CN101429207B - Process for producing 7-amino-3-[(1-methyl pyrrolidine) methyl]-3- cephalosporin-4-carboxylic dihydrochloride - Google Patents
Process for producing 7-amino-3-[(1-methyl pyrrolidine) methyl]-3- cephalosporin-4-carboxylic dihydrochloride Download PDFInfo
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Abstract
The invention discloses a method for preparing 7-amino-3-[(1-methylpyrro-lidinio)methyl]-3-cephem-4-carboxylic acid dihydrochloride, which comprises the following steps: imidazole, trimethylchlorosilane and 7-ACA react in a methylene dichloride solvent at a temperature of between 10 and 30 DEG C, and then are filtered; the temperature is reduced, and TMSI is dripped to react; THF is added into the mixture after methylene dichloride is distilled from a reaction feed liquid, and a N-methylpyrrolidine solution is dripped and stirred at a temperature of between 30 DEG C below zero and 25 DEG C below zero to react; methanol is dripped after the reaction, and then concentrated hydrochloric acid or hydriodic acid is dripped to hydrolyze; a hydrolysate is added with the methylene dichloride, and an aqueous phase is obtained through the separation; a yellow aqueous solution is obtained after the aqueous phase is decolored; and then acetone is added into the mixture to be filtered, washed and dried to obtain a 7-MPCA product. The methylene dichloride is distilled, so as to effectively improve the utilization rate of equipment, and the method can improve 30 percent of the utilization rate ofthe equipment compared with a process that the methylene dichloride is not distilled; and imidazole hydrochloride generated by the reaction which affects the subsequent layering and crystallization is filtered, which is favorable for the reaction, and ensures that the yield can reach 100 percent and the purity of a liquid phase is more than 99 percent.
Description
Technical field
The present invention relates in the medicine intermediate field, and the synthetic method that is specifically related to a kind of cephalosporins intermediate is 7-amino-3-[(1-methyl Pyrrolidine) methyl]-3-cephalo-4-carboxylic acid dihydrochloride's synthetic method.
Background technology
Cefepime Hydrochloride be the 4th generation cephalosporin for injections, step one by cloth and execute your treasured (Bristol-MyersSquibb) and develop, after Sweden's Initial Public Offering, be used to the treatment of various bacteria infectious diseases in 1993.The has a broad antifungal spectrum of cefepime, it had both kept the anti-microbial effect good to Gram-negative bacteria, has stronger staphylococcus activity again, anti-microbial effect is strong, stability to β-Nei Xiananmei is high, and therefore the medication better tolerance is a kind of rising microbiotic, the intermediate 7-amino-3-[(1-methyl Pyrrolidine that synthesizes it) methyl]-3-cephalo-4-carboxylic acid dihydrochloride (7-MPCA), its structural formula is:
U.S. Pat 4868294 and US 4714760 etc. disclose the preparation method of cefepime Hydrochloride; they all are to be raw material with 7-amino-cephalosporanic acid (7-ACA); as amino and carboxyl-protecting group, make 7-amino-3-[(1-methyl Pyrrolidine with " one kettle way " with hexamethyldisilazane (HMDS)) methyl]-3-cephalo-4-carboxylic acid dihydrochloride's (7-MPCA) synthetic route.This method uses HMDS that amino among the 7-ACA and carboxy protective are got up, and product need not separate and can further react and formation intermediate 7-MPCA with Iodotrimethylsilane (TMSI), N-crassitude (NMP), methyl alcohol, hydrochloric acid etc.This method synthetic reaction condition is simple to operate, the purity height of product 7-MPCA, and its yield can reach 50%～60%.But in this patent application with hexamethyldisilazane (HMDS) in Freon 113 (or naphthenic hydrocarbon, methylene dichloride, tetracol phenixin, chloroform etc.) solvent under reflux state amino and the carboxyl of protection 7-ACA; long reaction time; side reaction is many; product colour and second-rate has influence on the yield and the quality of the finished product.
Summary of the invention:
It is short to the invention provides a kind of reaction times; temperature of reaction is low; side reaction is few; what energy consumption was low protects the amino of 7-ACA and carboxyl to prepare 7-amino-3-[(1-methyl Pyrrolidine in methylene dichloride with imidazoles and trimethylchlorosilane (TMSC1)) methyl]-3-cephalo-4-carboxylic acid dihydrochloride is the method for cefepime, to overcome the drawback that prior art exists.
Be to realize the object of the invention, this 7-amino-3-[(1-methyl Pyrrolidine) methyl]-its feature of preparation method of 3-cephalo-4-carboxylic acid dihydrochloride may further comprise the steps:
A. in dichloromethane solvent, with amino and the carboxyl of imidazoles and trimethylchlorosilane protection 7-ACA;
B.A step reaction finishes after-filtration, removes the imidazole hydrochloride that dereaction generates;
C. the distillation of the filtrate of B step is concentrated, add the synthetic 3-position of Iodotrimethylsilane reaction iodo thing intermediate after steaming part methylene chloride;
D. the C step is distilled the cefepime intermediate that concentrated dichloromethane solution that contains 3-position iodo thing intermediate that obtains and activatory N-crassitude solution reaction obtain containing protecting group;
The 7-amino that the E.D one-step hydrolysis obtains-3-[(1-methyl Pyrrolidine) methyl]-3-cephalo-4-carboxylic acid solution adds growing the grain behind the acetone, and crystallization is filtered, dry 7-amino-3-[(1-methyl Pyrrolidine) methyl]-3-cephalo-4-carboxylic acid dihydrochloride.
The mol ratio of 7-ACA, imidazoles and trimethylchlorosilane is 1: 1.5～4: 2～4 in the described A step, be preferably 1: 2～3: 2～and 3.5; Its temperature of reaction is 10～30 ℃, is preferably 20～25 ℃, and its reaction only needed finish in 2～3 hours through the experimental data proof.
Described Iodotrimethylsilane (TMSI) is 1: 1.2～2 with the mol ratio of 7-ACA, and its temperature of reaction is 10～20 ℃, adopts HPLC to follow the tracks of reaction end, finishes less than 1% afterreaction when 7-ACA is residual.
The preparation method of described activatory N-crassitude solution is: the N that slowly drips 1～1.5 times of volume in container behind the DMF of the N-crassitude of 1 times of volume of adding and 2～2.5 times of volumes under vigorous stirring, the two silica-based ethanamides of front three (BSA) of O-, reaction got final product after 1 hour under 10～25 ℃ of stirring insulations.
The mol ratio of described activatory N-crassitude and 7-ACA is 1: 1.05～2, and temperature of reaction is-30～-25 ℃, adopts HPLC to follow the tracks of reaction end, when 3-position iodo thing intermediate residual less than 2% the time reaction finish.
Described strong acid adopts hydrochloric acid or hydroiodic acid HI, and the add-on of described acetone is 4～7 times of liquor capacity, and Tc is 0～10 ℃, crystallization time 1～6 hour.
Building-up reactions formula of the present invention:
The technical progress that the present invention obtains: 1. because in dichloromethane solvent; amino and carboxyl with imidazoles and trimethylchlorosilane protection 7-ACA; 20～25 ℃ of temperature of reaction; only experimental results show that needed to react completely in 2～3 hours; and temperature of reaction is low, and speed of response is fast, greatly reduces the decomposition of 7-ACA; side reaction is few, and the weight yield of product is up to 100%.And traditional technology 7-ACA adds hexamethyldisilazane (HMDS) in methylene dichloride, and temperature is up to 45～50 ℃ under the reflux state, and reaction in 8～15 hours just finishes, the temperature of reaction height, and long reaction time, side reaction is many, and yield is low.Since with imidazoles, trimethylchlorosilane and 7-ACA reaction generate influence subsequent hierarchy and the crystalline imidazole hydrochloride filters, help the carrying out of subsequent reactions.3. because the dichloromethane solvent that will react in the feed liquid distills, effectively improved plant factor,, can improve plant factor 30% with the not technology comparison of distilled dichloromethane; 4. owing to adopt hydrochloric acid or hydroiodic acid HI in the hydrolysis, cancelled with triethylamine during crystallization and transferred pH, and directly add acetone and prepare 7-amino-3-[(1-methyl Pyrrolidine) methyl]-3-cephalo-4-carboxylic acid dihydrochloride, not only it is than 7-amino-3-[(1-methyl Pyrrolidine) methyl]-3-cephalo-4-carboxylic acid one hydrochloride good fluidity, be convenient to centrifugal, washing and dry, can reach 100% with existing technology comparison in its weight yield of 7-ACA, liquid phase purity is greater than 99%.
Embodiment
The present invention will be further described below in conjunction with specific embodiment.
Embodiment 1:A. adds the 7-ACA of 30g imidazoles, 54g trimethylchlorosilane (TMSC1) and 40g0.147mol successively in the container that the 250ml dichloromethane solvent is housed after, under 20～25 ℃, whipped state, react, 2～3 hours after-filtration are carried out in above-mentioned reaction, influence subsequent hierarchy and the crystalline imidazole hydrochloride that are generated are filtered and remove, to help the carrying out of subsequent reactions;
The filtrate of B. going up step is the 7-ACA dichloromethane solution of silanization, when being cooled to 10～15 ℃, this filtrate drips Iodotrimethylsilane (TMSI) 50ml of 0.183mol, stir then after 15～20 minutes and under 15～20 ℃ of keeping warm modes, react, can adopt HPLC to follow the tracks of reaction end;
C. after the reaction of B step is carried out 3 hours, finish less than 1% afterreaction when 7-ACA is residual, will react feed liquid then and under 101Kp, distill, to distill out excessive dichloromethane solvent in the reaction feed liquid, to help improving plant factor with the HPLC detection;
D. add tetrahydrofuran (THF) (THF) 9ml in 0～5 ℃ when distilling out 130ml methylene dichloride and distillation temperature when being lower than 45 ℃, adding the back stirred 15 minutes, in 30 minutes, drip activatory N-crassitude solution 93ml then, dropwising the back reacted 3 hours under-30～-25 ℃ of insulated and stirred, can adopt HPLC to follow the tracks of reaction end, or sampling detect, when detecting iodo thing＜2%, then condensation reaction finishes, and reaction obtains containing the cefepime intermediate of protecting group;
E. in the solution of the cefepime intermediate that contains protecting group that above-mentioned reaction obtains, drip 20ml methyl alcohol, add that solution temperature is 0～5 ℃ behind the methyl alcohol, concentrated hydrochloric acid 250～the 280ml of dropping 36% is hydrolyzed after stirring 15～20 minutes under this temperature, and hydrolysis obtains 7-amino-3-[(1-methyl Pyrrolidine) methyl]-3-cephalo-4-carboxylic acid;
F. in the said hydrolyzed product, add methylene dichloride 260ml, hydrolysate dissolving this moment, system temperature rises and layering forms organic phase and water, separate obtaining water, and with after the 60ml water extracted organic phase with its with separate the water merging that obtains;
G. the water with above-mentioned merging obtains the yellow aqueous solution with gac after 20～25 ℃ of room temperatures are decoloured;
H. add 600ml acetone under whipped state in the above-mentioned yellow aqueous solution, growing the grain continues to drip 600ml acetone after 30 minutes, continues stirring 60 minutes at 9～10 ℃ then, stirs 60 minutes after-filtration at 8～9 ℃;
I. the crystallisate that leaches with the H step promptly obtains yellow-white 7-MPCA product 44g of the present invention with washing with acetone final vacuum drying (KF13～15%), be 7-amino-3-[(1-methyl Pyrrolidine) methyl]-3-cephalo-4-carboxylic acid dihydrochloride product, HPLC purity is greater than 99.2%.
The preparation method of above-mentioned activatory N-crassitude solution is: slowly drip N add 20mlN-crassitude (0.21mol) and DMF50ml in container after under vigorous stirring, the two silica-based ethanamide of front three (BSA) 25ml (0.105mol) of O-, reaction promptly can be used for the dropping of above-mentioned D step cryogenic fluid after 1 hour under 10～25 ℃ of stirring insulations.
Embodiment 2:
A. after in the container that the 250ml dichloromethane solvent is housed, adding the 7-ACA of 30g imidazoles, 54g trimethylchlorosilane (TMSC1) and 40g0.147mol successively, under 20～25 ℃, whipped state, react, 2～3 hours after-filtration are carried out in above-mentioned reaction, influence subsequent hierarchy and the crystalline imidazole hydrochloride that are generated are filtered and remove, to help the carrying out of subsequent reactions;
Drip Iodotrimethylsilane (TMSI) the solution 50ml of 0.183mol when B. above-mentioned filtrate filtered being cooled to 10～15 ℃, stir then after 15～20 minutes and under 15～20 ℃ of keeping warm modes, react, can adopt HPLC to follow the tracks of reaction end;
C. after the reaction of last step is carried out 3 hours with HPLC detect when the 7-ACA iodo be fully 7-ACA residual less than 1% after then reaction end, to react feed liquid then distills under 101Kp, to distill out excessive dichloromethane solvent in the reaction feed liquid, to help improving plant factor;
D. add tetrahydrofuran (THF) (THF) 9ml in 0～5 ℃ when distilling out 150ml methylene dichloride and distillation temperature when being lower than 25 ℃, adding the back stirred 15 minutes, in 30 minutes, drip activatory N-crassitude solution 93ml then, dropwising the back reacted 3 hours under-30～-25 ℃ of insulated and stirred, can adopt this moment HPLC to follow the tracks of reaction end or sampling detection, when detecting iodo thing＜2%, then condensation reaction finishes, and reaction obtains containing the cefepime intermediate of protecting group;
E. in the solution of the cefepime intermediate that contains protecting group that above-mentioned reaction obtains, drip 20ml methyl alcohol, add that solution temperature is 0～5 ℃ behind the methyl alcohol, drip weight concentration and be concentrated hydrochloric acid 250～280ml of 36% after stirring 15～20 minutes under this temperature and be hydrolyzed, hydrolysis obtains 7-amino-3-[(1-methyl Pyrrolidine) methyl]-3-cephalo-4-carboxylic acid;
F. in the said hydrolyzed product, add methylene dichloride 260ml, hydrolysate dissolving this moment, system temperature rises and layering forms organic phase and water, separate obtaining water, and with after the 60ml water extracted organic phase with its with separate the water merging that obtains;
G. the water with above-mentioned merging obtains the yellow aqueous solution with gac after 20～25 ℃ of room temperatures are decoloured;
H. add 600ml acetone under whipped state in the above-mentioned yellow aqueous solution, growing the grain continues to drip 600ml acetone after 30 minutes, continues stirring 60 minutes at 9～10 ℃ then, stirs 60 minutes after-filtration at 8～9 ℃;
I. the crystallisate that leaches with the H step promptly obtains yellow-white 7-MPCA product 44g of the present invention with washing with acetone final vacuum drying (KF13～15%), be 7-amino-3-[(1-methyl Pyrrolidine) methyl]-3-cephalo-4-carboxylic acid dihydrochloride product, HPLC purity is greater than 99.2%.
The preparation method of activatory N-crassitude solution is identical with embodiment 1 in the present embodiment.
Embodiment 3:
A. after in the container that the 250ml dichloromethane solvent is housed, adding the 7-ACA of 25g imidazoles, 48g trimethylchlorosilane (TMSC1) and 40g0.147mol successively, under 20～25 ℃, whipped state, react, 2～3 hours after-filtration are carried out in above-mentioned reaction, influence subsequent hierarchy and the crystalline imidazole hydrochloride that are generated are filtered and remove, to help the carrying out of subsequent reactions;
Drip Iodotrimethylsilane (TMSI) the solution 50ml of 0.183mol when B. above-mentioned filtrate filtered being cooled to 10～15 ℃, stir then after 15～20 minutes and under 15～20 ℃ of keeping warm modes, react, can adopt HPLC to follow the tracks of reaction end;
C. after carrying out 3 hours, the reaction of B step finishes less than 1% afterreaction when the 7-ACA iodo is that 7-ACA is residual fully with the HPLC detection, after reaction finishes, to react feed liquid and under 101Kp, distill, to distill out excessive methylene dichloride in the reaction feed liquid, to help improving plant factor;
D. add tetrahydrofuran (THF) (THF) 9ml in 0～5 ℃ when distilling out 140ml methylene dichloride and distillation temperature when being lower than 45 ℃, adding the back stirred 15 minutes, in 30 minutes, drip activatory N-crassitude solution 93ml then, dropwising the back reacted 3 hours under-30～-25 ℃ of insulated and stirred, can adopt HPLC to follow the tracks of reaction end, or sampling detect, when detecting iodo thing＜2%, then condensation reaction finishes, and reaction obtains containing the cefepime intermediate of protecting group;
E. in the solution of the cefepime intermediate that contains protecting group that above-mentioned reaction obtains, drip 20ml methyl alcohol, add that solution temperature is 0～5 ℃ behind the methyl alcohol, concentrated hydrochloric acid 250～the 280ml of dropping 36% is hydrolyzed after stirring 15～20 minutes under this temperature, and hydrolysis obtains 7-amino-3-[(1-methyl Pyrrolidine) methyl]-3-cephalo-4-carboxylic acid;
F. in the said hydrolyzed product, add methylene dichloride 260ml, hydrolysate dissolving this moment, system temperature rises and layering forms organic phase and water, separate obtaining water, and with after the 60ml water extracted organic phase with its with separate the water merging that obtains;
G. the water with above-mentioned merging obtains the yellow aqueous solution with gac after 20～25 ℃ of room temperatures are decoloured;
H. add 600ml acetone under whipped state in the above-mentioned yellow aqueous solution, growing the grain continues to drip 600ml acetone after 30 minutes, continues stirring 60 minutes at 9～10 ℃ then, stirs 60 minutes after-filtration at 8～9 ℃;
I. the crystallisate that leaches with the H step promptly obtains yellow-white 7-MPCA product 44g of the present invention with washing with acetone final vacuum drying (KF13～15%), be 7-amino-3-[(1-methyl Pyrrolidine) methyl]-3-cephalo-4-carboxylic acid dihydrochloride product, HPLC purity is greater than 99.2%.
The preparation method of activatory N-crassitude solution is identical with embodiment 1 in the present embodiment.
Embodiment 4:
A. after in the container that the 250ml dichloromethane solvent is housed, adding the 7-ACA of 25g imidazoles, 48g trimethylchlorosilane (TMSC1) and 40g0.147mol successively, under 20～25 ℃, whipped state, react, 2～3 hours after-filtration are carried out in above-mentioned reaction, influence subsequent hierarchy and the crystalline imidazole hydrochloride that are generated are filtered and remove, to help the carrying out of subsequent reactions;
Drip Iodotrimethylsilane (TMSI) the solution 50ml of 0.183mol when B. above-mentioned filtrate filtered being cooled to 10～15 ℃, stir then after 15～20 minutes and under 15～20 ℃ of keeping warm modes, react, can adopt HPLC to follow the tracks of reaction end;
C. after carrying out 3 hours, the reaction of B step finishes less than 1% afterreaction when the 7-ACA iodo is that 7-ACA is residual fully with HPLC, to react feed liquid after reaction finishes distills under 101Kp, to distill out excessive methylene dichloride in the reaction feed liquid, to help improving plant factor;
D. add tetrahydrofuran (THF) (THF) 9ml in 0～5 ℃ when distilling out 130ml methylene dichloride and distillation temperature when being lower than 45 ℃, adding the back stirred 15 minutes, in 30 minutes, drip activatory N-crassitude solution 93ml then, dropwising the back reacted 3 hours under-30～-25 ℃ of insulated and stirred, can adopt HPLC to follow the tracks of reaction end, or sampling detect, when detecting iodo thing＜2%, then condensation reaction finishes, and reaction obtains containing the cefepime intermediate of protecting group;
E. in the solution of the cefepime intermediate that contains protecting group that above-mentioned reaction obtains, drip 20ml methyl alcohol, add that solution temperature is 0～5 ℃ behind the methyl alcohol, hydroiodic acid HI 250～the 280ml of dropping 36% is hydrolyzed after stirring 15～20 minutes under this temperature, and hydrolysis obtains 7-amino-3-[(1-methyl Pyrrolidine) methyl]-3-cephalo-4-carboxylic acid;
F. in the said hydrolyzed product, add methylene dichloride 260ml, hydrolysate dissolving this moment, system temperature rises and layering forms organic phase and water, separate obtaining water, and with after the 60ml water extracted organic phase with its with separate the water merging that obtains;
G. the water with above-mentioned merging obtains the yellow aqueous solution with gac after 20～25 ℃ of room temperatures are decoloured;
H. add 600ml acetone under whipped state in the above-mentioned yellow aqueous solution, growing the grain continues to drip 600ml acetone after 30 minutes, continues stirring 60 minutes at 9～10 ℃ then, stirs 60 minutes after-filtration at 8～9 ℃;
I. the crystallisate that leaches with the H step promptly obtains yellow-white 7-MPCA product 44g of the present invention with washing with acetone final vacuum drying (KF13～15%), be 7-amino-3-[(1-methyl Pyrrolidine) methyl]-3-cephalo-4-carboxylic acid dihydrochloride product, HPLC purity is greater than 99.2%.
The preparation method of activatory N-crassitude solution is identical with embodiment 1 in the present embodiment.
Claims (7)
1. methyl 7-amino-3-[(1-methyl Pyrrolidine)]-3-cephalo-4-carboxylic acid dihydrochloride's preparation method, it is characterized in that it may further comprise the steps:
A. in dichloromethane solvent, with amino and the carboxyl of imidazoles and trimethylchlorosilane protection 7-ACA;
B.A step reaction finishes after-filtration, removes the imidazole hydrochloride that dereaction generates;
C. the filtrate of B step is concentrated, add the synthetic 3-position of Iodotrimethylsilane reaction iodo thing intermediate after steaming part methylene chloride;
D. the C step is distilled the cefepime intermediate that concentrated dichloromethane solution that contains 3-position iodo thing intermediate that obtains and activatory N-crassitude solution reaction obtain containing protecting group;
The cefepime intermediate that E. will contain protecting group adds and adds acetone behind the hydrochloric acid hydrolysis through crystallization, filtration, dry 7-amino-3-[(1-methyl Pyrrolidine) methyl]-3-cephalo-4-carboxylic acid dihydrochloride.
2. methyl 7-amino according to claim 1-3-[(1-methyl Pyrrolidine)]-3-cephalo-4-carboxylic acid dihydrochloride's preparation method, the mol ratio that it is characterized in that 7-ACA, imidazoles and the trimethylchlorosilane of described A step is 1: 1.5～4: 2～4,10～30 ℃ of its temperature of reaction, 2～3 hours reaction times.
3. methyl 7-amino according to claim 2-3-[(1-methyl Pyrrolidine)]-3-cephalo-4-carboxylic acid dihydrochloride's preparation method, the mol ratio that it is characterized in that described 7-ACA, imidazoles and trimethylchlorosilane is 1: 2～3: 2～3.5, and its temperature of reaction is 20～25 ℃.
4. methyl 7-amino according to claim 1-3-[(1-methyl Pyrrolidine)]-3-cephalo-4-carboxylic acid dihydrochloride's preparation method, the mol ratio that it is characterized in that described Iodotrimethylsilane and 7-ACA is 1: 1.2～2, its temperature of reaction is 10～20 ℃, finishes less than 1% afterreaction when 7-ACA is residual.
5. methyl 7-amino according to claim 1-3-[(1-methyl Pyrrolidine)]-3-cephalo-4-carboxylic acid dihydrochloride's preparation method, the preparation method who it is characterized in that described activatory N-crassitude solution is: the N that slowly drips 1～1.5 times of volume in container behind the DMF of the N-crassitude of 1 times of volume of adding and 2～2.5 times of volumes under vigorous stirring, the two silica-based ethanamides of front three (BSA) of O-, reaction got final product after 1 hour under 10～25 ℃ of stirring insulations.
6. methyl 7-amino according to claim 1-3-[(1-methyl Pyrrolidine)]-3-cephalo-4-carboxylic acid dihydrochloride's preparation method, the mol ratio that it is characterized in that described activatory N-crassitude and 7-ACA is 1: 1.05～2, temperature of reaction is-30～-25 ℃, and HPLC follows the tracks of reaction end.
7. methyl 7-amino according to claim 1-3-[(1-methyl Pyrrolidine)]-3-cephalo-4-carboxylic acid dihydrochloride's preparation method, the add-on that it is characterized in that described acetone is 4～7 times of liquor capacity, Tc is 0～10 ℃, crystallization time 1～6 hour.
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| CN2008100800868A CN101429207B (en) | 2008-12-12 | 2008-12-12 | Process for producing 7-amino-3-[(1-methyl pyrrolidine) methyl]-3- cephalosporin-4-carboxylic dihydrochloride |
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Owner name: HEBEI JIUPAI PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME: HEBEI JIUPAI PHARMACY CO., LTD. |
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Address after: 052165 Shijiazhuang economic and Technological Development Zone, the Three Gorges Road, Hebei Patentee after: Hebei Jiupai Pharmaceutical Co., Ltd. Address before: 052165 Shijiazhuang economic and Technological Development Zone, the Three Gorges Road, Hebei Patentee before: Hebei Jiupai Pharmacy Co., Ltd. |
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Granted publication date: 20110615 Termination date: 20201212 |