CN104910101A - Synthesis process of imatinib intermediate 4-(4-methylpiperazin-1-ylmethyl) benzoic acid hydrochloride - Google Patents
Synthesis process of imatinib intermediate 4-(4-methylpiperazin-1-ylmethyl) benzoic acid hydrochloride Download PDFInfo
- Publication number
- CN104910101A CN104910101A CN201510253597.5A CN201510253597A CN104910101A CN 104910101 A CN104910101 A CN 104910101A CN 201510253597 A CN201510253597 A CN 201510253597A CN 104910101 A CN104910101 A CN 104910101A
- Authority
- CN
- China
- Prior art keywords
- methylpiperazine
- methyl
- reaction
- ethanol
- benzoate hydrochlorate
- 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
Classifications
-
- 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
- C07D295/04—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—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 with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a green synthesis process of 4-(4-methylpiperazin-1-ylmethyl) benzoic acid. The process comprises the following steps: according to a stoichiometric molar ratio, p-cyanobenzylchloride is dissolved in a mixed solvent of ethanol and water; methylpiperazine is added; a heating reaction is carried out under a certain temperature; the material is cooled to room temperature, and most ethanol is recovered, such that 4-(4-methyl-1-piperazinyl) benzonitrile is obtained; sodium hydroxide is added, and reflux is carried out; when the reaction is finished, the material is cooled to room temperature; in an ice bath, dilute hydrochloric acid is dropped slowly until the material is acidic; sodium chloride is added until the sodium chloride is saturated; cooling is carried out, such that solid is precipitated; and filtering and drying are carried out, such that 4-(4-methylpiperazin-1-ylmethyl) benzoic acid hydrochloride is obtained. The method provided by the invention has the following advantages: 1, the method is simple and easy to operate; reaction steps are short; the raw materials are cheap and easy to obtain; an overall yield and product purity are greatly improved compared to prior arts; 2, the method has good environment friendliness, and no toxic gas is released during the reaction processes; 3, with the method, post treatment is simple to operate and is highly efficient.
Description
Technical field
The present invention relates to antitumour drug field, be specifically related to a kind of imatinib important intermediate 4-(4-methylpiperazine-1-yl methyl) benzoic green synthesis process.
Background technology
Imatinib mesylate (imatinib mesilate), chemistry 4-(4-methylpiperazine base-1-methyl)-N-by name [4-methyl-3-[4-(3-pyridyl) pyrimidine-2-is amino]-benzamide methanesulfonate.Imatinib mesylate is small molecule tyrosine kinase (TK) inhibitor, its mechanism of action is for Tyrosylprotein kinase bcr/abl receptor subtype, selective binding in conjunction with in nest, stops Tyrosylprotein kinase to be combined with ATP in the Nucleotide of bcr/abl protein tyrosine kinase catalytic domain competitively.The deactivation conformation of the activation ring of Tyrosylprotein kinase can be identified, and specific binding with it, prevent the phosphorylation of self-phosphorylation and tyrosine kinase substrate, reduce tyrosine kinase activity, suppress or control the generation of tumour, be used for the treatment of chronic myelocytic leukemia (CML) clinically, developed by Novartis of Switzerland (Novartis) company, obtain FDA approval listing in calendar year 2001.
The synthesis of imatinib mesylate, bibliographical information has two lines: route one: with 3-acetylpyridine, ethyl formate and dimethylamine for Material synthesis α, alpha, beta-unsaturated ketone 1 (Fig. 1), 2-methyl-5-nitro aniline and monoamine cyanogen are obtained by reacting guanidine 2,1 obtains 2-aniline substituted pyrimidines 3 with 2 one-tenth rings, then obtains 4 with palladium charcoal catalytic hydrogenation.
Route two: be first 2-methyl-5-nitro aniline and monoamine cyanogen are obtained by reacting guanidine 2, catalytic hydrogenation 2 obtains after 2-methyl-5-aminophenyl guanidine 6 and alpha, beta-unsaturated ketone 1 condensation obtains 4.4 obtain compound 5 with 4-(4-methylpiperazine-1-methyl) Benzoyl chloride 7 condensation, and 5 obtain target compound imatinib mesylate with methylsulfonic acid salify.
The key distinction of two lines is nitroreduction and the order becoming pyrimidine ring two-step reaction, and route one XianCheng ring restores, and route two just contrary (Fig. 2).
