WO2016178064A1 - Polymorphe d'éthanesulfonate de nintedanib, procédés et intermédiaires associés - Google Patents

Polymorphe d'éthanesulfonate de nintedanib, procédés et intermédiaires associés Download PDF

Info

Publication number
WO2016178064A1
WO2016178064A1 PCT/IB2015/054587 IB2015054587W WO2016178064A1 WO 2016178064 A1 WO2016178064 A1 WO 2016178064A1 IB 2015054587 W IB2015054587 W IB 2015054587W WO 2016178064 A1 WO2016178064 A1 WO 2016178064A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
nintedanib
solvent
reacting
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.)
Ceased
Application number
PCT/IB2015/054587
Other languages
English (en)
Inventor
Veera Reddy Arava
Surendra Reddy GOGIREDDY
Venkateswarlu Jasti
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Suven Life Sciences Ltd
Original Assignee
Suven Life Sciences Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Suven Life Sciences Ltd filed Critical Suven Life Sciences Ltd
Publication of WO2016178064A1 publication Critical patent/WO2016178064A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to novel crystalline Form of Nintedanib and process for its preparation.
  • the present invention also relates to a novel process for the preparation of Nintedanib.
  • the present invention further relates to novel intermediates used in the preparation of Nintedanib and process for their preparation.
  • Nintedanib inhibits multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs).
  • the chemical name of Nintedanib is lH-Indole-6-carboxylic acid, 2,3- dihydro-3-[[[4-[methyl-(4-methyl-l-iperazinyl)acetyl]amino]phenyl]amino]phenylmethylene] -2-oxo-,methylester, (3Z)-, ethanesulfonate (1 : 1) and is structurally represented by compound of Formula I.
  • IPF Idiopathic Pulmonary Fibrosis
  • U.S.Pat. No. 7,119,093 discloses Nintedanib monoethanesulphonate in crystalline form characterised by X-ray powder diffraction pattern having 2 ⁇ values at 7.70, 8.78, 9.47, 9.82, 11.59, 11.93, 13.15, 13.69, 14.17, 16.32, 16.72, 16.92, 17.43, 17.77, 18.58, 18.81, 19.03, 19.73, 19.87, 20.03, 20.61, 20.83, 21.26, 21.76, 22.05, 22.19, 22.57, 23.10, 23.81, 24.69, 24.78, 24.91, 25.42, 26.24, 26.91, 27.19, 27.61, 27.95, 28.71, 29.25.
  • Polymorphism the occurrence of different crystal forms, is a property of some molecules and molecular complexes.
  • a single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint and solid state NMR spectrum.
  • One polymorph may give rise to thermal behaviour different from that of another polymorph. Thermal behaviour can be measured in the laboratory by such techniques as capillary melting point, thermo gravimetric analysis (“TGA”) and differential scanning calorimetry (“DSC”), which have been used to distinguish polymorphic forms.
  • TGA thermo gravimetric analysis
  • DSC differential scanning calorimetry
  • the main objective of the present invention is to provide novel polymorph Form S of Nintedanib and process for its preparation.
  • Another objective of the present invention is to provide a robust and simple process for the preparation of Nintedanib monoethanesulphonate salt of Formula I with high yield and high purity.
  • the present invention is to provide a novel process for preparing Nintedanib monoethanesulphonate salt of Formula I, which is simple, industrially applicable and economically viable.
  • the present invention relates to novel intermediates used in the preparation of Nintedanib and process for their preparation.
  • the present invention provides a novel high melting crystalline Form S of Nintedanib ethanesulfonate of Formula I.
  • the present invention provides novel high melting crystalline Form S of Nintedanib ethanesulfonate of the Formula I having a DSC thermogram spectrum showing two characteristic endothermic peaks at 165-180° and at 295-305°C.
  • the present invention provides novel crystalline Form S of Nintedanib ethanesulfonate characterized by X-ray powder diffraction pattern having peaks at 9.38, 9.69, 11.47, 13.05, 13.56, 14.03, 16.18, 16.53, 17.29, 18.26, 18.96, 18.68, 19.22, 19.64, 19.86, 21.82, 22.99, 23.64 and 24.60 ⁇ 0.2° 2 ⁇ values.
  • the present invention provides a process for the preparation of novel crystalline Form S of Nintedanib ethanesulfonate of Formula I which comprises the steps: i) providing a solution of Nintedanib ethanesulfonate in a suitable solvent,
  • the present invention provides a process for the preparation of novel crystalline Form S of Nintedanib ethanesulfonate of Formula I which comprises the steps: i) providing a solution of Nintedanib ethanesulfonate in a suitable solvent,
  • the present invention provides a novel process for the preparation of Nintedanib ethanesulfonate of Formula I which comprises the steps of:
  • R represents alkyl, aryl, halogen and R' is acetyl
  • LG is a leaving group in a solvent to obtain compound of Formula IV;
  • LG and R' are as defined above;
  • the present invention provides a novel process for the preparation of Nintedanib ethanesulfonate of Formula I which comprises the steps of:
  • R represents alkyl, aryl, halogen and R' is acetyl; with a compound of Formula III,
  • LG is a leaving grou in a solvent to obtain compound of Formula IV;
  • LG and R' are as defined above;
  • the present invention provides a novel process for the preparation of Nintedanib ethanesulfonate of Formula I which comprises the steps of:
  • R' is as defined above
  • the present invention relates to novel intermediate of acetyl derivative of compound of Formula II
  • R represents alkyl, aryl, halogen and R' is acetyl.
  • the present invention relates to process for the preparation of novel intermediate of acetyl derivative of compound of Formula II which comprises the steps of: i) condensing methyl 2-oxoindolin -6-carboxylate of compound of Formula V.
  • LG is a leaving group and aryl halide and R' is acetyl.
  • the present invention relates to a process for the preparation of novel intermediate compound of Formula IV which comprises reacting acetyl derivative of compound of Formula II
  • the present invention provides a novel intermediate compound of Formula VIII
  • R' is as defined above.
  • the present invention provides a process for the preparation of intermediate compound of Formula VIII which comprises the steps of:
  • R' is as defined above.
  • Fig. l Represents Differential Scanning Calorimetry (DSC) thermogram of novel crystalline Form S of Nintedanib ethanesulfonate.
  • Fig. 2 Represents X-ray powder diffraction pattern of novel crystalline Form S of Nintedanib ethanesulfonate. Detailed Description of the Invention
  • the present invention provides a novel high melting crystalline Form S of Nintedanib ethanesulfonate of the Formula I having a DSC thermogram spectrum showing two endothermic peaks with a specific dehydration temperature at 165-180° and melting point at 295-305°C as depicted in Figure 1.
  • novel crystalline Form S of Nintedanib ethanesulfonate is also characterized by X-ray powder diffraction pattern having peaks at 11.47, 17.29, 18.68, 19.64, 19.86 ⁇ 0.2° 2 ⁇ values.
  • novel crystalline Form S of Nintedanib ethane sulfonate is further characterized by X-ray powder diffraction pattern having additional peaks at 9.38, 9.69, 13.05, 13.56, 14.03, 16.18, 16.53, 18.26, 18.96, 19.22, 21.82, 22.99, 23.64 and 24.60 ⁇ 0.2° 2 ⁇ values.
  • novel polymorph Form S of Nintedanib monoethane sulfonate is characterized by X-ray powder diffraction pattern having 2 ⁇ values, the interplanar spacing (d values) and relative intensities (I IQ) as shown in the table given below:
  • suitable solvent refers to the solvent selected from “polar protic solvents” such as water; “polar aprotic solvents” such as dimethylsulfoxide, dimethylacetamide, dimethyl formamide and the like; “nitrile solvents” such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like; “ether solvents” such as di-tert- butylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane; “alcohol solvents” such as methanol, ethanol, n- propanol, isopropanol, n-butanol and t-butanol and the like; “chloro solvents” such as methylene chloride, ethylene dichloride, ethylene dichloride, ethylene dich
  • the leaving group is selected from halogen (CI, Br, F or I), tosyl, mesyl and the like.
  • suitable base used in the present invention is selected from ammonia, sodium methoxide, sodium ethoxide, potassium methoxide, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium tert-pentoxide, sodium t-butoxide, potassium tert-butoxide, potassium n-butoxide, sodium hydride, triethylamine, N,N- diisopropylethylamine (DIPEA), pyridine and Dimethylaminopyridine (DMAP).
  • DIPEA N,N- diisopropylethylamine
  • DMAP Dimethylaminopyridine
  • the present invention provides a process for the preparation of novel crystalline Form S of Nintedanib ethanesulfonate of Formula I which comprises the steps of:
  • the present invention provides a process for the preparation of novel crystalline Form S of Nintedanib ethanesulfonate of Formula I which comprises the steps of:
  • the present invention provides a process for the preparation of novel crystalline Form S of Nintedanib ethanesulfonate of Formula I which comprises the steps:
  • the present invention provides a process for the preparation of novel crystalline Form S of Nintedanib ethanesulfonate of Formula I which comprises the steps:
  • the present invention provides a novel process for the preparation of Nintedanib ethanesulfonate of Formula I which comprises the steps of:
  • the present invention provides a novel process for the preparation of Nintedanib ethanesulfonate of Formula I which comprises the steps of: i) reacting acetyl derivative of compound of Formula Ila
  • the present invention provides a novel process for the preparation of Nintedanib ethanesulfonate of Formula I which comprises the steps of:
  • the present invention provides a novel process for the preparation of Nintedanib ethanesulfonate of Formula I which comprises the steps of: i) reacting acetyl derivative of compound of Formula Ila
  • the present invention provides a novel process for the preparation of Nintedanib ethanesulfonate of Formula I which comprises the steps of:
  • the present invention provides a novel process the preparation of Nintedanib ethanesulfonate of Formula I which comprises the steps of: i) acetylating the compound of Formula lib
  • the present invention provides a novel process for the preparation of Nintedanib ethanesulfonate of Formula I which comprises the steps of:
  • the present invention provides a novel process for the preparation of Nintedanib ethanesulfonate of Formula I which comprises the steps of: i) reacting the compound of Formula Ilia
  • the present invention relates to process for the preparation of novel intermediate of compound of Formula Ila which comprises the steps of: i) condensing methyl 2-oxoindoline-6-carboxylate of compound of Formula V with benzoyl chloride
  • the present invention relates to process for the preparation of novel intermediate of compound of Formula Ila which comprises the steps of: i) condensing methyl 2-oxoindolin -6-carboxylate of compound of Formula V
  • the present invention provides a novel process for the preparation of novel intermediate of compound of Formula IVa which comprises the steps of reacting acetyl derivative of compound of Formula Ila
  • the present invention provides a novel process for the preparation of novel intermediate of compound of Formula IVa which comprises the steps of reacting acetyl derivative of compound of Formula Ila
  • the present invention provides a novel intermediate of compound of Formula Ila
  • the present invention provides a novel intermediate of compound of Formula IVa.
  • Example 1 Process for the preparation of Nintedanib Monoethane Sulfonate:
  • Step-1 Preparation of methyl-3-(hydroxy(phenyl)methylene)-2-oxoindoline-6-carboxylate: To the suspension of methyl 2-oxoindoline-6-carboxylate (50 gm, 0.261 mol) in IPA (350 ml) was added slowly SMO-powder (33.8 gm, 0.626 mol) and stirred for about 15 min. Benzyl chloride (44 g, 0.313 mol) was added after completion of the reaction at a reaction temperature of -5 to -10°C for about 5hrs. The reaction mixture was quenched into ice-water (700 ml) and acidified with Cone. HC1 (2.0-2.5 ml).
  • Step-2 Preparation of methyl-3-(acetoxy(phenyl)methylene)-l-acetyl-2-oxoindoline-6- carboxylate (Acetyl derivative):
  • Step-3 Preparation of methyl- l-acetyl-3-(((4-(2-chloro-N-methylacetamido)phenyl)amino) (phenyl)methylene)-2-oxoindoline-6-carboxylate) (Chloroacetyl derivative) :
  • Step-4 Preparation of (Z)-methyl-3-(((4-(N-methyl-2-(4-methylpiperazin-lyl)acetamide) phenyl) amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate (Nintedanib free base):
  • Step-5 Preparation of (Z)-methyl-3-(((4-(N-methyl-2-(4-methylpiperazin-lyl)acetamide) phenyl) amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate ethane sulfonate salt:
  • Example 2 Process for the preparation of Polymorph Form S of Nintedanib monoethanesulf onate :

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une nouvelle forme cristalline de Nintedanib et son procédé de préparation. La présente invention concerne également un nouveau procédé pour la préparation de Nintedanib. La présente invention concerne en outre de nouveaux intermédiaires utilisés dans la préparation de Nintedanib et un procédé pour leur préparation.
PCT/IB2015/054587 2015-05-06 2015-06-18 Polymorphe d'éthanesulfonate de nintedanib, procédés et intermédiaires associés Ceased WO2016178064A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2307/CHE/2015 2015-05-06
IN2307CH2015 2015-05-06

Publications (1)

Publication Number Publication Date
WO2016178064A1 true WO2016178064A1 (fr) 2016-11-10

Family

ID=53724391

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2015/054587 Ceased WO2016178064A1 (fr) 2015-05-06 2015-06-18 Polymorphe d'éthanesulfonate de nintedanib, procédés et intermédiaires associés

Country Status (1)

Country Link
WO (1) WO2016178064A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106841495A (zh) * 2017-04-21 2017-06-13 常州佳德医药科技有限公司 乙磺酸尼达尼布中基因毒性杂质的高灵敏度分析方法
ITUA20164213A1 (it) * 2016-06-08 2017-12-08 Olon Spa Polimorfo di nintedanib
WO2018054077A1 (fr) 2016-09-26 2018-03-29 Reyoung (Suzhou) Biology Science & Technology Co., Ltd Composition destinée au traitement de maladies oculaires, et méthodes d'utilisation et procédés de fabrication
WO2018068733A1 (fr) * 2016-10-12 2018-04-19 浙江华海药业股份有限公司 Procédé de préparation de nintédanib et de son intermédiaire
WO2018165865A1 (fr) * 2017-03-14 2018-09-20 新源生物科技股份有限公司 Formes cristallines de 3-z-[1-(4-(n-((4-méthyl-pipérazin-1-yl)-méthylcarbonyl)-n-méthyl-amino)-phénylamino)-1-phényl-méthylène]-6-méthoxycarbonyl-2-indolinone
CN111848490A (zh) * 2020-08-24 2020-10-30 江西国药有限责任公司 一种高纯度乙磺酸尼达尼布的制备方法
CN111848486A (zh) * 2020-07-16 2020-10-30 赤峰经方医药技术开发有限责任公司 一种制备乙磺酸尼达尼布的方法
US11261158B2 (en) 2017-11-17 2022-03-01 Fermion Oy Synthesis of 2-indolinone derivatives
US11534399B2 (en) 2018-04-23 2022-12-27 Inspirmed Corp. Inhalable liposomal sustained release composition for use in treating pulmonary diseases
EP4178555A4 (fr) * 2020-08-07 2024-08-07 BDR Lifesciences Private Limited Procédé amélioré extrêmement efficace de préparation de nintédanib et d'un sel de qualité pharmaceutique de ce dernier

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1224170A1 (fr) 1999-10-13 2002-07-24 Boehringer Ingelheim Pharma KG Indolinones substituees en position 6, leur preparation et leur utilisation en tant que medicaments
US6762180B1 (en) 1999-10-13 2004-07-13 Boehringer Ingelheim Pharma Kg Substituted indolines which inhibit receptor tyrosine kinases
US20040176392A1 (en) * 2002-07-24 2004-09-09 Boehringer Ingelheim Pharma Gmbh & Co. Kg 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and the use thereof as a pharmaceutical composition
WO2009071523A1 (fr) * 2007-12-03 2009-06-11 Boehringer Ingelheim International Gmbh Procédé de fabrication d'un dérivé d'indolinone
US8067617B2 (en) 2007-12-03 2011-11-29 Boehringer Ingelheim International Gmbh Indolinone derivatives and process for their manufacture

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1224170A1 (fr) 1999-10-13 2002-07-24 Boehringer Ingelheim Pharma KG Indolinones substituees en position 6, leur preparation et leur utilisation en tant que medicaments
US6762180B1 (en) 1999-10-13 2004-07-13 Boehringer Ingelheim Pharma Kg Substituted indolines which inhibit receptor tyrosine kinases
US20040176392A1 (en) * 2002-07-24 2004-09-09 Boehringer Ingelheim Pharma Gmbh & Co. Kg 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and the use thereof as a pharmaceutical composition
US7119093B2 (en) 2002-07-24 2006-10-10 Boehringer Ingelheim Pharma Gmbh & Co. Kg 3-Z-[1-(4-(N-((4-Methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and the use thereof as a pharmaceutical composition
WO2009071523A1 (fr) * 2007-12-03 2009-06-11 Boehringer Ingelheim International Gmbh Procédé de fabrication d'un dérivé d'indolinone
US8067617B2 (en) 2007-12-03 2011-11-29 Boehringer Ingelheim International Gmbh Indolinone derivatives and process for their manufacture

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CAIRA: "Crystalline Polymorphism of Organic Compounds", TOPICS IN CURRENT CHEMISTRY, SPRINGER, BERLIN, DE, vol. 198, 1 January 1998 (1998-01-01), pages 163 - 208, XP008166276, ISSN: 0340-1022 *

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ITUA20164213A1 (it) * 2016-06-08 2017-12-08 Olon Spa Polimorfo di nintedanib
WO2017211777A1 (fr) * 2016-06-08 2017-12-14 Olon Spa Polymorphe de nintédanib
WO2018054077A1 (fr) 2016-09-26 2018-03-29 Reyoung (Suzhou) Biology Science & Technology Co., Ltd Composition destinée au traitement de maladies oculaires, et méthodes d'utilisation et procédés de fabrication
CN109803954A (zh) * 2016-10-12 2019-05-24 浙江华海药业股份有限公司 尼达尼布及其中间体的制备方法
WO2018068733A1 (fr) * 2016-10-12 2018-04-19 浙江华海药业股份有限公司 Procédé de préparation de nintédanib et de son intermédiaire
US10836751B2 (en) 2016-10-12 2020-11-17 Zhejiang Huahai Pharmaceutical Co., Ltd. Methods for preparing Nintedanib and intermediates thereof
CN109803954B (zh) * 2016-10-12 2021-12-07 浙江华海药业股份有限公司 尼达尼布及其中间体的制备方法
WO2018165865A1 (fr) * 2017-03-14 2018-09-20 新源生物科技股份有限公司 Formes cristallines de 3-z-[1-(4-(n-((4-méthyl-pipérazin-1-yl)-méthylcarbonyl)-n-méthyl-amino)-phénylamino)-1-phényl-méthylène]-6-méthoxycarbonyl-2-indolinone
CN110072849A (zh) * 2017-03-14 2019-07-30 新源生物科技股份有限公司 3-z-[1-(4-(n-((4-甲基-哌嗪-1-基)-甲羰基)-n-甲基-氨基)-苯氨基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的晶型
JP2020508979A (ja) * 2017-03-14 2020-03-26 オールジェネシス バイオセラピューティクス インコーポレイテッド ３−ｚ−［１−（４−（ｎ−（（４−メチル−ピペラジン−１−イル）−メチルカルボニル）−ｎ−メチル−アミノ）−フェニルアミノ）−１−フェニル−メチレン］−６−メトキシカルボニル−２−インドリノンの結晶形
JP7306697B2 (ja) 2017-03-14 2023-07-11 オールジェネシス バイオセラピューティクス インコーポレイテッド ３－ｚ－［１－（４－（ｎ－（（４－メチル－ピペラジン－１－イル）－メチルカルボニル）－ｎ－メチル－アミノ）－フェニルアミノ）－１－フェニル－メチレン］－６－メトキシカルボニル－２－インドリノンの結晶形
CN116063221A (zh) * 2017-03-14 2023-05-05 新源生物科技股份有限公司 尼达尼布的晶型
US10961203B2 (en) 2017-03-14 2021-03-30 Allgenesis Biotherapeutics Inc. Crystalline forms of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone
JP2021176899A (ja) * 2017-03-14 2021-11-11 オールジェネシス バイオセラピューティクス インコーポレイテッド ３−ｚ−［１−（４−（ｎ−（（４−メチル−ピペラジン−１−イル）−メチルカルボニル）−ｎ−メチル−アミノ）−フェニルアミノ）−１−フェニル−メチレン］−６−メトキシカルボニル−２−インドリノンの結晶形
CN106841495A (zh) * 2017-04-21 2017-06-13 常州佳德医药科技有限公司 乙磺酸尼达尼布中基因毒性杂质的高灵敏度分析方法
US11261158B2 (en) 2017-11-17 2022-03-01 Fermion Oy Synthesis of 2-indolinone derivatives
US11534399B2 (en) 2018-04-23 2022-12-27 Inspirmed Corp. Inhalable liposomal sustained release composition for use in treating pulmonary diseases
US12533313B2 (en) 2018-04-23 2026-01-27 Inspirmed Corp. Inhalable liposomal sustained release composition for use in treating pulmonary diseases
CN111848486A (zh) * 2020-07-16 2020-10-30 赤峰经方医药技术开发有限责任公司 一种制备乙磺酸尼达尼布的方法
EP4178555A4 (fr) * 2020-08-07 2024-08-07 BDR Lifesciences Private Limited Procédé amélioré extrêmement efficace de préparation de nintédanib et d'un sel de qualité pharmaceutique de ce dernier
CN111848490A (zh) * 2020-08-24 2020-10-30 江西国药有限责任公司 一种高纯度乙磺酸尼达尼布的制备方法

Similar Documents

Publication Publication Date Title
US8440831B2 (en) Process and intermediates for preparing integrase inhibitors
EP2451786A2 (fr) Procédé amélioré de préparation d'ambrisentan et nouveaux intermédiaires associés
WO2017221189A1 (fr) Procédé amélioré pour la préparation de ténofovir alafénamide ou de sels pharmaceutiquement acceptables de celui-ci
JP2018518489A (ja) アプレミラスト及びその中間体の調製方法
EP3490973B1 (fr) Formes polymorphiques du belinostat et leurs procédés de préparation
KR20180040694A (ko) 이브루티닙의 결정형 및 그 제조 방법
KR20110041431A (ko) 결정성 고체 두타스터라이드 및 그의 제조방법
CN108947884B (zh) 一种艾瑞昔布的制备方法及其中间体
CN113874359B (zh) 用于制备1-脱氧-1-甲基氨基-d-葡萄糖醇2-(3,5-二氯苯基)-6-苯并𫫇唑羧酸盐的方法
KR100794955B1 (ko) 트란스-4-아미노-1-시클로헥산카르복실산 유도체의 제조방법
WO2008090046A1 (fr) Nouveau procédé servant à préparer de la 3,5-di-omicron-acyl-2-fluoro-2-c-méthyl-d-ribono-gamma-lactone
CN1980939A (zh) 1－氧杂头孢菌素－7α－甲氧基－3－氯甲基衍生物的生产方法
JP2007523203A (ja) クロピドグレルの薬理学的に許容できる塩
WO2019150383A1 (fr) Procédé de préparation de luliconazole
WO2016046833A2 (fr) Procédé amélioré de préparation de l'agomélatine à l'aide de nouveaux intermédiaires
KR100900177B1 (ko) 트리테르펜 유도체의 제조 방법
JP5234856B2 (ja) Ｎｐｙｙ５受容体拮抗作用を有する化合物の結晶
WO2005030738A1 (fr) Procede ameliore de fabrication d'intermediaires utilises pour l'obtention de zonisamide
CN119301104A (zh) 用于制备4-取代的2-噁唑烷酮的方法
WO2025046257A1 (fr) Propentofylline sensiblement pure et sa préparation
EP4545523A1 (fr) Procédé de préparation de dichlorhydrate de jaktinib monohydraté
WO2022034427A1 (fr) Processus amélioré de préparation de 4-oxoisotrétinoïne
WO2024251276A1 (fr) Nouveau procédé de préparation d'un composé oxopyridine, intermédiaire clé et utilisation
KR101606395B1 (ko) 아고멜라틴의 제조방법
TW202506652A (zh) 製備４－羥基－４，５－二氫噻唑－２－甲腈及其衍生物之方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15742075

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15742075

Country of ref document: EP

Kind code of ref document: A1