CN102702019B - Method for synthesizing carbidopa - Google Patents
Method for synthesizing carbidopa Download PDFInfo
- Publication number
- CN102702019B CN102702019B CN201210198854.6A CN201210198854A CN102702019B CN 102702019 B CN102702019 B CN 102702019B CN 201210198854 A CN201210198854 A CN 201210198854A CN 102702019 B CN102702019 B CN 102702019B
- Authority
- CN
- China
- Prior art keywords
- carbidopa
- methyldopa
- oxaziridine
- ester
- preparation
- 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
- 229960004205 carbidopa Drugs 0.000 title claims abstract description 27
- TZFNLOMSOLWIDK-JTQLQIEISA-N carbidopa (anhydrous) Chemical compound NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 TZFNLOMSOLWIDK-JTQLQIEISA-N 0.000 title claims abstract description 27
- 238000000034 method Methods 0.000 title abstract description 9
- 230000002194 synthesizing effect Effects 0.000 title abstract description 5
- -1 methyldopa ester Chemical class 0.000 claims abstract description 29
- 229940083181 centrally acting adntiadrenergic agent methyldopa Drugs 0.000 claims abstract description 25
- SJGALSBBFTYSBA-UHFFFAOYSA-N oxaziridine Chemical compound C1NO1 SJGALSBBFTYSBA-UHFFFAOYSA-N 0.000 claims abstract description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 32
- 238000003756 stirring Methods 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 238000010189 synthetic method Methods 0.000 claims description 5
- 239000010410 layer Substances 0.000 claims description 4
- QDHHCQZDFGDHMP-UHFFFAOYSA-N Chloramine Chemical class ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 claims description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 2
- 239000011260 aqueous acid Substances 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000012044 organic layer Substances 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 238000010025 steaming Methods 0.000 claims description 2
- 238000001291 vacuum drying Methods 0.000 claims description 2
- 239000003643 water by type Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 230000002349 favourable effect Effects 0.000 abstract 1
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 description 4
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 description 4
- 229960004502 levodopa Drugs 0.000 description 4
- BSTJDAVUFBUULS-UHFFFAOYSA-N C1=CC=CC2=NC3=CC=CC=C3C=C12.[O] Chemical compound C1=CC=CC2=NC3=CC=CC=C3C=C12.[O] BSTJDAVUFBUULS-UHFFFAOYSA-N 0.000 description 3
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- CTENFNNZBMHDDG-UHFFFAOYSA-N Dopamine hydrochloride Chemical compound Cl.NCCC1=CC=C(O)C(O)=C1 CTENFNNZBMHDDG-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 239000012434 nucleophilic reagent Substances 0.000 description 2
- IVTMXOXVAHXCHI-YXLMWLKOSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid;(2s)-3-(3,4-dihydroxyphenyl)-2-hydrazinyl-2-methylpropanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1.NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 IVTMXOXVAHXCHI-YXLMWLKOSA-N 0.000 description 1
- MBKUFCLQPYLOCC-YDALLXLXSA-N (2s)-2-amino-3-(3,4-dimethoxyphenyl)-2-methylpropanoic acid;hydrochloride Chemical compound Cl.COC1=CC=C(C[C@](C)(N)C(O)=O)C=C1OC MBKUFCLQPYLOCC-YDALLXLXSA-N 0.000 description 1
- 102100038238 Aromatic-L-amino-acid decarboxylase Human genes 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 229940081615 DOPA decarboxylase inhibitor Drugs 0.000 description 1
- IXSDQLOWDWRLMH-UHFFFAOYSA-N O1NC1.N1OC1 Chemical compound O1NC1.N1OC1 IXSDQLOWDWRLMH-UHFFFAOYSA-N 0.000 description 1
- 108010035075 Tyrosine decarboxylase Proteins 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000000534 dopa decarboxylase inhibitor Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention belongs to the field of chemical synthesis, and in particular relates to a method for synthesizing carbidopa. The method is characterized by comprising the following steps of: reacting oxaziridine with methyldopa ester to obtain methyldopa imido ester, and hydrolyzing to obtain the carbidopa. The method has the advantages that the carbidopa is prepared by a brand-new process, the used raw materials are favorable for synthesizing a medicine, and the prepared carbidopa is high in yield and quality.
Description
Technical field
The invention belongs to the field of chemical synthesis, particularly a kind of synthetic method of carbidopa.
Background technology
Carbidopa, English name: Carbidopa, is (S)-Alpha-Methyl-α-diazanyl-3,4-dihydroxy-benzene propionic acid monohydrate, carbidopa has stronger periphery dopa decarboxylase inhibitor.Be difficult for seeing through hemato encephalic barrier, while share with levodopa, only suppress the activity of periphery dopa decarboxylase, reduce the generation of Dopamine HCL in peripheral tissues, alleviate its periphery untoward reaction, and then the levodopa of the maincenter that enters is increased, improve the concentration of Dopamine HCL in brain, strengthen the curative effect of levodopa, so be the important adjuvant drug of levodopa.Carbidopa is alone invalid, conventionally carbidopa and levodopa is made to compound preparation in 1:10 or 1:4 ratio compatibility clinically.
Synthesizing of carbidopa roughly has 3 routes:
Route one:
This route is take dimethoxy-methyl DOPA hydrochloride as raw material, and yield only has 20%, is eliminated.
Route two:
Patent 230865A1 describes, and take methyldopa methyl esters as raw material, with two hydroxyls of boric acid protection, then, with 3,3-, penta methylene radical oxygen acridine reaction, then hydrolysis makes, total recovery approximately 40%.
Route 3:
Patent WO200704828, take methyldopa methyl esters as raw material, directly with 3,3-penta methylene radical oxygen acridine reaction, then hydrolysis makes, total recovery approximately 70%.
This route yield is higher, simple to operate, good product quality.But also there are 2 deficiencies: 1. 3 in technique, it is raw material that pimelinketone is used in the preparation of 3-penta methylene radical oxygen acridine, it is synthetic that one side pimelinketone has carcinogenesis should not be used for medicine; Pimelinketone boiling point (155.6 ℃) height, is not easy to recovery and also easily causes in product residual defective on the other hand.2. in technique, select toluene to make solvent, prepare imines ester for 80-85 ℃, toluene boiling point is high, and the carbidopa of production easily causes Residual Toluene defective.
Summary of the invention
The object of this invention is to provide a kind of synthetic method of carbidopa, can be by easy technique, prepare the carbidopa of the high and good product quality of yield.
The synthetic method of a kind of carbidopa of the present invention, oxaziridine reacts with methyldopa ester and generates methyldopa imines ester, and then hydrolysis generates carbidopa.
Oxaziridine (Oxaziridine) is the three member ring heterocyclic compound that a class contains C, O, N, and it is just synthetic by Krimm and Emmons as far back as nineteen fifty-three.In oxaziridine molecule, contain triatomic ring and weak N-O key that tension force is stronger, show special activity, in reaction, oxaziridine principal feature is while reacting with nucleophilic reagent, not only can do aminating agent but also can make oxygenant.Nucleophilic reagent depends on substituent size and electronegativity on N atom to the attack position of ternary heterocycle, and in the time that the substituting group on N atom is less H, oxaziridine is aminating agent, otherwise, be oxygenant.Primary amine reacts with oxaziridine and generates azo-compound; Secondary amine generates hydrazine; Father-in-law's salt in tertiary amine generates.We have adopted this principle just, utilize the imido grpup of methyldopa ester to react generation imines ester with oxaziridine, and then carbidopa are produced in hydrolysis.
Wherein, oxaziridine is preferably used 3,3-dimethyl oxygen aziridine, and the concentration of 3,3-dimethyl oxygen aziridine is preferably 0.1 ~ 5mol/L, more preferably 0.5 ~ 3mol/L.3,3-dimethyl oxygen aziridine can be prepared from according to following reaction:
Then 3,3-dimethyl oxygen aziridine further reacts with methyldopa ester and generates methyldopa imines ester, and then hydrolysis generates carbidopa, can be expressed from the next:
Methyldopa ester is preferably with alpha-Methyldopa ethyl ester or methyldopa methyl esters.
The mol ratio of oxaziridine and methyldopa ester is preferably 1.2～1.3:1.
The solvent that oxaziridine reacts with methyldopa ester is preferably with methylene dichloride or ethylene dichloride.Select methylene dichloride or ethylene dichloride to make solvent, methyldopa ester, imines ester are had to good solvability, thereby temperature of reaction can be dropped to below 40 ℃, thereby reduced the generation of side reaction, product yield is also higher.
Oxaziridine and methyldopa ester temperature of reaction are preferably 10 ~ 45 ℃, more preferably 25 ~ 35 ℃.
Operating process: under vigorous stirring, the dilute alkaline soln of chloramines is added drop-wise in methylene dichloride (or ethylene dichloride) solution of acetone (or butanone, methylethylketone) and makes oxaziridine, stir under room temperature oxaziridine is joined in methylene dichloride (or ethylene dichloride) solution of methyldopa ester, continue stoichiometric number minute, cooling is filtered and is obtained methyldopa imines ester.Methyldopa imines ester is obtained to carbidopa with dilute hydrochloric acid hydrolysis.
The invention has the advantages that: adopted brand-new operational path to prepare carbidopa, raw materials used being all suitable for synthesizing of medicine, the carbidopa yield preparing is high, good product quality.
Embodiment
Below in conjunction with embodiment, the present invention will be further described.
Embodiment 1:
(1) preparation of oxaziridine
Under stirring, 0.044mol chloramines is added to wiring solution-forming in the NaOH solution 100ml of 1N, then under vigorous stirring, splashed into the 100ml dichloromethane solution that contains 10ml acetone, temperature is controlled at 20 ℃, finishes, and stirs 30 seconds, stops stirring branch vibration layer.In dichloromethane layer, contain 3 of theoretical amount 43.5%, 3-dimethyl oxygen aziridine.By organic layer anhydrous sodium sulfate drying, it is 0.9mol/L that control reflux ratio 1:3 is concentrated into oxaziridine content with fractional column.
(2) preparation of imines ester
By the dichloromethane solution of the above-mentioned oxaziridine of 0.073mol, controlling temperature is 25 ℃, is added drop-wise in the 50ml dichloromethane solution of methyldopa methyl esters of 0.068mol in 15 ~ 20 minutes, drip and finish, at this temperature, stir, cool to 0 ℃, filter, obtain methyldopa imines ester.
(3) carbidopa preparation
Under nitrogen protection, above-mentioned methyldopa imines ester 10.3g and 100ml20% hydrochloric acid soln are heated to 95 ℃ of reactions 4 hours; pressure reducing and steaming aqueous acid is to dry; under nitrogen protection, add 6 ml waters; with 6N ammoniacal liquor adjusting pH value to 3.5, separate out a large amount of solids, filter; vacuum-drying obtains carbidopa 6.0g; yield approximately 87%, 194 ℃ of fusing points, content is greater than 98.5%.
Claims (1)
1. a synthetic method for carbidopa, is characterized in that:
(1) preparation of oxaziridine
Under stirring, 0.044mol chloramines is added to wiring solution-forming in the NaOH solution 100ml of 1N, then under stirring, splashed into the 100ml dichloromethane solution that contains 10ml acetone, temperature is controlled at 20 ℃, finishes, and stirs 30 seconds, stop stirring, branch vibration layer, contains 3 of theoretical amount 43.5% in dichloromethane layer, 3-dimethyl oxygen aziridine, by organic layer anhydrous sodium sulfate drying, it is 0.9mol/L that control reflux ratio 1:3 is concentrated into oxaziridine content with fractional column;
(2) preparation of imines ester
By the dichloromethane solution of the above-mentioned oxaziridine of 0.073mol, controlling temperature is 25 ℃, is added drop-wise in the 50ml dichloromethane solution of methyldopa methyl esters of 0.068mol in 15 ~ 20 minutes, drip and finish, at this temperature, stir, cool to 0 ℃, filter, obtain methyldopa imines ester;
(3) carbidopa preparation
Under nitrogen protection, above-mentioned methyldopa imines ester 10.3g and 100ml20% hydrochloric acid soln are heated to 95 ℃ of reactions 4 hours; pressure reducing and steaming aqueous acid is to dry; under nitrogen protection, add 6 ml waters; with 6N ammoniacal liquor adjusting pH value to 3.5, separate out a large amount of solids, filter; vacuum-drying obtains carbidopa 6.0g; yield 87%, 194 ℃ of fusing points, content is greater than 98.5%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210198854.6A CN102702019B (en) | 2012-06-16 | 2012-06-16 | Method for synthesizing carbidopa |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210198854.6A CN102702019B (en) | 2012-06-16 | 2012-06-16 | Method for synthesizing carbidopa |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102702019A CN102702019A (en) | 2012-10-03 |
| CN102702019B true CN102702019B (en) | 2014-05-14 |
Family
ID=46895142
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210198854.6A Active CN102702019B (en) | 2012-06-16 | 2012-06-16 | Method for synthesizing carbidopa |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102702019B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106986772B (en) * | 2017-04-06 | 2019-01-18 | 宁波四明化工有限公司 | The synthetic method of 2- nitropropane |
| CN108276333A (en) * | 2018-04-26 | 2018-07-13 | 山东新华制药股份有限公司 | A kind of preparation process and its device of carbidopa midbody acridine |
| CN114478303A (en) * | 2022-02-23 | 2022-05-13 | 浙江野风药业股份有限公司 | Method for synthesizing carbidopa |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD230865B1 (en) * | 1982-08-09 | 1987-05-20 | Dresden Arzneimittel | PROCESS FOR THE PREPARATION OF HYDRAZINOCARBONSAEUREDERIVATES BY N-AMINATION OF AMINOCARBONSAEUREDERIVATES |
| HU227283B1 (en) * | 2005-10-12 | 2011-01-28 | Egis Gyogyszergyar Nyilvanosan Muekoedoe Reszvenytarsasag | Process for the preparation of carbidopa |
-
2012
- 2012-06-16 CN CN201210198854.6A patent/CN102702019B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN102702019A (en) | 2012-10-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101817795B (en) | Improved method for synthesizing valsartan | |
| CN102702019B (en) | Method for synthesizing carbidopa | |
| CN102584795A (en) | Preparing method of crizotinib | |
| EP2215050B1 (en) | Manufacturing method of 2-hydroxy-5-phenylalkylaminobenzoic acid derivatives and their salts | |
| CN103665032A (en) | Preparation method of glufosinate | |
| CN112079848A (en) | Synthesis method of baroxavir key intermediate | |
| CN110698419A (en) | Preparation method of cycleanine | |
| EP1846359A1 (en) | Inorganic acid salts of sibutramine | |
| CN103570638A (en) | Synthetic method of florfenicol intermediate cyclic product | |
| EP2081920A4 (en) | PROCESS FOR THE PREPARATION OF CRYSTALLINE 3-0-ALKYL-ASCORBIC ACID | |
| CN102442972A (en) | Industrial preparation method of pramipexole and dihydrochloride monohydrate thereof | |
| CN105732416A (en) | Method for synthesizing Carbidopa | |
| CN104130146B (en) | (4S) preparation method of-3,6,9-tri-azepine-3,6,9-tri-(carboxymethyl)-4-(4-ethoxy benzyl) undecane diacids | |
| CN104744336B (en) | A kind of Silodosin intermediate and preparation method thereof, and the method for preparing with the intermediate silodosin | |
| WO2011001976A1 (en) | Method for producing threo-3-(3,4-dihydroxyphenyl)-l-serine | |
| CN101130523A (en) | The preparation method of melamine hexaacetic acid chelating agent | |
| CN105745191A (en) | Method for preparing silodosin and intermediate thereof | |
| CN111533742A (en) | Method for synthesizing 2-methoxy trimethylpurine diketone by taking cyanamide as raw material | |
| KR20120131646A (en) | A process for the preparation of isoxazolidinone derivative, D-cycloserine | |
| CN113583003A (en) | Vardenafil analogue and synthetic method and application thereof | |
| CN105924400B (en) | The preparation method of Azilsartan impurity A and B | |
| CN106083631B (en) | A kind of preparation method of equal amido phenenyl acid | |
| CN101663266B (en) | Method for production of N-(2-amino-1,2-dicyanovinyl)imidate, method for production of N-(2-amino-1,2-dicyanovinyl)formamidine, and method for production of aminoimidazole derivative | |
| CN102911072B (en) | Method for preparing methyldopa by directly hydrolyzing 5-methyl-5-(3,4-dimethoxybenzyl)hydantoin with acid | |
| CN106749075A (en) | Crystal formation of oxazolidone intermediate of Ah Nagqu ripple and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |