CN110790690A - Synthetic method of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid - Google Patents
Synthetic method of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid Download PDFInfo
- Publication number
- CN110790690A CN110790690A CN201911123930.5A CN201911123930A CN110790690A CN 110790690 A CN110790690 A CN 110790690A CN 201911123930 A CN201911123930 A CN 201911123930A CN 110790690 A CN110790690 A CN 110790690A
- Authority
- CN
- China
- Prior art keywords
- difluoro
- methyl
- benzoic acid
- phenylthio
- acid
- 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
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
- C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of a baroxavir key intermediate, namely 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid. The method comprises the steps of carrying out reflux reaction on 3, 4-difluoro-2-methylbenzoic acid serving as a raw material, Azodiisobutyronitrile (AIBN) and N-bromosuccinimide (NBS) in a carbon tetrachloride solution to obtain 2-bromomethyl-3, 4-difluorobenzoic acid, and then reacting the 2-bromomethyl-3, 4-difluorobenzoic acid with sodium thiophenolate or diphenyl disulfide to obtain the 3, 4-difluoro-2- ((thiophenyl) methyl) benzoic acid. The method can obtain the target product by only two steps, and has the advantages of easily obtained raw materials, simple and convenient post-treatment and high yield.
Description
Technical Field
The invention relates to a synthetic method of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid.
Background
Influenza is a disease caused by the acute infection of respiratory tract by influenza virus, and symptoms of the disease comprise fever, listlessness, watery nasal discharge and the like. Antiviral drugs can be used for preventing and treating seasonal influenza, and currently, drugs comprising M2 (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir and zanamivir) are used for chemoprevention of influenza, and the effective rate is 70-90%. Barosavir (Baloxavir marboxil) is an innovative Cap-dependent endonuclease inhibitor and is a few new drugs which can inhibit the proliferation of influenza virus in the world. Compared with common cold medicines, the treatment method has the advantages of quick response, long duration of curative effect and small dosage.
There are only two current reports of correlation with baroxavir key intermediate 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid, of which WO2017221869 discloses a synthetic method:
the first step of the process uses n-butyllithium (n-BuLi), the reagents are flammable, handling is very careful, and the reaction is carried out at-40 ℃. The product purification is troublesome due to the regioselectivity problem in the practical operation of the route.
CN109721585 discloses another synthesis method of the intermediate:
the first step of the route requires the use of hydrogen bromide and the third step requires inert gas shielding and reaction at-35 ℃. Compared with the method disclosed in the patent WO2017221869, the method is simple and convenient to operate, but the synthesis can be realized only by three steps of reactions, and the raw material 2, 3-difluoro-6-bromobenzyl alcohol is not easy to be obtained commercially.
In view of the recent years that influenza incidence rate is increased year by year, the drug resistance of influenza viruses is continuously enhanced, and anti-influenza drugs are more and more concerned by scientists, so that a safer, more convenient, more efficient and lower-cost route for synthesizing 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid is necessary.
Disclosure of Invention
Aiming at the problems in the prior art, a reaction route which is cheap and easily available in raw materials, simple and convenient in steps and high in yield is designed. The product can be obtained by only two-step reaction, the reaction route does not relate to inconvenient requirements such as low temperature and inert gas protection, the post-treatment is simple and convenient, the yield is high, the raw material 3, 4-difluoro-2-methylbenzoic acid is an important intermediate for synthesizing the ATP competitive mTOR selective inhibitor XL388, and the product can also be conveniently prepared from 3, 4-difluorotoluene through one-step reaction.
The specific operation steps are as follows:
step 1: adding 3, 4-difluoro-2-methylbenzoic acid, azodiisobutyronitrile and N-bromosuccinimide into a carbon tetrachloride solution at room temperature, starting stirring, heating to reflux (60-80 ℃), reacting for 2-12h, stopping the reaction, removing the solvent under reduced pressure, adding ethyl acetate and water into the residue, separating the solution, washing the ethyl acetate with water for several times, washing with saturated saline solution, drying with anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain 2-bromomethyl-3, 4-difluorobenzoic acid.
Step 2: the method comprises the following steps: mixing 2-bromomethyl-3, 4-difluorobenzoic acid and sodium thiophenolate at room temperature, adding an organic solution A, stirring at room temperature for 2-6h, stopping reaction, adding an organic solvent B and water, washing the organic solvent B with water for several times, washing with saturated common salt water, drying with anhydrous sodium sulfate, adding a small amount of activated carbon, stirring at room temperature for 10min, filtering, and removing the solvent from the filtrate under reduced pressure to obtain the 3, 4-difluoro-2- ((thiophenyl) methyl) benzoic acid. The second method comprises the following steps: adding diphenyl disulfide into a double-mouth bottle, charging nitrogen, adding a reducing agent C and a solvent D or adding the reducing agent C, an alkali and the solvent D, heating to 30-80 ℃, reacting for 10-30min, adding 2-bromomethyl-3, 4-difluorobenzoic acid, continuing to react for 2-6h, after TLC tracking reaction is finished, adding an organic solvent E and a sodium hydroxide solution into a reaction liquid for extraction, extracting the sodium hydroxide solution with a hydrochloric acid solution and ethyl acetate, drying, decompressing and removing the organic solvent to obtain the 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid.
The specific implementation mode is as follows:
the present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
Example 1: preparation of 2-bromomethyl-3, 4-difluorobenzoic acid
A25 ml single-neck flask was charged with 3, 4-difluoro-2-methylbenzoic acid (0.500 g, 2.905 mmol), N-bromosuccinimide (0.517 g, 2.905 mmol), azobisisobutyronitrile (0.050 g, 0.304 mmol), and carbon tetrachloride (10 ml), and the reaction was refluxed at 80 ℃ for 2 hours and followed by TLC until the reaction was completed. The reaction mixture was cooled, and the solvent was removed under reduced pressure to give a white solid, which was dissolved in 30ml of ethyl acetate, washed with water (20 ml. times. 2), washed with 20ml of saturated brine, dried over anhydrous sodium sulfate, and ethyl acetate was removed under reduced pressure to give 0.711g of 2-bromomethyl-3, 4-difluorobenzoic acid in 97.5% yield.
EXAMPLE 2 preparation of 2-bromomethyl-3, 4-difluorobenzoic acid
3, 4-difluoro-2-methylbenzoic acid (0.500 g, 2.905 mmol), N-bromosuccinimide (0.550 g, 3.090 mmol), azobisisobutyronitrile (0.050 g, 0.304 mmol) and carbon tetrachloride (10 ml) are added into a 25ml single-neck flask, reflux reaction is carried out at 70 ℃ for 5h, TLC is carried out until the reaction is finished, the reaction solution is cooled, the solvent is removed under reduced pressure to obtain a white solid, the solid is dissolved in 30ml of ethyl acetate, washed with water (20ml x 2), washed with 20ml of saturated saline, dried by anhydrous sodium sulfate, and the ethyl acetate is removed under reduced pressure to obtain 0.707g of 2-bromomethyl-3, 4-difluorobenzoic acid, wherein the yield is 97.0%.
Example 3: preparation of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid
2-bromomethyl-3, 4-difluorobenzoic acid (0.200 g, 0.797 mmol), sodium thiophenolate (0.110 g, 0.832 mmol) and 6ml of ethyl acetate were charged into a 25ml single-neck flask, stirred at room temperature for 4 hours, added with 25ml of ethyl acetate, washed with water (20ml x 2), washed with saturated brine (20ml), added with 10mg of activated carbon, stirred at normal temperature for 10 minutes, filtered, added with anhydrous sodium sulfate to the filtrate, dried, and the solvent was removed under reduced pressure to give 176mg of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid with a yield of 78.8%.
Example 4: preparation of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid
2-bromomethyl-3, 4-difluorobenzoic acid (0.200 g, 0.797 mmol), sodium thiophenolate (0.106 g, 0.802 mmol) and 6ml of acetone are added into a 25ml single-neck flask, stirred for 4 hours at room temperature, added with ethyl acetate 25ml, washed with water (20 mlx 2), washed with saturated salt water (20ml), added with 10mg of activated carbon, stirred for 10 minutes at normal temperature and filtered, the filtrate is added with anhydrous sodium sulfate and dried, and the solvent is removed under reduced pressure to obtain 183mg of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid with the yield of 81.9%. The HPLC purity is 99.35%, and the liquid phase diagram is shown in figure 2.
Example 5: preparation of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid
In a 25ml two-necked flask were charged 0.348g (1.59 mmol) of diphenyldisulfide and 0.110g (2.91 mmol) of sodium borohydride, nitrogen was replaced three times at room temperature, 10ml of ethanol was added, reflux reaction was carried out at 70 ℃ for 30min, then 0.760g (3.03 mmol) of 2-bromomethyl-3, 4-difluorobenzoic acid was added, reaction was carried out for four hours, cooling was carried out to room temperature, 1mol/L of a sodium hydroxide solution (30ml) and ethyl acetate (50ml) were added to the reaction solution, liquid separation was carried out, the organic phase was washed with 1mol/L of a sodium hydroxide solution (30ml x2 times), alkali liquors were combined, pH was adjusted to 3-4 with 12mol/L of a concentrated hydrochloric acid solution (about 7 ml), ethyl acetate was extracted (25 ml x3 times), ethyl acetate was combined, sodium sulfate anhydrous was dried, the solvent was removed under reduced pressure, to obtain 0.647g of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid, the yield thereof was found to be 76.2%.
Example 6: preparation of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid
In a 25ml two-necked flask, 0.870g (3.98 mmol) of diphenyldisulfide was charged, nitrogen was replaced at room temperature three times, 8ml of tetrahydrofuran, 0.275g (7.27 mmol) of sodium borohydride, 0.916g of sodium hydroxide and 10ml of water were added, reflux reaction was carried out at 70 ℃ for 5min, 2.00g (7.97 mmol) of 2-bromomethyl-3, 4-difluorobenzoic acid was added, after four hours of reaction, 1mol/L of sodium hydroxide solution (30ml) and ethyl acetate (50ml) were added to the reaction solution, liquid separation was carried out, the organic phase was washed with 1mol/L of sodium hydroxide solution (30ml x2 times), alkali solution was combined, pH was adjusted to 3 to 4 with 12mol/L of concentrated hydrochloric acid solution (about 7 ml), ethyl acetate was extracted (25 ml x3 times), ethyl acetate was combined, sodium sulfate anhydrous was dried, and the solvent was removed under reduced pressure to obtain 2.149g of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid, the yield thereof was found to be 96.2%.
Description of the drawings: FIG. 1 is a nuclear magnetic hydrogen spectrum of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid
FIG. 2 is a high performance liquid phase diagram of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid.
Claims (10)
1. A synthetic method of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid comprises the following synthetic route:
the specific operation is as follows:
step 1: adding 3, 4-difluoro-2-methylbenzoic acid, azodiisobutyronitrile and N-bromosuccinimide into a carbon tetrachloride solution at room temperature, starting stirring, heating to reflux (60-80 ℃), reacting for 2-12h, stopping the reaction, removing the solvent under reduced pressure, adding ethyl acetate and water into the residue, separating the solution, washing an ethyl acetate layer with water for several times, washing with saturated saline solution, drying with anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain 2-bromomethyl-3, 4-difluorobenzoic acid;
step 2: the method comprises the following steps: mixing 2-bromomethyl-3, 4-difluorobenzoic acid and sodium thiophenolate at room temperature, adding an organic solvent A, stirring at room temperature for 2-6h, stopping reaction, adding an organic solvent B and water, separating liquid, washing an organic layer for several times by using water, washing by using saturated common salt solution, drying by using anhydrous sodium sulfate, adding a small amount of activated carbon, stirring at room temperature for 10min, filtering, and removing the solvent from a filtrate under reduced pressure to obtain 3, 4-difluoro-2- ((thiophenyl) methyl) benzoic acid;
the second method comprises the following steps: adding diphenyl disulfide into a double-mouth bottle, adding a reducing agent C and a solvent D or adding the reducing agent C, an alkali and the solvent D under the protection of nitrogen, heating to 30-80 ℃, reacting for 10-30min, then adding 2-bromomethyl-3, 4-difluorobenzoic acid, continuing to react for 2-6h, after TLC tracking reaction is finished, adding an organic solvent E and a sodium hydroxide solution into the reaction liquid, extracting for liquid separation, neutralizing the water phase with hydrochloric acid, extracting with ethyl acetate, drying, and then decompressing and removing the organic solvent to obtain the 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid.
