CN104211731B - Method for preparing high-purity voriconazole phosphate - Google Patents
Method for preparing high-purity voriconazole phosphate Download PDFInfo
- Publication number
- CN104211731B CN104211731B CN201410224332.8A CN201410224332A CN104211731B CN 104211731 B CN104211731 B CN 104211731B CN 201410224332 A CN201410224332 A CN 201410224332A CN 104211731 B CN104211731 B CN 104211731B
- Authority
- CN
- China
- Prior art keywords
- voriconazole
- acid
- salt
- phosphite ester
- reaction
- 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.)
- Active
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a method for preparing high-purity voriconazole phosphate. The method comprises the following steps of 1, dissolving voriconazole and organic weak base in an organic solvent, dropwisely adding a phosphorus trichloride solution into the solution and then carrying out stirring at a room temperature for a reaction, 2, cooling the reaction system obtained by the step 1, carrying out a hydrolysis process on the ice-water mixture, and after hydrolysis, removing the organic solution by evaporation to obtain a voriconazole phosphate intermediate, and 3, dissolving the voriconazole phosphate crude product and inorganic weak base in water, dropwisely adding an oxidant aqueous solution into the solution, carrying out stirring in an ice bath for a reaction, carrying out filtration, and adjusting a pH value of the filtrate until a lot of solids are precipitated, wherein the filtered solid is the high-purity voriconazole phosphate. The method is simple and practical, has a high yield, less impurities and short reaction time, is free of a high-pressure hydrogenation reactor and palladium-carbon and is especially suitable for industrial production. The invention also relates to a use of the voriconazole phosphate intermediate as an antifungal drug. An experiment proves that voriconazole phosphate has a strong fungal infection-resistant capability.
Description
Technical field
High-purity voriconazole phosphate ester method is prepared the present invention relates to one kind, and is lied prostrate by the intermediate that the method is obtained
The vertical application of health azoles phosphite ester and voriconazole phosphite ester in as antifungal drug.
Background technology
Voriconazole is that a kind of its indication of the triazole antifungal agent of wide spectrum is as follows：Treatment Aspergillosis.Treatment
To the sexy dye of the microbial bad attack of beads of fluconazole resistant（Including candida krusei）.Treatment by Scedosporium and
The severe infections that Fusarium causes.This product should be primarily used to treat the possibility life-threatening of progressive in immune deficient patients
Infection.Voriconazole phosphate ester is the pro-drug of voriconazole, can be hydrolyzed to voriconazole rapidly in vivo and work.Due to
Voriconazole water solubility is minimum, in order to solubilized injection voriconazole is using the method for hydroxypropylβ-cyclodextrin parcel, but this
Sample increased the incidence of side reaction.Hydroxypropylβ-cyclodextrin is a kind of new auxiliary material for occurring in recent years, due to the auxiliary material pair
Various insoluble drugs have preferable solubilization, thus use of the country to this auxiliary material has quick increased trend, but
Up to the present our securities to it understand not deeply.The document report auxiliary material have certain hemolytic, renal toxicity and
Carcinogenicity, and more serious toxic and side effect is there is likely to be still not known to us, thus its use is more preferably prudent.Foreign countries are only
There is the listing preparation of a few special indication（Such as treat the medicine of severe infection, tumour）Hydroxypropyl beta-ring has been used to paste
Essence, illustrates foreign countries to its security also without enough assurance.In this case, this kind of auxiliary material should be continued deeper into
Research and observation, further expose its toxic and side effect that may be present, and should not be used as a kind of conventional auxiliary material extensive use
In injection.The adverse reaction for being injected intravenously hydroxypropylβ-cyclodextrin mainly concentrates on renal toxicity and hemolytic, mainly
Known impurities beta-schardinger dextrin with the auxiliary material is relevant, and this impurity causes tubular distal vacuole sample lesion first, then in epidermis
It is intracellular huge lysosome and obvious acicular crystals occur, now speculate that the crystalline solid is likely to be that cyclodextrin is consolidated with courage
The compound of alcohol or lipoprotein.And then there is the conspicuousness change of organelle, such as mitochondrial swelling deformation, golgiosome and cunning
There is the irreversible fracture of intercellular tight junction in the cell of face endoplasmic reticulum basal part, and this result directly results in subtracting for renal function
Move back and even lose.Voriconazole phosphate ester is to reduce the effective means that these side reactions occur, and it is vertical that Chinese patent is referred to volt
Health azoles phosphate and preparation method thereof.
High-purity voriconazole phosphate ester method is prepared it is an object of the invention to provide one kind, the method is by as follows
What step was implemented：
（1）Voriconazole and organic weak base are dissolved in dichloromethane, to slowly being dripped in the dichloromethane solution of gained
Plus phosphorus trichloride solution, dropwise addition process makes the temperature of reaction system be kept for less than 10 DEG C, and drop is complete, and reaction is stirred at room temperature；
（2）By step（1）The reaction system cooling for obtaining, is slowly added into mixture of ice and water and is hydrolyzed, and frozen water is added dropwise and mixes
The process system temperature of compound is maintained at less than 10 DEG C, and stirring promotes hydrolysis, stands, and discards water layer, dichloromethane layer warp
Decompression steams solution, obtains residue intermediate（I）Voriconazole phosphite ester crude product；
（3）By the voriconazole phosphite ester（I）Crude product and inorganic weak bases are dissolved in the water, in ice bath and in stirring bar
Under part, the aqueous solution of oxidant is slowly added dropwise, drop finishes, stirring reaction in ice bath, filtering retains filtering；
With sour by step under stirring state（3）In the filtrate pH value adjust to separate out a large amount of solids, after filtering
The solid for obtaining as voriconazole phosphate ester.
The chemical equation of above-mentioned reaction is as follows：
Wherein, step（1）In organic solution be dichloromethane, the time that reactions steps are stirred at room temperature be 1 hour；
Step（2）Described in hydrolysis time be 30 minutes；Step（3）The time of stirring reaction is 2 hours in middle ice bath, by pH
Adjust to 1~2.
Further, the organic weak base is the one of which in following alkali cpd or several combinations：1- methyl miaows
Azoles, 1H-TETRAZOLE, pyridine, 4-dimethylaminopyridine, triethylamine, ethylenediamine.
Further, the inorganic base includes the one of which of following salt compound or several combinations：Carbonate, carbonic acid
Hydrogen salt, acetate.
Further, the oxidant is the combination of one or several in following compound：Permanganic acid or its salt, chlorine high
Acid or its salt, ferric acid or its salt, sulfuric acid high or its salt.
Further, step（4）In it is described acid for it is following acid in the combination of one or several：Hydrochloric acid, acetic acid, sulphur
Acid, nitric acid, phosphoric acid.
The invention further relates to prepare the new midbody compound of voriconazole phosphate ester（I）Also the water of this compound is included
Compound or its esters compound, such as trihydrate, two alkali metal salts, bis-amino acid salt etc..In the voriconazole phosphate ester
Intermediate compounds therefor（I）Chemical structural formula it is as follows：
In addition, the invention further relates to midbody compound（I）Voriconazole phosphite ester answering in as antifungal
With, wherein the voriconazole phosphite ester is voriconazole in human body metabolism, so as to play drug action.
Preparation method of the invention has following advantage compared with the prior art：
Prior art step when voriconazole phosphate ester is prepared is complicated, and the reaction time is more long, and uses High Pressure Hydrogen
Change reactor, this safety coefficient reduction after industrial production.Using to precious metal palladium charcoal the step of hydrogenation, increased and be produced into
This；And the simple and practical high income of voriconazole phosphate ester preparation method that my company is invented, impurity is few, and the reaction time is short, does not have
High-pressure hydrogenation kettle and palladium charcoal are used, industrialized production is especially suitable for.
Specific embodiment
The present invention is described in further detail with reference to embodiment, it should be understood that the scope of the present invention is non-to be only limitted to this
The scope of a little embodiments.
Embodiment 1：The preparation of voriconazole phosphate ester
The g of voriconazole phosphite ester 10 and the g of sodium carbonate 2 are dissolved in 20 ml water, ice bath stirring is put into, slowly dripped
Plus potassium permanganate solution（The ml of 2.5 g to 50）, drip and finish, reaction 2 hours, filtering, with the pH of hydrochloric acid conditioning solution is stirred at room temperature
To 2 or so, stirring has a large amount of solids to separate out, and filters the solid for separating out and obtains the g of voriconazole phosphate ester 8.8.
Embodiment 2：The preparation of voriconazole phosphate ester
Voriconazole phosphite ester 2kg and sodium carbonate 495g are dissolved in 4000ml water, ice bath stirring is put into, slowly added
Enter potassium permanganate 736g, finish, continue stirring reaction 1 hour, filtering, filtrate, to 2 or so, there is big with the pH of second acid-conditioning solution
Amount solid is separated out, and is filtered the solid for separating out and is obtained voriconazole phosphate ester 1.6kg.
Embodiment 3：The preparation of voriconazole phosphite ester
The g of voriconazole 10 and 9.4 g 1- methylimidazoles are dissolved in 50 ml dichloromethane, are slowly added dropwise at room temperature
The g of phosphorus trichloride solution 5, drop finishes, and reaction 1 hour is stirred at room temperature, and is cooled to 0 DEG C, is slowly added into 20 ml mixture of ice and water, stirs
Hydrolysis 30 minutes, removes water layer, and dichloromethane layer decompression steams solvent, and residue is voriconazole phosphite ester, is obtained
The g of voriconazole phosphite ester 12.
Embodiment 4：The preparation of voriconazole phosphite ester
Voriconazole 1kg and 900 g 1- methylimidazoles are dissolved in 5000ml dichloromethane, are slowly added dropwise at room temperature
Phosphorus trichloride solution 489g, drop finishes, and reaction 1 hour is stirred at room temperature, and is cooled to -5 DEG C, is slowly added into 1600 ml mixture of ice and water,
Stirring hydrolysis 30 minutes, removes water layer, and dichloromethane layer decompression steams solvent, and residue is voriconazole phosphite ester,
Obtain voriconazole phosphite ester 1.1kg.
Embodiment 5：The preparation of voriconazole phosphate ester trihydrate
By the g of voriconazole phosphate ester 10 with 8 times the 50% of amount of ethanol water, stirred 15 minutes under the conditions of 50 DEG C,
Filtering, filtrate room temperature crystallization 24 hours filters to obtain voriconazole phosphate ester trihydrate.
Embodiment 6：The preparation of voriconazole phosphite ester trihydrate
By the g of voriconazole phosphate ester 10 with 8 times the 50% of amount of ethanol water, stirred 15 minutes under the conditions of 50 DEG C,
Filtering, filtrate room temperature crystallization 24 hours filters to obtain voriconazole phosphite ester trihydrate.
Embodiment 7：The preparation of voriconazole phosphate ester disodium salt
The g of voriconazole phosphate ester 10 and 2 g sodium carbonate are dissolved in 20 ml methyl alcohol, 60 DEG C are heated 15 minutes, Ran Houzai
Add 100 ml acetone, cooling stirring has solid to separate out after being down to room temperature, then in 0 DEG C of stirring and crystallizing 4 hours, filtering, get Fu Li
Health azoles organic phosphate disodium salt.
Embodiment 8：The preparation of voriconazole phosphite ester disodium salt
The g of voriconazole phosphite ester 10 and 2 g sodium carbonate are dissolved in 20 ml methyl alcohol, 60 DEG C heat 15 minutes, then
Add 100 ml acetone, cooling stirring has solid to separate out after being down to room temperature, then in 0 DEG C of stirring and crystallizing 4 hours, filtering must be lied prostrate
Vertical health azoles phosphite ester disodium salt.
