CN104817563B - The preparation method of pemetrexed N, N dibenzyl ethylenediamine salt - Google Patents
The preparation method of pemetrexed N, N dibenzyl ethylenediamine salt Download PDFInfo
- Publication number
- CN104817563B CN104817563B CN201510239656.3A CN201510239656A CN104817563B CN 104817563 B CN104817563 B CN 104817563B CN 201510239656 A CN201510239656 A CN 201510239656A CN 104817563 B CN104817563 B CN 104817563B
- Authority
- CN
- China
- Prior art keywords
- pemetrexed
- dibenzyl
- dibenzyl ethylenediamine
- organic solvent
- 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
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The present invention relates to a kind of pemetrexed N, the preparation method of N dibenzyl ethylenediamine salts, pemetrexed N, the chemical name of N dibenzyl ethylenediamine salts is N [4 [2 (2 amino 4, the oxo 1H pyrrolo-es [2 of 7 dihydro 4, 3 d] 5 base of pyrimidine) ethyl] benzoyl] L glutamic acid Ns, N dibenzyl ethylenediamine salts, the pemetrexed N of the present invention, N dibenzyl ethylenediamine salts have preferable stability, both can also can exist with anhydrous in the form of hydrate, and pemetrexed N, N dibenzyl ethylenediamine salts have no report in the prior art, new selection is provided for the dosage form research of pemetrexed；Pemetrexed N of the present invention, the preparation method simple and reasonable steps of N dibenzyl ethylenediamine salts, HPLC >=99.70% of products therefrom, single contaminant content is less than 0.1%, and total moles yield reaches 75~80%.
Description
Technical field
The present invention relates to a kind of pemetrexed-N, the preparation method of N- dibenzyl ethylenediamine salts.
Background technology
Pemetrexed is a kind of antifol, be in the world first be also currently the only treatment malignant pleural mesothelium
The medicine of knurl.At present, the research of relevant pemetrexed treatment non-small cell lung cancer has been achieved for certain progress, studies
Structure shows that pemetrexed very likely turns into treatment NSCLC fiest-tire medication.
At present, the main formulation of pemetrexed is disodium salt, and United States Patent (USP) US5344932 discloses pemetrexed and its medicine
With the compound patent of salt, about pemetrexed disodium preparation method also disclosed in United States Patent (USP) US6013828.In state
It is interior, Publication No. CN1552713A Chinese patent《Pemetrexed salt and preparation method thereof》(application number：CN03138056.5)
Disclose a kind of reacted using pemetrexed bivalent metal ion salt, pemetrexed and organic amine or inorganic ammonia and obtain pemetrexed
The method of amine salt compound；Publication No. CN101033227A Chinese patent《Pemetrexed ethylenediamine salt and preparation method thereof》
(application number：200610024564.4) disclose a kind of pemetrexed and reacting ethylenediamine and obtain pemetrexed ethylenediamine salt chemical combination
The method of thing；Authorization Notice No. discloses a kind of pemetrexed amine salt compound for CN100364993C Chinese patent；Announce
Number disclose a kind of pemetrexed organic salt compound for CN104098573A Chinese patent.
Although having done more research to pemetrexed and its compound in the prior art, some trainings are have also been provided
Beautiful Qu Sai salt is as clinical medicine, but often existence and stability is poor for conventional medicine, the problems such as preparation process is complicated.
The content of the invention
The technical problem to be solved by the invention for the present situation of prior art is to provide a kind of pemetrexed-N, N- bis-
The preparation method of benzyl ethylenediamine salt, the preparation method simple and reasonable steps, gained single contaminant content is low, with higher pure
Degree and yield.
The present invention solve the technical scheme that is used of above-mentioned technical problem for：A kind of pemetrexed-N, N- dibenzyl second two
Amine salt, it is characterised in that：Structure with formula (I), the pemetrexed-N, the chemical name of N- dibenzyl ethylenediamine salts is N-
[4- [2- (2- amino -4,7- dihydro -4- oxo -1H- pyrrolo-es [2,3-d]-pyrimidine -5- bases) ethyl] benzoyl]-L- paddy
Propylhomoserin-N, N- dibenzyl ethylenediamine salt,
Preferably, pemetrexed-the N, N- dibenzyl ethylenediamine salts contain 0~10 crystalline water molecules.
Further preferably, the pemetrexed-N, N- dibenzyl ethylenediamine salts contain 1~7 crystalline water molecules.
A kind of pemetrexed-N, the preparation method of N- dibenzyl ethylenediamine salts, it is characterised in that comprise the following steps：
(1) pemetrexed disodium or its heptahydrate are put into the mixing of water or organic solvent or water and organic solvent
In liquid, N2Under protection, the temperature of control system is 20~35 DEG C；
(2) mixing that the aqueous solution or acetic acid and organic solvent of acetic acid or acetic acid are added in the system of step (1) is molten
Liquid, N2Under protection, the temperature of control system is 20~35 DEG C, reacts 1~1.5h；Suction filtration and drenched after completion of the reaction with organic solvent
Wash, gained filter cake is obtained into pemetrexed diacid in 12~16h of vacuum drying at 40~45 DEG C；
(3) pemetrexed diacid for obtaining step (2) dissolves in organic solvent, addition N, N- dibenzyl-ethylenediamins,
N2Under protection, control system temperature is 20~35 DEG C, reacts 3~3.5h；Temperature of reaction system is down to 10 after completion of the reaction~
18 DEG C, it is incubated 1~1.5h；
(4) eluted to mixture suction filtration obtained by step (3) and with organic solvent, by gained filter cake in being depressurized at 40~45 DEG C
12~16h is dried, that is, obtains described pemetrexed-N, N- dibenzyl ethylenediamine salt.
In such scheme, the mass ratio of the pemetrexed disodium or its heptahydrate and acetic acid is 1:1~10.
In above-mentioned each preferred scheme, the mol ratio of pemetrexed diacid and N, the N- dibenzyl-ethylenediamin is 1:1~
10。
Preferably, described organic solvent is methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, isopropyl acetate
In any one.
Compared with prior art, the advantage of the invention is that：
Pemetrexed-N, the N- dibenzyl ethylenediamine salt of the present invention has preferable stability, both can with anhydrous or
Exist in the form of hydrate, and the pemetrexed-N, N- dibenzyl ethylenediamine salt has no report in the prior art, it is beautiful for training
Qu Sai dosage form research provides new selection；
Pemetrexed-N of the present invention, the preparation method simple and reasonable steps of N- dibenzyl ethylenediamine salts, products therefrom
HPLC >=99.70%, single contaminant content is less than 0.1%, and total moles yield reaches 75~80%.
Brief description of the drawings
Fig. 1 is the HPLC collection of illustrative plates of the products therefrom of the embodiment of the present invention 1；
Fig. 2 is the DSC collection of illustrative plates of the products therefrom of the embodiment of the present invention 1.
Embodiment
The present invention is described in further detail below in conjunction with accompanying drawing embodiment.
Pemetrexed-N, the N- dibenzyl ethylenediamine salt of the present invention has formula (I) structure, pemetrexed-N, N- dibenzyl
The chemical name of base ethylenediamine salt is N- [4- [2- (2- amino -4,7- dihydros -4- oxo -1H- pyrrolo-es [2,3-d]-pyrimidines -
5- yls) ethyl] benzoyl]-Pidolidone-N, N- dibenzyl ethylenediamine salt,
Above-mentioned pemetrexed-N, reaction equation prepared by N- dibenzyl ethylenediamine salts is as follows：
The preparation method of 1~5 pair of pemetrexed-N, N- dibenzyl ethylenediamine salt is carried out specifically by the following examples
It is bright.
Embodiment 1：
The preparation method of pemetrexed-N in the present embodiment, N- dibenzyl ethylenediamine salt comprises the following steps：
(1)N2Under protection, the heptahydrate of 5.0g pemetrexed disodiums is put into the 250mL for filling 100mL purified waters
In four-hole boiling flask, in being stirred at 20 DEG C to being completely dissolved；
(2) in N2Under protection, the aqueous acetic acid that 26mL volumetric concentrations are 23% is added into the system of step (1), should
Aqueous acetic acid is complete in being dripped in 30min；The temperature of control system is 20 DEG C, stirring reaction 1h；Suction filtration after completion of the reaction, with purifying
Filter cake is eluted and drained twice by water, and each purified water usage amount is 25mL, then elutes filter cake with absolute ethyl alcohol and drain two
Secondary, each absolute ethyl alcohol usage amount is 10mL；Gained filter cake is taken to obtain pemetrexed diacid in vacuum drying 12h at 40 DEG C；
(3) in N2Under protective effect, the pemetrexed diacid input for taking 3.75g steps (2) to obtain fills 80mL acetone
In four-hole boiling flask, in being stirred at 20 DEG C to being completely dissolved；Then in N2Protective effect, at 20 DEG C, 2.2g N, N- dibenzyl is added dropwise
Dripped in the mixed solution that ethylenediamine is constituted with 20mL acetone, 30min, insulation reaction 3h after completion of dropping；After completion of the reaction
Temperature of reaction system is down to 10 DEG C, 1h is incubated；
(4) to mixture suction filtration obtained by step (3) and filter cake is eluted and drained twice with 10 DEG C of acetone, each acetone
Usage amount is 10mL；By gained filter cake in being dried under reduced pressure 12h at 40 DEG C, that is, obtain product pemetrexed-N, N- dibenzyl second two
Amine salt.
As shown in figure 1, HPLC >=99.74% of products therefrom, single contaminant is less than 0.1%, total moles yield 75~
80%；As shown in Fig. 2 pemetrexed-N, N- dibenzyl ethylenediamine salt has a wide endothermic peak between 78~150 DEG C,
There is a sharp endothermic peak between 180.5~184 DEG C, there is a sharp endothermic peak between 227~256 DEG C.
Embodiment 2：
The preparation method of pemetrexed-N in the present embodiment, N- dibenzyl ethylenediamine salt comprises the following steps：
(1)N2Under protection, the heptahydrate of 5.0g pemetrexed disodiums is put into and fills 100mL absolute ethyl alcohols
In 250mL four-hole boiling flasks, in being stirred at 35 DEG C to being completely dissolved；
(2) in N2Under protection, the ethanol acetate solution that 52mL volumetric concentrations are 23% is added into the system of step (1),
The ethanol acetate solution is complete in being dripped in 30min；The temperature of control system is 35 DEG C, stirring reaction 1.5h；Suction filtration after completion of the reaction,
Filter cake is eluted and drained twice with purified water, each purified water usage amount is 25mL, then is eluted filter cake simultaneously with absolute ethyl alcohol
Drain twice, each absolute ethyl alcohol usage amount is 10mL；Gained filter cake is taken to obtain pemetrexed two in vacuum drying 16h at 45 DEG C
Acid；
(3) in N2Under protective effect, the pemetrexed diacid input for taking 3.75g steps (2) to obtain fills 80mL acetic acid second
In the four-hole boiling flask of ester, in being stirred at 35 DEG C to being completely dissolved；Then in N2Protective effect, at 35 DEG C, 4.4g N, N- bis- is added dropwise
Dripped in the mixed solution that benzyl ethylenediamine is constituted with 20mL ethyl acetate, 30min, insulation reaction 3.5h after completion of dropping；
Temperature of reaction system is down to 18 DEG C after completion of the reaction, 1.5h is incubated；
(4) to mixture suction filtration obtained by step (3) and filter cake is eluted and drained twice with 20 DEG C of ethyl acetate, every time
Ethyl acetate usage amount is 10mL；By gained filter cake in being dried under reduced pressure 16h at 45 DEG C, that is, obtain product pemetrexed-N, N- bis-
Benzyl ethylenediamine salt.
Embodiment 3：
The preparation method of pemetrexed-N in the present embodiment, N- dibenzyl ethylenediamine salt comprises the following steps：
(1)N2Under protection, it is 50% that the heptahydrate of 5.0g pemetrexed disodiums, which is put into, and fills 100mL volumetric concentrations
Ethanol water four-hole boiling flask in, in being stirred at 25 DEG C to being completely dissolved；
(2) in N2Under protection, the aqueous acetic acid that 78mL volumetric concentrations are 23% is added into the system of step (1), should
Aqueous acetic acid is complete in being dripped in 30min；The temperature of control system is 25 DEG C, stirring reaction 1.2h；Suction filtration after completion of the reaction, with pure
Change water filter cake elute and drained twice, each purified water usage amount is 25mL, then filter cake eluted and drained with absolute ethyl alcohol
Twice, each absolute ethyl alcohol usage amount is 10mL；Gained filter cake is taken to obtain pemetrexed diacid in vacuum drying 14h at 42 DEG C；
(3) in N2Under protective effect, the pemetrexed diacid input for taking 3.75g steps (2) to obtain fills 80mL tetrahydrochysene furans
In the four-hole boiling flask muttered, in being stirred at 25 DEG C to being completely dissolved；Then in N2Protective effect, at 25 DEG C, 6.6g N, N- bis- is added dropwise
Dripped in the mixed solution that benzyl ethylenediamine is constituted with 20mL tetrahydrofurans, 30min, insulation reaction 3.2h after completion of dropping；
Temperature of reaction system is down to 15 DEG C after completion of the reaction, 1.2h is incubated；
(4) to mixture suction filtration obtained by step (3) and filter cake is eluted and drained twice with 15 DEG C of acetone, each acetone
Usage amount is 10mL；By gained filter cake in being dried under reduced pressure 13h at 43 DEG C, that is, obtain product pemetrexed-N, N- dibenzyl second two
Amine salt.
Embodiment 4：The preparation method of pemetrexed-N in the present embodiment, N- dibenzyl ethylenediamine salt comprises the following steps：
(1)N2Under protection, the heptahydrate of 5.0g pemetrexed disodiums is put into the 250mL for filling 100mL purified waters
In four-hole boiling flask, in being stirred at 23 DEG C to being completely dissolved；
(2) in N2Under protection, 218.6mL volumetric concentrations are added into the system of step (1) molten for 23% acetate methanol
Liquid, the acetate methanol solution is complete in being dripped in 30min；The temperature of control system is 23 DEG C, stirring reaction 1.3h；Take out after completion of the reaction
Filter, filter cake with purified water eluted and drained twice, and each purified water usage amount is 25mL, then is eluted filter cake with absolute ethyl alcohol
And drain twice, each absolute ethyl alcohol usage amount is 10mL；Gained filter cake is taken to obtain pemetrexed two in vacuum drying 13h at 44 DEG C
Acid；
(3) in N2Under protective effect, it is different that the pemetrexed diacid input for taking 3.75g steps (2) to obtain fills 80mL acetic acid
In the four-hole boiling flask of propyl ester, in being stirred at 23 DEG C to being completely dissolved；Then in N2Protective effect, at 23 DEG C, 10.6g N are added dropwise,
Dripped in the mixed solution that N- dibenzyl-ethylenediamins are constituted with 20mL isopropyl acetates, 30min, insulation reaction after completion of dropping
3.2h；Temperature of reaction system is down to 12 DEG C after completion of the reaction, 1.4h is incubated；
(4) to mixture suction filtration obtained by step (3) and filter cake is eluted and drained twice with 17 DEG C of isopropyl acetate, often
Secondary isopropyl acetate usage amount is 10mL；By gained filter cake in being dried under reduced pressure 15h at 44 DEG C, that is, product pemetrexed-N is obtained,
N- dibenzyl ethylenediamine salts.
Embodiment 5：
The preparation method of pemetrexed-N in the present embodiment, N- dibenzyl ethylenediamine salt comprises the following steps：
(1)N2Under protection, 5.0g pemetrexed disodiums are put into the 250mL four-hole boiling flasks for filling 100mL absolute methanols
In, in being stirred at 30 DEG C to being completely dissolved；
(2) in N2Under protection, 437.2mL volumetric concentrations are added into the system of step (1) molten for 23% acetate methanol
Liquid, the acetate methanol solution is complete in being dripped in 30min；The temperature of control system is 30 DEG C, stirring reaction 1.1h；Take out after completion of the reaction
Filter, filter cake with purified water eluted and drained twice, and each purified water usage amount is 25mL, then is eluted filter cake with absolute methanol
And drain twice, each absolute methanol usage amount is 10mL；Gained filter cake is taken to obtain pemetrexed two in vacuum drying 15h at 42 DEG C
Acid；
(3) in N2Under protective effect, the pemetrexed diacid input for taking 3.75g steps (2) to obtain fills 80mL MEKs
Four-hole boiling flask in, in being stirred at 22 DEG C to being completely dissolved；Then in N2Protective effect, at 22 DEG C, 21.1g N, N- bis- is added dropwise
Dripped in the mixed solution that benzyl ethylenediamine is constituted with 20mL MEKs, 30min, insulation reaction 3.1h after completion of dropping；Instead
Temperature of reaction system is down to 15 DEG C after should finishing, 1.4h is incubated；
(4) to mixture suction filtration obtained by step (3) and filter cake is eluted and drained twice with 12 DEG C of MEK, each first
Ethyl ketone usage amount is 10mL；By gained filter cake in being dried under reduced pressure 15h at 44 DEG C, that is, obtain product pemetrexed-N, N- dibenzyl
Ethylenediamine salt.
Claims (2)
1. a kind of pemetrexed-N, the preparation method of N- dibenzyl ethylenediamine salts, it is characterised in that：Pemetrexed-the N, N-
Dibenzyl ethylenediamine salt has formula (I) structure, and chemical name is N- [4- [2- (2- amino -4,7- dihydro -4- oxo -1H- pyrroles
Cough up simultaneously [2,3-d]-pyrimidine -5- bases) ethyl] benzoyl]-Pidolidone-N, N- dibenzyl ethylenediamine salt,
Described preparation method comprises the following steps：
(1) pemetrexed disodium or its heptahydrate are put into the mixed liquor of water or organic solvent or water and organic solvent,
N2Under protection, the temperature of control system is 20~35 DEG C；The mass ratio of the pemetrexed disodium or its heptahydrate and acetic acid
For 1:1~10；
(2) aqueous solution or acetic acid and the mixed solution of organic solvent of acetic acid or acetic acid, N are added in the system of step (1)2Protect
Under shield, the temperature of control system is 20~35 DEG C, reacts 1~1.5h；Suction filtration and eluted after completion of the reaction with organic solvent, by institute
Obtain filter cake and obtain pemetrexed diacid in 12~16h of vacuum drying at 40~45 DEG C；
(3) the pemetrexed diacid dissolving obtained step (2) in organic solvent, adds N, N- dibenzyl-ethylenediamins, N2Protection
Under, control system temperature is 20~35 DEG C, reacts 3~3.5h；Temperature of reaction system is down to 10~18 DEG C, guarantor after completion of the reaction
1~1.5h of temperature；The mol ratio of pemetrexed diacid and N, the N- dibenzyl-ethylenediamin is 1:1~10；
(4) eluted to mixture suction filtration obtained by step (3) and with organic solvent, gained filter cake is dried under reduced pressure at 40~45 DEG C
12~16h, that is, obtain described pemetrexed-N, N- dibenzyl ethylenediamine salt.
2. pemetrexed-N according to claim 1, the preparation method of N- dibenzyl ethylenediamine salts, it is characterised in that：Institute
The organic solvent stated is any one in methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, isopropyl acetate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510239656.3A CN104817563B (en) | 2015-05-11 | 2015-05-11 | The preparation method of pemetrexed N, N dibenzyl ethylenediamine salt |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510239656.3A CN104817563B (en) | 2015-05-11 | 2015-05-11 | The preparation method of pemetrexed N, N dibenzyl ethylenediamine salt |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104817563A CN104817563A (en) | 2015-08-05 |
| CN104817563B true CN104817563B (en) | 2017-10-27 |
Family
ID=53728062
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510239656.3A Active CN104817563B (en) | 2015-05-11 | 2015-05-11 | The preparation method of pemetrexed N, N dibenzyl ethylenediamine salt |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104817563B (en) |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CZ301563B6 (en) * | 1997-09-26 | 2010-04-14 | Eli Lilly And Company | Process for preparing pyrrolopyrimidine derivatives |
| CN100364993C (en) * | 2003-05-30 | 2008-01-30 | 江苏恒瑞医药股份有限公司 | Peimequizane salt and its preparation |
| CN101033227A (en) * | 2006-03-09 | 2007-09-12 | 上海金色医药科技发展有限公司 | Pemetrexed ethylenediamine salt and preparation method thereof |
-
2015
- 2015-05-11 CN CN201510239656.3A patent/CN104817563B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN104817563A (en) | 2015-08-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105541844B (en) | Simple preparation method of high-purity linagliptin | |
| CN106349245A (en) | Sitagliptin phosphate impurities, method for preparing same and application of sitagliptin phosphate impurities | |
| CN105859615B (en) | A kind of preparation method and intermediate of Dequalinium Chloride | |
| CN104231016A (en) | Etimicin sulfate preparation method | |
| CN110590805A (en) | Preparation method of high-purity II crystal form clopidogrel hydrogen sulfate | |
| CN104356038A (en) | Vitamin D2 and vitamin D3 eutectic crystal as well as preparation method and application thereof | |
| ES2957314T3 (en) | Processes for the preparation of pyrimidinylcyclopentane compounds | |
| CN103319422B (en) | A kind of Gefitinib crystal formation and preparation method thereof | |
| CN103145636B (en) | 1,4-diacyl-3,6-diphenyl-1,4-dihydrotetrazine compound as well as preparation method and application thereof | |
| CN104817563B (en) | The preparation method of pemetrexed N, N dibenzyl ethylenediamine salt | |
| CN107163060A (en) | A kind of bisulfate clopidogrel crystal formation II preparation methods | |
| CN104130146B (en) | (4S) preparation method of-3,6,9-tri-azepine-3,6,9-tri-(carboxymethyl)-4-(4-ethoxy benzyl) undecane diacids | |
| CN104327053A (en) | Deuterated crizotinib and derivative thereof, preparation method and application | |
| CN105273023A (en) | Preparation method of cytarabine 5'-O-L-valine ester hydrochloride | |
| CN103450157B (en) | Preparation method for high-purity hydroxyfasudil semihydrate | |
| CN102633779B (en) | Fasudil acetate as well as preparation method and application thereof | |
| CN105152949A (en) | Amino-acid ester derivative cation type chiral ionic liquid and preparation method thereof | |
| CN112707869B (en) | Dacotinib impurity and preparation method thereof | |
| CN102603594B (en) | Preparation method of (S)-oxiracetam | |
| CN104725349A (en) | Polycrystalline A-type crystal of alogliptin polycrystalline, preparation method and production purpose thereof | |
| CN106349145A (en) | Method for preparing intelligence-improving medicine (S)-oxiracetam | |
| CN104327014B (en) | A kind of preparation method of L-chloperastine fendizoic acid | |
| CN102786527B (en) | Tailed porphyrin compound modified by N1-substituted 3, 4-dihydropyrimidine-2-ketone and preparation method thereof | |
| CN102276442B (en) | Synthetic method of dichloroacetate | |
| CN105131050A (en) | Preparation method of chlorinating agent and method therewith for preparing sucralose |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| EXSB | Decision made by sipo to initiate substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |