TWI643848B - 製備嘧啶中間物之方法 - Google Patents
製備嘧啶中間物之方法 Download PDFInfo
- Publication number
- TWI643848B TWI643848B TW103124052A TW103124052A TWI643848B TW I643848 B TWI643848 B TW I643848B TW 103124052 A TW103124052 A TW 103124052A TW 103124052 A TW103124052 A TW 103124052A TW I643848 B TWI643848 B TW I643848B
- Authority
- TW
- Taiwan
- Prior art keywords
- compound
- formula
- ethylene glycol
- mixture
- isobutyl ketone
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 13
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 109
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims abstract description 35
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000000622 liquid--liquid extraction Methods 0.000 claims abstract description 8
- 238000000638 solvent extraction Methods 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 192
- 238000000034 method Methods 0.000 claims description 72
- 239000000203 mixture Substances 0.000 claims description 43
- 239000012074 organic phase Substances 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 239000007787 solid Substances 0.000 claims description 12
- 239000008346 aqueous phase Substances 0.000 claims description 11
- 239000003960 organic solvent Substances 0.000 claims description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 5
- 238000001704 evaporation Methods 0.000 claims description 5
- PTTPXKJBFFKCEK-UHFFFAOYSA-N 2-Methyl-4-heptanone Chemical compound CC(C)CC(=O)CC(C)C PTTPXKJBFFKCEK-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 4
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000013078 crystal Substances 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical group [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims 1
- 230000008020 evaporation Effects 0.000 claims 1
- 239000003791 organic solvent mixture Substances 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 10
- JGCMEBMXRHSZKX-UHFFFAOYSA-N macitentan Chemical compound C=1C=C(Br)C=CC=1C=1C(NS(=O)(=O)NCCC)=NC=NC=1OCCOC1=NC=C(Br)C=N1 JGCMEBMXRHSZKX-UHFFFAOYSA-N 0.000 abstract description 9
- 229960001039 macitentan Drugs 0.000 abstract description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 12
- 239000010410 layer Substances 0.000 description 11
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 238000004255 ion exchange chromatography Methods 0.000 description 8
- VLQVLNYSVLKZTI-UHFFFAOYSA-N n-[5-(4-bromophenyl)-6-(2-hydroxyethoxy)pyrimidin-4-yl]propane-1-sulfonamide Chemical compound CCCS(=O)(=O)NC1=NC=NC(OCCO)=C1C1=CC=C(Br)C=C1 VLQVLNYSVLKZTI-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000000769 gas chromatography-flame ionisation detection Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- WEEFLZORZXLIJE-UHFFFAOYSA-N 5-(4-bromophenyl)-4,6-dichloropyrimidine Chemical compound ClC1=NC=NC(Cl)=C1C1=CC=C(Br)C=C1 WEEFLZORZXLIJE-UHFFFAOYSA-N 0.000 description 2
- XPGIBDJXEVAVTO-UHFFFAOYSA-N 5-bromo-2-chloropyrimidine Chemical compound ClC1=NC=C(Br)C=N1 XPGIBDJXEVAVTO-UHFFFAOYSA-N 0.000 description 2
- -1 5-bromopyrimidin-2-yl Chemical group 0.000 description 2
- MDLPZLVTPXRAFB-UHFFFAOYSA-N CCCS(=O)(=O)NC1=C(C(Cl)=NC=N1)C1=CC=C(Br)C=C1 Chemical compound CCCS(=O)(=O)NC1=C(C(Cl)=NC=N1)C1=CC=C(Br)C=C1 MDLPZLVTPXRAFB-UHFFFAOYSA-N 0.000 description 2
- YASYEJJMZJALEJ-UHFFFAOYSA-N Citric acid monohydrate Chemical compound O.OC(=O)CC(O)(C(O)=O)CC(O)=O YASYEJJMZJALEJ-UHFFFAOYSA-N 0.000 description 2
- 229940126062 Compound A Drugs 0.000 description 2
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 229960002303 citric acid monohydrate Drugs 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- DROIHSMGGKKIJT-UHFFFAOYSA-N propane-1-sulfonamide Chemical compound CCCS(N)(=O)=O DROIHSMGGKKIJT-UHFFFAOYSA-N 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- SYBYTAAJFKOIEJ-UHFFFAOYSA-N 3-Methylbutan-2-one Chemical compound CC(C)C(C)=O SYBYTAAJFKOIEJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- DKTCWQULEMQHGL-UHFFFAOYSA-N N=C=O.SCl Chemical compound N=C=O.SCl DKTCWQULEMQHGL-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 239000005453 ketone based solvent Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- ZGHFDIIVVIFNPS-UHFFFAOYSA-N methyl alpha-methylvinyl ketone Natural products CC(=C)C(C)=O ZGHFDIIVVIFNPS-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000010979 pH adjustment Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 208000002815 pulmonary hypertension Diseases 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 239000012088 reference solution Substances 0.000 description 1
- 238000000956 solid--liquid extraction Methods 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
- C07D239/30—Halogen atoms or nitro radicals
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Detergent Compositions (AREA)
- Magnetic Heads (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Extraction Or Liquid Replacement (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Manufacturing Cores, Coils, And Magnets (AREA)
- Saccharide Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ??13176374.0 | 2013-07-12 | ||
| EP13176374 | 2013-07-12 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| TW201536759A TW201536759A (zh) | 2015-10-01 |
| TWI643848B true TWI643848B (zh) | 2018-12-11 |
Family
ID=48790244
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| TW103124052A TWI643848B (zh) | 2013-07-12 | 2014-07-11 | 製備嘧啶中間物之方法 |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US9556125B2 (enExample) |
| EP (1) | EP3019479B1 (enExample) |
| JP (1) | JP6375374B2 (enExample) |
| KR (1) | KR102305298B1 (enExample) |
| CN (1) | CN105636940B (enExample) |
| AR (1) | AR096865A1 (enExample) |
| CA (1) | CA2915736C (enExample) |
| DK (1) | DK3019479T3 (enExample) |
| ES (1) | ES2636937T3 (enExample) |
| HR (1) | HRP20171166T1 (enExample) |
| HU (1) | HUE034071T2 (enExample) |
| IL (1) | IL243477B (enExample) |
| MX (1) | MX360768B (enExample) |
| PL (1) | PL3019479T3 (enExample) |
| PT (1) | PT3019479T (enExample) |
| TW (1) | TWI643848B (enExample) |
| WO (1) | WO2015004265A1 (enExample) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ZA201605808B (en) | 2015-08-26 | 2017-08-30 | Cipla Ltd | Process for preparing an endothelin receptor antagonist |
| CN105461638A (zh) * | 2015-12-10 | 2016-04-06 | 合肥久诺医药科技有限公司 | 一种马西替坦晶型及其制备方法 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103724281A (zh) * | 2013-12-03 | 2014-04-16 | 镇江圣安医药有限公司 | N-[5-（4-溴苯基）-6-[2-[（5-溴-2-嘧啶基）氧基]乙氧基]-4-嘧啶基]-n′-丙基磺酰胺的新型衍生物及其应用 |
| CN103819411A (zh) * | 2014-03-14 | 2014-05-28 | 成都克莱蒙医药科技有限公司 | 一种马西替坦中间体新的制备方法 |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100432070C (zh) * | 2000-12-18 | 2008-11-12 | 埃科特莱茵药品有限公司 | 新颖的磺酰胺类化合物及其作为内皮素受体拮抗剂的应用 |
-
2014
- 2014-07-10 AR ARP140102549A patent/AR096865A1/es active IP Right Grant
- 2014-07-11 CA CA2915736A patent/CA2915736C/en active Active
- 2014-07-11 KR KR1020167003201A patent/KR102305298B1/ko not_active Expired - Fee Related
- 2014-07-11 DK DK14737272.6T patent/DK3019479T3/en active
- 2014-07-11 US US14/904,657 patent/US9556125B2/en active Active
- 2014-07-11 CN CN201480039832.2A patent/CN105636940B/zh active Active
- 2014-07-11 TW TW103124052A patent/TWI643848B/zh not_active IP Right Cessation
- 2014-07-11 PT PT147372726T patent/PT3019479T/pt unknown
- 2014-07-11 EP EP14737272.6A patent/EP3019479B1/en active Active
- 2014-07-11 WO PCT/EP2014/064904 patent/WO2015004265A1/en not_active Ceased
- 2014-07-11 MX MX2016000386A patent/MX360768B/es active IP Right Grant
- 2014-07-11 ES ES14737272.6T patent/ES2636937T3/es active Active
- 2014-07-11 HR HRP20171166TT patent/HRP20171166T1/hr unknown
- 2014-07-11 JP JP2016524837A patent/JP6375374B2/ja active Active
- 2014-07-11 HU HUE14737272A patent/HUE034071T2/en unknown
- 2014-07-11 PL PL14737272T patent/PL3019479T3/pl unknown
-
2016
- 2016-01-06 IL IL243477A patent/IL243477B/en active IP Right Grant
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103724281A (zh) * | 2013-12-03 | 2014-04-16 | 镇江圣安医药有限公司 | N-[5-（4-溴苯基）-6-[2-[（5-溴-2-嘧啶基）氧基]乙氧基]-4-嘧啶基]-n′-丙基磺酰胺的新型衍生物及其应用 |
| CN103819411A (zh) * | 2014-03-14 | 2014-05-28 | 成都克莱蒙医药科技有限公司 | 一种马西替坦中间体新的制备方法 |
Non-Patent Citations (1)
| Title |
|---|
| Martin H. Bolli et al.,"The Discovery of N‑[5-(4-Bromophenyl)-6-[2-[(5-bromo-2- pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]‑N′‑propylsulfamide (Macitentan), an Orally Active, Potent Dual Endothelin Receptor Antagonist", J. Med. Chem. ,2012, 55, 7849−7861 * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3019479B1 (en) | 2017-05-10 |
| KR20160030972A (ko) | 2016-03-21 |
| KR102305298B1 (ko) | 2021-09-27 |
| US9556125B2 (en) | 2017-01-31 |
| JP2016525094A (ja) | 2016-08-22 |
| MX2016000386A (es) | 2016-04-29 |
| IL243477B (en) | 2018-06-28 |
| PL3019479T3 (pl) | 2017-10-31 |
| US20160145215A1 (en) | 2016-05-26 |
| HRP20171166T1 (hr) | 2017-10-06 |
| DK3019479T3 (en) | 2017-07-17 |
| CN105636940B (zh) | 2018-02-27 |
| WO2015004265A1 (en) | 2015-01-15 |
| MX360768B (es) | 2018-11-15 |
| CA2915736C (en) | 2021-07-27 |
| EP3019479A1 (en) | 2016-05-18 |
| AR096865A1 (es) | 2016-02-03 |
| ES2636937T3 (es) | 2017-10-10 |
| HUE034071T2 (en) | 2018-01-29 |
| CA2915736A1 (en) | 2015-01-15 |
| JP6375374B2 (ja) | 2018-08-15 |
| CN105636940A (zh) | 2016-06-01 |
| TW201536759A (zh) | 2015-10-01 |
| PT3019479T (pt) | 2017-08-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Annulment or lapse of patent due to non-payment of fees |