CN102399199B - Preparation method of magnetic resonance imaging contrast agent - Google Patents
Preparation method of magnetic resonance imaging contrast agent Download PDFInfo
- Publication number
- CN102399199B CN102399199B CN201010288592.3A CN201010288592A CN102399199B CN 102399199 B CN102399199 B CN 102399199B CN 201010288592 A CN201010288592 A CN 201010288592A CN 102399199 B CN102399199 B CN 102399199B
- Authority
- CN
- China
- Prior art keywords
- preparation
- gadobutrol
- diethylenetriamine
- reaction
- nitrae
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Landscapes
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The invention relates to a preparation method of a magnetic resonance imaging contrast agent, especially a preparation method of gadobutrol and gadoteridol. The invention takes cheap diethylenetriamine and aminodiethanol as starting raw materials, which then undergo simple substitution, cyclization, and alkylation and other reactions as well as the processes of desalination, centrifugation, purification and the like, so that gadobutrol or gadoteridol can be prepared. Specifically, when R1=R2=-CH2OH (ethylene oxide 2, 3-dimethanol), the method can be used for preparing gadobutrol; and when R1=H, R2=-CH3 (propylene oxide), the method can be used for preparing gadoteridol. Compared with prior art, the method in the invention has the advantages of widely available and cheap raw materials, low requirement for equipment, simple technical operation, high total yield of synthesis, and environment friendliness, thus being suitable for large scale industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of magnetic resonance imaging contrast, particularly relate to the preparation method of a kind of gadobutrol (gadobutrol) and Ga Duoli road (gadoteridol).
Background technology
Nuclear magnetic resonance (magnetic resonance imaging, be called for short MRI) be to utilize certain nuclear nmr phenomena in tissue, the gained radiofrequency signal is processed through robot calculator, reconstructed the diagnostic techniques of the image of a certain aspect of human body.Realize from Lauterbur in 1973 that first nuclear magnetic resonance is so far over more than 30 years, MRI obtains fast development and widespread use in fields such as medical science, biology, Materials science.In diagnostic field, MRI is a kind of up-to-date Tomographic Diagnosis Technology after CT scan, has high resolving power, good contrast, imaging arbitrarily, contains much information, without advantages such as radiotherapy damages, for clinical, provides a kind of novel medical harmless video diagnostic technology.At present general being applied to is clinical, becomes requisite medical diagnosis on disease means.
Gadobutrol and Ga Duoli road are that a kind of extracellular distributes, non-tissue-specific, electric neutrality, non-ionic water-soluble be containing gadolinium MRI contrast medium, have that relaxation property is high, good stability, glutinousness and the characteristics such as perviousness is lower, mainly clear through glomerular filtration, toxicity is low, and its high concentrate formulation is unique advantage in the MRI imaging.But current all main synthetic method (DE4009119; Inorg.Chem.1997,36,6086-6093; DE19724186.7; DE10064467.8; MI97A001371) be all with Isosorbide-5-Nitrae basically, 7,10-tetraazacyclododecanand (cyclen) is raw material, and this cost of material is very expensive, and the industrial production cost is high.Inorg.Chem. (1997,36,6086-6093) once with trans 5-Amide-6-hydroxy-2-, 2-dimethyl-1, the 3-Dioxepane is as the synthetic gadobutrol of starting raw material, although this raw material is than Isosorbide-5-Nitrae, 7, the 10-tetraazacyclododecanand is comparatively cheap, but quite expensive, and synthetic total yield not high (<10%), be not suitable for suitability for industrialized production.Therefore, finding the applicable industrial preparation method of a kind of cheap synthesis material and final yield and prepare and produce gadobutrol and Ga Duoli road, is current urgent problem.
Summary of the invention
The object of the present invention is to provide the preparation method in a kind of gadobutrol and Ga Duoli road.The present invention is usingd cheap diethylenetriamine and amino di-alcohol as starting raw material, by simple replacement and the reactions such as cyclization and alkylation, the final yield in the gadobutrol obtained or Ga Duoli road is greater than 50%, be very suitable for industrial production, both cost-saved, also friendly to environment, synthetic method is simple, obviously is better than existing synthetic method.
Technical scheme of the present invention: the preparation method in a kind of gadobutrol and Ga Duoli road comprises the following steps:
In compound formula (I), work as R
1=R
2=-CH
2during OH, be gadobutrol (10-[2,3-dihydroxyl-1-(hydroxymethyl) propyl group]-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand-Isosorbide-5-Nitrae, the Gd coordination compound of 7-nitrilotriacetic); Work as R
1=H, R
2=-CH
3the time be the Ga Duoli road (10-[2,3-dihydroxyl-1-(hydroxymethyl) propyl group]-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand-Isosorbide-5-Nitrae, the Gd coordination compound of 7-nitrilotriacetic).Synthetic route is as follows:
Wherein:
A) be under the existence of carbonate catalyst, ethyl chloroacetate is added drop-wise to reaction in the solution of diethylenetriamine (V) and generates N, N ', N " tri-(2-oxyethyl group-2-carbonyl ethyl) diethylenetriamine, it can carry out step b without separation and purification);
B) " tri-(2-oxyethyl group-2-carbonyl ethyl) the diethylenetriamine disodium salt (IV) that is in alcoholic solution, by product and sodium ethylate reflux 2～10h a), reacting generating compound N, N ', N;
C) be under the existence of carbonate catalyst, IV and N, O, O '-tri-(p-toluenesulfonyl) two (2-hydroxyethyl) amine reacts in DMF or DMA solution, temperature of reaction is 80～150 ℃, generate product 1-(p-toluenesulfonyl)-4,7,10-tri-(2-oxyethyl group-2-carbonyl ethyl)-1,4,7,10-tetraazacyclododecanand, it need not separate can carry out steps d);
D) to c) add basic metal or alkaline earth metal hydroxides and ammoniacal liquor in reaction system, and be cooled to-20～-60 ℃, stirring reaction 3～10h obtains compound 1-(p-toluenesulfonyl)-4 with this understanding, 7,10-tricarboxylic methyl isophthalic acid, 4,7,10-tetraazacyclododecanand sodium salt (III);
E) be the alkylating by formula (VII), the epoxide of product carried out according to currently known methods in water, wherein R in formula (VII)
1=R
2=-CH
2during OH (oxyethane 2,3-dimethanol) for the production of preparing gadobutrol; Work as R
1=H, R
2=-CH
3when (propylene oxide), for the production of preparation Ga Duoli road, it need not separate is that available row carries out step O;
F) by e) product is dissolved in aqueous solution stirring reaction together with Gadolinium trichloride of regulating pH value with hydrochloric acid and generates product (I) gadobutrol or Ga Duoli road;
G) be the purification step of compound, by f) reaction soln be taken up in order of priority by weak base type anionite-exchange resin and weakly acidic cation-exchange resin desalination, the solution decompression evaporate to dryness obtained, ethanol disperses to reflux, cooling centrifugal, filter, precipitation obtains the elaboration in gadobutrol or Ga Duoli road.
Beneficial effect of the present invention:
1, current, raw material prepared by gadobutrol is Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand (cyclen), this expensive raw material price.It is starting raw material that the present invention adopts diethylenetriamine and amino di-alcohol, and these raw material sources are extensive, cheap, greatly reduce production costs;
2, the present invention is usingd diethylenetriamine and amino di-alcohol as starting raw material, adopts simple scientific and reasonable synthetic route, does not need to add toxicity and the larger reagent of contaminative in the manufacture process, environmentally friendly.
3, this building-up reactions is simple, and step is moderate, to plant and instrument, requires lower.
4, this preparation method's ultimate yield is greater than 50%, is applicable to the large production of industry.
Embodiment:
For preparing gadobutrol and Ga Duoli road, during complexing, accurate measurement adds gadolinium, can reduce like this precipitation capacity of the product that comprises gadolinium.
For from gadolinium complex, removing and desalt and other by products, the present invention has selected the ion exchange resin of different size to carry out desalination and removal of impurities.
Following embodiment describes the optimum test condition that carries out the inventive method in detail.
Embodiment 1: prepare gadobutrol
A) " tri-(2-oxyethyl group-2-carbonyl ethyl) diethylenetriamine for preparing N, N ', N
Diethylenetriamine 1.03kg (10mol), Anhydrous potassium carbonate 100g are scattered in the 3L acetonitrile, slowly drip while stirring into ethyl chloroacetate 3.43kg (28mol), control time for adding and be no less than 3 hours, stirring reaction 3 hours again after being added dropwise to complete, the reclaim under reduced pressure acetonitrile, obtain the compound of expecting.
B) " tri-(2-oxyethyl group-2-carbonyl ethyl) the diethylenetriamine disodium salt (IV) for preparing N, N ', N
By A) in product dissolve and to be scattered in 1.5L ethanol, add sodium ethylate 1.36kg (20mol), heated and stirred back flow reaction 5 hours, filter, and obtains N, N ', " tri-(2-oxyethyl group-2-carbonyl ethyl) diethylenetriamine disodium salt white solid 2.93kg (8.2mol, productive rate 82%), HPLC detects purity to N; MS, NMR determines structure.
C) prepare 1-(p-toluenesulfonyl)-4,7,10-tri-(2-oxyethyl group-2-carbonyl ethyl)-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand
By B) the product solid is dissolved in DNF; add wherein N; O; O '-tri-(p-toluenesulfonyl) two (2-hydroxyethyl) amine (by the simple sulfonylation gained of amino di-alcohol) 290g; Anhydrous potassium carbonate 200g; in 100 ℃ of stirring reactions 4 hours, HPLC or TLC detect did not have the raw material residue to finish for reaction.
D) prepare 1-(p-toluenesulfonyl)-4,7,10-tricarboxylic methyl isophthalic acid, 4,7,10-tetraazacyclododecanand sodium salt
By C) reaction solution is cooled to-40 ℃, slowly adds sodium Metal 99.5 565.5g, ammoniacal liquor 600ml, and stirring reaction 5 hours, filter, and a small amount of organic solvent washes away impurity, obtains white object product 3.25kg (6.26mol, productive rate 72%), and HPLC detects purity.
E) synthetic gadobutrol
By D) target product of gained is soluble in water, regulate PH to 12.3 with sodium hydroxide, add oxyethane 2,3-dimethanol 651g (6.26mol), respectively at 40 ℃ the reaction 4 hours and 80 ℃ the reaction 8 hours after, solution is cooled to 50 ℃, adds in the 5.5kg aqueous solution of the gadolinium trichloride that contains 6.2mol.After 1 hour, mixture is cooled to 17 ℃, and is acidified to PH1.7 with concentrated hydrochloric acid, keeps stirring reaction 2 hours.Then be warming up to 50 ℃, regulating PH with sodium hydroxide is 7, stirring reaction 1 hour.
F) gadobutrol desalination and purifying
The solution obtained after the back reaction is successively passed through to the D-315 weak base anion-exchange resin, D-113 type weakly acidic cation-exchange resin, wash-out obtains settled solution, be evaporated to dry, dissolve with ethanol, reflux, cooling, centrifugal, filter, obtain white powder gadobutrol 2.74kg, overall yield 53%, IR, MS and NMR are consistent with the structure of appointment, and it is 98.5% that HPLC analyzes its purity.
Embodiment 2: synthetic Ga Duoli road
A)-D) step is consistent with the synthetic method of embodiment 1 gadobutrol.
E) by D) target product of gained is soluble in water, regulate PH to 12.3 with hydrochloric acid, add propylene oxide 363g (6.26mol), respectively at 40 ℃ the reaction 4 hours and 80 ℃ the reaction 8 hours after, solution is cooled to 50 ℃, adds in the 5.5kg aqueous solution of the gadolinium trichloride that contains 6.2mol.After 1 hour, mixture is cooled to 17 ℃, and is acidified to PH1.7 with concentrated hydrochloric acid, keeps stirring reaction 2 hours.Then be warming up to 50 ℃, regulating PH with sodium hydroxide is 7, stirring reaction 1 hour.
The desalination in Ga Duoli road and purifying and embodiment mono-F) method is identical, finally obtains white powder 2.49kg, overall yield 55%, IR, MS and NMR are consistent with the structure of appointment, and it is 99.1% that HPLC analyzes its purity.
Claims (17)
1. the preparation method of a magnetic resonance imaging contrast (I),
In compound formula (I), work as R
1=R
2=-CH
2during OH, be gadobutrol (10-[2,3-dihydroxyl-1-(hydroxymethyl) propyl group]-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand-Isosorbide-5-Nitrae, the Gd coordination compound of 7-nitrilotriacetic); Work as R
1=H, R
2=-CH
3the time be Ga Duoli road (10-(2-hydroxypropyl)-Isosorbide-5-Nitrae, 7,10-tetraazacyclododecanand-Isosorbide-5-Nitrae, the Gd coordination compound of 7-nitrilotriacetic), the synthetic route of described magnetic resonance imaging contrast (I) is as follows:
A) be under the existence of Carbon Dioxide salt catalyst, the halogen acetic acid ethyl ester is added drop-wise to reaction in the solution of diethylenetriamine (V) and generates N, N ', N " tri-(2-oxyethyl group-2-carbonyl ethyl) diethylenetriamine, it can carry out step b without separation and purification);
B) " tri-(2-oxyethyl group-2-carbonyl ethyl) the diethylenetriamine disodium salt (IV) that is in alcoholic solution, by product and sodium ethylate reflux 3～10h a), reacting generating compound N, N ', N;
C) be under the existence of Carbon Dioxide salt catalyst, IV and N, O, O '-tri-(p-toluenesulfonyl) two (2-hydroxyethyl) amine reacting by heating in DMF or DMA solution, generate product 1-(p-toluenesulfonyl)-4,7,10-tri-(2-oxyethyl group-2-carbonyl ethyl)-Isosorbide-5-Nitrae, 7, the 10-tetraazacyclododecanand, it need not separate can carry out steps d);
D) to c) add basic metal or alkaline earth metal hydroxides and ammoniacal liquor in reaction system, and be cooled to certain temperature, stirring reaction obtains compound 1-(p-toluenesulfonyl)-4 with this understanding, 7,10-tricarboxylic methyl isophthalic acid, 4,7,10-tetraazacyclododecanand sodium salt (III);
E) be the alkylating with formula VII, the epoxide of product carried out according to currently known methods in water, wherein R in formula VII
1=R
2=-CH
2during OH (oxyethane 2,3-dimethanol) for the production of preparing gadobutrol; Work as R
1=H, R
2=-CH
3when (propylene oxide), for the production of preparation Ga Duoli road, it need not separate is that available row carries out step f);
F) by e) product is dissolved in aqueous solution stirring reaction together with Gadolinium trichloride of regulating pH value with hydrochloric acid and generates product (I) gadobutrol or Ga Duoli road;
G) be the purification step of compound, by f) reaction soln be taken up in order of priority by weak base type anionite-exchange resin and the desalination of weak-type Zeo-karb, the solution decompression evaporate to dryness obtained, ethanol disperses to reflux, cooling centrifugal, filter, precipitation obtains the elaboration in gadobutrol or Ga Duoli road.
2. preparation method as claimed in claim 1, wherein step a) in, the mol ratio of diethylenetriamine and halogen acetic acid ethyl ester is 1: 2.3～1: 2.9.
3. preparation method as described as claim 1-2, wherein step a) in, the mol ratio of diethylenetriamine and halogen acetic acid ethyl ester is 1: 2.5～1: 2.8.
4. preparation method as claimed in claim 1, wherein step a) in, anhydrous carbonate is sodium, potassium, magnesium salts.
5. preparation method as claimed in claim 1, wherein step a) in, halogen acetic acid ethyl ester used can be ethyl chloroacetate or ethyl bromoacetate.
6. preparation method as claimed in claim 1, wherein step b) in, the time of reflux is 2～10h.
7. preparation method as claimed in claim 6, wherein step b) in, the time of reflux is 5～6h.
8. preparation method as claimed in claim 1, wherein step c) in, anhydrous carbonate is sodium, potassium, magnesium salts.
9. preparation method as claimed in claim 1, wherein step c) in, temperature of reaction is 80～150 ℃.
10. preparation method as claimed in claim 9, wherein step c) in, temperature of reaction is 90～120 ℃.
11. preparation method as claimed in claim 1, wherein steps d) in, add the oxyhydroxide of alkali metallic sodium, potassium, magnesium or alkaline-earth metal sodium, potassium, magnesium.
12. preparation method as claimed in claim 1, wherein steps d) in, be cooled to-20～-60 ℃.
13. preparation method as claimed in claim 12, wherein steps d) in, be cooled to-30～-50 ℃.
14. preparation method as claimed in claim 1, wherein steps d) in, the stirring reaction time is 3～10h.
15. preparation method as claimed in claim 14, wherein steps d) in, the stirring reaction time is 5～8h.
16. preparation method as claimed in claim 1, wherein step g) in, weak base type anionite-exchange resin used is D315, D-301 or D-92 anionite-exchange resin.
17. preparation method as claimed in claim 1, wherein step g) in, weak-type Zeo-karb used is D-85, D-113, Diaion Relite CC, R& H IRC86 or Dow Chemical Dowex CCR3 Zeo-karb.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010288592.3A CN102399199B (en) | 2010-09-19 | 2010-09-19 | Preparation method of magnetic resonance imaging contrast agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010288592.3A CN102399199B (en) | 2010-09-19 | 2010-09-19 | Preparation method of magnetic resonance imaging contrast agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102399199A CN102399199A (en) | 2012-04-04 |
| CN102399199B true CN102399199B (en) | 2014-01-08 |
Family
ID=45881902
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010288592.3A Active CN102399199B (en) | 2010-09-19 | 2010-09-19 | Preparation method of magnetic resonance imaging contrast agent |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102399199B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103613557B (en) * | 2013-10-18 | 2015-07-29 | 武汉利宝瑞医药科技有限公司 | A kind of preparation method of magnetic resonance imaging contrast agent gadobutrol |
| CN105939994B (en) * | 2014-02-06 | 2018-05-29 | T2医药有限责任公司 | The method for purifying Cyclen -1,4,7,10- tetraacethyls |
| CN105037288B (en) * | 2015-07-23 | 2017-11-03 | 上海现代制药海门有限公司 | A kind of preparation method of cloth alcohol |
| KR102464647B1 (en) * | 2016-11-28 | 2022-11-08 | 바이엘 파마 악티엔게젤샤프트 | High Relaxation Gadolinium Chelate Compounds for Use in Magnetic Resonance Imaging |
| US20210284662A1 (en) * | 2018-07-10 | 2021-09-16 | Biophore India Pharmaceuticals Pvt. Ltd | Process for the preparation of 2,2',2''-(10-((2r,3s)-1,3,4-trihydroxy butan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid and its complexes |
| CN111039885B (en) * | 2019-12-06 | 2021-03-05 | 广州康瑞泰药业有限公司 | Method for preparing high-purity combretastatin |
| CN114539178B (en) * | 2020-11-26 | 2024-03-15 | 江苏恒瑞医药股份有限公司 | Purification method of gadobutrol |
| CN113549025B (en) * | 2021-07-14 | 2023-07-25 | 江苏美迪克化学品有限公司 | Preparation method of 1,4,7, 10-tetraazacyclododecane-1, 4, 7-triacetic acid and sodium salt thereof |
| CN113880850B (en) * | 2021-10-18 | 2022-10-04 | 苏州百灵威超精细材料有限公司 | Gadobutrol intermediate, preparation method and application in gadobutrol preparation |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4885363A (en) * | 1987-04-24 | 1989-12-05 | E. R. Squibb & Sons, Inc. | 1-substituted-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs |
| CN1259939A (en) * | 1997-06-11 | 2000-07-12 | 伯拉考公司 | Process for preparing macrocyclic chelants and chelates thereof with paramagnetic metal ions |
-
2010
- 2010-09-19 CN CN201010288592.3A patent/CN102399199B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4885363A (en) * | 1987-04-24 | 1989-12-05 | E. R. Squibb & Sons, Inc. | 1-substituted-1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane and analogs |
| CN1259939A (en) * | 1997-06-11 | 2000-07-12 | 伯拉考公司 | Process for preparing macrocyclic chelants and chelates thereof with paramagnetic metal ions |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102399199A (en) | 2012-04-04 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102399199B (en) | Preparation method of magnetic resonance imaging contrast agent | |
| CN108047151B (en) | Preparation method of gadobutrol with high yield | |
| ES2780599T3 (en) | Preparation of high purity gadobutrol | |
| KR102265637B1 (en) | Process for preparing 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid | |
| CN108299322B (en) | Method for preparing gadobutrol | |
| CN107001294A (en) | A kind of method for preparing Gadobutrol | |
| CN109134289A (en) | A kind of efficient contrast agent synthetic method and its application | |
| CN104169252B (en) | For the technique of purifying polyaminocarboxylic acid ester | |
| CN101412732B (en) | Trihydrate 3-amino propyl amine ethyl phosphorothioic acid high purity stable crystal and preparation thereof | |
| RU2405776C2 (en) | Synthesis of cyclene derivatives | |
| CA2801968A1 (en) | Process for preparing crystalline 3,6,9-triaza-3,6,9-tris(carboxymethyl)-4-(4-ethoxybenzyl)undecanedioic acid and use for production of primovist® | |
| CA2621339C (en) | Process for the preparation of contrast agents | |
| CN104011029A (en) | An improved process for the preparation of bendamustine hydrochloride | |
| JP6974788B2 (en) | Imidazopyrroloquinoline salt and its manufacturing method, as well as pharmaceuticals, cosmetics and foods | |
| AU2021314803A1 (en) | Manufacturing of dimeric contrast agents | |
| CN114685390A (en) | Preparation method of gadobutrol derivative | |
| CN105294734A (en) | Method for preparing cefonicid dibenzyl ethylenediamine salt | |
| AU2022317221A1 (en) | Manufacturing of dimeric contrast agents | |
| WO2023110863A1 (en) | Process for manufacturing a mixture comprising a dimeric macrocycle intermediate of a gadolinium complex | |
| CN114685391A (en) | Preparation method of tetraazacyclododecane derivative | |
| Mishra et al. | Convenient route for synthesis of bifunctional chelating agent: 1-(p-aminobenzyl) ethylenediaminetetramethylphosphonic acid–folate conjugate (Am-Bz-EDTMP–Folate) | |
| JPH11189588A (en) | Production of 2-mercaptothiazole | |
| CN102276650A (en) | Preparation method of zoledronic acid | |
| WO2011041275A1 (en) | Alkylation of triiodo-substituted arylamides in an aqueous mixed solvent system |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C53 | Correction of patent for invention or patent application | ||
| CB03 | Change of inventor or designer information |
Inventor after: Zheng Zhaoguang Inventor after: Duan Tingting Inventor after: Cheng Huichuo Inventor after: Huang Yunbin Inventor after: Huang Yanxia Inventor after: Chen Yuling Inventor after: Huang Xiaoling Inventor after: Zhu Chuo Inventor after: Shi Xinghua Inventor after: Ou Xiaomin Inventor after: Tang Dan Inventor after: Wang Rushang Inventor after: Gu Fei Inventor after: He Bao Inventor before: Zhu Chuo Inventor before: Cheng Huichuo Inventor before: Huang Xiaoling Inventor before: Huang Yunbin Inventor before: Huang Yanxia Inventor before: Chen Yuling Inventor before: Shi Xinghua Inventor before: Zheng Zhaoguang Inventor before: Ou Xiaomin Inventor before: Tang Dan Inventor before: Wang Rushang Inventor before: Gu Fei Inventor before: He Bao Inventor before: Duan Tingting |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: INVENTOR; FROM: ZHU QUAN SHI XINGHUA ZHENG ZHAOGUANG OU XIAOMIN TANG DAN WANG RUSHANG GU FEI HE BAO DUAN TINGTING CHENG HUIQUAN HUANG XIAOLING HUANG YUNBIN HUANG YANXIA CHEN YULING TO: ZHENG ZHAOGUANG HUANG XIAOLING ZHU QUAN SHI XINGHUA OU XIAOMIN TANG DAN WANG RUSHANG GU FEI HE BAO DUAN TINGTING CHENG HUIQUAN HUANG YUNBIN HUANG YANXIA CHEN YULING |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20160718 Address after: 510760, 71, Dongpeng Avenue, East Zone, Guangzhou economic and Technological Development Zone, Guangdong Patentee after: Kangchen Pharmaceutical Co., Ltd., Guangzhou Address before: 510530, 71, Dongpeng Avenue, East Zone, Guangzhou economic and Technological Development Zone, Guangdong Patentee before: Guangzhou Kangcheng Pharmaceutical Research Co.,Ltd. |