JP7379470B2 - レンバチニブの調製方法 - Google Patents
レンバチニブの調製方法 Download PDFInfo
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- JP7379470B2 JP7379470B2 JP2021512797A JP2021512797A JP7379470B2 JP 7379470 B2 JP7379470 B2 JP 7379470B2 JP 2021512797 A JP2021512797 A JP 2021512797A JP 2021512797 A JP2021512797 A JP 2021512797A JP 7379470 B2 JP7379470 B2 JP 7379470B2
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- lenvatinib
- chloro
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- WOSKHXYHFSIKNG-UHFFFAOYSA-N lenvatinib Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 title claims description 22
- 229960003784 lenvatinib Drugs 0.000 title claims description 18
- 238000000034 method Methods 0.000 title description 8
- 238000002360 preparation method Methods 0.000 title description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 26
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 17
- ZBTVNIDMGKZSGC-UHFFFAOYSA-N 4-chloro-7-methoxyquinoline-6-carboxamide Chemical compound C1=CC(Cl)=C2C=C(C(N)=O)C(OC)=CC2=N1 ZBTVNIDMGKZSGC-UHFFFAOYSA-N 0.000 claims description 16
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 13
- HTJDQJBWANPRPF-UHFFFAOYSA-N Cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 claims description 10
- PNLPXABQLXSICH-UHFFFAOYSA-N 4-amino-3-chlorophenol Chemical compound NC1=CC=C(O)C=C1Cl PNLPXABQLXSICH-UHFFFAOYSA-N 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 239000012074 organic phase Substances 0.000 claims description 7
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 6
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- 239000008346 aqueous phase Substances 0.000 claims description 4
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 5
- 239000012535 impurity Substances 0.000 description 13
- 238000006243 chemical reaction Methods 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- BSCCSDNZEIHXOK-UHFFFAOYSA-N phenyl carbamate Chemical class NC(=O)OC1=CC=CC=C1 BSCCSDNZEIHXOK-UHFFFAOYSA-N 0.000 description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 5
- QVPZNUIZEVRITP-UHFFFAOYSA-N 1-(2-chloro-4-hydroxyphenyl)-3-cyclopropylurea Chemical compound ClC1=CC(O)=CC=C1NC(=O)NC1CC1 QVPZNUIZEVRITP-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 238000005859 coupling reaction Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000003247 decreasing effect Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000008878 coupling Effects 0.000 description 2
- 238000010168 coupling process Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 150000003672 ureas Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- RFJVQGMBFQGZPV-UHFFFAOYSA-N 4-amino-3-chlorophenol;hydrochloride Chemical compound Cl.NC1=CC=C(O)C=C1Cl RFJVQGMBFQGZPV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 208000006265 Renal cell carcinoma Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 208000015799 differentiated thyroid carcinoma Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- 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)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Display Devices Of Pinball Game Machines (AREA)
- Holo Graphy (AREA)
Description
(1) 4-アミノ-3-クロロ-フェノール(II)の対応するフェニルカルバメート誘導体(III)への変換;
を含む。
4-アミノ-3-クロロ-フェノール塩酸塩(II)(60.0g、333.3mmol、1当量)を2-メチルテトラヒドロフラン(180mL、3V)に懸濁し、懸濁液を0-5℃で冷却した。NaHCO3(58.8g、699.9ミリモル、2.1当量)の水溶液(650ml)を25分間で滴下し、10℃未満に維持した。2-メチルテトラヒドロフラン(96mL)中のフェニルクロロホルメート(57.4g、46.0mL、366.7mmol、1.1当量)の溶液を、温度を10℃未満に保ちながら25分間で滴下した。混合物を0-5℃で10分間撹拌した。4-アミノ-3-クロロフェノールが1%未満になるまで、反応を定量TLC(95:5のDCM:MeOH;UV254nm)によってモニターした。
比較例2 4-(3-クロロ-4-(シクロプロピルアミノカルボニル)-アミノフェノキシ)-7-メトキシ-6-キノリンカルボキサミド(I)(US 7683172の実施例3によるカップリング条件)
4-クロロ-7-メトキシキノリン-6-カルボキサミド(VI)(0.983g、4.15mmol、1当量)および1-(2-クロロ-4-ヒドロキシフェニル)-3-シクロプロピル尿素(V)(1.13g、4.99mmol、1.2当量)を20mLのDMSOに懸濁した。炭酸セシウム(2.71g、8.32mmol、2当量)を加え、混合物を70℃で23時間撹拌した。反応混合物を室温に冷却し、水(50mL)を加えて生成物を沈殿させた。沈殿した結晶を濾過し、乾燥させて、暗青色固体(1.58g、3.70mmol、y=89%、表1に報告される不純物含有量)を得た。粗レンバチニブ(1.58g、3.70mmol)を70℃でDMSO(7.8mL、5V)に溶解した。溶液を室温に冷却し、ジクロロメタン(23.7mL、15V)を15分で添加した。混合物を室温で16時間、0-5℃で1時間撹拌した。懸濁液を濾過し、固体を1:3のDMSO:DCM(3.1mL、2V)で洗浄し、純粋なDCM(6.2mL、4V)で3回粉砕した。固体を真空下60℃で24時間乾燥させて、レンバチニブ(I)(34.07g、79.81mmol、結晶化収率=79%、全収率=67%)を得た。典型的なA%HPLC純度は99.6%である。
4-クロロ-7-メトキシキノリン-6-カルボキサミド(VI)(32.0g、135.2mmol、1当量)および1-(2-クロロ-4-ヒドロキシフェニル)-3-シクロプロピル尿素(V)(61.30g、270.4mmol、2当量)を、窒素下でDMSO(192mL、6V)中に懸濁した。炭酸セシウム(88.11g、270.4mmol、2当量を加え、混合物を窒素雰囲気下50℃で24時間撹拌した。反応混合物を室温に冷却し、水(192mL、6V)を40分間で滴下して加え、生成物を沈殿させた。得られた懸濁液を室温で1時間撹拌した。沈殿した結晶を濾別し、1:1のDMSO:H2O(64mL、2V)で洗浄し、水(130mL、4V)で3回粉砕した。固体を真空下60℃で18時間乾燥させて、淡褐色/灰色固体(53.25g、124.7mmol、y=85%、表1に報告される不純物含有量)を得た。粗レンバチニブ(53.25g、124.7mmol)を70℃でDMSO(450mL、5V)に溶解した。溶液を室温に冷却し、ジクロロメタン(1350mL、15V)を15分で添加した。混合物を室温で16時間、0-5℃で1時間撹拌した。懸濁液を濾過し、固体を1:3のDMSO:DCM(106mL、2V)で洗浄し、純粋なDCM(210mL、4V)で3回粉砕した。固体を真空下60℃で24時間乾燥させて、レンバチニブ(I)(34.07g、79.81mmol、結晶化収率=79%、全収率=67%)を得た。典型的なA%HPLC純度は99.5%であり、不純物含有量を表1に報告する。
実施例3に従って得られたレンバチニブ遊離塩基(6.81g、15.9mmol、1当量)を、酢酸(18.4mL、2.7V)に懸濁し、酢酸(2mL、0.3V)で希釈したメタンスルホン酸(1.0mL、15.9mmol、1当量)を添加した。混合物を60℃で30分撹拌して完全に溶解した。溶液をWhatman0.2μmフィルターを通し、60℃で再び加熱した。酢酸エチル(6.8mL、1V)を滴下し、混合物を40℃に冷却した。混合物を40℃で16時間、室温で1時間撹拌した。懸濁液を濾過し、固体を3:1の酢酸:EtOAc(6.8mL、1V)で洗浄した。湿った固体(ACA-1形態、18.25g)を真空中60℃で72時間、70℃でさらに24時間乾燥させて、標題化合物をACA-1-HT乾燥固体形態(6.22g、11.9mmol、y=75%)として得た。典型的なA%HPLC純度は99.8%であった。
Claims (4)
- 工程(a)が50℃で行われる、請求項1に記載の製造方法。
- 工程(a)が2当量の炭酸セシウムの存在下で実施される、請求項1または2に記載の製造方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP18193196.5A EP3620452B1 (en) | 2018-09-07 | 2018-09-07 | Process for the preparation of lenvatinib |
EP18193196.5 | 2018-09-07 | ||
PCT/EP2019/073442 WO2020048963A1 (en) | 2018-09-07 | 2019-09-03 | Process for the preparation of lenvatinib |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2021536481A JP2021536481A (ja) | 2021-12-27 |
JP7379470B2 true JP7379470B2 (ja) | 2023-11-14 |
Family
ID=63528608
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2021512797A Active JP7379470B2 (ja) | 2018-09-07 | 2019-09-03 | レンバチニブの調製方法 |
Country Status (14)
Country | Link |
---|---|
US (1) | US11214543B2 (ja) |
EP (1) | EP3620452B1 (ja) |
JP (1) | JP7379470B2 (ja) |
KR (1) | KR20210056390A (ja) |
CN (1) | CN112654603B (ja) |
CA (1) | CA3111875A1 (ja) |
DK (1) | DK3620452T3 (ja) |
ES (1) | ES2878275T3 (ja) |
HU (1) | HUE055374T2 (ja) |
IL (1) | IL281254B2 (ja) |
PL (1) | PL3620452T3 (ja) |
PT (1) | PT3620452T (ja) |
SI (1) | SI3620452T1 (ja) |
WO (1) | WO2020048963A1 (ja) |
Families Citing this family (2)
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WO2021217537A1 (zh) * | 2020-04-30 | 2021-11-04 | 天津睿创康泰生物技术有限公司 | 一种乐伐替尼游离碱晶型及其制备方法 |
CN113045492A (zh) * | 2021-03-26 | 2021-06-29 | 成都倍特药业股份有限公司 | 一种甲磺酸仑伐替尼杂质、其制备方法和检测方法 |
Citations (3)
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WO2005044788A1 (ja) | 2003-11-11 | 2005-05-19 | Eisai Co., Ltd. | ウレア誘導体およびその製造方法 |
CN104876864A (zh) | 2015-06-05 | 2015-09-02 | 北京康立生医药技术开发有限公司 | 一种乐伐替尼的制备方法 |
CN106632033A (zh) | 2016-10-28 | 2017-05-10 | 北京万全德众医药生物技术有限公司 | 乐伐替尼的一种制备方法 |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
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DE60134679D1 (de) | 2000-10-20 | 2008-08-14 | Eisai R&D Man Co Ltd | Stickstoff enthaltende aromatische Heterozyklen |
KR100951607B1 (ko) * | 2005-06-23 | 2010-04-09 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 4-(3-클로로-4-(시클로프로필아미노카르보닐)아미노페녹시)-7-메톡시-6-퀴놀린카르복사미드의 비정질 염 및 그 제조방법 |
CN107266363A (zh) | 2016-04-06 | 2017-10-20 | 杭州华东医药集团新药研究院有限公司 | 甲磺酸乐伐替尼药物杂质的制备方法 |
CN108299294A (zh) * | 2017-01-11 | 2018-07-20 | 江苏恒瑞医药股份有限公司 | 一种乐伐替尼杂质的制备方法 |
WO2019016664A1 (en) * | 2017-07-20 | 2019-01-24 | Bdr Lifesciences Private Limited | IMPROVED PROCESS FOR THE PREPARATION OF LENVATINIB |
CN107739335A (zh) * | 2017-12-01 | 2018-02-27 | 南京奇可药业有限公司 | 一种乐伐替尼的合成方法 |
CN108997214A (zh) * | 2018-06-13 | 2018-12-14 | 成都地奥制药集团有限公司 | 乐伐替尼中间体及其制备和乐伐替尼的制备 |
CN110818634B (zh) * | 2018-08-13 | 2021-11-30 | 上海新礼泰药业有限公司 | 甲磺酸乐伐替尼的精制方法 |
CN109734661B (zh) * | 2018-09-10 | 2021-12-21 | 江苏工程职业技术学院 | 一种乐伐替尼的合成方法 |
CN109456267A (zh) * | 2018-12-28 | 2019-03-12 | 南京天越星生物技术有限公司 | 一种合成乐伐替尼的方法 |
CN110981800A (zh) * | 2019-12-31 | 2020-04-10 | 安徽省诚联医药科技有限公司 | 一种乐伐替尼的制备方法 |
CN113307767A (zh) * | 2021-06-18 | 2021-08-27 | 山东汇海医药化工有限公司 | 一种乐伐替尼的合成方法 |
-
2018
- 2018-09-07 PL PL18193196T patent/PL3620452T3/pl unknown
- 2018-09-07 PT PT181931965T patent/PT3620452T/pt unknown
- 2018-09-07 ES ES18193196T patent/ES2878275T3/es active Active
- 2018-09-07 EP EP18193196.5A patent/EP3620452B1/en active Active
- 2018-09-07 DK DK18193196.5T patent/DK3620452T3/da active
- 2018-09-07 HU HUE18193196A patent/HUE055374T2/hu unknown
- 2018-09-07 SI SI201830300T patent/SI3620452T1/sl unknown
-
2019
- 2019-09-03 KR KR1020217010238A patent/KR20210056390A/ko active Search and Examination
- 2019-09-03 CA CA3111875A patent/CA3111875A1/en active Pending
- 2019-09-03 US US17/273,740 patent/US11214543B2/en active Active
- 2019-09-03 WO PCT/EP2019/073442 patent/WO2020048963A1/en active Application Filing
- 2019-09-03 IL IL281254A patent/IL281254B2/en unknown
- 2019-09-03 CN CN201980058309.7A patent/CN112654603B/zh active Active
- 2019-09-03 JP JP2021512797A patent/JP7379470B2/ja active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005044788A1 (ja) | 2003-11-11 | 2005-05-19 | Eisai Co., Ltd. | ウレア誘導体およびその製造方法 |
CN104876864A (zh) | 2015-06-05 | 2015-09-02 | 北京康立生医药技术开发有限公司 | 一种乐伐替尼的制备方法 |
CN106632033A (zh) | 2016-10-28 | 2017-05-10 | 北京万全德众医药生物技术有限公司 | 乐伐替尼的一种制备方法 |
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US11214543B2 (en) | 2022-01-04 |
HUE055374T2 (hu) | 2021-11-29 |
IL281254B2 (en) | 2024-02-01 |
PT3620452T (pt) | 2021-07-06 |
CN112654603B (zh) | 2024-05-03 |
CA3111875A1 (en) | 2020-03-12 |
ES2878275T3 (es) | 2021-11-18 |
EP3620452A1 (en) | 2020-03-11 |
IL281254A (en) | 2021-04-29 |
US20210246107A1 (en) | 2021-08-12 |
KR20210056390A (ko) | 2021-05-18 |
EP3620452B1 (en) | 2021-05-19 |
JP2021536481A (ja) | 2021-12-27 |
PL3620452T3 (pl) | 2021-10-25 |
CN112654603A (zh) | 2021-04-13 |
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