CN104725292A - Preparation method of (S)(-)-amisulpride - Google Patents

Preparation method of (S)(-)-amisulpride Download PDF

Info

Publication number
CN104725292A
CN104725292A CN201510127500.6A CN201510127500A CN104725292A CN 104725292 A CN104725292 A CN 104725292A CN 201510127500 A CN201510127500 A CN 201510127500A CN 104725292 A CN104725292 A CN 104725292A
Authority
CN
China
Prior art keywords
amisulpride
prepare
sodium
formula
acid
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
Application number
CN201510127500.6A
Other languages
Chinese (zh)
Other versions
CN104725292B (en
Inventor
王力
王诗宏
王华权
洪磊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jingjiang Source Hubei Pharmacy Stock Co Ltd
Original Assignee
Jingjiang Source Hubei Pharmacy Stock Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Jingjiang Source Hubei Pharmacy Stock Co Ltd filed Critical Jingjiang Source Hubei Pharmacy Stock Co Ltd
Priority to CN201510127500.6A priority Critical patent/CN104725292B/en
Publication of CN104725292A publication Critical patent/CN104725292A/en
Application granted granted Critical
Publication of CN104725292B publication Critical patent/CN104725292B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a preparation method of (S)(-)-amisulpride. According to the preparation method, by introducing an R2 group which is selected from benzyl, p-methoxybenzyl, 2,4-dimethoxybenzyl, p-nitrobenzyl and p-methylbenzyl, on one hand, the steric hindrance is increased, the side reaction is avoided, on the other hand, amino is activated, the nucleophilicity of amino is increased, and the condensation reaction can be easily carried out at mild conditions. The preparation method has the characteristics that the raw materials are low in toxicity and easily available, and the reaction conditions are mild; the generation of chiral isomer dextroisomers is avoided; the preparation method is applicable to the industrial production.

Description

A kind of preparation method of (S) (-)-amisulpride
Technical field
The invention belongs to pharmaceutical synthesis field, be specifically related to the preparation method of antipsychotic drug (S) (-)-amisulpride.
Background technology
Amisulpride be by francethe one of Sanofi-Sythelabo company exploitation novelatypical antipsychotic agents, alternative acts on dopamine D 2and D 3acceptor and playing a role, clinical benzamide derivatives is widely used in Europe and world wide, within 2011, in Discussion on Chinese Listed, be mainly used in the positive and the negative symptoms for the treatment of acute or chronic schizophrenia, have EPS few, can not the advantage such as raise blood sugar.Its levo form (S) (-)-amisulpride pharmacologically active is more than 2 times of raceme, and toxic side effect is less, and security is higher.(S) (-)-amisulpride structural formula is:
The synthetic method of the amisulpride of bibliographical information is had to have following a few class:
1)BE 0872585；ES 476755；FR 2415099；GB 2083458；JP 54145658；US 4294828；US 4401822；CN102838520；US6187807
2)FR 2460930；WO 9507877
3)WO2011158084
4)CN103819383，CN101898991
(S) (-)-amisulpride splits acquisition by the amisulpride of racemization, but its yield is low, separation and purification difficulty.Another kind of synthetic method first synthesizes key intermediate 4-amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid (II), then obtain product (I) with (S)-(-)-1-ethyl-2-aminomethylpentazaneand (III) condensation.
In above-mentioned various bibliographical information; synthesis for key intermediate (II) has many methods and patent protection; this intermediate and another intermediate (III) all domestic industryization are produced; but as the condensation process of amisulpride committed step; mostly use poisonous reagent Vinyl chloroformate; toxicity is large, is unfavorable for suitability for industrialized production.
In patent CN103819383 and CN101898991, although avoid using poisonous reagent, the yield of product and purity are also higher, but temperature of reaction is higher, scale effect is obvious, when being amplified to kilogram rank, speed of response is slow, the reaction times reaches the level that a couple of days could arrive laboratory lab scale, therefore, and also not easily suitability for industrialized production.
Therefore, develop an operational path being applicable to suitability for industrialized production and have important meaning.
Summary of the invention
The invention provides the operational path of new preparation (S) (-)-amisulpride, have that the reaction times is short, raw material low toxicity is easy to get, the advantage of reaction conditions gentleness.
Described method comprises:
(1) shown in compound shown in formula IV and formula (V), compound carries out condensation reaction in the basic conditions, generates compound shown in formula VI;
Wherein: R 1be selected from the direct-connected of 1-4 carbon atom or branched-chain alkyl, or the direct-connected or branched-chain alkyl of 1-4 carbon atom of halogen atom replacement; R 2be selected from benzyl, to methoxybenzyl, 2,4-veratryls, to nitrobenzyl, to methyl-benzyl;
(2) shown in formula VI, compound sloughs R 2group, obtained product (S) (-)-amisulpride shown in formula I.
Preferably, R 1carbonatoms is selected from 1,2,3,4; Concrete R1 is selected from methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl, chloromethyl, brooethyl; Preferably, R1 is the tertiary butyl.
Preferably, R 2it is 2,4-veratryl.
In the method for the invention, shown in step (2) formula VI, compound sloughs R in acid condition 2group; Described acid is selected from hydrogen chloride methanol solution, the molectron of hydrochloric acid and tetrahydrofuran (THF) molectron, hydrochloric acid and acetone, methylsulfonic acid or trifluoroacetic acid.
Wherein compound (IV) with commercially available 4-amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid (II) for starting raw material, with compound R 1cOX reacts obtained in the basic conditions, and X is chlorine, bromine atoms or hydroxyl.
Preferably, the temperature of reaction of step (1) is 10 ~ 20 DEG C.
Preferably, step (1) solvent for use is selected from one or more in acetone, acetonitrile, mibk, toluene; Preferably, solvent is acetonitrile.
Preferably, the alkali described in step (1) is selected from triethylamine, morpholine, N-methylmorpholine, salt of wormwood, sodium carbonate, sodium methylate, sodium ethylate, sodium tert-butoxide, sodium hydroxide or potassium hydroxide.
Preferably, in step (1), the mol ratio of compound (IV), compound (V) is 1:1.0 ~ 1.2.
Preferably, in step (1), the weight of compound (IV) and the volume ratio of solvent acetonitrile are 1:8 ~ 12.
The invention still further relates to a kind of intermediate, namely compound (V) is as the intermediate of synthesis (S) (-)-amisulpride, compound (V) with commercially available L-PROLINE for raw material, obtain through monobromethane replacement, condensation, reduction, concrete route is as follows:
Wherein, the reductive agent of described reduction reaction is selected from lithium aluminum hydride, lithium borohydride, sodium borohydride, diisobutyl aluminium hydride, diborane, sodium/liquefied ammonia; Preferred diborane.
Preferably, the solvent of described reduction reaction is tetrahydrofuran (THF), toluene, two sulphur methyl ethers.
Preferably, the condensing agent of described condensation reaction is selected from N, the composition of the composition of the composition of N-carbonyl dimidazoles (CDI), N, N'-dicyclohexylcarbodiimide (DCC), DMAP (DMAP), diisopropyl azodiformate (DIAD) and triphenylphosphine (Ph3P), the trimethyl carbinol and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (EDC), triethylamine and pivaloyl chloride.
Preferably, the temperature of described condensation reaction is-10 ~ 10 DEG C.
Preferably, the mol ratio of described condensation reaction (S)-1-ethyl pyrrolidine-2-carboxylic acid and condensing agent is 1:1.1 ~ 1.2.
Embodiment
Embodiment one: the preparation of (S)-1-ethyl pyrrolidine-2-carboxylic acid
L-PROLINE 75g, potassium hydroxide 131g and 500ml dehydrated alcohol are put in 1000ml four-hole bottle, is stirred in 25 DEG C and dissolves completely, then slowly drip the solution of monobromethane 85g and dehydrated alcohol 100ml.Dropwise, continue stirring reaction 4h, be then warming up to 35 DEG C of reaction 1.5h.React complete, adjust pH to 4 ~ 5 with concentrated hydrochloric acid, suction filtration, decompression recycling ethanol, separate out white solid, dry target product 88.1g, yield 94.7%.
Embodiment two: the preparation of (S)-N-(2,4-veratryl)-1-ethyl pyrrolidine-2-methane amide
By N, N-carbonyl dimidazoles (CDI) 112g, methylene dichloride 400ml join in 1000ml four-hole bottle, stirring and dissolving, add (S)-1-ethyl pyrrolidine-2-carboxylic acid 86g that step obtains in batches, stirring at room temperature 3h, then temperature control 0 ~ 10 DEG C is added drop-wise in the solution of 2,4-dimethoxybenzylamine 110g and methylene dichloride 100ml, drip and finish, be warmed up to 30 DEG C of reactions and spend the night.Add 300ml water, stirring, standing, layering, organic layer uses the solution washing of the sodium bicarbonate 300ml of 5% again, anhydrous sodium sulfate drying, filters, removes organic solvent under reduced pressure, obtain faint yellow solid 151.2g, yield 86.3%.
Embodiment three: (S)-(2,4-dimethoxy phenyl)-N-[(1-ethyl pyrrolidine-2-base) methyl] preparation of methylamine
Under nitrogen protection; (S)-N-(2 that upper step is obtained; 4-veratryl)-1-ethyl pyrrolidine-2-methane amide 146g, anhydrous tetrahydro furan (THF) 500ml join in 2000ml four-hole bottle; be cooled to-15 ~-10 DEG C, drip the tetrahydrofuran solution 750ml of the diborane of 1mol/L, drip and finish; be warming up to 35 DEG C of stirring reactions to spend the night; then be cooled to-15 DEG C, drip 200ml frozen water, release a large amount of gas.PH to 10 ~ 11 adjusted by the mixed solution potassium hydroxide of 10%, by 500ml ether extraction 3 times, merge organic layer, wash 2 times with saturated sodium-chloride water solution 50ml, wash 1 time with water 500ml, anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure in 25 DEG C, obtain pale yellow oil 118.3g.Yield 85.1%.
The preparation of embodiment four: 4-amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid trimethylacetic acid acid anhydride
Under the protection of nitrogen; acetone 400ml, 4-amino-2-methoxyl group-5-ethylsulfonyl phenylformic acid 100g is joined in 1000ml four-hole bottle; stir, be cooled to 0 ~ 10 DEG C, drip triethylamine 43g, dropwise; stir 15 minutes; then reaction solution is cooled to-5 ~ 0 DEG C, temperature control-5 ~ 5 DEG C, drip the solution of pivaloyl chloride 55.8g and 100ml acetone; dropwise, stirring reaction 1.5 hours.Reaction solution is directly used in the next step.
Embodiment five: (S)-N-(2,4-veratryl)-4-amino-N-[(1-ethyl pyrrolidine-2-base) methyl] preparation of-5-(ethylsulfonyl)-2-anisole acid amides
Temperature control 0 ~ 10 DEG C, by (S) that obtain-(2,4-dimethoxy phenyl)-N-[(1-ethyl pyrrolidine-2-base) methyl] methylamine 118g is dissolved in acetone 100ml, is added drop-wise in step reaction solution, drip and finish, be warmed up to 10 ~ 20 DEG C and stir 4 hours.Reaction terminates, and reclaim under reduced pressure major part acetone, add 500ml water, stir 1 hour, filter, filter cake use water 100ml drip washing, filter cake, in 50 DEG C of vacuum-dryings 6 hours, obtains off-white color crystal 156.6g, yield 78.2%
Embodiment six: the preparation of (S) (-)-amisulpride (I)
S by upper step obtains)-N-(2; 4-veratryl)-4-amino-N-[(1-ethyl pyrrolidine-2-base) methyl]-5-(ethylsulfonyl)-2-anisole acid amides 150g adds in the hydrogen chloride methanol solution 500ml of 1.25mol/L; stirring at room temperature 2h; then pH10 ~ 11 are adjusted with 40% sodium hydroxide solution; stir 2h; with 250ml dichloromethane extraction 3 times; merge organic layer; dense dry in 25 DEG C of decompressions; resistates 400ml water making beating 2h, suction filtration, dries (S) (-)-amisulpride 92.5g.

Claims (10)

1. prepare a method for (S) (-)-amisulpride, described method comprises:
(1) shown in compound shown in formula IV and formula (V), compound carries out condensation reaction in the basic conditions, generates compound shown in formula VI;
Wherein: R 1be selected from the direct-connected of 1-4 carbon atom or branched-chain alkyl, or the direct-connected or branched-chain alkyl of 1-4 carbon atom of halogen atom replacement; R 2be selected from benzyl, to methoxybenzyl, 2,4-veratryls, to nitrobenzyl, to methyl-benzyl;
(2) shown in formula VI, compound sloughs R 2group, obtained product (S) (-)-amisulpride.
2. prepare the method for (S) (-)-amisulpride according to claim 1, shown in above-mentioned steps (2) formula VI, compound sloughs R in acid condition 2group.
3. prepare the method for (S) (-)-amisulpride according to claim 1, wherein R 1for the tertiary butyl.
4. prepare the method for (S) (-)-amisulpride according to claim 1, wherein R 2it is 2,4-veratryl.
5. prepare the method for (S) (-)-amisulpride according to claim 1, the temperature of reaction of step (1) is 10 ~ 20 DEG C.
6. prepare the method for (S) (-)-amisulpride according to claim 1, it is characterized in that, described alkali is selected from triethylamine, morpholine, N-methylmorpholine, salt of wormwood, sodium carbonate, sodium methylate, sodium ethylate, sodium tert-butoxide, sodium hydroxide or potassium hydroxide.
7. prepare the method for (S) (-)-amisulpride according to claim 2, it is characterized in that, described acid is selected from hydrogen chloride methanol solution, the molectron of hydrochloric acid and tetrahydrofuran (THF) molectron, hydrochloric acid and acetone, methylsulfonic acid or trifluoroacetic acid.
8. synthesize an intermediate for (S) (-)-amisulpride, its structure is as follows:
Wherein, R2 be selected from benzyl, to methoxybenzyl, 2,4-veratryls, to nitrobenzyl, to methyl-benzyl.
9. synthesize a synthetic method for the intermediate of (S) (-)-amisulpride as claimed in claim 8, it is characterized in that, take L-PROLINE as raw material, and obtain through monobromethane replacement, condensation, reduction, its synthetic route is as follows:
Wherein, the reductive agent used that reduces is selected from lithium aluminum hydride, lithium borohydride, sodium borohydride, diisobutyl aluminium hydride, diborane, sodium/liquefied ammonia.
10. synthetic method as claimed in claim 9, it is characterized in that, described reductive agent is diborane.
CN201510127500.6A 2015-03-23 2015-03-23 A kind of preparation method of (S) () Amisulpride Expired - Fee Related CN104725292B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510127500.6A CN104725292B (en) 2015-03-23 2015-03-23 A kind of preparation method of (S) () Amisulpride

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510127500.6A CN104725292B (en) 2015-03-23 2015-03-23 A kind of preparation method of (S) () Amisulpride

Publications (2)

Publication Number Publication Date
CN104725292A true CN104725292A (en) 2015-06-24
CN104725292B CN104725292B (en) 2017-07-25

Family

ID=53449774

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510127500.6A Expired - Fee Related CN104725292B (en) 2015-03-23 2015-03-23 A kind of preparation method of (S) () Amisulpride

Country Status (1)

Country Link
CN (1) CN104725292B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019113084A1 (en) 2017-12-05 2019-06-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10576058B2 (en) 2017-12-05 2020-03-03 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US11160758B2 (en) 2019-06-04 2021-11-02 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4401822A (en) * 1978-01-20 1983-08-30 Societe De'etudes Scientifiques Et Industrielles De L'ile-De France Derivatives of 4-amino-5-alkyl sulphonyl orthoanisamides
CN101898991A (en) * 2009-05-31 2010-12-01 江苏天士力帝益药业有限公司 Synthesis method of (S) (-)-amisulprideD-(-)-tartrate
WO2011158084A1 (en) * 2010-06-17 2011-12-22 Lupin Limited An improved process for preparation of amisulpride
WO2012065102A2 (en) * 2010-11-12 2012-05-18 Promentis Pharmaceuticals, Inc. S-t-butyl protected cysteine di-peptide analogs and related compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4401822A (en) * 1978-01-20 1983-08-30 Societe De'etudes Scientifiques Et Industrielles De L'ile-De France Derivatives of 4-amino-5-alkyl sulphonyl orthoanisamides
CN101898991A (en) * 2009-05-31 2010-12-01 江苏天士力帝益药业有限公司 Synthesis method of (S) (-)-amisulprideD-(-)-tartrate
WO2011158084A1 (en) * 2010-06-17 2011-12-22 Lupin Limited An improved process for preparation of amisulpride
WO2012065102A2 (en) * 2010-11-12 2012-05-18 Promentis Pharmaceuticals, Inc. S-t-butyl protected cysteine di-peptide analogs and related compounds

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HAOBING WANG，等: "Highly diastereoselective synthesis of chiral aminophenolate zinc complexes and isoselective polymerization of rac-lactide", 《CHEM. COMMUN.》 *
王沙沙: "《STN检索报告》", 3 August 2016 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10874639B2 (en) 2017-12-05 2020-12-29 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
JP2021505595A (en) * 2017-12-05 2021-02-18 サノビオン ファーマシューティカルズ インクＳｕｎｏｖｉｏｎ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｉｎｃ． Crystal form and its manufacturing method
US10577317B2 (en) 2017-12-05 2020-03-03 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10576058B2 (en) 2017-12-05 2020-03-03 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10660875B1 (en) 2017-12-05 2020-05-26 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US10800738B2 (en) 2017-12-05 2020-10-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US10377708B2 (en) 2017-12-05 2019-08-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
CN112236138A (en) * 2017-12-05 2021-01-15 赛诺维信制药公司 Crystalline forms and methods of making the same
WO2019113084A1 (en) 2017-12-05 2019-06-13 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
CN112236138B (en) * 2017-12-05 2024-05-31 赛诺维信制药公司 Crystal forms and methods of making the same
US11370753B2 (en) 2017-12-05 2022-06-28 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US11517558B2 (en) 2017-12-05 2022-12-06 Sunovion Pharmaceuticals Inc. Nonracemic mixtures and uses thereof
US11767293B2 (en) 2017-12-05 2023-09-26 Sunovion Pharmaceuticals Inc. Crystal forms and production methods thereof
US11654113B2 (en) 2019-06-04 2023-05-23 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof
US11160758B2 (en) 2019-06-04 2021-11-02 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof

Also Published As

Publication number Publication date
CN104725292B (en) 2017-07-25

Similar Documents

Publication Publication Date Title
CN110627736B (en) Method for recycling 1-phenyl-5-hydroxy tetrazole
CN102985416B (en) Process of preparing a thrombin specific inhibitor
JP2013505259A5 (en)
CN104725292A (en) Preparation method of (S)(-)-amisulpride
CN102516122A (en) Environment friendly method for preparing DMF (Dimethyl Formamide) solution of 2-hydroxy-benzonitril, DMF solution of 2-hydroxy-benzonitril and application thereof
CN105254589A (en) Method for preparing midbody of heart failure medicine
CN104487436B (en) Improved process for preparing rivaroxaban using intermediates
CN102617434B (en) Process for preparing Vildagliptin by one-pot method
CN105753944B (en) His Wei of Dacca and its derivative prepare intermediate
CN106749259A (en) A kind of synthetic method of cyclopenta pyrimido azoles
CN103265482A (en) Preparation method of bosutinib
CN103012300A (en) Novel method for preparing valsartan
CN101481346B (en) Preparation of carbapenem antibiotic side chain
CN106565607A (en) Synthetic method of L-carnosine
CN103724291B (en) The synthetic method of body of Pramipexole dihydrochloride related substance B
CN107235853B (en) A kind of synthetic method being used to prepare Canton love-pea vine A prime and its isomers
RU2012155786A (en) COMPOUND POSSESSING AN INHIBITING ACTION REGARDING PHOSPHODESTHESIS TYPE 5, AND METHOD FOR PRODUCING IT
EP3564219B1 (en) Process for preparing oxadiazacyclo compound and use thereof
CN104030958A (en) Synthesis method of (S)-1-(2-chloracetyl) pyrrolidine-2-formonitrile
CN106892932A (en) A kind of preparation method of non_steroidal anti_inflammatory drug Lornoxicam
CN114805164A (en) Recycling method of 5-methyl-2-hydroxy-1, 3, 4-thiadiazole
CN102659657B (en) Method for synthesizing protease inhibitor PF429242
CN102993080B (en) A kind of synthetic method of gliclazide
CN104086475A (en) Preparation method of N-carbobenzoxy-L-prolinamide
CN105175490A (en) Preparation method of argatroban intermediate

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
EXSB Decision made by sipo to initiate 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: 20170725

Termination date: 20200323