WO2014086326A1 - Procédé pour la préparation et la purification de polymorphes et solvates nouveaux et connus du dasatinib - Google Patents

Procédé pour la préparation et la purification de polymorphes et solvates nouveaux et connus du dasatinib Download PDF

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Publication number
WO2014086326A1
WO2014086326A1 PCT/CZ2013/000160 CZ2013000160W WO2014086326A1 WO 2014086326 A1 WO2014086326 A1 WO 2014086326A1 CZ 2013000160 W CZ2013000160 W CZ 2013000160W WO 2014086326 A1 WO2014086326 A1 WO 2014086326A1
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dasatinib
solvate
acetonitrile
solvent
preparation
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PCT/CZ2013/000160
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English (en)
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Karel ZELENKA
Josef Hajicek
Ondrej Dammer
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Zentiva, K.S.
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Publication of WO2014086326A1 publication Critical patent/WO2014086326A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to a new production and purification method of polymorphs and solvates of dasatinib.
  • Dasatinib N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)- 1 -piperazinyl]-2- methyl-4-pyrimidmyl]amino]-5-thiazole carboxamide of formula I, also known as BMS- 354825, is a cancer treatment drug developed by Bristol-Myers Squibb and sold under the trade name Sprycel®.
  • Dasatinib is a multi- BCR/ABL and Src family tyrosine kinase inhibitor and it is used for treatment of chronic myelogenous leukaemia (CML) as a secondary drug after primary treatment with imatinib (Gleevec®).
  • CML chronic myelogenous leukaemia
  • dasatinib is prepared by reaction of the key intermediate of formula II with l-(2-hydroxyethyl)piperazine in the presence of a base and a suitable solvent (Scheme 1).
  • a similar preparation method was later used in a number of other process patents, only varying the corresponding base or solvent.
  • a suitable solvent or procedure Through the selection of a suitable solvent or procedure a great number of solvates or polymorphs can be prepared.
  • Polymorphs have been one of the most frequently studied physical characteristics of active pharmaceutical substances (API) recently. Thus, different polymorphs of one API may have entirely different physical-chemical properties such as solubility, melting point, mechanical resistance of crystals but they may also influence the chemical and physical stability.
  • the process patent WO2005077945A2 describes preparation of the following solvates of dasatinib: monohydrate, butanol solvate, as well as two anhydrous forms (N-6 and T1H1- 7).
  • a related patent also mentions two ethanol solvates, the hemi-ethanol and diethanol solvates (US 8 242 270 B2). Salts, various combinations of salts and their solvates have been described in detail in the patent application WO2007035874A1.
  • API solvates or salts are used in drug formulations in many cases.
  • the limits for individual solvents their contents or maximum daily doses have to be strictly observed. Then, these limits can dramatically restrict their effective use.
  • the clearly most convenient option is the use of sufficiently stable polymorphs of API that do not contain any solvents bound in the crystalline structure.
  • N-6 a stable anhydrous form of dasatinib
  • the main disadvantages of the preparation of N-6 is the necessity of desolvation of the solvated form of the API at high temperatures (WO2009053854A2), or application of an increased temperature (50°C and more) and vacuum for a relatively long time (8-12h; WO2010139981A2 and WO2005077945A2).
  • These procedures are very demanding from the point of view of general technology, energy and time, to say nothing of the necessity to work under an inert atmosphere to prevent possible oxidation-degradation reactions of the API.
  • dasatinib may be oxidized by atmospheric oxygen to the corresponding N-oxide (oxidation occurs in the piperazine ring), which may undergo the Cope elimination at increased temperatures. This secondary reaction may subsequently impair the purity of the prepared API.
  • the invention relates to a method for the preparation of dasatinib of formula I in the anhydrous form N-6, characterized by the following reflections in an X-ray powder diffraction pattern, measured using the CuKa radiation: 6.8; 12.3; 13.2; 13.8; 16.7; 21.0; 24.3 and 24.8 ⁇ 0.2° 2-theta
  • the preparation method in accordance with the invention is based on the surprising finding that the anhydrous polymorph of dasatinib N-6 can be obtained by re-crystallization of any form of dasatinib from a mixture of a suitable solvent and a suitable co-solvent.
  • This new preparation method of the anhydrous polymorph N-6 differs from the hitherto known procedures by excellent repeatability and, above all, simple execution. Intensive drying (at a high temperature, for a long time, in vacuo) is no longer required and the product aspirated directly after crystallization corresponds, according to the XRPD pattern, to the polymorph N- 6 as described in literature.
  • Dasatinib of formula I is prepared by a reaction of the intermediate of formula II with l-(2- hydroxyethyl)piperazine in the presence of diisopropylethylamine (DIPEA) in an organic solvent from the group of dipolar aprotic solvents, higher alcohols or diols.
  • DIPEA diisopropylethylamine
  • a dipolar aprotic solvent from the group of N-methyl-2-pyrrolidone (NMP), N ⁇ iV-dimethyl formamide (DMF), AyV-dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), formamide (FA), N,N -dimethyl propylene urea (DMPU) and l,3-dimethyl-2-imidazolidinone (DMI) is used, the reaction is carried out at 50-110°C under an inert atmosphere for 1/2-6 hours. In a preferable embodiment, NMP, DMSO, DMPU or DMI is used and the reaction is carried out at 90°C for 1-3 hours. The result of the reaction is crude dasatinib in the form of a solution in the corresponding solvent.
  • NMP N ⁇ iV-dimethyl formamide
  • DMA AyV-dimethyl acetamide
  • DMSO dimethyl sulfoxide
  • FA formamide
  • DMPU N,N -
  • the reaction mixture is heated at 120-160°C for 2-12 hours, in a preferable embodiment at 135°C for 3-6 hours.
  • step a) a precipitant is added to the hot solution (90°C) under continuous stirring in an inert atmosphere in a 2- 15 fold, most preferably 4-10fold (by volume) amount with respect to the dipolar aprotic solvent.
  • Suitable precipitants comprise especially acetonitrile, propionitrile, most preferably acetonitrile.
  • the obtained solution is withdrawn from the heating bath and is slowly left to cool down to 22°C under continuous stirring in an inert atmosphere. Crystallization occurs within 1-120 minutes (depending on the volume, until complete cooling). After having cooled down to 22°C (laboratory temperature), the suspension is stirred for another hour.
  • the corresponding solvate of dasatinib is aspirated by well-known techniques in an inert atmosphere at 10-35 °C, most preferably at 22°C, and washed with the respective co-solvent.
  • the solvate of dasatinib obtained this way can be directly used in the next step - recrystallization, without the necessity of drying.
  • the product may be dried at 10- 35°C, most preferably at 25°C, and at the pressure of 10-200 kPa, most preferably 50 kPa, for 6-24 hours, most preferably 12 hours.
  • NMP NMP is used as the solvent in step a
  • the corresponding NMP solvate is isolated.
  • the obtained dried crystalline NMP solvate (NM) of dasatinib has a characteristic XRPD pattern, which is presented in Figure no. 1.
  • the NMP solvate (NM) has the following characteristic peaks: 5.88; 6.73; 10.73; 11.92; 13.39; 14.97; 16.72; 18.95; 20.17; 21.46; 22.81; 24.65; 25.18; 26.02 and 28.06 ⁇ 0.2° 2-theta.
  • step a If isoamyl alcohol or 1,3-propanediol are used as the solvents in step a), the reaction mixture is left to cool down to 22°C after expiration of the reaction time (3-6 h). Crystallization generally begins when the inner temperature of the reaction mixture drops to 100°C. After cooling down to 22°C (laboratory temperature), the suspension is further stirred for another 1 hour. Crystalline dasatinib is aspirated by well-known techniques in an inert atmosphere at 10-35°C, most preferably at 22°C, and washed with the corresponding solvent.
  • the obtained product is dried at 10-35°C, most preferably at 25°C, and at the pressure of 10-200 kPa, most preferably 50 kPa, for 6-24 hours, most preferably 12 hours.
  • the obtained crystalline isoamyl alcohol solvate (SI) of dasatinib has a characteristic XRPD pattern, which is shown in Figure no. 2.
  • the solvate (SI) has the following characteristic peaks: 5.72; 10.35; 11.42; 12.61; 13.14; 14.27; 15.33; 17.18; 17.44; 17.97; 19.12; 19.95; 20.38; 22.05; 22.42; 23.01; 23.46; 23.68; 25.26; 26.20; 26.45; 26.62 and 27.78 ⁇ 0.2° 2-theta.
  • the obtained crystalline 1,3-propanediol solvate (SP) of dasatinib has a characteristic XRPD pattern, which is shown in Figure no. 3.
  • the solvate (SP) has the following characteristic peaks: 6.04; 12.01; 15.10; 17.95; 18.35; 18.77; 21.25; 21.51; 22.96; 24.08; 24.62; 25.80; 26.16; 28.16 and 33.6578 ⁇ 0.2° 2-theta.
  • the anhydrous polymorph form N-6 is prepared in the following way: any solvate or another polymorph is dissolved under an inert atmosphere at 90°C (reflux) in a 10-30 times, most preferably 20 times, the (weight) amount of the crystallization solvent.
  • Suitable crystallization solvents include especially methanol, ethanol, isopropanol, most preferably methanol.
  • a co-solvent is added in 0.1-10 times, most preferably 1 ⁇ 2-l times, the volume of the crystallization solvent used in an inert atmosphere at 90°C.
  • the co-solvent can be, e.g., acetonitrile, propionitrile and their mixtures, most preferably acetonitrile.
  • the obtained solution is withdrawn from the heating bath and is slowly left to cool down to 22°C under continuous stirring in an inert atmosphere. Crystallization occurs during 1-120 minutes (depending on the volume, until complete cooling). After having cooled down to 22°C (laboratory temperature), the suspension is stirred for another hour.
  • Crystalline dasatinib is aspirated by well-known techniques in an inert atmosphere at 10-35°C, most preferably at 22°C, and washed with the corresponding co-solvent.
  • the chemical purity of the obtained product is 99% (in accordance with HPLC); it is the polymorph form N-6 and its XRPD pattern is shown in Figure no. 4.
  • the polymorph form N-6 has the following characteristic peaks: 6.77; 12.31; 13.16; 13.75; 16.70; 17.20; 18.54; 19.34; 20.25; 20.95; 21.94; 24.28; 24.82; and 27.80 ⁇ 0.2° 2-theta.
  • Figure 1 shows an X-ray powder diffraction pattern of the crystalline solvate NM. Individual axes: independently variable: reflection angle 2 ⁇ , dependently variable: intensity of detected radiation.
  • Figure 2 shows an X-ray powder diffraction pattern of the isoamyl alcohol crystalline solvate SI. Individual axes: independently variable: reflection angle 2 ⁇ , dependently variable: intensity of detected radiation.
  • Figure 3 shows an X-ray powder diffraction pattern of the 1,3 propanediol crystalline solvate SP. Individual axes: independently variable: reflection angle 2 ⁇ , dependently variable: intensity of detected radiation.
  • Figure 4 shows an X-ray powder diffraction pattern of the crystalline anhydrous form N-6. Individual axes: independently variable: reflection angle 2 ⁇ , dependently variable: intensity of detected radiation.
  • the measurement was carried out using a flat powder sample that was placed on a Si plate.
  • Soller diaphragms 0.02 rad and an anti-dispersion diaphragm 1 ⁇ 4 were used.
  • Soller diaphragms 0.02 rad and an anti-dispersion diaphragm 5.0 mm were used.
  • HPLC method HPLC method:
  • Stock solution of samples dissolve 5.0 mg of the sample in 10.0 ml of 50% acetonitrile R with water.
  • - stationary phase Zorbax Eclipse Plus Phenyl-Hexyl RRHD 1.8 ⁇ ; temperature: 35 °C.
  • Mobile phase A: phosphate buffer (0.01 M sodium dihydrogen phosphate, pH treated by addition of sodium hydroxide to 7.00 ⁇ 0.05); B: acetonitrile R.
  • the crystalline substance was aspirated on frit S3, washed with acetonitrile (5 ml) and dried by suctioning under an inert nitrogen atmosphere for 15 minutes.
  • the XRPD pattern of the sample obtained this way corresponds to the NMP solvate (NM) and can be used in the subsequent steps without the necessity of drying. Drying after 6 hours in an exsiccator at the laboratory temperature in vacuo (50 kPa) provided 1.2 g of crystalline dasatinib; 80% of the theoretical yield. HPLC purity 99.12%.
  • the 1H NMR and 13 C NMR spectra correspond to the data known from the literature.
  • the XRPD pattern of the dried product corresponds to the NMP solvate (NM).
  • the NM solvate is characterized by the reflections presented in Table 1 :
  • the crystalline substance was aspirated on frit S3, washed with acetonitrile (10 ml) and dried in an desiccator at the laboratory temperature in vacuo (50 kPa) for 6 hours.
  • the yield was 0.52 g; 73% of the theoretical yield.
  • HPLC purity 98.12%.
  • the XRPD patterns before and after drying in the exsiccator correspond to the DMF solvate known from literature (WO2009053854A2).
  • the intermediate (II) (0.50 g; 1.27 mmol) and l-(2-hydroxyethyl)piperazine (0.8 g; 6.15 mmol) were dissolved in DMSO (2.5 ml) under an inert atmosphere and diisopropylethylamine (0.45 ml) was added to the reaction mixture.
  • the reaction mixture was stirred and heated up to 90°C for 3 hours and then the reaction was terminated by addition of acetonitrile (15 ml).
  • the mixture was withdrawn from the heating bath and stirred intensively. Crystallization started after 3 minutes, the suspension was left to cool under continuous stirring. After achieving the laboratory temperature it was stirred for another 2 hours.
  • the crystalline substance was aspirated on frit S3, washed with isoamyl alcohol (7 ml) and dried at the laboratory temperature in vacuo (2.5 kPa) for 5 hours. The yield was 0.5 g; 81% of the theoretical yield. HPLC purity 99.10%.
  • the XRPD pattern corresponds to the isoamyl alcohol solvate (SI).
  • the SI solvate is characterized by the reflections presented in Table 2:
  • the intermediate of formula II (0.25 g; 0.63 mmol), l-(2-hydroxyethyl)piperazine (0.42 g; 3.23 mmol) and diisopropylethylamine (0.22 ml, 1.26 mmol) were suspended in 1,3- propanediol (3 ml) under an inert atmosphere.
  • the reaction mixture was stirred and heated up to 140°C for 3 hours.
  • the reaction mixture was withdrawn from the heating bath and stirred intensively.
  • the suspension was left to cool under continuous stirring. After achieving the laboratory temperature it was stirred for another day.
  • the crystalline substance was aspirated on frit S3, washed with 1,3 -propanediol (6 ml), acetone (5 ml) and dried with a stream of nitrogen for 30 minutes. The yield was 0.1 g; 28% of the theoretical yield. HPLC purity 99.43%.
  • the XRPD pattern corresponds to the 1,3 -propanediol solvate (SP).
  • SP solvate is characterized by the reflections presented in Table 3:
  • any solvate of dasatinib (0.4 g, obtained in accordance with Example 1, or 2, 3, 4 or 5, respectively) was dissolved in MeOH (8 ml) under boiling; the mixture was stirred in an inert atmosphere for 5 minutes. Acetonitrile (4 ml) was added under continuous stirring and under boiling in an inert atmosphere. The clear solution was withdrawn from the heating bath, stirred intensively and left to cool under continuous stirriiig. After achieving the laboratory temperature the resulting suspension was stirred for another hour. The crystalline substance was aspirated on frit S3 and washed with acetonitrile (4 ml). The XRPD pattern of the undried sample obtained this way corresponds to the polymorph anhydrous form N-6.
  • any solvate of dasatinib (0.85 g, obtained in accordance with Example 1, or 2, 3, 4 or 5, respectively) was suspended in boiling IBMK (20 ml) and boiling was maintained under an inert atmosphere for 15 minutes. The suspension was withdrawn from the heating bath, intensively stirred and left to cool under continuous stirring. After achieving the laboratory temperature (20 minutes) the solvent was aspirated using an adapter for return filtration. The remaining crystalline substance was again overlayered with IBMK (20 ml), the suspension was brought to boil and heated up and stirred intensively for 15 minutes. The suspension was withdrawn from the heating bath, stirred intensively and left to cool under continuous stirring.
  • the IBMK solvate of dasatinib (0.4 g, 0.68 mmol; obtained in accordance with Example 7) was dissolved in a boiling mixture of MeOH (6 ml), acetonitrile (3 ml) in an inert atmosphere. Active carbon was added, the suspension was heated up to boil. After 5 minutes the hot solution was filtered through a Seitz filter, the filtration cake was washed with a hot mixture of MeOH/acetonitrile (3 ml, 2:1). The clear filtrate was stirred and left to cool under continuous stirring for 90 minutes. The crystalline substance was aspirated on frit S3, washed with 3 ml of acetonitrile.
  • the XRPD pattern of the undried sample obtained this way corresponds to the N- 6 polymorph anhydrous form. Drying at the laboratory temperature in vacuo (50 kPa) for 12 hours provided 0.22 g pf crystalline dasatinib; 66% of the theoretical yield. HPLC purity 99.90%. The XRPD pattern corresponds to the N-6 polymorph anhydrous form.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention porte sur un procédé de préparation de dasatinib anhydre sous la forme polymorphe N-6 de formule (I), caractérisée par les réflexions suivantes dans un diagramme de diffraction des rayons X sur poudre, mesuré à l'aide du rayonnement CuKα : 2-thêta de 6,8 ; 12,3 ; 13,2 ; 13,8 ; 16,7 ; 21,0 ; 24,3 et 24,8 ± 0,2°, ledit procédé étant constitué des étapes suivantes : a) la préparation et l'isolement de dasatinib sous la forme d'un solvate ou sous forme non solvatée ; b) la dissolution du dasatinib obtenu dans l'étape a) dans un solvant de cristallisation choisi parmi les alcools inférieurs ; c) l'ajout d'un cosolvant choisi entre l'acétonitrile et le propionitrile, ou un mélange de ceux-ci, et l'isolement de dasatinib cristallin sous la forme polymorphe N-6.
PCT/CZ2013/000160 2012-12-06 2013-12-04 Procédé pour la préparation et la purification de polymorphes et solvates nouveaux et connus du dasatinib WO2014086326A1 (fr)

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CZ2012-879A CZ306598B6 (cs) 2012-12-06 2012-12-06 Způsob přípravy a čištění nových i známých polymorfů a solvátů dasatinibu

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015090259A1 (fr) * 2013-12-19 2015-06-25 Zentiva, K.S. Procédé de préparation de forme n-6 polymorphe anhydre de dasatinib
CN105130977A (zh) * 2015-07-22 2015-12-09 山东罗欣药业集团股份有限公司 一种达沙替尼化合物、及其组合物
US20160264565A1 (en) * 2013-11-08 2016-09-15 Shilpa Medicare Limited Crystalline dasatinib process
WO2017002131A1 (fr) * 2015-06-29 2017-01-05 Msn Laboratories Private Limited Formes cristallines de n-(2-chloro-6-méthylphényl)-2-[[6-[4-(2-hydroxyéthyl)-1-pipérazinyl]-2-méthyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide et leurs procédés associés
WO2017098391A1 (fr) * 2015-12-11 2017-06-15 Shilpa Medicare Limited Procédé de préparation du dasatinib
WO2018100585A1 (fr) 2016-12-01 2018-06-07 Natco Pharma Limited Procédé amélioré de préparation de polymorphe de dasatinib
JP2019504090A (ja) * 2016-02-03 2019-02-14 ドクター レディズ ラボラトリーズ リミテッド ダサチニブの固体状態形態およびそれらの調製プロセス
WO2019209908A1 (fr) 2018-04-25 2019-10-31 Johnson Matthey Public Limited Company Formes cristallines de dasatinib
CN111108104A (zh) * 2017-07-07 2020-05-05 拜康有限公司 达沙替尼的多晶形式
US10799459B1 (en) 2019-05-17 2020-10-13 Xspray Microparticles Ab Rapidly disintegrating solid oral dosage forms containing dasatinib
US10940149B1 (en) 2018-06-15 2021-03-09 Handa Oncology, Llc Kinase inhibitor salts and compositions thereof
CN112569236A (zh) * 2019-09-28 2021-03-30 鲁南制药集团股份有限公司 一种达沙替尼甲醇溶剂合物及其制备方法

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000062778A1 (fr) 1999-04-15 2000-10-26 Bristol-Myers Squibb Co. Inhibiteurs cycliques de proteine tyrosine kinase
WO2005077945A2 (fr) 2004-02-06 2005-08-25 Bristol-Myers Squibb Company Procede de preparation de carboxamides 2-aminothiazole-5-aromatiques utiles comme inhibiteurs de kinases
WO2007035874A1 (fr) 2005-09-21 2007-03-29 Bristol-Myers Squibb Company Administration par voie orale de n-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-1,3-thiazole-5-carboxamide et sels de celui-ci
WO2009053854A2 (fr) 2007-10-23 2009-04-30 Teva Pharmaceutical Industries Ltd. Polymorphes de dasatinib et leur procédé de préparation
WO2010067374A2 (fr) 2008-12-08 2010-06-17 Hetero Research Foundation Polymorphes de dasatinib
WO2010139981A2 (fr) 2009-06-03 2010-12-09 Generics [Uk] Limited Procédés d'élaboration de formes cristallines
WO2010139979A2 (fr) * 2009-06-03 2010-12-09 Generics [Uk] Limited Procédés d'élaboration de formes cristallines
WO2011095059A1 (fr) 2010-02-08 2011-08-11 南京卡文迪许生物工程技术有限公司 Polymorphes du dasatinib, leurs procédés de préparation et leurs compositions pharmaceutiques
US8242270B2 (en) 2004-02-06 2012-08-14 Bristol-Myers Squibb Company Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102643275B (zh) * 2011-02-21 2016-04-20 江苏先声药物研究有限公司 一种达莎替尼n-6晶型新的制备方法

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000062778A1 (fr) 1999-04-15 2000-10-26 Bristol-Myers Squibb Co. Inhibiteurs cycliques de proteine tyrosine kinase
WO2005077945A2 (fr) 2004-02-06 2005-08-25 Bristol-Myers Squibb Company Procede de preparation de carboxamides 2-aminothiazole-5-aromatiques utiles comme inhibiteurs de kinases
US8242270B2 (en) 2004-02-06 2012-08-14 Bristol-Myers Squibb Company Process for preparing 2-aminothiazole-5-aromatic carboxamides as kinase inhibitors
WO2007035874A1 (fr) 2005-09-21 2007-03-29 Bristol-Myers Squibb Company Administration par voie orale de n-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-1,3-thiazole-5-carboxamide et sels de celui-ci
WO2009053854A2 (fr) 2007-10-23 2009-04-30 Teva Pharmaceutical Industries Ltd. Polymorphes de dasatinib et leur procédé de préparation
WO2010067374A2 (fr) 2008-12-08 2010-06-17 Hetero Research Foundation Polymorphes de dasatinib
WO2010139981A2 (fr) 2009-06-03 2010-12-09 Generics [Uk] Limited Procédés d'élaboration de formes cristallines
WO2010139979A2 (fr) * 2009-06-03 2010-12-09 Generics [Uk] Limited Procédés d'élaboration de formes cristallines
WO2011095059A1 (fr) 2010-02-08 2011-08-11 南京卡文迪许生物工程技术有限公司 Polymorphes du dasatinib, leurs procédés de préparation et leurs compositions pharmaceutiques

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160264565A1 (en) * 2013-11-08 2016-09-15 Shilpa Medicare Limited Crystalline dasatinib process
WO2015090259A1 (fr) * 2013-12-19 2015-06-25 Zentiva, K.S. Procédé de préparation de forme n-6 polymorphe anhydre de dasatinib
US10301302B2 (en) 2015-06-29 2019-05-28 Msn Laboratories Private Limited Crystalline forms of N-(2-chloro-6-methy]phenvn-2-[F6-[4-(2-hvdroxvethvl)-L-piperazin-vil-2-methvil-4-pvrimidinvllaminol-5-thiazolecarboxamide and their process thereof
WO2017002131A1 (fr) * 2015-06-29 2017-01-05 Msn Laboratories Private Limited Formes cristallines de n-(2-chloro-6-méthylphényl)-2-[[6-[4-(2-hydroxyéthyl)-1-pipérazinyl]-2-méthyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide et leurs procédés associés
CN105130977A (zh) * 2015-07-22 2015-12-09 山东罗欣药业集团股份有限公司 一种达沙替尼化合物、及其组合物
CN105130977B (zh) * 2015-07-22 2018-04-20 山东罗欣药业集团股份有限公司 一种达沙替尼化合物、及其组合物
WO2017098391A1 (fr) * 2015-12-11 2017-06-15 Shilpa Medicare Limited Procédé de préparation du dasatinib
EP3411372A4 (fr) * 2016-02-03 2019-07-17 Dr. Reddy's Laboratories Ltd. Formes solides de dasatinib et leurs procédés de préparation
JP2019504090A (ja) * 2016-02-03 2019-02-14 ドクター レディズ ラボラトリーズ リミテッド ダサチニブの固体状態形態およびそれらの調製プロセス
WO2018100585A1 (fr) 2016-12-01 2018-06-07 Natco Pharma Limited Procédé amélioré de préparation de polymorphe de dasatinib
US10800771B2 (en) 2016-12-01 2020-10-13 Natco Pharma Limited Process for the preparation of dasatinib polymorph
CN111108104A (zh) * 2017-07-07 2020-05-05 拜康有限公司 达沙替尼的多晶形式
JP2020526528A (ja) * 2017-07-07 2020-08-31 バイオコン・リミテッド ダサチニブの多形形態
WO2019209908A1 (fr) 2018-04-25 2019-10-31 Johnson Matthey Public Limited Company Formes cristallines de dasatinib
US11440908B2 (en) 2018-04-25 2022-09-13 Johnson Matthey Public Limited Company Crystalline forms of dasatinib
US10940149B1 (en) 2018-06-15 2021-03-09 Handa Oncology, Llc Kinase inhibitor salts and compositions thereof
US11007195B2 (en) 2018-06-15 2021-05-18 Handa Oncology, Llc Kinase inhibitor salts, and compositions thereof
US11160805B2 (en) 2018-06-15 2021-11-02 Handa Onocology, Llc Kinase inhibitor salts and compositions thereof
US11052088B2 (en) 2018-06-15 2021-07-06 Handa Oncology, Llc Kinase inhibitor salts, and compositions thereof
US10894018B1 (en) 2019-05-17 2021-01-19 Xspray Pharma Ab Rapidly disintegrating solid oral dosage forms containing dasatinib
US10894017B1 (en) 2019-05-17 2021-01-19 Xspray Pharma Ab Rapidly disintegrating solid oral dosage forms containing dasatinib
US10869836B1 (en) 2019-05-17 2020-12-22 Xspray Pharma Ab Rapidly disintegrating solid oral dosage forms containing dasatinib
US10869837B1 (en) 2019-05-17 2020-12-22 Xspray Pharma Ab Rapidly disintegrating solid oral dosage forms containing dasatinib
US10874613B1 (en) 2019-05-17 2020-12-29 Xspray Pharma Ab Rapidly disintegrating solid oral dosage forms containing dasatinib
US10874614B1 (en) 2019-05-17 2020-12-29 Xspray Pharma Ab Rapidly disintegrating solid oral dosage forms containing dasatinib
US11344500B2 (en) 2019-05-17 2022-05-31 Xspray Pharma Ab Rapidly disintegrating solid oral dosage forms containing dasatinib
US10799459B1 (en) 2019-05-17 2020-10-13 Xspray Microparticles Ab Rapidly disintegrating solid oral dosage forms containing dasatinib
US11833249B2 (en) 2019-05-17 2023-12-05 Xspray Pharma Ab Rapidly disintegrating solid oral dosage forms containing dasatinib
CN112569236A (zh) * 2019-09-28 2021-03-30 鲁南制药集团股份有限公司 一种达沙替尼甲醇溶剂合物及其制备方法

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