CN103880756A - Preparation method of azilsartan intermediate - Google Patents
Preparation method of azilsartan intermediate Download PDFInfo
- Publication number
- CN103880756A CN103880756A CN201410116645.1A CN201410116645A CN103880756A CN 103880756 A CN103880756 A CN 103880756A CN 201410116645 A CN201410116645 A CN 201410116645A CN 103880756 A CN103880756 A CN 103880756A
- Authority
- CN
- China
- Prior art keywords
- preparation
- formula
- ethanol
- azilsartan
- compound
- 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.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/26—Oxygen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of an azilsartan intermediate. The preparation method of the azilsartan intermediate comprises the following steps: dissociating hydroxylamine hydrochloride through alkali in ethanol which is 90-95% in mass percentage, filtering, adding a compound as shown in formula (II) in the specification, triethylamine and ethanol to filtrate, implementing a reflux reaction, cooling and crystallizing after the reaction, and filtering to obtain the target intermediate as shown in formula (I). The target intermediate prepared by the preparation method disclosed by the invention is high in content, and low in content of amide impurities, which is generally less than 10%.
Description
Technical field
The invention belongs to the preparation of medical compounds, particularly, relate to a kind of preparation method of Angiotensin Ⅱ receptor antagonist Azilsartan intermediate.
Background technology
Azilsartan (Azilsartan) is the Angiotensin Ⅱ receptor antagonist of being researched and developed by Japanese Takede Chemical Industries Ltd, can oral potent depressor.Its preparation and therepic use are described in the specification sheets of Chinese invention patent CN92105152.2.Wherein, lower formula I compound, that is, 2-oxyethyl group-1-{[((2'-hydroxyl ammonia auxotox radical) xenyl)-4-yl] methyl }-1H-benzoglyoxaline-7-carboxylic acid is the important intermediate of synthetic Azilsartan.
（Ⅰ）
Prepare the method for formula I compound at document J.Med.chem.1996.Vo39(26) 5528-5235 and the detailed description of Chinese patent CN92105152.2: get formula II compound, be 1-[((2 '-itrile group xenyl)-4-yl) methyl]-2-oxyethyl group-1H-benzoglyoxaline-7-carboxylate methyl ester, under oxammonium hydrochloride and triethylamine effect, the preparation taking methyl-sulphoxide as solvent.This reaction all can produce the following formula III of amides impurity, and this foreign matter content is too high very large on subsequent reactions impact, extremely difficult removal.Therefore the content that how to reduce this impurity is the key of this class synthetic method.
In Chinese patent CN92105152, formula II compound, under oxammonium hydrochloride and 28% sodium methylate effect, is prepared taking dimethyl sulfoxide (DMSO) (DMSO) as solvent.The method long reaction time, and can produce a large amount of acid amides by products (formula III compound), cause yield low, and need aftertreatment.
In Chinese patent CN201010245420.8, formula II compound is under aqueous hydroxylamine and triethylamine effect, and taking ethanol as solvent refluxing, reaction is prepared for 24 hours.The method needs 50% aqueous hydroxylamine, and this 50% aqueous hydroxylamine places after for some time that concentration can reduce and price is more expensive, and the reaction times is longer, and the growing amount of acid amides is higher and unstable.
In Chinese patent CN201210254405.9, use formula II compound and oxammonium hydrochloride and sodium hydroxide, tetrabutyl ammonium fluoride, the reaction preparation taking water as solvent refluxing.Use catalyzer tetrabutyl ammonium fluoride price, the method for the treatment of different things alike causes product very assorted, is unfavorable for next step reaction.
Summary of the invention
It is low and do not need the preparation method of the Azilsartan intermediate of aftertreatment that technical problem to be solved by this invention is to provide a kind of amide impurities content.