2. The method for synthesizing 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid as claimed in claim 1, wherein in step (1), the reflux temperature is between 60-80 ℃ and the reflux time is between 2-12 h.
3. The method for synthesizing 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid as claimed in claim 1, wherein in step (1), the ratio of the amounts of 3, 4-difluoro-2-methylbenzoic acid, N-bromosuccinimide and azobisisobutyronitrile substances is 1:1: 0.05-0.2.
4. The method for synthesizing 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid according to claim 1, wherein in step (2), the organic solvent A is acetone, ethyl acetate, dichloromethane and other organic solvents.
5. The method for synthesizing 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid as claimed in claim 1, wherein in step (2), the organic solvent B can be ethyl acetate, toluene, dichloromethane, etc.
6. The method for synthesizing 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid as claimed in claim 1, wherein in step (2), the ratio of the amount of 2-bromomethyl-3, 4-difluorobenzoic acid to the amount of sodium thiophenolate is 1: 1-1.5.
7. The method for synthesizing 3, 4-difluoro-2- ((thiophenyl) methyl) benzoic acid according to claim 1, characterized in that in step (2), the reaction time of 2-bromomethyl-3, 4-difluorobenzoic acid and sodium thiophenolate is 2-6 h.
8. The method for synthesizing 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid as claimed in claim 1, wherein in step (2), the reducing agent C is sodium borohydride; the solvent D can be one or a mixture of more than two of ethanol, tetrahydrofuran, toluene, 1, 4-dioxane, N-dimethylformamide, acetonitrile and water; the alkali is one or more of sodium hydroxide, lithium hydroxide and potassium hydroxide.
9. The method for synthesizing 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid as claimed in claim 1, wherein in step (2), the ratio of the amount of 2-bromomethyl-3, 4-difluorobenzoic acid to the amount of diphenyldisulfide species is 1: 0.4-0.6; the ratio of the diphenyl disulfide to the amount of the alkali and reducing agent is 1: 0.5-2: 0.5-2.
10. The method for synthesizing 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid as claimed in claim 1, characterized in that in step (2), 2-bromomethyl-3, 4-difluorobenzoic acid is reacted with diphenyldisulfide without adding base due to the difference of the reducing agent, for example, sodium borohydride is used as the reducing agent.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911123930.5A CN110790690A (en) | 2019-11-18 | 2019-11-18 | Synthetic method of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201911123930.5A CN110790690A (en) | 2019-11-18 | 2019-11-18 | Synthetic method of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110790690A true CN110790690A (en) | 2020-02-14 |
Family
ID=69444875
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201911123930.5A Pending CN110790690A (en) | 2019-11-18 | 2019-11-18 | Synthetic method of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110790690A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115784836A (en) * | 2022-12-08 | 2023-03-14 | 南京康立瑞生物科技有限公司 | High-selectivity method for preparing trans-menthyl-2,8-diene-1-alcohol |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109721585A (en) * | 2018-12-19 | 2019-05-07 | 浙江工业大学 | A kind of preparation method of Ba Luoshawei key intermediate |
| CN109796386A (en) * | 2018-12-19 | 2019-05-24 | 浙江工业大学 | (the bromo- 2,3- difluorobenzyl of 6-) aralkyl sulfid and preparation method thereof |
| CN110105327A (en) * | 2019-06-05 | 2019-08-09 | 南京焕然生物科技有限公司 | A kind of preparation method of the fluoro- 6,11- dihydro-dibenzothiophenes of 7,8- bis- simultaneously -11- alcohol |
| CN110357850A (en) * | 2018-03-26 | 2019-10-22 | 广东东阳光药业有限公司 | A kind of preparation method of sulfur heterocyclic compound |
-
2019
- 2019-11-18 CN CN201911123930.5A patent/CN110790690A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110357850A (en) * | 2018-03-26 | 2019-10-22 | 广东东阳光药业有限公司 | A kind of preparation method of sulfur heterocyclic compound |
| CN109721585A (en) * | 2018-12-19 | 2019-05-07 | 浙江工业大学 | A kind of preparation method of Ba Luoshawei key intermediate |
| CN109796386A (en) * | 2018-12-19 | 2019-05-24 | 浙江工业大学 | (the bromo- 2,3- difluorobenzyl of 6-) aralkyl sulfid and preparation method thereof |
| CN110105327A (en) * | 2019-06-05 | 2019-08-09 | 南京焕然生物科技有限公司 | A kind of preparation method of the fluoro- 6,11- dihydro-dibenzothiophenes of 7,8- bis- simultaneously -11- alcohol |
Non-Patent Citations (2)
| Title |
|---|
| HAMMERICH, MELANIE等: "Heterodiazocines: Synthesis and Photochromic Properties, Trans to Cis Switching within the Bio-optical Window", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| MOHAMMED, IDREES等: "SAR and Lead Optimization of an HIV-1 Vif-APOBEC3G Axis Inhibitor", 《ACS MEDICINAL CHEMISTRY LETTERS 》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115784836A (en) * | 2022-12-08 | 2023-03-14 | 南京康立瑞生物科技有限公司 | High-selectivity method for preparing trans-menthyl-2,8-diene-1-alcohol |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109516998B (en) | Synthesis method of Barosavir intermediate | |
| CN112174782A (en) | Application of metal deuteride/palladium compound catalytic reduction system in deuteration reaction | |
| US20230219990A1 (en) | Method for synthesizing c-nucleoside compound | |
| CN113861057A (en) | Oseltamivir phosphate intermediate impurity compound and preparation method and application thereof | |
| WO2021000248A1 (en) | Method and apparatus for continuous synthesis of cyclopropane compounds | |
| CN103044468B (en) | Preparation method of N-(2-pyrazine carbonyl)-L-phenylalanine-L- leucine boracic acid | |
| CN110790690A (en) | Synthetic method of 3, 4-difluoro-2- ((phenylthio) methyl) benzoic acid | |
| CN103073439B (en) | Synthesis method of ambroxol hydrochloride compound | |
| CN108148089A (en) | A kind of preparation method of four (dimethylamino) titaniums | |
| CN109796386B (en) | (6-bromo-2, 3-difluorobenzyl) phenyl sulfide and preparation method thereof | |
| WO2019037161A1 (en) | Method for synthesizing key clofazimine intermediate n-(4-chlorphenyl)-1,2-phenylenediamine | |
| CN108164423B (en) | Preparation method of naftifine hydrochloride | |
| CN103788010A (en) | Febuxostat intermediate and preparation method thereof | |
| CN114181117B (en) | Preparation method of peramivir intermediate | |
| CN107573230B (en) | Synthetic method of p-bromomethyl phenylpropionic acid | |
| CN114315626A (en) | Preparation method of oseltamivir dealkylation impurity | |
| CN110551052A (en) | Preparation method of (R) -4-hydroxy-2-oxo-1-pyrrolidine acetate | |
| CN110229111B (en) | Ambroxol impurity and preparation method and application thereof | |
| CN111533656A (en) | Synthesis method of tert-butyl 4-methoxy-3-oxobutyrate | |
| CN113072514A (en) | Preparation method of cycleanine and intermediate thereof | |
| CN102757399B (en) | Preparation method of aliskiren intermediate | |
| CN108863812B (en) | Purification method of N-ethyl-3-phenylpropylamine | |
| CN114773340B (en) | N-heteroatom multi-ring indolizine and derivative as well as synthesis process and application thereof | |
| CN108840793B (en) | Method for preparing gamma-thujaplicin by using simulated moving bed chromatography | |
| CN108997171B (en) | Synthetic method of 3+2 closed ring |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20200214 |