CN106478487A - Pyrrolidines and its synthetic method - Google Patents
Pyrrolidines and its synthetic method Download PDFInfo
- Publication number
- CN106478487A CN106478487A CN201610831473.5A CN201610831473A CN106478487A CN 106478487 A CN106478487 A CN 106478487A CN 201610831473 A CN201610831473 A CN 201610831473A CN 106478487 A CN106478487 A CN 106478487A
- Authority
- CN
- China
- Prior art keywords
- benzyl
- pyrrolidines
- synthetic method
- hydrogen
- silicon hydrogen
- 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
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/62—Naphtho [c] pyrroles; Hydrogenated naphtho [c] pyrroles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/72—4,7-Endo-alkylene-iso-indoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
A kind of pyrrolidines and its synthetic method, the cyclic imide class compound being dissolved in organic solvent is mixed with the silicon hydrogen reagent as reducing agent and as the lewis acid of catalyst, and aromatic rings and cycloaliphatic ring pyrrolidines are prepared under conditions of backflow.Synthetic route of the present invention is succinct, efficient and economic, mild condition, and applicability is wide, and the later stage industrialized production to pyrrolidines will play great impetus.
Description
Technical field
The present invention relates to a kind of technology of chemical field, specifically a kind of Louis acid catalysis cyclic imide class
The silicon hydrogenation of compound prepares the synthetic method of pyrrolidines.
Background technology
Pyrrolidines are a kind of important kind in heterocyclic compound, are prevalent in some natural products, medicine
In thing intermediate, drug molecule, functional material, thus the synthesis of pyrrolidines is with important in terms of organic synthesis
Meaning.
It is most straightforward approach by reducing imide analog compounds come synthesis of pyrrolidine class compound, prepares pyrroles at present
The method of reducing of the classics of alkyl compound is realized as reducing agent using compounds such as Lithium Aluminium Hydride, borines.Due to acyl
There are multiple intermediates in the reduction of imine compound, cause the formation of accessory substance, and this kind of reduction using this kind of reducing agent
The functional group compatibility of reagent is poor.While because the activity of reducing agent is higher, the shortcomings of to water sensitive, making the reaction usually need
Carry out in the environment of being strict controlled in anhydrous and low temperature, and the post-processing step for reacting is comparatively laborious.
Content of the invention
The present invention is directed to deficiencies of the prior art, proposes a kind of pyrrolidines and its synthetic method,
From imide analog compounds, the silicon hydrogen species compound by the use of cheap and simple is reducing agent, boron-containing compound as catalyst
Catalyzed hydrosilation reduction cyclic imide class compound is realized, and its synthetic route is succinct, mild condition, it is adaptable to large scale quantities
Produce.
The present invention is achieved by the following technical solutions：
The present invention relates to a kind of pyrrolidines, its structural formula is：Or
Wherein：
R1It is benzyl containing different substituents, alkane, alkene, alkynyl, aryl or containing all kinds of functional group (cyano group, halogen, carbonyls
Base, alkoxyl, amino, hydroxyl) alkyl chain；
R2For halogen, alkoxyl, carbonyl, naphthalene nucleus, amino or protection amino；
R3It is benzyl containing different substituents, alkane, alkene, alkynyl, aryl or containing all kinds of functional group (cyano group, halogen, carbonyls
Base, alkoxyl, amino, hydroxyl) alkyl chain；
R4For hydrogen, cycloalkane, norbornane, ENB or hexahydropyridine.
The present invention relates to the synthetic method of above-mentioned pyrrolidines, will be dissolved in the cyclic imide in organic solvent
Class compound is mixed with the silicon hydrogen reagent as reducing agent and the lewis acid as catalyst, is prepared under conditions of backflow
To aromatic rings and cycloaliphatic ring pyrrolidines, its reaction equation is as follows：
Described lewis acid is more preferably：Three (pentafluorophenyl group) boron, phenyl boric acid, the phenyl boric acid for replacing or trifluoro
Change borate ether etc..
Described reducing agent be more preferably three silicon hydrogen of aryl, three silicon hydrogen of alkyl, diaryl silicon hydrogen, dialkyl group silicon hydrogen,
1,1,3,3 tetramethyl disiloxanes, PMHS (containing hydrogen silicone oil) or triaryl silicon hydrogen etc..
Described organic solvent is toluene, 1,4 dioxane, 1,2 dichloroethanes or chloroform.
In described cyclic imide class compound and silicon hydrogen reagent, the reaction mol ratio of the amount of hydrogen is 1/6 1/4, catalysis
The consumption of agent is 0.1 2.0mol% of cyclic imide.
Described backflow refers to that back flow reaction under 110 DEG C of environment adds water to be quenched remaining silicon hydrogen examination after the completion of reaction
Agent, concentrates after extraction organic layer, and direct column chromatography obtains target product.
The present invention relates to the application of pyrrolidines that said method is prepared, by pyrrolidines
At least one compound is used for the manufacture of the important fragment of MOXIFLOXACIN, Mitiglinide Calcium and procyclidine etc..
Technique effect
Compared with prior art, the present invention is with " high selectivity " as background, using gently cheap reducing agent silicon hydrogen reagent,
In the presence of a lewis acid catalyst, preferably with common toluene as solvent, various substituted pyrroles are prepared in the case of backflow
Cough up alkyl compound.Existing preparation technology is compared, the reducing agent used in the present invention is easy to operate, high selectivity, substrate is fitted
Wide, the high income with property.
Specific embodiment
Embodiment 1
The present embodiment is related to N benzyl isoindolineSynthesis, which comprises the following steps that：
N benzylphthalimide (237.3mg, 1.0mmol), B (C is added in reaction tube6F5)3(10.2mg,
2.0mol%), slow addition silicon hydrogen reagent TMDS (335.8mg, 2.5mmol) in system after toluene (2mL) stirring and dissolving, will
Reaction temperature rises to 110 DEG C of backflows.Addition water is reacted and remaining silicon hydrogen reagent has been quenched, concentrated after extraction organic layer, direct post
Chromatography obtains target product, yield：95%.1H NMR(400MHz,CDCl3)δ7.44–7.42(m,2H),7.38–7.34(m,
2H),7.31–7.26(m,1H),7.18(s,4H),3.94(s,4H),3.92(s,2H).13C NMR(100MHz,CDCl3)δ
140.3,139.2,128.89,128.5,127.2,126.7,122.4,60.4,59.0.
Embodiment 2
The present embodiment is related to N ((4 trifluoromethyl) benzyl) isoindolineSynthesis, its tool
Body step is as follows：
According to operation same as Example 1, target compound, yield is obtained：90%.1H NMR(400MHz,CDCl3)δ
7.62–7.60(m,2H),7.55–7.53(m,2H),7.20(s,4H),3.97(s,2H),3.94(s,4H).13C NMR
(100MHz,CDCl3) δ 143.5,140.1,129.5 (q, J=32.1Hz), 129.0,126.9,125.5 (q, J=3.7Hz),
124.4 (q, J=270.1Hz), 122.5,59.9,59.1.
Embodiment 3
The present embodiment is related to 2,6 dibenzyl, 1,2,3,5,6,7 hexahydrobenzene parallel connection pyrrolesSynthesis, which comprises the following steps that：
According to operation same as Example 1, target compound, yield is obtained：90%.1H NMR(400MHz,CDCl3)δ
7.41–7.39(m,4H),7.36–7.32(m,4H),7.29–7.27(m,2H),6.97(s,2H),3.89(s,4H),3.87(s,
8H).13C NMR(100MHz,CDCl3)δ139.2,139.0,128.9,128.5,127.2,116.5,60.5,58.9.
Embodiment 4
The present embodiment is related to 2,3 dihydrobenzo iso-indoles of N benzylSynthesis, its tool
Body step is as follows：
According to operation same as Example 1, target compound, yield is obtained：89%.1H NMR(400MHz,CDCl3)δ
7.81–7.79(m,2H),7.63(s,2H),7.49–7.39(m,6H),7.35–7.32(m,1H),4.06(s,4H),3.97(s,
2H).13C NMR(100MHz,CDCl3)δ139.4,139.1,133.1,129.0,128.5,127.8,127.3,125.4,
120.6,60.6,58.7.
Embodiment 5
The present embodiment is related to 4,7 endo-methylene group hexahydroisoindoline of N benzylSynthesis, its tool
Body step is as follows：
According to operation same as Example 1, target compound, yield is obtained：94%.1H NMR(400MHz,CDCl3)δ
7.36 7.28 (m, 4H), 7.24 7.21 (m, 1H), 3.52 (s, 2H), 2.76 (d, J=10.0Hz, 2H), 2.35 2.34 (m,
2H),2.11(s,2H),2.02–1.98(m,2H),1.77–1.75(m,2H),1.41–1.33(m,2H),1.26–1.24(m,
2H).13C NMR(100MHz,CDCl3)δ140.5,128.5,128.2,126.7,60.7,55.4,44.1,42.3,41.4,
24.1.
Embodiment 6
The present embodiment is related to N benzyl hexahydroisoindolineSynthesis, which comprises the following steps that：
According to operation same as Example 1, target compound, yield is obtained：90%.1H NMR(400MHz,CDCl3)δ
7.38–7.32(m,4H),7.29–7.24(m,1H),3.76(s,2H),2.83–2.79(m,2H),2.57–2.53(m,2H),
2.21–2.15(m,2H),1.60–1.46(m,6H),1.38–1.30(m,2H).13C NMR(100MHz,CDCl3)δ139.9,
128.8,128.3,126.9,61.4,58.4,37.3,27.0,23.0.
Embodiment 7
The present embodiment is related to N benzyl-pyrrole alkaneSynthesis, which comprises the following steps that：
According to operation same as Example 1, target compound, yield is obtained：82%.1H NMR(400MHz,CDCl3)δ
7.35–7.23(m,5H),3.65(s,2H),2.55–2.53(m,4H),1.82–1.78(m,4H).13C NMR(100MHz,
CDCl3)δ139.2,129.0,128.3,127.0,60.8,54.2,23.5.
Embodiment 8
The present embodiment is related to 6 benzyl octahydro pyrrolo- [3,4 B] pyridinesSynthesis, which is concrete
Step is as follows：
According to operation same as Example 1, target compound, yield is obtained：85%.1H NMR(400MHz,CDCl3)δ
7.34–7.29(m,4H),7.27–7.22(m,1H),3.82–3.69(m,2H),3.28–3.26(m,1H),3.04–3.00(m,
1H),2.87–2.84(m,1H),2.80–2.75(m,1H),2.71–2.55(m,3H),2.29–2.21(m,1H),1.69–1.64
(m,2H),1.52–1.43(m,2H).13C NMR(100MHz,CDCl3)δ139.0,128.7,128.2,126.9,60.5,
59.8,56.1,55.0,43.8,36.2,23.9,21.4.
It is above-mentioned that be embodied as can be by those skilled in the art with difference on the premise of without departing substantially from the principle of the invention and objective
Mode local directed complete set is carried out to which, protection scope of the present invention is defined by claims and is not embodied as institute by above-mentioned
Limit, each implementation in the range of which is all by the constraint of the present invention.
Claims (10)
1. a kind of pyrrolidines, it is characterised in that structural formula is：Its
In：
R1Be benzyl containing different substituents, alkane, alkene, alkynyl, aryl or containing cyano group, halogen, carbonyl, alkoxyl, amino,
The alkyl chain of hydroxyl；
R2For halogen, alkoxyl, carbonyl, naphthalene nucleus, amino or protection amino；
R3Be benzyl containing different substituents, alkane, alkene, alkynyl, aryl or containing cyano group, halogen, carbonyl, alkoxyl, amino or
The alkyl chain of hydroxyl；
R4For hydrogen, cycloalkane alkane, norbornane, ENB or hexahydropyridine.
2. pyrrolidines according to claim 1, is characterized in that, specially：
N benzyl isoindoline
N ((4 trifluoromethyl) benzyl) isoindoline
2,6 dibenzyl, 1,2,3,5,6,7 hexahydrobenzene parallel connection pyrroles
2,3 dihydrobenzo iso-indoles of N benzyl
4,7 endo-methylene group hexahydroisoindoline of N benzyl
N benzyl hexahydroisoindoline
N benzyl-pyrrole alkane
6 benzyl octahydro pyrrolo- [3,4 B] pyridines
3. the synthetic method of pyrrolidines described in a kind of claim 1 or 2, it is characterised in that will be dissolved in organic
Cyclic imide class compound in solvent is mixed with the silicon hydrogen reagent as reducing agent and the lewis acid as catalyst,
Aromatic rings and cycloaliphatic ring pyrrolidines are prepared under conditions of backflow, and its reaction equation is：
4. synthetic method according to claim 3, is characterized in that, described lewis acid is three (pentafluorophenyl group) boron, benzene
Boric acid, the phenyl boric acid for replacing or BFEE.
5. synthetic method according to claim 3, is characterized in that, described reducing agent is three silicon hydrogen of aryl, three silicon of alkyl
Hydrogen, diaryl silicon hydrogen, dialkyl group silicon hydrogen, 1,1,3,3 tetramethyl disiloxane, containing hydrogen silicone oil or triaryl silicon hydrogen.
6. synthetic method according to claim 3, is characterized in that, described organic solvent is toluene, Isosorbide-5-Nitrae dioxane,
1,2 dichloroethanes or chloroform.
7. synthetic method according to claim 3, is characterized in that, described cyclic imide class compound and silicon hydrogen reagent
The reaction mol ratio of the amount of middle hydrogen is 1/6 1/4.
8. the synthetic method according to claim 3 or 7, is characterized in that, the consumption of described catalyst is cyclic imide
0.1 2.0mol%.
9. synthetic method according to claim 3, is characterized in that, described backflow is referred to, flow back anti-under 110 DEG C of environment
Should, adding water to be quenched remaining silicon hydrogen reagent after the completion of reaction, concentrate after extraction organic layer, direct column chromatography obtains target product
Thing.
10. a kind of application according to pyrrolidines described in any of the above-described claim, it is characterised in that for Moses
The manufacture of Sha Xing, Mitiglinide Calcium and procyclidine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610831473.5A CN106478487B (en) | 2016-09-19 | 2016-09-19 | Pyrrolidines and its synthetic method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610831473.5A CN106478487B (en) | 2016-09-19 | 2016-09-19 | Pyrrolidines and its synthetic method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106478487A true CN106478487A (en) | 2017-03-08 |
| CN106478487B CN106478487B (en) | 2019-01-25 |
Family
ID=58268715
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610831473.5A Expired - Fee Related CN106478487B (en) | 2016-09-19 | 2016-09-19 | Pyrrolidines and its synthetic method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106478487B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115611693A (en) * | 2022-05-12 | 2023-01-17 | 常州大学 | Method for catalytically synthesizing isochroman-1-ketone or aromatic ketone compounds |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103497138A (en) * | 2013-10-18 | 2014-01-08 | 河南中医学院 | Method of preparing cis-octahydroisoindole by zinc chloride and potassium borohydride |
| CN103772320A (en) * | 2013-12-24 | 2014-05-07 | 浙江海翔药业股份有限公司 | Method for synthesizing tertiary amine by using alpha-amino acid as raw material |
-
2016
- 2016-09-19 CN CN201610831473.5A patent/CN106478487B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103497138A (en) * | 2013-10-18 | 2014-01-08 | 河南中医学院 | Method of preparing cis-octahydroisoindole by zinc chloride and potassium borohydride |
| CN103772320A (en) * | 2013-12-24 | 2014-05-07 | 浙江海翔药业股份有限公司 | Method for synthesizing tertiary amine by using alpha-amino acid as raw material |
Non-Patent Citations (5)
| Title |
|---|
| CAS: "806623-06-3", 《STN-REGISTRY》 * |
| RUGGLI,P.ET AL.: "Heterocyclic nitrogen compounds. LXI.Dipyrrolino-3",4";1,2:3"",4"";4,5-benzene", 《HELVETICA CHIMICA ACTA》 * |
| SHOUBHIK DAS,ET AL.: "Selective Catalytic Monoreduction of Phthalimides and Imidazolidine-2,4-diones", 《ANGEW. CHEM. INT. ED.》 * |
| 刘明亮等: "莫西沙星的合成", 《中国医药工业杂志》 * |
| 李海波等: "顺式全氢异吲哚的合成", 《华西药学杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115611693A (en) * | 2022-05-12 | 2023-01-17 | 常州大学 | Method for catalytically synthesizing isochroman-1-ketone or aromatic ketone compounds |
| CN115611693B (en) * | 2022-05-12 | 2023-11-28 | 常州大学 | Method for catalytic synthesis of isochroman-1-one or aromatic ketone compound |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106478487B (en) | 2019-01-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Osyanin et al. | Convenient one-step synthesis of 4-unsubstituted 2-amino-4H-chromene-2-carbonitriles and 5-unsubstituted 5H-chromeno [2, 3-b] pyridine-3-carbonitriles from quaternary ammonium salts | |
| CN112430187B (en) | Alpha, beta-deuterated amine compound, deuterated drug and preparation method thereof | |
| JP2010509393A5 (en) | ||
| CN107602320A (en) | It is a kind of that the synthetic method for preparing three substituted olefines is catalyzed based on nickel | |
| CN104177395A (en) | Benzyne precursor and synthesis method thereof | |
| Giuglio-Tonolo et al. | An expeditious method for the selective cyclotrimerization of isocyanates initiated by TDAE | |
| CN106478487B (en) | Pyrrolidines and its synthetic method | |
| CN103804432B (en) | Double-functionalized amine-thiourea organic catalyst based on ferrocene and preparation method and application thereof | |
| CN109096174A (en) | A kind of synthetic method of unsubstituted [60] fulleropyrrolidine derivative of N- alkyl -2,5- | |
| CN105688987A (en) | Novel chiral phosphoric acid catalyst as well as synthetic method and application thereof | |
| CN109053460A (en) | A method of catalysis benzalcohol derivatives amination | |
| CN108658717A (en) | A kind of decarboxylic reaction prepares the synthetic method of three substituted olefines | |
| GB2620096A (en) | Use of chiral bisphosphonate diamine compound | |
| CN106316953A (en) | Synthetic method of 6-cyanophenanthridine compounds | |
| CN103288876B (en) | A kind of Chiral phosphamide compound and preparation method thereof | |
| Zou et al. | New bis (1-ferrocenylethyl) amine-derived monodentate phosphoramidite ligands for highly enantioselective copper-catalyzed 1, 4-conjugate addition | |
| CN103087062A (en) | Method for preparing N-sulfonyl substituted tetrahydro-beta-carboline derivative | |
| CN101372458A (en) | Method for synthesizing acylated enamine without catalyst or solvent | |
| CN107337573B (en) | Green and novel decarbonylation and hydrogenation method for disubstituted amide derivative | |
| CN115677609B (en) | Method for cyclizing and cyanating allyl phenyl carbamate derivative | |
| KR101731952B1 (en) | Preparation method of 4-substituted coumarin derivative under iron catalyst and basic additives | |
| CN109251217A (en) | Application of the o-aminoanisole base lithium in catalysis imines and borine hydroboration | |
| CN103087100A (en) | Synthesis method of alpha-aminophosphonate | |
| Vardelle et al. | An efficient access to new Tröger’s bases using superacidic chemistry | |
| CN109251216A (en) | Application of the open-chain crown ether base lithium in catalysis imines and borine hydroboration |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for 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 |
Granted publication date: 20190125 Termination date: 20210919 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |