WO2022208552A1 - Formes cristallines du [1,1'-biphényl]-3-carboxamide, n-[(1,2-dihydro-4,6-diméthyl-2-oxo-3-pyridinyl)méthyl]-5-[éthyl(tétrahydro-2h-pyran-4-yl)amino]-4-méthyl-4'-(4-morpholinylméthyl)-, bromhydrate (1:1) et son procédé de préparation - Google Patents

Formes cristallines du [1,1'-biphényl]-3-carboxamide, n-[(1,2-dihydro-4,6-diméthyl-2-oxo-3-pyridinyl)méthyl]-5-[éthyl(tétrahydro-2h-pyran-4-yl)amino]-4-méthyl-4'-(4-morpholinylméthyl)-, bromhydrate (1:1) et son procédé de préparation Download PDF

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WO2022208552A1
WO2022208552A1 PCT/IN2022/050325 IN2022050325W WO2022208552A1 WO 2022208552 A1 WO2022208552 A1 WO 2022208552A1 IN 2022050325 W IN2022050325 W IN 2022050325W WO 2022208552 A1 WO2022208552 A1 WO 2022208552A1
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Prior art keywords
tazemetostat
crystalline form
hydrobromide
formula
mixture
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PCT/IN2022/050325
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English (en)
Inventor
Thirumalai Rajan Srinivasan
Eswaraiah Sajja
Vijayavitthal T MATHAD
Venkata Narasayya SALADI
Bal Raju Kammari
Beerappa DODLE
Kiran babu GANDHAM SHYAM
Kumaraswamy LUNAVATH
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Msn Laboratories Private Limited, R&D Center
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Publication of WO2022208552A1 publication Critical patent/WO2022208552A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol

Definitions

  • the present invention relates to crystalline forms of [1,1 ’-Biphenyl] -3 -carboxamide, N- [(l,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-5-[ethyl(tetrahydro-2H-pyran-4- yl)amino]-4-methyl-4’-(4-morpholinylmethyl)-, hydrobromide and process for its preparation thereof.
  • Tazemetostat hydrobromide is chemically known as [1,1 ’-Biphenyl] -3-carboxamide, N- [(l,2-dihydro-4,6-dimethyl-2-oxo-3-pyridinyl)methyl]-5-[ethyl(tetrahydro-2H-pyran-4-yl) amino]-4-methyl-4’-(4-morpholinylmethyl)-, hydrobromide (1:1) represented by the following structural formula.
  • Tazemetostat is a selective, orally bioavailable, small molecule inhibitor of the enhancer of zeste homolog 2 (EZH2), a histone methyltransferase.
  • EZH2 is the catalytic subunit of the polycomb repressive complex 2, catalyzing mono, di-, and trimethylation of lysine 27 of histone H3, which leads to repression (transcriptional regulation) of certain important gene sets such as tumor suppressors, differentiation markers, cell cycle regulators, and apoptotic machinery.
  • Tazemetostat is approved in US as TAZVERIK tablet for oral administration for the treatment of adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.
  • Tazemetostat is disclosed in US8410088 B2 and this patent also discloses process for the preparation of Tazemetostat trihydrochloride.
  • Tazemetostat hydrobromide is disclosed in US9394283 B2 (herein described as US‘283). This patent also discloses process for the preparation of Tazemetostat hydrobromide.
  • US’283 discloses crystalline Form-A and Form-B of Tazemetostat hydrobromide.
  • Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.
  • Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances.
  • the present invention relates to crystalline forms of Tazemetostat hydrobromide.
  • the present invention also relates to process for the preparation of crystalline forms of Tazemetostat hydrobromide.
  • the present invention also relates to crystalline forms of Tazemetostat and process for its preparation.
  • Figure 1 Illustrates the PXRD pattern of crystalline Form-M of Tazemetostat hydrobromide.
  • Figure 2 Illustrates the PXRD pattern of crystalline Form-S of Tazemetostat hydrobromide.
  • Figure 3 Illustrates the PXRD pattern of crystalline Form-N of Tazemetostat hydrobromide.
  • Figure 4 Illustrates the PXRD pattern of Form-A of Tazemetostat hydrobromide.
  • Figure 5 Illustrates the PXRD pattern of crystalline Form-M of Tazemetostat.
  • Figure 6 Illustrates the PXRD pattern of crystalline Form-Mi of Tazemetostat.
  • Figure 7 Illustrates the PXRD pattern of crystalline Form-M2 of Tazemetostat.
  • Figure 8 Illustrates the PXRD pattern of crystalline Form-M3 of Tazemetostat.
  • the present invention provides crystalline Form-M of Tazemetostat hydrobromide characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 5.6, 9.1 and 11.2 ⁇ 0.2 degrees of 2-theta.
  • XRD X-ray powder diffraction
  • the crystalline Form-M of Tazemetostat hydrobromide is further characterized by the X- ray powder diffraction (XRD) pattern as illustrated in figure- 1.
  • the present invention provides a process for the preparation of crystalline Form-M of Tazemetostat hydrobromide, which comprises: a) providing a solution of Tazemetostat in a mixture of acetone and tetrahydrofuran; and b) isolating the crystalline Form-M of Tazemetostat hydrobromide.
  • providing a solution of Tazemetostat comprises dissolving Tazemetostat in a mixture of acetone and tetrahydrofuran at a suitable temperature of about 30°C and above.
  • the solution may be filtered to make it particle free.
  • step-a) treating a solution obtained in step-a) with a mixture of isopropyl acetate and aqueous hydrobromic acid to provide crystalline Form-M of Tazemetostat hydrobromide.
  • isolating crystalline Form-M of Tazemetostat hydrobromide can be carrying out by any methods known in the art or crystalline Form-M of Tazemetostat hydrobromide can be isolated by employing any of the techniques, but not limited to: precipitation, decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
  • drying crystalline Form-M of Tazemetostat hydrobromide by a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
  • the drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures.
  • the drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
  • the present invention provides crystalline Form-S of Tazemetostat hydrobromide characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 6.7, 8.9 and 11.5 ⁇ 0.2 degrees of 2-theta.
  • XRD X-ray powder diffraction
  • the crystalline Form-S of Tazemetostat hydrobromide is further characterized by the X- ray powder diffraction (XRD) pattern as illustrated in figure-2.
  • the present invention provides a process for the preparation of crystalline Form-S of Tazemetostat hydrobromide, which comprises: a) providing a solution of Tazemetostat hydrobromide in a mixture of acetone and water; and b) isolating the crystalline Form-S of Tazemetostat hydrobromide.
  • providing a solution of Tazemetostat hydrobromide comprises dissolving Tazemetostat hydrobromide in a mixture of acetone and water at a suitable temperature of about 30°C and above.
  • the solution can be filtered to make it particle free.
  • isolating the crystalline Form-S of Tazemetostat hydrobromide can be carrying out by any methods known in the art or crystalline Form-S of Tazemetostat hydrobromide can be isolated by employing any of the techniques, but not limited to: precipitation, decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
  • drying the crystalline Form-S of Tazemetostat hydrobromide by a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
  • the drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures.
  • the drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
  • the present invention provides crystalline Form-N of Tazemetostat hydrobromide.
  • the present invention provides a process for the preparation of crystalline Form-N of Tazemetostat hydrobromide, which comprises: a) providing a solution of Tazemetostat in dichlorome thane; and b) isolating the crystalline Form-N of Tazemetostat hydrobromide.
  • providing a solution of Tazemetostat comprises dissolving Tazemetostat in dichloromethane at a suitable temperature of about 30°C and above.
  • the solution can be filtered to make it particle free.
  • step-a) treating the solution obtained in step-a) to a mixture of methyl tertiary butyl ether, acetone and aqueous hydrobromic acid or hydrobromic acid in acetic acid to provide crystalline Form-N of Tazemetostat hydrobromide.
  • isolating the crystalline Form-N of Tazemetostat hydrobromide can be carrying out by any methods known in the art or crystalline Form-N of Tazemetostat hydrobromide can be isolated by employing any of the techniques, but not limited to: precipitation, decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
  • drying the crystalline Form-N of Tazemetostat hydrobromide by a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
  • the drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures.
  • the drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
  • the present invention provides a process for the preparation of crystalline Form- A of Tazemetostat hydrobromide, which comprises: a) providing a solution of Tazemetostat in a mixture of acetone and tetrahydrofuran; and b) isolating the crystalline Form- A of Tazemetostat hydrobromide.
  • providing solution of Tazemetostat comprises dissolving Tazemetostat in a mixture of acetone and tetrahydrofuran at a suitable temperature of about 30°C and above.
  • the solution can be filtered to make it particle free.
  • step-a) treating the solution obtained in step-a) to a mixture of isopropyl acetate, aqueous hydrobromic acid and water to provide crystalline Form-A of Tazemetostat hydrobromide.
  • isolating the crystalline Form-A of Tazemetostat hydrobromide can be carrying out by any methods known in the art or crystalline form-A of Tazemetostat hydrobromide can be isolated by employing any of the techniques, but not limited to: precipitation, decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
  • drying the crystalline Form- A of Tazemetostat hydrobromide by a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
  • the drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures.
  • the drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
  • the present invention provides a process for the preparation of crystalline Form-A of Tazemetostat hydrobromide, which comprises: a) contacting crystalline Form-N of Tazemetostat hydrobromide with suitable solvent or a mixture of solvents; and b) isolating the crystalline Form-A of Tazemetostat hydrobromide.
  • the suitable solvent used in step-a) is selected from ketone solvents, chloro solvents, ester solvents, polar-aprotic solvents, nitrile solvents and ether solvents.
  • the present invention provides a process for the preparation of crystalline Form- A of Tazemetostat hydrobromide, which comprises: a) suspending crystalline Form-N of Tazemetostat hydrobromide with acetone; and b) isolating the crystalline Form-A of Tazemetostat hydrobromide.
  • the present invention provides a process for the preparation of crystalline Form-A of Tazemetostat hydrobromide, which comprises: a) suspending crystalline Form-N of Tazemetostat hydrobromide with a mixture of acetone and dichloromethane; and b) isolating the crystalline Form-A of Tazemetostat hydrobromide.
  • the present invention provides a process for the preparation of crystalline Form- A of Tazemetostat hydrobromide, which comprises: a) suspending crystalline Form-N of Tazemetostat hydrobromide with a mixture of acetone, dichloromethane and methyl tert-butyl ether; and b) isolating the crystalline Form- A of Tazemetostat hydrobromide.
  • the present invention provides a process for the preparation of crystalline Form- A of Tazemetostat hydrobromide, which comprises: a) suspending crystalline Form-N of Tazemetostat hydrobromide with a mixture of isobutyl acetate and methyl tert-butyl ether; and b) isolating the crystalline Form- A of Tazemetostat hydrobromide.
  • the present invention provides a process for the preparation of crystalline Form- A of Tazemetostat hydrobromide, which comprises: a) suspending crystalline Form-N of Tazemetostat hydrobromide with dimethyl sulfoxide and acetonitrile; and b) isolating the crystalline Form- A of Tazemetostat hydrobromide.
  • step-a) heating the solution of step-a) to a suitable temperature of about 50°C to 80°C.
  • the solution can be filtered to make it particle free.
  • step-a adding acetonitrile to the solution obtained in step-a) and cooling the mixture to 40-45 °C to provide crystalline Form- A of Tazemetostat hydrobromide.
  • isolating the crystalline Form-A of Tazemetostat hydrobromide can be carrying out by any methods known in the art or crystalline Form-A of Tazemetostat hydrobromide can be isolated by employing any of the techniques, but not limited to: precipitation, decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
  • drying the crystalline Form-A of Tazemetostat hydrobromide by a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
  • the drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures.
  • the drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
  • the present invention provides crystalline Form-M of Tazemetostat of formula-2 characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 9.7, 16.9 and 18.6 ⁇ 0.2 degrees of 2-theta.
  • XRD X-ray powder diffraction
  • the crystalline Form-M of Tazemetostat of formula-2 is further characterized by the X- ray powder diffraction (XRD) pattern as illustrated in figure-5.
  • the present invention provides a process for the preparation of crystalline Form-M of Tazemetostat of formula-2, which comprises: a) reacting compound of formual-4 with compound of formula-3 in the presence of EDC.HC1, HOBt and triethylamine in dimethylformamide; and b) isolating to provide crystalline Form-M of Tazemetostat of formula-2.
  • the present invention provides crystalline Form-M 1 of Tazemetostat of formula-2 characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 6.6, 11.1 and 19.1 ⁇ 0.2 degrees of 2-theta.
  • XRD X-ray powder diffraction
  • the crystalline Form-M 1 of Tazemetostat of formula-2 is further characterized by the X- ray powder diffraction (XRD) pattern as illustrated in figure-6.
  • the present invention provides a process for the preparation of crystalline Form-Mi of Tazemetostat of formula-2, which comprises: a) contacting crystalline Form-M of Tazemetostat of formula-2 with isopropanol; and b) isolating the crystalline Form-M 1 of Tazemetostat of formula-2.
  • the present invention provides crystalline Form-M2 of Tazemetostat of formula-2 characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 6.6, 14.2 and 20.7 ⁇ 0.2 degrees of 2-theta.
  • XRD X-ray powder diffraction
  • the crystalline Form-M2 of Tazemetostat of formula-2 is further characterized by the X- ray powder diffraction (XRD) pattern as illustrated in figure-7.
  • the present invention provides a process for the preparation of crystalline Form-M2 of Tazemetostat of formula-2, which comprises: a) contacting crystalline Form-Mi of Tazemetostat of formula-2 with dichloromethane; b) adding ethanol and water to the mixture obtained in step-a); and c) isolating the crystalline Form-M2 of Tazemetostat of formula-2.
  • step-a) optionally treating a mixture obtained in step-a) with carbon and filtering through hyflow bed.
  • the present invention provides crystalline Form-M3 of Tazemetostat of formula-2 characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 9.6, 12.2 and 20.2 ⁇ 0.2 degrees of 2-theta.
  • XRD X-ray powder diffraction
  • the crystalline Form-M3 of Tazemetostat of formula-2 is further characterized by the X- ray powder diffraction (XRD) pattern as illustrated in figure-8.
  • the present invention provides a process for the preparation of crystalline Form-M3 of Tazemetostat of formula-2, which comprises: a) contacting crystalline Form-M2 of Tazemetostat of formula-2 with ethanol and water; and b) isolating the crystalline Form-M3 of Tazemetostat of formula-2.
  • the present invention provides a process for the preparation of crystalline Form- A of Tazemetostat hydrobromide of formula- 1, which comprises: a) suspending crystalline Form-N of Tazemetostat hydrobromide of formula- 1 with a mixture of acetone, n-heptane and cyclohexane; and b) seeding the solution obtained in step-a), c) isolating the crystalline Form- A of Tazemetostat hydrobromide of formula- 1.
  • seeding the mixture obtained in step-a) with crystalline form- A of Tazematostat hydrobromide wherein seeding the mixture obtained in step-a) with crystalline form- A of Tazematostat hydrobromide.
  • isolating the crystalline Forms M, Ml, M2 and M3 of Tazemetostat can be carrying out by any methods known in the art or crystalline form- M3 of Tazemetostat can be isolated by employing any of the techniques, but not limited to: precipitation, decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
  • drying the crystalline Forms M, Ml, M2 and M3 of Tazemetostat by a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
  • the drying can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures.
  • the drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
  • crystalline Form- A of Tazemetostat hydrobromide obtained according to the present invention has a particle size distribution of D90 less than 150 pm, preferably less than 100 pm; more preferably 50 pm.
  • Crystalline Form- A of Tazemetostat hydrobromide of formula- 1 obtained according to the present invention is having Tazemetostat hydrobromide amine impurity, Acid impurity, Amide impurity and Ester impurity less than 0.05% as measured by HPLC.
  • crystalline Form-A of Tazemetostat hydrobromide of formula- 1 obtained according to the present invention is having N-Oxide impurity, Des ethyl THP impurity, Dimer impurity, Des ethyl impurity less than 0.05% as measured by HPLC.
  • the starting material compounds of formulae 3, 6, 9 and 13 used in the present invention are obtained from any of the prior art known processes.
  • Tazemetostat hydrobromide prepared according to the present invention can be further micronized or milled in conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that can be used for particle size reduction include, but not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or micronization can be performed before drying, or after the completion of drying of the product.
  • the invention also encompasses pharmaceutical compositions comprising crystalline Forms A, M, S and N of Tazemetostat hydrobromide compound of formula- 1 of the present invention.
  • pharmaceutical compositions or “pharmaceutical formulations” include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • P-XRD Method of Analysis PXRD analysis of compound of formula- 1 was carried out by using BRUKER/D8 ADVANCE diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min.
  • PSD method of Analysis Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 3000 instrument.
  • Example-1 Preparation of crystalline Form-M of Tazemetostat hydrobromide.
  • Tazemetostat (3.0 gms) was dissolved in a mixture of acetone (36 ml) and tetrahydrofuran (18 ml) at 25-30°C and stirred for 20 minutes. Filtered the mixture to make it particle free. The obtained solution was added to pre-cooled mixture of isopropyl acetate (160 ml) and aqueous hydrobromide (0.591 ml) at 0-5°C and stirred for 70-80 minutes. Filtered the solid and dried to get the title compound. Yield: 2.95 gms.
  • Example-2 Preparation of crystalline Form-M of Tazemetostat hydrobromide.
  • Tazemetostat (1.0 gms) was dissolved in a mixture of acetone (12 ml) and tetrahydrofuran (6.0 ml) at 25-30°C and stirred for 20 minutes. Filtered the solution to make it particle free. The obtained solution was added to pre-cooled mixture of isopropyl acetate (60 ml) and aqueous hydrobromide (0.197 ml) at 0-5°C and stirred for 70-80 minutes. Filtered the solid and dried to get the title compound. Yield: 0.91 gm; HBr content: 11.81 %.
  • Example-3 Preparation of crystalline Form-S of Tazemetostat hydrobromide.
  • Tazemetostat hydrobromide (1.0 gms) was dissolved in a mixture of acetone (50 ml) and water (5.0 ml) at 25-30°C and stirred for 10 minutes. Heated the mixture to 50-55°C. The obtained solution was added to pre-cooled isopropyl acetate (60 ml) at 0-5°C and stirred for 1 hour. Filtered the solid and dried to get the title compound. Yield: 0.95 gms.
  • Example-4 Preparation of crystalline Form-N of Tazemetostat hydrobromide.
  • Tazemetostat 50 gms was dissolved in pre-cooled dichloromethane (200 ml) at 0-5°C and stirred for 20 minutes. Filtered the solution to make it particle free and washed with acetone. The obtained solution was added to pre-cooled mixture of MTBE (1000 ml), acetone (100) and aqueous hydrobromide (9.85 ml) at 0-5°C and stirred for 90 minutes. Filtered the solid and dried to get the title compound. Yield: 50.28 gms; HBr content: 12.53%.
  • Example-5 Preparation of crystalline Form-A of Tazemetostat hydrobromide.
  • Acetone 50 ml was added to crystalline Form-N of Tazemetostat hydrobromide (5.0 gms) at 25-30°C and stirred for 90 minutes. Filtered the solid and dried to get the title compound. Yield: 4.3 gms; HBr content: 12.67%.
  • Example-6 Preparation of crystalline Form-A of Tazemetostat hydrobromide.
  • Example-7 Preparation of crystalline Form-A of Tazemetostat hydrobromide.
  • Example-8 Preparation of crystalline Form-A of Tazemetostat hydrobromide.
  • Example-9 Preparation of crystalline Form-A of Tazemetostat hydrobromide.
  • Tazemetostat (3.0 gms) was dissolved in a mixture of acetone (36 ml) and tetrahydrofuran (18 ml) at 25-30°C and stirred for 20 minutes. Filtered the solution to make it particle free. The obtained solution was added to pre-cooled mixture of isopropyl acetate (160 ml), aqueous hydrobromide (0.591 ml) and water (0.3 ml) at 0-5°C and stirred for 70-80 minutes. Filtered the solid and dried to get the title compound. Yield: 2.93 gms.
  • Example-10 Preparation of crystalline Form-M of Tazemetostat.
  • Dimethylformamide (600.0 ml) was added to 5-(ethyl(tetrahydro-2H-pyran-4-yl) amino)- 4-methyl-4'-(morpholinomethyl)-[l,l'-biphenyl]-3-carboxylic acid of formula-4 (100.0 gm) and triethyl amine (30.35 gm) at 25-30°C and stirred for 10 minutes.
  • 3-(aminomethyl)-4, 6-dimethyl pyridin-2(lH)-one hydrochloride of formula-3 (52.82 gm) and HOBt (47.29 gm) were added to the mixture at 25-30°C and stirred for 40 minutes.
  • Triethylamine (40.47 gm) and EDC.HC1 (67.10) were added to the mixture at 25-30°C and stirred for 6 hours. Cooled the mixture to 10- 15°C. Water (4200.0 ml) was slowly added to the mixture at 10-15°C and stirred for 1 hour. Heated the mixture to 25-30°C and stirred for 2 hours. Filtered the solid and washed with water to get the title compound.
  • Example-11 Preparation of crystalline Form-Mi of Tazemetostat.
  • Isopropanol (1500.0) was added to the solid obtained in example-10 at 25-30°C and stirred for 2 hours. Filtered the solid, washed with isopropanol and dried to get the title compound.
  • the PXRD pattern of the obtained compound is illustrated in Figure-6.
  • Example-12 Preparation of crystalline Form-M2 of Tazemetostat.
  • Example-13 Preparation of crystalline Form-M3 of Tazemetostat.
  • Example-14 Preparation of crystalline Form-N of Tazemetostat hydrobromide.
  • Tazemetostat (1.50 kg) was dissolved in pre-cooled dichloromethane (5.25 lit) at 0-5°C and stirred for 10 minutes. Filtered the solution to make it particle free and washed with dichloromethane and acetone. The obtained solution was added to pre-cooled mixture of acetone (4.50 lit), hydrobromic acid in acetic acid (0.562 lit) and MTBE (30.0 lit) at 0-5°C and stirred for 2 hours. Filtered the solid and washed with MTBE to get the title compound.
  • Example-15 Preparation of crystalline Form-A of Tazemetostat hydrobromide.
  • Example-16 Preparation of crystalline Form-N of Tazemetostat hydrobromide.
  • Tazemetostat (4.0 kg) was dissolved in pre-cooled dichloromethane (8.75 lit) at 0-5°C and stirred for 10 minutes. Filtered the solution to make it particle free and washed with dichloromethane. The obtained solution was slowly added to pre-cooled mixture of acetone (4.0 lit), hydrobromic acid in acetic acid (1.40 lit), water (0.028 lit) and MTBE (80.0 lit) at 0-5°C and stirred for 2 hours. Filtered the solid and washed with MTBE to get the title compound.
  • the PXRD pattern of the obtained compound is illustrated in Figure-3.
  • Example-17 Preparation of crystalline Form-A of Tazemetostat hydrobromide.
  • Dimethylsulfoxide (18.3 lit) was added to the solid obtained in example-16 at 25-30°C. Raised the temperature of the mixture to 60-65°C and stirred for 15 minutes. Acetonitrile (54.9 lit) was slowly added to the mixture at 60-65°C. Cooled the mixture to 40-45°C and stirred for 3 hours. Filtered the solid, washed with acetone and dried to get the title compound. Yield: 2.10 kg; Particle size distribution: D90: 87.69 pm.
  • Example-18 Preparation of crystalline Form-N of Tazemetostat hydrobromide.
  • Tazemetostat (150.0 gm) was dissolved in pre-cooled dichloromethane (525.0 ml) at 0- 5°C and stirred for 25 minutes. Filtered the solution for particle free and washed with dichloromethane. The obtained solution was slowly added to pre-cooled mixture of MTBE (750.0 ml), acetone (150.0 ml) and hydrobromic acid in acetic acid (21.0 gm) at 0-5°C and stirred for 3 hours. Filtered the solid and washed with MTBE to get the title compound.
  • Example-19 Preparation of crystalline Form-A of Tazemetostat hydrobromide.
  • Acetone (1.5 lit), n-heptane (6.61 lit) and cyclohexane (6.61 lit) were added to the crystalline Form-N of Tazemetostat hydrobromide (4.9 kg) at 25-30°C and stirred for 3 hours. Filtered the solid, washed with acetone and dried to get the title compound.
  • Example-22 Preparation of methyl 5-bromo-2-methyl-3-nitrobenzoate of Formula- 11.
  • Example-23 Preparation of methyl 3-amino-5-bromo-2-methylbenzoate of Formula-10.
  • Example-24 Preparation of methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl) amino (benzoate of Formula-8.
  • Example-25 Preparation of methyl 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino) -2- methylbenzoate of Formula-7.
  • Example-26 Preparation of methyl 5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl - 4'-(morpholinomethyl)-[l,l'-biphenyl]-3-carboxylate of Formula-5.
  • Dioxane 800.0 ml was added to methyl 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4- yl)amino)-2-methylbenzoate of Formula-7 (100.0 gm) at 25-30°C and stirred for 10 minutes.

Abstract

La présente invention concerne des formes cristallines du [1,1'-biphényl]-3-carboxamide, N-[(1,2-dihydro-4,6-diméthyl-2-oxo-3-pyridinyl)méthyl]-5-[éthyl(tétrahydro-2H-pyran-4-yl)amino]-4-méthyl-4'-(4-morpholinylméthyl)-, bromhydrate (1:1) et son procédé de préparation. Plus précisément, la présente invention concerne des formes cristallines du [1,1'-biphényl]-3-carboxamide, N-[(1,2-dihydro-4,6-diméthyl-2-oxo-3-pyridinyl)méthyl]-5-[éthyl(tétrahydro-2H-pyran-4-yl)amino]-4-méthyl-4'-(4-morpholinylméthyl)-, bromhydrate (1:1) représenté par la formule structurale 1 suivante et un procédé de préparation associé.
PCT/IN2022/050325 2021-03-31 2022-03-31 Formes cristallines du [1,1'-biphényl]-3-carboxamide, n-[(1,2-dihydro-4,6-diméthyl-2-oxo-3-pyridinyl)méthyl]-5-[éthyl(tétrahydro-2h-pyran-4-yl)amino]-4-méthyl-4'-(4-morpholinylméthyl)-, bromhydrate (1:1) et son procédé de préparation WO2022208552A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9394283B2 (en) * 2012-04-13 2016-07-19 Epizyme, Inc. Salt form of a human histone methyltransferase EZH2 inhibitor

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9394283B2 (en) * 2012-04-13 2016-07-19 Epizyme, Inc. Salt form of a human histone methyltransferase EZH2 inhibitor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CAIRA M. R. ET AL.: "CRYSTALLINE POLYMORPHISM OF ORGANIC COMPOUNDS", TOPICS IN CURRENT CHEMISTRY, vol. 198, 1 January 1998 (1998-01-01), BERLIN, DE, pages 163 - 208, XP001156954 *

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