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WO2021162647A1 - Nouveau procédé pour la préparation de chlorhydrate de pazopanib - Google Patents

Nouveau procédé pour la préparation de chlorhydrate de pazopanib Download PDF

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Publication number
WO2021162647A1
WO2021162647A1 PCT/TR2020/050088 TR2020050088W WO2021162647A1 WO 2021162647 A1 WO2021162647 A1 WO 2021162647A1 TR 2020050088 W TR2020050088 W TR 2020050088W WO 2021162647 A1 WO2021162647 A1 WO 2021162647A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
base
pazopanib
process according
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/TR2020/050088
Other languages
English (en)
Inventor
Philipp Daniel Haas
Hartwig Andreas Steckel
Esen Bellur Atici
Halil Yilmaz
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.)
Deva Holding AS
Original Assignee
Deva Holding AS
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 Deva Holding AS filed Critical Deva Holding AS
Priority to PCT/TR2020/050088 priority Critical patent/WO2021162647A1/fr
Publication of WO2021162647A1 publication Critical patent/WO2021162647A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to an alternative and improved method for the synthesis of an intermediate which is useful for the preparation of pazopanib or pharmaceutically acceptable salts thereof.
  • the structure of intermediate is represented by formula 4.
  • the present invention further provides a novel crystalline polymorph of pazopanib hydrochloride and its use for manufacturing crystalline forms of pazopanib hydrochloride, especially Form I.
  • Pazopanib hydrochloride is chemically designated as 5-((4-((2,3-dimethyl-2H-indazol-6- yl)(methyl)amino)pyrimidin-2-yl)amino)-2-methylbenzenesulfonamide hydrochloride and structurally represented as below.
  • Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase inhibitor. Pazopanib is marketed as its hydrochloride salt by GlaxoSmithKline in Europe and by Novartis in United States under the trade name Votrient. Votrient is indicated for the treatment of advanced Renal Cell Carcinoma (RCC) and advanced Soft-Tissue Sarcoma (STS) who have received prior chemotherapy.
  • RCC Renal Cell Carcinoma
  • STS Soft-Tissue Sarcoma
  • the commercial tablet formulation of pazopanib hydrochloride, Votrient, contains crystalline Form I.
  • pazopanib hydrochloride is a white to slightly yellow, non-hygroscopic, crystalline substance and the manufacturing process consistently gives pazopanib hydrochloride Form I.
  • EMEA does not describe any particular characterization data for the disclosed polymorphic form.
  • WO 2015068175 discloses crystalline forms of pazopanib hydrochloride.
  • a process for preparation of Form I and the characteristic powder X-ray diffraction (XRD) pattern of Form I are also disclosed in the said patent application.
  • first and second step products were reacted by using concentrated hydrochloric acid and pazopanib hydrochloride was obtained as a result.
  • This invention provides an economically preferable process for the preparation of N-(2- chloropyrimidin-4-yl)- N,2,3-trimethyl-2H-indazol-6-amine as a key intermediate in the synthesis of pazopanib or its pharmaceutically acceptable salts thereof.
  • the present invention provides excellent yields and purity.
  • Active pharmaceutical ingredients are individual components or mixture of components that are used as a part of a finished pharmaceutical drug or medicinal product, where they provide the pharmacological activity.
  • 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 crystalline forms having distinct crystal structures and physical properties.
  • the difference in the physical properties of different crystalline forms results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid.
  • polymorphic forms of pharmaceutically active substance and pharmaceutical product is well known in the pharmaceutical industry.
  • Pharmaceutical formulation is affected by polymorphic form of the pharmaceutically active substance.
  • the discovery of new polymorphic forms and solvates of an active pharmaceutical ingredient provides a new opportunity to improve the performance characteristics of pharmaceutical finished product, the development of new polymorphic forms is always encouraged.
  • APIs can be synthesized using any of several alternative pathways.
  • a first aspect of the present invention relates to a process for preparing the compound of formula 2, wherein the process comprises of reacting 6-halo-2,3-dimethyl-2H-indazole (compound of formula 1) with a methylamine in presence of solvent, catalyst and a base to obtain iV,2,3-trimethyl-2H-indazol-6-amine (compound of formula 2)
  • a second aspect of the present invention relates to a process for preparing of the compound of formula 4, wherein the compound of formula 2 reacted with 2,4-dichloropryrimidine (compound of formula 3) to prepare the compound of formula 4.
  • the present invention process for the synthesis of compound of formula 4 comprises the step of;
  • X is a halogen (eg: Cl, Br, I).
  • the base employed in the step (i) and step (ii) is selected from the group of organic base or inorganic base, wherein organic base is selected from cyclic or acyclic amines, while bases diethylamine, triethylamine and diisopropylethylamine, the reaction may be operated in alcoholic solvents.
  • Inorganic base may be selected from the groups of alkali metal hydroxide like sodium hydroxide, calcium hydroxide, potassium hydroxide or alkali metal carbonate like sodium carbonate, potassium carbonate, sodium bicarbonate, while base is alkali metal salt, the reaction may be operated in aqueous solvent systems.
  • the base employed in the step (ii) is an inorganic base such as sodium carbonate or potassium carbonate or sodium bicarbonate.
  • the process of the invention conducted in a suitable solvent.
  • the suitable solvent employed in step (i) and step (ii) is selected from the group of alcohols such as methanol, ethanol, 1- propanol, 2-propanol or organic solvents such as THF, DMF, NMP, EtOAc, etc.
  • the solvent used in step (i) and step (ii) is DMF.
  • the catalyst employed in the step (i) is selected from copper halides or copper oxide like Cul, CuBr, CuCl, CU2O, Cu powder, Cu(0Ac) 2 .H 2 0, Cu(acac), etc.
  • the catalyst employed in the step (i) is copper halides like Cul.
  • a temperature range for performing reaction in step (i) is 60 - 100 °C.
  • the reaction may preferably be carried out at temperatures in the range from about 70 - 90 °C, more preferably at about 65 - 80 °C.
  • a temperature range for performing reaction in step (ii) is 50 - 100 °C, more preferable is 60 - 90 °C.
  • a third aspect of the present invention relates to a process for preparing pazopanib hydrochloride, wherein the process comprises of reacting compound of formula 4 with 5- amino-2-methylbenzenesulfonamide.
  • the method is simple, cost effective and suitable for industrial scale manufacturing.
  • the process according to the invention claimed in the present application and involving the key intermediate compound of formula 4 is outlined in Scheme 2.
  • a fourth aspect of the present invention relates to a novel polymorphic solvate form of pazopanib hydrochloride.
  • This new solvate form is dimethylformamide (DMF) solvate form, herein after designated as Form D.
  • Form D is characterized by an XRPD pattern having characteristic peaks at 6.59 ⁇ 0.2, 9.64 ⁇ 0.2, 12.83 ⁇ 0.2, 15.00 ⁇ 0.2, 16.94 ⁇ 0.2, 18.95 ⁇ 0.2 and 23.99 ⁇ 0.2 degree 2-theta.
  • Form D can be characterized by an XRPD pattern with characteristic peaks at 14.59 ⁇ 0.2, 18.28 ⁇ 0.2, 18.64 ⁇ 0.2, 21.57 ⁇ 0.2, 23.77 ⁇ 0.2, 26.31 ⁇ 0.2, 27.88 ⁇ 0.2, 30.02 ⁇ 0.2 and 30.64 ⁇ 0.2 degree 2-theta.
  • a fifth aspect of the present invention relates to a novel process for preparing polymorph of pazopanib hydrochloride.
  • the present invention relates to a process of applying Form D in the synthesis of anhydrous crystalline Form I of pazopanib hydrochloride.
  • the crystalline Form I according to the present invention may be obtained by: a) dissolving or suspending Form D in a mixture of water and C1-C3 alcohol, preferably ethanol, b) heating and stirring the solution at reflux temperature, c) cooling the solution to room temperature, d) isolating the obtained solid, e.g. by filtration, e) optionally washing the obtained solid and with C1-C3 alcohol, preferably with ethanol f) drying the solid.
  • Fig. 1 shows a powder X-ray diffraction pattern of pazopanib hydrochloride designated as Form D obtained in example 5
  • Fig. 2 shows a powder X-ray diffraction pattern of pazopanib hydrochloride designated as Form I obtained in example 6
  • Fig.3 shows a powder X-ray diffraction pattern of Form D(Bottom one) versus a powder X- ray diffraction pattern of Form I (Upper one)
  • Scan range 2.00 - 40.00°
  • Scan mode Continuous scan
  • Scan speed 2.07min
  • Sampling pitch 0.02°
  • Preset time 0.60 s

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (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)

Abstract

La présente invention concerne un nouveau procédé pour la préparation d'un composé intermédiaire clé et son utilisation dans un procédé de synthèse pour la préparation de chlorhydrate de pazopanib. Le procédé présente les avantages d'une opération simple, d'un rendement élevé et de faibles coûts. La présente invention concerne également un nouveau polymorphe de chlorhydrate de pazopanib.
PCT/TR2020/050088 2020-02-10 2020-02-10 Nouveau procédé pour la préparation de chlorhydrate de pazopanib Ceased WO2021162647A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/TR2020/050088 WO2021162647A1 (fr) 2020-02-10 2020-02-10 Nouveau procédé pour la préparation de chlorhydrate de pazopanib

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/TR2020/050088 WO2021162647A1 (fr) 2020-02-10 2020-02-10 Nouveau procédé pour la préparation de chlorhydrate de pazopanib

Publications (1)

Publication Number Publication Date
WO2021162647A1 true WO2021162647A1 (fr) 2021-08-19

Family

ID=77292782

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2020/050088 Ceased WO2021162647A1 (fr) 2020-02-10 2020-02-10 Nouveau procédé pour la préparation de chlorhydrate de pazopanib

Country Status (1)

Country Link
WO (1) WO2021162647A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015068175A2 (fr) * 2013-11-05 2015-05-14 Laurus Labs Private Limited Procédé perfectionné de préparation de pazopanib ou d'un sel de qualité pharmaceutique de celui-ci
CN107721989A (zh) * 2017-11-14 2018-02-23 苏州东南药业股份有限公司 一种帕唑帕尼的制备方法及其中间体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015068175A2 (fr) * 2013-11-05 2015-05-14 Laurus Labs Private Limited Procédé perfectionné de préparation de pazopanib ou d'un sel de qualité pharmaceutique de celui-ci
CN107721989A (zh) * 2017-11-14 2018-02-23 苏州东南药业股份有限公司 一种帕唑帕尼的制备方法及其中间体

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MATIER CARSON D., SCHWABEN JONAS, PETERS JONAS C., FU GREGORY C.: "Copper-Catalyzed Alkylation of Aliphatic Amines Induced by Visible Light", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, vol. 139, no. 49, 13 December 2017 (2017-12-13), pages 17707 - 17710, XP055848442, ISSN: 0002-7863, DOI: 10.1021/jacs.7b09582 *

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