CN103113443B - Novel chemical synthesis method for preparing mecobalamine - Google Patents
Novel chemical synthesis method for preparing mecobalamine Download PDFInfo
- Publication number
- CN103113443B CN103113443B CN201310038988.6A CN201310038988A CN103113443B CN 103113443 B CN103113443 B CN 103113443B CN 201310038988 A CN201310038988 A CN 201310038988A CN 103113443 B CN103113443 B CN 103113443B
- Authority
- CN
- China
- Prior art keywords
- mecobalamin
- solution
- acetone
- vitral
- bottle
- 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
Abstract
The invention discloses a novel chemical synthesis method for preparing mecobalamine. The novel chemical synthesis method comprises the steps of: dissolving cyanocobalamin and cobalt chloride hexahydrate in deionized water to obtain reaction liquid, simultaneously dropwise adding a sodium borohydride aqueous solution and a methanol/formaldehyde solution to the reaction liquid, and generating mecobalamine in one step through reductive methylation. According to the novel chemical synthesis method, the cyanocobalamin is taken as a raw material, and the mecobalamine is synthesized in one step; and therefore, the novel chemical synthesis method is simple in operation and has low requirements on equipment, little pollution and wide application prospect, and conditions are easy to control.
Description
Technical field
The present invention relates to a kind of chemical synthesis process of synthesis mecobalamin of novelty.
Background technology
Mecobalamin (Methylcobalamin), chemical name: cobalt-α-[α-5,6-dimethylbenzimidazole base]-cobalt-Beta-methyl cobamide, molecular formula: C63H91CoN13O14P, molecular weight: 1344.38 is a kind of deep red crystalline or crystalline powder, odorless, tasteless, water absorbability is strong, sees that light easily decomposes.Mecobalamin is a kind of coenzyme type vitamins B of Japanese Eisai Co., Ltd exploitation
12, be medically mainly used in treatment peripheral nerve disease and the B that is deficient in vitamin
12the megaloblastic anemia caused, with other coenzyme type vitamins Bs
12class medicine is compared, and mecobalamin has good conductivity to nervous tissue, can enter in neurocyte smoothly, promote nucleic acid, protein, lipid metabolism, by stimulating the regeneration of aixs cylinder and sheath, repairing impaired nerve, is that one treats the more effective medicine of peripheral nerve disease.
Up to the present, the chemical synthesis process of mecobalamin mainly contains several below:
(1) to methylate the method (Japanese Patent 45038059) preparing mecobalamin with methyl iodide again with after sodium borohydride reduction Vitral;
(2) to methylate the method (German Patent 2058892) preparing mecobalamin with methyl tosylate again with after sodium borohydride reduction Vitral;
(3) with methylpyridinium iodide mercury or methyl hexafluorosilicic acid amine, hydroxocobalamin is methylated the method (German Patent 2149150) preparing mecobalamin;
(4) under cobalt salt exists, with zinc powder and oxalic acid methyl monoester, the method (German Patent 2255203) methylating and prepare mecobalamin reduced to hydroxocobalamin;
(5) under cobalt salt exists, with zinc powder and methyl oxalate, the method (German Patent 2434967) methylating and prepare mecobalamin reduced to Vitral;
(6) under cobalt or molysite exist, carry out with Trimethylsulfoxonium Iodide or trimethylammonium thionyl bromide the method (European patent 1236737) preparing mecobalamin that methylates again with sodium borohydride reduction Vitral or hydroxocobalamin;
(7) carry out with methylcarbonate the method (European patent WO2006100059) preparing mecobalamin that methylates again with sodium borohydride reduction Vitral;
Some defects of existence all in various degree of several synthetic methods above, method 1, 2 have all used and have had more supervirulent methylating reagent (methyl iodide, p-methyl benzenesulfonic acid methyl esters), method 3, 4, what 5 methylating reagents used had can not buy (oxalic acid methyl monoester on a large scale by business, dimethyl oxalate, methyl hexafluorosilicic acid amine), some environmental pollutions relatively more serious (methylpyridinium iodide mercury), react 6 methylating reagents used and can generate the dimethyl sulfide with environmental pollution in the reaction, the methyl-sulphoxide simultaneously generated is due to high boiling point (189 DEG C), with reasons such as the good consistencies of water, extremely difficulty is removed from reaction system, and easily by product is generated in methylation procedure.There is the shortcomings such as low temperature crystallization yield losses is larger in method 7.
