CN106397371A - Method for producing 10-DAB (deacetylbaccatin) III at high yield by using taxus media - Google Patents
Method for producing 10-DAB (deacetylbaccatin) III at high yield by using taxus media Download PDFInfo
- Publication number
- CN106397371A CN106397371A CN201610791733.0A CN201610791733A CN106397371A CN 106397371 A CN106397371 A CN 106397371A CN 201610791733 A CN201610791733 A CN 201610791733A CN 106397371 A CN106397371 A CN 106397371A
- Authority
- CN
- China
- Prior art keywords
- dab iii
- solution
- high yield
- taxus media
- dab
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
Abstract
The invention relates to a method for producing 10-DAB (deacetylbaccatin) III at a high yield by using taxus media. The method for producing 10-DAB III at the high yield by using taxus media provided by the invention comprises the following steps of performing stirring extraction on the taxus media by using a solution; performing reduced pressure concentration to obtain an extract; adding organic solvents into the extract; performing stirring dissolution to obtain a dissolving solution; adding acid into the dissolving solution for acidizing an acidified solution; adding alkali into the acidified solution for neutralization; then, adding hydrazine hydrate, and performing stirring for hydrolyzation; adding reaction terminating agents until the solution is neutral to obtain hydrolysate; performing reduced pressure concentration on the hydrolysate to the thick state; then, performing extraction; concentrating the organic phase; then, performing re-crystallization purification to obtain a product. The content of the 10-DAB III in the 10-DAB III crude product prepared by the method is as high as 5.5 percent to 8.6 percent; the substances comprising 10-DAB III structures in the taxus media can be sufficiently used, so that the substances are changed from waste into valuable materials. The method is very suitable for industrial production. The 10-DAB III produced by the method can be used as synthesis raw materials of taxol and docetaxel to be applied in the field of medicine.
Description
Technical field
This belongs to natural plant composition and extracts field, more particularly, to a kind of use Taxus media high yield 10-DAB's III
Method.
Background technology
Taxus media (Taxus X media) is a kind of natural hybrid variety, and its female parent is Japanese Ramulus et folium taxi cuspidatae
(T.cuspidata), male parent is Taxus baccata (T.baccata), is 7-8 times of domestic Ramulus et folium taxi cuspidatae of increment.
Bearing taxanes are the class chemical combination being extracted from the positions such as bark, root and the leaf of high gymnosperm Ramulus et folium taxi cuspidatae
Thing, mainly contains paclitaxel, Cephalomannine, 10-DAB III (i.e. 10- deacetylate baccatin III), 7- xylosyl taxol
Deng having many to have been demonstrated with cytotoxicity and anti-tumor activity, and be used for extracting the natural taxus resource of paclitaxel etc.
Limited, thus the production and supply of natural Japanese yew raw polyol medicine is restricted, and far can not meet the clinical application of paclitaxel.
10-DAB III is the raw material of taxol biosynthesis, docetaxel, Cabazitaxel, therefore it belongs in antitumor drug research and development
Highly important composition.Every material containing 10-DAB III structure can hydrolyze and be prepared into 10- deacetylate baccatin III,
As Cephalomannine, paclitaxel C, paclitaxel D, Bakating III, 7- xylosyl taxol, 10- deacetylate paclitaxel, 10- go
Acetyl group Cephalomannine, 7- xylosyl -10- deacetylate paclitaxel, 7- xylosyl -10- deacetylate Cephalomannine etc.,
These materials can hydrolyze makes 10- deacetylate baccatin III.
There is the defects such as extraction ratio is not high and solvent load is big and operating procedure is complicated in the existing method preparing 10-DAB III,
It is unfavorable for carrying out large-scale production to it.Such as Authorization Notice No. is a kind of " antitumor drug intermediate of CN101798294B
The preparation method of 10- deacetylate Bakating III " patent, the method for disclosed extraction taxaneses effective ingredient is：First by three
The peaceful alkali alcosol of sharp China fir is contacted with hydrazine hydrate, converts it into 10-DAB III, product is separated with silica gel column chromatography, with oil
Ether-acetone (3: 1) is eluant, obtains 10-DAB III principal piece, then this principal piece is carried out secondary recrystallization, obtain highly purified
10-DABⅢ.The major defect of the method is：1. raw materials used single, it is Cephalomannine；2. 10- deacetylate Bakating III
Purifying process employ the mode of column chromatography, solvent load is big.
