1h, and then adding 60mL of acetone for crystallization for 1 h. Suction filtering, vacuum drying to obtain cefazedone sodium 15.45g, yield 90.5%, HPLC detection purity 99.7%, maximum single impurity 0.09%.
Example 2
(1) Adding 60mL of dimethyl carbonate and 9.86g of 2-hydroxysuccinic acid into a 500mL three-necked flask, adding 4.85g of MMTD while stirring, adding 7-ACA10.00g, slowly adding 40.62g of boron trifluoride-dimethyl carbonate complex, controlling the temperature to 20-30 ℃ for reaction, after 1h, monitoring the reaction by HPLC (high performance liquid chromatography), adding 1.28g of sodium hydrosulfite, stirring for 10min, adding 80mL of n-butyl alcohol into water, slowly dropwise adding triethylamine to adjust the pH to 4.5, controlling the dropwise adding time to 30-60 min, cooling to 0-10 ℃ and crystallizing for 1 h. Vacuum-filtering, and vacuum-drying to obtain 7-TDA11.65g with yield of 92.1%, purity of 99.2% by HPLC detection, and maximum single impurity of 0.10%.
(2) 150mL of dichloromethane is added into a 500mL three-necked bottle, 10.00g of 3, 5-dichloropyridone acetic acid is added, the temperature is reduced to-10-0 ℃, 3.31g of DMF is slowly dripped, and 10.86g of pivaloyl chloride is slowly added. Controlling the temperature to be-10-0 ℃ for reaction, monitoring the reaction by HPLC after 30min to finish the reaction to obtain a mixed anhydride reaction solution, and detecting the purity by HPLC to be 99.6%.
(3) Cooling the mixed anhydride reaction liquid obtained in the step (2) to-5 ℃, adding 7-TDA4.00g obtained in the step (1), adding triethylamine to adjust the pH value to 7.0, adding 7-TDA4.00g, adding triethylamine to adjust the pH value to 6.5, adding 7-TDA2.32g, adding triethylamine to adjust the pH value to 5.0, adding 2, 6-dimethylpyridine 0.32g, controlling the temperature to be-10-0 ℃ for reaction, monitoring the reaction by HPLC, adding 10% sodium bicarbonate solution to adjust the pH value to 7.0-8.0, raising the temperature to room temperature, adding acetone 60mL for crystallization for 1h, and then adding acetone 60mL for crystallization for 1 h. Suction filtering, vacuum drying to obtain cefazedone sodium 15.64g, yield 91.6%, HPLC detection purity 99.8%, maximum single impurity 0.07%.
Example 3
(1) Adding 60mL of dimethyl carbonate and 6.62g of acetic acid into a 500mL three-necked flask, adding 4.85g of MMTD while stirring, adding 7-ACA10.00g, slowly adding 46.42g of boron trifluoride-dimethyl carbonate complex, controlling the temperature to 20-30 ℃ for reaction, after 1h, monitoring the reaction by HPLC, adding 1.28g of sodium hydrosulfite, stirring for 10min, transferring to water, adding 80mL of isopropanol, slowly adding sodium hydroxide to adjust the pH to 4.0, controlling the dropping time to 30-60 min, cooling to 0-10 ℃ and crystallizing for 1 h. Suction filtering, vacuum drying to obtain 7-TDA 11.64g, yield 92.0%, HPLC detection purity 99.3%, maximum single impurity 0.08%.
(2) 150mL of dichloromethane is added into a 500mL three-necked bottle, 10.00g of 3, 5-dichloropyridone acetic acid is added, the temperature is reduced to-10-0 ℃, 3.94g of DMAC is slowly dripped, and 10.86g of pivaloyl chloride is slowly added. Controlling the temperature to be-10-0 ℃ for reaction, monitoring the reaction by HPLC after 30min to finish the reaction to obtain a mixed anhydride reaction solution, and detecting the purity by HPLC to be 99.6%.
(3) Cooling the mixed anhydride reaction liquid obtained in the step (2) to-5 ℃, adding 7-TDA4.00g obtained in the step (1), adding triethylamine to adjust the pH value to 6.5, adding 7-TDA4.00g, adding triethylamine to adjust the pH value to 6.0, adding 7-TDA2.32g, adding triethylamine to adjust the pH value to 4.8, adding 0.34g of N-methylcyclohexylamine, controlling the temperature to be-10-0 ℃ for reaction, monitoring the reaction by HPLC, adding 10% sodium bicarbonate solution to adjust the pH value to 7.0-8.0, raising the temperature to room temperature, adding 60mL of acetone for crystallization for 1h, and then adding 60mL of acetone for crystallization for 1 h. Suction filtering, vacuum drying to obtain cefazedone sodium 15.43g, yield 90.4%, HPLC detection purity 99.8%, maximum single impurity 0.08%.
Example 4
(1) Adding 60mL of dimethyl carbonate and 14.12g of citric acid into a 500mL three-necked flask, adding 4.85g of MMTD while stirring, adding 7-ACA10.00g, slowly adding 34.82g of boron trifluoride-dimethyl carbonate complex, controlling the temperature to 20-30 ℃ for reaction, after 1h, monitoring the reaction by HPLC, adding 1.28g of sodium hydrosulfite, stirring for 10min, transferring to water, adding 80mL of isopropanol, slowly adding concentrated ammonia water to adjust the pH value to 3.5, controlling the adding time to 30-60 min, cooling to 0-10 ℃ and crystallizing for 1 h. Vacuum-filtering, and vacuum-drying to obtain 7-TDA11.70g with yield of 92.5%, purity of 99.5% by HPLC detection, and maximum single impurity of 0.07%.
(2) 150mL of dichloromethane is added into a 500mL three-necked bottle, 10.00g of 3, 5-dichloropyridone acetic acid is added, the temperature is reduced to-10-0 ℃, 5.85g of N, N-diisopropylethylamine is slowly dripped, and 10.86g of pivaloyl chloride is slowly added. Controlling the temperature to be-10-0 ℃ for reaction, and after 30min, monitoring the reaction by HPLC to finish to obtain a mixed anhydride reaction solution with the purity of 99.5% by HPLC detection.
(3) Cooling the mixed anhydride reaction liquid obtained in the step (2) to-5 ℃, adding 4.00g of 7-TDA obtained in the step (1), adding triethylamine to adjust the pH value to 6.5, adding 4.00g of 7-TDA, adding triethylamine to adjust the pH value to 6.0, adding 2.32g of 7-TDA, adding triethylamine to adjust the pH value to 5.0, adding 0.37g of DMAP0, controlling the temperature to be-10-0 ℃ for reaction, monitoring the reaction by using HPLC, adding 10% sodium bicarbonate solution to adjust the pH value to 7.0-8.0, raising the temperature to room temperature, adding 60mL of acetone for crystallization for 1h, and adding 60mL of acetone for crystallization for 1 h. Suction filtering, vacuum drying to obtain cefazedone sodium 15.58g, yield 91.3%, HPLC detection purity 99.9%, maximum single impurity 0.06%.
Comparative example 1
Adding 60mL of dimethyl carbonate into a 500mL three-necked flask, adding 4.85g of MMTD while stirring, adding 7-ACA10.00g, slowly adding 34.82g of boron trifluoride-dimethyl carbonate complex, controlling the temperature to be 20-30 ℃ for reaction, after 1h, monitoring the reaction by HPLC, adding 1.28g of sodium hydrosulfite, stirring for 10min, transferring to water, adding 80mL of isopropanol, slowly dropwise adding 5% sodium hydroxide to adjust the pH to 3.0, controlling the dropwise adding time to be 30-60 min, cooling to 0-10 ℃ and crystallizing for 1 h. Vacuum-filtering, and vacuum-drying to obtain 7-TDA 9.23g with yield 73.0%, purity 97.5% by HPLC detection, and maximum single impurity 0.43%.
Comparative example 2:
adding 60mL of dimethyl carbonate into a 500mL three-necked flask, adding 6.33g of p-toluenesulfonic acid, adding 4.85g of MMTD while stirring, adding 7-ACA10.00g, slowly adding 34.82g of boron trifluoride-dimethyl carbonate complex, controlling the temperature to 20-30 ℃ for reaction, after 1h, monitoring the reaction by HPLC, adding 1.28g of sodium hydrosulfite, stirring for 10min, transferring to water, adding 80mL of isopropanol, slowly dropwise adding 5% sodium hydroxide to adjust the pH to 3.0, controlling the dropwise adding time to 30-60 min, cooling to 0-10 ℃ and crystallizing for 1 h. Vacuum-filtering, and vacuum-drying to obtain 7-TDA 9.51g, yield 75.2%, purity 97.9% by HPLC detection, and maximum single impurity 0.51%.
Comparative example 3:
the reaction solution of 7-TDA and mixed acid anhydride was prepared in accordance with the procedure (1) and the procedure (2) of example 1. Cooling the mixed anhydride reaction liquid to-5 ℃, adding 10.32g of 7-TDA, adding triethylamine to adjust the pH value to 5.0, adding 0.32g of 2, 6-lutidine, controlling the temperature to-10-0 ℃ for reaction, monitoring the completion of the reaction by HPLC, adding 10% sodium bicarbonate solution to adjust the pH value to 7.0-8.0, heating to room temperature, adding 60mL of acetone for crystallization for 1h, and then adding 60mL of acetone for crystallization for 1 h. Suction filtration and vacuum drying are carried out to obtain 13.47g of cefazedone sodium, the yield is 78.9 percent, the purity is 96.2 percent by HPLC detection, and the maximum single impurity content is 0.49 percent.
Comparative example 4:
the reaction solution of 7-TDA and mixed acid anhydride was prepared in accordance with the procedure (1) and the procedure (2) of example 1. Cooling the mixed anhydride reaction liquid to-5 ℃, adding 4.00g of 7-TDA obtained in the step (1), adding triethylamine to adjust the pH value to 5.5, adding 4.00g of 7-TDA, adding triethylamine to adjust the pH value to 5.0, adding 2.32g of 7-TDA, adding triethylamine to adjust the pH value to 4.0, adding 0.37g of DMAP, controlling the temperature to-10-0 ℃ for reaction, monitoring the reaction completion by HPLC, adding 10% sodium bicarbonate solution to adjust the pH value to 7.0-8.0, raising the temperature to room temperature, adding 60mL of acetone to crystallize for 1h, and adding 60mL of acetone to crystallize for 1 h. Suction filtering, vacuum drying to obtain cefazedone sodium 15.00g, yield 87.9%, HPLC detection purity 99.1%, maximum single impurity 0.16%.
Claims (7)
1. A preparation process of cefazedone sodium is characterized by comprising the following steps:
(1) adding a compound I and a compound II into a dimethyl carbonate solvent, adding another solvent, adding a catalyst, adding an alkali after the reaction is finished to adjust the pH value to obtain a compound III, wherein the another solvent is one or more of citric acid, 2-malic acid and acetic acid;
(2) the compound IV and pivaloyl chloride generate a compound V under the action of a catalyst, wherein the catalyst is one or more of N, N-dimethylformamide, N-dimethylacetamide and N, N-diisopropylethylamine;
(3) adding the compound III into the reaction solution of the compound V in three batches, adjusting the pH value with an acid-binding agent after each addition, adding a catalyst, reacting to obtain cefazedone sodium, and adjusting the pH value for three times to 6.0-7.0, 5.5-6.5 and 4.5-5.0 respectively;
the reaction route is as follows:
2. the cefazedone sodium preparation process according to claim 1, characterized in that the molar ratio of the other solvent used in step (1) to compound I is 1-3: 1.
3. the cefazedone sodium preparation process according to claim 1, wherein the catalyst in step (1) is boron trifluoride-dimethyl carbonate complex, and the molar ratio of boron trifluoride-dimethyl carbonate complex to compound I is 6-8: 1.
4. the cefazedone sodium preparation process according to claim 1, characterized in that the base used in step (1) is one or more of concentrated ammonia water, triethylamine and sodium hydroxide.
5. The process for preparing cefazedone sodium according to claim 1, wherein the pH is adjusted to 3.0 to 4.5 in step (1).
6. The cefazedone sodium preparation process according to claim 1, characterized in that the acid-binding agent used in step (3) is one or more of concentrated ammonia water, triethylamine and sodium hydroxide.
7. The cefazedone sodium preparation process according to claim 1, characterized in that in step (3), the catalyst is one or more of 4-dimethylaminopyridine, 2, 6-dimethylpyridine, N-methylcyclohexylamine, and DIPEA.
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Inventor after: Li Minghua Inventor after: Li Mingjie Inventor after: Sun Ju Inventor after: Li Qiang Inventor before: Li Mingjie Inventor before: Sun Ju Inventor before: Li Qiang |