Above-mentioned route finds in an experiment, first reduce when closing ring afterwards and have a by product, and be not easy removing, cause product not easily purifying, thus based on the synthetic method of route one synthesising target compound, and each step reaction conditions to be optimized: document with 3-acetylpyridine, ethyl formate and dimethylamine for Material synthesis α, alpha, beta-unsaturated ketone 1, trivial operations, consuming time many, yield is also lower.
2008, Li Mingdong etc. directly obtained alpha, beta-unsaturated ketone 1 with 3-acetylpyridine and DMF two contracting carbinol condensation, improve, operation is simplified to aftertreatment, and yield improves (Fig. 1).1 and 2 when closing ring, and substitute Virahol with ethanol and make solvent, and the optimum charging ratio determining NaOH, ketone 1 and guanidine 2 is 1.4: 1: 1.3, yield reaches 79.8%.The reduction of nitro-compound 3, changing expensive palladium catalyst is Raney's nickel, obtains same effect.4 use dry chloroform give solvent instead with the acylation reaction of acyl chlorides, and reaction product 5 solubleness in chloroform is less, directly separates out from solvent, simplifies operation steps, and after improving, yield reaches 69.3%.5 in hot ethanol with methylsulfonic acid salify, through partial concentration, cooling, directly separate out from solvent, yield 87.0%, following reaction formula.
The synthesis of 3-(3-dimethylamino allyl acyl group) pyridine
The synthesis of imatinib mesylate
Above-mentioned intermediate 7 is important intermediate raw materials of synthesizing methanesulfonic acid imatinib, but the synthetic method of this intermediate yet there are no the detailed report of pertinent literature, therefore market price is higher.Present method provides the green synthesis method of a kind of 4-(4-methylpiperazine-1-yl methyl) benzoate hydrochlorate, greatly can reduce the production cost of intermediate 7 and imatinib mesylate, and the method environmental protection, simple to operation, be applicable to industrialized production, to the production of antineoplastic drug imatinib, there is great value.
Summary of the invention
The present invention aims to provide the green synthesis method of a kind of 4-(4-methylpiperazine-1-yl methyl) benzoate hydrochlorate, this synthetic method is simple, reactions steps is short, easy to operate, organic solvent consumption is little, aftertreatment is simple, product purity is high, and product yield is high, and purity is high, environmental protection pressure is little, is convenient to industrial production.
The present invention solves the problems of the technologies described above adopted technical scheme: the synthesis technique of imatinib intermediate 4-(4-methylpiperazine-1-yl methyl) benzoate hydrochlorate, it is characterized in that including following steps: nonstoichiometric molar ratio is dissolved in ethanol and water mixed solvent to cyano group benzyl chloride, add methylpiperazine, reacting by heating at a certain temperature, be cooled to room temperature, reclaim most of ethanol, obtain 4-(4-methyl isophthalic acid-piperazinyl) cyanophenyl, add sodium hydroxide, backflow, question response is complete, be cooled to room temperature, dilute hydrochloric acid is slowly dripped to acid under ice bath, add sodium-chlor to saturated, solid is separated out in cooling, filter, dry, obtain 4-(4-methylpiperazine-1-yl methyl) benzoate hydrochlorate.
By such scheme, with molar ratio computing, to cyano group benzyl chloride: methylpiperazine: sodium hydroxide=1:1.2-1.5:6-6.5; With volume basis, ethanol in mixed solvent: water=2:1.
By such scheme, the described concentration to cyano group benzyl chloride is 0.1g/mL-0.15g/mL; The concentration of 4-(4-methyl isophthalic acid-piperazinyl) cyanophenyl is 0.05g/mL-0.10g/mL.
By such scheme, be 70-100 DEG C to cyano group benzyl chloride and methylpiperazine temperature of reaction, the reaction times is 1-2 hour; 4-(4-methyl isophthalic acid-piperazinyl) cyanophenyl and sodium hydroxide temperature of reaction are 70-100 DEG C, and the reaction times is 5-6 hour.
By such scheme, be 1-2 with dilute hydrochloric acid neutralization reaction liquid to pH.
Involved by synthetic method of the present invention, reaction equation is as follows:
The invention has the advantages that:
1, the easy easy handling of present method, reactions steps is short, and raw material is cheap and easy to get, and overall production rate and the more original method of product purity improve greatly, greatly can reduce the production cost of antineoplastic drug imatinib.Method expensive starting materials in document and being difficult to obtain, step is many, and each step yield is low, and comprehensive yield is not high, consumes a large amount of raw materials and solvent, causes high cost, and reaction process release toxic gas, causes heavy environmental pressure.The working conditions of reagent is harsh, causes the road of industrialization remote;
2, present method feature of environmental protection is good, does not discharge toxic gas in reaction process, and reaction is carried out in ethanol, after reaction terminates, reclaims ethanol, separates out solid, obtain 4-(4-methyl isophthalic acid-piperazinyl) cyanophenyl, be applicable to industrialized production;
3, present method post-processing operation is simple, efficiently, reaction terminates rear dropping dilute hydrochloric acid to acid, adds sodium-chlor to saturated, solid is separated out in cooling, filter, purifying, dry, obtain 4-(4-methylpiperazine-1-yl methyl) benzoate hydrochlorate, for industrialized production without pressure, and productive rate is up to 90%, high purity 99.8%.
Accompanying drawing explanation
Fig. 1 is high-efficient liquid phase chromatogram (the J & K HPLC C18 5 μm of the embodiment of the present invention 1 products therefrom 4-(4-methylpiperazine-1-yl methyl) benzoate hydrochlorate, 4.6*150mm Column, column temperature 30 DEG C, wavelength 254nm, 1% acetic acid aqueous solution: methyl alcohol=70:30);
Fig. 2 is the infrared absorpting light spectra (IR spectrum test instrument: BrukerVECTOR-22, test condition: KBr compressing tablet) of the embodiment of the present invention 1 products therefrom 4-(4-methylpiperazine-1-yl methyl) benzoate hydrochlorate;
Fig. 3 is the hydrogen nuclear magnetic resonance spectrogram (NMR VARIANMercury Plus400 type test condition: 500MHz) of the embodiment of the present invention 1 products therefrom 4-(4-methylpiperazine-1-yl methyl) benzoate hydrochlorate;
Fig. 4 is the carbon-13 nmr spectra figure (NMR VARIANMercury Plus400 type test condition: 75MHz) of the embodiment of the present invention 1 products therefrom 4-(4-methylpiperazine-1-yl methyl) benzoate hydrochlorate.
Embodiment
Below in conjunction with specific embodiment, illustrate the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.
Embodiment 1:
Will to cyano group benzyl chloride (1g, 6.6mmol) be dissolved in the mixed solvent (10mL of second alcohol and water, ethanol in mixed solvent: water=2:1) in, add methylpiperazine (1.2eq, 0.792g, 7.92mmol), reacting by heating at 70 DEG C, reaction times is 1-2 hour, be cooled to room temperature, reclaim most of ethanol, obtain 4-(4-methyl isophthalic acid-piperazinyl) cyanophenyl, add sodium hydroxide (6eq, 1.584g, 39.6mmol), reacting by heating at 70 DEG C, question response is complete, be cooled to room temperature, dilute hydrochloric acid is slowly dripped to pH=1 under ice bath, add sodium-chlor to saturated, solid is separated out in cooling, filter, dry, obtain 4-(4-methylpiperazine-1-yl methyl) benzoate hydrochlorate (2.0g).
As shown in Figure 1, be product peak at about 4.098min, consistent with the peak retention time of bibliographical information, this compound is correct as seen.By area normalization method, can this product purity up to 99.8%.
As shown in Figure 2, at 3403cm
-1place is O-H peak, 1722, and 1712cm
-1place is C=O peak, and consistent with the spectrogram of bibliographical information, this compound is correct as seen;
As shown in Figure 3, this structure has the hydrogen that five class chemical environments are different, lay respectively at 8.09 (2H), 7.65 (2H), 4.55 (2H), 3.68 (8H), 3.03 (3H) ppm, consistent with the spectrogram of bibliographical information, this compound is correct as seen;
As shown in Figure 4, this structure has the carbon that nine class chemical environments are different, lays respectively at 167.30,134.07,133.05,132.09,131.82,130.15,56.48,44.71,19.01ppm, consistent with the spectrogram of bibliographical information, and this compound is correct as seen.
Embodiment 2:
Will to cyano group benzyl chloride (13.5g, 89.1mmol) be dissolved in the mixed solvent (135mL of second alcohol and water, ethanol in mixed solvent: water=2:1) in, add methylpiperazine (1.2eq, 10.7g, 106.9mmol), reacting by heating at 100 DEG C, reaction times is 1-2 hour, be cooled to room temperature, reclaim most of ethanol, obtain 4-(4-methyl isophthalic acid-piperazinyl) cyanophenyl, add sodium hydroxide (6eq, 21.4g, 534.6mmol), reacting by heating at 100 DEG C, question response is complete, be cooled to room temperature, dilute hydrochloric acid is slowly dripped to pH=1.5 under ice bath, add sodium-chlor to saturated, solid is separated out in cooling, filter, dry, obtain 4-(4-methylpiperazine-1-yl methyl) benzoate hydrochlorate (27g).
Embodiment 3:
Will to cyano group benzyl chloride (111g, 723.6mmol) be dissolved in the mixed solvent (1120mL of second alcohol and water, ethanol in mixed solvent: water=2:1) in, add methylpiperazine (1.2eq, 87.9g, 879.1mmol), reacting by heating at 90 DEG C, reaction times is 1-2 hour, be cooled to room temperature, reclaim most of ethanol, obtain 4-(4-methyl isophthalic acid-piperazinyl) cyanophenyl, add sodium hydroxide (6eq, 175.8g, 4396mmol), reacting by heating at 90 DEG C, question response is complete, be cooled to room temperature, dilute hydrochloric acid is slowly dripped to pH=2 under ice bath, add sodium-chlor to saturated, solid is separated out in cooling, filter, dry, obtain 4-(4-methylpiperazine-1-yl methyl) benzoate hydrochlorate (220g).
Claims (5)
1. the synthesis technique of imatinib intermediate 4-(4-methylpiperazine-1-yl methyl) benzoate hydrochlorate, it is characterized in that including following steps: nonstoichiometric molar ratio is dissolved in ethanol and water mixed solvent to cyano group benzyl chloride, add methylpiperazine, reacting by heating at a certain temperature, be cooled to room temperature, reclaim most of ethanol, obtain 4-(4-methyl isophthalic acid-piperazinyl) cyanophenyl, add sodium hydroxide, backflow, question response is complete, be cooled to room temperature, dilute hydrochloric acid is slowly dripped to acid under ice bath, add sodium-chlor to saturated, solid is separated out in cooling, filter, dry, obtain 4-(4-methylpiperazine-1-yl methyl) benzoate hydrochlorate.
2. the synthesis technique of imatinib intermediate 4-according to claim 1 (4-methylpiperazine-1-yl methyl) benzoate hydrochlorate, it is characterized in that with molar ratio computing, to cyano group benzyl chloride: methylpiperazine: sodium hydroxide=1:1.2-1.5:6-6.5; With volume basis, ethanol in mixed solvent: water=2:1.
3. the synthesis technique of imatinib intermediate 4-according to claim 1 (4-methylpiperazine-1-yl methyl) benzoate hydrochlorate, is characterized in that the described concentration to cyano group benzyl chloride is 0.1g/mL-0.15g/mL; The concentration of 4-(4-methyl isophthalic acid-piperazinyl) cyanophenyl is 0.05g/mL-0.10g/mL.
4. the synthesis technique of imatinib intermediate 4-according to claim 1 (4-methylpiperazine-1-yl methyl) benzoate hydrochlorate, it is characterized in that: be 70-100 DEG C to cyano group benzyl chloride and methylpiperazine temperature of reaction, the reaction times is 1-2 hour; 4-(4-methyl isophthalic acid-piperazinyl) cyanophenyl and sodium hydroxide temperature of reaction are 70-100 DEG C, and the reaction times is 5-6 hour.
5. the synthesis technique of imatinib intermediate 4-according to claim 1 (4-methylpiperazine-1-yl methyl) benzoate hydrochlorate, is characterized in that: be 1-2 with dilute hydrochloric acid neutralization reaction liquid to pH.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510253597.5A CN104910101A (en) | 2015-05-18 | 2015-05-18 | Synthesis process of imatinib intermediate 4-(4-methylpiperazin-1-ylmethyl) benzoic acid hydrochloride |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510253597.5A CN104910101A (en) | 2015-05-18 | 2015-05-18 | Synthesis process of imatinib intermediate 4-(4-methylpiperazin-1-ylmethyl) benzoic acid hydrochloride |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104910101A true CN104910101A (en) | 2015-09-16 |
Family
ID=54079600
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510253597.5A Pending CN104910101A (en) | 2015-05-18 | 2015-05-18 | Synthesis process of imatinib intermediate 4-(4-methylpiperazin-1-ylmethyl) benzoic acid hydrochloride |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104910101A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112321535A (en) * | 2020-11-10 | 2021-02-05 | 江苏八巨药业有限公司 | Preparation method of immaric acid or hydrochloride thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102775411A (en) * | 2012-08-17 | 2012-11-14 | 浙江大德药业集团有限公司 | Aryl ethynyl benzamide compound used as protein kinase inhibitor |
| WO2013035102A1 (en) * | 2011-09-05 | 2013-03-14 | Natco Pharma Limited | Processes for the preparation of imatinib base and intermediates thereof |
-
2015
- 2015-05-18 CN CN201510253597.5A patent/CN104910101A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2013035102A1 (en) * | 2011-09-05 | 2013-03-14 | Natco Pharma Limited | Processes for the preparation of imatinib base and intermediates thereof |
| CN102775411A (en) * | 2012-08-17 | 2012-11-14 | 浙江大德药业集团有限公司 | Aryl ethynyl benzamide compound used as protein kinase inhibitor |
Non-Patent Citations (3)
| Title |
|---|
| AMALA KOMPELLA ET AL.: "A Facile Total Synthesis for Large-Scale Production of Imatinib Base", 《ORG. PROCESS RES. DEV.》 * |
| HAIYAN LIU ET AL.: "A novel synthesis of imatinib and its intermediates", 《MONATSH. CHEM.》 * |
| 程*** 等.: "4-[(4-甲基哌嗪-1-基)甲基]苯甲酸二盐酸盐的合成研究", 《广州化工》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112321535A (en) * | 2020-11-10 | 2021-02-05 | 江苏八巨药业有限公司 | Preparation method of immaric acid or hydrochloride thereof |
| CN112321535B (en) * | 2020-11-10 | 2022-04-19 | 江苏八巨药业有限公司 | Preparation method of immaric acid or hydrochloride thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI513691B (en) | Method for preparation of benzimidazole derivatives | |
| Kompella et al. | A facile total synthesis for large-scale production of imatinib base | |
| CN113620891B (en) | Method for preparing quinoxaline-2-ketone derivative by controllable catalysis | |
| CN105693603B (en) | The maleic acid datro preparation process of improvement | |
| CN107118215B (en) | A kind of preparation method for treating breast cancer medicines Rui Boxini intermediate | |
| CN105646447A (en) | Synthesis method of dipeptidyl peptidase inhibitor | |
| CN104910101A (en) | Synthesis process of imatinib intermediate 4-(4-methylpiperazin-1-ylmethyl) benzoic acid hydrochloride | |
| CN107522742B (en) | A kind of homogeneous " one kettle way " preparation method of Brigatinib key intermediate | |
| CN102351799B (en) | Bendamustine hydrochloride crystal and preparation method thereof | |
| Urbonas et al. | A Novel Highly Site-Selective Synthesis of 2, 4, 7-Triarylpyrrolo [2, 3-d] pyrimidines by a Combination of Palladium (0)-, Nickel (0)-, and Copper (I)-Catalyzed Cross-Coupling Reactions | |
| US9045456B2 (en) | Method for producing imatinib base | |
| CN102659629A (en) | Compound and application thereof in preparing erlotinib | |
| CN105949196B (en) | A kind of preparation method of MER/FLT3 double inhibitors intermediate | |
| CN105272921A (en) | Method for preparing Ceritinib and intermediate compound of Ceritinib | |
| CN103755636A (en) | Method for synthesizing Lorcaserin raceme derivative | |
| CN108912059B (en) | Synthetic method of nitrogenous heterocyclic inflammation inhibiting compound | |
| CN108658999B (en) | Synthesis method of 2-phenyl heterocyclic [2,3-d ] pyrimidine-4 (3H) -ketone compound | |
| CN102702196B (en) | Method for synthesizing 3-methyl-7-diazaindene | |
| CN108863950B (en) | Diaryl substituted quinazoline compound and synthetic method thereof | |
| EP3015460B1 (en) | Process for the preparation of erlotinib | |
| CN102796074B (en) | Method for preparing imatinib mesylate intermediate | |
| CN112694468B (en) | Preparation method of pezopanib related substance | |
| CN102199146A (en) | Preparation method for N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidinamine | |
| CN108912061B (en) | Synthetic method of quinazoline inflammation inhibition compound | |
| CN108912060B (en) | Quinazoline anti-inflammatory compound and synthesis method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| AD01 | Patent right deemed abandoned | ||
| AD01 | Patent right deemed abandoned |
Effective date of abandoning: 20180112 |