Content of the invention
The invention aims to providing a kind of preparation technology, production equipment and operating procedure simple, 10-DAB III produces
The method of high, the practical use Taxus media high yield 10-DAB III of rate.
For achieving the above object, the technical solution used in the present invention is：One kind Taxus media high yield 10-DAB III
Method include step：
A. solution extracts：Using methanol or ethanol water, Taxus media is stirred with extraction 2-8h must extract
Liquid, extracting solution is concentrated under reduced pressure to give extractum；
B. dissolving acidifying：Add organic solvent to be stirred dissolving in gained extractum and obtain lysate, in lysate
Add acid, stirring acidifying 1-24h, obtains souring soln at 0-40 DEG C；
C. hydrolyze：Add alkali to be neutralized to after neutrality in souring soln, then add hydrazine hydrate in solution, at 0-60 DEG C
After stirring hydrolysis 2-72h, terminating reaction agent is added to obtain final product hydrolyzed solution to solution in neutrality；
D. purification：Hydrolyzed solution is evaporated to thick, after extraction, organic faciess is concentrated and purify and must produce through recrystallization again
Product.
Further, in described step A, the volume/mL of methanol used or ethanol water is the 5- of Ramulus et folium taxi cuspidatae quality/g
30 times.That is the methanol that 1g Taxus media is used or the volume of ethanol water are 5-30mL.
It is further preferred that volume/the mL of methanol or ethanol water is 5-20 times of Ramulus et folium taxi cuspidatae quality/g.
Further, in described step B, the volume fraction of methanol or ethanol water is 40-99.5%.
Further, the acid being used for neutralizing hydrolysis liquid in described step B is formic acid, acetic acid, trichloroacetic acid, trifluoroacetic acid
One or more mixing.
Further, the weight of acid described in described step B is 0.1-1 times of extractum weight, the weight of described hydrazine hydrate
For extractum weight 1-5 times.
Further, organic solvent described in described step B be methanol, ethanol, isopropanol, oxolane, dichloromethane,
One or more mixing of ethyl acetate, the volumetric usage/mL of described organic solvent is 5-20 times of extractum weight/g.Namely 1g
Extractum needs to be dissolved with the organic solvent of 5-20mL.
Further, terminating reaction agent described in described step C is to be 5-20% sodium hydroxide/hydrogen-oxygen containing mass fraction
Change the aqueous solution of potassium and 5-20% ammonium chloride/ammonium sulfate/ammonium carbonate/ammonium nitrate.That is terminating reaction agent is containing two kinds
The aqueous solution of material, a kind of material is sodium hydroxide or potassium hydroxide, and its mass fraction is 5-20%, and another kind of material is chlorination
One of ammonium, ammonium sulfate, ammonium carbonate, ammonium nitrate, phase intelligence community of stock number is 5-20%.
Further, alkali described in described step C is sodium hydroxide and/or potassium hydroxide.
Further, described in described step D, extraction step is：Add extractant to carry out 1-4h extraction, be subsequently adding water
Layering, takes organic layer concentrating under reduced pressure to obtain 10-DAB III crude product after reclaiming extractant, 10-DAB III crude product carries out recrystallization purification；Institute
Volume/the mL stating extractant is 10-30 times of extractum weight/g, and the volume/mL of water is 10-30 times of extractum weight/g.
Further, extractant described in described step D is ethyl acetate, dichloromethane, one kind of chloroform or many
Plant mixing.
The method preparation 10-DAB III being provided using the present invention is had the advantages that：
1. the inventive method, with Taxus media as raw material, obtains extractum, is acidified and hydrolyzes extractum using first extracting
Thus obtaining 10-DAB III, 10-DAB III crude yield is up to 10- in 0.065%～0.163%, 10-DAB III crude product to solution
DAB III content up to 5.5%～8.6%.
2. the inventive method take full advantage of the material containing 10-DAB III structure in taxus resource so as to become give up into
Precious.
3. production equipment used by the inventive method is conventional equipment, and solvent for use is Conventional solvents, and working condition is easily implemented,
Easy to operate suitable industrialized production.
The method that the composite can be widely applied to obtain 10- deacetylate baccatin III from Ramulus et folium taxi cuspidatae, using the present invention
The 10- deacetylate baccatin III that method produces can be used for the synthesis material of paclitaxel, docetaxel, is applied to medicine and receives
In.
Specific embodiment
With reference to specific embodiment, the present invention will be further described.Described embodiment is only being preferable to carry out of the present invention
Example, is not limited to the present invention, and for a person skilled in the art, the present invention can have various changes and become
Change.All any modification, equivalent substitution and improvement within the spirit and principles in the present invention, made etc., should be included in the present invention
Protection domain within.
Embodiment one
It is methanol aqueous solution that 40%, volume/mL is 5 times of Taxus media quality/g to graceful using volume fraction
Sub- Ramulus et folium taxi cuspidatae is stirred extracting 2 hours, filters and obtains extracting solution, obtains extractum to after extracting solution concentrating under reduced pressure, in extractum
The methanol for extractum weight/5 times of g for the addition volume/mL is stirred dissolving and obtains lysate, adds extractum weight in lysate
0.1 times of formic acid of amount, stirring acidifying 1 hour at 0 DEG C, the solution after being acidified, add hydrogen-oxygen in the solution after acidifying
Change the hydrazine hydrate of add extractum weight after sodium is neutralized to neutrality 1 times, stirring hydrolysis 2 hours, molten after being hydrolyzed at 0 DEG C
Liquid, adding in the solution after hydrolysis containing mass fraction is 5% sodium hydroxide and 5% aqueous ammonium chloride solution is neutrality to pH,
Then it is thick for being evaporated to concentrated solution, and addition volume/mL is the ethyl acetate of extractum weight/10 times of g as extractant
It is stirred extracting 1 hour, adds layering after the water that volume/mL is extractum weight/10 times of g is stirred, taking-up has
Machine layer, concentrating under reduced pressure obtains 10-DAB III crude product after reclaiming extractant, and 10-DAB III crude yield is 0.065%, 10-DAB III
In crude product, 10-DAB III content is to reach 5.5%, after 10-DAB III crude product is processed using conventional recrystallization method
Obtain 10-DAB III product that content is more than 98%.
Embodiment two
The ethanol solution being 30 times that 99.5%, volume/mL is Taxus media quality/g using volume fraction is to graceful
Sub- Ramulus et folium taxi cuspidatae is stirred extracting 8 hours on ground, filters and obtains extracting solution, obtains extractum to after extracting solution concentrating under reduced pressure, to extractum
The ethyl acetate for extractum weight/20 times of g for the middle addition volume/mL is stirred dissolving and obtains lysate, adds in lysate
The trifluoroacetic acid that 1 times of extractum weight, stirring acidifying 24 hours, the solution after being acidified, the solution to after acidifying at 40 DEG C
The middle hydrazine hydrate adding sodium hydroxide to add 5 times of extractum weight after being neutralized to neutrality, at 60 DEG C, stirring hydrolysis 72 hours, obtain
Solution after hydrolysis, adding in the solution after hydrolysis containing mass fraction is the water-soluble of 20% potassium hydroxide and 20% ammonium nitrate
Liquid is neutrality to pH, and it is thick for being then evaporated to concentrated solution, and addition volume/mL is the trichlorine of extractum weight/30 times of g
Methane as extractant stirring extraction 4 hours, add volume/mL be extractum weight/30 times of g water be stirred after
Layering, takes out organic layer, and concentrating under reduced pressure obtains 10-DAB III crude product after reclaiming extractant, and 10-DAB III crude yield is
In 0.163%, 10-DAB III crude product, 10-DAB III content is 8.6%, to 10-DAB III crude product using conventional recrystallization method
10-DAB III product that content is more than 98% can be obtained after being processed.
Embodiment three
It is methanol solution that 80%, volume/mL is 20 times of Taxus media quality/g to graceful using volume fraction
Sub- Ramulus et folium taxi cuspidatae is stirred extracting 4 hours, filters and obtains extracting solution, obtains extractum to after extracting solution concentrating under reduced pressure, in extractum
The oxolane of 12 times of extractum weight of addition is stirred dissolving and obtains lysate, adds 0.5 times of extractum weight in lysate
Acetic acid, at 20 DEG C stirring acidifying 12 hours, the solution after be acidified, to acidifying after solution in addition sodium hydroxide in
Hydrazine hydrate with adding 3 times of extractum weight to neutrality, stirs at 40 DEG C and hydrolyzes 30 hours, the solution after being hydrolyzed, to
The aqueous solution being 10% sodium hydroxide and 10% ammonium sulfate containing mass fraction is added to be neutrality to pH in solution after hydrolysis, so
After to be evaporated to concentrated solution be thick, additions volume/mL stirs as extractant for the dichloromethane of extractum weight/20 times of g
Mix extraction 2 hours, add layering after the water that volume/mL is extractum weight/20 times of g is stirred, take out organic layer,
Concentrating under reduced pressure obtains 10-DAB III crude product after reclaiming extractant, and 10-DAB III crude yield is in 0.138%, 10-DAB III crude product
10-DAB III content is 7.9%, can obtain content after 10-DAB III crude product is processed using conventional recrystallization method
10-DAB III product for more than 98%.
Claims (10)
1. a kind of method of use Taxus media high yield 10-DAB III it is characterised in that：Including step：
A. solution extracts：Extraction 2-8h is stirred using methanol or ethanol water to Taxus media and obtains extracting solution, carry
Liquid is taken to be concentrated under reduced pressure to give extractum；
B. dissolving acidifying：Add organic solvent to be stirred dissolving in gained extractum and obtain lysate, add in lysate
Acid, at 0-40 DEG C, stirring acidifying 1-24h, obtains souring soln；
C. hydrolyze：Add alkali to be neutralized to after neutrality in souring soln, then add hydrazine hydrate in solution, stir at 0-60 DEG C
After hydrolysis 2-72h, terminating reaction agent is added to obtain final product hydrolyzed solution to solution in neutrality；
D. purification：Hydrolyzed solution is evaporated to thick, after extraction, organic faciess is concentrated and purify to obtain product through recrystallization again.
2. use Taxus media high yield 10-DAB III according to claim 1 method it is characterised in that：Described step
In A, the volume/mL of methanol used or ethanol water is 5-30 times of Ramulus et folium taxi cuspidatae quality/g.
3. use Taxus media high yield 10-DAB III according to claim 1 method it is characterised in that：Described step
In B, the volume fraction of methanol or ethanol water is 40-99.5%.
4. use Taxus media high yield 10-DAB III according to claim 1 method it is characterised in that：Described step
The acid being used for neutralizing hydrolysis liquid in B is formic acid, one or more mixing of acetic acid, trichloroacetic acid, trifluoroacetic acid.
5. use Taxus media high yield 10-DAB III according to claim 1 method it is characterised in that：Described step
Described in B, the weight of acid is 0.1-1 times of extractum weight, and the weight of described hydrazine hydrate is 1-5 times of extractum weight.
6. use Taxus media high yield 10-DAB III according to claim 1 method it is characterised in that：Described step
Organic solvent described in B is methanol, one or more mixing of ethanol, isopropanol, oxolane, dichloromethane, ethyl acetate,
Volumetric usage/the mL of described organic solvent is 5-20 times of extractum weight/g.
7. use Taxus media high yield 10-DAB III according to claim 1 method it is characterised in that：Described step
Terminating reaction agent described in C is to be 5-20% sodium hydroxide/potassium hydroxide and 5-20% ammonium chloride/sulphuric acid containing mass fraction
The aqueous solution of ammonium/ammonium carbonate/ammonium nitrate.
8. use Taxus media high yield 10-DAB III according to claim 1 method it is characterised in that：Described step
Alkali described in C is sodium hydroxide and/or potassium hydroxide.
9. use Taxus media high yield 10-DAB III according to claim 1 method it is characterised in that：Described step
Described in D, extraction step is：Add extractant to carry out 1-4h extraction, be subsequently adding water stratification, take organic layer concentrating under reduced pressure to reclaim
10-DAB III crude product is obtained, 10-DAB III crude product carries out recrystallization purification after extractant；Volume/the mL of described extractant is extractum weight
10-30 times of amount/g, the volume/mL of water is 10-30 times of extractum weight/g.
10. use Taxus media high yield 10-DAB III according to claim 9 method it is characterised in that：Described step
Extractant described in rapid D is ethyl acetate, one or more mixing of dichloromethane, chloroform.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610791733.0A CN106397371A (en) | 2016-08-31 | 2016-08-31 | Method for producing 10-DAB (deacetylbaccatin) III at high yield by using taxus media |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610791733.0A CN106397371A (en) | 2016-08-31 | 2016-08-31 | Method for producing 10-DAB (deacetylbaccatin) III at high yield by using taxus media |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106397371A true CN106397371A (en) | 2017-02-15 |
Family
ID=58001698
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610791733.0A Pending CN106397371A (en) | 2016-08-31 | 2016-08-31 | Method for producing 10-DAB (deacetylbaccatin) III at high yield by using taxus media |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106397371A (en) |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5736366A (en) * | 1992-10-05 | 1998-04-07 | Rhone-Poulenc Rorer S.A. | Process for obtaining 10-deacetylbaccatin III |
| US6281368B1 (en) * | 2000-03-16 | 2001-08-28 | Napro Biotherapeutics, Inc. | Simple and efficient hydrazinolysis of C-10 and C-13 ester functionalities of taxanes to obtain 10-DAB III |
| US20040063976A1 (en) * | 2002-09-26 | 2004-04-01 | John Findlay | Conversion 9-dihydro-13-acetylbaccatin iii into 10-deacetylbaccatin iii |
| CN1538963A (en) * | 2001-07-05 | 2004-10-20 | 拿坡罗生物治疗股份有限公司 | Etticient process for production of 10-DAB III by selective hydrazinolysis of various taxanes |
| CN101798294A (en) * | 2010-02-23 | 2010-08-11 | 沈阳天峰生物工程技术有限公司 | Preparation method of anti-tumour medicine intermediate 10-deacetylbacctin III |
| CN103508984A (en) * | 2013-10-22 | 2014-01-15 | 北京和谐伟业化学科技有限公司 | Method for extracting 10-DAB from taxus chinensis according to continuous leaching adsorption enrichment method |
| CN105671089A (en) * | 2016-03-03 | 2016-06-15 | 重庆市碚圣医药科技股份有限公司 | Method for co-producing taxane effective ingredients and ethyl alcohol by utilizing Chinese yew |
| CN105669602A (en) * | 2016-03-03 | 2016-06-15 | 重庆市碚圣医药科技股份有限公司 | Method for efficiently and quickly extracting paclitaxel, cephalomannine and 10-DAB III from Taxus chinensis |
-
2016
- 2016-08-31 CN CN201610791733.0A patent/CN106397371A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5736366A (en) * | 1992-10-05 | 1998-04-07 | Rhone-Poulenc Rorer S.A. | Process for obtaining 10-deacetylbaccatin III |
| US6281368B1 (en) * | 2000-03-16 | 2001-08-28 | Napro Biotherapeutics, Inc. | Simple and efficient hydrazinolysis of C-10 and C-13 ester functionalities of taxanes to obtain 10-DAB III |
| CN1538963A (en) * | 2001-07-05 | 2004-10-20 | 拿坡罗生物治疗股份有限公司 | Etticient process for production of 10-DAB III by selective hydrazinolysis of various taxanes |
| US20040063976A1 (en) * | 2002-09-26 | 2004-04-01 | John Findlay | Conversion 9-dihydro-13-acetylbaccatin iii into 10-deacetylbaccatin iii |
| CN101798294A (en) * | 2010-02-23 | 2010-08-11 | 沈阳天峰生物工程技术有限公司 | Preparation method of anti-tumour medicine intermediate 10-deacetylbacctin III |
| CN103508984A (en) * | 2013-10-22 | 2014-01-15 | 北京和谐伟业化学科技有限公司 | Method for extracting 10-DAB from taxus chinensis according to continuous leaching adsorption enrichment method |
| CN105671089A (en) * | 2016-03-03 | 2016-06-15 | 重庆市碚圣医药科技股份有限公司 | Method for co-producing taxane effective ingredients and ethyl alcohol by utilizing Chinese yew |
| CN105669602A (en) * | 2016-03-03 | 2016-06-15 | 重庆市碚圣医药科技股份有限公司 | Method for efficiently and quickly extracting paclitaxel, cephalomannine and 10-DAB III from Taxus chinensis |
Non-Patent Citations (1)
| Title |
|---|
| 张静 等: "UPLC法同时测定曼地亚红豆杉中3个有效成分的含量", 《药物分析杂志》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102382119B (en) | Extraction method of tetrandrine and demethyltetrandrine | |
| CN105734109A (en) | Producing and refining method for high-purity cycloastragenol | |
| CN113666824B (en) | Cannabidiol-2-propionate and application thereof | |
| CN103804438A (en) | Semi-synthesis method for high-purity and high-stability gastrodin | |
| CN102050822B (en) | Method for extracting tabersonine from voacanga seed | |
| CN113735709A (en) | Cannabidiol-2-butyrate and application thereof | |
| CN102351933A (en) | Method for preparing hydroxycobalamin salt | |
| CN105671089B (en) | Utilize the method for Chinese yew coproduction taxanes effective component and ethyl alcohol | |
| CN104774171B (en) | The methylol Oxoindole of 3 amino 3, the methylol oxoindole derivative of 3 hydroxyl 3 and its preparation method and application | |
| CN1724685A (en) | Method of extracting diosgenin by bioenzyme gradient catalysis | |
| CN106397371A (en) | Method for producing 10-DAB (deacetylbaccatin) III at high yield by using taxus media | |
| CN102311474A (en) | Method for preparing protopanaxadiol and protopanaxatriol by solvent-free method | |
| CN1149584A (en) | Preparing matrine and matrine oxide from sophora alopecuroide and its producing technology | |
| CN101798294B (en) | Preparation method of anti-tumour medicine intermediate 10-deacetylbacctin III | |
| CN1932022B (en) | Process of preparing high purity solanesol with potato leaf as material | |
| CN114292241A (en) | Cannabidiol-2-dioxopiperazinoate and application thereof | |
| CN107686472A (en) | A kind of synthetic method of chrysoeriol | |
| CN103588736B (en) | 13-acetyl-9-dihydrobaccatin III extraction separation method | |
| CN106749098A (en) | A kind of friendly process for preparing dioxopromethazine hydrochloride as oxidant with oxygen | |
| CN103087013B (en) | Paclitaxel preparation method | |
| CN110305083B (en) | Process for preparing 5-chloromethyl furfural from fructose | |
| CN106632159A (en) | Method for preparing 10-deacetylbaccatin III by utilizing paclitaxel-semisynthesis impurity | |
| CN106117281B (en) | The method that rhodioside is extracted from rhodiola root | |
| CN114292224B (en) | Cannabidiol-2- (N-acetyl) piperidine acid ester and application thereof | |
| CN107459500A (en) | A kind of pipeline synthesis technique for arranging net class medicine |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170215 |