CN109467577A - A kind of preparation method of Suo Feibuwei crystal form and amorphous products - Google Patents
A kind of preparation method of Suo Feibuwei crystal form and amorphous products Download PDFInfo
- Publication number
- CN109467577A CN109467577A CN201811487312.4A CN201811487312A CN109467577A CN 109467577 A CN109467577 A CN 109467577A CN 201811487312 A CN201811487312 A CN 201811487312A CN 109467577 A CN109467577 A CN 109467577A
- Authority
- CN
- China
- Prior art keywords
- suo feibuwei
- preparation
- crystal form
- amorphous products
- suo
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
- C07H1/06—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
A kind of preparation method of Suo Feibuwei crystal form and amorphous products; include the following steps: the preparation of (1) Suo Feibuwei: under the conditions of anhydrous and oxygen-free; the fluoro- 2'- methylurea glycosides of (2'R) -2'- deoxidation -2'-, N- [(S)-(2; 3; 4; 5,6- phenyl-pentafluoride oxygroups) phenoxy group phosphoryl]-l-Alanine isopropyl ester grignard reagent effect under Suo Feibuwei crude product is prepared；(2) preparation of Suo Feibuwei crystal form product: taking Suo Feibuwei crude product, be placed in ketones solvent, and decolorising agent is added, and dissolves, and decoloration, crystallization is dried to obtain Suo Feibuwei crystal form product；(3) preparation of Suo Feibuwei amorphous products: taking Suo Feibuwei crude product, be placed in alcohols solvent, and decolorising agent is added, and dissolves, and decoloration, crystallization crushes, is dried to obtain Suo Feibuwei amorphous products.The beneficial effects of the present invention are: preparation method is simple, strong operability, waste generate less, cost is relatively low, efficiently solves the deficiency in existing product crystal form preparation method.
Description
Technical field
The present invention relates to a kind of preparation methods of potent anti-hepatitis C virus drug, and in particular to a kind of Suo Feibuwei crystal form and
The preparation method of amorphous products.
Background technique
Suo Feibuwei, Sofosbuvir, Chinese chemical name are N- [ (S) -2- (S)-(2R, 3R, 4 R, 5R) -5-
(- 1 (2H)-yl of 2,4- dioxo -3,4- dihydro-pyrimidin) -4- fluoro -3- hydroxy-4-methyl tetrahydrofuran -2- base) first
Oxygroup) (phenoxy group) phosphinylidyne amino) isopropyl propionate (structural formula is as shown in Equation 1):
Formula 1.
It is well known that polymorph in pharmaceuticals is generally existing phenomenon, the drug physics and chemistry of different crystal forms in chemicals
Matter difference, also has more apparent influence to the process of Subsequent pharmacological preparation, therefore in bulk pharmaceutical chemicals and formulation process
In, it should focus on to consider drug crystal forms problem.According to the literature, there are polymorphisies by Suo Feibuwei, mainly with crystal form I, crystalline substance
Based on type VI, in addition to this, there is also the crystal forms such as unformed, crystal form A by Suo Feibuwei.
Patent WO2011123645 reports the preparation method of Suo Feibuwei amorphous products；Patent WO2016097173 report
The road preparation method of Suo Feibuwei crystal form product, i.e., prepare in two or three of organic solvent such as ethyl alcohol, isopropyl ether, acetone
Crystal form product out.The crystal form preparation process reported in above-mentioned patent, is crystallized, in turn using the organic solvent compared with multiple types
Mixed solvent is brought to be difficult to recycle, the technical problems such as waste liquid yield is larger.Meanwhile having in bulk pharmaceutical chemicals to Determination of Residual Organic Solvents
The use of stringent regulation, multi-solvents also brings bigger difficulty to the removal of organic solvent.
Summary of the invention
To solve the problems, such as existing preparation process, the present invention provides a kind of Suo Feibuwei crystal form and unformed productions
The preparation method of product, preparation method is simple for this, strong operability, waste generate less, cost is relatively low, efficiently solves
Deficiency in existing product preparation method.
The present invention adopts the following technical scheme that solve the above problems:
(1) preparation of Suo Feibuwei: under the conditions of anhydrous and oxygen-free, the fluoro- 2'- methylurea glycosides of (2'R) -2'- deoxidation -2'-, N-
[(S)-(2,3,4,5,6- phenyl-pentafluoride oxygroup) phenoxy group phosphoryl]-l-Alanine isopropyl ester and grignard reagent are deposited in reaction dissolvent
It reacts under conditions, after completion of the reaction, concentrated hydrochloric acid and water quenching reaction is added dropwise, removes reaction dissolvent under reduced pressure, then extracts, merge
Organic phase, re-dry filter, and are concentrated under reduced pressure, obtain grease crude product, and methylene chloride is added into grease crude product, heat dissolved clarification,
Then it is cooled to stirring and crystallizing at 0-10 DEG C, obtains Suo Feibuwei crude product；
(2) preparation method of Suo Feibuwei crystal form product: taking Suo Feibuwei crude product, be placed in ketones solvent, and stirring is warming up to
55-65 DEG C of reaction, adds decolorising agent, is stirred to react, filter while hot, and cool down crystallization, and decompression drying obtains crystal form product；
(3) the unformed preparation method of Suo Feibuwei: taking Suo Feibuwei crude product, be placed in alcohols solvent, and stirring is warming up to 60-
80 DEG C of back flow reactions, add decolorising agent, are stirred to react, filter while hot, evaporating solvent under reduced pressure, crush, and drying obtains unformed
Product.
In above-mentioned technical proposal, in the preparation process of Suo Feibuwei crude product, the grignard reagent is isopropylmagnesium chloride, institute
Stating reaction dissolvent is tetrahydrofuran.
In the preparation process of Suo Feibuwei crystal form product, the ketones solvent is methylisobutylketone, 2- butanone or methyl- tert
Butyl ketone, the decolorising agent are activated carbon or silica gel.
Wherein, in the preparation process of Suo Feibuwei crystal form product, the temperature of the temperature reaction is controlled at 55-65 DEG C, institute
The temperature for stating Crystallization Process is controlled at 10-15 DEG C.
In the preparation process of Suo Feibuwei amorphous products, the alcohols solvent is methanol, ethyl alcohol or isopropanol, described de-
Toner is activated carbon or silica gel.
Wherein, the temperature control of the temperature rising reflux reaction is 60-80 DEG C, and the vacuum distillation temperature is 30-40 DEG C.
The beneficial effects of the present invention are: preparation method is simple, strong operability, waste generate less, cost compared with
It is low, efficiently solve the deficiency in existing product crystal form preparation method；The type that organic solvent uses is less, and subsequent removal has
The difficulty of solvent is smaller.
Detailed description of the invention
Fig. 1 is that the XRPD of Suo Feibuwei crystal form product schemes.
Fig. 2 is that the DSC of Suo Feibuwei crystal form product schemes.
Fig. 3 is that the TGA of Suo Feibuwei crystal form product schemes.
Fig. 4 is that the XRPD of Suo Feibuwei amorphous products schemes.
Fig. 5 is that the DSC of Suo Feibuwei amorphous products schemes.
Fig. 6 is that the TGA of Suo Feibuwei amorphous products schemes.
X-ray powder diffraction (XRPD): in XRPD map, ordinate is diffracted intensity, with counting (counts) table
Show；Abscissa is 2 θ of the angle of diffraction, and expenditure (°) indicates.
Differential scanning calorimetry (DSC): in DSC figure, ordinate is the heat flow that the substance of unit quality is released, and is used
(Heat, Flow, W/g) is indicated；Abscissa is temperature, is indicated with (DEG C).
Thermogravimetry (TGA): in TGA figure, ordinate is weightless percentage composition, is indicated with (Weight, %)；It is horizontal
Coordinate is temperature, is indicated with (DEG C).
Specific embodiment
In order to deepen the understanding of the present invention, below with reference to embodiment and attached drawing, the invention will be further described, the reality
It applies example for explaining only the invention, is not intended to limit the scope of the present invention..
Embodiment 1
The preparation of Suo Feibuwei:
In reaction flask, under the conditions of anhydrous and oxygen-free, the fluoro- 2'- methylurea glycosides of 48g (2'R) -2'- deoxidation -2'-, 300mL is added
Tetrahydrofuran, stirring are cooled to -30 DEG C, and 106g 2.0M isopropylmagnesium chloride is added dropwise；Drop finishes, and is stirred to react 1 hour, then rises
99g N- [(S)-(2,3,4,5,6- phenyl-pentafluoride oxygroup) phenoxy group phosphoryl]-l-Alanine isopropyl ester is added dropwise to -10 DEG C in temperature
200mL tetrahydrofuran solution；Drop finishes, and reacts 1 hour at -10 DEG C, then heats to room temperature reaction, TLC monitoring reaction.Reaction
It finishes, is cooled to 0 DEG C, start that concentrated hydrochloric acid/water (100mL/300mL) quenching reaction is added dropwise；Remove tetrahydrofuran under reduced pressure, then plus
Entering 300mL ether, stirs liquid separation, water layer is extracted with ether (200mL × 3), merge organic phase, with saturated sodium bicarbonate solution,
Saturated sodium-chloride, anhydrous sodium sulfate is dry, filters, and is concentrated under reduced pressure, obtains 75g grease crude product.3 times are added into grease crude product
Methylene chloride is measured, dissolved clarification is heated, is then cooled to stirring and crystallizing at 0-10 DEG C, filters, dries to obtain 68g Suo Feibuwei crude product.
Embodiment 2
The preparation of Suo Feibuwei crystal form product:
10g Suo Feibuwei crude product is taken, is placed in 80mL methyl tert-butyl ketone solvent, stirring and dissolving, is warming up to 60-65 DEG C, reaction 1 is small
When, 1g activated carbon is added, is stirred to react 1 hour.End of reaction, slow cooling filter while hot to 35-40 DEG C, filter cake heat
Methylisobutylketone rinsing, filtrate are cooled to 10-15 DEG C of crystallization again, filter, and filter cake decompression drying at 50 DEG C obtains 9.4g Suo Fei
Cloth Wei crystal form product.
10g Suo Feibuwei crude product is taken, is placed in 80mL 2- butanone solvent, stirring and dissolving, is warming up to 55-60 DEG C, reaction 1
Hour, 1g silica gel is added, is stirred to react 1 hour, end of reaction, slow cooling filters while hot to 35-40 DEG C, filter cake heat
The rinsing of 2- butanone, filtrate are cooled to 10-15 DEG C of crystallization again, filter, and filter cake decompression drying at 50 DEG C obtains 9.2g Suo Feibuwei
Crystal form product.
Suo Feibuwei prepared by embodiment 2 is a kind of crystal form product, can be obtained in embodiment 2 from the map of Fig. 1-3
The characteristic spectrum of Suo Feibuwei and existing identical, but method described in embodiment 2, it is easy to operate, it is molten using single ketone
Agent, usage amount is few and is easily recycled and applies, and product yield is high, and purity is high is very suitable for industrialized production.
Embodiment 3
The preparation of Suo Feibuwei amorphous products:
10g Suo Feibuwei crude product is taken, is placed in 100ml isopropanol solvent, stirring and dissolving, 60-65 DEG C of reflux is warming up to, is reacted
30min adds 1g activated carbon, is stirred to react 1 hour, filters while hot, and with hot isopropyl alcohol filter cake, filtrate is at 30-35 DEG C
Lower evaporating solvent under reduced pressure, obtains foaming solid, then crushes, dries, and obtains 9.8g Suo Feibuwei amorphous products.
10g Suo Feibuwei crude product is taken, is placed in 100ml alcohol solvent, stirring and dissolving, 75-80 DEG C of reflux is warming up to, is reacted
30min adds 1g silica gel, is stirred to react 1 hour, filters while hot, rinses filter cake with hot ethanol, filtrate subtracts at 35-40 DEG C
Solvent is evaporated off in pressure, obtains foaming solid, then crush, dry, obtains 9.7g Suo Feibuwei amorphous products.
Suo Feibuwei manufactured in the present embodiment is amorphous products, from the rope that can be obtained in embodiment 3 in the map of Fig. 4-6
The characteristic spectrum of Fei Buwei with it is existing identical, but method described in embodiment 3 prepare the amorphous products, operation letter
Just, using single alcohols solvent, usage amount is few, and product yield is high, and purity is high is very suitable for industrialized production.
Claims (8)
1. a kind of preparation method of Suo Feibuwei crystal form product, under the conditions of anhydrous and oxygen-free, the fluoro- 2'- of (2'R) -2'- deoxidation -2'-
Methylurea glycosides, N- [(S)-(2,3,4,5,6- phenyl-pentafluoride oxygroup) phenoxy group phosphoryl]-l-Alanine isopropyl ester and grignard reagent
It is reacted under reaction dissolvent existence condition, by extraction, concentration and crystallization obtain Suo Feibuwei crude product, it is characterised in that: it is special
Sign is: Suo Feibuwei crude product obtained being placed in ketones solvent, is stirred, temperature reaction, decolorising agent is added, stirring is anti-
It answers, filters while hot, cool down crystallization, and decompression drying obtains Suo Feibuwei crystal form product.
2. a kind of preparation method of Suo Feibuwei crystal form product according to claim 1, it is characterised in that: the format examination
Agent is isopropylmagnesium chloride, and the reaction dissolvent is tetrahydrofuran.
3. a kind of preparation method of Suo Feibuwei crystal form product according to claim 1 or 2, it is characterised in that: the ketone
Class solvent is methylisobutylketone, 2- butanone or methyl tertbutyl ketone, and the decolorising agent is activated carbon or silica gel.
4. a kind of preparation method of Suo Feibuwei crystal form product according to claim 1 or 2, it is characterised in that: the liter
The temperature of temperature reaction is controlled at 55-65 DEG C, and the temperature of the Crystallization Process is controlled at 10-15 DEG C.
5. a kind of preparation method of Suo Feibuwei amorphous products, under the conditions of anhydrous and oxygen-free, (2'R) -2'- deoxidation -2'- is fluoro-
2'- methylurea glycosides, N- [(S)-(2,3,4,5,6- phenyl-pentafluoride oxygroup) phenoxy group phosphoryl]-l-Alanine isopropyl ester and format examination
Agent is reacted under reaction dissolvent existence condition, and by extraction, concentration and crystallization obtain Suo Feibuwei crude product, it is characterised in that: take
Suo Feibuwei crude product, is placed in alcohols solvent, stirring, and temperature rising reflux reaction adds decolorising agent, is stirred to react, filters while hot,
Evaporating solvent under reduced pressure crushes, and drying obtains amorphous products.
6. a kind of preparation method of Suo Feibuwei amorphous products according to claim 5, it is characterised in that: the format
Reagent is isopropylmagnesium chloride, and the reaction dissolvent is tetrahydrofuran.
7. a kind of preparation method of Suo Feibuwei amorphous products according to claim 5 or 6, it is characterised in that: described
Alcohols solvent is methanol or ethyl alcohol or isopropanol, and the decolorising agent is activated carbon or silica gel.
8. a kind of preparation method of Suo Feibuwei amorphous products according to claim 5 or 6, it is characterised in that: described
The temperature control of temperature rising reflux reaction is 60-80 DEG C, and the vacuum distillation temperature is 30-40 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811487312.4A CN109467577A (en) | 2018-12-06 | 2018-12-06 | A kind of preparation method of Suo Feibuwei crystal form and amorphous products |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811487312.4A CN109467577A (en) | 2018-12-06 | 2018-12-06 | A kind of preparation method of Suo Feibuwei crystal form and amorphous products |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109467577A true CN109467577A (en) | 2019-03-15 |
Family
ID=65675728
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811487312.4A Pending CN109467577A (en) | 2018-12-06 | 2018-12-06 | A kind of preparation method of Suo Feibuwei crystal form and amorphous products |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109467577A (en) |
Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104130302A (en) * | 2014-08-08 | 2014-11-05 | 广东东阳光药业有限公司 | Crystal form of nucleotide medicines and preparation method of crystal form |
| CN104558079A (en) * | 2015-01-30 | 2015-04-29 | 南京正大天晴制药有限公司 | Preparation method of high-purity sofosbuvir compound and related substances |
| CN105017359A (en) * | 2015-07-08 | 2015-11-04 | 苏州晶云药物科技有限公司 | Preparation method of Sofosbuvir crystal form |
| WO2016035006A1 (en) * | 2014-09-01 | 2016-03-10 | Dr. Reddy’S Laboratories Limited | Novel nucleotide analogs, process for the preparation of sofosbuvir and its analogs, novel forms of sofosbuvir and solid dispersion of sofosbuvir |
| WO2016038542A2 (en) * | 2014-09-10 | 2016-03-17 | Mylan Laboratories Limited | Polymorphic forms of sofosbuvir |
| CN105669804A (en) * | 2016-03-28 | 2016-06-15 | 南通常佑药业科技有限公司 | Preparation method of sofosbuvir |
| CN106687470A (en) * | 2014-08-01 | 2017-05-17 | Hc-制药股份公司 | Sofosbuvir in crystalline form and process for its preparation |
| CN106699740A (en) * | 2016-12-26 | 2017-05-24 | 上海博志研新药物技术有限公司 | Ledipasvir and sofosbuvir compound tablet and preparation method and applications thereof |
| WO2017190715A1 (en) * | 2016-05-05 | 2017-11-09 | Zentiva, K.S. | An amorphous form of sofosbuvir, a method of its preparation and its stabilization |
| CN107427495A (en) * | 2015-02-13 | 2017-12-01 | 桑多斯股份公司 | Include Lei Dipawei and Suo Feibuwei pharmaceutical composition |
-
2018
- 2018-12-06 CN CN201811487312.4A patent/CN109467577A/en active Pending
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106687470A (en) * | 2014-08-01 | 2017-05-17 | Hc-制药股份公司 | Sofosbuvir in crystalline form and process for its preparation |
| CN104130302A (en) * | 2014-08-08 | 2014-11-05 | 广东东阳光药业有限公司 | Crystal form of nucleotide medicines and preparation method of crystal form |
| WO2016035006A1 (en) * | 2014-09-01 | 2016-03-10 | Dr. Reddy’S Laboratories Limited | Novel nucleotide analogs, process for the preparation of sofosbuvir and its analogs, novel forms of sofosbuvir and solid dispersion of sofosbuvir |
| WO2016038542A2 (en) * | 2014-09-10 | 2016-03-17 | Mylan Laboratories Limited | Polymorphic forms of sofosbuvir |
| CN104558079A (en) * | 2015-01-30 | 2015-04-29 | 南京正大天晴制药有限公司 | Preparation method of high-purity sofosbuvir compound and related substances |
| CN107427495A (en) * | 2015-02-13 | 2017-12-01 | 桑多斯股份公司 | Include Lei Dipawei and Suo Feibuwei pharmaceutical composition |
| CN105017359A (en) * | 2015-07-08 | 2015-11-04 | 苏州晶云药物科技有限公司 | Preparation method of Sofosbuvir crystal form |
| CN105669804A (en) * | 2016-03-28 | 2016-06-15 | 南通常佑药业科技有限公司 | Preparation method of sofosbuvir |
| WO2017190715A1 (en) * | 2016-05-05 | 2017-11-09 | Zentiva, K.S. | An amorphous form of sofosbuvir, a method of its preparation and its stabilization |
| CN106699740A (en) * | 2016-12-26 | 2017-05-24 | 上海博志研新药物技术有限公司 | Ledipasvir and sofosbuvir compound tablet and preparation method and applications thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105801645B (en) | The method for preparing Suo Feibuwei crystal form 6 | |
| CN105175401A (en) | Preparation method of brexpiprazole | |
| EP2387556B1 (en) | Separation of an enantiomer mixture of (r)- and (s)-3-amino-1-butanol | |
| CN101863948B (en) | High-purity (2 beta, 3 alpha, 5 alpha, 16 beta, 17 beta)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-androstane-3,17-diol or composition thereof and preparation method thereof | |
| CN106349138A (en) | Process for the preparation of chemically stable novel crystalline form of bimatoprost | |
| CN106565627A (en) | Preparation method for pharmaceutical crystal form of febuxostat | |
| AU2016365535B2 (en) | Method for producing N-retinoylcysteic acid alkyl ester | |
| EP2593459B1 (en) | Process for the preparation of sitagliptin orotate | |
| CN109467577A (en) | A kind of preparation method of Suo Feibuwei crystal form and amorphous products | |
| CN106256833B (en) | The method for preparing 3,7- bis- (trimethyl silicon substrate oxygroup) -5 β of -6- alkene-cholane -24- acid methyl esters | |
| CN110511193B (en) | Alpha-ketothioamide compound and synthetic method thereof | |
| CN105884644A (en) | Advantage forms and preparation method of neutral endopeptidase inhibitor salt | |
| CN105968026A (en) | Preparation method of high-purity Ubenimex | |
| CN104356086A (en) | Preparation method of 3-morpholone suitable for industrial production | |
| CN100408554C (en) | New technique for synthesizing hydrazinomethyl ester carbonate in high purity | |
| CN107715909A (en) | A kind of Proline-Catalyzed agent of pentaerythrite support and preparation method and application | |
| CN113816837A (en) | Synthesis method of 4,4' -dimethoxy triphenylchloromethane | |
| CN107089942B (en) | The preparation method of tegafur, gimeracil and oteracil potassium impurity B CB | |
| CN105753733A (en) | AHU377 crystal form and preparation method and uses thereof | |
| CN112375039A (en) | Novel crystal form A of (R) - (+) -1- (1-phenethyl) -2-mercaptoimidazole-5-carboxylic acid ethyl ester and preparation method thereof | |
| CN104844524A (en) | Synthetic method of ambrisentan | |
| CN104292149B (en) | A kind of method preparing ornithine lactams | |
| CN112939855B (en) | Process for preparing 1, 4-dihydropyridine derivatives containing azulene ring structure | |
| CN116239538A (en) | New lopinavir crystal form and preparation method thereof | |
| CN113754664B (en) | Linagliptin crystal form and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190315 |
|
| RJ01 | Rejection of invention patent application after publication |