The present invention addresses the above problem adopted technical scheme: a kind of preparation method of Azilsartan intermediate is provided, has comprised the following steps:
In the ethanol that hydroxylammonium salt is 90%-95% at mass percent through alkaline hydrolysis from after, filter, in filtrate, add lower formula II compound, acid binding agent and ethanol, back flow reaction is to after completing, cooling crystallization, filters, and makes the target intermediate of formula I;
（Ⅱ）。
The preparation method of Azilsartan intermediate of the present invention, can also specifically comprise the following steps:
In the ethanol that hydroxylammonium salt is 90%-95% at mass percent, add siccative, solid alkali, while stopping heat release to reaction system, stop, filter, in filtrate, add lower formula II compound, acid binding agent and ethanol, back flow reaction is to after completing, cooling crystallization, filter, make the target intermediate of formula I;
（Ⅱ）。
Wherein, in preparation method of the present invention, the ethanol adding in back flow reaction is fresh ethanol, and the concentration of this ethanol there is no and specifies.
In preparation method of the present invention, hydroxylammonium salt through alkaline hydrolysis from after obtain azanol, azanol makes the target intermediate of formula I again with formula II compound back flow reaction under the condition of acid binding agent and ethanol, the equation of this back flow reaction is as follows:
Wherein, described hydroxylammonium salt is selected from oxammonium sulfate or oxammonium hydrochloride, preferably oxammonium hydrochloride.
Wherein, the preferred anhydrous sodium sulphate of described siccative.
Wherein, described solid alkali is at least one in following material: sodium hydroxide, potassium hydroxide, salt of wormwood, sodium carbonate, further preferred sodium hydroxide.
Wherein, described acid binding agent is diethylamine or triethylamine, further preferred triethylamine.
Wherein, the mol ratio of described hydroxylammonium salt and solid alkali can be 1:0.7-1:0.9.Further, the preferred 1:0.7 of the mol ratio of described hydroxylammonium salt and solid alkali.The inventor, by test of many times, finds that, in the time that the mol ratio of described hydroxylammonium salt and solid alkali is 1:0.7, the amides foreign matter content that described preparation method produces obviously still less.
Wherein, the mol ratio of described formula II compound and described acid binding agent can be 1:4-1:10, preferably 1:5.
Wherein, the mol ratio of described formula II compound and described hydroxylammonium salt can be 1:4-1:10, preferably 1:5.
Wherein, in alkali dissociation process of the present invention, the mass percent adding is that the addition of 90%-95% ethanol is not particularly limited, and those skilled in the art can be according to any selection so that described hydroxylammonium salt in this ethanol fully alkaline hydrolysis from being advisable.
Wherein, the weight of described anhydrous sodium sulphate can be hydroxylammonium salt weight 0.23-0.24 doubly.
Wherein, the temperature of the back flow reaction in the method for the invention is 72-80 DEG C, preferably 78 DEG C.
Wherein, the back flow reaction in the method for the invention 16 hours.
Wherein, the recrystallization temperature in the method for the invention is room temperature.
The amides impurity that preparation method of the present invention produces is few, is conventionally less than 10%, is more preferably less than 5%.
To sum up, the invention has the beneficial effects as follows:
1, amide impurities content is lower, and product purity is high, has improved the yield of target product;
2, reacted without aftertreatment, directly carried out the next step;
3, cost is low, and solvent toxicity is low and recovery is simple, little to environmental influence;
4, continuous dosing, easy and simple to handle, be easy to industrial production.
Embodiment
Below in conjunction with embodiment, the present invention is done to detailed description further, but embodiments of the present invention are not limited to this.
Azilsartan intermediate of the present invention adopts following standard testing:
HPLC detects: get this product, adding volume ratio is that acetonitrile and the aqueous solution of 1:1 dissolves also and is quantitatively diluted to 0.4mg/ml solution, makes need testing solution.Get need testing solution appropriate, dilution is 4 μ g/ml, in contrast solution.Detect according to high performance liquid chromatography (two annex VD of Chinese Pharmacopoeia version in 2010).
Embodiment 1
Get oxammonium hydrochloride 42.4g(0.61mol), add in 85ml 95% ethanol, stir, 0-20 DEG C, adds anhydrous sodium sulphate 10g, slowly adds sodium hydroxide 19.45g(0.49mol), when stopping heat release, reaction system filters, in filtrate, add 25g formula II compound (0.061mol), 61.5g triethylamine (0.61mol), 125ml ethanol, 75-80 DEG C is refluxed 16 hours, be cooled to room temperature, filter, make the intermediate 15.4g of formula I.Detecting HPLC obtains: formula I intermediate 83.363%, acid amides 8.784%.
Embodiment 2
Get oxammonium sulfate 196.8g(1.2mol), add in 420ml 90% ethanol, stir, 0-20 DEG C, adds anhydrous sodium sulphate 50g, slowly adds potassium hydroxide 60.5g(1.08mol), when stopping heat release, reaction system filters, in filtrate, add 125g formula II compound (0.3mol), 87.6g diethylamine (1.2mol), 600ml ethanol, 75-80 DEG C is refluxed 16 hours, be cooled to room temperature, filter, make the intermediate 79.0g of formula I.Detecting HPLC obtains: formula I intermediate 85.741%, acid amides 7.518%.
Embodiment 3
Get oxammonium hydrochloride 210g(3mol), add in 420ml 95% ethanol, stir, 0-20 DEG C, adds anhydrous sodium sulphate 50g, slowly adds sodium hydroxide 84g(2.1mol), when stopping heat release, reaction system filters, in filtrate, add 125g formula II compound (0.3mol), 310g triethylamine (3mol), 600ml ethanol, 75-80 DEG C is refluxed 16 hours, be cooled to room temperature, filter, make the intermediate 79.0g of formula I.Detecting HPLC obtains: formula I intermediate 86.906%, acid amides 3.076%.
Embodiment 4
Get oxammonium hydrochloride 1056.4g(15.2mol), add in 4.2L 95% ethanol whipped state, 0-20 DEG C, adds anhydrous sodium sulphate 500g, sodium hydroxide 486.4g(12.16mol), when stopping heat release, reaction system filters, in filtrate, add 1250g formula II compound (3.04mol), 1538.2g triethylamine (15.2mol), 6L ethanol, 75-80 DEG C is refluxed 16 hours, be cooled to room temperature, filter, make the intermediate 814g of formula I.Detecting HPLC obtains: formula I intermediate 93.160%, acid amides 4.304%.
Embodiment 5
Get oxammonium hydrochloride 1056.4g(15.2mol), add in 4.2L 95% ethanol whipped state, 0-20 DEG C, adds anhydrous sodium sulphate 500g, sodium hydroxide 486.4g(12.16mol), when reaction system stops heat release, filter, filtrate sealing was placed after 5 hours, add 1250g formula II compound (3.04mol), 1538.2g triethylamine (15.2mol), 6L ethanol, 75-80 DEG C is refluxed 16 hours, is cooled to room temperature, filter, make the intermediate 788g of formula I.Detecting HPLC obtains: formula I intermediate 93.502%, acid amides 4.711%.
Comparative example 1
Add 10g formula II compound, 8.45 g oxammonium hydrochlorides, 12.3g triethylamine, 60mlDMSO, 85 DEG C of oil baths, back flow reaction 24h.TLC(thin-layer chromatography) to detect raw material reaction complete, and the 240ml that adds water stirs, and is cooled to after room temperature, filters, and 25ml tetrahydrofuran (THF) washing, makes the intermediate of formula I.Detecting HPLC obtains: formula I intermediate 51.505%, acid amides 32.402%.
Comparative example 2
Add 10g formula II compound, 8.45 g oxammonium hydrochlorides, 12.3g triethylamine, 100ml ethanol, 82 DEG C of oil baths, back flow reaction 24h.It is complete that TLC detects raw material reaction, and the 100ml that adds water stirs, and is cooled to after room temperature, filters, and makes the intermediate of formula I.Detecting HPLC obtains: formula I intermediate 40.525%, acid amides 49.503%.
Comparative example 3
Add 10g formula II compound, 50% aqueous hydroxylamine 17g, triethylamine 2.5g, ethanol 100ml, 82 DEG C of oil bath heating, back flow reaction 24h.Cooling, to filter, 60 DEG C of vacuum-dryings, obtain the thick product of 7.7g.Detect HPLC and obtain, formula I intermediate: acid amides: raw material=77.316%: 16.195%: 0.32%.
Comparative example 4
Add 10g formula II compound, sealed the 50% aqueous hydroxylamine 17g having placed 5 hours, triethylamine 2.5g, ethanol 100ml, 82 DEG C of oil bath heating, back flow reaction 24h.Cooling, to filter, 60 DEG C of vacuum-dryings, obtain the thick product of 5.7g.Detect HPLC and obtain, formula I intermediate: acid amides: raw material=57.254%: 36.085%: 0.32%.
Compare from above-described embodiment 1-5 and comparative example 1-4, the amide impurities content in comparative example 1-2 is high, and the thick product making in comparative example 3-4 can not be directly used in next step, also needs to carry out aftertreatment.Can find out, compared to the preparation method of Azilsartan intermediate in prior art, in the Azilsartan intermediate that method of the present invention makes, amide content is low, and does not need aftertreatment can be directly used in next step.
The amides impurity that preparation method of the present invention produces is few, is conventionally less than 10%, is more preferably less than 5%.
Embodiment 1 and embodiment 3 contrast, and can find out, when the mol ratio of all the other components is constant, in the time that the mol ratio of described hydroxylammonium salt and solid alkali is 1:0.7, the amides foreign matter content of described preparation method's generation obviously reduces.
Embodiment 1 and embodiment 4 contrast, can find out, when the mol ratio of all the other components is constant, in the time that the mol ratio of described formula II compound and the described acid binding agent mol ratio that is 1:5 and described formula II compound and described hydroxylammonium salt is 1:5, the amides foreign matter content that described preparation method produces obviously reduces.
From embodiment 4-5 and comparative example 3-4 contrast, can find out, compared with the aqueous hydroxylamine of placing after the long period, the hydroxylammonium salt in the present invention through alkaline hydrolysis from after solution to place the content of the formula I intermediate preparing after the long period still stable, and amides foreign matter content is less.
As mentioned above, can realize preferably the present invention.
Claims (10)
1. a preparation method for Azilsartan intermediate, comprises the following steps:
In the ethanol that hydroxylammonium salt is 90%-95% at mass percent through alkaline hydrolysis from after, filter, in filtrate, add lower formula II compound, acid binding agent and ethanol, back flow reaction is to after completing, cooling crystallization, filters, and makes the target intermediate of formula I;
2. a preparation method for Azilsartan intermediate, comprises the following steps:
In the ethanol that hydroxylammonium salt is 90%-95% at mass percent, add siccative, solid alkali, while stopping heat release to reaction system, stop, filter, in filtrate, add lower formula II compound, acid binding agent and ethanol, back flow reaction is to after completing, cooling crystallization, filter, make the target intermediate of formula I;
（Ⅰ），
（Ⅱ）。
3. the preparation method of Azilsartan intermediate according to claim 1 and 2, is characterized in that, described hydroxylammonium salt is selected from oxammonium sulfate or oxammonium hydrochloride.
4. the preparation method of Azilsartan intermediate according to claim 2, is characterized in that, described siccative is anhydrous sodium sulphate.
5. the preparation method of Azilsartan intermediate according to claim 2, is characterized in that, described solid alkali is at least one in following material: sodium hydroxide, potassium hydroxide, salt of wormwood, sodium carbonate.
6. the preparation method of Azilsartan intermediate according to claim 1 and 2, is characterized in that, described acid binding agent is diethylamine or triethylamine.
7. the preparation method of Azilsartan intermediate according to claim 2, is characterized in that, the mol ratio of described hydroxylammonium salt and solid alkali is 1:0.7-1:0.9.
8. the preparation method of Azilsartan intermediate according to claim 7, is characterized in that, the mol ratio of described hydroxylammonium salt and solid alkali is 1:0.7.
9. the preparation method of Azilsartan intermediate according to claim 1 and 2, is characterized in that, the mol ratio of described formula II compound and described acid binding agent is 1:4-1:10.
10. the preparation method of Azilsartan intermediate according to claim 2, is characterized in that, the mol ratio of described formula II compound and described solid alkali is 1:4-1:10.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410116645.1A CN103880756B (en) | 2014-03-26 | 2014-03-26 | The preparation method of a kind of Azilsartan intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410116645.1A CN103880756B (en) | 2014-03-26 | 2014-03-26 | The preparation method of a kind of Azilsartan intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103880756A true CN103880756A (en) | 2014-06-25 |
| CN103880756B CN103880756B (en) | 2016-06-01 |
Family
ID=50949925
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410116645.1A Active CN103880756B (en) | 2014-03-26 | 2014-03-26 | The preparation method of a kind of Azilsartan intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103880756B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106478515A (en) * | 2016-10-13 | 2017-03-08 | 艾美科健（中国）生物医药有限公司 | A kind of preparation method of Azilsartan intermediate |
| CN107840827A (en) * | 2017-11-06 | 2018-03-27 | 江苏中邦制药有限公司 | A kind of synthetic method of Azilsartan intermediate |
| CN108456202A (en) * | 2017-12-15 | 2018-08-28 | 江苏联环药业股份有限公司 | A kind of Azilsartan preparation method of low amide impurities content |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013186792A2 (en) * | 2012-06-11 | 2013-12-19 | Msn Laboratories Limited | Process for the preparation of (5-methyl-2-oxo-l,3-dioxoi-4-vl)methvl 2- ethoxv-l-{[2'-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-vl)biphenyi-4-vl]methyl}- lh-benzimidazole-7-carboxyiate and its salts |
| CN103476758A (en) * | 2011-03-04 | 2013-12-25 | 赞蒂瓦有限合伙公司 | A method of manufacturing 2-ethoxy-1-((2'-((hydroxyamino) iminomethyl)biphenyl-4- yl)methyl)-1h-benzo [d] imidazole-7-carboxylic acid and its esters |
| CN103554031A (en) * | 2013-11-01 | 2014-02-05 | 深圳科兴生物工程有限公司 | Preparation method of azilsartan intermediate |
| CN103588765A (en) * | 2013-11-11 | 2014-02-19 | 浙江永宁药业股份有限公司 | Synthesis method for azilsartan medoxomil or salt thereof, intermediate of azilsartan medoxomil or salt thereof and synthesis method for intermediate |
-
2014
- 2014-03-26 CN CN201410116645.1A patent/CN103880756B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103476758A (en) * | 2011-03-04 | 2013-12-25 | 赞蒂瓦有限合伙公司 | A method of manufacturing 2-ethoxy-1-((2'-((hydroxyamino) iminomethyl)biphenyl-4- yl)methyl)-1h-benzo [d] imidazole-7-carboxylic acid and its esters |
| WO2013186792A2 (en) * | 2012-06-11 | 2013-12-19 | Msn Laboratories Limited | Process for the preparation of (5-methyl-2-oxo-l,3-dioxoi-4-vl)methvl 2- ethoxv-l-{[2'-(5-oxo-4,5-dihvdro-l,2,4-oxadiazol-3-vl)biphenyi-4-vl]methyl}- lh-benzimidazole-7-carboxyiate and its salts |
| CN103554031A (en) * | 2013-11-01 | 2014-02-05 | 深圳科兴生物工程有限公司 | Preparation method of azilsartan intermediate |
| CN103588765A (en) * | 2013-11-11 | 2014-02-19 | 浙江永宁药业股份有限公司 | Synthesis method for azilsartan medoxomil or salt thereof, intermediate of azilsartan medoxomil or salt thereof and synthesis method for intermediate |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106478515A (en) * | 2016-10-13 | 2017-03-08 | 艾美科健（中国）生物医药有限公司 | A kind of preparation method of Azilsartan intermediate |
| CN106478515B (en) * | 2016-10-13 | 2018-11-23 | 艾美科健（中国）生物医药有限公司 | A kind of preparation method of Azilsartan intermediate |
| CN107840827A (en) * | 2017-11-06 | 2018-03-27 | 江苏中邦制药有限公司 | A kind of synthetic method of Azilsartan intermediate |
| CN108456202A (en) * | 2017-12-15 | 2018-08-28 | 江苏联环药业股份有限公司 | A kind of Azilsartan preparation method of low amide impurities content |
| CN108456202B (en) * | 2017-12-15 | 2021-10-29 | 江苏联环药业股份有限公司 | Preparation method of azilsartan with low amide impurity content |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103880756B (en) | 2016-06-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104693114A (en) | Improved method for preparing betrixaban | |
| CN106349245A (en) | Sitagliptin phosphate impurities, method for preparing same and application of sitagliptin phosphate impurities | |
| CN102127005B (en) | Intermediate of alvimopan and synthesis method thereof | |
| CN101817795A (en) | Improved method for synthesizing valsartan | |
| CN101870653B (en) | Synthesis method of 2 - methyl -3 - fluoride - 6 -nitrobenzoic acid | |
| CN103880756A (en) | Preparation method of azilsartan intermediate | |
| CN104045602A (en) | Improved method for preparing tetrazole for valsartan | |
| CN103554031B (en) | Preparation method of azilsartan intermediate | |
| CN105330581A (en) | Preparation method for (S)-oxiracetam | |
| CN105061405A (en) | Preparation method of fimasartan potassium salt hydrate | |
| CN108440409B (en) | Green and efficient preparation method of rebamipide | |
| CN105777581A (en) | Cis-1-cyano-4-methoxycyclohexyl-2-(2, 5-dimethylphenyl)acetamide, preparation method and application thereof | |
| CN106518758A (en) | Preparation method of Betrixaban intermediate N-(5-chloro-2-pyridyl)-2-(4-cyanobenzeneformamido)-5-metoxybenzamide | |
| CN105801438A (en) | Synthetic method of mirabegron intermediate | |
| WO2014139410A1 (en) | Method for preparing intermediate of azelnidipine | |
| CN112939893B (en) | Synthesis method of 4- (4-aminophenyl) -3-morpholinone | |
| CN103992241B (en) | The preparation method of N-substituted-phenyl glycine | |
| CN103724248A (en) | Preparation method of vildagliptin process impurities | |
| CN104910068A (en) | 2-cyano isonicotinic acid hydrazide 1.5 p-toluenesulfonate synthetic method | |
| CN106518751B (en) | Method for preparing pimavanserin | |
| CN104003887A (en) | Preparation method of bromhexine hydrochloride | |
| CN114990590B (en) | Novel method for electrocatalytic metal-free transamidation reaction | |
| CN112062785B (en) | Preparation method of ozagrel and intermediate thereof | |
| CN105924400A (en) | Preparation method for azilsartan impurity A and azilsartan impurity B | |
| CN110386884B (en) | Preparation method of florfenicol intermediate compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| 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: 20160930 Address after: 610000, No. four, No. 22, sheep Road, Qionglai City, Sichuan Province Patentee after: Sichuan Open Medicine Co., Ltd. Address before: 610000, No. 16, herb Road, hi tech West District, Sichuan, Chengdu Patentee before: Aobang Pharmaceutical Co., Ltd., Sichuan |