CN111518151B - Preparation method of high-purity hydrocortisone - Google Patents
Preparation method of high-purity hydrocortisone Download PDFInfo
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- CN111518151B CN111518151B CN202010343252.XA CN202010343252A CN111518151B CN 111518151 B CN111518151 B CN 111518151B CN 202010343252 A CN202010343252 A CN 202010343252A CN 111518151 B CN111518151 B CN 111518151B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
- C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
- C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
Abstract
The invention discloses a preparation method of high-purity hydrocortisone, and belongs to the technical field of preparation and processing of medicines. The method takes 17 alpha-hydroxypregna-4, 9(11) -diene-3, 20-diketone-21-acetate as a starting material, and prepares the high-purity hydrocortisone through three steps of hydroxyl bromination, debromination and hydrolysis. The preparation method of the high-purity hydrocortisone can effectively shorten the reaction process, control the generation of impurities in the reaction process, avoid the use of iodine with high toxicity and unfriendliness to the environment, and reduce the pollution to the environment by improving the defects of the traditional process.
Description
Technical Field
The invention relates to the technical field of preparation of medicines, and particularly relates to a preparation method of high-purity hydrocortisone.
Background
Hydrocortisone and derivatives thereof are high-activity adrenocortical hormone drugs with the effects of influencing glycometabolism, resisting inflammation, allergy, shock and the like, and products thereof comprise hydrocortisone, hydrocortisone acetate, hydrocortisone sodium phosphate and the like. The product is widely applied to the treatment of anaphylactic diseases such as adrenal cortex function insufficiency, rheumatoid diseases, lupus erythematosus, bronchial asthma, dermatitis and the like, and has wide market prospect.
At present, hydrocortisone is mainly prepared by two methods, namely a chemical synthesis method and a biological synthesis method, wherein the chemical synthesis method has the problems of overlong reaction route, complex reaction process, excessive impurities and easy pollution, such as: 1) ZL200710061260.X discloses a chemical synthesis route of hydrocortisone, which is prepared by taking 17-hydroxy-4, 9-diene-pregna-3, 20-diketone as a starting material through bromination, debromination, iodination, replacement and hydrolysis, and the route is as follows:
2) ZL201110201729.1 discloses a preparation method of hydrocortisone, which takes an intermediate 17 alpha-hydroxy-4-pregnene-3, 11, 20-trione (II) of a rhizopus nigricans method as a raw material, and ethylene glycol, triethyl orthoformate and p-toluenesulfonic ketal are reacted to obtain 17 alpha-hydroxy-4-pregnene-11-one-3, 20-diethylene glycol ketal (III); reducing with borohydride to obtain 11 beta, 17 alpha-dihydroxy-4-pregnene-3, 20-diethylene glycol ketal (IV); hydrolyzing with inorganic acid to obtain 11 beta, 17 alpha-dihydroxy-4-pregnene-3, 20-diketone (V); iodine reacts on calcium oxide by iodine to obtain 21-iodine-11 beta, 17 alpha-dihydroxy-4-pregnene-3, 20-diketone (VI); performing replacement reaction by using potassium acetate and acetic acid to obtain hydrocortisone acetate (VII); finally, the hydrocortisone (I) is obtained by hydrolysis reaction with sodium hydroxide, and the reaction route is as follows:
the two chemical synthesis routes have the problems of long route and the like, iodine with high toxicity and unfriendly environment is required to be used in the reaction process, and more impurities are generated in the iodine replacement process, so that the iodine replacement process is difficult to remove and is not suitable for industrial production.
In addition, the biosynthesis method can overcome the problems of too long reaction route, more impurities, easy pollution generation and the like of the chemical synthesis method, is widely welcomed, but has low yield and is still in the stage of further research at present.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method of hydrocortisone with short reaction route, simple reaction process, low pollution and high purity.
The purpose of the invention is realized by the following modes: a preparation method of high-purity hydrocortisone comprises the following synthetic route:
the method specifically comprises the following steps:
1) and (3) carrying out hydroxyl bromine reaction: dissolving 17 alpha-hydroxypregna-4, 9(11) -diene-3, 20-diketone-21-acetate (1) in an organic solvent A, adding an acid catalyst, cooling to-5 ℃, adding a brominating agent, stirring for reaction, adding an alkali liquor A for neutralization after the reaction is finished, concentrating to remove the organic solvent, performing water separation, and filtering to obtain an intermediate 2;
2) debromination reaction: under the protection of nitrogen, dissolving the intermediate (2) obtained in the step 1) in an organic solvent B, adding thioglycolic acid, zinc powder and chromium trichloride hexahydrate, controlling the temperature to be minus 5-10 ℃ for stirring reaction, after the reaction is finished, adding an alkali liquor A for neutralization, concentrating, elutriating, filtering to obtain a crude product of hydrocortisone acetate (3), dissolving the obtained crude product of hydrocortisone acetate (3) in an organic solvent C, sequentially adding a saline solution, glacial acetic acid and a sodium hypochlorite aqueous solution, controlling the temperature to be 15-40 ℃ for stirring reaction, after the reaction is finished, filtering, concentrating, cooling to be minus 5-5 ℃ for crystallization, filtering, and drying to obtain a fine product of hydrocortisone acetate (3);
3) and (3) hydrolysis reaction: dissolving the fine hydrocortisone acetate (3) obtained in the step 2) in an organic solvent C, cooling to-10 ℃, adding an alkali liquor B, stirring for reaction, neutralizing with glacial acetic acid after the reaction is finished, concentrating to remove the organic solvent, performing water precipitation, filtering, and refining to obtain the hydrocortisone (4).
Further, the organic solvent A in the step 1) is acetone or butanone, and the volume amount of the organic solvent A is 5-30 times of that of the substrate 17 alpha-hydroxypregna-4, 9(11) -diene-3, 20-dione-21-acetate (1); wherein the acid catalyst is one of perchloric acid, fluoroboric acid, methanesulfonic acid or trifluoroacetic acid, the mass concentration is 5-30%, and the volume consumption of the acid catalyst is 0.5-1.5 times of that of 17 alpha-hydroxypregna-4, 9(11) -diene-3, 20-diketone-21-acetate (1) serving as a substrate; wherein the brominating agent is dibromodimethylhydantoin or N-bromosuccinimide, and the weight consumption of the brominating agent is 0.4-1.2 times of that of 17 alpha-hydroxypregna-4, 9(11) -diene-3, 20-diketone-21-acetate (1) serving as a substrate; the alkali liquor A is one of a sodium sulfite aqueous solution, a sodium carbonate aqueous solution, a sodium bicarbonate aqueous solution, a sodium metabisulfite aqueous solution or ammonia water, and the mass concentration of the alkali liquor A is 5-30%.
Further, in the step 2), the organic solvent B is at least one of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, acetone, tetrahydrofuran or 2-methyltetrahydrofuran, and the volume amount of the organic solvent B is 5-15 times that of the intermediate (2); wherein the volume usage amount of the thioglycolic acid is 0.2-1.2 times of that of the intermediate (2); wherein the weight amount of the zinc powder is 0.2-1.0 time of that of the intermediate (2); wherein the weight amount of the chromium trichloride hexahydrate is 0.03-0.1 time of that of the intermediate (2); the organic solvent C is a mixed solvent of dichloromethane and at least one alcohol of methanol, ethanol or isopropanol, the volume ratio of the dichloromethane to the alcohol is 1: 0.5-3, and the volume consumption of the organic solvent C is 10-30 times of that of the crude hydrocortisone acetate (3); wherein the saline solution is one of sodium chloride, potassium chloride, ammonium chloride or lithium chloride, the mass concentration of the saline solution is 0.5-5%, and the volume consumption of the saline solution is 0.5-3 times of that of the crude hydrocortisone acetate (3); wherein the volume dosage of the glacial acetic acid is 0.03-0.1 time of the crude product of the hydrocortisone acetate (3); wherein the mass concentration of the sodium hypochlorite aqueous solution is 5-13%, and the volume consumption of the sodium hypochlorite aqueous solution is 0.1-0.5 times of that of the crude product of hydrocortisone acetate (3).
Further, in the step 3), the volume usage amount of the organic solvent C is 10-30 times of that of the refined hydrocortisone acetate (3); wherein the alkali liquor B is at least one of sodium hydroxide, potassium carbonate, sodium sulfite, triethylamine, 1, 8-diazabicycloundece-7-ene or potassium hydroxide aqueous solution, the mass concentration of the alkali liquor is 1-10%, and the volume consumption of the alkali liquor is 1-5 times of that of the fine hydrocortisone acetate (3).
Compared with the prior art, the invention has the beneficial effects that:
1. the method has the advantages of short process route, convenient operation, no use of iodine with high toxicity and unfriendly environment, and suitability for industrial production.
2. The method is particularly added with the reaction step of removing impurities, so that raw materials which are not completely reacted can be well removed, the product purity is improved, and the product purity is higher than 99.5%.
3. The invention has mild reaction, is carried out under the condition of low temperature or room temperature, and has the total mass yield higher than 75 percent.
4. Low requirement on a reaction device, low running cost, simple and convenient operation, suitability for industrial production and better market prospect.
Detailed Description
The invention is further illustrated with reference to the following examples, which are not intended to limit the invention.
The specific experimental procedures or conditions are not shown in the examples, and the procedures can be performed according to the conventional experimental methods described in the publications in the field, and the reagents or equipment used are not indicated by manufacturers, and are all conventional products which can be obtained commercially.
Example 1 a method for preparing high purity hydrocortisone, comprising the steps of:
1) and (3) carrying out hydroxyl bromine reaction: adding 50 g of 17 alpha-hydroxypregna-4, 9(11) -diene-3, 20-dione-21-acetate (1) into 300 ml of acetone, adding 70 ml of perchloric acid aqueous solution with the mass concentration of 5%, cooling to 5 ℃, adding 25 g of N-bromosuccinimide, stirring for reaction, neutralizing with 5% of sodium sulfite aqueous solution with the mass concentration after the reaction is finished, concentrating the organic solvent, carrying out water precipitation, and filtering to obtain 66 g of an intermediate (2).
2) Debromination reaction: under the protection of nitrogen, 66 g of the intermediate (2) is dissolved in 130 ml of N, N-dimethylformamide and 300 ml of tetrahydrofuran, 33 ml of thioglycolic acid, 40 g of zinc powder and 2 g of chromium trichloride hexahydrate are added, the mixture is stirred and reacted at the controlled temperature of 5 ℃, after the reaction is finished, the mixture is neutralized by a 5% sodium bicarbonate aqueous solution, 2-methyltetrahydrofuran is concentrated, water is separated out, and 50 g of a crude product of hydrocortisone acetate (3) is obtained by filtering; and dissolving the obtained 50 g of hydrocortisone acetate (3) crude product in 400 ml of dichloromethane and 300 ml of methanol, adding 100 ml of 1% potassium chloride aqueous solution, 3 ml of glacial acetic acid and 5 ml of 13% sodium hypochlorite aqueous solution, controlling the temperature to 25 ℃, stirring for reaction, filtering, concentrating, cooling to-5 ℃ for crystallization, filtering, and drying to obtain 45 g of hydrocortisone acetate (3) refined product.
3) And (3) hydrolysis reaction: dissolving 45 g of the refined hydrocortisone acetate (3) in 200 ml of dichloromethane and 250 ml of isopropanol mixed organic solvent, cooling to-10 ℃, adding 45 ml of 2% sodium hydroxide aqueous solution, stirring for reaction, neutralizing with glacial acetic acid after the reaction is finished, concentrating to remove the organic solvent, carrying out water precipitation, filtering, and refining once with the mixed organic solvent to obtain 37.7 g of hydrocortisone (4), wherein the melting point of the product is 212.3-213.4 ℃, the HPLC content is 99.6%, and the total mass yield is 75.4%.
Embodiment 2 a method for preparing high purity hydrocortisone, comprising the steps of:
1) and (3) carrying out hydroxyl bromine reaction: adding 50 g of 17 alpha-hydroxypregne-4, 9(11) -diene-3, 20-dione-21-acetate (1) into 1500 ml of acetone, adding 50 ml of a fluoroboric acid aqueous solution with the mass concentration of 10%, cooling to-5 ℃, adding 60 g of dibromodimethylhydantoin, stirring for reaction, neutralizing with a sodium carbonate aqueous solution with the mass concentration of 10% after the reaction is finished, concentrating to remove an organic solvent, carrying out water precipitation, and filtering to obtain 67 g of an intermediate (2).
2) Debromination reaction: under the protection of nitrogen, 67 g of the intermediate (2) is dissolved in 300 ml of dimethyl sulfoxide and 500 ml of 2-methyltetrahydrofuran, 14 ml of thioglycolic acid, 15 g of zinc powder and 3 g of chromium trichloride hexahydrate are added, the temperature is controlled to be minus 5 ℃ for stirring reaction, after the reaction is finished, 10% of ammonia water is added for neutralization, concentration and water precipitation are carried out, 52 g of a crude product of hydrocortisone acetate (3) is obtained by filtration, then the obtained 52 g of the crude product of hydrocortisone acetate (3) is dissolved in 250 ml of dichloromethane and 300 ml of ethanol, 26 ml of 5% sodium chloride aqueous solution, 1.6 ml of glacial acetic acid and 25 ml of 5% sodium hypochlorite aqueous solution by mass concentration are added, the temperature is controlled to be 40 ℃ for stirring reaction, after the reaction is finished, filtration and concentration are carried out, the temperature is reduced to be 5 ℃ for crystallization, the filtration and.
3) And (3) hydrolysis reaction: dissolving 45.5 g of the refined hydrocortisone acetate (3) in 300 ml of dichloromethane and 600 ml of methanol mixed organic solvent, cooling to-5 ℃, adding 100 ml of potassium hydroxide aqueous solution with the mass concentration of 1% and 45 ml of potassium carbonate aqueous solution with the mass concentration of 1% to obtain mixed alkali solution, stirring for reaction, neutralizing with glacial acetic acid after the reaction is finished, concentrating to remove the organic solvent, carrying out water precipitation, filtering, and refining with the mixed organic solvent once to obtain 38.0 g of hydrocortisone (4), wherein the melting point of the product is 212.5-213.6 ℃, the HPLC content is 99.7%, and the total mass yield is 76.0%.
Embodiment 3 a method for preparing high purity hydrocortisone, comprising the steps of:
1) and (3) carrying out hydroxyl bromine reaction: adding 50 g of 17 alpha-hydroxypregna-4, 9(11) -diene-3, 20-dione-21-acetate (1) into 1000 ml of butanone, adding 25 ml of methanesulfonic acid aqueous solution with the mass concentration of 30%, cooling to 0 ℃, adding 45 g of dibromodimethylhydantoin, stirring for reaction, neutralizing with ammonia water with the mass concentration of 30% after the reaction is finished, concentrating to remove the organic solvent, carrying out water precipitation, filtering, and obtaining an intermediate 2 by 65 g.
2) Debromination reaction: under the protection of nitrogen, 65 g of the intermediate (2) is dissolved in 200 ml of N, N-dimethylformamide and 750 ml of acetone, 70 ml of thioglycolic acid, 65 g of zinc powder and 6.5 g of chromium trichloride hexahydrate are added, the mixture is stirred and reacted at 10 ℃ under the control of temperature, after the reaction is finished, sodium carbonate aqueous solution with the mass concentration of 30% is added for neutralization, concentration and water separation are carried out, 49 g of crude hydrocortisone acetate (3) is obtained through filtration, then the obtained 49 g of crude hydrocortisone acetate (3) is dissolved in 1000 ml of dichloromethane and 450 ml of isopropanol, 145 ml of 0.5% ammonium chloride aqueous solution, 4.9 ml of glacial acetic acid and 10 ml of 10% aqueous solution of sodium hypochlorite are added, the stirring and reaction is carried out at 15 ℃ under the control of temperature, after the reaction is finished, filtration and concentration are carried out, the temperature is reduced to 0 ℃ for crystallization, the filtration and the drying.
3) And (3) hydrolysis reaction: dissolving the refined hydrocortisone acetate (3) 44.8 g in a mixed solvent of dichloromethane and ethanol 840 ml, cooling to 10 ℃, adding 200 ml of 10% by mass triethylamine aqueous solution alkali liquor, stirring for reaction, neutralizing with glacial acetic acid after the reaction is finished, concentrating to remove the organic solvent, carrying out water precipitation, filtering, and refining once with the organic solvent to obtain hydrocortisone (4) 37.5 g, wherein the melting point of the product is 212.1-213.3 ℃, the HPLC content is 99.5%, and the total mass yield is 75.0%.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any changes or substitutions that can be easily conceived by those skilled in the art within the technical scope of the present invention are included in the scope of the present invention.
Claims (1)
1. A preparation method of high-purity hydrocortisone is characterized in that the synthetic route of the method is as follows:
the method specifically comprises the following steps:
1) and (3) carrying out hydroxyl bromine reaction: dissolving 17 alpha-hydroxypregna-4, 9(11) -diene-3, 20-diketone-21-acetate (1) in an organic solvent A, adding an acid catalyst, cooling to-5 ℃, adding a brominating agent, stirring for reaction, adding an alkali liquor A for neutralization after the reaction is finished, concentrating to remove the organic solvent, performing water separation, and filtering to obtain an intermediate 2;
wherein the organic solvent A is acetone or butanone, and the volume consumption of the organic solvent A is 5-30 times of that of 17 alpha-hydroxypregna-4, 9(11) -diene-3, 20-dione-21-acetate (1) serving as a substrate; wherein the acid catalyst is one of perchloric acid, fluoroboric acid, methanesulfonic acid or trifluoroacetic acid, the mass concentration is 5-30%, and the volume consumption of the acid catalyst is 0.5-1.5 times of that of 17 alpha-hydroxypregna-4, 9(11) -diene-3, 20-diketone-21-acetate (1) serving as a substrate; wherein the brominating agent is dibromodimethylhydantoin or N-bromosuccinimide, and the weight consumption of the brominating agent is 0.4-1.2 times of that of 17 alpha-hydroxypregna-4, 9(11) -diene-3, 20-diketone-21-acetate (1) serving as a substrate; wherein the alkali liquor A is one of sodium sulfite aqueous solution, sodium carbonate aqueous solution, sodium bicarbonate aqueous solution, sodium metabisulfite aqueous solution or ammonia water, and the mass concentration of the alkali liquor A is 5-30%;
2) debromination reaction: under the protection of nitrogen, dissolving the intermediate (2) obtained in the step 1) in an organic solvent B, adding thioglycolic acid, zinc powder and chromium trichloride hexahydrate, controlling the temperature to be minus 5-10 ℃ for stirring reaction, after the reaction is finished, adding an alkali liquor A for neutralization, concentrating, elutriating, filtering to obtain a crude product of hydrocortisone acetate (3), dissolving the obtained crude product of hydrocortisone acetate (3) in an organic solvent C, sequentially adding a saline solution, glacial acetic acid and a sodium hypochlorite aqueous solution, controlling the temperature to be 15-40 ℃ for stirring reaction, after the reaction is finished, filtering, concentrating, cooling to be minus 5-5 ℃ for crystallization, filtering, and drying to obtain a fine product of hydrocortisone acetate (3);
wherein the organic solvent B is at least one of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, acetone, tetrahydrofuran or 2-methyltetrahydrofuran, and the volume consumption of the organic solvent B is 5-15 times that of the intermediate (2); wherein the volume usage amount of the thioglycolic acid is 0.2-1.2 times of that of the intermediate (2); wherein the weight amount of the zinc powder is 0.2-1.0 time of that of the intermediate (2); wherein the weight amount of the chromium trichloride hexahydrate is 0.03-0.1 time of that of the intermediate (2); the organic solvent C is a mixed solvent of dichloromethane and at least one alcohol of methanol, ethanol or isopropanol, the volume ratio of the dichloromethane to the alcohol is 1: 0.5-3, and the volume consumption of the organic solvent C is 10-30 times of that of the crude hydrocortisone acetate (3); wherein the saline solution is one of sodium chloride, potassium chloride, ammonium chloride or lithium chloride, the mass concentration of the saline solution is 0.5-5%, and the volume consumption of the saline solution is 0.5-3 times of that of the crude hydrocortisone acetate (3); wherein the volume dosage of the glacial acetic acid is 0.03-0.1 time of the crude product of the hydrocortisone acetate (3); wherein the mass concentration of the sodium hypochlorite aqueous solution is 5-13%, and the volume consumption of the sodium hypochlorite aqueous solution is 0.1-0.5 time of that of the crude product of hydrocortisone acetate (3);
3) and (3) hydrolysis reaction: dissolving the fine hydrocortisone acetate (3) obtained in the step 2) in an organic solvent C, cooling to-10 ℃, adding an alkali liquor B, stirring for reaction, neutralizing with glacial acetic acid after the reaction is finished, concentrating to remove the organic solvent, performing water precipitation, filtering, and refining to obtain the hydrocortisone (4);
wherein the volume consumption of the organic solvent C is 10-30 times of that of the refined hydrocortisone acetate (3); wherein the alkali liquor B is at least one of sodium hydroxide, potassium carbonate, sodium sulfite, triethylamine, 1, 8-diazabicycloundece-7-ene or potassium hydroxide aqueous solution, the mass concentration of the alkali liquor is 1-10%, and the volume consumption of the alkali liquor is 1-5 times of that of the fine hydrocortisone acetate (3).
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| CN112125943A (en) * | 2020-08-14 | 2020-12-25 | 浙江神洲药业有限公司 | Preparation method of high-purity 16 alpha-hydroxy prednisolone |
| CN113583071A (en) * | 2021-08-12 | 2021-11-02 | 丽江映华生物药业有限公司 | Preparation method of hydrocortisone crude product |
| CN113583072A (en) * | 2021-08-17 | 2021-11-02 | 丽江映华生物药业有限公司 | Refining method of hydrocortisone |
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| CN101397321A (en) * | 2007-09-29 | 2009-04-01 | 天津药业研究院有限公司 | Preparation of hydrocortisone and derivatives thereof |
| CN107400153A (en) * | 2017-04-23 | 2017-11-28 | 浙江仙琚制药股份有限公司 | A kind of preparation method of hydrocortisone acetate |
| CN109851653A (en) * | 2018-11-21 | 2019-06-07 | 奥锐特药业股份有限公司 | The preparation method of 16 alpha-hydroxy prednisonlones |
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| US5426198A (en) * | 1987-08-14 | 1995-06-20 | The Upjohn Company | 9α-dehalogenation process |
| CN101397321A (en) * | 2007-09-29 | 2009-04-01 | 天津药业研究院有限公司 | Preparation of hydrocortisone and derivatives thereof |
| CN107400153A (en) * | 2017-04-23 | 2017-11-28 | 浙江仙琚制药股份有限公司 | A kind of preparation method of hydrocortisone acetate |
| CN109851653A (en) * | 2018-11-21 | 2019-06-07 | 奥锐特药业股份有限公司 | The preparation method of 16 alpha-hydroxy prednisonlones |
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Denomination of invention: A preparation method of high purity hydrocortisone Effective date of registration: 20210728 Granted publication date: 20210302 Pledgee: Xianju Branch of Industrial and Commercial Bank of China Ltd. Pledgor: ZHEJIANG SHENZHOU PHARMACEUTICAL Co.,Ltd. Registration number: Y2021330001013 |
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