WO2018014866A1 - 达格列净中间体的晶型及其制备方法 - Google Patents
达格列净中间体的晶型及其制备方法 Download PDFInfo
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- WO2018014866A1 WO2018014866A1 PCT/CN2017/093833 CN2017093833W WO2018014866A1 WO 2018014866 A1 WO2018014866 A1 WO 2018014866A1 CN 2017093833 W CN2017093833 W CN 2017093833W WO 2018014866 A1 WO2018014866 A1 WO 2018014866A1
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- WIPO (PCT)
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- compound
- formula
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- dapagliflozin
- propanol
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H7/00—Compounds containing non-saccharide radicals linked to saccharide radicals by a carbon-to-carbon bond
- C07H7/04—Carbocyclic radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
-
- 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
- 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
Definitions
- the invention belongs to the field of chemistry, relates to a crystalline form A of a key intermediate of dapagliflozin and a method for preparing the same, and in particular, the invention relates to (2S, 3R, 4S, 5S, 6R)-2-(4- Crystal form of chloro-3-(4-ethoxybenzyl)phenyl)-2-ethoxy-6-(methylhydroxy)tetrahydro-2H-pyran-3,4,5-triol, And its crystal form preparation method.
- Dapagliflozin 2-chloro-5-( ⁇ -D-glucopyranose-1-yl)-4'-ethoxydiphenylmethane, has the structural formula shown by formula (2):
- Diabetes is a group of endocrine-metabolic diseases that are marked by high blood sugar. Sugar, protein, fat and secondary water and electrolyte metabolism disorders caused by absolute or relative insufficient secretion of insulin. It can involve chronic damage, dysfunction, and even many fatal complications in various systems of the body, especially the eyes, kidneys, heart, blood vessels, and nerves. With the aging of the world's population, diabetes has become a common and frequently-occurring disease, and it is a disease that seriously endangers human health. Research data shows that the number of diabetic patients worldwide has increased from 150 million in 2000 to 280 million. It is estimated that nearly 500 million people worldwide will have diabetes by 2030.
- SGLT Sodium-glucose cotransporter
- SGLT includes SGLT1 and SGLT2, where SGLT1 is expressed in the small intestine and renal proximal convoluted tubules In the distal S3 segment, about 10% of the sugar is absorbed; SGLT2 is mainly expressed in the pre-spleen SI segment of the renal proximal convoluted tube, and more than 90% of the glucose reabsorption is responsible for the SGLT2. Therefore, inhibition of SGLT, particularly inhibition of SGLT2, can further inhibit the reabsorption of sugar, thereby allowing the sugar to be excreted in the urine, thereby reducing the concentration of sugar in the blood.
- Patent WO2008002824 discloses Ig and If of dagliflozin intermediate compound B, which loses crystallinity within a few hours of being open, and methyl ether butanediol crystal form Ig is dried at 30 ° C under vacuum. It also loses crystallinity and the stability of the crystal form is poor. At the same time, the purity of dapagliflozin prepared by the compound B disclosed in the patent is not high, and only oil can be obtained after concentration under reduced pressure, and further purification by acetylation reaction is required, and the process is cumbersome and the yield is not high.
- High-purity dapagliflozin intermediates are essential for obtaining high-purity dapagliflozin.
- the general preparation process of dapagliflozin intermediates is about 90% pure. Only intermediates with such purity can only obtain purity. Low daglibine.
- the purification of dapagliflozin by column chromatography is costly and inefficient, which is not conducive to industrial production. If it is purified by crystallization, it is difficult to crystallize the intermediates of dapagliflozin due to its own structure. Therefore, it is urgent to develop A chemically stable dapagliflozin intermediate that can be purified by crystallization, making dapagliflozin purification easier and simpler.
- the present invention provides a dapagliflozin intermediate.
- the dapagliflozin intermediate of the present invention has the chemical name (2S, 3R, 4S, 5S, 6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-2 -ethoxy-6-(methylhydroxy)tetrahydro-2H-pyran-3,4,5-triol, the structural formula is as shown in formula (1):
- Another object of the present invention is to provide a crystalline form A of a compound of formula (1).
- the present invention provides a crystalline form A of a compound of formula (1) having an X-ray powder diffraction pattern at a value of 2 ⁇ of 5.5 ⁇ 0.2, 13.0 ⁇ 0.2, 15.0 ⁇ 0.2, 17.0 ⁇ 0.2 °, 18.3 ⁇ 0.2 °, 20.6 ⁇ There are characteristic peaks at 0.2°, 21.6 ⁇ 0.2° and 23.1 ⁇ 0.2°.
- the crystal form A of the compound of the formula (1) of the present invention has an X-ray powder diffraction pattern with a 2 ⁇ value of 5.5 ⁇ 0.2°, 9.7 ⁇ 0.2°, 11.7 ⁇ 0.2°, 13.0 ⁇ 0.2°, 14.2 ⁇ 0.2.
- the crystalline form A of the compound of the formula (1) of the present invention contains n-propanol in an amount of about 0 to 15%, preferably 5% to 10%, more preferably 5% to 7.5%, in terms of mass ratio, and different n-propyl groups.
- n-propanol in an amount of about 0 to 15%, preferably 5% to 10%, more preferably 5% to 7.5%, in terms of mass ratio, and different n-propyl groups.
- a typical example of the crystal form A of the compound of the formula (1) of the present invention has an XRPD pattern as shown in FIG.
- a typical example of the crystal form A of the compound of the formula (1) of the present invention has a TGA map as shown in FIG.
- the process for the preparation of Form A of the compound of formula (1) according to the invention comprises crystallization from an alcoholic solution comprising from 0.1 g/ml to 2.0 g/ml of a compound of formula (I) at 0-30 °C.
- the process for the preparation of the crystalline form A of the compound of the formula (1) according to the invention comprises crystallization from an alcohol solution comprising from 0.1 g/ml to 2.0 g/ml of the compound of the formula (I) at 0-30 ° C, and in the same To the n-propanol solution, C 5-8 hydrocarbon was added dropwise at a temperature.
- the compound of the formula (1) is dissolved in an alcohol solution at a concentration of from about 0.1 g/ml to 1.0 g/ml, preferably from 0.1 g/ml to 0.56 g/ml, more preferably from 0.20 g/ml to 0.50 g/ml.
- a solution of n-propanol containing the compound of the above formula (1) is placed or stirred to crystallize.
- the mixture may be about
- the compound is dissolved by heating at 30 ° C to 60 ° C, and then concentrated under reduced pressure to give a specific concentration of about 0.1 g / ml to 2.0 g / ml.
- the method for preparing the crystalline form A of the compound of the formula (1) according to the present invention it is also possible to selectively add a seed crystal to the solution.
- the addition of the seed crystals includes the addition of seed crystals before or during the dropwise addition of the C 5-8 hydrocarbons to the solution.
- the method for producing the crystalline form A of the compound of the formula (1) according to the present invention wherein the seed crystal is obtained by dissolving a compound of the formula (1) in n-propanol at a low temperature, adding n-heptane dropwise, and crystallizing.
- a typical example of the seed crystal of the present invention comprises: weighing about 1 g of the compound of the formula (1) into the reactor, adding 2.0 mL of n-propanol at room temperature, dissolving the sample to clear, and then at -20 ° C The mixture was allowed to stand under the conditions, and after 2 days, a solid was precipitated, and 5 ml of n-heptane was added to the above-mentioned reactor, and the mixture was stirred for 24 hours, and the suspension was filtered to obtain a solid which was used as a seed crystal.
- the method for producing the crystalline form A of the compound of the formula (1) according to the present invention wherein the crystallization temperature is from about 0 ° C to 30 ° C, preferably from 10 ° C to 25 ° C, more preferably from 20 ° C to 25 ° C.
- the method for producing the crystalline form A of the compound of the formula (1) according to the present invention wherein the volume of the C 5-8 hydrocarbon is 2 to 40 times, preferably 8 to 25 times, more preferably 11 to 20 times the mass of the (I) compound. .
- the method for producing the crystalline form A of the compound of the formula (1) according to the present invention, wherein the crystalline form can be isolated by, for example, filtration, centrifugation or the like.
- the separated crystal form can be dried by, for example, vacuum drying, direct current drying, air drying, or the like.
- the crystal form A of the compound of the formula (1) of the present invention is not only high in purity but also good in stability. It has greatly promoted the purification of dapagliflozin.
- the preparation method of the crystal form A of the compound of the formula (1) of the invention has the advantages of simple and controllable process and good reproducibility, and can effectively separate and purify the intermediate from the reaction liquid, remove impurities generated during the reaction, and make the intermediate The purity increased from 90% to over 99.3%.
- Figure 1 is an X-ray powder diffraction pattern of Form A of the compound of the formula (1) of Example 1.
- Figure 3 is a TGA spectrum of Form A of the compound of the formula (1) of Example 2.
- dapagliflozin prepared from the intermediate of the present invention can be obtained in a high purity solid form without further acetylation purification, which simplifies the reaction step and improves product yield.
- Form A prepared in Example 1 was dried under vacuum at 50 ° C for 3 hours, and Form A did not change.
- Form A prepared in Example 1 was stored at room temperature (25 ° C) for 3 months, and Form A did not change.
- the crystal form A prepared by the invention is placed under dry conditions and room temperature for 3 months, and the crystal form is not changed, thereby improving the stability of the dapagliflozin intermediate, solving the defects of the prior art, and facilitating the intermediate. Storage and product quality improvements.
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Endocrinology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Emergency Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyrane Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
Description
Claims (13)
- 式(1)化合物的晶型A,其特征在于,其X射线粉末衍射图谱在2θ值为5.5±0.2°,13.0±0.2°,15.0±0.2°,17.0±0.2°,18.3±0.2°,20.6±0.2°,21.6±0.2°和23.1±0.2°处具有特征峰;优选其X射线粉末衍射图谱在2θ值为5.5±0.2°,9.7±0.2°,11.7±0.2°,13.0±0.2°,14.2±0.2°,15.0±0.2°,16.4±0.2°,17.0±0.2°,18.3±0.2°,19.7±0.2°,20.6±0.2°,21.6±0.2°,23.1±0.2°,23.7±0.2°,24.5±0.2°,25.0±0.2°,25.8±0.2°,26.3±0.2°,28.7±0.2°,29.9±0.2°,30.6±0.2°,31.2±0.2°和32.1±0.2°处具有特征峰。
- 根据权利要求2所述的晶型A,其特征在于,晶型A含正丙醇约0~15%,优选5%~10%,更优选5%~8%,进一步优选5%~7.5%。
- 根据权利要求2所述的晶型A,其特征在于,其X射线粉末衍射图谱基本如图1。
- 一种权利要求2所述的晶型A的制备方法,包括在0-30℃下,从包含0.1g/ml~2.0g/ml的式(I)化合物的正丙醇溶液中结晶。
- 一种权利要求2所述的晶型A的制备方法,包括在0-30℃下,从包含0.1g/ml~2.0g/ml的式(I)化合物的正丙醇溶液中结晶,以及在相同温度下,向该正丙醇溶液中滴加C5-8烃。
- 根据权利要求5或6所述的晶型A的制备方法,其特征在于,式(I) 化合物在正丙醇溶液中的浓度为0.1g/ml~1.0g/ml,优选0.1g/ml~0.56g/ml,更优选0.20g/ml~0.50g/ml。
- 根据权利要求5或6所述的晶型A的制备方法,其特征在于,还包括添加晶种的步骤。
- 根据权利要求5或6所述的晶型A的制备方法,其特征在于,结晶温度在10℃~25℃,优选20℃~25℃。
- 根据权利要求5或6所述的晶型A的制备方法,其特征在于,所述正丙醇溶液中还可以加入水,加入水的体积为式(I)化合物质量的0.05~0.5倍,优选0.1~0.2倍。
- 根据权利要求6所述的晶型A的制备方法,其特征在于,所述C5-8烃选自正戊烷、正己烷、正庚烷或正辛烷,优选正庚烷。
- 根据权利要求6所述的晶型A的制备方法,其特征在于,所述C5-8烃的体积为(I)化合物质量的2~40倍,优选8~25倍,更优选11~20倍。
- 权利要求1所述式(I)化合物或权利要求2-4任一项所述的晶型A作为达格列净关键中间体在制备治疗II型糖尿病药物达格列净中的应用。
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16/317,636 US10836786B2 (en) | 2016-07-22 | 2017-07-21 | Crystal form of dapagliflozin intermediate and preparation method therefor |
EP17830500.9A EP3489250A4 (en) | 2016-07-22 | 2017-07-21 | CRYSTALLINE FORM OF A DAPAGLIFLOZIN INTERMEDIATE AND PRODUCTION METHOD THEREFOR |
MX2019000582A MX2019000582A (es) | 2016-07-22 | 2017-07-21 | Forma cristalina de un intermediario de la dapagliflozina y metodo de preparacion del mismo. |
BR112019000521-8A BR112019000521A2 (pt) | 2016-07-22 | 2017-07-21 | forma de cristal de intermediário de dapagliflozina e método de preparação do mesmo |
CN201780033823.6A CN109219611B (zh) | 2016-07-22 | 2017-07-21 | 达格列净中间体的晶型及其制备方法 |
KR1020197001816A KR20190031485A (ko) | 2016-07-22 | 2017-07-21 | 다파글리플로진 중간물질의 결정형 및 이의 제조 방법 |
JP2019501701A JP2019521151A (ja) | 2016-07-22 | 2017-07-21 | ダパグリフロジン中間体の結晶形及びその製造方法 |
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CN201610587582.7A CN107641139A (zh) | 2016-07-22 | 2016-07-22 | 达格列净中间体的晶型及其制备方法 |
CN201610587582.7 | 2016-07-22 |
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WO2018014866A1 true WO2018014866A1 (zh) | 2018-01-25 |
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PCT/CN2017/093833 WO2018014866A1 (zh) | 2016-07-22 | 2017-07-21 | 达格列净中间体的晶型及其制备方法 |
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US (1) | US10836786B2 (zh) |
EP (1) | EP3489250A4 (zh) |
JP (1) | JP2019521151A (zh) |
KR (1) | KR20190031485A (zh) |
CN (2) | CN107641139A (zh) |
BR (1) | BR112019000521A2 (zh) |
MX (1) | MX2019000582A (zh) |
WO (1) | WO2018014866A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2021176096A1 (en) | 2020-03-05 | 2021-09-10 | Krka, D.D., Novo Mesto | Pharmaceutical composition comprising sglt2 inhibitor |
Families Citing this family (4)
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WO2020151672A1 (zh) * | 2019-01-23 | 2020-07-30 | 苏州科睿思制药有限公司 | 一种达格列净晶型及其制备方法和用途 |
CN111748004A (zh) * | 2020-06-30 | 2020-10-09 | 药璞(上海)医药科技有限公司 | 一种高纯度达格列净中间体的晶型及其制备方法 |
CN114539334A (zh) * | 2021-03-31 | 2022-05-27 | 浙江美诺华药物化学有限公司 | 一种达格列净中间体化合物晶型及其制备方法 |
CN116813675B (zh) * | 2023-08-23 | 2023-11-24 | 北京远大九和药业有限公司 | 一种化合物晶型及其制备、组合物和用途 |
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WO2013152654A1 (en) * | 2012-04-10 | 2013-10-17 | Theracos, Inc. | Process for preparation of benzylbenzene sodium-dependent glucose cotransporter 2 (sglt2) inhibitors |
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WO2015132803A2 (en) * | 2014-03-06 | 2015-09-11 | Msn Laboratories Private Limited | Process for the preparation of (1s)-1,5-anhydro-1-c-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-d-glucitol and its solvate thereof |
CN105481915A (zh) * | 2014-09-19 | 2016-04-13 | 北京万生药业有限责任公司 | 一种sglt-2抑制剂化合物的制备方法 |
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CA2557801C (en) * | 2004-03-16 | 2013-06-25 | Boehringer Ingelheim International Gmbh | Glucopyranosyl-substituted benzol derivatives, drugs containing said compounds, the use thereof and method for the production thereof |
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US9193751B2 (en) * | 2012-04-10 | 2015-11-24 | Theracos, Inc. | Process for the preparation of benzylbenzene SGLT2 inhibitors |
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2016
- 2016-07-22 CN CN201610587582.7A patent/CN107641139A/zh active Pending
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2017
- 2017-07-21 JP JP2019501701A patent/JP2019521151A/ja active Pending
- 2017-07-21 KR KR1020197001816A patent/KR20190031485A/ko not_active Application Discontinuation
- 2017-07-21 MX MX2019000582A patent/MX2019000582A/es unknown
- 2017-07-21 EP EP17830500.9A patent/EP3489250A4/en not_active Withdrawn
- 2017-07-21 BR BR112019000521-8A patent/BR112019000521A2/pt not_active IP Right Cessation
- 2017-07-21 WO PCT/CN2017/093833 patent/WO2018014866A1/zh unknown
- 2017-07-21 US US16/317,636 patent/US10836786B2/en active Active
- 2017-07-21 CN CN201780033823.6A patent/CN109219611B/zh active Active
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WO2013152654A1 (en) * | 2012-04-10 | 2013-10-17 | Theracos, Inc. | Process for preparation of benzylbenzene sodium-dependent glucose cotransporter 2 (sglt2) inhibitors |
CN104109179A (zh) * | 2013-04-16 | 2014-10-22 | 杭州华东医药集团生物工程研究所有限公司 | 一类c-芳基葡萄糖苷衍生物、制备方法及其用途 |
WO2015132803A2 (en) * | 2014-03-06 | 2015-09-11 | Msn Laboratories Private Limited | Process for the preparation of (1s)-1,5-anhydro-1-c-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-d-glucitol and its solvate thereof |
CN105481915A (zh) * | 2014-09-19 | 2016-04-13 | 北京万生药业有限责任公司 | 一种sglt-2抑制剂化合物的制备方法 |
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Cited By (1)
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WO2021176096A1 (en) | 2020-03-05 | 2021-09-10 | Krka, D.D., Novo Mesto | Pharmaceutical composition comprising sglt2 inhibitor |
Also Published As
Publication number | Publication date |
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CN109219611A (zh) | 2019-01-15 |
US20190284220A1 (en) | 2019-09-19 |
BR112019000521A2 (pt) | 2019-04-24 |
CN109219611B (zh) | 2022-03-29 |
MX2019000582A (es) | 2019-04-01 |
KR20190031485A (ko) | 2019-03-26 |
EP3489250A4 (en) | 2020-02-26 |
EP3489250A1 (en) | 2019-05-29 |
US10836786B2 (en) | 2020-11-17 |
CN107641139A (zh) | 2018-01-30 |
JP2019521151A (ja) | 2019-07-25 |
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