CN104650074A - Apixaban compound - Google Patents
Apixaban compound Download PDFInfo
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- CN104650074A CN104650074A CN201310591473.9A CN201310591473A CN104650074A CN 104650074 A CN104650074 A CN 104650074A CN 201310591473 A CN201310591473 A CN 201310591473A CN 104650074 A CN104650074 A CN 104650074A
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- eliquis
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- eliquis crystal
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- 0 COC(CC1)CCC1C1*C(C(*)I(CC2)C(CC3)CCC3I3C(*)CCCC3)C2C(CO)*1 Chemical compound COC(CC1)CCC1C1*C(C(*)I(CC2)C(CC3)CCC3I3C(*)CCCC3)C2C(CO)*1 0.000 description 2
- HPXRVTGHNJAIIH-UHFFFAOYSA-N OC1CCCCC1 Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of medicine and chemical engineering, concretely relates to a novel crystal form gamma of apixaban, and discloses a preparation method of the crystal form. The method has the advantages of simple process, convenient operation, mild conditions, and no need of special reaction conditions, so the method is suitable for industrial production.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, be specifically related to the crystalline form that a kind of Eliquis is new, and disclose the method for this crystalline form of preparation.
Background technology
Eliquis (Apixaban), its chemical name is 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-c] pyridine-3-carboxamide, having the chemical structure shown in formula I, is the oral Selective activation X factor inhibitors of a new generation that Pfizer and Bristol Myers Squibb are developed jointly.In the inhibitor of numerous factor Xa, Eliquis shows the selectivity of height, good bioavailability and efficient result for the treatment of, its performance is better than razaxaban (Razaxaban) greatly, be mainly applicable to treatment deep venous thrombosis (DVT) and pulmonary infarction in interior phlebothrombosis.In May, 2011, Eliquis goes through, in European Union's listing, to occur venous thromboembolism (VTE) event for preventing the adult patients accepting to select a time hip joint or knee replacements; In December, 2012, U.S. FDA ratified this medicine for reducing non-valve patients with atrial fibrillation cerebral apoplexy and systemic embolism risk.
Formula I
In the document of current report, WO2003026652 and Chinese CN1578660A of the same clan thereof discloses the compound of Eliquis, its preparation method and the application in the medicine for the preparation for the treatment of thromboembolic disorders thereof.Patent documentation US2009076069 discloses multiple deuterated compound of Eliquis; WO03049681, CN101967145A, CN102675314A disclose the method preparing Eliquis in succession; First US20060160841 discloses non-solvent (non-solvate) crystal formation N-1 and dihydrate (dihydrate) the crystal formation H2-2 of Eliquis, and discloses concrete unit cell parameters, position coordinate parameters, X-ray diffraction characteristic peak positions, the SSNMR(solid-state nuclear magnetic resonance of crystal formation N-1 and crystal formation H2-2 at patent documentation WO2007001385 and Chinese CN101065379A of the same clan thereof) the crystal characterization parameter such as displacement; WO2012168364 then disclose in detail crystal formation α and the sign thereof of Eliquis; For other solvates, US20070203178 then discloses crystal formation DMF-5 and the formamide solvent compound crystal formation FA-2 of the DMF solvate of Eliquis.
Summary of the invention
Contriver, through a large amount of experimental studies, has wonderfully found the crystalline form that Eliquis is new, the present invention is based on this and finds and complete.
The invention provides a kind of crystal formation γ of Eliquis, it uses Cu-K α radiation, the X-ray powder diffraction represented with 2 θ angles at 4.4 ± 0.2 °, 10.3 ± 0.2 °, 16.0 ± 0.2 °, 16.3 ± 0.2 °, 19.9 ± 0.2 °, 20.9 ± 0.2 °, 21.6 ± 0.2 °, 23.3 ± 0.2 °, there is characteristic peak at 24.0 ± 0.2 ° of places.
Further, described crystal γ uses Cu-K α radiation, the X-ray powder diffraction represented with 2 θ angles at 4.4 ± 0.2 °, 7.3 ± 0.2 °, 10.3 ± 0.2 °, 12.7 ± 0.2 °, 13.2 ± 0.2 °, 16.0 ± 0.2 °, 16.3 ± 0.2 °, 16.8 ± 0.2 °, 17.5 ± 0.2 °, 18.2 ± 0.2 °, 18.9 ± 0.2 °, 19.9 ± 0.2 °, 20.9 ± 0.2 °, 21.6 ± 0.2 °, 23.3 ± 0.2 °, 24.0 ± 0.2 °, there is characteristic peak at 25.1 ± 0.2 ° of places.
Further, described crystal formation γ, use Cu-K α radiation, its X-ray powder diffraction represented with 2 θ angles is at 4.4 ± 0.2 °, 7.3 ± 0.2 °, 10.3 ± 0.2 °, 12.7 ± 0.2 °, 13.2 ± 0.2 °, 16.0 ± 0.2 °, 16.3 ± 0.2 °, 16.8 ± 0.2 °, 17.5 ± 0.2 °, 18.2 ± 0.2 °, 18.9 ± 0.2 °, 19.9 ± 0.2 °, 20.9 ± 0.2 °, 21.6 ± 0.2 °, 23.3 ± 0.2 °, 24.0 ± 0.2 °, 25.1 ± 0.2 ° 25.7 ± 0.2 °, 26.4 ± 0.2 °, 27.7 ± 0.2 °, 28.0 ± 0.2 °, 30.1 ± 0.2 °, 30.6 ± 0.2 °, 32.7 ± 0.2 °, there is characteristic peak at 36.5 ± 0.2 ° of places.
Eliquis crystal formation γ of the present invention is through differential scanning calorimetric analysis (DSC), and detected result is presented at endotherm(ic)peak within the scope of 122-169 DEG C and 210-233 DEG C; More specifically, the differential scanning calorimetric analysis (DSC) of described Eliquis crystal formation γ detects has mild absorption peak at 141 ± 2 DEG C, and has sharp-pointed endotherm(ic)peak at 227 ± 2 DEG C of places.
The present invention provides a kind of method preparing above-mentioned Eliquis crystal formation γ on the other hand, and the method comprises the following steps:
(1) Eliquis is joined in the mixed solution of dimethyl sulfoxide (DMSO) and other solvents, heating for dissolving;
(2) step (1) gained organic solvent solution is cooled to recrystallization temperature, stirring and crystallizing;
(3) filter, dry, obtain Eliquis crystal formation γ;
Wherein, other solvents described are selected from C
1-5saturated straight chain or branched-chain alcoho, ester, ketone, ether and C
4-6cyclic ethers in one or more; One or more in particular methanol, ethanol, Virahol, ethyl acetate, isopropyl acetate, acetone, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF); More preferably one or more in methyl alcohol, ethyl acetate, isopropyl acetate, methyl tertiary butyl ether; Dimethyl sulfoxide (DMSO) and other volume ratio are 1:0.1-10, preferred 1:0.5-2, more preferably 1:1-1.5; Recrystallization temperature is-5-20 DEG C, preferred 0-10 DEG C, more preferably 0-5 DEG C; The crystallization time is 0.5-4h, preferred 1-2h;
The temperature of heating for dissolving is the temperature that can make dissolution of solid in above-mentioned steps (1), and preferably 60 DEG C to reflux temperature, more preferably 80-reflux temperature, and most preferably 100 DEG C to reflux temperature; The temperature of heating for dissolving is reflux temperature in one embodiment.
Further aspect of the present invention provides the purposes of Eliquis crystal formation γ of the present invention in preparation high purity Eliquis, this purposes can realize by the following method: 5g Eliquis crystal formation γ heating is dissolved in 50ml methanol/ethanol solution (V methyl alcohol: V ethanol=1:1), cooling crystallization, drying, obtains highly purified Eliquis; Wherein, described " high purity " refers to that its HPLC purity is more than 99.9.
Eliquis crystal formation γ provided by the invention has higher purity and good yield, and its purity is more than 99.3%, and its method technique is simple, and easy to operate, mild condition, does not need special reaction conditions, is therefore applicable to suitability for industrialized production.
In the present invention, disclosed in Eliquis crude product reference patent documentation CN1639147A, method prepares; In the X-ray powder diffraction characteristic peak represented with 2 θ angles, the reasonable measuring error scope that " ± 0.2 ° " representation feature peak position allows.
Embodiment
Further illustrate the present invention below by concrete preparation embodiment, but should be understood to, these embodiments are only used for the use specifically described more in detail, and should not be construed as limiting the present invention in any form.
The reagent used in the embodiment of the present invention and the method for employing be the conventional reagent of this area and the working method of routine all.Although for realizing many materials that the object of the invention uses and working method is well known in the art, the present invention still describes in detail as far as possible.It will be apparent to those skilled in the art that hereinafter, if not specified, material therefor of the present invention and working method are well known in the art, and embodiment Eliquis used crude product is that preparation example 1 prepares or the method identical with it prepares.
The inspection apparatus that the present invention is used:
(1) X-ray powder diffractometer
INSTRUMENT MODEL: PANalytical Empyrean X-ray powder diffraction analyser
Testing method: the sample (100mg) after porphyrize is filled out in sheet glass groove, after its plane and glass surface hung flushing with slide glass, sample is placed in PANalytical Empyrean X-ray powder diffraction analyser, use the copper X-ray source of 40kV, 40mA, sweep limit is 3 ~ 45 ° (2 θ), sweep velocity 4 °/minute, 6 minutes sweep times.Scanning errors is generally ± 0.2 degree (2 θ).
