WO2023157030A1 - Procédé de préparation de 1-(4-(((6-amino-5-(4-phénoxyphényl)pyrimidin-4-yl) amino)méthyl)pipéridin-1-yl)prop-2-én-1-one - Google Patents

Procédé de préparation de 1-(4-(((6-amino-5-(4-phénoxyphényl)pyrimidin-4-yl) amino)méthyl)pipéridin-1-yl)prop-2-én-1-one Download PDF

Info

Publication number
WO2023157030A1
WO2023157030A1 PCT/IN2023/050168 IN2023050168W WO2023157030A1 WO 2023157030 A1 WO2023157030 A1 WO 2023157030A1 IN 2023050168 W IN2023050168 W IN 2023050168W WO 2023157030 A1 WO2023157030 A1 WO 2023157030A1
Authority
WO
WIPO (PCT)
Prior art keywords
evobrutinib
formula
solvent
compound
acetate
Prior art date
Application number
PCT/IN2023/050168
Other languages
English (en)
Inventor
Thirumalai Rajan Srinivasan
Eswaraiah Sajja
Vijayavitthal T MATHAD
. Ismail
Praveen SUBUDDHI
Venkata Narasayya SALADI
Bal Raju Kammari
Original Assignee
Msn Laboratories Private Limited, R&D Center
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 Msn Laboratories Private Limited, R&D Center filed Critical Msn Laboratories Private Limited, R&D Center
Publication of WO2023157030A1 publication Critical patent/WO2023157030A1/fr

Links

Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to an improved process for the preparation of l-(4-(((6- amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-l-yl)prop-2-en-l-one which is represented by the following structural formula- 1.
  • the present invention also relates to a solid dispersion of Evobrutinib of formula- 1
  • Evobrutinib is in clinical development to investigate its potential as a treatment for multiple sclerosis (MS). It is an oral, highly selective inhibitor of Bruton’s tyrosine kinase (BTK) which is important in the development and functioning of various immune cells including B lymphocytes and macrophages.
  • BTK tyrosine kinase
  • Evobrutinib is designed to inhibit primary B cell responses such as proliferation and antibody and cytokine release, without directly affecting T cells.
  • BTK inhibition is thought to suppress autoantibody-producing cells, which preclinical research suggests may be therapeutically useful in certain autoimmune diseases.
  • U.S. Patent No. 9073947 discloses a pyrimidine derivative of Evobrutinib which chemically named as l-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl) piperidin-l-yl)prop-2-en-l-one and pharmaceutically acceptable salts, solvates and pharmaceutical compositions thereof.
  • the present invention provides a simple, cost-effective, industrially feasible process for the preparation of Evobrutinib of formula- 1.
  • 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 provides an improved process for the preparation of Evobrutinib of formula- 1.
  • the present invention also provides a solid dispersion of Evobrutinib of formula- 1 and process for its preparation.
  • Figure-1 Illustrates the PXRD pattern of solid dispersion of Evobrutinib with PVP-K30.
  • Figure-2 Illustrates the PXRD pattern of solid dispersion of Evobrutinib with co-povidone.
  • Figure-3 Illustrates the PXRD pattern of solid dispersion of Evobrutinib with HPMC-ES.
  • Figure-4 Illustrates the PXRD pattern of solid dispersion of Evobrutinib with HPMC-AS.
  • Figure-5 Illustrates the PXRD pattern of solid dispersion of Evobrutinib with Eudragit.
  • Figure-6 Illustrates the PXRD pattern of solid dispersion of Evobrutinib with Syloid.
  • Figure-7 Illustrates the PXRD pattern of amorphous Evobrutinib.
  • suitable solvent used in the present invention refers to “hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane, cycloheptane, methyl cyclohexane, m-, o-, or p-xylene, and the like; “ether solvents” such as dimethoxy methane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl acetate, isopropy
  • the base as used in the present invention is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; ammonia; and organic bases such as “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; triethyl amine, methyl amine, ethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo
  • the acid is selected from inorganic acids such as hydrochloric acid, hydrochloric acid in a solvent, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid or phosphoric acid; and organic acids such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, 2- chloromandelate, paratoluenesulfonic acid, ethane- 1,2-disulfonic acid, camphorsulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid.
  • inorganic acids such as hydrochloric acid, hydrochloric acid in a solvent, hydrobro
  • the N-protecting group as used in the present invention is selected from but not limited to di-tert.butyl dicarbonate (DIBOC), benzyl chloro formate, acetic anhydride, alkyl haloformates such as methyl chloroformate, ethyl chloro formate, isopropyl chloroformate and the like, tosyl halides, tosyl anhydrides, alkyl trifluoro acetates such as methyl trifluoro acetate, ethyl trifluoroacetate, isopropyltrifluoroacetate, vinyltrifluoro acetate, trifluoroacetic acid, tnfluoroacetyl chloride, trichloroethoxycarbonyl chloride, pivaloyl chloride, triphenyl methyl chloride (tritylchloride), benzyloxy carbonyl (Cbz), 2,2,2-trichloroethoxycarbonyl (Troc
  • phosphine ligands used in the present invention refers to phosphine ligands selected from trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropyl phosphine, tributylphosphine, tricyclohexylphosphine, trimethylphosphite, triethylphosphite, tripropylphosphite, triisopropylphosphite, tributylphosphite, tricyclohexyl phosphite, 2,2'- bis(diphenylphosphino)-l,l'-binaphthyl (BINAP), l,2-bis(dimethylphosphino)ethane, 1,2-bis (diethylphosphino)ethane, 1 ,2-bi s(dipropylphosphino)ethane, 1 ,2-bi
  • solid dispersion refers to dispersion of drug in a solid matrix where the matrix is either a small molecule or polymer.
  • solid dispersion relates to a molecular dispersion where the API (active pharmaceutical ingredient) and polymer molecules are uniformly but irregularly dispersed in a non-ordered way.
  • the two or more components form a homogeneous one-phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size.
  • excipient refers to play a significant role in stabilizing solid dispersions, maximizing bioavailability, and overcoming absorption issues associated with poorly soluble drugs.
  • solid dispersion and premix are used interchangeably to describe solid states disclosed herein.
  • the present invention provides an improved process for the preparation of Evobrutinib of formula- 1, comprising one or more of the following steps: wherein ‘PG’ is H or N-protecting group; X is F, Cl, Br or I. a) reacting the compound of general formula-2 with compound of general formula-3 in presence of a suitable nitrogen bicyclic base in a suitable solvent to provide compound of general formula-4, b) reacting the compound of general formula-4 with compound of formula-5 in presence of a suitable palladium catalyst and a suitable phosphine ligand in a suitable solvent to provide compound of general formula-6, c) deprotecting the compound of general formula-6 with a suitable acid in a suitable solvent to provide compound of formula-7, d) reacting the compound of formula-7 with compound of general formula-8 in presence of a suitable base in a suitable solvent to provide Evobrutinib of formula- 1, e) optionally purifying the compound of formula- 1 in a suitable solvent to provide pure form of Evobrutinib.
  • the nitrogen bicyclic base used in step-a) is selected from l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,4-diazabicyclo[2.2.2]octane (DABCO), l,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD).
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • DABCO l,4-diazabicyclo[2.2.2]octane
  • TBD l,5,7-triazabicyclo[4.4.0]dec-5-ene
  • palladium catalyst used in step-b) is selected from l,l'-bis(diphenylphosphino)ferrocene]dichloro palladium (II) (Pd(dppf)C12), tetrakis (triphenylphosphine)palladium(O) (Pd(PPh3)4), palladium(II)acetate (Pd(OAc)2), palladium (II)chloride (PdCh), bis(benzonitrile)palladium(II)dichloride (Pd(PhCN)2C12), bis(triphenyl phosphine)palladium(II) dichloride (Pd(PPh3)2C12), and allyl palladium(II)chloride dimer (PdCl(C3H5)] 2 ).
  • the palladium catalyst used in step-b) is in the range of 0.03 to 0.1 moles with respect to one mole of compound of general formula-4.
  • reaction temperature in step-b) is 100°C or less than 100°C.
  • the suitable acid used in step-c) is organic or inorganic acid.
  • the suitable base used in step-b) and step-d) is selected from organic base or inorganic base.
  • the suitable solvent used in step-a) to step-e) is selected from alcohol solvent, ester solvent, nitrile solvent, ketone solvent, chloro solvent, ether solvent, hydrocarbon solvent, polar aprotic solvent, water or mixture thereof.
  • the present invention provides an improved process for the preparation of Evobrutinib of formula- 1, comprising one or more of the following steps: a) reacting the compound of formula-2a with compound of formula-3 a in presence of l,8-diazabicyclo[5.4.0]undec-7-ene in dimethylformamide to provide compound of formula-4a, b) reacting the compound of formula-4a with compound of formula-5 in presence of palladium acetate, 2-dicyclo-hexylphosphino-2',6'-dimethoxybiphenyl and potassium carbonate in 1,4-di oxane to provide compound of formula-6a, c) deprotecting the compound of formula-6a with hydrochloric acid in ethyl acetate to provide compound of formula-7, d) reacting the compound of formula-7 with compound of formula-8a in presence of aqueous sodium bicarbonate in tetrahydrofuran to provide Evobrutinib of formula- 1, comprising one or more of
  • the compound of formula-2a, formula-3a, formula-5a and formula-8a used in the present invention is synthesized from any of the process known in the prior art.
  • Prior art processes for the preparation of Evobrutinib are uneconomical and not suitable on commercial scale.
  • the present invention provides process for the preparation of formula-6 which avoids microwave assisted reaction method by replacing it with conventional reaction conditions at lower temperature.
  • the present invention also involves use of minimal mole ratio of palladium catalyst and avoids column purification.
  • compound of formula-6 produced by the present invention is having HPLC purity of at least 97.66% with high yield of 86%.
  • the present invention uses hydrochloric acid in ester solvent, which is advantageous at large scale production.
  • the present invention uses base and solvent treatment (instead of uneconomical lyophilization technique) to provide compound of formula-7 as a solid with high yield (95%) and HPLC purity of 76.4%.
  • the present invention involves simple purification techniques, which are comfortable to carry on large scale production and provides Evobrutinib with good yield and optimal purity of 97.6%.
  • the present invention provides an improved process for the preparation of Evobrutinib of formula- 1, which comprises: a) reacting the compound of general formula-2 with compound of general formula-3 in presence of a suitable nitrogen bicyclic base in a suitable solvent to provide compound of general formula-4,
  • the present invention provides an improved process for the preparation of Evobrutinib of formula- 1, which comprises: a) reacting the compound of general formula-4 with compound of formula-5 in presence of a suitable palladium catalyst, suitable phosphine ligand and a suitable base in a suitable solvent to provide compound of general formula-6, wherein, ‘PG’ is H or N-protecting group; X is F, Cl, Br or I. Palladium catalyst is same as defined above. b) converting the compound of general formula-6 to provide Evobrutinib of formula- 1.
  • the present invention provides an improved process for the preparation of Evobrutinib of formula- 1, which comprises: a) deprotecting the compound of general formula-6 in presence of hydrochloric acid in ester solvent to provide compound of formula-7, wherein, ‘PG’ is H or N-protecting group. b) converting the compound of formula-7 to provide Evobrutinib of formula- 1.
  • the present invention provides acid addition salt of formula-7a.
  • Formula- 7 a wherein the acid addition salt is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid or phosphoric acid; and organic acids such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, 2- chloromandelate, paratoluenesulfonic acid, ethane- 1,2-disulfonic acid, camphorsulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, n
  • the present invention provides a process for the purification of compound of formula-7, comprising treating the compound of formula-7 with a suitable acid in a solvent to provide its corresponding acid addition salts of compound of formula-7a. Further, treating the acid addition salt of compound of formula-7a with a base in a suitable solvent to provide pure compound of formula-7.
  • the present invention provides an improved process for the preparation of Evobrutinib of formula- 1, which comprises: a) reacting the compound of formula-7 with compound of general formula- 8 in presence of a suitable base in a solvent to provide compound of formula- 1, wherein X is F, Cl, Br or I. b) optionally purifying the compound of formula- 1 in a solvent to provide pure
  • the present invention provides an amorphous form of Evobrutinib, which is characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure-7.
  • XRD X-ray powder diffraction
  • the present invention provides a process for the preparation of amorphous form of Evobrutinib of formula-1, which comprises: a) providing a solution of Evobrutinib of formula- 1 in a solvent or a mixture of solvents; and b) isolating the amorphous form of Evobrutinib of formula- 1.
  • the solvent used in step-a) is selected from alcohol solvent, ester solvent, nitrile solvent, ketone solvent, chloro solvent, ether solvent, hydrocarbon solvent, polar aprotic solvent, water or mixture thereof.
  • the present invention provides a process for the preparation of amorphous form of Evobrutinib of formula- 1, which comprises: a) providing a solution of Evobrutinib of formula- 1 in alcohol solvent; and b) isolating the amorphous form of Evobrutinib of formula- 1.
  • the present invention provides a process for the preparation of amorphous form of Evobrutinib of formula- 1, which comprises: a) providing a solution of Evobrutinib of formula- 1 in methanol; and b) isolating the amorphous form of Evobrutinib of formula- 1.
  • the present invention provides a solid dispersion of Evobrutinib comprising Evobrutinib and one or more pharmaceutically acceptable excipients.
  • the suitable pharmaceutically acceptable excipient is selected from but not limited to syloid, polyvinylpyrrolidone (povidone or PVP; PVP of different grades like K-15, K-30, K-60, K-90 and K-120 may be used), co-povidone, cros- polyvinylpolypyrrolidone, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), cros-copovidone, 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, hydroxymethylcellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropy
  • the present invention provides a process for the preparation of solid dispersion of Evobrutinib, comprising Evobrutinib with one or more pharmaceutically acceptable excipients, which comprises: a) providing a solution of Evobrutinib with one or more pharmaceutically acceptable excipients in a solvent; and b) isolating the solid dispersion of Evobrutinib with one or more pharmaceutically acceptable excipients.
  • the suitable solvent used in step-a) is selected from alcohol solvent, ester solvent, nitrile solvent, ketone solvent, chloro solvent, ether solvent, hydrocarbon solvent, polar aprotic solvent, water or mixture thereof.
  • the suitable pharmaceutically acceptable excipient used in step-a) is same as defined above.
  • the present invention provides a process for the preparation of a solid dispersion of Evobrutinib comprising Evobrutinib with one or more pharmaceutically acceptable excipients, which comprises: a) providing a solution of Evobrutinib with one or more pharmaceutically acceptable excipients in an alcohol solvent; and b) isolating the solid dispersion of Evobrutinib with one or more pharmaceutically acceptable excipients.
  • the suitable alcohol solvent used in step-a) is methanol.
  • the suitable pharmaceutically acceptable one or more excipients used in step-a) is PVP-K30, Copovodone, HPMC-ES, Eudragit, Syloid.
  • the present invention provides a process for the preparation of a solid dispersion of Evobrutinib comprising Evobrutinib with one or more pharmaceutically acceptable excipients, which comprises: a) providing a solution of Evobrutinib with one or more pharmaceutically acceptable excipients in a mixture of alcohol solvent and chloro solvent; and b) isolating the solid dispersion of Evobrutinib with one or more pharmaceutically acceptable excipients.
  • the suitable alcohol solvent used in step-a) is methanol
  • the suitable chloro solvent used in step-a) is dichloromethane.
  • the suitable pharmaceutically acceptable excipient used in step-a) is HPMC-AS.
  • Evobrutinib of formula- 1 is carried out by dissolving Evobrutinib and an excipient in a solvent.
  • suitable temperature ranging from about 25°C to the reflux temperature of the solvent used in the reaction.
  • the resulting solution can be filtered to make it particle free.
  • isolating involves removal of solvent is carried out by suitable techniques which includes but not limited to decantation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as buchi rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray -freeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration by gravity or suction, thin film drying, centrifugation or by any other suitable techniques known in the art.
  • suitable techniques which includes but not limited to decantation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as buchi rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray -freeze drying, cooling the clear
  • drying of amorphous or solid dispersion of Evobrutinib of formula- 1 can be carried out in 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.
  • Amorphous or solid dispersion of Evobrutinib 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 may 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 starting material of Evobrutinib of formula- 1, used for the preparation of solid dispersion of Evobrutinib or amorphous Evobrutinib of present invention can be prepared from any of the processes known in the art or obtained from the present process.
  • the starting material of Evobrutinib of formula- 1, used for the preparation of solid dispersion of Evobrutinib of present invention can be used in the form of amorphous, crystalline or any other physical form with the process prepared form any of the processes known in the art.
  • pharmaceutically acceptable excipient used for the preparation of solid dispersion can be amorphous, crystalline or any other physical form.
  • solid dispersion of Evobrutinib can be amorphous, crystalline or a mixture thereof.
  • the stability of solid dispersions of Evobrutinib were determined by storing the samples at 2°C to 8°C temperature and ambient temperature. The samples were analyzed by PXRD. Solid dispersions of Evobrutinib were found to be stable at 2°C to 8°C temperature condition and ambient temperatures condition.
  • the objective of the present invention was achieved through the preparation of storage stable solid dispersions of Evobrutinib.
  • the present invention provides pharmaceutical composition comprising solid dispersion of Evobrutinib or amorphous Evobrutinib of formula- 1 and one or more pharmaceutically acceptable excipients.
  • excipient can be selected from those reported in Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems 2006.
  • composition comprising solid dispersion of Evobrutinib or amorphous Evobrutinib of formula- 1 and one or more pharmaceutically acceptable excipients is formulated in a manner suitable for the route of administration to be used.
  • pharmaceutical compositions 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 is 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.
  • Example-1 Preparation of tert-butyl 4-(((6-amino-5-chloropyrimidin-4-yl)amino) met hy 1 jpiperid ine- 1 -carboxylate
  • Example-2 Preparation of tert-butyl 4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl) amino)methyl)piperidine-l-carboxylate
  • Example-5 Preparation of solid dispersion of Evobrutinib with PVP-K30
  • Evobrutinib 250 mg
  • PVP-K30 250 mg
  • methanol 25 ml
  • Example-6 Preparation of solid dispersion of Evobrutinib with Copovidone
  • Example-7 Preparation of solid dispersion of Evobrutinib with HPMC-ES Evobrutinib (250 mg) and HPMC-ES (250 mg) were added to methanol (40 ml) at 25- 30°C. Stirred and filtered the mixture to make it particle free. Heated the mixture to 55-60°C and stirred for 5 minutes. Distilled off the mixture completely and dried to get the title compound. Yield: 380 mg.
  • Example-8 Preparation of solid dispersion of Evobrutinib with HPMC-AS
  • Example-9 Preparation of solid dispersion of Evobrutinib with eudragit
  • Example-10 Preparation of solid dispersion of Evobrutinib with syloid
  • Syloid 250 mg was added to particle free solution of Evobrutinib (250 mg) in methanol (25 ml) at 25-30°C. Heated the mixture to 55-60°C and stirred for 5 minutes. Distilled off the mixture completely and dried to get the title compound. Yield: 385 mg.
  • the P-XRD pattern of the obtained compound is illustrated in figure-6.
  • Evobrutinib (1 gm) was added to methanol (10 ml) at 25-30°C. Heated the mixture to 45-50°C and stirred for 5 minutes. Filtered the mixture to make it particle free. Distilled off the solvent completely from the mixture and dried to get the title compound.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé amélioré pour la préparation de 1-(4-(((6-amino-5-(4-phénoxyphényl)pyrimidin-4-yl)amino)méthyl)pipéridin-1-yl)prop-2-én-1-one de formule 1, et un procédé pour la préparation d'une forme amorphe de formule 1. La présente invention concerne également une dispersion solide de 1-(4-(((6-amino-5-(4-phénoxyphényl)pyrimidin-4-yl)amino)méthyl)pipéridin-1-yl)prop-2-én-1-one de formule 1. N N N H NH2 O N O
PCT/IN2023/050168 2022-02-21 2023-02-21 Procédé de préparation de 1-(4-(((6-amino-5-(4-phénoxyphényl)pyrimidin-4-yl) amino)méthyl)pipéridin-1-yl)prop-2-én-1-one WO2023157030A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN202241009108 2022-02-21
IN202241009108 2022-02-21
IN202241013239 2022-03-11
IN202241013239 2022-03-11

Publications (1)

Publication Number Publication Date
WO2023157030A1 true WO2023157030A1 (fr) 2023-08-24

Family

ID=87577712

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2023/050168 WO2023157030A1 (fr) 2022-02-21 2023-02-21 Procédé de préparation de 1-(4-(((6-amino-5-(4-phénoxyphényl)pyrimidin-4-yl) amino)méthyl)pipéridin-1-yl)prop-2-én-1-one

Country Status (1)

Country Link
WO (1) WO2023157030A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018154131A1 (fr) * 2017-02-27 2018-08-30 Merck Patent Gmbh Nouvelles formes cristallines de 1-(4-{[6-amino-5-(4-phénoxy-phényl)-pyrimidin-4-ylamino]-méthyl}-pipéridin-1-yl)-propénone

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018154131A1 (fr) * 2017-02-27 2018-08-30 Merck Patent Gmbh Nouvelles formes cristallines de 1-(4-{[6-amino-5-(4-phénoxy-phényl)-pyrimidin-4-ylamino]-méthyl}-pipéridin-1-yl)-propénone

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RICHARD D. CALDWELL ET AL.: "Discovery of Evobrutinib: An Oral, Potent, and Highly Selective, Covalent Bruton's Tyrosine Kinase (BTK) Inhibitor for the Treatment of Immunological Diseases", J. MED. CHEM., vol. 62, 1 August 2019 (2019-08-01), pages 7643 - 7655, XP055783020, DOI: 10.1021/acs.jmedchem.9b00794 *

Similar Documents

Publication Publication Date Title
JP2019521110A (ja) ベネトクラクスの固体形態およびベネトクラクスの調製のためのプロセス
US10703731B2 (en) Process for the preparation of Trisodium (4- {[1S,3R)-1-([1,1′-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-petanoyl-N-{[2′-(1H-tetrazol-1-1D-5-yl)[1,1′-biphenyl]-4-yl]methyl}- L-valinate) and its polymorphs thereof
TWI750685B (zh) 二取代吡唑化合物
US20220105033A1 (en) Stable solid dispersion of a b-raf kinase dimer inhibitor, methods of preparation, and uses therefor
US20120122915A1 (en) Crystalline forms of palonosetron hydrochloride
WO2019016828A1 (fr) Nouveaux procédés pour la préparation de chlorhydrate de trans-n-{4-[2-[4-(2,3-dichlorophényl)pipérazine-1-yl]éthyl] cyclohexyl}-n',n'-diméthyl urée et polymorphes de celui-ci
WO2019049174A1 (fr) Formes à l'état solide de chlorhydrate de 5-chloro-6-[(2-iminopyrrolidin-1-yl)méthyl]pyrimidine-2,4-(1h,3h)-dione et procédés de préparation associés
WO2023157030A1 (fr) Procédé de préparation de 1-(4-(((6-amino-5-(4-phénoxyphényl)pyrimidin-4-yl) amino)méthyl)pipéridin-1-yl)prop-2-én-1-one
US20240018152A1 (en) Novel process for the preparation of (s)-7-(1-acryloylpiperidin-4-yl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxamide or its salts thereof
WO2020141562A1 (fr) Nouvelles formes cristallines et procédé de préparation de 4-{8-amino-3-[(2s)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl)}-n-(pyridine-2-yl)benzamide
WO2023002502A1 (fr) Nouveau procédé de préparation de 1-(2-{4[(4-carbamoylpipéridin-1-yl)méthyl]- n-méthylbenzamido}éthyl)pipéridin-4-yl n-({1,1'biphényl}-2-yl)carbamate
WO2023119327A1 (fr) Procédé de préparation d'une forme amorphe pure d'ubrogepant
WO2021140525A1 (fr) Nouvelle forme cristalline de 1-(2,2-difluoro-2h-1,3-benzodioxol-5-yl)-n-{1-[(2r)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-méthylpropan-2-yl)-1h-indol-5-yl}cyclopropane-1-carboxamide et son procédé de préparation
WO2019058387A1 (fr) Procédé amélioré de préparation de (5α,6α)-17-allyl-6-(2,5,8,11,14,17,20-heptaoxadocosan-22-yloxy) -4,5-époxymorphinane-3,14-diol et de ses sels pharmaceutiquement acceptables
WO2018029699A1 (fr) Formes à l'état solide de (2e)-n-hydroxy-3-[3- (phénylsulfamoyl) phényl] prop-2-énamide et leur procédé de préparation
WO2022009235A1 (fr) Procédé de préparation de fumarate de giltéritinib
WO2021117062A1 (fr) 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
Rajan et al. Novel process for the preparation of methyl N-{(2S)-1-[(4-{3-[5-chloro-2-fluoro-3 (methanesulfonamido) phenyl]-1-(propan-2-yl)-1H-pyrazol-4-yl} pyrimidin-2-yl) amino] propan-2yl} carbamate
CN110382468B (zh) 具有聚(adp-核糖)聚合酶(parp)抑制活性的二氢吡啶并二氮杂萘酮化合物及其用途
CN101781300B (zh) 一种恩替卡韦的盐化合物，其制备方法和药物应用
WO2020225831A1 (fr) Procédé amélioré pour la préparation de 4-{8-amino-3-[(2s)-1-(but-2-ynoyl)pyrrolidin-2-yl] imidazo[1,5-a]pyrazin-1-yl)}-n-(pyridine-2-yl)benzamide
EP2162434B1 (fr) Sels de périndopril
WO2016132383A1 (fr) Procédé pour la préparation d'ibrutinib
Rajan et al. A process for the preparation of 2-[3, 5-dichloro-4-(5-isopropyl-6-oxo-1, 6-dihydropyridazin-3-yloxy) phenyl]-3, 5-dioxo-2, 3, 4, 5-tetrahydro [1, 2, 4] triazine-6-carbonitrile
WO2023175632A1 (fr) Formes à l'état solide de (5s,6s,9r)-5-amino-6-(2,3-difluorophényl)-6,7,8,9-tétrahydro-5h-cyclohepta[b]pyridin-9-yl 4-(2-oxo-2,3-dihydro-1h-imidazo[4,5-b]pyridin-1-yl)-1-pipéridinecarboxylate hémisulfate et leurs procédés de préparation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23756030

Country of ref document: EP

Kind code of ref document: A1