CN108383857B - Preparation method of cefmenoxime hydrochloride - Google Patents
Preparation method of cefmenoxime hydrochloride Download PDFInfo
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- 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
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- 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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Abstract
The invention discloses a preparation method of cefmenoxime hydrochloride. The method comprises the steps of carrying out trimethylsilyl protection on the cefotaxime acid, then activating carboxyl by using an activating reagent, then reacting with 7-ATCA hydrochloride, finally acidifying by hydrochloric acid, cooling and growing crystal to obtain cefmenoxime hydrochloride, wherein the purity of the cefmenoxime hydrochloride produced by the method is more than 99.5%, and the molar yield of the product is more than 88%. The invention has the advantages of cheap and easily obtained raw materials, high product purity and high yield, and is beneficial to realizing industrial production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a preparation method of an antibiotic drug cefmenoxime hydrochloride.
Background
Cefmenoxime hydrochloride belongs to the third-generation semi-synthetic cephalosporin antibiotics, has better antibacterial effect than cefotaxime and cefoperazone, is widely applied to treatment of bacterial infection of gram-positive bacteria, gram-negative bacteria and the like, and has stronger antibacterial effect on proteus, serratia marcescens, haemophilus influenzae and enterobacter. It also has antibacterial and antibacterial effects against Pediococcus and Peptostreptococcus, and can be used for treating septicemia, respiratory infection, liver and gallbladder infection, meningitis, empyema, peritonitis, reproductive system infection, urinary tract infection, burn, and wound infection caused by sensitive bacteria.
Cefmenoxime hydrochloride, known in the chinese name: (6R,7R) -7- [ (Z) -2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido ] -3- [ [ (1-methyl-1H-tetrazol-5-yl) -thio ] methyl ] -8-oxo-thio-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid hydrochloride (2: 1) is a third generation of broad spectrum cephalosporin antibiotic developed by Wutian chemical industries, Inc., and marketed in Japan, USA, etc. in 1983. The sales volume has increased year by year since the marketing and is loaded in the pharmacopoeias of various countries. The structure of the compound is shown as a formula (I).
Many documents are reported on the synthetic route of cefmenoxime hydrochloride, for example, European patent DE27132, US3262932, 1999 edition of organic drug Synthesis (first volume) edited by Chen Feng, all use 7-ACA (3-acetoxymethyl-5-thio-7-amino-8-oxo-1-azabicyclooctan-2-ene-2-carboxylic acid) as starting material, the process route is relatively long, the operation steps are complicated, the yield is not high, and the prepared final product has high impurity level and deep color grade.
The synthesis method reported in Chinese patent CN103613604A comprises the following steps: the method comprises the following steps of carrying out condensation reaction on 3- (1-methyl-1H-tetrazole-5-yl) methyl-7-amino-cephalosporanic acid hydrochloride (namely 7-ATCA. HCl) serving as an initial raw material and 2- (2-amino-4-thiazolyl) -2-methoxyimino-acetyl-benzothiazole thioester (namely AE active ester) in the presence of an alkalinizing agent, and then carrying out sterile treatment to obtain the sterile cefmenoxime sodium.
The synthesis method reported in Chinese patent CN104447798A comprises the following steps: dissolving 7-ATCA or 7-ATCA hydrochloride and AE active ester in dichloromethane, dripping organic alkali at-5-15 ℃, adding water for multiple times of extraction after the reaction is finished, adding a hydrophilic solvent after the water phase is decolored, and dripping hydrochloric acid at 10-35 ℃ to crystallize and separate cefmenoxime hydrochloride.
The two methods have low synthesis yield and poor purity.
The synthesis method reported in Chinese patent CN101550150 comprises the following steps: reacting 2- (2-aminothiazole-4-yl) -2-methoxyimino acetic acid with triphenylchloromethane to obtain 2- (2-trityl aminothiazole-4-yl) -2-methoxyimino acetic acid hydrochloride; activating carboxyl groups in the 2- (2-trityl aminothiazole-4-yl) -2-methoxyimino acetic acid by using p-toluenesulfonyl chloride, enabling the carboxyl groups to react with 7-ACA to obtain cefotaxime hydrochloride, reacting with 1-methyl-5-mercapto-1H-tetrazole, and adjusting the pH value by using sodium carbonate and hydrochloric acid respectively to finally obtain the cefmenoxime hydrochloride. The raw materials of triphenylchloromethane and p-toluenesulfonyl chloride used in the method are expensive, the cost is increased greatly in the industrial production process, and the purity and the yield of the obtained product are low.
Disclosure of Invention
The invention overcomes the defects of the prior art and provides an improved method for preparing cefmenoxime hydrochloride with high yield. The invention carries out trimethylsilyl protection on the cefotaxime acid, then uses an activating reagent to activate the carboxyl of the cefotaxime acid, then reacts with 7-ATCA hydrochloride, and finally carries out acidification by hydrochloric acid and cooling crystal growth to obtain the cefmenoxime hydrochloride. The invention has the advantages of cheap and easily obtained raw materials, high product purity and high yield, and is beneficial to realizing industrial production.
The technical scheme of the invention is as follows: the preparation method of cefmenoxime hydrochloride is characterized by comprising the following steps:
(1) in an organic solvent, carrying out a reaction on aminothiazoly loximate (a compound shown in a formula II) and a trimethylsilyl protective agent to obtain a reaction solution of a compound shown in a formula III;
(2) adding an activating agent and organic base into the reaction liquid generated in the step (1) for reaction, and activating carboxyl of a compound in a formula III; then adding 7-ATCA hydrochloride (compound of formula IV) for reaction; after the reaction is finished, adding water and a hydrochloric acid solution into the reaction solution to adjust the pH value to be 6.0-7.0, stirring and separating liquid, and keeping a water phase;
(3) and (3) decolorizing the water phase, adding an organic solvent, dropwise adding a hydrochloric acid solution until the pH value of the system is 2.0-3.0, and cooling and growing crystals after the dropwise adding is finished to obtain the cefmenoxime hydrochloride (I).
The reaction equation is shown below.
The solvent used in step (1) is dichloromethane, acetonitrile, tetrahydrofuran, N-dimethylformamide, etc., preferably dichloromethane.
The reaction temperature in the step (1) is 20-50 ℃, preferably 40 ℃.
The amino protecting agent described in step (1) includes, but is not limited to, N, O-bis (trimethylsilyl) acetamide (BSA), Hexamethyldisilazane (HMDS), etc., preferably N, O-bis (trimethylsilyl) acetamide. The amount of the protecting agent is 1.0eq to 1.5eq, preferably 1.05eq (based on the amount of aminothiazoly loximate, the same applies hereinafter).
The reaction time in the step (1) is 1-4 h, preferably 2 h.
The reaction temperature for activating the carboxyl in the step (2) is-5 ℃ to 5 ℃, and preferably 0 ℃.
The activating reagent described in the step (2) includes thionyl chloride, pivaloyl chloride, ethyl chloroformate and the like, and thionyl chloride is preferable. The dosage of the activating reagent is 1.0 eq-1.2 eq, preferably 1.05 eq.
The organic base in the step (2) can be triethylamine, N-diisopropylethylamine, pyridine and the like, and triethylamine is preferred. The amount of the organic base is 1.5eq to 5.0eq, preferably 4.5 eq.
The reaction time for activating the carboxyl in the step (2) is 1-4 h, preferably 2 h.
The reaction temperature for the reaction with 7-ATCA hydrochloride in the step (2) is-20 to-10 ℃, preferably-15 ℃.
The dosage of the 7-ATCA hydrochloride in the step (2) is 0.85eq to 1.0eq, preferably 0.95 eq.
The reaction time with 7-ATCA hydrochloride in the step (2) is 0.5h to 3h, preferably 2 h.
The organic solvent in the step (3) is alcohols, ketones, tetrahydrofuran, acetonitrile and the like. The alcohol can be one of ethanol, propanol, isopropanol, and n-butanol, preferably isopropanol. The ketone can be acetone, butanone, etc., preferably acetone.
The temperature of the dropwise adding hydrochloric acid in the step (3) is 20-30 ℃ in the temperature control process, and is preferably 25 ℃.
The decolorization in the step (3) is performed by adopting activated carbon and alumina, and the mass ratio of the activated carbon to the alumina is preferably 1: 1.
the temperature of crystal growth in the step (3) is 5-20 ℃, preferably 10 ℃.
The time for growing the crystal in the step (3) is 1-4 h, preferably 2 h.
The volume ratio of the organic solvent to the water in the step (3) is 1: 1-1: 10, preferably 1: 5.
The mass concentration of the hydrochloric acid solution used in the invention is 17-35%, preferably 35%.
Due to the adoption of the technical scheme, compared with the prior art, the invention has the following advantages:
1. the process of the invention adopts the protective agent for protection and has reasonable temperature control, reduces the degradation of the product and has low impurity content.
2. The invention adopts active carbon and alumina for decolorization, thereby improving the color of the product.
3. The purity of the cefmenoxime hydrochloride obtained by the invention is more than 99.5%, and the content is more than 98.5%. Meets the quality standard of cefmenoxime hydrochloride of the second edition in the Chinese pharmacopoeia 2015 year. The product molar yield is more than 88 percent, which is higher than that reported in various literatures.
4. The reaction process of the invention adopts a one-pot method, and the solvent used in the preparation process can be recycled, so that the invention has the advantages of little pollution and environmental protection pressure, and is suitable for industrial production.
Drawings
FIG. 1 is a diagram of related substances of cefmenoxime hydrochloride prepared in example 1 of the present invention.
Detailed Description
The following examples are specific illustrations of the process of the present invention, but the invention is not limited to the following examples. The synthetic routes and conditions involved in the present invention can be reasonably modified by those skilled in the art.
Example 1
(1) Adding 100.0g (0.5mol) of aminothiazoly loximate into 1000ml of dichloromethane under stirring, dropwise adding 106.0g (0.52mol) of N, O-bis (trimethylsilyl) acetamide for about 0.5h, and then heating to 40 ℃;
(2) 227.7g (2.25mol) of triethylamine is dropwise added into the solution of the compound shown in the formula III, 62.0g (0.52mol) of thionyl chloride is dropwise added, the addition is finished for about 0.5h, the temperature is controlled to be 0 ℃ for reaction for 2h, then the temperature is reduced to minus 17 ℃ to minus 13 ℃, 7-ATCA. HCl174.2g (0.47mol) is added, the reaction is carried out for 2h at the temperature, and the reaction is monitored to ensure that the 7-ATCA. HCl is less than or equal to 1.0 percent. After the reaction is finished, adding 1000ml of water, adjusting the pH value to 6-7 by using 35% hydrochloric acid solution, stirring and separating liquid, and keeping a water phase; the organic phase was extracted with 500ml, 300ml of water in this order and the aqueous phases were combined.
(3) After the combination, 25g of activated carbon and 25g of alumina are added into the water phase for decolorization for 0.5h, the mixture is filtered, and the filter cake is washed by 200ml of water. Collecting the filtrate, adding 400ml of acetone into the filtrate, controlling the temperature to be 25 ℃, slowly dropwise adding a 35% hydrochloric acid solution until the pH value is 2.0-3.0, and finishing dropwise adding for about 2 hours. Then cooling to 10 ℃ for crystal growth for 2h, filtering, washing with 400ml × 2 of water, washing with 400ml of acetone, and vacuum drying at 40-45 ℃ for 6h to obtain 226.5g of white crystal powder, wherein the molar yield is 90.5%, the purity is 99.6%, and the maximum single impurity is 0.13%, and the related substance diagram is shown in figure 1.
Example 2
(1) 100.0g (0.5mol) of aminothiazoly loximate are added with stirring to 1000ml of dichloromethane, 84.0g (0.52mol) of hexamethyldisilazane are added dropwise over about 0.5h, heated to 45 ℃ and stirred for 4h and then cooled to 2 ℃ to give a solution of the compound of formula III which is used directly in the next reaction.
(2) 258.5g (2.0mol) of N, N-diisopropylethylamine is dropwise added into the solution of the compound shown in the formula III, 62.7g (0.52mol) of pivaloyl chloride is dropwise added, the reaction is finished for about 0.5h, the temperature is controlled to be 2 ℃ for 3h, then the temperature is reduced to-19 to-15 ℃, 7-ATCA.HCl166.0g (0.45mol) is added, the reaction is carried out for 3h at the temperature, and the reaction is monitored to be 7-ATCA.HCl and is less than or equal to 1.0 percent. After the reaction is finished, adding 1000ml of water, adjusting the pH value to 6-7 by using 35% hydrochloric acid solution, stirring and separating liquid, and keeping a water phase; the organic phase was extracted with 500ml, 400ml of water in that order and the aqueous phases were combined.
(3) After the combination, 12.5g of activated carbon and 12.5g of alumina are added into the water phase for decolorization for 0.5h, the mixture is filtered, and the filter cake is washed by 200ml of water. Collecting the filtrate, adding 500ml of isopropanol into the filtrate, slowly dropwise adding 35% hydrochloric acid solution at a controlled temperature of 22 ℃ until the pH value is 2.0-3.0, and finishing dropwise adding for about 2 hours. Then cooling to 5 ℃ for crystal growing for 4h, filtering, washing with 500ml multiplied by 2 of water, washing with 300ml of isopropanol, and vacuum drying at 40-45 ℃ for 6h to obtain 211.2g of white crystal powder with the molar yield of 88.6%. Purity 99.59%, maximum single impurity 0.13%.
Example 3
(1) 100.0g (0.5mol) of the compound of formula II, aminothiazoly loximate, was added to a mixed solvent of 900ml of dichloromethane and 100ml of N, N-Dimethylformamide (DMF) with stirring, 82.3g (0.51mol) of hexamethyldisilazane was added dropwise over about 0.5h, then heated to 42 ℃, stirred for 2h, and then cooled to 2 ℃ to give a solution of the compound of formula III, which was used directly in the next reaction.
(2) Adding 258.5g (2.0mol) of N, N-diisopropylethylamine dropwise into the solution of the compound shown in the formula III, adding 59.5g (0.50mol) of thionyl chloride dropwise, reacting for 2h after about 0.5h, cooling to-17-13 ℃, adding 174.2g (0.47mol) of 7-ATCA. HCl, reacting for 2h at the temperature, and monitoring the reaction to ensure that the 7-ATCA. HCl is less than or equal to 1.0%. After the reaction is finished, adding 1000ml of water, adjusting the pH value to 6-7 by using 35% hydrochloric acid solution, stirring and separating liquid, and keeping a water phase; the organic phase was extracted with 500ml, 300ml of water in this order and the aqueous phases were combined.
(3) After the combination, 25g of activated carbon and 25g of alumina are added into the water phase for decolorization for 0.5h, the mixture is filtered, and the filter cake is washed by 200ml of water. Collecting the filtrate, adding 400ml of ethanol into the filtrate, controlling the temperature at 26 ℃, slowly dropwise adding a 35% hydrochloric acid solution until the pH value is 2.0-3.0, and finishing dropwise adding for about 2 hours. Then cooling to 8 ℃ for crystal growing for 2h, filtering, washing with 400ml of water multiplied by 2, washing with 400ml of ethanol, and vacuum drying at 40-45 ℃ for 6h to obtain 223.1g of white crystal powder with the molar yield of 89.6%. Purity 99.54%, maximum individual impurity 0.14%.
Example 4
(1) 100.0g (0.5mol) of aminothiazoly loximate was added to a mixed solvent of 950ml of dichloromethane and 50ml of N, N-Dimethylformamide (DMF) with stirring, 106.0g (0.52mol) of N, O-bis (trimethylsilyl) acetamide was added dropwise over about 0.5h, then heated to 42 ℃, stirred for 3h, and then cooled to 2 ℃ to obtain a solution of the compound of formula III which was directly used for the next reaction.
(2) 158.2g (2.0mol) of pyridine is added dropwise into the solution of the compound shown in the formula III, 62.7g (0.52mol) of pivaloyl chloride is added dropwise, the reaction is carried out for about 0.5h, the temperature is controlled to be 0 ℃ for 2h, then the temperature is reduced to-13 to-17 ℃, 174.2g (0.47mol) of 7-ATCA. HCl is added, the reaction is carried out for 2h at the temperature, and the reaction is monitored to ensure that the 7-ATCA. HCl is less than or equal to 1.0 percent. After the reaction is finished, adding 1000ml of water, adjusting the pH value to 6-7 by using 35% hydrochloric acid solution, stirring and separating liquid, and keeping a water phase; the organic phase was extracted with 500ml, 300ml of water in this order and the aqueous phases were combined.
(3) After the combination, 25g of activated carbon, 25g of alumina and 1.0g of sodium bisulfite are added into the water phases for decolorization for 0.5h, the mixture is filtered, and the filter cake is washed by 200ml of water. Collecting the filtrate, adding 400ml of isopropanol into the filtrate, controlling the temperature at 23 ℃, slowly dropwise adding a 35% hydrochloric acid solution until the pH value is 2.0-3.0, and finishing dropwise adding for about 2 hours. Then cooling to 6 ℃ for crystal growth for 2h, filtering, washing with 400ml of water multiplied by 2, washing with 400ml of isopropanol, and vacuum drying at 40-45 ℃ for 6h to obtain 221.4g of white crystal powder with the molar yield of 88.9%. Purity 99.56%, maximum single impurity 0.13%.
Comparative example the example in Chinese patent CN101550150
(1) Synthesis of 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetic acid hydrochloride
201 g of 2- (2-aminothiazole-4-yl) -2-methoxyiminoacetic acid and 280 g of triphenylchloromethane are added to 600ml of DMF and reacted at room temperature for 4 hours, then 1 l of diisopropyl ether is slowly added thereto, and stirring is carried out to precipitate a solid which is filtered, washed with a small amount of diisopropyl ether and dried to obtain 460 g of a product with a yield of 96%.
(2) Synthesis of cefotaxime hydrochloride
326 g of 2- (2-tritylaminothiazol-4-yl) -2-methoxyiminoacetic acid hydrochloride and N, N-diisopropylethylamine were added to 500ml of DMF, the reaction was cooled to 10 ℃, 130 g (0.68mol) of p-toluenesulfonyl chloride was added, the reaction was stirred at this temperature for 1 hour, 185 g (0.68mol) of 7-ACA and 300ml of triethylamine were added, the mixture was vigorously stirred at 5 to 10 ℃ for 0.5 hour, 500ml of 6mol/L hydrochloric acid was added, the temperature was raised to 45 ℃, the reaction was stirred for 1.5 hours, the mixture was cooled to room temperature, 4L of acetone and 300ml of water were added, the solid was precipitated by stirring at room temperature, the mixture was filtered, washed with acetone, and dried under vacuum at 40 ℃ to obtain 314 g of a product with a yield of 94%.
(3) Synthesis of cefmenoxime
Dissolving 200 g of cefotaxime hydrochloride in 5000ml of mixed solvent of distilled water and 2500ml of acetone, adding 1-methyl-5-mercapto-1H-tetrazole, stirring and heating to 55 ℃, then adjusting the pH value of a reaction system to 6.5-7 by using 3% sodium carbonate aqueous solution, reacting for 4 hours at the temperature, adding activated carbon for decolorization, then cooling to room temperature, filtering, adjusting the pH value of filtrate to 6 by using 2mol/L hydrochloric acid, respectively extracting twice by using 500ml of ethyl acetate, adjusting the pH value of an aqueous phase to 2.5 by using 2mol/L hydrochloric acid, stirring and precipitating solids, filtering, washing a filter cake by using water, and drying to obtain 202 g of a product, wherein the yield is 93.7%. White-like crystalline powder in product properties. The purity is 99.4%.
The total yield of the comparative example is 84.6%, the purity and the yield are obviously different from those of the method, and the raw materials of the triphenylchloromethane and the paratoluensulfonyl chloride used in the method are expensive, so the cost is increased greatly in the industrial production process.
The cefmenoxime hydrochloride product obtained by the invention is confirmed by elemental analysis and mass spectrometry, and is specifically shown in tables 1-2.
TABLE 1 elemental analysis (C)16H17N9O5S3)2·HCl
TABLE 2 Mass Spectrometry results
| Mass to charge ratio (m/z) | Relative abundance (%) | Remarks for note |
| 533 | 33.8 | M-H+Na |
| 511 | 41.7 | M |
| 395 | 72.4 | M+-116 |
| 367 | 32.2 | M+-144 |
| 323 | 100 | M+-188 |
The present invention has been described in detail for the purpose of illustration, and it is not intended to limit the scope of the invention to the exact construction and operation of the invention, and all equivalent changes and modifications made without departing from the spirit and scope of the invention are intended to be covered by the appended claims.
Claims (7)
1. The preparation method of cefmenoxime hydrochloride is characterized by comprising the following steps:
(1) in an organic solvent, carrying out a reaction on the aminothiazoly loximate and a trimethylsilyl protective agent at the reaction temperature of 20-50 ℃ to obtain a reaction solution of a compound shown in a formula III; the trimethylsilyl protective agent is N, O-bis (trimethylsilyl) acetamide or hexamethyldisilazane;
(2) adding an activating agent and organic base into the reaction liquid generated in the step (1) to react at a temperature of between 5 ℃ below zero and 5 ℃ to activate the carboxyl of the compound shown in the formula III; then adding 7-ATCA hydrochloride to react at-20 to-10 ℃; after the reaction is finished, adding water and a hydrochloric acid solution into the reaction liquid to adjust the pH value to be 6.0-7.0, stirring and separating liquid, and keeping a water phase; the activating reagent is thionyl chloride, pivaloyl chloride or ethyl chloroformate; the organic base is triethylamine, N-diisopropylethylamine or pyridine;
(3) and (3) decolorizing the water phase, adding an organic solvent, dropwise adding a hydrochloric acid solution until the pH value of the system is 2.0-3.0, and cooling and growing crystals after the dropwise adding is finished to obtain the cefmenoxime hydrochloride.
2. The method for preparing cefmenoxime hydrochloride according to claim 1, wherein the solvent used in step (1) is dichloromethane, acetonitrile, tetrahydrofuran or N, N-dimethylformamide.
3. The method for preparing cefmenoxime hydrochloride according to claim 1, wherein the amount of trimethylsilyl protective agent used in step (1) is 1.0eq to 1.5eq based on the amount of aminothiazoly loximate.
4. The method for preparing cefmenoxime hydrochloride according to claim 1, wherein the amount of the activating reagent is 1.0eq to 1.2eq, the amount of the organic base is 1.5eq to 5.0eq, and the amount of 7-ATCA hydrochloride is 0.85eq to 1.0eq, based on the amount of the aminothiazoly loximate in step (2).
5. The method for preparing cefmenoxime hydrochloride according to claim 1, wherein the organic solvent in step (3) is an alcohol, a ketone, tetrahydrofuran or acetonitrile; the volume ratio of the organic solvent to the water is 1: 1-1: 10.
6. The method for preparing cefmenoxime hydrochloride according to claim 1, wherein the temperature is controlled to be 20 ℃ to 30 ℃ during the dropwise addition of the hydrochloric acid solution in the step (3).
7. The method for preparing cefmenoxime hydrochloride according to any one of claims 1 to 6, wherein the temperature of crystal growth in step (3) is 5 ℃ to 20 ℃ and the time of crystal growth is 1h to 4 h.
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| CN108383857A (en) | 2018-08-10 |
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Denomination of invention: A preparation method of cefuroxime hydrochloride Effective date of registration: 20211214 Granted publication date: 20210205 Pledgee: Bank of Qilu Co.,Ltd. Dezhou Pingyuan sub branch Pledgor: SHANDONG SIHUAN PHARMACEUTICAL CO.,LTD. Registration number: Y2021980014872 |