(2) TGA/DSC1 synchronous solving
INSTRUMENT MODEL: METTLERTGA/DSC1.
Testing method: the sample of heavy 10mg is placed in the sealed aluminum pan with little pin hole, keeps balance at 30 DEG C, be then heated to 250 DEG C with the scanning speed of 10 DEG C/min.Drying nitrogen is used as sweeping gas.
Preparation example 1: the preparation of Eliquis
(a) 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo piperidine-1-base)-benzene
Base] preparation of-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-C] pyridine-3-carboxylic acid ethyl esters:
Under 0-5 DEG C and nitrogen protection condition, by 100g3-morpholine-4-base-1-[4-(2-oxo piperidine-1-base)-phenyl]-5, 6-dihydro-1H-pyridin-2-ones, 86.2g chloro [(4-p-methoxy-phenyl) hydrazono-] ethyl acetate and 56.7g triethylamine join in 1000ml toluene, stirring reaction 3h at 60-80 DEG C, after reaction terminates, be cooled to room temperature, decompression steams toluene and obtains enriched material, enriched material is dissolved in ethyl acetate, purified water washs 3 times, gained ethyl acetate uses anhydrous sodium sulfate drying mutually, suction filtration, add in the ethyl acetate solution of gained and use the hydrochloric acid of 4.0mol/L to regulate the pH of gained ethyl acetate filtrate between 3-4, then stirred at ambient temperature 2h, suction filtration, obtain 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidines-1-base)-phenyl]-4, 5, 6, 7-tetrahydrochysene-1H-pyrazolo [3, 4-C] pyridine-3-carboxylic acid, ethyl ester, yield 60%, HPLC purity 95%.
The preparation of (b) Eliquis crude product
At room temperature, by 80g1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidines-1-base)-phenyl]-4, 5, 6, 7-tetrahydrochysene-1H-pyrazolo [3, 4-C] pyridine-3-carboxylic acid, ethyl ester and 368g methane amide join 400mlN, in N-dimethyl formamide, then the methanol solution (400ml) of 40g sodium methylate is dripped, maintain reaction system 0-5 DEG C of reaction 30 minutes, then react at maintaining 40-50 DEG C, HPLC detects to reacting end, then in reaction system, appropriate purified water is added, suction filtration, namely the vacuum-drying of gained filter cake obtain Eliquis 60.19g, yield 80%, HPLC purity 98%.
Embodiment 1
5.0g Eliquis crude product is joined in 50ml dimethyl sulfoxide (DMSO) and 50ml acetone, heating for dissolving, be cooled to-5 DEG C of crystallization 2h, suction filtration, 60 DEG C of vacuum-dryings, obtain 4.1g white Eliquis crystal formation γ, yield about 82%, HLPC purity 99.8%.
Embodiment 2
5.0g Eliquis crude product is joined in 60ml dimethyl sulfoxide (DMSO) and 75ml acetone, is heated to dissolve, is cooled to 0-5 DEG C of crystallization 1h, suction filtration, 40 DEG C of vacuum-dryings, obtain 3.6g white Eliquis crystal formation γ, yield 72%, HLPC purity 99.6%.
Stability test:
For investigating the stable of Eliquis crystal formation γ, investigate its stability in different condition, test-results is in table 1;
The each portion of Eliquis crystal formation γ of Example 1, embodiment 2 preparation, is placed on 40 DEG C/75%R.H. condition lower 30 days, investigates its stability, the results are shown in Table 1.
The method of concrete study on the stability can with reference to the method for Chinese Pharmacopoeia 2010 editions second annex XIX C; Purity detecting HPLC method, can with reference to the method for Chinese Pharmacopoeia 2010 editions second annex V D; The detection of crystal formation is with the method for embodiment.
The stability test of table 1 Eliquis crystal formation γ
Above data show, the present invention obtains Eliquis crystal formation γ, and its purity and crystal formation all have satisfactory stability at typical condition.
Claims (9)
1. a new Eliquis crystal formation γ, use Cu-K α radiation, its X-ray powder diffraction represented with 2 θ angles at 4.4 ± 0.2 °, 10.3 ± 0.2 °, 16.0 ± 0.2 °, 16.3 ± 0.2 °, 19.9 ± 0.2 °, 20.9 ± 0.2 °, 21.6 ± 0.2 °, 23.3 ± 0.2 °, there is characteristic peak at 24.0 ± 0.2 ° of places.
2. Eliquis crystal formation γ according to claim 1, it is characterized in that, use Cu-K α radiation, its X-ray powder diffraction represented with 2 θ angles is at 4.4 ± 0.2 °, 7.3 ± 0.2 °, 10.3 ± 0.2 °, 12.7 ± 0.2 °, 13.2 ± 0.2 °, 16.0 ± 0.2 °, 16.3 ± 0.2 °, 16.8 ± 0.2 °, 17.5 ± 0.2 °, 18.2 ± 0.2 °, 18.9 ± 0.2 °, 19.9 ± 0.2 °, 20.9 ± 0.2 °, 21.6 ± 0.2 °, 23.3 ± 0.2 °, 24.0 ± 0.2 °, there is characteristic peak at 25.1 ± 0.2 ° of places.
3. Eliquis crystal formation γ according to claim 1, it is characterized in that, Eliquis crystal formation γ, use Cu-K α radiation, its X-ray powder diffraction represented with 2 θ angles is at 4.4 ± 0.2 °, 7.3 ± 0.2 °, 10.3 ± 0.2 °, 12.7 ± 0.2 °, 13.2 ± 0.2 °, 16.0 ± 0.2 °, 16.3 ± 0.2 °, 16.8 ± 0.2 °, 17.5 ± 0.2 °, 18.2 ± 0.2 °, 18.9 ± 0.2 °, 19.9 ± 0.2 °, 20.9 ± 0.2 °, 21.6 ± 0.2 °, 23.3 ± 0.2 °, 24.0 ± 0.2 °, 25.1 ± 0.2 ° 25.7 ± 0.2 °, 26.4 ± 0.2 °, 27.7 ± 0.2 °, 28.0 ± 0.2 °, 30.1 ± 0.2 °, 30.6 ± 0.2 °, 32.7 ± 0.2 °, there is characteristic peak at 36.5 ± 0.2 ° of places.
4. the Eliquis crystal formation γ according to any one of claim 1-3, is characterized in that, differential scanning calorimetric analysis (DSC) detected result of described Eliquis crystal formation γ is presented at endotherm(ic)peak within the scope of 122-169 DEG C and 210-233 DEG C; Preferably, the differential scanning calorimetric analysis (DSC) of described Eliquis crystal formation γ detects has mild absorption peak at 141 ± 2 DEG C, and has sharp-pointed endotherm(ic)peak at 227 ± 2 DEG C of places.
5. prepare a method of Eliquis crystal formation γ described in any one of claim 1-4, the method comprises the following steps:
(1) Eliquis is joined in the mixed solution of dimethyl sulfoxide (DMSO) and other solvents, heating for dissolving;
(2) step (1) gained organic solvent solution is cooled to recrystallization temperature, stirring and crystallizing;
(3) filter, dry, obtain the Eliquis crystal formation γ of crystalline form.
6. method according to claim 5, is characterized in that, other solvents described be selected from the saturated straight chain of C1-5 or the cyclic ethers of branched-chain alcoho, ester, ketone, ether and C4-6 one or more; One or more in particular methanol, ethanol, Virahol, ethyl acetate, isopropyl acetate, acetone, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF); More preferably one or more in methyl alcohol, ethyl acetate, isopropyl acetate, methyl tertiary butyl ether.
7. method according to claim 5, is characterized in that, dimethyl sulfoxide (DMSO) and other volume ratio are 1:0.1-10, preferred 1:0.5-2, more preferably 1:1-1.5.
8. the method according to any one of claim 5-7, its spy is being, described recrystallization temperature is-5-20 DEG C, preferred 0-10 DEG C, more preferably 0-5 DEG C; The crystallization time is 0.5-10h, preferred 1-2h.
9. Eliquis crystal formation γ described in claim 1-4 is in the purposes of preparation high purity Eliquis, and described " high purity " refers to that HPLC purity is more than 99.9%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310591473.9A CN104650074A (en) | 2013-11-22 | 2013-11-22 | Apixaban compound |
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| CN201310591473.9A CN104650074A (en) | 2013-11-22 | 2013-11-22 | Apixaban compound |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106279149A (en) * | 2015-06-02 | 2017-01-04 | 天津药物研究院有限公司 | A kind of method preparing high-purity Eliquis |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013119328A1 (en) * | 2012-02-07 | 2013-08-15 | Assia Chemical Industries Ltd. | Solid state forms of apixaban |
| CN103360391A (en) * | 2013-08-06 | 2013-10-23 | 齐鲁制药有限公司 | Novel apixaban crystal form and preparation method thereof |
-
2013
- 2013-11-22 CN CN201310591473.9A patent/CN104650074A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013119328A1 (en) * | 2012-02-07 | 2013-08-15 | Assia Chemical Industries Ltd. | Solid state forms of apixaban |
| CN103360391A (en) * | 2013-08-06 | 2013-10-23 | 齐鲁制药有限公司 | Novel apixaban crystal form and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 陶海燕等: "阿哌沙班的合成工艺研究", 《中国药物化学杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106279149A (en) * | 2015-06-02 | 2017-01-04 | 天津药物研究院有限公司 | A kind of method preparing high-purity Eliquis |
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