Summary of the invention
The object of the invention is to overcome existing for existing mecobalamin synthetic method shortcoming and defect, thus provide a kind of synthetic method of new mecobalamin.
The synthetic method of mecobalamin of the present invention, comprises the following steps:
A), by Vitral, cobalt chloride hexahydrate is dissolved in deionized water, stirs, and keep reaction solution, temperature is 10-15 DEG C;
B), by sodium borohydride be dissolved in deionized water, keep temperature to be about 0 DEG C;
C), formalin is dissolved in methanol solution;
D), the methanol solution of sodium borohydride aqueous solution, formalin is instilled in the aqueous solution of Vitral, cobalt chloride, stirring reaction simultaneously, keep reacting liquid temperature to be 10-15 DEG C simultaneously;
E), after above step reaction, the PH of regulator solution is 6.0;
F), upper step gained reaction solution obtains filtrate through centrifuging;
G), vacuum concentration walks gained filtrate and obtain concentrated solution;
H), upper step gained concentrated solution obtains crude product mecobalamin through macroporous resin adsorption, washing, acetone-water mixing solutions wash-out, neutral alumina absorption, acetone-water mixing solutions wash-out, crystallization;
I), upper step gained crude product mecobalamin recrystallization obtains fine work mecobalamin.
The present invention is in the initial stage of specific implementation process, keep the temperature of initial action liquid all the time in 10-15 DEG C of interval, because the rising of temperature of reaction system makes formaldehyde and sodium borohydride other reactions occur thus produce to consume when avoiding the methanol solution one kettle way dripping sodium borohydride aqueous solution and formalin at the same time to prepare mecobalamin.
In specific implementation process of the present invention, when dissolving sodium borohydride, the moderate temperature of solvent be kept to remain on about 0 DEG C, avoid in dissolution process because heat release promotes hydroboration sodium and water reaction consumption of boron sodium hydride.
In specific implementation process of the present invention, drip in reaction solution sodium borohydride aqueous solution, formalin methanol solution time, keep drip solution flow rate unanimous on the whole.
The invention provides a kind of method of synthesis mecobalamin newly, carry out reduction by utilizing sodium borohydride and formaldehyde to Vitral to methylate, obtain high yield, highly purified mecobalamin, simultaneously prepare in the process of mecobalamin methylating with the inventive method reduction, avoid the generation of some by products, avoid the application of toxic substance in synthesis, avoid the generation causing environmental pollution gas in building-up process.In reduction methylation procedure, the consumption of formaldehyde can carry out suitable increase or minimizing according to the practical situation of reaction, but best ratio is recommended as: the envelope-bulk to weight ratio of formaldehyde (37-40%) aqueous solution and Vitral is 2.0-3.4:1, the consumption of corresponding borane reducing agent sodium hydride also can carry out pro rata increase or minimizing according to the actual amount of formaldehyde.
specific implementation method
Below in conjunction with concrete case study on implementation, the present invention will be further described:
Embodiment 1
1), reduction methylates
In 500ml glass reaction bottle, add 20g Vitral by proportioning, 1.4g cobalt chloride hexahydrate, 250ml purified water, stir and be cooled to 10-15 DEG C of dissolving, keep 10-15 DEG C of stirring, start to drip to dissolve NaBH simultaneously
4purification of aqueous solutions (6g/60ml), the methanol solution (40.5ml formalin/25.5ml methyl alcohol) of formaldehyde (37-40% w/w) aqueous solution, about 45min drips off, and continues reaction 2 hours, after reaction terminates, adjust reaction solution PH to 6.0 with 36% acetic acid, stir 15 minutes repetition measurements and remain unchanged to PH, then control vacuum tightness-0.08 MPa, temperature less than 40 DEG C underpressure distillation, to when steaming without cut, cooling, reaction solution is for subsequent use.
2), wash-out
By reaction solution macroporous resin column absorption (macroporous resin model: Amberlite XAD-2), first remove inorganic salt with purified water repetitive scrubbing.Add 20% acetone wash-out subsequently, the elutriant containing mecobalamin is merged.
An elutriant, with neutral alumina column absorption (post dress 20-300 order), is first used 10% acetone wash-out, then is used 50% acetone wash-out, merged by the elutriant containing mecobalamin.
3), crude product
By in secondary elutriant suction crystallization bottle, in bottle, add acetone, in 20-25 DEG C of crystallization 2 hours under stirring, stop stirring in 20 DEG C of insulations 2 hours, rejection filter, filter cake pulverizes rear drying and obtains crude product 21.1g.
4), refining
Acetone and purified water are added in refining bottle, opens stirring heating and make acetone water mixed liquid be warming up to 40 DEG C, in refining bottle, add crude product, continue to heat up, reflux 5 minutes; Stop heating, after backflow stops, adding activated carbon, continue to heat up, reflux 0.5 hour, press filtration while hot, filtrate is depressed in crystallization bottle, after filtrate is cooled to 20-25 DEG C, in crystallization bottle, adds acetone, continue cooling, when being cooled to 0-5 DEG C, stop stirring, 0-5 DEG C of static insulation 10 hours, whizzer rejection filter, filter cake is to baking oven in vacuum tightness-0.08 MPa, 40-50 DEG C of drying, obtains vancomin fine work 17.27g (productive rate 86.3%, purity 99.79%).
Embodiment 2
1), reduction methylates
In 500ml glass reaction bottle, add 20g Vitral by proportioning, 1.4g cobalt chloride hexahydrate, 250ml purified water, stir and be cooled to 10-15 DEG C of dissolving, keep 10-15 DEG C of stirring, start to drip to dissolve NaBH simultaneously
4purification of aqueous solutions (8g/80ml), the methanol solution (54ml formalin/34ml methyl alcohol) of formalin (37-40% w/w), drips off for about 1 hour, continues reaction 2 hours, after reaction terminates, adjust reaction solution PH to 6 with 36% acetic acid, stir 15 minutes repetition measurements and remain unchanged to PH, then control vacuum tightness-0.08 MPa, temperature less than 40 DEG C underpressure distillation, to when steaming without cut, cooling, reaction solution is for subsequent use.
2), wash-out
By reaction solution macroporous resin column absorption (macroporous resin model: Amberlite XAD-2), first remove inorganic salt with purified water repetitive scrubbing.Add 20% acetone wash-out subsequently, the elutriant containing mecobalamin is merged.
An elutriant, with neutral alumina column absorption (post dress 20-300 order), is first used 10% acetone wash-out, then is used 50% acetone wash-out, merged by the elutriant containing mecobalamin.
3), crude product
By in secondary elutriant suction crystallization bottle, in bottle, add acetone, in 20-25 DEG C of crystallization 2 hours under stirring, stop stirring in 20 DEG C of insulations 2 hours, rejection filter, filter cake pulverizes rear drying and obtains crude product 23.1 g.
4), refining
Acetone and purified water are added in refining bottle, opens stirring heating and make acetone water mixed liquid be warming up to 40 DEG C, in refining bottle, add crude product, continue to heat up, reflux 5 minutes; Stop heating, after backflow stops, adding activated carbon, continue to heat up, reflux 0.5 hour, press filtration while hot, filtrate is depressed in crystallization bottle, after filtrate is cooled to 20-25 DEG C, in crystallization bottle, adds acetone, continue cooling, when being cooled to 0-5 DEG C, stop stirring, 0-5 DEG C of static insulation 10 hours, whizzer rejection filter, filter cake is to baking oven in vacuum tightness-0.08 MPa, 40-50 DEG C of drying, obtains vancomin fine work 18g (productive rate 90.07%, purity 99.83%).
Embodiment 3
1), reduction methylates
In 500ml glass reaction bottle, add 20g Vitral by proportioning, 1.4g cobalt chloride hexahydrate, 250ml purified water, stir and be cooled to 10-15 DEG C of dissolving, keep 10-15 DEG C of stirring, start to drip to dissolve NaBH simultaneously
4purification of aqueous solutions (10g/100ml), the methanol solution (67.5ml formalin/42.5ml methyl alcohol) of formalin (37-40% w/w), drips off for about 1.5 hours, continues reaction 2 hours, after reaction terminates, adjust reaction solution PH to 6 with 36% acetic acid, stir 15 minutes repetition measurements and remain unchanged to PH, then control vacuum tightness-0.08 MPa, temperature less than 40 DEG C underpressure distillation, to when steaming without cut, cooling, reaction solution is for subsequent use.
2), wash-out
By reaction solution macroporous resin column absorption (macroporous resin model: Amberlite XAD-2), first remove inorganic salt with purified water repetitive scrubbing.Add 20% acetone wash-out subsequently, the elutriant containing mecobalamin is merged.
An elutriant, with neutral alumina column absorption (post dress 20-300 order), is first used 10% acetone wash-out, then is used 50% acetone wash-out, merged by the elutriant containing mecobalamin.
3), crude product
By in secondary elutriant suction crystallization bottle, in bottle, add acetone, in 20-25 DEG C of crystallization 2 hours under stirring, stop stirring in 20 DEG C of insulations 2 hours, rejection filter, filter cake pulverizes rear drying and obtains crude product 23.05g.
4), refining
Acetone and purified water are added in refining bottle, opens stirring heating and make acetone water mixed liquid be warming up to 40 DEG C, in refining bottle, add crude product, continue to heat up, reflux 5 minutes; Stop heating, after backflow stops, adding activated carbon, continue to heat up, reflux 0.5 hour, press filtration while hot, filtrate is depressed in crystallization bottle, after filtrate is cooled to 20-25 DEG C, in crystallization bottle, adds acetone, continue cooling, when being cooled to 0-5 DEG C, stop stirring, 0-5 DEG C of static insulation 10 hours, whizzer rejection filter, filter cake is to baking oven in vacuum tightness-0.08 MPa, 40-50 DEG C of drying, obtains vancomin fine work 17.88g (productive rate 90.1%, purity 99.81%).
Although by describing the present invention to the discussion of embodiment of the present invention and nonlimiting examples, but according to this explanation and claims, those skilled in the art can expect other embodiments and work-around solution, they are also contained in desired extent of the present invention, so scope of the present invention should be explained by claim and be defined.
Attached: mecobalamin analytical data:
Attached 1:
1hNMR composes
1, INSTRUMENT MODEL: Switzerland INOVA-300
2, test condition: mark TMS in solvent DMSO
3, test data
Claims (8)
1. prepare a method for mecobalamin, its step comprises:
A), by Vitral, cobalt chloride hexahydrate is dissolved in deionized water, and stir, maintenance reacting liquid temperature is 10-15 DEG C;
B), by sodium borohydride be dissolved in deionized water, keep temperature to be about 0 DEG C;
C), formalin is dissolved in methyl alcohol;
D), the methanol solution of sodium borohydride aqueous solution, formalin is instilled in the aqueous solution of Vitral, cobalt chloride, stirring reaction simultaneously, keep reacting liquid temperature to be 10-15 DEG C simultaneously;
E), after above step reaction, the pH of regulator solution is 6.0;
F), upper step gained reaction solution obtains filtrate through centrifuging;
G), vacuum concentration walks gained filtrate and obtain concentrated solution;
H), upper step gained concentrated solution obtains crude product mecobalamin through macroporous resin adsorption, washing, acetone-water mixing solutions wash-out, neutral alumina absorption, acetone-water mixing solutions wash-out, crystallization;
I), upper step gained crude product mecobalamin recrystallization obtains fine work mecobalamin.
2. the preparation method of mecobalamin according to claim 1, it is characterized in that: described step a) in, the concentration of Vitral in reaction solution is 0.08g/ml, and the weight ratio of cobalt chloride hexahydrate used and Vitral is 0.07:1, and reaction solution keeps temperature to be 10-15 DEG C.
3. the preparation method of mecobalamin according to claim 1, is characterized in that: described step b) in, keep solution temperature to be about 0 DEG C when being dissolved in water by sodium borohydride; The concentration of sodium borohydride aqueous solution is 0.2g/ml, and the weight ratio of sodium borohydride and Vitral is 0.3-0.5:1.
