CN104311822A - Carbene-diazo compound-olefine aldehyde terpolymer and application of carbene-diazo compound-olefine aldehyde terpolymer as bidirectional conversion fluorescent material and anti-cancer drug - Google Patents
Carbene-diazo compound-olefine aldehyde terpolymer and application of carbene-diazo compound-olefine aldehyde terpolymer as bidirectional conversion fluorescent material and anti-cancer drug Download PDFInfo
- Publication number
- CN104311822A CN104311822A CN201410607989.2A CN201410607989A CN104311822A CN 104311822 A CN104311822 A CN 104311822A CN 201410607989 A CN201410607989 A CN 201410607989A CN 104311822 A CN104311822 A CN 104311822A
- Authority
- CN
- China
- Prior art keywords
- terpolymer
- preparation
- carbene
- diazo compound
- aryl
- 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
Landscapes
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a carbene-diazo compound-olefine aldehyde terpolymer and a preparation method thereof. The preparation method comprises the following steps: a diazo compound and olefine aldehyde are used as polymerization reaction monomers and after reaction, reprecipitation, centrifugation and vacuum drying of precipitates are carried out to obtain the product. The polymer is mainly prepared by copolymerization of C1/C1N2/C2 and a main chain of the polymer mainly comprises carbene, diazo compound and olefine aldehyde. The polymer not only has a down-conversion fluorescent property, but also has an up-conversion fluorescent property, meanwhile, has high optical stability, can be widely applied to the field of optics and optical detection; meanwhile, the polymer has anti-cancer activity and can be applied to the field of medicine.
Description
Technical field
The present invention relates to a kind of terpolymer of Cabbeen-diazonium compound-olefine aldehydr and the purposes as bi-directional conversion fluorescent material and cancer therapy drug thereof, belong to macromolecular material and biomedical sector.
Background technology
The concept of Cabbeen (carbene) is proposed in time within 1903, studying the cyclopropanization reaction of ethyl diazoacetate (EDA) by Eduard Buchner.In organic synthesis, Cabbeen is widely used as a kind of important intermediate.Diazonium compound has prepares the features such as simple, relatively stable, safe, is usually used in the precursor of Cabbeen.The reaction of usual diazonium compound and alkene is divided into two kinds: one is that denitrogenation forms Cabbeen and alkene generation cyclopropanization reaction; Another kind is generation 1,3-Dipolar Cycloaddition, generates pyrazoline.
The copolyreaction of diazonium compound and alkene is a routine rare C1/C1N2/C2 copolyreaction, by monomer directly by functional group as thiazolinyl, alkynyl, aromatic nucleus, aldehyde radical etc. directly introduce main polymer chain, make present method possess very large advantage and application prospect.
Up-conversion luminescent material is that a class absorbs long wavelength, energy photons, launch the novel fluorescent material of short wavelength's high-energy photons, the optical stability of its excellence, high chemical stability, have under near infrared light excites in addition tissue penetration dark, to plurality of advantages such as biological tissue's not damaged, the interference of near-zero background fluorescence, image sensitivity are high, therefore have a wide range of applications in biomedicine.But traditional up-conversion luminescent material is standby is all be mixed with rare earth metal, and is mainly fluorochemical and oxygen fluoride, therefore its biological safety remains focus and the difficult point of research.Meanwhile, the performance of the not upper conversion of general down-conversion luminescent material.
Summary of the invention
The invention provides a kind of terpolymer of Cabbeen-ethyl diazoacetate-olefine aldehydr, concrete general formula is as follows:
Wherein, x, y, z be greater than zero arbitrary integer, R is hydrogen atom, alkyl, aryl, alkoxyl group or aryloxy, and R ' is hydrogen atom, alkyl or aryl, R " be hydrogen atom, alkyl or aryl, R " ' be alkyl or aryl.
The preparation method of the terpolymer of above-mentioned Cabbeen-diazonium compound-olefine aldehydr, is specially:
By diazonium compound RCOCHN
2mix with olefine aldehydr, wherein R is hydrogen atom, alkyl, aryl, alkoxyl group or aryloxy, polyreaction at-70 ~ 150 DEG C, is cooled to room temperature, obtains the terpolymer of Cabbeen-diazonium compound-olefine aldehydr through reprecipitation and vacuum-drying after reaction terminates.
Polyreaction can be mass polymerization, also can be solution polymerization.
During solution polymerization, suitable solvent comprises methyl alcohol, ethanol, acetonitrile, tetrahydrofuran (THF), chloroform, 1,2-ethylene dichloride, methylene dichloride, tetracol phenixin, toluene, benzene, pyridine etc., in order to prevent solvent evaporates, can add reflux.
Diazonium compound RCOCHN used
2, R is hydrogen atom, alkyl, aryl, alkoxyl group or aryloxy, can be obtained by prior art synthesis.As by glycine ethyl ester hydrochloride cheap and easy to get and Sodium Nitrite, ethyl diazoacetate can be prepared more easily; By two (p-methylphenyl alkylsulfonyl) hydrazine of 1,2-, bromoacetyl bromide and corresponding alcohol, can prepare α-diazoacetate, as diazoacetic acid benzyl ester etc.; By diazo transfer method, the compounds such as the diazoacetic acid tert-butyl ester can be prepared; By acyl chlorides and diazomethane, the compounds such as diazonium ethanoyl benzene can be prepared.
The preparation method of the terpolymer of a kind of Cabbeen-ethyl diazoacetate-olefine aldehydr provided by the invention, reaction completed at 2 minutes-120 hours usually.
The preparation method of the terpolymer of a kind of Cabbeen-ethyl diazoacetate-olefine aldehydr provided by the invention, the mol ratio of diazonium compound and olefine aldehydr is between 10:1 to 1:10.
The synthetic route of the terpolymer of Cabbeen-diazonium compound-olefine aldehydr of the present invention is as follows:
This polyreaction is a kind of C1/C1N2/C2 copolymerization.Reaction monomers is diazonium compound and olefine aldehydr, Cabbeen RCOCH: slough nitrogen by diazonium compound and formed, and reacts by Cabbeen, diazonium compound and olefine aldehydr terpolymer, obtains product.
The main polymer chain that synthetic method provided by the invention obtains is made up of Cabbeen, diazonium compound and olefine aldehydr.Preparation method in the existing reference of diazonium compound employing that the present invention is used prepares.
Prepare a kind of material with bi-directional conversion luminescent properties by method of the present invention, all can send fluorescence when low wavelength excites and excites with high wavelength, and the wavelength of fluorescence launched is at same wave band.
This kind of bi-directional conversion luminescent material provided by the present invention is not containing rare earth metal, under near infrared light excites, have that tissue penetration is dark, to biological tissue's not damaged, the aspect such as fluorescence imaging and tumor photo-thermal treatment has good application prospect in vivo.
This kind of bi-directional conversion luminescent material provided by the present invention, under dual wavelength excites, can launch fluorescence stronger when exciting than single wavelength, thus strengthens its fluorescence intensity further, also for sensitivity when improving bio-imaging provides a kind of novel method.
The terpolymer of a kind of Cabbeen-ethyl diazoacetate-olefine aldehydr provided by the invention, also has antitumour activity, can apply and biological medicine aspect.This polymkeric substance take aldehyde radical as side chain, and being easy to combines with protein detects it and interact; Meanwhile, aldehyde radical is convenient to modify target group, can be used for the exploitation of targeted drug; Send fluorescence because the distinctive fluorescent characteristic of polymkeric substance itself and near infrared can be excited, and cost is very low, has larger advantage relative to the conventional anti-cancer medicines Zorubicin etc. of costliness, larger application prospect can be had.
Beneficial effect of the present invention is:
1, ter-polymers of the present invention has good bi-directional conversion photoluminescent property, can be applied to the field such as optics and optical detection.
2, ter-polymers of the present invention not only has fluorescent characteristic but also have antitumour activity, by having easy adorned functional group, its application prospect in biological medicine is increased greatly.
3, ter-polymers of the present invention by monomer directly by functional group as thiazolinyl, alkynyl, aromatic nucleus, aldehyde radical etc. directly introduce main polymer chain, possess very large advantage and application prospect.
4, the reaction monomers that prepared by ter-polymers of the present invention is easy to get, and preparation method is simple, can without the need to catalysts and solvents, even can without the need to heating, convenient post-treatment.Polymerization rate is fast, substantially can complete the soonest within 2 minutes.
Accompanying drawing explanation
Fig. 1 is the time-of-fight mass spectrometry of the polymkeric substance of preparation in embodiment 1.
Fig. 2 is the fluorescence spectrum of the polymkeric substance of preparation in embodiment 1.
Fig. 3 is the fluorescence spectrum of the polymkeric substance of preparation in embodiment 3.
Fig. 4 is the fluorescence spectrum of the polymkeric substance of preparation in embodiment 5.
Fig. 5 is the fluorescence spectrum of the polymkeric substance of preparation in embodiment 6.
Fig. 6 is the fluorescence spectrum of the polymkeric substance of preparation in embodiment 7.
Fig. 7 is the fluorescence spectrum of the polymkeric substance of preparation in embodiment 8.
Fig. 8 is the cell imaging figure of the polymkeric substance of preparation in embodiment 1,2.
Fig. 9 is the cytotoxicity experiment of the polymkeric substance of preparation in embodiment 1,3.
Embodiment
Below by embodiment, illustrate outstanding feature of the present invention and marked improvement further, be only the present invention is described and does not limit the present invention.
Embodiment 1
Phenylacrolein (1.32g, 0.01mol) and diazoacetic acid methyl esters (MDA) (1.00g, 0.001mol) are added 10ml round-bottomed flask, and flask is connected with the safety flack that mineral oil is housed.Room temperature reaction 120h, is cooled to room temperature after terminating, and with chloroform/ether reprecipitation, vacuum-drying obtains polymkeric substance.
Fig. 1 is the time-of-fight mass spectrometry of embodiment 1 resulting polymers, can parse from spectrogram the terpolymer that polymer architecture is Cabbeen, diazonium compound and phenylacrolein.Fig. 2 is its fluorescence spectrum, excites all can obtain fluorescence from ultraviolet and near infrared light, and being more or less the same of the near ultraviolet excitated fluorescence intensity that obtains and burst of ultraviolel, and has good up-conversion fluorescence effect.
Embodiment 2
Phenylacrolein (1.32g, 0.01mol) and ethyl diazoacetate (2.28g, 0.02mol) are added 10ml round-bottomed flask, and flask is connected with the safety flack that mineral oil is housed.Be heated to 150 DEG C of reaction 60min, be cooled to room temperature after reaction terminates, with chloroform/normal hexane reprecipitation, vacuum-drying obtains polymkeric substance.
Embodiment 3
By trans-2-butene aldehyde (0.70g, 0.01mol) with ethyl diazoacetate (0.57g, 0.005mol) add 10ml round-bottomed flask, use toluene is solvent refluxing, prolong is connected with the safety flack that mineral oil is housed, be cooled to room temperature after reaction 2min, with chloroform/normal hexane reprecipitation, vacuum-drying obtains polymkeric substance.Fig. 3 is its fluorescence spectrum, excites all can obtain fluorescence from ultraviolet and near infrared light, has good up-conversion fluorescence effect.
Embodiment 4
Phenylacrolein (0.132g, 0.001mol) and diazoacetic acid allyl ester (1.26g, 0.01mol) are added 10ml round-bottomed flask, and use chloroform is solvent refluxing, and prolong is connected with the safety flack that mineral oil is housed, reaction 24h.Be cooled to room temperature after end, with chloroform/normal hexane reprecipitation, vacuum-drying obtains polymkeric substance.
Embodiment 5
Citral (1.52g, 0.01mol) and ethyl diazoacetate (0.57g, 0.005mol) are added 10ml round-bottomed flask, and use toluene is solvent refluxing, and prolong is connected with the safety flack that mineral oil is housed, reaction 48h.Be cooled to room temperature after end, with chloroform/normal hexane reprecipitation, vacuum-drying obtains polymkeric substance.Fig. 4 is its fluorescence spectrum, excites all can obtain fluorescence from ultraviolet and near infrared light, has good up-conversion fluorescence effect.
Embodiment 6
By 3-(2-furyl) propenal (1.22g, 0.01mol) add 10ml round-bottomed flask with diazoacetic acid Bian ester (3.52g, 0.02mol), use methyl alcohol is solvent refluxing, prolong is connected with the safety flack that mineral oil is housed, reaction 72h.Be cooled to room temperature after end, with chloroform/normal hexane reprecipitation, vacuum-drying obtains polymkeric substance.Fig. 5 is its fluorescence spectrum, excites all can obtain fluorescence from ultraviolet and near infrared light, has good up-conversion fluorescence effect.
Embodiment 7
4-methoxycinnamic aldehyde (1.62g, 0.01mol) and the diazoacetic acid tert-butyl ester (1.14g, 0.01mol) are added 10ml round-bottomed flask, and use toluene is solvent refluxing, and prolong is connected with the safety flack that mineral oil is housed, reaction 120h.Be cooled to room temperature after end, with chloroform/normal hexane reprecipitation, vacuum-drying obtains polymkeric substance.Fig. 6 is its fluorescence spectrum, excites all can obtain fluorescence from ultraviolet and near infrared light, has good up-conversion fluorescence effect.
Embodiment 8
4-nitro cinnamaldehyde (1.77g, 0.01mol) and diazoacetic acid allyl ester (1.14g, 0.01mol) are added 10ml round-bottomed flask, and use methylene dichloride is solvent refluxing, and prolong is connected with the safety flack that mineral oil is housed, reaction 24h.Be cooled to room temperature after end, with chloroform/normal hexane reprecipitation, vacuum-drying obtains polymkeric substance.Fig. 7 is its fluorescence spectrum, excites all can obtain fluorescence from ultraviolet and near infrared light, has good up-conversion fluorescence effect.
Embodiment 9
Isodihydrolavandulal (1.54g, 0.01mol) and diazonium ethanoyl benzene (1.46g, 0.01mol) are added 10ml round-bottomed flask, and flask is connected with the safety flack that mineral oil is housed.-70 DEG C of reactions, are cooled to room temperature after terminating, and with chloroform/ether reprecipitation, vacuum-drying obtains polymkeric substance.
Embodiment 10
Polymkeric substance in embodiment 1,3 and HeLa cell (cervical cancer cell) are mixed together cultivation, observation of cell under confocal microscope, its cell imaging figure can be obtained, as Fig. 8 (the cell imaging figure of the first behavior embodiment 1 sample, the cell imaging figure of the second behavior embodiment 3 sample).First is classified as cellular form figure under light field.Secondary series and the 3rd arranges and excites the image obtained under 405nm and 760nm respectively, can see that polymkeric substance has good Color to tenuigenin.4th row can find out and excite with ultraviolet and near infrared light simultaneously can have reinforced effects to cell imaging.
Embodiment 11
Cytotoxicity is detected with mtt assay.The substratum that 100 μ l contain HeLa cell (cervical cancer cell) is added 96 well culture plates, planting cell density is 6000/hole, wherein, substratum is the DMEM substratum containing 10%FBS, cultivate 24h at 37 DEG C, add different samples, after continuing to cultivate 48h, by substratum sucking-off, add fresh culture and 20 μ l MTT (5mg/ml) solution continuation cultivation 4h.Careful absorption supernatant liquor, every hole adds 200 μ l DMSO, jolting 5min dissolves the bluish voilet first a ceremonial jade-ladle, used in libation crystal obtained by the succinodehydrogenase reduction MTT in viable cell plastosome gently, measures the OD value of solution by microplate reader (Bio-rad 550) at 570nm place.Not add cell in the hole of nanoparticle in contrast.Cell survival rate is tried to achieve by formula below:
Cell survival rate (%)=[OD
570 (samples)/ OD
570 (control)] × 100%
OD
570 (samples)represent and added the value of mixture, OD
570 (control)represent the value not adding mixture.Each sample does 3 Duplicate Samples measurements and averages.
Fig. 9 is that the medium lethal dose of sample in embodiment 1,3 is respectively 7 μ g/mL and 18 μ g/mL, has good antitumour activity.
Claims (8)
1. a terpolymer for Cabbeen-ethyl diazoacetate-olefine aldehydr, concrete general formula is as follows:
Wherein, x, y, z be greater than zero arbitrary integer, R is hydrogen atom, alkyl, aryl, alkoxyl group or aryloxy, and R ' is hydrogen atom, alkyl or aryl, R " be hydrogen atom, alkyl or aryl, R " ' be alkyl or aryl.
2. the preparation method of the terpolymer of Cabbeen-diazonium compound-olefine aldehydr according to claim 1, is characterized in that:
By diazonium compound RCOCHN
2mix with olefine aldehydr, wherein R is hydrogen atom, alkyl, aryl, alkoxyl group or aryloxy, polyreaction at-70 ~ 150 DEG C, is cooled to room temperature, obtains the terpolymer of Cabbeen-diazonium compound-olefine aldehydr through reprecipitation and vacuum-drying after reaction terminates.
3. preparation method according to claim 2, is characterized in that, polyreaction is mass polymerization or solution polymerization.
4. preparation method according to claim 3, is characterized in that, during solution polymerization, solvent is methyl alcohol, ethanol, acetonitrile, tetrahydrofuran (THF), chloroform, 1,2-ethylene dichloride, methylene dichloride, tetracol phenixin, toluene, benzene or pyridine.
5. preparation method according to claim 2, is characterized in that, the reaction times was at 2 minutes-120 hours.
6. preparation method according to claim 2, is characterized in that, the mol ratio of diazonium compound and olefine aldehydr is between 10:1 to 1:10.
7. terpolymer according to claim 1 is as the purposes of bi-directional conversion fluorescent material.
8. terpolymer according to claim 1 is preparing the purposes on cancer therapy drug.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410607989.2A CN104311822B (en) | 2014-10-31 | 2014-10-31 | The terpolymer and its purposes as bi-directional conversion fluorescent material and cancer therapy drug of a kind of Cabbeen diazonium compound olefine aldehydr |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201410607989.2A CN104311822B (en) | 2014-10-31 | 2014-10-31 | The terpolymer and its purposes as bi-directional conversion fluorescent material and cancer therapy drug of a kind of Cabbeen diazonium compound olefine aldehydr |
Publications (2)
Publication Number | Publication Date |
---|---|
CN104311822A true CN104311822A (en) | 2015-01-28 |
CN104311822B CN104311822B (en) | 2017-08-08 |
Family
ID=52367149
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201410607989.2A Expired - Fee Related CN104311822B (en) | 2014-10-31 | 2014-10-31 | The terpolymer and its purposes as bi-directional conversion fluorescent material and cancer therapy drug of a kind of Cabbeen diazonium compound olefine aldehydr |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN104311822B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113061340A (en) * | 2021-06-04 | 2021-07-02 | 武汉柔显科技股份有限公司 | Display device, polyimide precursor composition, polyimide film, and laminate |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102977364A (en) * | 2012-11-30 | 2013-03-20 | 武汉大学 | Diazoacetate-ethoxycarbonyl carbene copolymer and preparation method thereof |
CN102977365A (en) * | 2012-12-03 | 2013-03-20 | 武汉大学 | Terpolymer of diazoacetate, carbethoxy cabbeen and cyclic lactone and preparation method thereof |
CN103319709A (en) * | 2013-07-04 | 2013-09-25 | 武汉大学 | Terpolymer of carbene-diazo compound-acraldehyde and preparation method thereof |
-
2014
- 2014-10-31 CN CN201410607989.2A patent/CN104311822B/en not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102977364A (en) * | 2012-11-30 | 2013-03-20 | 武汉大学 | Diazoacetate-ethoxycarbonyl carbene copolymer and preparation method thereof |
CN102977365A (en) * | 2012-12-03 | 2013-03-20 | 武汉大学 | Terpolymer of diazoacetate, carbethoxy cabbeen and cyclic lactone and preparation method thereof |
CN103319709A (en) * | 2013-07-04 | 2013-09-25 | 武汉大学 | Terpolymer of carbene-diazo compound-acraldehyde and preparation method thereof |
Non-Patent Citations (2)
Title |
---|
EIJI IHARA, ET AL: "Thermally induced polymerization and copolymerization with styrene of diazoketones in the presence of benzoquinone", 《POLYM.BULL》 * |
李焰, 等: "C1/C1N2/C2的快速共聚合反应", 《2013年全国高分子学术论文报告会》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113061340A (en) * | 2021-06-04 | 2021-07-02 | 武汉柔显科技股份有限公司 | Display device, polyimide precursor composition, polyimide film, and laminate |
Also Published As
Publication number | Publication date |
---|---|
CN104311822B (en) | 2017-08-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Ren et al. | Clusterization-triggered color-tunable room-temperature phosphorescence from 1, 4-dihydropyridine-based polymers | |
Hu et al. | AIE polymers: Synthesis and applications | |
Christopherson et al. | 1, 8-Naphthalimide-based polymers exhibiting deep-red thermally activated delayed fluorescence and their application in ratiometric temperature sensing | |
Tonge et al. | Color-tunable thermally activated delayed fluorescence in oxadiazole-based acrylic copolymers: photophysical properties and applications in ratiometric oxygen sensing | |
Qin et al. | Click polymerization | |
Nicol et al. | Functionalized AIE nanoparticles with efficient deep-red emission, mitochondrial specificity, cancer cell selectivity and multiphoton susceptibility | |
Wang et al. | Supramolecular engineering of efficient artificial light-harvesting systems from cyanovinylene chromophores and pillar [5] arene-based polymer hosts | |
Wang et al. | Ultra bright red AIE dots for cytoplasm and nuclear imaging | |
Zhang et al. | Metal-free room-temperature phosphorescent systems for pure white-light emission and latent fingerprint visualization | |
Li et al. | Synthesis and optical properties of novel anthracene-based stilbene derivatives containing an 1, 3, 4-oxadiazole unit | |
Xu et al. | Fluorescent detection of heparin by a cationic conjugated polyfluorene probe containing aggregation-induced emission units | |
Wang et al. | Two-component design strategy: TADF-Type organic afterglow for time-gated chemodosimeters | |
Cravcenco et al. | Interplay between Förster and Dexter Energy Transfer Rates in Isomeric Donor–Bridge–Acceptor Systems | |
Margar et al. | Red and near-infrared emitting bis-coumarin analogues based on curcumin framework-synthesis and photophysical studies | |
Liu et al. | Acid-induced tunable white light emission based on triphenylamine derivatives | |
Hu et al. | Aggregation-induced emission-active biomacromolecules: progress, challenges, and opportunities | |
Su et al. | One‐Step Multicomponent Polymerizations for the Synthesis of Multifunctional AIE Polymers | |
Li et al. | A red-emissive oxadiazol-triphenylamine BODIPY dye: synthesis, aggregation-induced fluorescence enhancement and cell imaging | |
Sun et al. | The synthesis, characterization and properties of coumarin-based chromophores containing a chalcone moiety | |
Du et al. | Bathochromic-shifted emissions by postfunctionalization of nonconjugated polyketones | |
Fukasawa et al. | Enhanced Red Persistent Room-Temperature Phosphorescence Induced by Orthogonal Structure Disruption during Electronic Relaxation | |
CN105061403B (en) | A kind of multifunctional groups pyridazinone compound, it is used as application of orange luminous organic material and preparation method thereof | |
Zhang et al. | Controllable synthesis and AIE properties of fluorescent polyesters | |
CN104311822A (en) | Carbene-diazo compound-olefine aldehyde terpolymer and application of carbene-diazo compound-olefine aldehyde terpolymer as bidirectional conversion fluorescent material and anti-cancer drug | |
Kumar et al. | Synthesis and properties of hexaarylated AzaBODIPYs |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20170808 Termination date: 20181031 |