CN113135831A - Preparation method of alminoprofen intermediate - Google Patents
Preparation method of alminoprofen intermediate Download PDFInfo
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- CN113135831A CN113135831A CN202110468334.1A CN202110468334A CN113135831A CN 113135831 A CN113135831 A CN 113135831A CN 202110468334 A CN202110468334 A CN 202110468334A CN 113135831 A CN113135831 A CN 113135831A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
Abstract
The invention relates to a preparation method of an alminoprofen intermediate, which belongs to the field of organic chemical synthesis and aims to overcome the defects of the synthesis reaction of ethyl 2- (4-amino-phenyl) propionate, and provides a new technical route which comprises the following steps of 1) taking p-fluoronitrobenzene and diethyl methylmalonate as raw materials, adding alkali, heating, cooling after the reaction is finished, and hydrolyzing with the alkali; after the reaction is finished, layering, washing with water, extracting impurities, adjusting pH, extracting a product, and concentrating to obtain AMLF 02; 2) heating AMLF02 in a solvent to 55-75 ℃, and dropwise adding thionyl chloride for esterification reaction; and (3) reducing the temperature, adjusting the pH value, directly adding a catalyst for reduction at the temperature of 70-80 ℃, after the reaction is finished, assisting filtration by using diatomite, and neutralizing the filtrate to 7-8. Concentrating to remove ethanol, extracting the water phase with toluene, and concentrating to obtain AMLF 04. The invention has the advantages of solving the problem of slow filtration, omitting extraction, saving time and cost; after the reaction is finished, the layers are directly separated, so that the amount of hydrochloric acid is reduced, and the treatment difficulty of three wastes is reduced; safe hydrazine hydrate replaces active nickel.
Description
Technical Field
The invention belongs to the field of organic chemical synthesis, and particularly relates to a preparation method of an alminoprofen intermediate.
Background
Alminoprofen belongs to nonsteroidal anti-inflammatory analgesic drugs, is an aromatic phenylpropionic acid derivative, and plays roles of anti-inflammatory analgesia and detumescence by inhibiting cyclooxygenase, bradykinin and phosphatase A2. The curative effect is equivalent to or better than that of indometacin, ibuprofen and the like, and the Chinese medicinal composition is suitable for treating rheumatic and rheumatoid arthritis, radiculodynia, tendonitis, trauma (fracture, contusion and sprain), dysmenorrheal, postpartum uterine colic, toothache, otitis media and the like. In addition, the medicine has strong permeation resistance, so that the medicine can prevent and treat acute hydrops in joint cavity.
The ethyl 2- (4-amino-phenyl) propionate is an important intermediate for synthesizing alminoprofen and has wide market prospect.
At present, the important intermediate is mainly synthesized by the following route:
the route mainly comprises 4 steps of reaction, and each step is briefly described as follows:
step1, taking p-fluoronitrobenzene and diethyl malonate as raw materials, taking DMSO (dimethyl sulfoxide) as a reaction solvent, heating, filtering after the reaction is finished, washing a filter cake in an anti-kettle, and concentrating to remove the washing solvent, namely the DMSO solution of AMLF 01.
And Step2, adding water and solid alkali into the DMSO solution of the AMLF01 in the previous Step, heating for hydrolysis, and finishing the reaction. Adjusting pH, extracting impurities, adjusting acid, extracting the product, and concentrating to obtain orange red oily substance AMLF 02.
Step3, the AMLF03 in the last Step is esterified by sulfuric acid in an ethanol solution, the reaction is finished, and the mixture is concentrated, the pH value is adjusted, extracted and concentrated to obtain an orange-red solid AMLF 03.
And Step4, adding active nickel into the AMLF03 obtained in the previous Step in an ethanol solution, and reducing by hydrogen to finish the reaction. Filtering, and concentrating to obtain AMLF 04.
The above route has the following problems:
step1, powdered potassium carbonate is used, and DMSO has larger viscosity, so the filtration is very slow;
step2, the post-treatment is complex, and the pH value is adjusted by using a large amount of acid, so that the three wastes are extremely large.
Step3, the post-treatment extraction concentration takes longer time;
step4, active nickel is very flammable, and the safety risk is very high.
Disclosure of Invention
In order to overcome the defects of the synthesis reaction of the ethyl 2- (4-amino-phenyl) propionate (intermediate for synthesizing alminoprofen), the invention provides a new technical route, and the specific synthesis route and the reaction conditions are as follows:
1) taking p-fluoronitrobenzene and diethyl methylmalonate (1.1-1.3 eq.) as raw materials, adding powdery alkali (1.2-2.5 eq.) into a reaction solvent A (3-4 vol.), heating to 70-80 ℃, and carrying out addition reaction for 15-17 h; cooling to 20-30 ℃, controlling the temperature to 20-50 ℃, dropwise adding alkali (4.2-5.5eq.), and heating to 50-60 ℃ for hydrolysis reaction for 1-2h after dropwise adding; standing for 1h after the reaction is finished, and separating a lower-layer high-salt water phase; cooling the upper organic phase to 20-30 ℃, adding water (6-8 vol.), and adjusting the pH to 7-8 by using concentrated hydrochloric acid; adding dichloromethane for extraction (6-8 vol.) and taking impurities twice; controlling the temperature to be 20-30 ℃, using concentrated hydrochloric acid to adjust the pH value to 2-3, and adding dichloromethane (6-8 vol.) to extract once. And (3) adding water (7-8 vol.) into the organic phase, washing once, and concentrating and drying under reduced pressure to obtain AMLF 02.
In this step:
the reaction solvent A includes DMF, NMP, DMSO, etc., and DMSO is preferable.
The powdery alkali) is prepared from sodium carbonate and potassium carbonate by anhydrous pulverization, preferably potassium carbonate.
The base for hydrolysis includes sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, etc., preferably sodium hydroxide; the alkali equivalent for hydrolysis is 4.2-4.5 eq.
Hydrolysis temperature: the temperature is controlled to be 40-60 ℃, preferably 50-60 ℃.
The extraction solvent includes dichloromethane, methyltetrahydrofuran, ethyl acetate, etc., preferably dichloromethane.
2) Heating AMLF02 in a reaction solvent B (3-5 vol.), heating to 55-75 ℃, preferably 60-65 ℃, dropwise adding thionyl chloride (0.4-1.0eq.) for esterification reaction, after dropwise adding, keeping the temperature at 60-65 ℃ for 1-2h, and finishing the reaction. Cooling to 25-30 ℃, and adjusting the pH value to 6.5-7.5 by using a sodium bicarbonate aqueous solution. Adding a prepared catalyst (water, ferric trichloride, activated carbon and sodium bicarbonate), stirring and heating to 70-80 ℃ (starting to dropwise add at 75 ℃), dropwise adding hydrazine hydrate (2-2.5eq.), and reacting for 1-2h under heat preservation. The reaction was complete. Cooling to 20-30 ℃, adding diatomite into the reaction kettle, stirring for 1h, filtering, and neutralizing the filtrate to 7-8% by using concentrated hydrochloric acid. Concentrating under reduced pressure to remove ethanol, adding toluene (7-9 vol.) into the residual water phase, extracting twice, filtering with silica gel, and concentrating the filtrate under reduced pressure at 60-65 ℃ to obtain AMLF 04.
In this step:
the reaction solvent B includes methanol, ethanol, isopropanol, etc., preferably ethanol.
The catalyst ratio is very critical, preferably 0.07eq of ferric chloride, 0.07eq of sodium bicarbonate; the catalyst is prepared by adding sodium bicarbonate water solution, adding active carbon (dispersing function), controlling pH to about 8, and adding the catalyst in batches.
The equivalent weight of hydrazine hydrate is controlled to be 1.8eq to 2eq.
The extraction solvent includes toluene, methyl t-butyl ether and the like, and toluene is preferred.
The prior art compares the unit operation with the process unit operation of the application in short form:
by optimizing the process, the route is shortened to 2 steps, while the post-treatment operations are reduced, wherein
Step1, potassium carbonate filtering is omitted, so that the problem of slow filtering is solved, a large amount of time is saved, and particularly, the cost can be greatly saved in industrial production;
step2, after the reaction is finished, direct layering is carried out, so that the amount of hydrochloric acid (neutralizing alkali) is greatly reduced, the three wastes are greatly reduced, the treatment difficulty of the three wastes is greatly reduced, and the cost is saved;
step3, extraction is omitted, a large amount of time is saved, and particularly, cost is further saved during industrial production;
and Step4, adopting safer hydrazine hydrate for reduction, and compared with inflammable active nickel, the method has the advantages of increased safety performance and reduced cost.
Detailed Description
Comparative example 1
(1) Synthesis of AMLF01
P-fluoronitrobenzene (30kg), diethyl malonate (40.7kg) and DMSO (90kg) were added to a 20L reaction flask, respectively. The temperature of the reaction solution is raised to 45-50 ℃, and crushed potassium carbonate (100kg) is rapidly added at one time, so that the system is rapidly changed into brown-purple. The reaction is carried out under the condition of heat preservation at 65-70 ℃. The reaction solution was filtered. The filtrate was put into a bucket. The filter cake was transferred to another vat and slurried with DCM (80kg) for 1 hour, filtered and the filter cake was slurried once more with DCM (80 kg). Concentrating DCM filtrate under reduced pressure, and mixing with DMSO filtrate; the whole reaction takes about 54 hours.
(2) Synthesis of AMLF02
Water (250kg) was added to the reaction solution in the previous step, NaOH solid (70kg) was added in portions, the reaction temperature was kept at 50-60 ℃ and the reaction was completed. The pH was adjusted to 8 with concentrated hydrochloric acid (80 kg). Extract twice with DCM (450 kg). The solvent was recovered by vacuum concentration of EA (120kg), and the residue was discarded. The aqueous phase was further adjusted to pH 3-4 with concentrated hydrochloric acid (100 kg). The aqueous phase was extracted once with DCM (670kg), and the DCM layer was washed with saturated brine, dried and concentrated to dryness. Crude oil AMLF 0224 kg was obtained with a crude purity of 99.28%. The whole reaction takes about 60 hours.
(3) Synthesis of AMLF03
AMLF02(24kg) was added to a 20L reaction flask, followed by absolute ethanol (40L). After stirring well, concentrated sulfuric acid (1.6kg) was added. The temperature of the reaction liquid is raised to 80 ℃ for heat preservation reaction. The ethanol was concentrated to small volume under reduced pressure and poured into ice saturated sodium bicarbonate solution (362 kg). EA (192) was added for extraction. Concentrating to obtain oil AMLF0318.4kg. The above-described entire reaction took about 90 hours.
(4) Synthesis of AMLF04
AMLF03(18.4kg) was added to a 20L reaction flask, followed by absolute ethanol (60L). After stirring well, aqueous active nickel (3kg) was added. The reaction system was replaced with nitrogen three times, and then nitrogen was evacuated to replace hydrogen. Hydrogenation is carried out at room temperature under normal pressure. After the reaction was complete, the active nickel was filtered. Concentrating the filtrate under reduced pressure, adding toluene (147kg), filtering with silica gel, concentrating the filtrate under reduced pressure at 60-65 deg.C, and drying to obtain AMLF0426.7 kg with purity of 98.42%. The total yield of the four steps is 65 percent. The whole reaction takes about 40 hours.
Example 1
(1) Synthesis of AMLF02
Adding parafluoronitrobenzene (50kg), DMSO (190.25kg) and diethyl methylmalonate (70.4kg) into a reaction kettle, starting stirring, adding anhydrous powdered potassium carbonate (73kg), heating to 70-80 ℃, and reacting for 15-17 h. Cooling to 20-30 ℃, controlling the temperature to 20-50 ℃, and dropwise adding 30% sodium hydroxide solution (432 kg). After dripping, heating to 50-60 ℃ and reacting for 1-2 h. Standing for 1h, and separating the lower high-salt water phase. Cooling to 20-30 ℃, adding water (350kg), and adjusting the pH to 7-8 by using concentrated hydrochloric acid. Dichloromethane (390kg) was added to extract the impurities twice. Controlling the temperature to be 20-30 ℃, using concentrated hydrochloric acid to adjust the pH value to 2-3, and adding dichloromethane (455kg) for extraction once. The organic phase is washed once by adding water (300kg), and concentrated to dryness under reduced pressure to obtain AMLF02128.6 kg, and the purity of the crude product is 98.92%. The above-described entire reaction took about 35 hours.
(2) Synthesis of AMLF04
AMLF02(100kg) was added to the reaction flask, absolute ethanol (400L) was added, the temperature was raised to 50-55 deg.C, and thionyl chloride (42.6kg) was added dropwise. After dripping, keeping the temperature at 60-65 ℃ for reacting for 2h, and finishing the reaction. Cooling to 25-30 ℃, and adjusting the pH value to 6.5-7.5 by using a sodium bicarbonate aqueous solution. Adding a prepared catalyst (230kg) (2 vol. + ferric trichloride 0.07eq. + activated carbon 4eq. + sodium bicarbonate 0.07eq.), starting stirring and heating to 70-80 ℃ (dropwise addition is started at 75 ℃), dropwise adding hydrazine hydrate (1.8eq.) and keeping the temperature for reaction for 1 h. The reaction was complete. Cooling to 20-30 ℃, adding diatomite into the reaction kettle, stirring for 1h, filtering, and neutralizing the filtrate to 7-8% by using concentrated hydrochloric acid. Concentrating under reduced pressure to remove ethanol, extracting the residual water phase with toluene (640kg) twice, filtering with silica gel, concentrating the filtrate under reduced pressure at 60-65 deg.C, and drying to obtain AMLF0479.1kg with purity of 98.5%. The total yield of the two steps is 74%. The above-described entire reaction takes about 50 hours.
Example 2
(1) Synthesis of AMLF02
Adding parafluoronitrobenzene (50kg), DMF (190.25kg) and diethyl methylmalonate (70.4kg) into a reaction kettle, starting stirring, adding anhydrous sodium carbonate (56kg), heating to 70-80 ℃, and reacting for 15-16 h. After the reaction is finished, cooling to 20-30 ℃, controlling the temperature to 20-50 ℃, and dropwise adding 30% potassium hydroxide solution (432 kg). After dripping, heating to 50-60 ℃ and reacting for 1-2 h. Standing for 1h, and separating the lower high-salt water phase. Cooling to 20-30 ℃, adding water (350kg), and adjusting the pH to 7-8 by using concentrated hydrochloric acid. Ethyl acetate (390kg) was added to extract the impurities twice. Controlling the temperature to be 20-30 ℃, using concentrated hydrochloric acid to adjust the pH value to 2-3, and adding ethyl acetate (455kg) for extraction once. The organic phase is washed once by adding water (300kg), and is concentrated and dried under reduced pressure to obtain AMLF02127.5 kg, and the purity of the crude product is 98.82%. The above-described entire reaction took about 35 hours.
(2) Synthesis of AMLF04
AMLF02(100kg) was added to the reaction flask, anhydrous methanol (400L) was added, the temperature was raised to 50-55 deg.C, and thionyl chloride (42.6kg) was added dropwise. After dripping, keeping the temperature at 55-65 ℃ for reacting for 2h, and finishing the reaction. Cooling to 25-30 ℃, and adjusting the pH value to 6.5-7.5 by using a sodium bicarbonate aqueous solution. Adding a prepared catalyst (230kg) (2 vol. + ferric trichloride 0.07eq. + activated carbon 4eq. + sodium bicarbonate 0.07eq.), starting stirring and heating to 70-80 ℃ (dropwise addition is started at 75 ℃), dropwise adding hydrazine hydrate (1.8eq.) and keeping the temperature for reaction for 1 h. The reaction was complete. Cooling to 20-30 ℃, adding diatomite into the reaction kettle, stirring for 1h, filtering, and neutralizing the filtrate to 7-8% by using concentrated hydrochloric acid. Concentrating under reduced pressure to remove ethanol, extracting the residual water phase with methyl tert-butyl ether (640kg) twice, filtering with silica gel, concentrating the filtrate under reduced pressure at 60-65 deg.C to obtain AMLF0478.6 kg with purity of 98.6%. The total yield of the two steps is 74%. The above-described entire reaction takes about 50 hours.
The following comparisons are made for comparative example 1 and examples 1 and 2 above:
note: kg/kg represents the amount of three wastes generated per 1kg of product produced.
Claims (8)
1. The preparation method of the alminoprofen intermediate is characterized by comprising the following steps:
1) taking p-fluoronitrobenzene and diethyl methylmalonate as raw materials, adding powdery alkali into a reaction solvent A, heating to 70-80 ℃, and carrying out addition reaction;
cooling to 20-30 ℃, controlling the temperature to be 20-50 ℃, dropwise adding alkali, heating to 50-60 ℃ after dropwise adding, carrying out hydrolysis reaction, standing for layering after the reaction is finished, and separating a lower-layer high-salt water phase;
cooling to 20-30 ℃, adding water, adjusting the pH to 7-8 by using concentrated hydrochloric acid, and adding dichloromethane to extract impurities;
controlling the temperature to be 20-30 ℃, adjusting the pH value to be 2-3 by using concentrated hydrochloric acid, adding dichloromethane for extraction once, adding an organic phase, washing with water, and concentrating under reduced pressure to obtain AMLF 02;
2) heating AMLF02 in a reaction solvent B to 55-75 ℃, dropwise adding thionyl chloride for esterification reaction, keeping the temperature at 60-65 ℃ for reaction after dropwise adding is finished, and finishing the reaction;
cooling to 25-30 ℃, adjusting the pH to 6.5-7.5 by using a sodium bicarbonate aqueous solution, adding a catalyst, stirring and heating to 70-80 ℃, dropwise adding hydrazine hydrate, and carrying out heat preservation reaction;
after the reaction is finished, cooling to 20-30 ℃, adding diatomite, stirring, filtering, and neutralizing the filtrate to 7-8 by using concentrated hydrochloric acid;
concentrating under reduced pressure to remove ethanol, extracting the residual water phase with toluene twice, filtering with organic phase pad silica gel, concentrating the filtrate under reduced pressure at 60-65 deg.C, and drying to obtain AMLF 04.
2. The method for preparing an alminoprofen intermediate according to claim 1, wherein the reaction solvent a in the step 1) is DMF, NMP and/or DMSO.
3. A process for the preparation of an alminoprofen intermediate as claimed in claim 1, wherein the powdered base in step 1) is sodium carbonate and/or potassium carbonate.
4. A process for the preparation of an alminoprofen intermediate as claimed in claim 1, wherein the base used for the hydrolysis in step 1) is sodium hydroxide, potassium hydroxide, lithium hydroxide and/or potassium carbonate.
5. The method for preparing an alminoprofen intermediate according to claim 1, wherein the extraction solvent used in step 1) is dichloromethane, methyltetrahydrofuran and/or ethyl acetate.
6. The method for preparing an alminoprofen intermediate according to claim 1, wherein the reaction solvent B in the step 2) is methanol, ethanol and/or isopropanol.
7. The method for preparing an alminoprofen intermediate according to claim 1, wherein the catalyst in step 2) is prepared by the following method:
catalyst proportioning (2 vol. + ferric trichloride 0.07eq. + activated carbon 4eq. + sodium bicarbonate 0.07 eq.): respectively adding water, ferric trichloride and activated carbon into a reaction bottle, uniformly stirring, adding sodium bicarbonate (generated by gas) in batches, controlling the pH to be 8-9, and stirring for 1-2 hours for later use.
8. The method for preparing an alminoprofen intermediate according to claim 1, wherein the extraction solvent in step 2) comprises toluene and/or methyl t-butyl ether.
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Non-Patent Citations (3)
| Title |
|---|
| MARCO MIGLIORE ET AL.: "Potent multitarget FAAH-COX inhibitors: design and structure-activity relationship studies", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 唐洪等: "芳香族硝基化合物的水合肼催化还原反应的研究", 《精细化工》 * |
| 杨锦宗: "《工业有机合成基础》", 31 December 1998, 中国石化出版社 * |
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Application publication date: 20210720 |