CN103641848B - The process for purification of cefotiam hexetil hydrochloride - Google Patents
The process for purification of cefotiam hexetil hydrochloride Download PDFInfo
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- CN103641848B CN103641848B CN201310631141.9A CN201310631141A CN103641848B CN 103641848 B CN103641848 B CN 103641848B CN 201310631141 A CN201310631141 A CN 201310631141A CN 103641848 B CN103641848 B CN 103641848B
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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
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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
- C07D501/12—Separation; Purification
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Abstract
The invention belongs to field of medicaments, be specifically related to a kind of process for purification of cefotiam hexetil hydrochloride.Cefotiam salt is made cefotiam sodium salt; The dimethyl formamide solution generation esterification of cefotiam sodium salt and carbonic acid 1-iodine ethyl ester cyclohexyl ester; The reaction solution obtained is added extraction agent, extraction; The organic phase obtained after extraction is added crystallization organic solvent, carries out crystallization under placing it in Ultrasonic Conditions, finally filter to obtain cefotiam hexetil hydrochloride.The present invention utilizes hyperacoustic sound wave irradiation to have strong orienting effect, has and strengthens forming the wave action needed for critical nucleus, can accelerate seeding process, generate nucleus fast; Can prevent there is coalescent situation during crystal growth, crystal particle diameter distribution uniform simultaneously.And safe and reliable, the granularity of the finished product prepared is large, and be easy to filter, quality product is high; And aftertreatment is simply easy, well can improve quality and the yield of product.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to a kind of process for purification of cefotiam hexetil hydrochloride.
Background technology
Cefotiam hexetil (structural formula I), English name: Cefotiam Hexetil, English another name: Pansporin, CTM-HE.Itself is unstable, therefore medicinal forms is that cefotiam hexetil hydrochloride (formula II) cefotiam hexetil is as the oral antibacterial cephalosporin element of s-generation wide spectrum, itself there is no anti-microbial effect, is hydrolyzed to rapidly cefotiam (CTM) (formula II I) and is absorbed after oral at intestinal mucosa.。CTM is identical with in the past oral cynnematin with the anti-microbial activity of negative bacterium to gram-positive, and stablizes β-lactamase.This product, to the streptococcus aureus of clinical separation, coagulase negative staphylococcus, streptococcus pneumoniae, gonococcus, resistance to Ampicillin Trihydrate gonococcus (ABPC), moraxelle catarrhalis, intestinal bacteria, citric acid Pseudomonas, Providencia, micrococcus scarlatinae, streptococcus agalactiae, klebsiella pneumoniae, Proteus mirabilis, Hemophilus influenzae, all has stronger anti-microbial activity.Be used for the treatment of responsive microbial pharyngolaryngitis, acute bronchitis, tonsillitis, pneumonia, pyelonephritis, urocystitis, pouring mattress urethritis, purulence acne, erysipelas, perianal abscess, mazoitis, ocular infection, otitis media, sinusitis paranasal sinusitis etc.
In the process of producing cefotiam hexetil hydrochloride, there is the situation of crystal coalesces at present, cause the granularity of the finished product very little, during filtration, difficulty is large, is mingled with a large amount of crystalline mother solutions, have impact on the quality of product in product.
In prior art, cefotiam hexetil hydrochloride also exists the problem of crystal coalesces in process of production, to such an extent as to the granularity of product is very little, and during filtration, difficulty is large, is mingled with a large amount of crystalline mother solutions, have impact on the quality of product in product.For the deficiencies in the prior art, the present invention utilizes hyperacoustic sound wave irradiation to have strong orienting effect, has and strengthens forming the wave action needed for critical nucleus, can accelerate seeding process, generate nucleus fast; Ultrasonic wave can make the particle in medium obtain very large acceleration in liquid medium simultaneously, can produce cavatition, can prevent there is coalescent situation during crystal growth, crystal particle diameter distribution uniform.Meanwhile, under Ultrasonic Conditions, add crystallization organic solvent crystallization, when this prevent crystal growth, there is coalescent situation, crystal particle diameter distribution uniform, well can improve the quality of product.The method is safe and reliable, and the granularity of the finished product prepared is large, and be easy to filter, quality product is high; And aftertreatment is simply easy, well can improve product yield.
Compared with prior art, the present invention has the following advantages:
(1) the present invention utilizes hyperacoustic sound wave irradiation to have strong orienting effect, has and strengthens forming the wave action needed for critical nucleus, can accelerate seeding process, generate nucleus fast; Ultrasonic wave can make the particle in medium obtain very large acceleration in liquid medium simultaneously, can produce cavatition, can prevent there is coalescent situation during crystal growth, crystal particle diameter distribution uniform.
(2) under Ultrasonic Conditions, add crystallization organic solvent crystallization, when this prevent crystal growth, there is coalescent situation, crystal particle diameter distribution uniform, well can improve the quality of product.
(3) the present invention is safe and reliable, and the granularity of the finished product prepared is large, and be easy to filter, quality product is high; And aftertreatment is simply easy, well can improve quality and the yield of product.
Summary of the invention
For the deficiencies in the prior art, the object of the present invention is to provide a kind of process for purification of cefotiam hexetil hydrochloride, can prevent crystal from there is coalescent situation when growing, the method is safe and reliable, and aftertreatment is simply easy, effectively can improve the quality of product.
The process for purification of cefotiam hexetil hydrochloride of the present invention, comprises the following steps:
(1) cefotiam salt is made cefotiam sodium salt;
(2) the dimethyl formamide solution generation esterification of cefotiam sodium salt and carbonic acid 1-iodine ethyl ester cyclohexyl ester;
(3) reaction solution that step (2) obtains is added extraction agent, extraction;
(4) organic phase obtained after step (3) being extracted adds crystallization organic solvent, carries out crystallization, finally filter to obtain cefotiam hexetil hydrochloride under placing it in Ultrasonic Conditions.
Step (1) is that cefotiam salt and salt forming agent are stirred 0.5 ~ 1h under normal temperature condition, generates cefotiam sodium salt; Wherein: salt forming agent is the one in sodium carbonate, sodium bicarbonate or Sodium isooctanoate, sodium carbonate is preferably; Cefotiam salt is preferably cefotiam chloride, and the mol ratio of cefotiam salt and salt forming agent is 1:1.5 ~ 2.
The reaction equation of step (1) is:
In step (2), the compound method of the dimethyl formamide solution of carbonic acid 1-iodine ethyl ester cyclohexyl ester is: joined in dimethyl formamide by carbonic acid 1-iodine ethyl ester cyclohexyl ester, and stir; Wherein: the amount ratio of carbonic acid 1-iodine ethyl ester cyclohexyl ester and dimethyl formamide is 1 ~ 2:400 ~ 600, carbonic acid 1-iodine ethyl ester cyclohexyl ester is in mol, and dimethyl formamide is in mL.
In step (2), the temperature of reaction of esterification is-9 ~ 15 DEG C, and the reaction times is 10 ~ 20min; Wherein: the mol ratio of cefotiam sodium salt and carbonic acid 1-iodine ethyl ester cyclohexyl ester is 1:1 ~ 2.
The reaction equation of step (2) is:
Extraction agent is that one or more in acetone, ethyl acetate, methyl alcohol, methylene dichloride or ether mix with arbitrary proportion in step (3); Ethyl acetate.
In step (4), crystallization organic solvent is: massfraction is the mixed solvent of the organic reagent of HCl and 96-99.5% of 0.5 ~ 4%; Wherein: organic reagent is that one or both in acetone, ethanol, methyl alcohol or Virahol mix with arbitrary proportion, preferred acetone.The precipitation that this crystallization organic solvent contributes to cefotiam hexetil hydrochloride crystallization is added in organic phase.When adding this crystallization organic solvent, can increase the crystallisation process of product, better separate out cefotiam hexetil hydrochloride, effect is better.
Step (4) is be positioned in ultrasonic wave generation trough by the organic phase obtained after extraction, control temperature is 10 ~ 25 DEG C, add the crystallization organic solvent of 3-5 parts by volume under stirring, then open ultrasonic wave seeding, ultrasonic frequency is preferably 20KHz ~ 80KHz, seeding process is more conducive in this scope, stir again, and then add the crystallization organic solvent of 15-20 parts by volume, growing the grain, filtration, washing, suction filtration, vacuum-drying obtains cefotiam hexetil hydrochloride.
The seeding time is 30 ~ 50min, then churning time is 20 ~ 35min.Growing the grain temperature is 10 ~ 15 DEG C, and rearing crystal time is 1 ~ 2h.
Embodiment
Below in conjunction with embodiment, the present invention will be further described.
Embodiment 1
(1) in three-necked bottle, be dissolved in 600mL distilled water by 1.5mol sodium carbonate, then add 1mol cefotiam chloride, stir under normal temperature condition, reaction 1h, obtains cefotiam sodium salt.
(2) in 400mL solvent dimethylformamide, add 1mol cefotiam sodium salt obtained above and 1.5mol carbonic acid 1-iodine ethyl ester cyclohexyl ester, temperature of reaction is 10 DEG C, and reaction times 12min, under agitation uses water cooling.
(3) in the reaction solution obtained, add 1000ml ethyl acetate to extract.
(4) organic phase after step (3) being extracted moves in 5000ml three-necked bottle, be positioned in ultrasonic wave generation trough, control temperature is 15 DEG C, the mixed solvent (mixed solvent is massfraction is the HCl of 3% and the acetone of 97%) of 5 parts by volume is added under stirring, drip off and open ultrasonic wave seeding 40min, ultrasonic frequency is 60KHz, stir 25min more afterwards, then the mixed solvent (mixed solvent is massfraction is the HCl of 3% and the acetone of 97%) adding 15 parts by volume in three-necked bottle is continued, control temperature is at about 14 DEG C, after growing the grain 2h, filter, with the washing with acetone filter cake of 3 parts by volume, suction filtration, 50 DEG C of vacuum-dryings obtain cefotiam hexetil hydrochloride, HPLC detects purity 97.5%, productive rate 90%.
Embodiment 2
(1) in three-necked bottle, be dissolved in 700mL distilled water by 2mol sodium bicarbonate, then add 1mol cefotiam chloride, stir under normal temperature condition, reaction 0.5h, obtains cefotiam sodium salt.
(2) in 600mL solvent dimethylformamide, add 1mol cefotiam sodium salt obtained above and 2mol carbonic acid 1-iodine ethyl ester cyclohexyl ester, temperature of reaction is 15 DEG C, and reaction times 10min, under agitation uses water cooling.
(3) in the reaction solution obtained, add 1500ml methyl alcohol to extract.
(4) organic phase after step (3) being extracted moves in 5000ml three-necked bottle, be positioned in ultrasonic wave generation trough, control temperature is 10 DEG C, the mixed solvent (mixed solvent is massfraction is the HCl of 0.5% and the acetone of 99.5%) of 4 parts by volume is added under stirring, drip off and open ultrasonic generator seeding 50min, ultrasonic frequency is 20KHz, stir 20min more afterwards, then the mixed solvent (mixed solvent is massfraction is the HCl of 0.5% and the acetone of 99.5%) adding 20 parts by volume in three-necked bottle is continued, control temperature is at about 10 DEG C, after growing the grain 1h, filter, with the washing with acetone filter cake of 4 parts by volume, suction filtration, 50 DEG C of vacuum-dryings obtain cefotiam hexetil hydrochloride, HPLC detects purity 96.7%, productive rate 89.5%.
Embodiment 3
(1) in three-necked bottle, be dissolved in 700mL distilled water by 1.8mol Sodium isooctanoate, then add 1mol cefotiam chloride, stir under normal temperature condition, reaction 0.8h, obtains cefotiam sodium salt.
(2) in 500mL solvent dimethylformamide, add 1mol cefotiam sodium salt obtained above and 1.2mol carbonic acid 1-iodine ethyl ester cyclohexyl ester, temperature of reaction is-9 DEG C, and reaction times 20min, under agitation uses water cooling.
(3) in the reaction solution obtained, add 1200ml methylene dichloride to extract.
(4) organic phase after step (3) being extracted moves in 5000ml three-necked bottle, be positioned in ultrasonic wave generation trough, control temperature is 25 DEG C, the mixed solvent (mixed solvent is massfraction is the HCl of 4% and the methyl alcohol of 96%) of 3 parts by volume is added under stirring, drip off and open ultrasonic generator seeding 30min, ultrasonic frequency is 80KHz, stir 35min more afterwards, then the mixed solvent (mixed solvent is massfraction is the HCl of 4% and the methyl alcohol of 96%) adding 18 parts by volume in three-necked bottle is continued, control temperature is at about 15 DEG C, after growing the grain 1h, filter, with the methanol wash filter cake of 3 parts by volume, suction filtration, 40 DEG C of vacuum-dryings obtain cefotiam hexetil hydrochloride, HPLC detects purity 96.3%, productive rate 87.9%.
Embodiment 4
(1) in three-necked bottle, be dissolved in 800mL distilled water by 2mol sodium carbonate, then add 1mol cefotiam chloride, stir under normal temperature condition, reaction 1h, obtains cefotiam sodium salt.
(2) in 500mL solvent dimethylformamide, add 1mol cefotiam sodium salt obtained above and 1mol carbonic acid 1-iodine ethyl ester cyclohexyl ester, temperature of reaction is 0 DEG C, and reaction times 18min, under agitation uses water cooling.
(3) in the reaction solution obtained, add 1000ml ethyl acetate to extract.
(4) organic phase after step (3) being extracted moves in 5000ml three-necked bottle, be positioned in ultrasonic wave generation trough, control temperature is 15 DEG C, the mixed solvent (mixed solvent is massfraction is the HCl of 2% and the ethanol of 98%) of 4 parts by volume is added under stirring, drip off and open ultrasonic generator seeding 40min, ultrasonic frequency is 50KHz, stir 25min more afterwards, then the mixed solvent (mixed solvent is massfraction is the HCl of 2% and the ethanol of 98%) adding 16 parts by volume in three-necked bottle is continued, control temperature is at about 14 DEG C, after growing the grain 1.5h, filter, with the washing with alcohol filter cake of 3 parts by volume, suction filtration, 50 DEG C of vacuum-dryings obtain cefotiam hexetil hydrochloride, HPLC detects purity 97.2%, productive rate 86%.
Claims (1)
1. a process for purification for cefotiam hexetil hydrochloride, is characterized in that:
(1) in three-necked bottle, be dissolved in 600mL distilled water by 1.5mol sodium carbonate, then add 1mol cefotiam chloride, stir under normal temperature condition, reaction 1h, obtains cefotiam sodium salt;
(2) in 400mL solvent dimethylformamide, add 1mol cefotiam sodium salt obtained above and 1.5mol carbonic acid 1-iodine ethyl ester cyclohexyl ester, temperature of reaction is 10 DEG C, and reaction times 12min, under agitation uses water cooling;
(3) in the reaction solution obtained, add 1000ml ethyl acetate to extract;
(4) organic phase after step (3) being extracted moves in 5000ml three-necked bottle, be positioned in ultrasonic wave generation trough, control temperature is 15 DEG C, the mixed solvent of 5 parts by volume is added under stirring, drip off and open ultrasonic wave seeding 40min, ultrasonic frequency is 60KHz, stir 25min more afterwards, then continue to add the mixed solvent of 15 parts by volume in three-necked bottle, control temperature at 14 DEG C, after growing the grain 2h, filter, with the washing with acetone filter cake of 3 parts by volume, suction filtration, 50 DEG C of vacuum-dryings obtain cefotiam hexetil hydrochloride;
In step (4), mixed solvent is massfraction is the HCl of 3% and the acetone of 97%.
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|---|---|---|---|---|
| CN101619069A (en) * | 2009-07-28 | 2010-01-06 | 余小强 | Preparation method of cefotiam hexetil hydrochloride |
| CN101863907A (en) * | 2010-07-07 | 2010-10-20 | 福建省福抗药业股份有限公司 | Method for crystallizing cefoperazone sodium |
| CN101955493A (en) * | 2010-08-03 | 2011-01-26 | 宁宗超 | Method for preparing cefotiam hexetil hydrochloride and composition of cefotiam hexetil hydrochloride |
| CN102675343A (en) * | 2011-03-15 | 2012-09-19 | 陈婧 | Method for preparing cefotiam hexetil hydrochloride by cefotiam hydrochloride |
| CN102775426A (en) * | 2012-08-10 | 2012-11-14 | 天津新丰制药有限公司 | Crystallization method of ceftezole sodium |
| CN103030650A (en) * | 2012-11-23 | 2013-04-10 | 深圳华润九新药业有限公司 | Method for preparing cefotiam hexetil and method for preparing cefotiam hexetil dihydrochloride |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101619069A (en) * | 2009-07-28 | 2010-01-06 | 余小强 | Preparation method of cefotiam hexetil hydrochloride |
| CN101863907A (en) * | 2010-07-07 | 2010-10-20 | 福建省福抗药业股份有限公司 | Method for crystallizing cefoperazone sodium |
| CN101955493A (en) * | 2010-08-03 | 2011-01-26 | 宁宗超 | Method for preparing cefotiam hexetil hydrochloride and composition of cefotiam hexetil hydrochloride |
| CN102675343A (en) * | 2011-03-15 | 2012-09-19 | 陈婧 | Method for preparing cefotiam hexetil hydrochloride by cefotiam hydrochloride |
| CN102775426A (en) * | 2012-08-10 | 2012-11-14 | 天津新丰制药有限公司 | Crystallization method of ceftezole sodium |
| CN103030650A (en) * | 2012-11-23 | 2013-04-10 | 深圳华润九新药业有限公司 | Method for preparing cefotiam hexetil and method for preparing cefotiam hexetil dihydrochloride |
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Denomination of invention: Refining method of cefotiam axetil hydrochloride Effective date of registration: 20211216 Granted publication date: 20150819 Pledgee: Commercial Bank of China Yiyuan branch of Limited by Share Ltd. Pledgor: SHANDONG XINQUAN PHARMACEUTICAL Co.,Ltd. Registration number: Y2021980015208 |
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