CN109851543B - Method for preparing S-pregabalin lactam - Google Patents
Method for preparing S-pregabalin lactam Download PDFInfo
- Publication number
- CN109851543B CN109851543B CN201910068340.0A CN201910068340A CN109851543B CN 109851543 B CN109851543 B CN 109851543B CN 201910068340 A CN201910068340 A CN 201910068340A CN 109851543 B CN109851543 B CN 109851543B
- Authority
- CN
- China
- Prior art keywords
- pregabalin
- reaction
- lactam
- manufacturing according
- acidic
- 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
- 238000000034 method Methods 0.000 title claims description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 42
- AYXYPKUFHZROOJ-ZETCQYMHSA-N pregabalin Chemical compound CC(C)C[C@H](CN)CC(O)=O AYXYPKUFHZROOJ-ZETCQYMHSA-N 0.000 claims abstract description 34
- 229960001233 pregabalin Drugs 0.000 claims abstract description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 22
- 230000002378 acidificating effect Effects 0.000 claims description 13
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 239000005995 Aluminium silicate Substances 0.000 claims description 8
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 8
- 235000012211 aluminium silicate Nutrition 0.000 claims description 8
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 239000000741 silica gel Substances 0.000 claims description 7
- 229910002027 silica gel Inorganic materials 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 claims description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 239000008096 xylene Substances 0.000 claims description 4
- 229910044991 metal oxide Inorganic materials 0.000 claims description 2
- 150000004706 metal oxides Chemical class 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 2
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- 239000000047 product Substances 0.000 description 16
- 239000000706 filtrate Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000002253 acid Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000012535 impurity Substances 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 208000004296 neuralgia Diseases 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- -1 azo methyl trimethyl silane Chemical compound 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 208000001640 Fibromyalgia Diseases 0.000 description 1
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 208000020431 spinal cord injury Diseases 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
Landscapes
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a preparation method of S-pregabalin lactam, wherein a reaction accelerator added in the reaction step is low in price and easy to obtain, meanwhile, water generated by intramolecular cyclization of pregabalin is separated by a water separator, so that a reaction substrate pregabalin is promoted to thoroughly convert the product S-pregabalin lactam, the purity of the obtained S-pregabalin lactam product can reach more than 99 percent, the yield is more than 94 percent, and the preparation method is simple to operate and easy to operate in a laboratory.
Description
Technical Field
The invention relates to the technical field of medicine manufacturing, in particular to a method for rapidly and efficiently preparing S-pregabalin lactam.
Background
Pregabalin (pregabalin), chemical name: (S) -3-aminomethyl-5-methylhexanoic acid, formula C 8 H 17 NO 2 The molecular weight is 159.23, and the structural formula is as follows:
pregabalin commercial name Le Ruika
In 2004, the united states was marketed, and in 2010, the first drug to be co-certified by the united states and europe for the treatment of 2 kinds of neuralgia, the main indications being diabetic peripheral neuralgia, postherpetic neuralgia, fibromyalgia, spinal cord injury neuralgia.
In the stability study of the pregabalin bulk drug and the pregabalin tablet, the S-pregabalin lactam is the main degradation impurity in the pregabalin bulk drug and the pregabalin tablet, especially when the parameter control of the preparation condition of the pregabalin bulk drug or the pregabalin preparation prescription is not good, or the stability condition of the product is too long, the content of the impurity S-pregabalin lactam can reach more than 0.5 percent and exceeds the limit index that the single impurity of the product exceeds 0.20 percent, so that the quality study of the pregabalin bulk drug and the preparation product thereof by synthesizing the impurity reference substance has important significance. The structural formula of the S-pregabalin lactam is as follows:
at present, a plurality of synthesis methods are adopted for the S-pregabalin lactam, wherein, in journal documents Advanced Synthesis and Catalysis and 360 (2018), the reported method of P768-778 is to adopt pregabalin as a raw material, add azo methyl trimethyl silane as a cyclization agent to synthesize the S-pregabalin lactam, the patent WO2016075082 also adopts the same synthesis strategy, the azo methyl trimethyl silane reagent used in the methods is expensive, and meanwhile, the reagent also has stronger toxicity and is not suitable for laboratory operation; in another journal document Tetrahedron,67 (2001), P636-640 adopts 2-methoxycarbonyl-pregabalin lactam as a raw material, naOH methoxycarbonyl is added to hydrolyze into carboxyl, and then one molecule of carbon dioxide is removed under heating condition to obtain S-pregabalin lactam, wherein the raw material 2-methoxycarbonyl-pregabalin lactam adopted in the method is not easy to obtain, and the synthesis steps are complicated; meanwhile, in the patent CN107641093, oxalyl chloride or thionyl chloride is adopted to activate carboxyl of pregabalin, and then intramolecular cyclization is carried out on the carboxyl and amino groups to generate S-pregabalin lactam; in addition, patent CN104829515 adopts hydrochloric acid or acetic acid as a cyclization mixture, and the molecules of pregabalin are cyclized and dehydrated under heating to produce S-pregabalin lactam, but the S-pregabalin lactam product produced under the preparation condition can be continuously hydrolyzed and converted into the raw material pregabalin, so that the reaction conversion rate is low, and the product yield is low.
Disclosure of Invention
The invention provides a simple and convenient method for preparing S-pregabalin lactam, which has the following specific reaction formula:
the method comprises the following steps:
(a) Under the action of a reaction promoter, carrying out reflux reaction on pregabalin in an organic solvent for 1-36 hours, and removing water generated in the reaction process in the reflux process;
(b) And separating and purifying to obtain the target product S-pregabalin lactam.
Preferably, the organic solvent in step (a) is a water-immiscible solvent. Toluene, benzene, xylene, n-hexane, cyclohexane, n-heptane and the like are further preferable. Toluene or xylene is still more preferable.
The volume-mass ratio of the organic solvent to the pregabalin in the step (a) is 3-30ml/g; preferably the volume mass is 10-20ml/g
Preferably, the reaction promoter in step (a) is selected from acidic metal oxides, silica gel or kaolin, or a mixture thereof; further preferred are acidic alumina, acidic silica gel or acidic kaolin.
Preferably, the mass ratio of the reaction promoter to pregabalin in step (a) is 0.01 to 10:1, preferably 0.5 to 1:1.
Preferably, the reflux time of step (a) is from 4 to 20 hours.
The method for preparing the S-pregabalin lactam provided by the invention has the following advantages:
1. the reaction promoter used in the invention, such as acidic alumina, acidic silica gel or acidic kaolin, is cheap and very easy to obtain.
2. The content of the target product S-pregabalin lactam in the reaction solution can reach more than 99%, the remaining other components mainly comprise a small amount of unreacted pregabalin, the operation is simple, the S-pregabalin lactam product with high purity can be obtained without complex separation, and the yield can reach more than 94%.
Detailed Description
The invention is further illustrated below in connection with examples, which are not intended to be limiting, but any changes or modifications to the invention are intended to fall within the scope of the invention.
Example 1:
10g of pregabalin is added into 100mL of toluene, then 5g of acid alumina is added, then a water separator is connected, the mixture is heated and refluxed for 12 hours, and water generated in the reaction process is separated in real time in the reaction process; after the reaction, slowly cooling to room temperature, filtering to remove insoluble substances, evaporating the solvent from the obtained filtrate by using a rotary evaporator, and obtaining solid by using ethyl acetate: the cyclohexane (1:1) is recrystallized to obtain 8.42g of target product S-pregabalin lactam, the purity of HPLC is 99.4%, and the yield is 95%.
Example 2:
10g of pregabalin is added into 100mL of dimethylbenzene, 5g of acid alumina is added, a water separator is connected, the mixture is heated and refluxed for 6 hours, and water generated in the reaction process is separated in real time; after the reaction was completed, the mixture was slowly cooled to room temperature, filtered to remove insoluble matters, the solvent was distilled off from the obtained filtrate, and the obtained solid was further treated with ethyl acetate: the cyclohexane (2:3) is recrystallized to obtain 8.51g of the target product S-pregabalin lactam, the purity of HPLC is 99.2%, and the yield is 96%.
Example 3
10g of pregabalin is added into 150mL of toluene, then 9.5g of acidic alumina is added, a water knockout drum is connected, the reaction is carried out for 9 hours under heating and reflux, and the water generated in the reaction process is separated in real time; after the reaction, slowly cooling to room temperature, filtering, removing insoluble matters, evaporating filtrate to dryness, and obtaining solid by using ethyl acetate: the cyclohexane (1:1) is recrystallized to obtain 8.51g of the target product S-pregabalin lactam, the purity of HPLC is 99.3%, and the yield is 96%.
Example 4
10g of pregabalin is added into 100mL of toluene, then 5g of acid silica gel is added, a water knockout drum is connected, the reaction is carried out for 15 hours under heating and refluxing, and the water generated in the reaction process is separated in real time; after the reaction was completed, the mixture was slowly cooled to room temperature, filtered, the solvent was evaporated from the filtrate by a rotary evaporator, and ethyl acetate was used as the solid obtained: the cyclohexane (1:1) is recrystallized to obtain 8.34g of target product S-pregabalin lactam, the purity of HPLC is 99.5%, and the yield is 94%.
Example 5:
firstly, adding 10g of pregabalin into 100mL of cyclohexane, then adding 5g of acidic silica gel, connecting a water separator, heating and refluxing for reaction for 5 hours, and separating out water generated in the reaction process in real time in the reaction process; after the reaction, slowly cooling to room temperature, filtering to remove insoluble substances, evaporating the solvent from the obtained filtrate by using a rotary evaporator, and obtaining solid by using ethyl acetate: cyclohexane (1:1) is crystallized to obtain the target product S-pregabalin lactam 8.43g, the purity of HPLC is 99.2%, and the yield is 95%.
Example 6:
10g of pregabalin is added into 100mL of toluene, then 5g of acid kaolin is added, then a water separator is connected, the mixture is heated and refluxed for 16 hours, and water generated in the reaction process is separated in real time in the reaction process; after the reaction, slowly cooling to room temperature, filtering to remove insoluble substances, evaporating the solvent from the obtained filtrate by using a rotary evaporator, and obtaining solid by using ethyl acetate: cyclohexane (1:1) is crystallized to obtain 8.51g of target product S-pregabalin lactam, the purity of HPLC is 99.5%, and the yield is 96%.
Example 7:
10g of pregabalin is added into 100mL of dimethylbenzene, 5g of acid kaolin is added, then a water separator is connected, the mixture is heated and refluxed for reaction for 6 hours, and water generated in the reaction process is separated in real time; after the reaction, slowly cooling to room temperature, filtering to remove insoluble substances, evaporating the solvent from the obtained filtrate by using a rotary evaporator, and obtaining solid by using ethyl acetate: cyclohexane (1:1) is crystallized to obtain 8.60g of target product S-pregabalin lactam, the purity of HPLC is 99.3%, and the yield is 97%.
Example 8:
10g of pregabalin is added into 100mL of n-heptane, 5g of acid kaolin is added, a water separator is connected, the mixture is heated and refluxed for 18 hours, and water generated in the reaction process is separated in real time; after the reaction, slowly cooling to room temperature, filtering to remove insoluble substances, evaporating the solvent from the obtained filtrate by using a rotary evaporator, and obtaining solid by using ethyl acetate: cyclohexane (1:1) is crystallized to obtain the target product S-pregabalin lactam 8.34g, with HPLC purity 99.2% and yield 94%.
Claims (10)
1. A preparation method of S-pregabalin lactam, which has the following reaction formula:
the method is characterized by comprising the following steps of:
(a) Under the action of a reaction promoter, carrying out reflux reaction on pregabalin in an organic solvent for 1-36 hours, and removing water generated in the reaction process in the reflux process;
(b) Separating and purifying to obtain a target product S-pregabalin lactam;
wherein the reaction promoter in step (a) is selected from acidic metal oxides, silica gel or kaolin, or a mixture thereof.
2. The method of manufacturing according to claim 1, characterized in that: the reaction promoter in the step (a) is acidic alumina, acidic silica gel or acidic kaolin.
3. The method of manufacturing according to claim 1, characterized in that: the organic solvent in the step (a) is a solvent which is not mutually soluble with water.
4. A process according to claim 3, characterized in that the water-immiscible solvent is selected from toluene, benzene, xylene, n-hexane, cyclohexane, n-heptane.
5. The method of manufacturing according to claim 4, wherein: the water-immiscible solvent is selected from toluene or xylene.
6. The preparation method according to claim 2, characterized in that: the volume-mass ratio of the organic solvent to the pregabalin is 3-30ml/g.
7. The method of manufacturing according to claim 6, wherein: the volume-mass ratio of the organic solvent to the pregabalin is 10-20ml/g.
8. The method of manufacturing according to claim 1, characterized in that: the mass ratio of the reaction promoter to the pregabalin in the step (a) is 0.01-10:1.
9. The method of manufacturing according to claim 8, wherein: the mass ratio of the reaction promoter to the pregabalin in the step (a) is 0.5-1:1.
10. The method of manufacturing according to claim 1, characterized in that: the reflux time in step (a) is 4-20 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910068340.0A CN109851543B (en) | 2019-01-24 | 2019-01-24 | Method for preparing S-pregabalin lactam |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910068340.0A CN109851543B (en) | 2019-01-24 | 2019-01-24 | Method for preparing S-pregabalin lactam |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109851543A CN109851543A (en) | 2019-06-07 |
| CN109851543B true CN109851543B (en) | 2023-07-07 |
Family
ID=66895936
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910068340.0A Active CN109851543B (en) | 2019-01-24 | 2019-01-24 | Method for preparing S-pregabalin lactam |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109851543B (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1349982A (en) * | 2000-10-24 | 2002-05-22 | 大连化学工业股份有限公司 | Prepn of lactam |
| CN1427821A (en) * | 2000-05-03 | 2003-07-02 | 巴斯福股份公司 | Method for producing cyclic lactams |
| CN104829515A (en) * | 2015-06-02 | 2015-08-12 | 浙江华海药业股份有限公司 | Pregabalin impurity preparation method |
| CN107641093A (en) * | 2016-07-20 | 2018-01-30 | 江西科维协同创新药物有限公司 | The method that one kind prepares the pyrrolidones of 4 (S) isobutyl group 2 |
| CN107793414A (en) * | 2016-09-06 | 2018-03-13 | 上虞京新药业有限公司 | The synthetic method of (S, S) 2,8 diazabicyclo [4.3.0] nonane |
-
2019
- 2019-01-24 CN CN201910068340.0A patent/CN109851543B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1427821A (en) * | 2000-05-03 | 2003-07-02 | 巴斯福股份公司 | Method for producing cyclic lactams |
| CN1349982A (en) * | 2000-10-24 | 2002-05-22 | 大连化学工业股份有限公司 | Prepn of lactam |
| CN104829515A (en) * | 2015-06-02 | 2015-08-12 | 浙江华海药业股份有限公司 | Pregabalin impurity preparation method |
| CN107641093A (en) * | 2016-07-20 | 2018-01-30 | 江西科维协同创新药物有限公司 | The method that one kind prepares the pyrrolidones of 4 (S) isobutyl group 2 |
| CN107793414A (en) * | 2016-09-06 | 2018-03-13 | 上虞京新药业有限公司 | The synthetic method of (S, S) 2,8 diazabicyclo [4.3.0] nonane |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109851543A (en) | 2019-06-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105272865A (en) | Novel process for preparation of glycine by using chloroacetic acid aqueous phase ammoniation method | |
| CN112592356A (en) | Method for synthesizing lornoxicam | |
| CN113214133A (en) | Synthesis method of melatonin | |
| CN101417960A (en) | Method for preparing 1,1-cyclohexanediacetic acid mono amide | |
| CN102453011A (en) | Preparation method of high-purity naringenin | |
| CN1109017C (en) | Preparation of 1.1-cyclohexyl oxalic amide | |
| CN109851543B (en) | Method for preparing S-pregabalin lactam | |
| CN106397241A (en) | Eco-friendly aftertreatment method of 4-methyl-3-oxo-N-phenylvaleramide | |
| CN112047851B (en) | Preparation method of D-panthenol | |
| CN107540538B (en) | Composition, reaction system and method for preparing 5-methyl isophthalic acid | |
| CN101857550B (en) | Method for producing 6-aminocaproic acid hydrochloride and 6-aminocaproic acid by using nylon-6 waste through depolymerization | |
| CN109721496B (en) | Synthetic method of 3-nitro-o-xylene | |
| JP6028606B2 (en) | Method for producing amine compound | |
| CN112142713A (en) | Synthesis method of imazethapyr | |
| CN102241599B (en) | Method for preparing glycine | |
| CN115896188A (en) | Preparation method of high-purity (S) -5-chloro-2-methoxycarbonyl-2-hydroxy-1-indanone | |
| CN112939900B (en) | Preparation method of buvaracetam intermediate | |
| CN103951596A (en) | Preparation method of medicinal D, L-alpha-hydroxymethionine calcium | |
| CN112661727B (en) | Purification method of 7- (2, 2-trichloroethyl oxycarbonyl) taxol | |
| CN101074241A (en) | Method for preparing acephate | |
| CN1242996C (en) | Method for synthesizing 1H-1, 2,3 triazole | |
| CN103772224B (en) | Preparation method of D-threonine | |
| CN113754538B (en) | Vigabatrin acid intermediate and preparation method thereof | |
| CN112174966B (en) | New method for preparing piroxicam hydrochloride | |
| CN102372743B (en) | Synthesizing method for aminobenzene arsenic acid |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |