CN104418810A - New synthetic route of levosimendan - Google Patents
New synthetic route of levosimendan Download PDFInfo
- Publication number
- CN104418810A CN104418810A CN201310396124.1A CN201310396124A CN104418810A CN 104418810 A CN104418810 A CN 104418810A CN 201310396124 A CN201310396124 A CN 201310396124A CN 104418810 A CN104418810 A CN 104418810A
- Authority
- CN
- China
- Prior art keywords
- pyridazinone
- simdax
- production method
- methyl
- levosimendan
- 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
- WHXMKTBCFHIYNQ-SECBINFHSA-N levosimendan Chemical compound C[C@@H]1CC(=O)NN=C1C1=CC=C(NN=C(C#N)C#N)C=C1 WHXMKTBCFHIYNQ-SECBINFHSA-N 0.000 title claims abstract description 23
- 229960000692 levosimendan Drugs 0.000 title claims abstract description 23
- 238000004519 manufacturing process Methods 0.000 claims abstract description 12
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims abstract description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 8
- GDMRFHZLKNYRRO-UHFFFAOYSA-N 3-(4-aminophenyl)-4-methyl-4,5-dihydro-1h-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C1=CC=C(N)C=C1 GDMRFHZLKNYRRO-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- 235000010288 sodium nitrite Nutrition 0.000 claims abstract description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims abstract description 5
- CUONGYYJJVDODC-UHFFFAOYSA-N malononitrile Chemical compound N#CCC#N CUONGYYJJVDODC-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000000926 separation method Methods 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 2
- 230000003287 optical effect Effects 0.000 abstract description 7
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 4
- 239000000463 material Substances 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical compound OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 description 15
- 238000000034 method Methods 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000001035 drying Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 206010013786 Dry skin Diseases 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- FEWJPZIEWOKRBE-LWMBPPNESA-N levotartaric acid Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- JJNZXLAFIPKXIG-UHFFFAOYSA-N 2-Chlorobenzylidenemalononitrile Chemical compound ClC1=CC=CC=C1C=C(C#N)C#N JJNZXLAFIPKXIG-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical group [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 description 2
- 210000005252 bulbus oculi Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 229940122434 Calcium sensitizer Drugs 0.000 description 1
- 206010007556 Cardiac failure acute Diseases 0.000 description 1
- 208000007201 Myocardial reperfusion injury Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000002371 cardiac agent Substances 0.000 description 1
- 230000005961 cardioprotection Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 230000006340 racemization Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010583 slow cooling Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a production method of a levosimendan raw material medicament, belonging to the technical field of chemical synthesis. The production method is characterized by comprising the steps of carrying out chiral resolution on 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3 (2H)-pyridazinone which is an initial material by virtue of L-tartaric acid, and reacting with sodium nitrite, diluted hydrochloric acid and malononitrile so as to obtain the levosimendan raw material medicament. The production method has the advantages of being high in yield and optical purity, low in cost, good in environmental friendless and suitable for industrial production.
Description
Technical field
The present invention relates to one 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3 (2H)-pyridazinone is starting raw material, obtains (-) through splitting
-6-(4-aminophenyl)-5-methyl--4,5-dihydrogen dazin-3(2H) ketone, then reacts by it and Sodium Nitrite, dilute hydrochloric acid, propane dinitrile to obtained Simdax (1).
formula (1).
Background technology
Simdax (Levosimendan) is researched and developed by Finland Orion Corporation, go on the market in Switzerland first in October, 2000, within 2005, go on the market in the U.S., chemical name: (R)-(2)-[[4-(1,4,5,6-tetrahydrochysene-4-methyl-6-oxo-3-pyridazinyl) phenyl]-hydrazono-] propane dinitrile, be calcium sensitizer class cardiac drug of new generation, be mainly used in clinically treating various acute heart failure illness.This medical instrument has unique dual function pattern, can improve Cardial pump function, have cardioprotection effect when myocardial ischemia and reperfusion injury.
Synthesis Simdax needs an important starting raw material, 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3 (2H)-pyridazinone (being called for short: pyridazinone), and structural formula is as follows:
Pyridazinone
ALLRED benefactor department reports the synthesis technique of Simdax in Chinese patent CN1036265C, this technique is with 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3 (2H)-pyridazinone is starting raw material, obtained Simdax is reacted with Sodium Nitrite, dilute hydrochloric acid, propane dinitrile, obtaining in compound patent is racemization product, and reactional equation is as follows:
From the structural formula (1) of Simdax, containing a chiral carbon atom in the structural formula of Simdax, so the Simdax wanting to obtain high-optical-purity must obtain (-)-6-(4-the aminophenyl)-5-methyl-4 of high-optical-purity, 5-dihydro-3 (2H)-pyridazinone (being called for short: left-handed pyridazinone), so (-)-6-(4-aminophenyl)-5-methyl-4,5-dihydro-3 (the 2H)-pyridazinone how obtaining high-optical-purity is the key of Simdax synthesis.
Left-handed pyridazinone
ALLRED benefactor department reports by chirality HPLC column separation (±) 6-(4-aminophenyl in US Patent No. 5424428)-5-methyl-4,5-dihydrogen dazin-3(2H) ketone obtains left-handed pyridazinone, although good separating effect, the optical purity of products obtained is higher, but yield is very low, simultaneously but be not suitable for suitability for industrialized production.
ALLRED benefactor department reports the chemical resolution method of pyridazinone in Chinese patent CN1149994C, solvent used during chiral separation is ethyl acetate, resolution reagent is D-tartrate, be 93/7 by splitting (-/+) the pyridazinone enantiomorph ratio obtained, after purifying, enantiomorph ratio can reach 94/6, and optical purity is still lower.The yield of chiral separation is 15 ~ 20%.
Therefore, there is a need in the field to provide a kind of applicable suitability for industrialized production newly, yield is high, the chiral separation technique of the pyridazinone that optical purity is high, and then can obtain the Simdax bulk drug of high-optical-purity.
Summary of the invention
For the problems referred to above of prior art, one of main purpose of the present invention provides a kind of applicable suitability for industrialized production newly, and yield is high, the chiral separation preparation technology of the pyridazinone that optical purity is high.
Two of main purpose of the present invention is to provide a kind of technique obtaining the Simdax of high-optical-purity.
The beneficial effect of the invention
First, the present invention is in the chiral separation technique of pyridazinone, have employed the chemical resolution method of applicable suitability for industrialized production, the reagent selected during chiral separation is L-TARTARIC ACID, L-TARTARIC ACID is the most cheap photolytic activity tartrate, the advantage on production cost is had more than D-tartrate, cross and split (-/+) the pyridazinone enantiomorph ratio obtained and be greater than 99/1, far above the enantiomorph ratio that ALLRED benefactor department reports in Chinese patent CN1149994C, yield can reach 30% simultaneously, improves 5 ~ 10% than the yield of ALLRED benefactor department.
Secondly, with split the left-handed pyridazinone obtained be the Simdax bulk drug of Material synthesis have compared with optical purity, optical purity is greater than 99.5%.
Again, the mother liquor produced in this technique can recycle (±) 6-(4-aminophenyl obtaining DL)-5-methyl-4,5-dihydrogen dazin-3(2H) ketone; continue after reclaiming to split to use; while reducing production cost, also reduce the generation of solid waste, be conducive to the protection of environment.
Below by way of specific embodiment, the present invention is specifically described, but the present invention is not limited to following examples.
Concrete embodiment
Below in conjunction with the embodiment of the present invention, the present invention will be further described.What be necessary to herein means out is that following examples are only for further instruction of the present invention; can not be interpreted as limiting the scope of the invention, the person skilled in the art in this field can make some nonessential improvement and adjustment according to foregoing invention content to the present invention.
Embodiment 1: the preparation of left-handed pyridazinone
In 1000L reactor, add L-TARTARIC ACID 18Kg and 600L Virahol, stir and be warming up to 70 DEG C, after solids dissolves completely, add pyridazinone 12.2Kg in multiple times on a small quantity, then temperature in reaction is slowly down to 50 DEG C, then spends the night 50 DEG C of stirrings, adularescent solid is separated out.Reaction solution heat filtering, adds filter cake in 80L water, adjusts pH=8 ~ 9 to filter with solution of potassium carbonate, and 50 ~ 60 DEG C of dryings obtain white solid for 8 ~ 12 hours and are about 4Kg.By this solid dioxane heating for dissolving, slow cooling to 20 ~ 25 DEG C crystallize out, 20 ~ 25 DEG C of insulations, 1 hour suction filtration, DL product (directly continuing after recovery to split) is obtained after drying, filtrate decompression evaporate to dryness, 50 ~ 60 DEG C of dryings obtain left-handed product 3.65 Kg for 8 ~ 12 hours, yield about 30%.
By filtered Virahol mother liquor concentrations, reclaim Virahol, filter cake is drained, and add water 120L, adjusts pH=8 ~ 9 with solution of potassium carbonate, the solid filtering of precipitation, and 50 ~ 60 DEG C of dryings obtain white solid about 5.2 Kg in 8 ~ 12 hours.To obtain DL product (directly continuing after recovery to split) after this solid dioxane recrystallization, filtrate decompression evaporate to dryness, 50 ~ 60 DEG C of dryings obtain dextrorotation product for 8 ~ 12 hours and are about 3Kg.
Embodiment 2: the preparation of Simdax
The left-handed pyridazinone of 12.2Kg is added in 1000L reactor, then the hydrochloric acid soln that 30L concentrated hydrochloric acid is dissolved in 450L water is added, stir molten clear rear cooling, temperature control 0 ~ 5 DEG C drips sodium nitrite solution (4.56Kg Sodium Nitrite is dissolved in 30L water), the third two eyeball solution (3.96kg the third two eyeball be dissolved in 30L water) are added after 10 minutes, then stirring at room temperature 2 hours are maintained, then its PH to 6.0 filtering product is adjusted with sodium acetate solution, 50 ~ 60 DEG C of dryings obtain Simdax 15 ~ 16Kg, yield 89% ~ 95% in 8 ~ 12 hours.
Claims (3)
1. the production method of a Simdax, this route is with 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3 (2H)-pyridazinone is starting raw material, by reacting obtained Simdax after L-TARTARIC ACID chiral separation with Sodium Nitrite, dilute hydrochloric acid, propane dinitrile.
2. the production method of a kind of Simdax as claimed in claim 1, is characterized in that, solvent used during chiral separation can be methyl alcohol, ethanol, Virahol etc.
3. the production method of a kind of Simdax as claimed in claim 1, it is characterized in that, the reagent selected during chiral separation is L-TARTARIC ACID, and the mol ratio of L-TARTARIC ACID and 6-(4-aminophenyl)-5-methyl-4,5-dihydro-3 (2H)-pyridazinone is 1:2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310396124.1A CN104418810A (en) | 2013-09-04 | 2013-09-04 | New synthetic route of levosimendan |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310396124.1A CN104418810A (en) | 2013-09-04 | 2013-09-04 | New synthetic route of levosimendan |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104418810A true CN104418810A (en) | 2015-03-18 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310396124.1A Pending CN104418810A (en) | 2013-09-04 | 2013-09-04 | New synthetic route of levosimendan |
Country Status (1)
| Country | Link |
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| CN (1) | CN104418810A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104987310A (en) * | 2015-06-03 | 2015-10-21 | 青岛农业大学 | Synthesis process of levosimendan |
| CN111548310A (en) * | 2020-05-12 | 2020-08-18 | 成都欣捷高新技术开发股份有限公司 | Levosimendan sodium crystal form and preparation method thereof |
| KR20210157134A (en) * | 2020-06-19 | 2021-12-28 | 한국과학기술연구원 | Novel oxopyridazinyl-phenyl-carbonohydrazonoyl dicyanide compounds and use thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5512571A (en) * | 1991-01-03 | 1996-04-30 | Orion-Yhtyma Oy | (-) 4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl!-hydra-zono!propanedinitrile |
| CN1271282A (en) * | 1997-09-26 | 2000-10-25 | 欧里恩公司 | Oral compositions of levosimendan |
| CN1616437A (en) * | 2004-09-27 | 2005-05-18 | 广西大学 | The racemization method of 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone |
-
2013
- 2013-09-04 CN CN201310396124.1A patent/CN104418810A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5512571A (en) * | 1991-01-03 | 1996-04-30 | Orion-Yhtyma Oy | (-) 4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl!-hydra-zono!propanedinitrile |
| CN1271282A (en) * | 1997-09-26 | 2000-10-25 | 欧里恩公司 | Oral compositions of levosimendan |
| CN1616437A (en) * | 2004-09-27 | 2005-05-18 | 广西大学 | The racemization method of 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3-(2H)-pyridazinone |
Non-Patent Citations (1)
| Title |
|---|
| 张丽娟 等: "6-(4-氨基苯基)-5-甲基-4 , 5-二氢-3(2H)-哒嗪酮的拆分及左西孟旦的合成", 《沈阳药科大学学报》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104987310A (en) * | 2015-06-03 | 2015-10-21 | 青岛农业大学 | Synthesis process of levosimendan |
| CN111548310A (en) * | 2020-05-12 | 2020-08-18 | 成都欣捷高新技术开发股份有限公司 | Levosimendan sodium crystal form and preparation method thereof |
| CN111548310B (en) * | 2020-05-12 | 2021-07-02 | 成都欣捷高新技术开发股份有限公司 | Levosimendan sodium crystal form and preparation method thereof |
| KR20210157134A (en) * | 2020-06-19 | 2021-12-28 | 한국과학기술연구원 | Novel oxopyridazinyl-phenyl-carbonohydrazonoyl dicyanide compounds and use thereof |
| KR102356644B1 (en) | 2020-06-19 | 2022-01-28 | 한국과학기술연구원 | Novel oxopyridazinyl-phenyl-carbonohydrazonoyl dicyanide compounds and use thereof |
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Application publication date: 20150318 |