WO2017098391A1 - Procédé de préparation du dasatinib - Google Patents

Procédé de préparation du dasatinib Download PDF

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Publication number
WO2017098391A1
WO2017098391A1 PCT/IB2016/057337 IB2016057337W WO2017098391A1 WO 2017098391 A1 WO2017098391 A1 WO 2017098391A1 IB 2016057337 W IB2016057337 W IB 2016057337W WO 2017098391 A1 WO2017098391 A1 WO 2017098391A1
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WO
WIPO (PCT)
Prior art keywords
dasatinib
methyl
chloro
crystalline
sdn
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PCT/IB2016/057337
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English (en)
Inventor
Sriram RAMPALLI
Pradeep POTHANA
Suresh GARBAPU
Akshaykant CHATURVEDI
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Shilpa Medicare Limited
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Publication of WO2017098391A1 publication Critical patent/WO2017098391A1/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 present invention relates to a process for preparation of Dasatinib (I).
  • Dasatinib is chemically described as N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2- hydroxyethyl)- 1 -piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazolecarboxamide and is represented by Formula I).
  • the monohydrate form of Dasatinib is a kinase inhibitor and has been approved by USFDA as SPRYCELTM for the treatment of chronic phase Philadelphia chromosome- positive (Ph+) Chronic Myeloid Leukemia (CML), in newly diagnosed adult patients or patients having resistance or intolerance to prior therapy like Imatinib.
  • SPRYCELTM is also indicated for the treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.
  • Das et al in US patent No. 6596746 Bl provided the first disclosure of the compound Dasatinib along with the process for preparation thereof. Further to this Lajeunesse et al. in US 7491725 B2 provided the crystalline monohydrate, crystalline butanol solvate, crystalline ethanol solvate and neat forms of Dasatinib.
  • Chidambaram et al in WO2007035874 Al disclosed various pharmaceutically acceptable salt forms of Dasatinib.
  • the pharmaceutically acceptable salts disclosed in WO2007035874 Al are for example, fumaric acid, hydrobromic acid, maleic acid, methanesulfonic acid, phosphoric acid, salicylic acid, sulfuric acid, tartaric acid, or p- toluenesulfonic acid.
  • Hl-7 Several crystalline forms of Dasatinib are described in the literature; these are designated as Hl-7, BU-2, E2-1, N-6, T1H1-7, and T1E2-1.
  • Crystalline dasatinib monohydrate (Hl-7) and butanol solvate (BU-2)) along with the processes for their preparation are described in WO 2005077945. Additionally US 2006/0004067, also describe two ethanol solvates (E2-1 ; T1E2-1) and two anhydrous forms (N-6; T1H1 -7).
  • WO 2009053854 discloses various Dasatinib solvates including their crystalline form, amorphous form and anhydrous form.
  • US patent No. 7973045 further discloses the anhydrous form of Dasatinib and process for preparation thereof.
  • the anhydrous form disclosed therein has typical characteristic XRD peaks at about 7.2, 11.9, 14.4, 16.5, 17.3, 19.1, 20.8, 22.4, 23.8, 25.3 and 29.1 on the 2- theta value.
  • the process involves by drying Dasatinib at 200°C under nitrogen atmosphere for 2hours, which is not feasible in bulk prospective. Further, this patent not disclosed the process related impurities formed during the development of Dasatinib.
  • WO 2010062715 discloses isosorbide dimethyl ether solvate, N, '- dimethylethylene urea solvate and N,N'-dimethyl-N,N'-propylene urea solvate of Dasatinib.
  • WO 2010067374 discloses novel crystalline form I, solvates of DMF, DMSO, toluene, isopropyl acetate and processes for their preparation.
  • WO 2010139979 discloses MDC solvate of Dasatinib, process of its preparation and use in the manufacture of pure Dasatinib.
  • WO 2010139980 discloses a process for the preparation of crystalline Dasatinib monohydrate.
  • WO 2014086326 discloses a process for the preparation crystalline Form N-6 of dasatinib, consisting preparation and isolation of Dasatinib in the form of a solvate or in unsolvated form; dissolution of Dasatinib obtained in a crystallization solvent selected from lower alcohols;addition of a co-solvent selected from acetonitrile and propionitrile, or a mixture thereof, and isolation of crystalline dasatinib in the polymorph form N-6.
  • the present inventors now developed a process for the crystalline Dasatinib Form-SDN without using any co-solvent system selected from acetonitrile and propionitrile, or a mixture thereof
  • WO 2015090259 discloses a processof preparing the crystalline Form N-6 of dasatinib, consisting drying a dasatinib solvate from the group of the ethanol solvate, methanol solvate, and acetonitrile solvate of dasatinib, or their mixtures.
  • Dasatinib being an important drug in the treatment of cancer, there still appears to be a need for new forms of Dasatinib having further improved physical and/or chemical properties. Hence it was thought worthwhile by the inventors of the present application to explore novel forms of Dasatinib, which may further improve the characteristics of drug Dasatinib.
  • Crystalline Form-SDN of Dasatinib are sufficiently stable and pharmaceutically acceptable. This stable form offers various advantages in terms of storage, shelf life and favorable impurity profile.
  • Amorphous Dasatinib is sufficiently stable and pharmaceutically acceptable. This stable form offers various advantages in terms of storage, shelf life and favorable impurity profile.
  • Present invention also provides a process for preparation of crystalline Form-SDN of Dasatinib, which is industrially amenable and commercially viable.
  • Crystalline Form-SDN of Dasatinib can be a valuable input for the preparation of various pharmaceutically acceptable pure salt forms of Dasatinib without any requirement for repeated purification processes, thus giving both economic and operational advantage.
  • Particular aspects of the present invention relates to a process for preparing crystalline Dasatinib (I),
  • Another aspect of the present invention relates to Crystalline Dasatinib designated as Form- SDN, characterized by
  • DSC isotherm comprising an endothermic peaks ranging between 280-290°C; and c) Crystalline Dasatimb Form-SDN containing the process related impurities A, B, C, D, E, F, and G collectively below 0.3%.
  • Fig. 1 is an example of X-ray powder diffraction ("XRPD") pattern of crystalline Form-SDN of Dasatinib.
  • Fig. 2 is an example of Differential Scanning Calorimetry ("DSC") curve of crystalline Form-SDN of Dasatinib.
  • DSC Differential Scanning Calorimetry
  • Fig. 3 is an example of X-ray powder diffraction ("XRPD") pattern of Amorphous Dasatinib (I) base.
  • the present invention relates to a rocess for preparing crystalline Dasatinib (I),
  • the present inventors found that the condensation is carried without using any base to form Dasatinib amyl alcohol solvate at specific temperature 135-140°C.
  • Dasatinib has a tendency to form a solvate
  • use of mixture of solvents in this step leads to the formation of mixture of Dasatinib solvates.
  • the present inventors found the use of single solvent system directly yields in the formation of pure Dasatinib amyl alcohol solvate, which is free of other solvents.
  • Dasatinib amyl alcohol solvate obtained above was charged in to a reaction flask containing Methanol at 25-30°C. Raised the temperature of the reaction mass to reflux temperature and stirred the reaction mass for 30 minutes at reflux (65-70°C). Filtered the reaction mass at 60-65 °C and collected the filtrate. The collected filtrate was partially distilled off under atmospheric pressure at 65-70°C. Cooled the reaction mass temperature slowly to 0-5°C and stirred for 1 hour to 2 hours at 0-5°C. Filtered the reaction mass and washed with Methanol and suck dried the material at 25-30°C for 15 to 20 minutes. Again, charged the wet material in to a reaction flask containing Methanol at 25-30°C.
  • Crystalline Dasatinib obtained by the above process is designated as Form-SDN, characterized by X-ray powder diffraction pattern comprising peaks at 6.9, 13.2, 13.7, 16.7, 24.3 ⁇ 0.2° 2 ⁇ as disclosed in Figure 1.
  • Crystalline Dasatinib obtained by the above process is designated as Form-SDN, characterized by DSC isotherm comprising an endothermic peaks ranging between 280- 290°C.
  • amorphous Dasatinib comprises treating Dasatinib amyl alcohol solvate obtained above was charged in to a reaction flask containing dimethyl formamide at 25-30°C. Stirred the reaction mass for 15 minutes to 30 minutes at 25-30°C and then cooled the reaction mass slowly to 0-5°C. Charged cold water in to the reaction flask at 0-5°C and then stir the reaction mass for 60 minutes to 80 minutes at 0-5°C. Filtered the reaction mass and washed the material with DM water. Suck dried the material at 25-30°C for 15-20 min. Dried the material under vacuum at 60-65°C for 12 hours to 15 hours to yield amorphous Dasatinib. The PXRD obtained as per this process is disclosed in Fig.3.
  • amorphous Dasatinib obtained by the above process containing the process related impurities A, B, C, D, E, F and G collectively below 0.3%.
  • embodiments of the present invention relate to the novel crystalline Form-SDN of Dasatinib (I) and processes for its preparation.
  • Process of isolating crystalline Form-SDN of Dasatinib may comprise processes but not limited to conventional processes including scrapping, if required filtering from slurry and optional further drying, which may be carried out at room temperature for the suitable durations to retain the characteristics of crystalline Form-SDN of Dasatinib.
  • the process of the present invention is advantageous in being commercially viable and industrially feasible as the crystalline Form-SDN of Dasatinib is directly obtained from the reaction without any additional purification steps.
  • the process related impurities, including unreacted intermediates, side products, degradation products and other medium dependent impurities, that appear in the impurity profile of the Dasatinib may be substantially removed by the process of the present invention resulting in the formation of pure Form-SDN of Dasatinib in high yield.
  • the process may require in- process quality checks to avoid unnecessary prolongation/repetitions of the same process steps.
  • Substantially pure Form-SDN of Dasatinib obtained according to the process of the present invention results in the final API purity by HPLC of more than 99% w/w.
  • the crystalline Form-SDN of Dasatinib obtained by the process of the present invention can be further used for the preparation of substantially pure pharmaceutically acceptable salts of Dasatinib.
  • Other non-limiting examples of salts of Dasatinib that can be prepared from crystalline Form-SDN of Dasatinib include Dasatinib hydrochloride. Conversion of crystalline Form-SDN of Dasatinib to other salt forms of Dasatinib can be achieved by the person skilled in the art according to any process available in the prior art.In one of the preferred embodiment, preparation of the pharmaceutically acceptable salt of Dasatinib involved the treatment of the reaction mass obtained as end product, with an organic solvent characterized by boiling point of less than 70 °C.
  • Organic solvent characterized by boiling point of less than 70 °C may be selected from ether solvents like Diisopropyl ether (DIPE), Tetrahydrofuran (THF) and MTBE or a mixture thereof.
  • DIPE Diisopropyl ether
  • THF Tetrahydrofuran
  • MTBE MTBE
  • Use of crystalline Form-SDN as starting material is advantageous for preparation of pharmaceutically acceptable salts of Dasatinib as the required salt forms are obtained in the substantially pure form without any requirement for repeated purification processes, thus giving both economic and operational advantage.
  • Crystalline Form-SDN of Dasatinib is found to be a very stable crystal lattice which is adequately stable to handle and store for longer time without any significant or measurable change in its morphology and physicochemical characteristics. Crystalline Form-SDN of Dasatinib retains its stoichiometry even on drying for more than 24hrs at 60-65 °C. This stable form thus, offers various advantages in terms of storage, shelf life and favorable impurity profile.
  • Crystalline Dasatinib obtained by the above process is designated as Form-SDN, characterized by X-ray powder diffraction pattern comprising peaks at 6.9, 13.2, 13.7, 16.7, 24.3 ⁇ 0.2° 2 ⁇ as disclosed in Figure 1.
  • Crystalline Form-SDN of Dasatinib is further characterized by X-ray powder diffraction pattern comprising peaks at 12.3, 16.4, 18.5, 24.8, 27.8 ⁇ 0.20 2 ⁇ 0 .
  • the crystalline Form-SDN of Dasatinib produced by the process of the present invention is characterized by- a) X-ray powder diffraction pattern comprising peaks at 6.9, 13.2, 13.7, 16.7, 24.3 ⁇ 0.2° 2 ⁇
  • DSC isotherm comprising an endothermic peaks ranging between280-290°C.
  • substantially pure crystalline Form- SDN of Dasatinib exhibits an X-ray powder diffraction pattern as shown in Fig-l andDSC isothermal pattern as shown in Fig-2.
  • the characteristic 20°peaks and their d- spacing values, for the new crystalline Form-SDN are tabulated in the Table- 1.
  • the preferred method of comparing X-ray powder diffraction patterns in order to identify a particular crystalline form is to overlay the X-ray powder diffraction pattern of the unknown fnrm nypr thf in the art can overlay an X-ray powder diffraction pattern of an unidentified crystalline form of Dasatinib over FIG. 1 and readily determine whether the X-ray diffraction pattern of the unidentified form is substantially the same or different w.r.t. the X-ray powder diffraction pattern of the crystalline form SDN of this invention.
  • the crystalline Form-SDN described herein may be characterized by X-ray powder diffraction pattern (XRPD) and Thermal techniques such as differential scanning calorimetry (DSC) analysis.
  • XRPD X-ray powder diffraction pattern
  • DSC differential scanning calorimetry
  • the samples of crystalline Form-SDN of Dasatinib were analyzed by XRPD on a Bruker AXS D8 Advance Diffractometer using X-ray source - Cu Ka radiation using the wavelength 1.5418 A and lynx Eye detector. DSC was done on a Perkin Elmer Pyris 7.0 instrument.
  • Illustrative examples of analytical data for crystalline Form-SDN of Dasatinibobtained in the Examples are set forth in the Figs. 1-2.
  • the invention also relates to a composition containing crystalline Form-SDN in which at least 95% by total weight of Dasatinib in the composition is in the form of the crystalline Form- SDN.
  • the composition may be substantially free of any other known forms of Dasatinib.
  • the crystalline Form-SDN obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules.
  • the active product is mixed with one or more pharmaceutically acceptable excipients.
  • the drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.
  • compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions.
  • a solvent or vehicle propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed.
  • These compositions can contain adjuvant, especially wetting, emulsifying and dispersing agents.
  • the sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
  • compositions comprising crystalline Form-SDN of the present application include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, Croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like.
  • Other pharmaceutically acceptable excipients that are of use include but not limited
  • compositions of crystalline Form- SDN of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
  • Example-01 Process for preparation of N-(2-chIoro-6-methyI phenyl)-2-[6-chloro-2- methyl-4-pyrimidinyl) amino]-5-thiazolecarboxamide (IV)
  • Example-02 Process for preparation of Dasatinib Amyl alcohol
  • N-(2-chloro-6-methylphenyl)-2-[6-chloro-2-methyl-4-pyrimidinyl)amino]-5-thiazole carboxamide (IV) was charged in to a reaction flask containing amyl alcohol (2000 mL) and stirred the reaction mass for 10-15 min at 25-30°C. Raised the reaction mass temperature to 135-140°C and then chargedHydroxyethylpiperazine solution (82.5g of Hydroxyethylpiperazine in 500 ml of amyl alcohol) over 5-10 minutes at 130-140°C. Stirred the reaction mass for 4 hours to 5 hours at 135-140°C and then cooled the reaction mass temperature gradually to 25-30°C.
  • Example-03 Process for preparation of crystalline Dasatinib Form-SDN.
  • Dasatinib amyl alcohol solvate (75 g) obtained from example-2 was charged in to a reaction flask containing Methanol(3000 mL) at 25-30°C. Raised the temperature of the reaction mass to reflux temperature and stirred the reaction mass for 30 minutes at reflux (65-70°C). Filtered the reaction mass at 60-65°C and collect the filtrate. The collected filtrate was partially distilled off under atmospheric pressure at 65-70°C. Cooled the reaction mass slowly to 0-5°C and stirred for 1 hour to 2 hours at 0-5°C. Filtered the reaction mass and washed with Methanol (150 mL). Suck dried the material at 25-30°C for 15 to 20 minutes.
  • Example-04 Process for preparation of amorphous Dasatinib.
  • Dasatinib amyl alcohol solvate (1.0 gm) obtained from example-2 was charged in to a reaction flask containing dimethyl formamide (10 mL) at 25-30°C. Stirredthe reaction mass for 15 minutes to 30 minutes at 25-30°C and then cooled the reaction mass slowly to 0-5°C. Charged cold water (80 mL) in to the reaction flask at 0-5°C and then stir the reaction mass for 60 minutes to 80 minutes at 0-5°C. Filtered the reaction mass and washed the material with DM water (2 x 5 mL). Suck dried the material at 25-30°C for 15-20 min. Dried the material under vacuum at 60-65°C for 12 hours to 15 hours to yield amorphous Dasatinib. The PXRD obtained as per this process is disclosed in Fig.3.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation d'une base de dasatinib stable (I). La présente invention concerne en outre un procédé de préparation d'une base de dasatinib amorphe (I). Ladite base de dasatinib stable (I) peut être utilisée pour préparer une forme posologique pharmaceutique destinée au traitement du cancer.
PCT/IB2016/057337 2015-12-11 2016-12-03 Procédé de préparation du dasatinib WO2017098391A1 (fr)

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IN6648CH2015 2015-12-11
IN6648/CHE/2015 2015-12-11

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018078392A1 (fr) * 2016-10-29 2018-05-03 Cipla Limited Polymorphes de dasatinib
CN108548872A (zh) * 2018-02-06 2018-09-18 珠海润都制药股份有限公司 一种达沙替尼中1-（2-羟乙基）哌嗪的检测方法
WO2019008555A1 (fr) * 2017-07-07 2019-01-10 Biocon Limited Formes polymorphes de dasatinib
CN111217807A (zh) * 2018-11-26 2020-06-02 安礼特（上海）医药科技有限公司 一种达沙替尼无定型及其制备方法
RU2777433C2 (ru) * 2019-07-04 2022-08-03 Общество с ограниченной ответственностью "АКСЕЛЬФАРМ" Способ получения безводной аморфной формы n-(2-хлор-6-метилфенил)-2-[[6-[4-(2-гидроксиэтил)-1-пиперазинил]-2-метил-4-пиримидинил]амино]-5-тиазолкарбоксамида

Citations (4)

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Publication number Priority date Publication date Assignee Title
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
WO2009053854A2 (fr) * 2007-10-23 2009-04-30 Teva Pharmaceutical Industries Ltd. Polymorphes de dasatinib et leur procédé de préparation
WO2014086326A1 (fr) * 2012-12-06 2014-06-12 Zentiva, K.S. Procédé pour la préparation et la purification de polymorphes et solvates nouveaux et connus du dasatinib
WO2015068055A1 (fr) * 2013-11-08 2015-05-14 Shilpa Medicare Limited Procédé de préparation de dasatinib cristallin

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2009053854A2 (fr) * 2007-10-23 2009-04-30 Teva Pharmaceutical Industries Ltd. Polymorphes de dasatinib et leur procédé de préparation
WO2014086326A1 (fr) * 2012-12-06 2014-06-12 Zentiva, K.S. Procédé pour la préparation et la purification de polymorphes et solvates nouveaux et connus du dasatinib
WO2015068055A1 (fr) * 2013-11-08 2015-05-14 Shilpa Medicare Limited Procédé de préparation de dasatinib cristallin

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018078392A1 (fr) * 2016-10-29 2018-05-03 Cipla Limited Polymorphes de dasatinib
WO2019008555A1 (fr) * 2017-07-07 2019-01-10 Biocon Limited Formes polymorphes 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
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
US11059813B2 (en) 2017-07-07 2021-07-13 Biocon Limited Polymorphic forms of Dasatinib
CN108548872A (zh) * 2018-02-06 2018-09-18 珠海润都制药股份有限公司 一种达沙替尼中1-（2-羟乙基）哌嗪的检测方法
CN111217807A (zh) * 2018-11-26 2020-06-02 安礼特（上海）医药科技有限公司 一种达沙替尼无定型及其制备方法
RU2777433C2 (ru) * 2019-07-04 2022-08-03 Общество с ограниченной ответственностью "АКСЕЛЬФАРМ" Способ получения безводной аморфной формы n-(2-хлор-6-метилфенил)-2-[[6-[4-(2-гидроксиэтил)-1-пиперазинил]-2-метил-4-пиримидинил]амино]-5-тиазолкарбоксамида

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