WO2021117062A1 - Procédé de préparation de 4-[7-(6-cyano-5-trifluorométhylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-n-méthylbenzamide et de ses polymorphes - Google Patents

Procédé de préparation de 4-[7-(6-cyano-5-trifluorométhylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-n-méthylbenzamide et de ses polymorphes Download PDF

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Publication number
WO2021117062A1
WO2021117062A1 PCT/IN2020/051022 IN2020051022W WO2021117062A1 WO 2021117062 A1 WO2021117062 A1 WO 2021117062A1 IN 2020051022 W IN2020051022 W IN 2020051022W WO 2021117062 A1 WO2021117062 A1 WO 2021117062A1
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apalutamide
formula
solvent
substantially pure
mixture
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PCT/IN2020/051022
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English (en)
Inventor
Thirumalai Rajan Srinivasan
Eswaraiah Sajja
Satyanarayana Revu
Suresh Challa
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Msn Laboratories Private Limited, R&D Center
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Publication of WO2021117062A1 publication Critical patent/WO2021117062A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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 application relates a process for the preparation of 4-[7-(6-Cyano-5- trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methyl benzamide of formula- 1 and its polymorphs.
  • Apalutamide 4-[7-(6-Cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7- diazaspiro[3.4]oct- 5-yl]-2-fluoro-N-methylbenzamide is generally known as Apalutamide.
  • Apalutamide was approved in US and Europe under the brand name of ERLEADA and it is an androgen receptor inhibitor indicated for the treatment of patients with non-metastatic, castration- resistant prostate cancer.
  • US patent number 8445507 discloses the process for the preparation of Apalutamide.
  • the present inventors identified a disulfur impurity in Apalutamide having the following structure:
  • the present inventors developed an improved process to provide substantially pure Apalutamide having less than about 0.15% of disulfur impurity of formula-Aby HPLC.
  • US patent number 9481663 (hereinafter referred as the US' 663 patent) describes form-A, form-B, form-C, form-D, form-E, form-F, form-G, form-H, form-I and form-J polymorphic forms of compound of formula-1, characterized by XRD, DSC, single crystal X-Ray diffraction and TGA.
  • WO2019016747A1 WO2019135254A1, IN201741043701, IN201841002315 and IN 201841030693 also describes various polymorphs of Apalutamide.
  • the first embodiment of the present invention provides a novel crystalline form of Apalutamide of formula- 1, herein after designated as crystalline form -Ml.
  • the second embodiment of the present invention provides a process for the preparation of crystalline form-Ml of Apalutamide.
  • the third embodiment of the present invention provides a compound of formula-A as an impurity in Apalutamide of formula- 1.
  • the fourth embodiment of the present invention provides a substantially pure crystalline form-Ml of Apalutamide having the disulfur impurity of formula-A less than about 0.2% by HPLC.
  • the fifth embodiment of the present invention provides a substantially pure amorphous form of Apalutamide having the disulfur impurity of formula-A less than about 0.2% by HPLC.
  • the sixth embodiment of the present invention provides a substantially pure Apalutamide having the disulfur impurity of formula-A less than about 0.15% by HPLC.
  • Figure-1 Illustrates the PXRD pattern of crystalline form-Ml of Apalutamide obtained as per example- 1.
  • Figure-2 Illustrates the PXRD pattern of crystalline form-Ml of Apalutamide obtained as per example-2.
  • Figure-3 Illustrates the DSC histogram of crystalline form-Ml of Apalutamide.
  • Figure-4 Illustrates the PXRD pattern of amorphous form of Apalutamide obtained as per example-5.
  • Figure-5 Illustrates the Tg histogram of amorphous form of Apalutamide obtained as per example-5.
  • Figure-6 Illustrates the PXRD pattern of amorphous form of Apalutamide obtained as per example-7.
  • Figure-7 Illustrates the Tg histogram of amorphous form of Apalutamide obtained as per example-7.
  • suitable solvent used in the present invention can be selected from but not limited to “hydrocarbon solvents” such as n-pentane, n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and mixtures thereof; “ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and mixtures thereof; “ester solvents” such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and mixtures thereof; “polar-aprotic solvents” such as dimethylacetamide, dimethylform
  • the first embodiment of the present invention provides novel crystalline form of Apalutamide of formula- 1, herein after designated as crystalline form -Ml.
  • the first aspect of first embodiment provides crystalline form-Ml of Apalutamide of formula- 1 characterized by its powder X-Ray diffractogram as illustrated in figure- 1.
  • the second aspect of the first embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising crystalline form-Ml of Apalutamide of formula- 1 and at least one pharmaceutically acceptable excipient.
  • pharmaceutical compositions or “pharmaceutical formulations” include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • the third aspect of the first embodiment provides a pharmaceutical composition comprising crystalline form-Ml of Apalutamide of formula- 1 and one or more pharmaceutically acceptable carriers for the treatment of patients with non-metastatic castration-resistant prostate cancer.
  • the second embodiment of the present invention provides a process for the preparation of crystalline form-Ml of Apalutamide of formula- 1, comprising: a) dissolving Apalutamide in a solvent, b) isolating crystalline form-Ml of Apalutamide of formula- 1.
  • Dissolving Apalutamide in step-a) can be done at a temperature ranging from about 25°C to reflux temperature of the solvent used; solvent is selected from ester solvents, nitrile solvents or mixtures thereof and the like; isolating crystalline form-Ml of Apalutamide in step-b) is by solvent removal by known techniques which are selected from distillation, decanting, filtration, cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture, crystallization; or by combining with an anti-solvent; wherein anti solvent is selected from ether solvents, hydrocarbon solvents or mixtures thereof.
  • the said impurity is isolated by preparative HPLC [High performance liquid chromatography] and it has 493.50 m/z value.
  • the fourth embodiment of the present invention provides a substantially pure crystalline form-Ml of Apalutamide having the disulfur impurity of formula-A less than about 0.2% or less than about 0.15% or less than about 0.1% or less than about 0.05% or less than about 0.02% as measured by HPLC (High performance liquid chromatography) method.
  • the first aspect of the fourth embodiment provides process for the preparation of substantially pure crystalline form-Ml of Apalutamide comprising: a) dissolving Apalutamide of formula- 1 in a mixture of ester solvent and nitrile solvents, b) isolating the substantially pure crystalline form-Ml of Apalutiamide.
  • Dissolving Apalutamide in step-a) can be done at a temperature ranging from about 25°C to reflux temperature of the solvent used; solvent is selected from ester solvents, nitrile solvents or mixtures thereof and the like; isolating substantially pure crystalline form-Ml of Apalutamide in step-b) is by solvent removal by known techniques which are selected from cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture, crystallization; or by combining with an anti-solvent; wherein anti-solvent is selected from ether solvents, hydrocarbon solvents or mixtures thereof.
  • the fifth embodiment of the present invention provides a substantially pure amorphous form of Apalutamide having the disulfur impurity of formula-A less than about 0.2% or less than about 0.15% or less than about 0.1% or less than about 0.05% or less than about 0.02% as measured by HPLC method.
  • the first aspect of the fifth embodiment provides process for the preparation of substantially pure amorphous form of Apalutamide comprising: a) dissolving Apalutamide of formula- 1 in a solvent, b) isolating the substantially pure amorphous form of Apalutiamide.
  • Dissolving Apalutamide in step-a) can be done at a temperature ranging from about 25°C to reflux temperature of the solvent used; the said solvent is selected from chloro solvents, ester solvents, ketone solvents or mixtures thereof and the like;
  • Isolating substantially pure amorphous form of Apalutamide in step-b) is by solvent removal by known techniques which are selected from using a rotational distillation device such as a Buchi Rotavapor, vacuum drying, spray drying, spray granulating, freeze drying and spray-freeze drying, agitated thin film drying (ATFD) or melt extrusion or freeze drying (lyophilization) or by any other suitable techniques.
  • a rotational distillation device such as a Buchi Rotavapor, vacuum drying, spray drying, spray granulating, freeze drying and spray-freeze drying, agitated thin film drying (ATFD) or melt extrusion or freeze drying (lyophilization) or by any other suitable techniques.
  • the above process for the preparation of amorphous form of Apalutamide further comprises optionally slurring in hydrocarbon solvent selected from cyclohexane, heptane, hexane or mixtures thereof.
  • the sixth embodiment of the present invention provides a substantially pure Apalutamide having the disulfur of formula- A less than about 0.2% or less than about 0.15% or less than about 0.1% or less than about 0.05% or less than about 0.02% as measured by HPLC method.
  • the first aspect of the sixth embodiment provides process for the preparation of substantially pure Apalutamide having the disulfur of formula- A less than about 0.2% or less than about 0.15% or less than about 0.1% or less than about 0.05% or less than about 0.02% as measured by HPLC method comprising: a) dissolving Apalutamide of formula- 1 in a mixture of solvents, b) isolating the substantially pure Apalutiamide.
  • Dissolving Apalutamide in step-a) can be done at a temperature ranging from about 25°C to reflux temperature of the solvent used; solvent is selected from solvent is selected from ester solvents, nitrile solvents or mixtures thereof and the like; isolating substantially pure Apalutamide in step-b) by solvent removal by known techniques which are selected from distillation, decanting, filtration, cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture, crystallization; or by combining with an anti solvent; wherein anti-solvent is selected from ether solvents, hydrocarbon solvents or mixtures thereof.
  • the second aspect of the sixth embodiment provides process for the preparation of substantially pure Apalutamide having the disulfur of formula- A less than about 0.2% or less than about 0.15% or less than about 0.1% or less than about 0.05% or less than about 0.02% as measured by HPLC method comprising: a) dissolving Apalutamide of formula- 1 in a mixture of ester solvent, nitrile solvent and/or hydrocarbon solvent, b) isolating the substantially pure Apalutiamide.
  • Dissolving Apalutamide in step-a) can be done at a temperature ranging from about 25°C to reflux temperature of the solvent used; isolating substantially pure Apalutamide in step-b) by solvent removal by known techniques which are selected from distillation, decanting, filtration, cooling the mixture to lower temperatures to precipitate the solid followed by filtration of the mixture, crystallization; or by combining with an anti-solvent; wherein anti solvent is selected from ether solvents, hydrocarbon solvents or mixtures thereof.
  • substantially pure or “pure” in relation to compound of formula- 1 or crystalline form-Ml of Apalutamide or amorphous form of Apalutamide prepared by the process of the present invention is substantially free from the impurities.
  • the said compound of formula- 1 or crystalline form-Ml of Apalutamide or amorphous form of Apalutamide obtained according to the present invention is substantially pure having a purity of >99%, preferably >99.5% by HPLC.
  • the pharmaceutically acceptable excipient of the present invention is selected from but not limited to polyvinylpyrrolidone (povidone or PVP; PVP of different grades like K-15, K-30, K-60, K-90 and K-120 may be used), polyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), Eudragit, polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl
  • Crystalline form of Apalutamide or amorphous form of Apalutamide produced by the processes of the present invention can be further micronized or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include but not limited to single or multi-stage micronization using cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling or micronization may be performed before drying or after drying of the product.
  • Crystalline form-Ml or amorphous form of Apalutamide obtained according to the present invention has particle size of less than about 250 pm or less than about 200 pm or less than about 150 pm or less than about 100 pm or less than about 50 pm or any other suitable particle sizes.
  • Apalutamide of formula- 1 used as an input for the preparation of crystalline form-Ml and amorphous form of Apalutamide in the present invention is prepared by any of the processes disclosed in the literature such as US8445507B2 or as described in the present application as per the scheme- 1 hereunder.
  • Formula-6 Formula-7 Formula-5 F propyl acetate, 1, Methanol
  • the PXRD analysis of compounds of the present invention was carried out by using BROKER- Axis/D 8 ADVANCE (DAVTNCI) X-Ray diffractometer using CuKa radiation of wavelength 1.5406A 0 and at a continuous scan speed of 0.03°/min.
  • DAVTNCI BROKER- Axis/D 8 ADVANCE
  • a liquid chromatograph is equipped with variable wavelength UV Detector.
  • Mobile phase-A Buffer 100%
  • Mobile phase-B Acetonitrile: Water.
  • a liquid chromatograph is equipped with variable wavelength UV Detector & integrator.
  • Example-2 Purification of crystalline form-Ml of Apalutamide
  • Example-3 Purification of crystalline form-Ml of Apalutamide
  • Example-4 Preparation of pure crystalline form-Ml of Apalutamide A mixture of dimethylformamide (50 ml) and isopropyl acetate (100 ml) were added to 4-(l- cyanocyclobutylamino)-2-fluoro-N-methyl benzamide (50 g) was stirred for 10 minutes at 25-30°C. 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (92 g) was added in lot-wise to the mixture at 25-30°C. After addition of every lot, heated the reaction mixture to 65-70°C and stirred it for 6 hours at the same temperature. Cooled the reaction mixture to 25-30°C.
  • Example-5 Preparation of substantially pure amorphous form of Apalutamide
  • Crystalline form-Ml of Apalutamide (10 g) was dissolved in dichloromethane (50 ml) at 25- 30°C and stirred for 10 minutes at the same temperature. Distilled off solvent completely from the solution. Cyclohexane (50 ml) was added to the obtained compound at 25-30°C and stirred for 20 minutes at the same temperature. Filtered the solid, washed with cyclohexane and dried to get the title compound.
  • Apalutamide (30 g) was dissolved in dichloromethane (150 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Distilled off solvent completely from the solution. Cyclohexane (300 ml) was added to the obtained compound at 25-30°C and stirred for 20 minutes at the same temperature. Filtered the solid, washed with cyclohexane and dried to get the title compound.
  • Apalutamide (25 g) was dissolved in the mixture of dichloromethane (142.5 ml) and acetone (7.5 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Distilled off solvent completely from the solution. Cyclohexane (250 ml) was added to the obtained compound at 25-30°C and stirred for 20 minutes at the same temperature. Filtered the solid, washed with cyclohexane and dried to get the title compound.
  • PXRD of the obtained compound is as illustrated in figure-6.
  • Tg of the obtained compound is as illustrated in figure-7.
  • Iron powder 49 g was added to the mixture of 2-Fluoro-N-methyl-4-nitrobenzamide (50 g), ethyl acetate (500 ml) and water (250 ml) at 25-30°C and heated the reaction mixture to 55- 60°C.
  • Acetic acid 71 ml was slowly added to the reaction mixture at 55-60°C. Heated the reaction mixture to 70-75°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 25-30°C.
  • the mixture was filtered through hyflow bed and washed with the mixture of ethyl acetate and water. Both the aqueous and organic layers were separated from the obtained filtrate.
  • Acetic acid (170 ml) was slowly added to the mixture of tetrahydrofuran (100 ml), 4-amino- 2-fluoro-N-methylbenzamide (50 g), cyclobutanone (31.25 g), sodium cyanide (21.85) at 25- 30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 80- 85°C and stirred it for 26 hours at the same temperature. Cooled the reaction mixture to 25- 30°C and quenched with water. Filtered the solid, washed with water. Slurried the obtained compound in water. Filtered the solid, washed with water and followed by cyclohexane.
  • Apalutamide (80 g) was dissolved in dichloromethane (400 ml) at 25-30°C. Distilled off solvent completely from the solution. Again dissolved the obtained compound in 400 ml of dichloromethane, filtered the resultant solution and washed with dichlormethane. Distilled off solvent completely from the filtrate and co-distilled with cyclohexane. Slurried the obtained compound in cylohexane at 25-30°C and dried. Obtained compound is further micronized and dried to get the title compound.
  • Example-14 Preparation of Apalutamide disulphur impurity of formula- A.
  • 5-isothiocyanato-3-(trifluoromethyl)picolinonitrile (46.3 g) was added to the mixture of dimethylformamide (20 ml), isopropyl acetate (40 ml) and 4-(l-cyanocyclobutylamino)-2- fluoro-N-methyl benzamide (20 g) in lot-wise at 25-30°C. After addition of every lot, heated the reaction mixture to 65-70°C, stirred at the same temperature and cooled the reaction mixture to 25-30°C. To this reaction mixture aqueous sodium hydroxide solution was added at 25-30°C, separated both organic aqueous layers.

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Abstract

L'invention concerne un procédé de préparation de 4-[7-(6-Cyano-5-trifluoro-méthyl-pyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-méthylbenzamide de formule 1. L'invention concerne également des procédés de préparation d'une forme amorphe et cristalline du composé de formule 1. Formule 1
PCT/IN2020/051022 2019-12-11 2020-12-11 Procédé de préparation de 4-[7-(6-cyano-5-trifluorométhylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-n-méthylbenzamide et de ses polymorphes WO2021117062A1 (fr)

Applications Claiming Priority (2)

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IN201941051350 2019-12-11
IN201941051350 2019-12-11

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WO2021117062A1 true WO2021117062A1 (fr) 2021-06-17

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019135254A1 (fr) * 2018-01-02 2019-07-11 Mylan Laboratories Limited Polymorphes d'apalutamide et leur préparation
WO2019229625A1 (fr) * 2018-05-30 2019-12-05 Olon S.P.A. Procédé pour la préparation d'apalutamide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019135254A1 (fr) * 2018-01-02 2019-07-11 Mylan Laboratories Limited Polymorphes d'apalutamide et leur préparation
WO2019229625A1 (fr) * 2018-05-30 2019-12-05 Olon S.P.A. Procédé pour la préparation d'apalutamide

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