4. the preparation method of mecobalamin according to claim 1, is characterized in that: described step c) in, by 37-40%(w/w) formalin keeps temperature to be about 0 DEG C when being dissolved in methyl alcohol; 37-40%(w/w) volume ratio of formalin and methyl alcohol is 1.6:1,37-40%(w/w) volume of formalin and the weight ratio of Vitral be 2.0-3.4:1.
5. the preparation method of mecobalamin according to claim 1, is characterized in that: described step e) in, after completion of the reaction, regulate reaction solution pH to be 6.0; The reagent regulating reacting liquid pH value used is 36% aqueous acetic acid.
6. the preparation method of mecobalamin according to claim 1, is characterized in that: described step h) in, big pore resin model is Amberlite XAD-2, and after macroporous resin adsorption, elutriant used is 20% aqueous acetone solution; After the absorption of post dress 200-300 order neutral alumina, elutriant used is respectively 10% aqueous acetone solution, 50% aqueous acetone solution.
7. the preparation method of mecobalamin according to claim 1, it is characterized in that: described step h) in, about the crystallisation process concrete grammar of crude product mecobalamin is: by secondary elutriant suction crystallization bottle, acetone is added in bottle, in 20-25 DEG C of crystallization 2 hours under stirring, stop stirring in 20 DEG C of insulations 2 hours, rejection filter, filter cake pulverizes rear collection and obtains crude product.
8. the preparation method of mecobalamin according to claim 1, it is characterized in that: described step I) in, about the crystallisation process concrete operations of fine work mecobalamin are: acetone and purified water are added in refining bottle, opening stirring heating makes acetone water mixed liquid be warming up to 40 DEG C, crude product is added in refining bottle, continue to heat up, reflux 5 minutes; Stop heating, after backflow stops, adding activated carbon, continue to heat up, reflux 0.5 hour, press filtration while hot, filtrate is depressed in crystallization bottle, after filtrate is cooled to 20-25 DEG C, in crystallization bottle, adds acetone, continue cooling, when being cooled to 0-5 DEG C, stop stirring, 0-5 DEG C of static insulation 10 hours, whizzer rejection filter, filter cake is to baking oven in vacuum tightness-0.08 MPa, 40-50 DEG C of drying, obtains vancomin fine work.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310038988.6A CN103113443B (en) | 2013-02-01 | 2013-02-01 | Novel chemical synthesis method for preparing mecobalamine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310038988.6A CN103113443B (en) | 2013-02-01 | 2013-02-01 | Novel chemical synthesis method for preparing mecobalamine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103113443A CN103113443A (en) | 2013-05-22 |
| CN103113443B true CN103113443B (en) | 2015-02-11 |
Family
ID=48411865
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310038988.6A Active CN103113443B (en) | 2013-02-01 | 2013-02-01 | Novel chemical synthesis method for preparing mecobalamine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103113443B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106349313B (en) * | 2016-08-23 | 2019-05-14 | 宁夏泰瑞制药股份有限公司 | A method of Mecobalamin crude product is synthesized using cyanocobalamin |
| CN107805267B (en) * | 2016-09-08 | 2023-03-28 | 重庆莱美隆宇药业有限公司 | Purification method of mecobalamin and derivatives thereof |
| CN107698642B (en) * | 2017-10-09 | 2020-11-13 | 广州普星药业有限公司 | Method for preparing mecobalamin |
| CN108546278A (en) * | 2018-03-17 | 2018-09-18 | 山东辰龙药业有限公司 | The process for purification of Mecobalamin |
| CN108329373A (en) * | 2018-04-24 | 2018-07-27 | 江苏四环生物制药有限公司 | A kind of synthetic method of Mecobalamin |
| CN108948116A (en) * | 2018-08-30 | 2018-12-07 | 上海应用技术大学 | A kind of green synthesis process of Mecobalamin |
| CN114539331B (en) * | 2020-11-25 | 2024-04-12 | 哈尔滨三联药业股份有限公司 | Method for synthesizing, refining and purifying mecobalamin |
| CN114874276A (en) * | 2022-04-21 | 2022-08-09 | 南京工业大学 | Improved method for synthesizing mecobalamin |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3928320A (en) * | 1971-11-10 | 1975-12-23 | Jean Boige | Process for the preparation of methylcobalamine |
| CN101175764A (en) * | 2005-03-23 | 2008-05-07 | 菲尔若国际公司 | Process for the production of methylcobalamin |
| CN102391340A (en) * | 2011-10-31 | 2012-03-28 | 河北玉星生物工程有限公司 | Preparation method of mecobalamin |
| WO2012165934A1 (en) * | 2011-05-30 | 2012-12-06 | Interquim, S.A. De C.V. | Methylcobalamin synthesis process |
-
2013
- 2013-02-01 CN CN201310038988.6A patent/CN103113443B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3928320A (en) * | 1971-11-10 | 1975-12-23 | Jean Boige | Process for the preparation of methylcobalamine |
| CN101175764A (en) * | 2005-03-23 | 2008-05-07 | 菲尔若国际公司 | Process for the production of methylcobalamin |
| WO2012165934A1 (en) * | 2011-05-30 | 2012-12-06 | Interquim, S.A. De C.V. | Methylcobalamin synthesis process |
| CN102391340A (en) * | 2011-10-31 | 2012-03-28 | 河北玉星生物工程有限公司 | Preparation method of mecobalamin |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103113443A (en) | 2013-05-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103113443B (en) | Novel chemical synthesis method for preparing mecobalamine | |
| CN104447739A (en) | Deuterated palbociclib derivative, and preparation method and application thereof | |
| CN105461772B (en) | A kind of preparation method of Trifluridine intermediate and Trifluridine | |
| CN111484499B (en) | Method for preparing drug intermediate chromene pyrimido indazolone derivative through catalysis | |
| CN101967140A (en) | Deuterated crizotinib as well as derivant, preparation method and application thereof | |
| CN102079737B (en) | Method for preparing apigenin | |
| CN114044777B (en) | Preparation method of tricitabinib phosphate | |
| CN104447934A (en) | Method for purifying abiraterone acetate | |
| CN103254265B (en) | Abiraterone acetate trifluoroacetate and its preparation method and application | |
| EP3202769B1 (en) | Purification method for phosphaplatin compounds | |
| CN107417603B (en) | Preparation method of crizotinib intermediate | |
| CN103214421B (en) | The industrialized preparing process of 2-sulfydryl-1-Methylimidazole | |
| CN102516219B (en) | Halogenated polyhydroxy xanthene derivatives, preparation method and use thereof | |
| CN103130855B (en) | Preparation method of decitabine | |
| CN111559995A (en) | Preparation process of ascorbic acid ethyl ether | |
| CN104592122A (en) | Preparation method for 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline | |
| CN101450958B (en) | Synthetic method of isoflavone 7-O-glucose glycoside | |
| CN101812071A (en) | Method for processing mother liquor obtained by splitting clopidogrel hydrogen sulfate intermediate | |
| CN106588786A (en) | Preparation method of high purity favipiravir impurity | |
| CN104650160A (en) | Novel synthesis method of capecitabine key intermediate 1,2,3-O-triacetyl-5-deoxy-D-ribose | |
| CN109942442A (en) | A kind of preparation method of the dapoxetine hydrochloride in relation to substance I | |
| CN104557965A (en) | Preparation technology for beta-artemether | |
| CN101735296A (en) | Method for preparing fludarabine | |
| CN113979891A (en) | Preparation method of Cliborol and intermediate product thereof | |
| CN107011146A (en) | A kind of preparation method of Idebenone |
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 | ||
| CB03 | Change of inventor or designer information |
Inventor after: Sun Jinrui Inventor after: Shen Naitao Inventor after: Ren Yeming Inventor after: Zhao Sitai Inventor after: Feng Guangling Inventor after: Zhang Wen Inventor after: Duan Chonggang Inventor before: Shen Naitao Inventor before: Ren Yeming Inventor before: Zhao Sitai Inventor before: Feng Guangling Inventor before: Zhang Wen Inventor before: Duan Chonggang |
|
| COR | Change of bibliographic data |
Free format text: CORRECT: INVENTOR; FROM: SHEN NAITAO REN YEMING ZHAO SITAI FENG GUANGLING ZHANG WEN DUAN CHONGGANG TO: SUN JINRUI SHEN NAITAO REN YEMING ZHAO SITAI FENG GUANGLING ZHANG WEN DUAN CHONGGANG |
|
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |