CN108912109A - A kind of high-purity, small particle and azilsartan crude drug of low solvent residue and preparation method thereof - Google Patents
A kind of high-purity, small particle and azilsartan crude drug of low solvent residue and preparation method thereof Download PDFInfo
- Publication number
- CN108912109A CN108912109A CN201810934114.1A CN201810934114A CN108912109A CN 108912109 A CN108912109 A CN 108912109A CN 201810934114 A CN201810934114 A CN 201810934114A CN 108912109 A CN108912109 A CN 108912109A
- Authority
- CN
- China
- Prior art keywords
- reaction
- compound
- added
- azilsartan
- crystallization
- 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
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses azilsartan crude drug of a kind of high-purity, small particle and low solvent residue and preparation method thereof, azilsartan crude drug purity >=99.9%, granularity D90≤20 μm, dissolvent residual≤500ppm.The invention also discloses a kind of intermediate and preparation method thereof for being used to prepare azilsartan crude drug of high-purity, purity >=99.9% of the intermediate.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, are related to a kind of Azilsartan, specifically a kind of to have high-purity, granule
Degree and the Azilsartan of low solvent residue and preparation method thereof.
Background technique
The chemistry of Azilsartan (AzIlsartan) is entitled：2- ethyoxyl -1- [[2 '-(oxo -1,2 4,5- dihydro -5-,
4- oxadiazoles -3- base) biphenyl -4- base] methyl] benzimidazole -7- carboxylic acid, molecular formula：C25H20N4O5, molecular weight：456.45
Structural formula I is：
Azilsartan is by Japanese military field（Takeda）The AT1 subtype angiotensin II receptor antagonist of company's exploitation（ARB）,
It goes through to list in Japan on January 18th, 2012.It is used as dual function ARBs of new generation, not only antagonizing angiotensin II
1 receptor（AT1 receptor）, it is also possible to the risk of cardiovascular disease and diabetes is reduced by number of mechanisms.Clinical test card
Bright, Azilsartan has good therapeutic effect, and adverse reaction rate is lower, the preferable feature of compliance.
It is synthesized in the prior art about Azilsartan, there are mainly two types of, sees route 1 and route 2 respectively：
The two lines main distinction is the method for Formula II compound preparation, and the method that route 1 uses is formula III compound through acyl
Change, cyclization obtains formula IV compound, and the method that route 2 uses is formula III compound and N, N- dicarbapentaborane imidazoles（CDI）It is acylated
The direct cyclization of agent obtains formula IV compound.
Azilsartan purity is low prepared by the prior art and/or preparation method is cumbersome, and/or need to be thick to Azilsartan
Product refined and/or product in dissolvent residual it is high.
Patent CN102766138A（2012, authorization）A kind of preparation method of Azilsartan is disclosed, is original with formula IV -1
Material, water is solvent, and -1 compound of Formula II is prepared through addition, acylation and cyclization " one kettle way "（Azilsartan methyl esters）, through water
Solution obtains Azilsartan crude product, then obtains Azilsartan through ethyl alcohol recrystallization, and the purity of product is low, is 98 ~ 99%.
Patent WO2014049512A2 discloses a kind of preparation method of Azilsartan, and cyclization reaction is solvent-free anti-
It answers, reaction temperature is 110 ~ 115 DEG C and obtains cyclocomplex, Azilsartan is obtained through hydrolysis, 70 ~ 75 DEG C of hydrolysising reacting temperature,
Reaction temperature is high, obtains that product purity is low.
Patent CN103601723A discloses a kind of industrialized preparing process of Azilsartan, but this method, addition reaction
It is cumbersome, it needs to be beaten, recrystallization, yield is low, and only 68%, with acylating reagent such as CDI, dimethyl carbonate or carbonic acid diethyl
Cyclised products are prepared in ester, and purity is only 98% or so after purification, are recrystallized to give to obtain Azilsartan through hydrolysis, gained produces
Product purity is low, and granularity is big, and residual solvent is high.
It is miscellaneous that patent CN107056766A mentions the de- ethyl for being mainly trapped in above two method and generating in ring closure reaction
Matter is more, is difficult to be down to 0.1% hereinafter, and in this way by being repeatedly refining to obtain qualified Azilsartan also yield by refining
Extremely low, process is cumbersome, at high cost, is unfavorable for industrialized production, which, which uses, carries out ring with carbon dioxide in microreactor
Conjunction reaction is prepared cyclocomplex and is hydrolyzed again, is refining to obtain Azilsartan, but its obtained purity about 99.8%, and the party
Method realizes industrialization, and there are certain difficulty.
Patent CN104230909B discloses a kind of preparation method of Azilsartan, is prepared using addition and cyclization one kettle way
Cyclocomplex is obtained, wherein cyclization reaction uses acylating agent CDI, high income, but purity is low, hydrolyzes through 50 ~ 55 DEG C, ethyl alcohol recrystallization
Product is obtained, product purity is low, most preferred embodiment purity only 99.7%, and the granularity for being recrystallized to give product is big and residual solvent
It is high.
Patent CN103408500B discloses a kind of preparation method of Azilsartan, and compound IV is through using water and organic molten
The mixed solvent addition reaction of agent obtains compound III, and the reaction time is up to 18h.It is acylated further across acylation reaction
Product V, the intermediate is unstable, is not easy long term storage.Azilsartan is obtained through one pot of two-step method of cyclization-hydrolysis, this method obtains
To product purity still less than 99.9%.
Patent CN104119326B discloses a kind of preparation method of Azilsartan, first hydrolyzes compound II to obtain A Qi
Sodium salt, sylvite or the lithium salts of Sha Tan obtains Azilsartan acidified, and product purity is prepared less than 99.9% in this method,
It can further be refined with ethyl alcohol, purity can reach 99.99%, but since Azilsartan dissolubility is small, the volume of alcohols used is big,
And the dissolvent residual of product is high after purification, granularity is big.
Patent CN105712984A discloses a kind of preparation method of Azilsartan, and the thick of Azilsartan is first prepared
Product are refining to obtain product purity greater than 99.9% through ethyl alcohol, but the dosage of ethyl alcohol used is big, dissolvent residual height and grain in product
Degree is big.
Azilsartan easily causes organic solvent residual excessively high when recrystallizing, as disclosed in patent CN92105152C using second
Acetoacetic ester recrystallization, obtains colourless rhomboidan, and gained compound is solvate.
Patent CN106749216A discloses a kind of refining methd of crystal form A Azilsartan, mixed using ethyl acetate-ethanol
Solvent recrystallization is closed, most preferred embodiment ethyl alcohol residual is 800ppm, and granularity D90 is greater than 100 μm, and purity is less than 99.9%.
Azilsartan belongs to insoluble drug, solubility in water less than 9 μ g/ml, and prepared by the prior art Ah
Qi Shatan granularity is larger, it is difficult to be directly used in preparation, therefore in the preparation of its preparation, often need to carry out azilsartan crude drug
Micronization processes, disclosed technology have Mechanical Method, spray drying process and supercritical fluid extraction.Mechanical Method is most common
It is ball mill grinding and air-flow crushing, the frictional force generated in crushing process can be such that temperature of charge increases, and cause Azilsartan former
The degradation impurity of material medicine sharply increases；Spray drying process needs the consumption of high heat, high temperature will lead to while flinging to solvent Ah
The degradation impurity of Qi Shatan bulk pharmaceutical chemicals sharply increases；Although supercritical fluid extraction low operation temperature, it is miscellaneous to can avoid degradation
The generation of matter, but it needs high pressure, the high requirements on the equipment, increases cost, and there are bulk pharmaceutical chemicals crystal forms to turn brilliant risk.
Patent CN103831159B discloses a kind of Azilsartan method of micronization, in order to avoid what is generated in crushing process
Heat causes Azilsartan to degrade, and inventor is handled using cryogenic technique, 10 μm of product D90 < being micronized, the party
Method is at high cost, and there are still the risk that new impurity generates, there are certain difficulty for industrialization.
Patent CN103755694A discloses a kind of processing method of azilsartan crude drug, anti-molten using supercritical fluid
Agent method is to prepare superfines, acquired 15 μm of product D90 <, but this method pressure is high, the high requirements on the equipment is increased into
This, and there are bulk pharmaceutical chemicals crystal forms to turn brilliant risk.
The Azilsartans preparation such as patent CN105853384A, CN104306344A, CN105030711A, CN103705510A
Patent is required to micronization Azilsartan, 20 μm of partial size D90 <, and is micronized first is that cost is increased, second is that the content of impurity
Increase.
For the deficiency of existing azilsartan crude drug, as purity is low, granularity is big or dissolvent residual is high, it is necessary to develop one
The Azilsartan and preparation method thereof of kind high quality.
Summary of the invention
For the deficiency of existing azilsartan crude drug, the present invention provides a kind of Azilsartan, the Azilsartan
With purity is high, the feature that partial size is small and dissolvent residual is low.
The purity is high refers to purity not less than 99.5%, further refers to that purity is not less than 99.9%, further refers to pure
Degree is not less than 99.94%.
The partial size is small, refers to partial size D90 no more than 20 μm, further refers to that partial size D90 is not more than 15 μm, further
Refer to that partial size D90 is not more than 10 μm.
The dissolvent residual is low, refers to dissolvent residual no more than 500ppm, further refers to that dissolvent residual is not more than 250 μ
M, further finger dissolvent residual are not more than 100 μm.
The solvent refers to methanol, ethyl alcohol, ethyl acetate.
Further, the crystal form of the Azilsartan is crystal form A.
The X-ray powder diffraction figure of the crystal form A is indicated with the degree of 2 θ degree of diffraction, 9.1,12.7,19.3,21.4
With 23.5 ± 0.2 degree at have characteristic peak.
Further, the X-ray powder diffraction figure of the crystal form A is indicated with the degree of 2 θ degree of diffraction, 9.1,12.7,
15.3, there is at 18.6,19.3,20.1,20.4,21.4,23.5,25.2,25.5 and 26.6 ± 0.2 degree characteristic peak.
Further, the X-ray powder diffraction figure of the crystal form A is as shown in Figure 1.
The present invention also provides a kind of Azilsartan, the Azilsartan purity is high.
The purity is high refers to purity not less than 99.9%, further refers to that purity is not less than 99.95%.
The Azilsartan ester structure is as shown in Formula II：
Wherein R1 is selected from methyl, ethyl.
The present invention also provides a kind of preparation methods of above-mentioned Azilsartan, and route is as follows, includes the following steps：
1）Inorganic base is added in reaction dissolvent, stirs evenly, hydroxylamine hydrochloride is added, is stirred to react, compound IV is added, stirring is anti-
It answers, after reaction, cool down crystallization, filters to obtain compound III crude product；Compound III crude product is added in solvent, is crystallized,
Filtering, dry compound III finished product.
2）Acylation reaction：Compound III and organic base are added in reaction dissolvent, stirs evenly, is slowly added to acyl chlorides examination
Agent reaction, after reaction plus water quenching is gone out, liquid separation, and organic layer is concentrated under reduced pressure to give solid V；Cyclization reaction：Reaction dissolvent is added,
It is stirred to react, after reaction, cool down crystallization, filters to obtain compound II crude product.Compound II crude product is added in solvent, knot
Crystalline substance filters, dry, obtains compound II finished product.
3）Compound II is added in alkaline aqueous solution, is stirred to react, active carbon is added and continues to stir, filters, collects filter
Liquid.Cooling, with acid solution tune pH, is filtered, washed, dries to obtain compound I finished product.
Wherein step 1）Described in reaction dissolvent be selected from DMSO（Dimethyl sulfoxide）,DMF（N,N-dimethylformamide）,
DMAC（Dimethyl acetamide）, preferably DMSO；The inorganic base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, saleratus, hydrogen
Sodium oxide molybdena, preferably sodium bicarbonate.
Wherein step 1）The weight ratio of middle compound IV and reaction dissolvent is 1:2~1:8, preferably 1:4；Compound IV with
The molar ratio of inorganic base is 1:3~1:8, preferably 1:5；The molar ratio of compound IV and hydroxylamine hydrochloride is 1:2~1:6, preferably 1:4.
Wherein step 1）The temperature reacted after middle addition hydroxylamine hydrochloride is 35 ~ 75 DEG C, and the reaction time is 0.5h ~ 2h.
Wherein step 1）After middle addition compound IV reaction temperature be 60 ~ 90 DEG C, the reaction time be 20 ~ for 24 hours.
Wherein step 1）In after reaction crystallization temperature be 10 ~ 30 DEG C, the crystallization time be 1 ~ 3h.
Wherein step 1）Solvent used by middle crystallization is selected from DMSO, DMF, DMAC, ethyl alcohol, methanol, tetrahydrofuran, acetic acid
Or mixtures thereof one of ethyl ester, acetone.It is preferred that the mixture of DMSO and ethyl alcohol, DMSO and ethyl alcohol weight ratio are 1:0.3~1:
3, preferably 1:1.
Wherein step 1）Middle compound III crude product and the weight ratio for crystallizing used solvent are 1:2~1:5, preferably 1:
3；.
Wherein step 1）Temperature is 40 ~ 80 DEG C when middle crystallization, and crystallization time is 1 ~ 3h, and crystallization temperature is 10 after crystallization
~ 30 DEG C, the crystallization time is 1 ~ 3h.
Wherein step 1）Middle drying temperature is 40 DEG C ~ 60 DEG C, and drying time is 15h ~ for 24 hours.
Wherein step 2）The reaction dissolvent of middle acylation reaction is selected from methylene chloride, ethyl acetate, toluene, chloroform, preferably two
Chloromethanes；The organic base is selected from triethylamine, trimethylamine, diisopropyl ethyl amine, triethanolamine, preferably triethylamine；The acyl
Chlorine reagent is selected from ethyl chloroformate, isopropyl chlorocarbonate, preferably ethyl chloroformate.
Wherein step 2）The weight ratio of middle compound III and reaction dissolvent is 1:2~1:8, preferably 1:4；
Wherein step 2）The molar ratio of middle compound III and organic base is 1:1.5 ~ 2.5, preferably 1:1.8；Compound III and acyl
The molar ratio of chlorine reagent is 1:1.1 ~ 2, preferably 1:1.35.
Wherein step 2）Middle addition acylating reagent and acylation reaction temperature are 5 ~ 30 DEG C, and the reaction time is 0.5h ~ 2h.
Wherein step 2）The organic solvent that middle extraction uses is selected from methylene chloride, ethyl acetate, toluene, chloroform, preferably two
Chloromethanes.
Wherein step 2）The reaction dissolvent of middle cyclization reaction is selected from anhydrous methanol, dehydrated alcohol, toluene, isopropanol, preferably
Dehydrated alcohol；Reaction temperature is 70 ~ 100 DEG C, and the reaction time is 18 ~ 26h.
Wherein step 2）The weight ratio 1 of compound V and reaction dissolvent in middle cyclization reaction:3~1:8, preferably 1:4.
Wherein step 2）Crystallization temperature is 10 ~ 30 DEG C after reaction for middle cyclization, and the crystallization time is 1h ~ 3h.
Wherein step 2）Solvent used in middle crystallization is selected from anhydrous methanol, methylene chloride, toluene, dehydrated alcohol, acetic acid second
Or mixtures thereof one of ester, preferably anhydrous methanol/ethyl acetate mixture, the wherein weight of anhydrous methanol and ethyl acetate
Ratio is 1:1~1:4, preferably 1:3.
Wherein step 2）The weight ratio of compound II crude product and solvent is 1 in middle crystallization:2 ~ 5, preferably 1:4.
Wherein step 2）Middle crystallization temperature is 50 ~ 70 DEG C, and beating time is 1 ~ 3h.
Wherein step 2）Crystallization temperature is 10 ~ 30 DEG C after middle crystallization, and the crystallization time is 1 ~ 3h.
Wherein step 3）Described in alkaline aqueous solution mass percentage concentration be 5% ~ 20%；In the alkaline aqueous solution
Alkali is selected from potassium hydroxide, sodium hydroxide, sodium bicarbonate, saleratus, preferably sodium hydroxide.
Wherein step 3）The molar ratio of middle compound II and alkali is 1:2~1:6, preferably 1:4.
Wherein step 3）Middle reaction temperature is 50 ~ 80 DEG C, and the reaction time is 1 ~ 3h.
Wherein step 3）Middle addition active carbon stirring mixing time is 20mIn ~ 60mIn, preferably 30mIn.
Wherein step 3）Temperature is 10 ~ 20 DEG C when middle adjusting pH, and pH is 1 ~ 5.
Wherein step 3）Described in acid be selected from hydrochloric acid, sulfuric acid, glacial acetic acid, preferably hydrochloric acid.
Wherein step 3）Middle drying temperature is 35 ~ 65 DEG C, and drying time is 10 ~ 30h.
The present invention also provides a kind of preparation methods of above-mentioned Azilsartan, and route is as follows, includes the following steps：
1）Inorganic base is added in reaction dissolvent, stirs evenly, hydroxylamine hydrochloride is added, is stirred to react, compound IV, stirring is added
Reaction, after reaction, cool down crystallization, filters to obtain compound III crude product；Compound III crude product is added in solvent, is tied
Crystalline substance, filtering, dry compound III finished product.
2）Acylation reaction：Compound III and organic base are added in reaction dissolvent, stirs evenly, is slowly added to acyl chlorides examination
Agent reaction, after reaction plus water quenching is gone out, liquid separation, and organic layer is concentrated under reduced pressure to give solid V；Cyclization reaction：Reaction dissolvent is added,
It is stirred to react, after reaction, cool down crystallization, filters to obtain compound II crude product.Compound II crude product is added in solvent, knot
Crystalline substance filters, dry, obtains compound II finished product.
Wherein step 1）Described in reaction dissolvent be selected from DMSO（Dimethyl sulfoxide）,DMF（N,N-dimethylformamide）,
DMAC（Dimethyl acetamide）, preferably DMSO；The inorganic base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, saleratus, hydrogen
Sodium oxide molybdena, preferably sodium bicarbonate.
Wherein step 1）The weight ratio of middle compound IV and reaction dissolvent is 1:2~1:8, preferably 1:4；Compound IV with
The molar ratio of inorganic base is 1:3 ~ 8, preferably 1:5；The molar ratio of compound IV and hydroxylamine hydrochloride is 1:2~1:6, preferably 1:4.
Wherein step 1）The temperature reacted after middle addition hydroxylamine hydrochloride is 35 ~ 75 DEG C, and the reaction time is 0.5h ~ 2h.
Wherein step 1）After middle addition compound IV reaction temperature be 60 ~ 90 DEG C, the reaction time be 20 ~ for 24 hours.
Wherein step 1）In after reaction crystallization temperature be 10 ~ 30 DEG C, the crystallization time be 1 ~ 3h.
Wherein step 1）Solvent used by middle crystallization is selected from DMSO, DMF, DMAC, ethyl alcohol, methanol, tetrahydrofuran, acetic acid
Or mixtures thereof one of ethyl ester, acetone.It is preferred that the mixture of DMSO and ethyl alcohol, DMSO and ethyl alcohol weight ratio are 1:0.3~1:
3, preferably 1:1.
Wherein step 1）Middle compound III crude product and the weight ratio for being beaten used solvent are 1:2~1:5, preferably 1:
3；.
Wherein step 1）Temperature is 40 ~ 80 DEG C when middle crystallization, and crystallization time is 1 ~ 3h, and crystallization temperature is 10 after crystallization
~ 30 DEG C, the crystallization time is 1 ~ 3h.
Wherein step 1）Middle drying temperature is 40 DEG C ~ 60 DEG C, and drying time is 15h ~ for 24 hours.
Wherein step 2）The reaction dissolvent of middle acylation reaction is selected from methylene chloride, ethyl acetate, toluene, chloroform, preferably two
Chloromethanes；The organic base is selected from triethylamine, trimethylamine, diisopropyl ethyl amine, triethanolamine, preferably triethylamine；The acyl
Chlorine reagent is selected from ethyl chloroformate, isopropyl chlorocarbonate, preferably ethyl chloroformate.
Wherein step 2）The molar ratio of middle compound III and organic base is 1:1.5 ~ 2.5, preferably 1:1.8；Compound III
Molar ratio with acyl chlorides reagent is 1:1.1 ~ 2, preferably 1:1.35.
Wherein step 2）Middle addition acylating reagent and acylation reaction temperature are 5 ~ 30 DEG C, and the reaction time is 0.5h ~ 2h.
Wherein step 2）The organic solvent that middle extraction uses is selected from methylene chloride, ethyl acetate, toluene, chloroform, preferably two
Chloromethanes.
Wherein step 2）The reaction dissolvent of middle cyclization reaction is selected from anhydrous methanol, dehydrated alcohol, toluene, isopropanol, preferably
Dehydrated alcohol；Reaction temperature is 70 ~ 100 DEG C, and the reaction time is 18 ~ 26h.
Wherein step 2）The weight ratio 1 of compound V and reaction dissolvent in middle cyclization reaction:3~1:8, preferably 1:4.
Wherein step 2）Crystallization temperature is 10 ~ 30 DEG C after reaction for middle cyclization, and the crystallization time is 1h ~ 3h.
Wherein step 2）Solvent used in middle crystallization is selected from anhydrous methanol, methylene chloride, toluene, dehydrated alcohol, acetic acid second
Or mixtures thereof one of ester, preferably anhydrous methanol/ethyl acetate mixture, the wherein weight of anhydrous methanol and ethyl acetate
Ratio is 1:1~1:4, preferably 1:3.
Wherein step 2）The weight ratio of compound II crude product and solvent is 1 in middle crystallization:2 ~ 5, preferably 1:4.
Wherein step 2）Middle crystallization temperature is 50 ~ 70 DEG C, and beating time is 1 ~ 3h.
Wherein step 2）Crystallization temperature is 10 ~ 30 DEG C after middle crystallization, and the crystallization time is 1 ~ 3h.
The Azilsartan obtained according to the method for the present invention has following physicochemical property：
Powder x-ray diffraction：Instrument：PANalytIcal X'Pert3 powder x-ray diffraction；Target：Cu, K α；Wavelength：Kα1：
1.54060Å; Kα2：1.54443Å；Pipe pressure：45kV；Guan Liu：40mA；Step-length：0.0260°；Every step sweep time：
38.7090s。
The X-ray diffraction diagram data of the crystal such as table 1：
Table 1-X-ray diffraction diagram data
| Position（°2θ） | Spacing d（Å） | Peak height relative intensity I（%） |
| 4.8619 | 18.17582 | 0.09 |
| 9.1272 | 9.68933 | 100.00 |
| 11.7371 | 7.53995 | 0.99 |
| 12.0077 | 7.37066 | 1.00 |
| 12.7339 | 6.95189 | 18.17 |
| 14.8933 | 5.94847 | 7.32 |
| 15.3781 | 5.76201 | 11.87 |
| 15.6039 | 5.67911 | 2.23 |
| 16.2384 | 5.45862 | 6.32 |
| 17.9429 | 4.94373 | 6.98 |
| 18.3201 | 4.84278 | 8.63 |
| 18.6705 | 4.75268 | 17.21 |
| 19.3541 | 4.58632 | 21.60 |
| 19.9481 | 4.45109 | 9.45 |
| 20.1787 | 4.40073 | 13.14 |
| 20.4048 | 4.35249 | 12.40 |
| 21.4691 | 4.13905 | 31.29 |
| 21.8131 | 4.07455 | 9.48 |
| 22.4889 | 3.95362 | 4.07 |
| 23.5185 | 3.78281 | 39.64 |
| 23.9678 | 3.71291 | 8.36 |
| 24.5666 | 3.62376 | 2.60 |
| 25.2375 | 3.52892 | 15.25 |
| 25.5281 | 3.48940 | 11.66 |
| 25.6829 | 3.46872 | 8.48 |
| 26.6632 | 3.34337 | 15.04 |
| 27.0943 | 3.29115 | 2.84 |
| 27.6819 | 3.22261 | 6.19 |
| 2837455 | 3.10575 | 7.46 |
| 29.0454 | 3.07436 | 4.26 |
| 29.3036 | 3.04786 | 6.88 |
| 29.9433 | 2.98172 | 2.01 |
| 30.0674 | 2.97706 | 1.88 |
| 31.0329 | 2.87946 | 4.07 |
| 31.7603 | 2.81515 | 0.17 |
| 32.4211 | 2.75927 | 4.36 |
| 33.0869 | 2.70525 | 2.46 |
| 33.6033 | 2.66485 | 0.73 |
| 34.3850 | 2.60603 | 0.38 |
| 35.5635 | 2.52233 | 0.60 |
| 36.3999 | 2.46626 | 1.82 |
| 37.0703 | 2.42319 | 0.57 |
| 37.6227 | 2.38887 | 2.18 |
| 39.0448 | 2.30508 | 1.72 |
With ScIrocco 2000（Malvern company）Measure 20 μm of the size distribution D90 < of Azilsartan prepared by the present invention.
What is not yet explicitly indicated herein is all conventionally.
Detailed description of the invention
9 compound I of Fig. 1 embodiment（Azilsartan）XRPD map.
9 compound I of Fig. 2 embodiment（Azilsartan）Purity map.
9 compound I of Fig. 3 embodiment（Azilsartan）Granularity map.
9 compound I of Fig. 4 embodiment（Azilsartan）1H-NMR map
7 compound I of Fig. 5 embodiment（Azilsartan）Purity map.
Specific embodiment
The preparation of 1 compound III-1 of embodiment
60g n,N-Dimethylformamide is added in reaction flask, is added with stirring 19.5g sodium carbonate, stirs evenly, is added
8.5g hydroxylamine hydrochloride is warming up to 35 DEG C, is stirred to react 30 minutes, and 25g compound IV-1 is added, and is continuously heating to 60 DEG C, stirring
For 24 hours, after reaction, cool down crystallization, and filtering obtains compound III-1 crude product for reaction.Gained crude product, DMSO are added to reaction
In bottle, heating crystallization 1 hour, cool down crystallization, filtering, dry compound III-1, yield 75%.
The preparation of 2 compound II-1 of embodiment
30g ethyl acetate, 15g compound III-1,3g trimethylamine are added in reaction flask, stirring is cooled to 5 DEG C, is slowly added to
5.1g isopropyl chlorocarbonate, finishes, and the reaction was continued at this temperature, and water quenching is added after reaction and goes out, aqueous layer with ethyl acetate
It washed once, combined ethyl acetate liquid, ethyl acetate washed with water washed once, and solid V-1 is concentrated under reduced pressure to obtain.By obtained solid V-
1 and toluene be added in reaction flask, stirring be warming up to 100 DEG C of reactions, after reaction, cooling crystallization, filter to obtain compound II-1
Crude product.Gained II-1 crude product is added in toluene, in 50 DEG C of stirred crystallization 1h, 10 DEG C of stirring and crystallizing 1h is cooled to, crosses and be filtered dry
It is dry to obtain compound II-1, yield 77%.
The preparation of 3 compound III-2 of embodiment
200g DMSO is added in reaction flask, is added with stirring 18g sodium hydroxide, stirs evenly, 24g hydroxylamine hydrochloride is added, rises
Temperature is stirred to react 2h to 70 DEG C, and 25g compound IV-2 is added, is continuously heating to 85 DEG C, is stirred to react 20h, after reaction,
Cool down crystallization, and filtering obtains compound III-2 crude product.Gained crude product, DMF and acetone mixed solution are added in reaction flask, risen
Temperature crystallization 3h, cool down crystallization, filtering, dry compound III-2, yield 80%.
The preparation of 4 compound II-2 of embodiment
120g toluene is added in reaction flask, 15g compound III-2,12.5g triethanolamine stirs evenly, at 30 DEG C, slowly
7.1g ethyl chloroformate is added, finishes, the reaction was continued, and water quenching is added after reaction and goes out, stands liquid separation, toluene layer is washed with water
Once, saturated sodium chloride solution washed once, and solid V-2 is concentrated under reduced pressure to obtain.Obtained solid V-2 and isopropanol are added to reaction flask
In, stirring is warming up to 70 DEG C of reactions, and after reaction, cool down crystallization, filters to obtain compound II-2 crude product.By gained II-2 crude product
Be added in ethyl acetate, in 70 DEG C of stirred crystallization 3h, be cooled to 30 DEG C of stirring and crystallizing 3h, filtration drying obtain compound II-2 at
Product, yield 73%.
The preparation of 5 compound III-2 of embodiment
100g DMSO is added in reaction flask, is added with stirring 24.6g sodium bicarbonate, 16.3g hydroxylamine hydrochloride is added, is warming up to
55 DEG C, it is stirred to react 1h, 25g compound IV-2 is added, is continuously heating to 65 DEG C, is stirred to react 22h, after reaction, cooling
Crystallization, filtering, obtains compound III-1 crude product.By gained crude product, mixed solvent DMSO and ethyl alcohol（Weight ratio is 1:1）It is added to
In reaction flask, heating crystallization, cool down crystallization, filtering, dry compound III-2, yield 82%.
The preparation of 6 compound II-2 of embodiment
60g methylene chloride is added in reaction flask, 15g compound III-2,6g triethylamine stirs evenly, is cooled to 15 DEG C, delays
It is slow that 4.8g ethyl chloroformate is added, it finishes, the reaction was continued, and water quenching is added after reaction and goes out, and stands liquid separation, and dichloromethane layer is used
Water washing is primary, and solid V-2 is concentrated under reduced pressure to obtain.Obtained solid V-2 and dehydrated alcohol are added in reaction flask, stirring is warming up to 80
DEG C reaction, after reaction, cool down crystallization, filter to obtain compound II-2 crude product.Gained II-2 crude product is added to anhydrous methanol
With the mixed solvent of ethyl acetate（Anhydrous methanol and ethyl acetate weight ratio are 1:3）In, in 50 DEG C of stirred crystallization 2h, it is cooled to
15 DEG C of stirring and crystallizing 2h, filtration drying obtain compound II-2, yield 80%, purity 99.95%.
The preparation of 7 compound I of embodiment
20g compound II-1 is added in 5% KOH aqueous solution, stirring is warming up to 50 DEG C of reaction 1h, and active carbon is added and continues to stir
It mixes, filters, collect filtrate.10 DEG C are cooled to, is 1 with hydrochloric acid tune pH, is filtered, washed, dries to obtain compound I, yield 88% is pure
Degree 99.94%, granularity D90 are 5.9 μm, residual solvent methanol 63ppm.Compound I（Azilsartan）Purity map such as Fig. 5 institute
Show.
MS[M+H] +:457.1。
1H NMR (500MHz, CD4O-d4) δ: 7.65(~d, 2H), 7.62 (m, 1H), 7.60(m, 1H),
7.49 (m, 1H), 7.46 (m, 1H), 7.23 (AAB’B’, 2H), 7.19 (t, 1H), 7.08 (AAB’B’,
2H), 5.74 (brs, 2H), 4.60 (q, 2H), 1.46 (t, 3H)。
The preparation of 8 compound I of embodiment
20g compound II-2 is added in 10% NaOH aqueous solution, stirring is warming up to 80 DEG C of reaction 3h, and active carbon is added and continues
Filtrate is collected in stirring, filtering.20 DEG C are cooled to, is 5 with hydrochloric acid tune pH, is filtered, washed, dries to obtain compound I finished product, yield
83%, purity 99.94%, granularity D90 is 8.4 μm, residual solvent methanol 52ppm, ethyl alcohol 80ppm.
MS[M+H] +:457.1。
1H NMR (500MHz, CD4O-d4) δ: 7.65(~d, 2H), 7.62 (m, 1H), 7.60(m, 1H),
7.49 (m, 1H), 7.46 (m, 1H), 7.23 (AAB’B’, 2H), 7.19 (t, 1H), 7.08 (AAB’B’,
2H), 5.74 (brs, 2H), 4.60 (q, 2H), 1.46 (t, 3H)。
The preparation of 9 compound I of embodiment
20g compound II-2 is added in 15% NaOH aqueous solution, stirring is warming up to 55 DEG C of reaction 2h, and active carbon is added and continues
Filtrate is collected in stirring, filtering.15 DEG C are cooled to, is 3 with hydrochloric acid tune pH, filters, is washed with water, drying and to obtain compound I finished product,
Yield 91%, purity 99.95%, granularity D90 are 10.3 μm, residual solvent methanol 17ppm, ethyl alcohol 84ppm.Compound I（A Qisha
It is smooth）XRPD map as shown in Figure 1, compound I（Azilsartan）Purity map as shown in Fig. 2, compound I（Azilsartan）
Granularity map as shown in figure 3, compound I（Azilsartan）1H-NMR map it is as shown in Figure 4.
MS[M+H] +:457.1。
1H NMR (500MHz, CD4O-d4) δ: 7.65(~d, 2H), 7.62 (m, 1H), 7.60(m, 1H),
7.49 (m, 1H), 7.46 (m, 1H), 7.23 (AAB’B’, 2H), 7.19 (t, 1H), 7.08 (AAB’B’,
2H), 5.74 (brs, 2H), 4.60 (q, 2H), 1.46 (t, 3H)。
Claims (10)
1. a kind of azilsartan crude drug, which is characterized in that purity >=99.9%, granularity D90≤20 μm, dissolvent residual≤
500ppm。
2. azilsartan crude drug according to claim 1, which is characterized in that purity >=99.94%, the μ of granularity D90≤10
M, dissolvent residual≤100ppm.
3. azilsartan crude drug according to claim 1, which is characterized in that the azilsartan crude drug is crystal form
The X-ray powder diffraction figure of A, crystal form A indicate that 2 θ degree of diffraction are in 9.1,12.7,19.3,21.4 and with the degree of 2 θ degree of diffraction
There is characteristic diffraction peak at 23.5 ± 0.2 degree.
4. a kind of method for preparing azilsartan crude drug described in claim 1, which is characterized in that preparation includes following step
Suddenly：
1）Inorganic base is added in reaction dissolvent, stirs evenly, hydroxylamine hydrochloride is added, is stirred to react, compound IV, stirring is added
Reaction, after reaction, cool down crystallization, filters to obtain compound III crude product；Compound III crude product is added in solvent, is tied
Crystalline substance, filtering, dry compound III finished product；
2）Acylation reaction：Compound III and organic base are added in reaction dissolvent, stirs evenly, it is anti-to be slowly added to acyl chlorides reagent
It answers, after reaction plus water quenching is gone out, liquid separation, and organic layer is concentrated under reduced pressure to give solid V；Cyclization reaction：Reaction dissolvent, stirring is added
Reaction, after reaction, cool down crystallization, filters to obtain compound II crude product；Compound II crude product is added in solvent, crystallization, mistake
Filter, it is dry, obtain compound II finished product；
3）Compound II is added in alkaline aqueous solution, is stirred to react, active carbon is added and continues to stir, filters, collects filtrate；Drop
Temperature is filtered, washed with acid solution tune pH, is dried to obtain compound I finished product.
5. a kind of compound that is shown below for being used to prepare azilsartan crude drug described in claim 1, which is characterized in that
Purity >=99.9%,
Wherein R1 is selected from methyl, ethyl.
6. compound according to claim 5, further, it is characterised in that purity >=99.95%.
7. a kind of method for preparing compound described in claim 5, it is characterised in that preparation includes the following steps：
1）Inorganic base is added in reaction dissolvent, stirs evenly, hydroxylamine hydrochloride is added, is stirred to react, compound IV, stirring is added
Reaction, after reaction, cool down crystallization, filters to obtain compound III crude product；Compound III crude product is added in solvent, is tied
Crystalline substance, filtering, dry compound III finished product；
2）Acylation reaction：Compound III and organic base are added in reaction dissolvent, stirs evenly, it is anti-to be slowly added to acyl chlorides reagent
It answers, after reaction plus water quenching is gone out, liquid separation, and organic layer is concentrated under reduced pressure to give solid V；Cyclization reaction：Reaction dissolvent, stirring is added
Reaction, after reaction, cool down crystallization, filters to obtain compound II crude product；Compound II crude product is added in solvent, crystallization, mistake
Filter, it is dry, obtain compound II finished product.
8. a kind of method of the purification of compound described in claim 5, it is characterised in that compound II crude product is added in solvent,
Crystallization is filtered, dry, obtains compound II finished product.
9. according to the method described in claim 8, wherein the solvent is selected from anhydrous methanol, methylene chloride, toluene, anhydrous second
Or mixtures thereof one of alcohol, ethyl acetate.
10. according to the method described in claim 9, wherein the solvent is anhydrous methanol and ethyl acetate mixture.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810934114.1A CN108912109A (en) | 2018-08-17 | 2018-08-17 | A kind of high-purity, small particle and azilsartan crude drug of low solvent residue and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810934114.1A CN108912109A (en) | 2018-08-17 | 2018-08-17 | A kind of high-purity, small particle and azilsartan crude drug of low solvent residue and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108912109A true CN108912109A (en) | 2018-11-30 |
Family
ID=64404743
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810934114.1A Pending CN108912109A (en) | 2018-08-17 | 2018-08-17 | A kind of high-purity, small particle and azilsartan crude drug of low solvent residue and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108912109A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108774217A (en) * | 2018-09-07 | 2018-11-09 | 浙江宏元药业股份有限公司 | A kind of preparation process of Azilsartan powder material medicine |
| CN110746415A (en) * | 2019-11-18 | 2020-02-04 | 南京恒通医药开发有限公司 | Synthesis process for continuously preparing azilsartan under microchannel reactor |
| CN111454255A (en) * | 2020-06-03 | 2020-07-28 | 迪嘉药业集团有限公司 | Preparation method of small-particle-size azilsartan |
| JP2021001140A (en) * | 2019-06-21 | 2021-01-07 | 金剛化学株式会社 | Method for producing stable azilsartan fine crystals |
| CN113278016A (en) * | 2021-05-13 | 2021-08-20 | 山东创新药物研发有限公司 | Preparation method of azilsartan with small particle size |
| CN113466360A (en) * | 2021-06-16 | 2021-10-01 | 珠海润都制药股份有限公司 | Azilsartan 6 related substance detection method |
Citations (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102766138A (en) * | 2012-07-23 | 2012-11-07 | 上海凯谱林医药开发有限公司 | Preparation method of azilsartan |
| CN102766139A (en) * | 2012-08-14 | 2012-11-07 | 江苏先声药物研究有限公司 | Azilsartan polymorphic substance and preparation method thereof |
| CN103435604A (en) * | 2013-08-28 | 2013-12-11 | 合肥久诺医药科技有限公司 | Refining method of high-purity azilsartan |
| CN103664921A (en) * | 2013-11-27 | 2014-03-26 | 湖南千金湘江药业股份有限公司 | Azilsartan of crystal form A, and preparation method thereof |
| CN103880830A (en) * | 2013-03-22 | 2014-06-25 | 江西同和药业有限责任公司 | Novel synthesis method of azilsartan |
| CN103880829A (en) * | 2012-12-21 | 2014-06-25 | 上海医药工业研究院 | Azilsartan crystal and preparation method and application thereof |
| CN103930419A (en) * | 2011-09-30 | 2014-07-16 | 广东东阳光药业有限公司 | Crystalline forms of azilsartan and preparation and uses thereof |
| CN104230910A (en) * | 2014-09-16 | 2014-12-24 | 常州大学 | Preparation methods of crystal form and crystal of azilsartan intermediate |
| CN104262334A (en) * | 2014-09-16 | 2015-01-07 | 常州大学 | Azilsartan crystal and preparation method thereof |
| CN104341408A (en) * | 2013-08-02 | 2015-02-11 | 江苏柯菲平医药股份有限公司 | Novel crystal form of azilsartan and preparation method thereof |
| CN104557899A (en) * | 2014-11-17 | 2015-04-29 | 江苏中邦制药有限公司 | Preparation method of azilsartan I-form crystal |
| WO2016147120A1 (en) * | 2015-03-18 | 2016-09-22 | Smilax Laboratories Limited | An improved process for the preparation of substantially pure azilsartan |
| CN106749216A (en) * | 2016-12-30 | 2017-05-31 | 湖南千金湘江药业股份有限公司 | A kind of process for purification of crystal formation A Azilsartans |
| CN106749217A (en) * | 2017-01-22 | 2017-05-31 | 鲁南制药集团股份有限公司 | A kind of Azilsartan I crystal |
| CN108101900A (en) * | 2018-01-26 | 2018-06-01 | 山东科兴生物制品有限公司 | The preparation method of Azilsartan |
-
2018
- 2018-08-17 CN CN201810934114.1A patent/CN108912109A/en active Pending
Patent Citations (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103930419A (en) * | 2011-09-30 | 2014-07-16 | 广东东阳光药业有限公司 | Crystalline forms of azilsartan and preparation and uses thereof |
| CN102766138A (en) * | 2012-07-23 | 2012-11-07 | 上海凯谱林医药开发有限公司 | Preparation method of azilsartan |
| CN102766139A (en) * | 2012-08-14 | 2012-11-07 | 江苏先声药物研究有限公司 | Azilsartan polymorphic substance and preparation method thereof |
| CN103880829A (en) * | 2012-12-21 | 2014-06-25 | 上海医药工业研究院 | Azilsartan crystal and preparation method and application thereof |
| CN103880830A (en) * | 2013-03-22 | 2014-06-25 | 江西同和药业有限责任公司 | Novel synthesis method of azilsartan |
| CN104341408A (en) * | 2013-08-02 | 2015-02-11 | 江苏柯菲平医药股份有限公司 | Novel crystal form of azilsartan and preparation method thereof |
| CN103435604A (en) * | 2013-08-28 | 2013-12-11 | 合肥久诺医药科技有限公司 | Refining method of high-purity azilsartan |
| CN103664921A (en) * | 2013-11-27 | 2014-03-26 | 湖南千金湘江药业股份有限公司 | Azilsartan of crystal form A, and preparation method thereof |
| CN104230910A (en) * | 2014-09-16 | 2014-12-24 | 常州大学 | Preparation methods of crystal form and crystal of azilsartan intermediate |
| CN104262334A (en) * | 2014-09-16 | 2015-01-07 | 常州大学 | Azilsartan crystal and preparation method thereof |
| CN104557899A (en) * | 2014-11-17 | 2015-04-29 | 江苏中邦制药有限公司 | Preparation method of azilsartan I-form crystal |
| WO2016147120A1 (en) * | 2015-03-18 | 2016-09-22 | Smilax Laboratories Limited | An improved process for the preparation of substantially pure azilsartan |
| CN106749216A (en) * | 2016-12-30 | 2017-05-31 | 湖南千金湘江药业股份有限公司 | A kind of process for purification of crystal formation A Azilsartans |
| CN106749217A (en) * | 2017-01-22 | 2017-05-31 | 鲁南制药集团股份有限公司 | A kind of Azilsartan I crystal |
| CN108101900A (en) * | 2018-01-26 | 2018-06-01 | 山东科兴生物制品有限公司 | The preparation method of Azilsartan |
Non-Patent Citations (1)
| Title |
|---|
| AMBATI V.RAGHAVA REDDY ET AL.: "IMPROVED SYNTHESIS OF AZILSARTAN: DEVELOPMENT AND CONTROL OF PROCESS RELATED IMPURITIES", 《INDO AMERICAN JOURNAL OF PHARMACEUTICAL RESEARCH》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108774217A (en) * | 2018-09-07 | 2018-11-09 | 浙江宏元药业股份有限公司 | A kind of preparation process of Azilsartan powder material medicine |
| JP2021001140A (en) * | 2019-06-21 | 2021-01-07 | 金剛化学株式会社 | Method for producing stable azilsartan fine crystals |
| JP7486763B2 (en) | 2019-06-21 | 2024-05-20 | 金剛化学株式会社 | Method for producing stable fine crystals of azilsartan |
| CN110746415A (en) * | 2019-11-18 | 2020-02-04 | 南京恒通医药开发有限公司 | Synthesis process for continuously preparing azilsartan under microchannel reactor |
| CN111454255A (en) * | 2020-06-03 | 2020-07-28 | 迪嘉药业集团有限公司 | Preparation method of small-particle-size azilsartan |
| CN113278016A (en) * | 2021-05-13 | 2021-08-20 | 山东创新药物研发有限公司 | Preparation method of azilsartan with small particle size |
| CN113466360A (en) * | 2021-06-16 | 2021-10-01 | 珠海润都制药股份有限公司 | Azilsartan 6 related substance detection method |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108912109A (en) | A kind of high-purity, small particle and azilsartan crude drug of low solvent residue and preparation method thereof | |
| CN111423452B (en) | Intermediate of Rayleigh Lu Geli and preparation method and application thereof | |
| CN111333633B (en) | Intermediate compound of Rayleigh Lu Geli and preparation method and application thereof | |
| CN103664921B (en) | A kind of Azilsartan crystal formation A and preparation method thereof | |
| CA2614334C (en) | Crystalline forms of 4-methyl-n-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide | |
| EP2220031A1 (en) | Polymorphic forms of aliskiren hemifumarate and process for preparation thereof | |
| EP2896609A1 (en) | Crystalline fingolimod citrate for the treatment of relapsing-remitting multiple sclerosis | |
| US11787814B2 (en) | Method for preparing 2-indolinospirone compound and intermediate thereof | |
| US6610718B2 (en) | Processes for making- and a new crystalline form of- leflunomide | |
| CN103664922A (en) | Novel crystal-form azilsartan and preparation method for same | |
| CN103554031B (en) | Preparation method of azilsartan intermediate | |
| CN105517992B (en) | Novel crystalline aralkylamine compound and its manufacturing method | |
| CN107954936B (en) | Method for preparing deuterated imidazoldione compound | |
| JP2019147763A (en) | Manufacturing method of proline amide compound | |
| CN109694330A (en) | A kind of preparation method of acid | |
| CN113582880A (en) | Preparation method of (3-aminobicyclo [1.1.1] pentane-1-yl) carbamic acid tert-butyl ester | |
| CN105315169B (en) | A kind of preparation method for the treatment of cardiovascular disease drug | |
| CN111848505A (en) | Preparation method of vatacostat intermediate | |
| WO2006117977A1 (en) | Process for production of carbostyril compound | |
| CN111732586B (en) | Crystal form of alkynyl-containing compound salt, preparation method and application | |
| CN111018736B (en) | Novel method for preparing 3-hydroxy-4-amino-5-nitro-N, N-dimethyl benzamide | |
| CN105753733A (en) | AHU377 crystal form and preparation method and uses thereof | |
| WO2017050092A1 (en) | Method for preparing intermediate for odanacatib | |
| CN110105222A (en) | A kind of novel processing step of 4- aminoidan class compound | |
| CN107286111B (en) | Preparation method of oxazolidinone compound |
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: 20181130 |
|
| RJ01 | Rejection of invention patent application after publication |