CN105315274A - Process for synthesizing quinuclidine hydrochloride - Google Patents
Process for synthesizing quinuclidine hydrochloride Download PDFInfo
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- CN105315274A CN105315274A CN201410317125.7A CN201410317125A CN105315274A CN 105315274 A CN105315274 A CN 105315274A CN 201410317125 A CN201410317125 A CN 201410317125A CN 105315274 A CN105315274 A CN 105315274A
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- rubane
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- hydrochloride
- ethyl
- extraction
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- 238000000034 method Methods 0.000 title claims abstract description 16
- BZLBBZLOMXKMTA-UHFFFAOYSA-N 1-azoniabicyclo[2.2.2]octane;chloride Chemical compound Cl.C1CC2CCN1CC2 BZLBBZLOMXKMTA-UHFFFAOYSA-N 0.000 title abstract 3
- 230000002194 synthesizing effect Effects 0.000 title abstract 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 239000013078 crystal Substances 0.000 claims description 10
- 238000003786 synthesis reaction Methods 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 7
- 238000001914 filtration Methods 0.000 claims description 7
- 150000007857 hydrazones Chemical class 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 238000009835 boiling Methods 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 3
- 239000012141 concentrate Substances 0.000 claims description 3
- 238000006114 decarboxylation reaction Methods 0.000 claims description 3
- 239000012452 mother liquor Substances 0.000 claims description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 3
- 230000002829 reductive effect Effects 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 238000010025 steaming Methods 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims 6
- 238000006243 chemical reaction Methods 0.000 claims 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims 3
- 239000002253 acid Substances 0.000 claims 3
- 239000008346 aqueous phase Substances 0.000 claims 3
- 239000002904 solvent Substances 0.000 claims 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims 2
- 230000001476 alcoholic effect Effects 0.000 claims 2
- 239000000706 filtrate Substances 0.000 claims 2
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 claims 2
- 238000000967 suction filtration Methods 0.000 claims 2
- 238000005406 washing Methods 0.000 claims 2
- DNUTZBZXLPWRJG-UHFFFAOYSA-N 1-Piperidine carboxylic acid Chemical compound OC(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-N 0.000 claims 1
- ZKMZPXWMMSBLNO-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-3-one Chemical compound C1CC2C(=O)CN1CC2 ZKMZPXWMMSBLNO-UHFFFAOYSA-N 0.000 claims 1
- RGHQKFQZGLKBCF-UHFFFAOYSA-N 2-bromoethyl acetate Chemical group CC(=O)OCCBr RGHQKFQZGLKBCF-UHFFFAOYSA-N 0.000 claims 1
- GHVZOJONCUEWAV-UHFFFAOYSA-N [K].CCO Chemical compound [K].CCO GHVZOJONCUEWAV-UHFFFAOYSA-N 0.000 claims 1
- 229910052728 basic metal Inorganic materials 0.000 claims 1
- 150000003818 basic metals Chemical class 0.000 claims 1
- 238000002425 crystallisation Methods 0.000 claims 1
- 230000008025 crystallization Effects 0.000 claims 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 claims 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims 1
- 239000012074 organic phase Substances 0.000 claims 1
- 230000003252 repetitive effect Effects 0.000 claims 1
- 230000000630 rising effect Effects 0.000 claims 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims 1
- 238000010792 warming Methods 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000007792 addition Methods 0.000 abstract description 3
- 238000009833 condensation Methods 0.000 abstract description 3
- 230000005494 condensation Effects 0.000 abstract description 3
- 230000032050 esterification Effects 0.000 abstract description 3
- 238000005886 esterification reaction Methods 0.000 abstract description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 abstract 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 abstract 1
- FUFZNHHSSMCXCZ-UHFFFAOYSA-N 5-piperidin-4-yl-3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole Chemical compound FC(F)(F)C1=CC=CC(C=2N=C(ON=2)C2CCNCC2)=C1 FUFZNHHSSMCXCZ-UHFFFAOYSA-N 0.000 abstract 1
- 238000006473 carboxylation reaction Methods 0.000 abstract 1
- 235000019253 formic acid Nutrition 0.000 abstract 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 229910000497 Amalgam Inorganic materials 0.000 description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 3
- 229910052725 zinc Inorganic materials 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical group CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 2
- SRJOCJYGOFTFLH-UHFFFAOYSA-N isonipecotic acid Chemical compound OC(=O)C1CCNCC1 SRJOCJYGOFTFLH-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- RFDPHKHXPMDJJD-UHFFFAOYSA-N 1-azabicyclo[2.2.2]octan-3-one;hydron;chloride Chemical compound Cl.C1CC2C(=O)CN1CC2 RFDPHKHXPMDJJD-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- -1 ethylene glycol Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 1
- 150000002902 organometallic compounds Chemical class 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- ZIBGPFATKBEMQZ-UHFFFAOYSA-N triethylene glycol Chemical compound OCCOCCOCCO ZIBGPFATKBEMQZ-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for synthesizing quinuclidine hydrochloride includes the steps of esterification, addition, condensation, de-carboxylation and finally reduction to prepare the quinuclidine hydrochloride with 4-piperidine formic acid as a start raw material.
Description
Technical field
For the synthesis of a technique for rubane hydrochloride, be with 4-piperidine carboxylic acid for starting raw material, through esterification, addition, condensation, decarboxylation, then obtain rubane hydrochloride through reduction.
Background technology
Rubane is the complexing agent of organometallic compound, and it is also important medicine intermediate simultaneously, the emphasis being domestic and international pharmaceutical industries research always and paying close attention to.Document (JournaloftheChemicalSociety; 1937; 1989) report two kinds with 3-quininone hydrochlorate for starting raw material is to synthesize the method for rubane: one, with 3-quininone hydrochlorate for starting raw material, take hydrazine hydrate as reductive agent, in sodium ethylate/ethanol system, obtain target compound through high pressure, pyroreaction.Synthetic route have employed high pressure-temperature, and operation inconvenience, unsuitable industry's enlarging production; Two, with 3-Quinuclidinone hydrochloride for starting raw material, take zinc amalgam as reductive agent, concentrated hydrochloric acid exist under backflow obtain target compound.The zinc amalgam reagent adopted in route, and the preparation of zinc amalgam itself just needs to use the contour toxic agent of mercury bichloride, this just greatly limit the feasibility of its suitability for industrialized production.So, find a kind of comparatively safe, with low cost while can the method for large-scale industrial production, be the emphasis that researchist pays close attention to all the time.
Summary of the invention
Technical scheme of the present invention is: for the synthesis of the technique of rubane hydrochloride, with 4-piperidine carboxylic acid for starting raw material, through esterification, addition, condensation, decarboxylation, then obtains rubane hydrochloride through reduction.Reduction obtains rubane hydrochloride.
The synthesis of rubane hydrochloride (V), is realized by following step:
1) method one: get 1Kg quininone (I work work) hydrochloride, under condition of ice bath in a small amount repeatedly join in the sodium hydroxide solution of the 2N of 2.9L, then 65.6g sodium carbonate solid is added, stir 0.5h, then methylene dichloride (1.5L × 3) is used to extract, combined dichloromethane layer, anhydrous sodium sulfate drying, concentrate drying obtains 670g intermediate quininone, yield 87%.Repeatedly joined at leisure in 1.3L95% hydrazine hydrate on a small quantity by above-mentioned quininone, then 120 DEG C of heated overnight at reflux, cooling, place 3h in 0 DEG C, crystal is separated out.Filter, the crystal tertiary butyl ether rinsing of 800mL 3 times, the mother liquor of filtration is placed refrigerator and is repeated aforesaid operations, merges and obtains white crystal 3-rubane hydrazone 670g.Above-mentioned 67093-rubane hydrazone, alkali (the present embodiment is 810g potassium hydroxide) and 3.4L high-boiling point alcohol (can be the water soluble high boiling point alcohols such as ethylene glycol, tirethylene glycol, triethylene Glycol) 175 DEG C are stirred 5 ~ 6h (wherein having a large amount of nitrogen to produce).Cooling, pressure reducing and steaming 2.5L high-boiling point alcohol, (3L × 3) extraction is carried out, anhydrous sodium sulfate drying with methylene dichloride or trichloromethane or tetracol phenixin or 1,2-ethylene dichloride etc., rapid filtration, in the 2N ethyl acetate hydrogen chloride solution stirred under pouring 2.5L ice bath at leisure into, concentrated, filter, gained white solid is recrystallization in 1.0L Virahol or methyl alcohol or ethanol or n-propyl alcohol, cold filtration obtains rubane hydrochloride 500g, yield 70%.Purity: 99.5%.
2) method two: get 1Kg quininone (work I work) hydrochloride, under condition of ice bath in a small amount repeatedly join in the sodium hydroxide solution of the 2N of 2.9L, then 65.6g sodium carbonate solid is added, stir 0.5h, then methylene dichloride (1.5L × 3) is used to extract, combined dichloromethane layer, anhydrous sodium sulfate drying, concentrate drying obtains 665g intermediate quininone.Repeatedly joined at leisure in 1.3L95% hydrazine hydrate on a small quantity by above-mentioned quininone, then 120 DEG C of heated overnight at reflux, cooling, place 3h in 0 DEG C, crystal is separated out.Filter, the crystal tertiary butyl ether rinsing of 800mL 3 times, the mother liquor of filtration is placed refrigerator and is repeated aforesaid operations, merges and obtains white crystal 3-rubane hydrazone 668g.Above-mentioned 66893-rubane hydrazone, 2300g potassium tert.-butoxide (triplication) and 3.4L ethylene glycol 175 DEG C are stirred 5 ~ 6h (wherein having a large amount of nitrogen to produce).Cooling, pressure reducing and steaming 2.5L ethylene glycol, with methylene dichloride (3L × 3) extraction, anhydrous sodium sulfate drying, rapid filtration, stir in the ethyl acetate hydrogen chloride solution of 2N under pouring 2.5L ice bath at leisure into, concentrated, filter, gained white solid is recrystallization in 1.0L Virahol, cold filtration obtains rubane hydrochloride 400g, yield 56%.Purity: 99%.
Accompanying drawing explanation
Fig. 1 is synthesis rubane hydrochloride process figure.
Claims (5)
1. for the synthesis of a technique for rubane hydrochloride, it is characterized in that, comprise the following steps:
1) in alcoholic solvent, piperidine carboxylic acid (I) and sulfur oxychloride react under condition of ice bath, after, drip halogenated acetic acids ethyl ester, temperature rising reflux 1-3h, be down to less than 50 DEG C, process filtrate, through extraction, merges organic phase, drying, suction filtration, filtrate concentrate, and obtain oily object---1-ethoxy carbonyl acyl ethyl-4-piperidine ethyl formate (work work);
2) 1-ethoxy carbonyl acyl ethyl-4-piperidine ethyl formate (work work) and toluene react in the basic conditions, system temperature 80-90 DEG C, solvent in system is boiled off to system temperature 80 ~ 110 DEG C under normal pressure, reaction 6 ~ 10h, after question response, stopped reaction, be down to room temperature, add diluted acid to stir, leave standstill and separate aqueous phase, again to toluene mutually in add diluted acid, stir, leave standstill and separate aqueous phase, merge aqueous phase, be warming up to 110 ~ 120 DEG C of decarboxylation 8 ~ 12h that are hydrolyzed, stopped reaction, remove moisture under reduced pressure, be down to room temperature, add acid in alkali He unnecessary, pH is adjusted to be 10 ~ 12, extraction, dry, suction filtration, concentrated, obtain brown solid powder---quinuclidone (work I work),
3) by a small amount of for above-mentioned quinuclidone (II work) repeatedly slowly join in hydrazine hydrate, heated overnight at reflux at 110 ~ 120 DEG C, cooling, crystallization.Filter, washing crystal, the mother liquor after washing and filtering puts into refrigerator repetitive operation, merge to obtain more white crystal 3-rubane hydrazones, this white crystal 3-rubane hydrazone and doses alkali, high-boiling point alcohol are stirred 5 ~ 6h, cooling, pressure reducing and steaming high-boiling point alcohol, extraction, dry, filter, in the ethyl acetate/hydrogen chloride solution stirred under slowly pouring ice bath into, concentrated, filter, reflux in Virahol or methyl alcohol or ethanol or n-propyl alcohol, cools to obtain rubane hydrochloride (V).
2. the synthesis technique of rubane hydrochloride according to claim 1, is characterized in that, described step 1) in alcoholic solvent be ethanol, halogenated acetic acids ethyl ester is bromoethyl acetate or ethyl chloroacetate.
3. the synthesis technique of rubane hydrochloride according to claim 1, is characterized in that, described step 2) in alkaline condition be the solution of sodium ethylate, potassium ethylate, potassium tert.-butoxide or basic metal and alcohol direct reaction.
4. the synthesis technique of rubane hydrochloride according to claim 1, is characterized in that, described step 3) in alkali be potassium hydroxide, sodium ethylate or potassium tert.-butoxide, its used in molar ratio is 3 times amount of white crystal 3-rubane hydrazone.
5. the synthesis technique of rubane hydrochloride according to claim 1, is characterized in that, described step 3) in extraction be take methylene dichloride or trichloromethane or tetracol phenixin or 1,2-ethylene dichloride to extract.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410317125.7A CN105315274A (en) | 2014-07-04 | 2014-07-04 | Process for synthesizing quinuclidine hydrochloride |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410317125.7A CN105315274A (en) | 2014-07-04 | 2014-07-04 | Process for synthesizing quinuclidine hydrochloride |
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| Publication Number | Publication Date |
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| CN105315274A true CN105315274A (en) | 2016-02-10 |
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| CN201410317125.7A Pending CN105315274A (en) | 2014-07-04 | 2014-07-04 | Process for synthesizing quinuclidine hydrochloride |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110922401A (en) * | 2018-09-19 | 2020-03-27 | 广东东阳光药业有限公司 | Preparation method of quininone derivative |
-
2014
- 2014-07-04 CN CN201410317125.7A patent/CN105315274A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110922401A (en) * | 2018-09-19 | 2020-03-27 | 广东东阳光药业有限公司 | Preparation method of quininone derivative |
| CN110922401B (en) * | 2018-09-19 | 2022-07-26 | 广东东阳光药业有限公司 | Preparation method of quinuclidone derivative |
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| C06 | Publication | ||
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Application publication date: 20160210 |
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| WD01 | Invention patent application deemed withdrawn after publication |