Embodiment 9：The preparation of voriconazole phosphate ester double arginine salt
The g of voriconazole phosphate ester 10 and 5 g arginine are dissolved in 30 ml methyl alcohol, 60 DEG C are heated 15 minutes, Ran Houzai
Add 100 ml acetone, cooling stirring has solid to separate out after being down to room temperature, then in 0 DEG C of stirring and crystallizing 4 hours, filtering, get Fu Li
Health azoles phosphate double arginine salt.
Embodiment 10：The preparation of voriconazole phosphite ester double arginine salt
The g of voriconazole phosphite ester 10 and 5 g arginine are dissolved in 30 ml methyl alcohol, 60 DEG C heat 15 minutes, then
Add 100 ml acetone, cooling stirring has solid to separate out after being down to room temperature, then in 0 DEG C of stirring and crystallizing 4 hours, filtering must be lied prostrate
Vertical health azoles phosphite ester double arginine salt.
Embodiment 11：Pharmacology pharmacodynamic is tested
1st, the diffusivity aspergillosis and candidiasis in guinea pig
All used without specific pathogen in all experiments（SPF）Guinea pig（Body weight is 400~500 g）.Conduit is put
Enter in the left neck vein of the animal for having venous perfusion treatment to be subjected, vein combined, and connect the conductive pipe to micro control to fill
On note pump.By animal via the lateral vein of penis or via the conduit being implanted into, with aspergillus fumigatus（4,000 CFU/g body weight）Or with
Candida albicans（4,000 CFU/g body weight）Infection.In after infection 1 hour, intravenous therapy is carried out（5 mg/kg/ days）.
To every group of experimental animal（Every group of experimental animal number is shown in " N " column）, it is recorded in the mean survival time in each number of days
（MST）, and percentage survival（%surv）.To each group during experiment the animal of death and in experiment survival but later
The animal being killed, research counts its deep tissues（Liver,spleen,kidney, lung are in brain）In, aspergillus fumigatus and candida albicans quantity.Survey
The CFU/g of the remnants in culture positive hepatic is measured, and is shown in table 1（After intravenous treatment）, with average log10 CFU/g tables
Show." %neg " in table 1 is shown in the deep tissues percentage in culture-feminine gender after processing.Therefore, more effective experiment
There is value high in " MST ", " %surv " and " %neg " each column of compound, and there is low value in " CFU/g " column.
Table 1
By data, voriconazole phosphate ester and voriconazole phosphite ester have the energy of stronger anti-fungal infection
Power.
Claims (5)
1. voriconazole phosphite ester, it is characterised in that molecular structural formula is as shown in I
2. voriconazole phosphite ester according to claim 1, it is characterised in that preparation method is comprised the following steps：
Step 1：Voriconazole and organic weak base are dissolved in dichloromethane, to being slowly added dropwise in the dichloromethane solution of gained
Phosphorus trichloride solution, dropwise addition process makes the temperature of reaction system be kept for less than 10 DEG C, and drop finishes, and reaction is stirred at room temperature；
Step 2：The reaction system cooling that step (1) is obtained, is slowly added into mixture of ice and water and is hydrolyzed, and frozen water mixing is added dropwise
The process system temperature of thing is maintained at less than 10 DEG C, and stirring promotes hydrolysis, stands, and discards water layer, and dichloromethane layer is through subtracting
Pressure steams dichloromethane, obtains residue voriconazole phosphite ester crude product；
Wherein, the reaction time is stirred at room temperature described in step (1) for 1 hour；The time of hydrolysis described in step (2) is 30
Minute；
The organic weak base is one of which or several combinations in following alkali cpd：1- methylimidazoles, 1H-TETRAZOLE, pyrrole
Pyridine, 4-dimethylaminopyridine, triethylamine, ethylenediamine.
3. voriconazole phosphite ester according to claim 1, it is characterised in that its existence form includes that voriconazole is sub-
Phosphoric acid ester waterless compound, voriconazole phosphite ester trihydrate, the alkali metal salt of voriconazole phosphite ester two, voriconazole are sub-
Phosphate bis-amino acid salt.
4. a kind of method for preparing high-purity voriconazole phosphate ester, the preparation method is comprised the following steps：
Step 1：Voriconazole phosphite ester crude product and inorganic weak bases are dissolved in the water, in ice bath and under agitation, are delayed
The slow aqueous solution that oxidant is added dropwise, drop finishes, stirring reaction in ice bath, and filtering retains filtrate；
Step 2：The pH value of the filtrate in step (1) is adjusted to a large amount of solids for separating out, filtering with acid under stirring state
The solid for obtaining afterwards as voriconazole phosphate ester；
The time of stirring reaction is 2 hours in step (1) ice bath, and step (2) adjusts to 1~2 pH value；
The inorganic weak bases include the one of which of following salt compound or several combinations：Carbonate, bicarbonate, acetic acid
Salt；The oxidant is permanganic acid or its salt, perchloric acid or its salt, ferric acid or its salt, sulfuric acid high or its salt, in step (2)
It is described acid for it is following acid in the combination of one or several：Hydrochloric acid, acetic acid, sulfuric acid, nitric acid, phosphoric acid.
5. application of the voriconazole phosphite ester described in claim 1 in anti-fungal infection medicine is prepared.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410224332.8A CN104211731B (en) | 2013-06-01 | 2014-05-24 | Method for preparing high-purity voriconazole phosphate |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013102127731 | 2013-06-01 | ||
| CN201310212773.1 | 2013-06-01 | ||
| CN201310212773 | 2013-06-01 | ||
| CN201410224332.8A CN104211731B (en) | 2013-06-01 | 2014-05-24 | Method for preparing high-purity voriconazole phosphate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104211731A CN104211731A (en) | 2014-12-17 |
| CN104211731B true CN104211731B (en) | 2017-05-17 |
Family
ID=52093670
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410224332.8A Active CN104211731B (en) | 2013-06-01 | 2014-05-24 | Method for preparing high-purity voriconazole phosphate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104211731B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107652325A (en) * | 2016-07-25 | 2018-02-02 | 天地人和生物科技有限公司 | Unformed crystal formation of voriconazole phosphate ester disodium and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101389333A (en) * | 2006-02-22 | 2009-03-18 | 卫材R&D管理有限公司 | Stabilized pharmaceutical composition |
| CN101744778A (en) * | 2010-02-01 | 2010-06-23 | 陕西合成药业有限公司 | Voriconazole phosphate ester for injection and preparation method thereof |
| CN101824002A (en) * | 2010-05-13 | 2010-09-08 | 南京华威医药科技开发有限公司 | Water soluble triazole compound and synthesis method thereof |
| CN102439018A (en) * | 2009-03-19 | 2012-05-02 | 塞普斯制药有限公司 | Fosfluconazole derivatives, synthesis, and use in long acting formulations |
| CN103304600A (en) * | 2013-03-04 | 2013-09-18 | 陕西合成药业有限公司 | Voriconazole phosphate trihydrate and preparation method and application thereof |
-
2014
- 2014-05-24 CN CN201410224332.8A patent/CN104211731B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101389333A (en) * | 2006-02-22 | 2009-03-18 | 卫材R&D管理有限公司 | Stabilized pharmaceutical composition |
| CN101890028A (en) * | 2006-02-22 | 2010-11-24 | 卫材R&D管理有限公司 | Stabilized pharmaceutical composition |
| CN102439018A (en) * | 2009-03-19 | 2012-05-02 | 塞普斯制药有限公司 | Fosfluconazole derivatives, synthesis, and use in long acting formulations |
| CN101744778A (en) * | 2010-02-01 | 2010-06-23 | 陕西合成药业有限公司 | Voriconazole phosphate ester for injection and preparation method thereof |
| CN101824002A (en) * | 2010-05-13 | 2010-09-08 | 南京华威医药科技开发有限公司 | Water soluble triazole compound and synthesis method thereof |
| CN103304600A (en) * | 2013-03-04 | 2013-09-18 | 陕西合成药业有限公司 | Voriconazole phosphate trihydrate and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104211731A (en) | 2014-12-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102249975B (en) | (S)-4-hydroxy-2-oxo-1-pyrrolidineacetamide crystal form I and preparation method and application thereof | |
| CN102558393B (en) | Preparation process of dalteparin sodium | |
| EP3023410B1 (en) | 5-BROMINE-2-(alpha-HYDROXYPENTYL)BENZOIC ACID SODIUM SALTS IN DIFFERENT CRYSTAL FORMS, AND PREPARATION METHOD THEREOF | |
| US9650400B2 (en) | Voriconazole sodium phosphate hydrates and polymorphs thereof | |
| CA3076282A1 (en) | Tricyclic oxepane derivative from limax, methods of isolation, and uses thereof | |
| CN104211731B (en) | Method for preparing high-purity voriconazole phosphate | |
| CN101744778B (en) | Voriconazole phosphate ester for injection and preparation method thereof | |
| EP3380193A1 (en) | Method for obtaining saponins from plants | |
| CN102367254A (en) | More stable doxofylline compound and pharmaceutical composite thereof | |
| CN102627689B (en) | Hydrate of cyclopeptide compound as well as preparation method and application thereof | |
| CN104860992A (en) | Preparation method of high-purity fosfluconazole | |
| CN105218629A (en) | Isoquinoline 99.9-3-formyl-RC-OBzl, its preparation, nanostructure, active and application | |
| US9139551B2 (en) | Preparation of a new class of water-soluble ammonium 2,3-dihydroxy-5-((2R,3R)-3,5,7-trihydroxy-4-oxochroman-2-yl) phenolates and their biological activity of alcohol elimination | |
| CN102432467A (en) | Salvianolic acid A magnesium salt, preparation method and use of the salvianolic acid A magnesium salt, and salvianolic acid A magnesium salt-containing freeze-dried powder injection composition | |
| CN101732287A (en) | Injection of mannite and glycerol and preparation method thereof | |
| CN101347412B (en) | Amifostine trihydrate crystal lyophilized preparation and method of preparing the same | |
| CN103804207A (en) | Sinapine chloride preparation method and medicine application thereof | |
| CN103613681B (en) | Tea polysaccharide derivative and preparation method thereof | |
| CN101440116B (en) | Glycyrrhizin, preparation and use thereof | |
| CN103012542A (en) | Method for extracting high-purity ursolic acid from paulownia leaves | |
| CN103304600B (en) | A kind of voriconazole phosphate ester trihydrate and its preparation method and application | |
| WO2013119059A1 (en) | Injectable composition containing phosphatidylcholine devoid of sodium deoxycholate and preparing method thereof | |
| CN106883282B (en) | Rotundic acid derivative is preparing the application in anti-tumor drug | |
| CN105153238B (en) | A kind of preparation method of Miboplatin | |
| CN112778369B (en) | Triazole derivative and preparation method and application 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 | ||
| C53 | Correction of patent for invention or patent application | ||
| CB02 | Change of applicant information |
Address after: 710075 Shaanxi city of Xi'an province high tech Zone Three New Road No. 2 building 30803 commercial sea cloud chamber Applicant after: Shaanxi Hecheng Pharmaceutical Co., Ltd. Address before: 710075 Shaanxi city of Xi'an province high three road No. 2 Haijia Genting C building room 803 Applicant before: Shaanxi Synthetic Pharmaceutical Co, Ltd. |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: APPLICANT; FROM: SHAANXI SYNTHETIC PHARMACEUTICAL CO., LTD. TO: SHAANXI HECHENG PHARMACEUTICAL CO., LTD. |
|
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CP01 | Change in the name or title of a patent holder |
Address after: No.30803, Haijia Road, hi tech District, Shaanxi Province Patentee after: Huachuang Synthetic Pharmaceutical Co.,Ltd. Address before: No.30803, Haijia Road, hi tech District, Shaanxi Province Patentee before: SHAANXI SYNTHETIC PHARMACEUTICAL Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder |