CN106905388B - Method for synthesizing gastrodin - Google Patents
Method for synthesizing gastrodin Download PDFInfo
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- CN106905388B CN106905388B CN201710074600.6A CN201710074600A CN106905388B CN 106905388 B CN106905388 B CN 106905388B CN 201710074600 A CN201710074600 A CN 201710074600A CN 106905388 B CN106905388 B CN 106905388B
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- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
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Abstract
The invention discloses a method for synthesizing gastrodin, which comprises the following steps: 4-formylphenyl-2 ', 3', 4 ', 6' -tetra-0-acetyl-beta-D-glucopyranoside and a reducing agent are put into a solvent and react for 0 to 3 hours at the temperature of 0 to 30 ℃; after the reaction is completed, adding water to quench the reaction; separating an organic phase, concentrating the organic phase under vacuum, and adding 2-5 times of methanol; adding organic amine for reflux reaction for alcoholysis; after the reaction is completed, adding activated carbon to decolorize, filtering, concentrating, crystallizing and drying. The synthetic method reduces the production process, has safe and simple operation, low cost and little pollution, is suitable for large-scale production, and the prepared gastrodin product has stable quality and the purity higher than 99.9 percent.
Description
Technical Field
The invention relates to the field of drug synthesis, and mainly relates to a method for synthesizing gastrodin.
Background
Most manufacturers for preparing gastrodin by chemical synthesis use 4-formylphenyl-2 ', 3', 4 ', 6' -tetra-0-acetyl-beta-D-glucopyranoside as an important intermediate and prepare the gastrodin by reduction, acetylation and deprotection. The main preparation methods at present comprise the following 3 methods:
the method comprises the following steps: 4-formylphenyl-2 ', 3', 4 ', 6' -tetra-0-acetyl-beta-D-glucopyranoside is subjected to reflux reaction in an alcohol solvent by using potassium borohydride or sodium borohydride, then acetic anhydride is used for acetylation, and then sodium methoxide is used for deprotection in an alcohol solution, and then the gastrodin finished product is obtained by decoloring and recrystallization, wherein the synthetic route is shown as the following formula:
according to the method, potassium borohydride or sodium borohydride is reduced under high-temperature reflux, acetylation is carried out, and deprotection is carried out to prepare the gastrodin.
The second method comprises the following steps: the 4-formylphenyl-2 ', 3', 4 ', 6' -tetra-0-acetyl-beta-D-glucopyranoside is reduced under high pressure by introducing hydrogen under the condition of raney nickel or palladium carbon, and then is deprotected to prepare gastrodin or is acetylated and deprotected to prepare the gastrodin, and the synthetic route is shown as the following formula:
the method needs hydrogenation reduction in the production process, has higher requirements on equipment under high pressure, uses highly flammable catalysts and has certain danger in operation, and heavy metal catalysts are used in the production process, so that the risk of introducing heavy metals into products is brought to users.
And (3) square flow three: the synthesis process of the 4-formylphenyl-2 ', 3', 4 ', 6' -tetra-0-acetyl-beta-D-glucopyranoside is completed in one step by reduction and deprotection after reflux reaction of potassium borohydride or sodium borohydride in an alcohol solvent, and the synthetic route is shown as the following formula:
the method adopts potassium borohydride or sodium borohydride to carry out reduction under high-temperature reflux, the reduction condition is severe, a large amount of hydrogen is generated in the reaction process, certain potential safety hazards exist, a large amount of impurities are generated by reduction at high temperature, and the reduction selectivity is not high.
Accordingly, the prior art is yet to be improved and developed.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide a method for synthesizing gastrodin, and aims to solve the problem of potential safety hazard in the existing gastrodin synthesis process.
The technical scheme of the invention is as follows:
a method for synthesizing gastrodin, which comprises the following steps:
4-formylphenyl-2 ', 3', 4 ', 6' -tetra-0-acetyl-beta-D-glucopyranoside and a reducing agent are put into a solvent and react for 0 to 3 hours at the temperature of 0 to 30 ℃;
after the reaction is completed, adding water to quench the reaction;
separating an organic phase, concentrating the organic phase under vacuum, and adding 2-5 times of methanol;
adding organic amine for reflux reaction for alcoholysis;
after the reaction is completed, adding activated carbon to decolorize, filtering, concentrating, crystallizing and drying.
The method for synthesizing gastrodin is characterized in that the reducing agent is potassium triacetoxyborohydride or sodium triacetoxyborohydride, and the dosage of the reducing agent is 0.4-0.6 time of the weight of a substrate.
The synthetic method of gastrodin, wherein the dosage of the solvent is 1 to 10 times of the weight of the substrate; the solvent is one of ester solvent, halogenated hydrocarbon or aromatic hydrocarbon.
The synthetic method of gastrodin, wherein the dosage of the ester solvent is 2 to 5 times of the weight of the substrate; the solvent is ethyl acetate.
The synthetic method of gastrodin is characterized in that the addition amount of organic amine is 0.20-0.24 time of the weight of a substrate.
The method for synthesizing gastrodin is characterized in that the organic amine is diethylamine.
The synthesis method of gastrodin is characterized in that the crystallization process adopts a solvent method for crystallization.
The synthesis method of gastrodin is characterized in that acetone with the weight 3-5 times of that of a substrate is added for crystallization.
The method for synthesizing gastrodin is characterized in that water is added into reactants for quenching reaction, wherein the weight of the water added into the reactants is 3-5 times that of the substrates for quenching reaction.
The synthesis method of gastrodin is characterized in that the reduction reaction process is carried out for 0.5 to 1 hour at the temperature of 20 to 30 ℃.
Has the advantages that: compared with the prior art, the method for synthesizing the gastrodin adopts potassium triacetoxyborohydride or sodium triacetoxyborohydride as a reducing agent, so that the process for preparing the gastrodin in a large scale is reduced from three original steps (reduction, acetylation and deprotection) to two steps (reduction and deprotection) and production process, and is safe and simple to operate, low in cost, small in pollution and suitable for large-scale production. Moreover, the gastrodin product prepared by the method provided by the invention has stable quality, various quality indexes are higher than the national standard, and the purity is higher than 99.9%.
Drawings
FIG. 1 is a diagram showing the results of HPLC analysis of the product obtained in example 1 of the present invention.
FIG. 2 is a diagram showing the results of HPLC analysis of the product obtained in example 2 of the present invention.
FIG. 3 is a diagram showing the results of HPLC analysis of the product obtained in example 3 of the present invention.
FIG. 4 is a diagram showing the results of HPLC analysis of the product obtained in example 4 of the present invention.
Detailed Description
The invention provides a method for synthesizing gastrodin, which is further described in detail below in order to make the purpose, technical scheme and effect of the invention clearer and clearer. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The synthetic method of gastrodin provided by the invention has the following synthetic route shown as the following formula, and comprises the following steps:
putting 4-formylphenyl-2 ', 3', 4 ', 6' -tetra-0-acetyl-beta-D-glucopyranoside into an ester solvent, putting a reducing agent, reacting for 0 to 3 hours at the temperature of between 0 and 30 ℃, and monitoring by TLC in the reaction process; after the reaction is completed, adding water to quench the reaction; separating an organic phase, concentrating the organic phase under vacuum, and adding 2-5 times of methanol; adding organic amine for carrying out alcoholysis by reflux reaction, and monitoring by TLC in the reaction process; after the reaction is completed, adding activated carbon for decoloring, filtering, concentrating to one third of the original volume, crystallizing by adopting a solvent crystallization method, and drying to obtain a finished product.
Wherein the ester solvent is used in an amount of 1 to 10 times, preferably 2 to 5 times, the weight of the substrate. The ester solvent can be ethyl acetate or butyl acetate. In the embodiment scheme of the invention, ethyl acetate is adopted as the specific example of the ester solvent. The solvent may be a halogenated hydrocarbon or an aromatic hydrocarbon.
The reducing agent is potassium triacetoxyborohydride or sodium triacetoxyborohydride, and the dosage of the reducing agent is about 0.4-0.6 time of the weight of the substrate. The two reducing agents are widely used in reducing aldehyde and ketone, the reaction condition is mild, the substrate can be quickly reduced at normal temperature, the reduction has high selectivity, other impurities are not easy to generate in the reaction process, the reduction yield is high, other groups of 4-formylphenyl-2 ', 3', 4 ', 6' -tetra-0-acetyl-beta-D-glucopyranoside cannot be reduced, and the safety of generating a large amount of hydrogen in the reaction process is greatly improved. However, if sodium borohydride or potassium borohydride is directly used as a reducing agent, when the 4-formylphenyl-2 ', 3', 4 ', 6' -tetra-0-acetyl-beta-D-glucopyranoside is reduced by an alcohol solvent, an acetyl group is partially reduced, acetylation is required to be performed again, deprotection is performed, purification and crystallization are required after an intermediate is prepared, and finally gastrodin is prepared through alcoholysis; and the reaction can not be carried out when the 4-formylphenyl-2 ', 3', 4 ', 6' -tetra-0-acetyl-beta-D-glucopyranoside is reduced by sodium borohydride or potassium borohydride in an ester solvent. Preferably, the reduction reaction is carried out at 20 to 30 ℃ for 0.5 to 1 hour.
Quenching the reaction with water may be quenching the reaction by adding the reactants to water 3 to 5 times the weight of the substrate.
The organic amine used in the alcoholysis process can be aliphatic amine, such as diethylamine, isopropylamine, butanediamine, hexanediamine, etc. In the invention, diethylamine is adopted as an embodiment, and the addition amount of organic amine is 0.20-0.24 times of the weight of the substrate.
The solvent method can be used for crystallization by adding acetone which is 3 to 5 times of the weight of the substrate, and the adopted solvent can be ester solvent, halogenated hydrocarbon solvent and alcohol solvent besides acetone.
The synthesis method provided by the invention reduces the original three steps (reduction, acetylation and deprotection) of the large-scale gastrodin preparation process into two steps of reactions (reduction and deprotection) and reduces the production process, and is safe and simple to operate, low in cost, small in pollution and suitable for large-scale production. Moreover, the gastrodin product prepared by the method provided by the invention has stable quality, various quality indexes are higher than the national standard, and the purity is higher than 99.9%.
The invention is further illustrated by the following examples.
Example 1
Adding 300g of ethyl acetate into a reactor, adding 50g of potassium triacetoxyborohydride, then adding 100g of 4-formylphenyl-2 ', 3', 4 ', 6' -tetra-0-acetyl-beta-D-glucopyranoside, keeping the temperature of 20-30 ℃ for reaction, sampling, monitoring the reaction by TLC (thin layer chromatography), completely reacting for 1 hour, adding the reaction solution into 300ml of water for quenching, then taking an upper organic phase, concentrating the organic phase to a solid under vacuum, then adding 300g of methanol and 22g of diethylamine for reflux reaction for 2 hours, sampling, monitoring the reaction by TLC, adding 10g of activated carbon for decoloring for 10 minutes after completely reacting, filtering, concentrating the filtrate to one third of the original volume, then adding 300g of acetone into the reaction solution, stirring for crystallization for 1 hour, filtering to obtain 70g of gastrodin, drying at 70 deg.C to obtain 55g dry product of gastrodin. All quality indexes of the obtained product meet the national standard through detection. HPLC (high performance liquid chromatography) spectrum detection is carried out on the obtained product, and the result is shown in figure 1, wherein the purity of the product is 99.9673%, and the content of impurities is 0.0327%. The purity is more than 99.9 percent, only one impurity is less than 0.1 percent, and the purity is far lower than the pharmacopoeia standard.
Example 2
Adding 300g of ethyl acetate into a reactor, adding 50g of sodium triacetoxyborohydride, then adding 100g of 4-formylphenyl-2 ', 3', 4 ', 6' -tetra-0-acetyl-beta-D-glucopyranoside, controlling the temperature to be 20-30 ℃, keeping the temperature for reaction, sampling, monitoring the reaction by TLC (thin layer chromatography), completely reacting for 2 hours, adding the reaction solution into 300ml of water for quenching, then taking an upper organic phase, concentrating the organic phase to a solid under vacuum, then adding 300g of methanol and 22g of diethylamine for reflux reaction for 2 hours, sampling, monitoring the reaction by TLC, adding 10g of activated carbon for decoloring for 10 minutes after completely reacting, filtering, concentrating the filtrate to one third of the original volume, then adding 300g of acetone into the reaction solution, stirring for crystallization for 1 hour, filtering to obtain 65g of gastrodin, oven drying at 70 deg.C to obtain dry gastrodine 52 g. HPLC (high performance liquid chromatography) spectrum detection is carried out on the obtained product, and the result is shown in figure 2, wherein the purity of the product is 99.9277%, and the content of impurities is 0.0723%. The purity is more than 99.9 percent, only one impurity is less than 0.1 percent, and the purity is far lower than the pharmacopoeia standard.
Example 3
Putting 200g of ethyl acetate into a reactor, then putting 50g of potassium triacetoxyborohydride, then putting 100g of 4-formylphenyl-2 ', 3', 4 ', 6' -tetra-0-acetyl-beta-D-glucopyranoside, controlling the temperature to be 20-30 ℃, carrying out heat preservation reaction, sampling, monitoring the reaction by TLC, carrying out complete reaction for 1.5 hours, adding the reaction solution into 300ml of water for quenching, then taking an upper organic phase, concentrating the organic phase to a solid under vacuum, then adding 300g of methanol and 22g of diethylamine for reflux reaction for 2 hours, sampling, monitoring the reaction by TLC, adding 10g of activated carbon for decoloring for 10 minutes after complete reaction, filtering, concentrating the filtrate to one third of the original volume, then adding 300g of acetone into the reaction solution, stirring for crystallization for 1 hour, filtering to obtain 68g of gastrodin, drying at 70 deg.C to obtain 53g dry gastrodin. HPLC (high performance liquid chromatography) spectrum detection is carried out on the obtained product, and the result is shown in figure 3, wherein the purity of the product is 99.9514%, and the content of impurities is 0.0486%. The purity is more than 99.9 percent, only one impurity is less than 0.1 percent, and the purity is far lower than the pharmacopoeia standard.
Example 4
Adding 500g of ethyl acetate into a reactor, adding 50g of potassium triacetoxyborohydride, then adding 100g of 4-formylphenyl-2 ', 3', 4 ', 6' -tetra-0-acetyl-beta-D-glucopyranoside, controlling the temperature to be 20-30 ℃, keeping the temperature for reaction, sampling, monitoring the reaction by TLC (thin layer chromatography), completely reacting for 1 hour, adding the reaction solution into 300ml of water for quenching, then taking an upper organic phase, concentrating the organic phase to a solid under vacuum, then adding 300g of methanol and 22g of diethylamine for reflux reaction for 2 hours, sampling, monitoring the reaction by TLC, adding 10g of activated carbon for decoloring for 10 minutes after completely reacting, filtering, concentrating the filtrate to one third of the original volume, then adding 300g of acetone into the reaction solution, stirring for crystallization for 1 hour, filtering to obtain 72g of gastrodin, drying at 70 deg.C to obtain 55g dry product of gastrodin. HPLC (high performance liquid chromatography) spectrum detection is carried out on the obtained product, and the result is shown in figure 4, wherein the purity of the product is 99.9572%, and the content of impurities is 0.0428%. The purity is more than 99.9 percent, only one impurity is less than 0.1 percent, and the purity is far lower than the pharmacopoeia standard.
It is to be understood that the invention is not limited to the examples described above, but that modifications and variations may be effected thereto by those of ordinary skill in the art in light of the foregoing description, and that all such modifications and variations are intended to be within the scope of the invention as defined by the appended claims.
Claims (1)
1. A method for synthesizing gastrodin is characterized by comprising the following steps:
4-formylphenyl-2 ', 3', 4 ', 6' -tetra-0-acetyl-beta-D-glucopyranoside and a reducing agent are put into a solvent and react for 0.5 to 1 hour at the temperature of between 20 and 30 ℃; the reducing agent is potassium triacetoxyborohydride or sodium triacetoxyborohydride, and the dosage of the reducing agent is 0.4-0.6 time of the weight of the substrate;
after the reaction is completed, adding water to quench the reaction; the amount of water is 3 to 5 times of the weight of the substrate;
separating an organic phase, concentrating the organic phase under vacuum, and adding 2-5 times of methanol;
adding organic amine for reflux reaction for alcoholysis;
after the reaction is completed, adding activated carbon for decoloring, filtering, concentrating, crystallizing and drying;
the solvent is ethyl acetate, and the dosage of the solvent is 2 to 5 times of the weight of the substrate;
the organic amine is diethylamine, and the addition amount of the organic amine is 0.20-0.24 times of the weight of the substrate;
the crystallization process is crystallization by adopting a solvent method; acetone was added in an amount of 3 to 5 times the weight of the substrate to conduct crystallization.
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| CN107325136B (en) * | 2017-08-10 | 2018-09-28 | 昆药集团股份有限公司 | A kind of Acegastrodine compound and preparation method thereof, pharmaceutical composition, preparation and application |
| CN107383125A (en) * | 2017-08-15 | 2017-11-24 | 昆药集团股份有限公司 | A kind of Acegastrodine compound and preparation method thereof, preparation and application |
| CN114685575A (en) * | 2020-12-29 | 2022-07-01 | 昆药集团股份有限公司 | Gastrodin anhydrous crystal form and preparation method thereof |
| CN114685576A (en) * | 2020-12-29 | 2022-07-01 | 昆药集团股份有限公司 | High-purity gastrodin unstable crystal form, preparation method thereof and preparation method of gastrodin crystal form FormA |
| CN114478655B (en) * | 2022-01-04 | 2023-12-26 | 天方药业有限公司 | Preparation method of high-purity gastrodin hemihydrate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101048384A (en) * | 2004-10-28 | 2007-10-03 | 默克公司 | Pyrimidine and quinoline potentiators of metabotropic glutamate receptors |
| CN102477051A (en) * | 2010-11-30 | 2012-05-30 | 重庆礼邦药物开发有限公司 | Technology for preparing key intermediate of telbivudine |
| CN103342656A (en) * | 2013-07-04 | 2013-10-09 | 苏州永健生物医药有限公司 | Synthesis method of Telaprevir intermediate |
| CN104628803A (en) * | 2015-02-06 | 2015-05-20 | 大连理工大学 | Total synthesis method for rape pollen alkali A and caper alkali B and analogues thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CA2515715C (en) * | 2003-02-19 | 2012-05-08 | Eisai Co., Ltd. | Methods for producing cyclic benzamidine derivatives |
| CN103804438B (en) * | 2012-11-12 | 2016-09-07 | 昆药集团股份有限公司 | A kind of high-purity, the semisynthesis of high stability Gastrodin |
| CN103896998B (en) * | 2014-03-13 | 2016-08-24 | 广安凯特医药化工有限公司 | The preparation method of Gastrodin Intermediate and the synthetic method of Gastrodin |
| CN104744529B (en) * | 2014-05-30 | 2016-02-24 | 昆药集团股份有限公司 | A kind of efficient high yield preparation method being suitable for suitability for industrialized production Gastrodine |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101048384A (en) * | 2004-10-28 | 2007-10-03 | 默克公司 | Pyrimidine and quinoline potentiators of metabotropic glutamate receptors |
| CN102477051A (en) * | 2010-11-30 | 2012-05-30 | 重庆礼邦药物开发有限公司 | Technology for preparing key intermediate of telbivudine |
| CN103342656A (en) * | 2013-07-04 | 2013-10-09 | 苏州永健生物医药有限公司 | Synthesis method of Telaprevir intermediate |
| CN104628803A (en) * | 2015-02-06 | 2015-05-20 | 大连理工大学 | Total synthesis method for rape pollen alkali A and caper alkali B and analogues thereof |
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