An improved process for the preparation of pure n-[3-[6-amino-5-[2-[methyl(prop-2-enoyl)amino] ethoxy]pyrimidin-4-yl]-5-fluoro-2-methylphenyl]-4-cyclopropyl-2-fluorobenzamide

Abstract

The present invention provides an improved process for the preparation of pure N-[3- [6-amino-5-[2-[methyl(prop-2-enoyl)amino]ethoxy]pyrimidin-4-yl]-5-fluoro-2- methylphenyl]-4-cyclopropyl-2-fluorobenzamide of formula-1. The present invention also relates to a solid dispersion of Remibrutinib and its process for the preparation.

Description

[0001] An improved process for the preparation of pure N-[3-[6-amino-5-[2-2-

[0002]

[0003] enoyl)amino1ethoxy1pyrimidin-4-yl1-5-fluoro-2-methylphenyl1-4-cvclopropyl-2- fluorobenzamide

[0004] Related Application:

[0005] This application claims the benefit of priority of our Indian patent application number 202541023225 filed on 15thMarch 2025 and 202541043047 filed on 03rdMay 2025 which are incorporated herein by reference.

[0006] Field of the Invention:

[0007] The present invention provides an improved process for the preparation of pure N-[3-[6-amino-5-[2-[methyl(prop-2-enoyl)amino]ethoxy]pyrimidin-4-yl]-5-fluoro-2-methylphenyl] -4-cyclopropyl-2-fluorobenzamide which is referred as Remibrutinib and represented by the following structural formula- 1.

[0008]

[0009] Formula- 1

[0010] Background of the Invention:

[0011] Remibrutinib acts as a Bruton's tyrosine kinase (BTK) inhibitor. It is used in the development for the treatment of chronic spontaneous urticaria. In November 2023, Novartis announced that the compound "demonstrated clinically meaningful and statistically significant reduction in urticaria activity vs placebo" in a Phase III trial.

[0012] US9512084 B2 discloses the Remibrutinib and processes for its preparation.

[0013] Journal of Medicinal Chemistry 2020, 63(10), 5102-5118 describes the synthetic process of Remibrutinib.

[0014] CN117024354 & W02024069507 describes the synthetic process of Remibrutinib.The prior art processes involve the use of acrylic anhydride or acrylic acid for the synthesis of Remibrutinib, resulting in lower yield and higher impurity levels. In contrast, the present invention utilizes highly reactive and cost-effective synthetic mechanism with an improved process using acrylolyl chloride, which provides Remibrutinib with an optimal yield and purity.

[0015] None of the prior art references disclose methods for controlling impurity content, including dimer impurity and propinoyl impurity.

[0016]

[0017] Propinoyl Impurity Dimer Impurity

[0018] Identification of impurities is a critical analytical activity in the drug development process, aimed at fully elucidating the chemical structures of unknown impurities present in drug substances or drug products above a defined threshold. In pharmaceutical products, impurities primarily pose a quality concern, as they may compromise the efficacy of the drug. Additionally, impurities raise significant safety concerns. Therefore, it is essential to identify plausible impurities to assess their toxicological implications. This knowledge is crucial for refining the synthetic chemical pathway and optimizing the formulation, ultimately ensuring a safer and more effective drug product.

[0019] In view of the above, there is a need to develop an improved process for the preparation of Remibrutinib with higher purity and substantially free from one or more impurities

[0020] Brief description of the Invention:

[0021] The present invention provides an improved process for the preparation of pure N-[3-[6-amino-5-[2-[methyl(prop-2-enoyl)amino]ethoxy]pyrimidin-4-yl]-5-fluoro-2-methylphenyl] -4-cyclopropyl-2-fluorobenzamide.Brief description of the Drawings:

[0022] Figure-1: Illustrates the PXRD pattern of solid dispersion of Remibrutinib with HPMC-K100.

[0023] Figure-2: Illustrates the PXRD pattern of solid dispersion of Remibrutinib with Eudragit Detailed description of the Invention:

[0024] As used herein the term “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, nitromethane and the like; “ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, methyl t-butyl ether, 1 ,2-dimethoxy ethane, anisole and the like; “ester solvents” such as methyl formate, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, vinyl acetate and the like; “polar-aprotic solvents such as dimethyl acetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methyl pyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, acetyl acetone, methyl isobutyl ketone and the like; “nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, polyethylene glycol, polyethylene gly col-400, 2-methoxyethanol, 1,2-ethoxyethanol, di ethylene glycol, 1, 2, or 3 -pentanol, neo pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethylether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar solvents” such as water and or mixtures thereof.

[0025] 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; andorganic 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(4.3.0)non-5-ene (DBN), lithiumdiisopropylamide (LDA), n-butyl lithium, tribenzylamine, isopropylamine, diisopropylamine, diisopropylethylamine, N-methyl morpholine, N-ethylmorpholine, piperidine, dimethylaminopyridine, morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1 -methylimidazole, 1 ,2,4-triazole, 1,4-diaza bicyclo[2.2.2]octane (DABCO) or mixtures thereof.

[0026] The “acid” as used in the present invention is selected from "inorganic acids" such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid; and "organic acids" such as formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, oxalic acid, malonic acid, maleic acid, fumaric acid, malic acid, succinic acid, citric acid, aspartic acid, tartaric acid, mandelic acid, benzoic acid, salicylic acid, substituted / unsubstituted alkyl / aryl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and the like or mixtures thereof.

[0027] The “palladium catalyst” as used in the present invention is selected from 1,1'-bis(diphenylphosphino)ferrocene] di chloro palladium (II) (Pd(dppf)C12), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), palladium(II)acetate (Pd(OAc)2), palladium(II) chloride (PdC12), bis(benzonitrile)palladium(II)dichloride (Pd(PhCN)2C12), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2C12), and allyl palladium(II) chloride dimer(PdCl(C3H5)]2).

[0028] In the present invention, the suitable "amine protecting group" or "N-protecting group" or 'PG' can be selected from but not limited to alkoxycarbonyl such methoxycarbonyl (Moc), ethoxycarbonyl, tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), p- methoxybenzyl carbonyl (Moz or MeOZ), 9-fluorenylmethyloxy carbonyl (Fmoc), acetyl (Ac), benzoyl (Bz), benzyl (Bn), carbamate group, p-methoxyphenyl (PMP), p- methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), tosyl (Ts), tnfluoroacetyl (TFA), trichloroethoxycarbonyl (Troc),pivaloyl (Piv), triphenylmethyl (trityl or Trt) and the like.

[0029] “pure” in relation to compound of formula- 1 of Remibrutinib prepared by the process of the present invention is substantially free from the impurities. The said compound of formula-1 of Remibrutinib obtained according to the present invention is substantially pure having a purity of >99%, preferably >99.5% by HPLC.

[0030] The term “about” when used in the present invention preceding a number and referring to it, is meant to designate any value which lies within the range defined by the number ±10% of its value, preferably a range defined by the number ±5%, more preferably a range defined by the number ±2%, still more preferably a range defined by the number ±1%. For example “about 10” should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.

[0031] The inventors of the present invention have developed a cost-effective and industrially feasible process for preparing Remibrutinib using acryloyl chloride. The use of acryloyl chloride is significantly more efficient in achieving optimal purity and yield compared to acrylic acid or its anhydride

[0032] Before developing the present invention, the inventors repeatedly attempted to reproduce the synthetic process of Remibrutinib described in prior art, including synthesis using acrylic acid with propylphosphonic anhydride and acrylic anhydride with sodium carbonate. However, these methods resulted in low yields with significant impurities, including dimer impurity formation of up to 30%.

[0033] Whereas, the present invention’s acryloyl-chloride based process significantly reduces dimer impurity formation and simplifies the purification process, resulting in optimal yield and purity.In the first embodiment, the present invention provides an improved process for the preparation of Remibrutinib of formula- 1, comprising of the following steps:

[0034] a) reacting N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methyl phenyl)-4-cyclopropyl-2-fluorobenzamide compound of formula-2 with acryloyl chloride in presence of a suitable base in a suitable solvent to provide Remibrutinib of formula- 1,

[0035]

[0036] Formula-2 Formula-1

[0037] b) optionally treating the obtained Remibrutinib with an acid followed by treatment with a base; and

[0038] c) optionally purifying the Remibrutinib of step a) or b) in a solvent or mixture of solvents to obtain pure Remibrutinib.

[0039] Wherein, the suitable base used in step-a) or b) is selected from organic base or inorganic base; the acid is selected from inorganic acid or organic acid; the suitable solvent used in step-a) and step-c) is selected from alcohol solvent, ester solvent, chloro solvent, ether solvent, ketone solvent, nitrile solvent, polar-aprotic solvent, water or mixtures thereof.

[0040] The starting material of compound of formula-2 used in the present invention, can be prepared by the present invention or any of the processes known in the art.

[0041] In the second embodiment, the present invention provides an improved process for the preparation of Remibrutinib of formula- 1, comprising of the following steps:

[0042] a) suspending or dissolving the N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4- yl)-5-fluoro-2-methyl phenyl)-4-cyclopropyl-2-fluorobenzamide of formula-2 and a suitable base in a suitable solvent or mixture of solvents,

[0043] b) adding ‘pure acryloyl chloride’ to the mixture obtained in step a),c) isolating the Remibrutinib of formula- 1 into a suitable solvent or mixture of solvents, d) treating the mixture obtained in step c) with suitable acid,

[0044] e) treating the mixture obtained in step d) with suitable base to provide Remibrutinib of formula- 1,

[0045] f) optionally purifying the Remibrutinib of formula- 1 in a suitable solvent to provide pure Remibrutinib.

[0046] Wherein, the suitable base used in step-a) and e) is selected from organic base or inorganic base; the suitable acid used in step-d) is selected from organic acid or inorganic acid; the suitable solvent used in step-a), step-c) and step-f) is selected from alcohol solvent, ester solvent, chloro solvent, ether solvent, ketone solvent, nitrile solvent, polar-aprotic solvent, water or mixtures thereof.

[0047] As used herein, 'pure acryloyl chloride' refers to acryloyl chloride having a purity greater than about 99.5% by weight and / or containing one or more impurities selected from acetic acid or acetyl chloride, propanoic acid or propionyl chloride in amounts less than about 0.5% or less than about 0.1% or less than about 0.05% as measured by the High-Performance Liquid Chromatography (HPLC) method."

[0048] In the third embodiment, the present invention provides a process for the purification of Remibrutinib of formula- 1, comprising of the following steps:

[0049] a) providing a solution of Remibrutinib of formula- 1 in a suitable solvent or mixture of solvents,

[0050] b) treating the mixture obtained in step a) with charcoal and / or silica,

[0051] c) filtering or isolating the solution obtained in step b),

[0052] d) concentrating the filtrate obtained in step c), to provide Remibrutinib,

[0053] e) treating the Remibrutinib with a suitable solvent or mixture of solvents,

[0054] f) isolating pure Remibrutinib of formula- 1.

[0055] wherein, the suitable solvent used in step-a) and step-e) is selected from alcohol solvent, ester solvent, chloro solvent, ether solvent, ketone solvent, nitrile solvent, polar-aprotic solvent, water or mixtures thereof.In the fourth embodiment, the present invention provides an improved process for the preparation of Remibrutinib of formula- 1, comprising one or more of the following steps: a) reacting a compound of formula-6 with a compound of formula-5 in the presence of a palladium catalyst and a base to obtain a compound of formula-4,

[0056]

[0057] Formula-4

[0058] b) reacting the compound of formula-4 with a compound of formula-7 in the presence of a base to obtain a compound of formula-3,

[0059]

[0060] c) deprotecting the compound of formula-3 with an acid in a solvent to obtain a compound of formula-2,

[0061]

[0062] d) reacting the compound of formula-2 with acryloyl chloride to obtain Remibrutinib of formula- 1,

[0063]

[0064] e) optionally purifying the Remibrutinib in a solvent to obtain pure Remibrutinib.

[0065] Wherein ‘PG’ is H or N-protecting group; X is F, Cl, Br or I

[0066] In an aspect of the fourth embodiment, wherein ‘PG’ is H, then step c) is not required.

[0067] In the fifth embodiment, the present invention provides a pure Remibrutinib of formula- 1 having a purity greater than about 99.0% as measured by HPLC. Which is substantially free from one or more impurities selected from ‘propinoyl impurity’, ‘dimer impurity’, ‘acetyl impurity’ and ‘chloro impurity’ as measured by HPLC (High performance liquid chromatography) method.

[0068]

[0069] Acetyl Impurity Chloro ImpurityAs used herein, 'substantially free' refers to pure Remibrutinib containing one or more impurities selected from 'propinoyl impurity,' 'dimer impurity,' 'acetyl impurity,' and 'chloro impurity,' in amounts less than about 1.0% or less than about 0.5% or less than about 0.1% or less than about 0.05% as measured by the High-Performance Liquid Chromatography (HPLC) method.

[0070] The first aspect of the fifth embodiment provides a pure Remibrutinib of formula- 1 having a purity greater than about 99.0% by weight. Which is substantially free from ‘propinoyl impurity’ less than about 1.0% or less than about 0.5% or less than about 0.1% or less than about 0.05% as measured by HPLC (High performance liquid chromatography) method.

[0071] The second aspect of the fifth embodiment provides a pure Remibrutinib of formula- 1 having a purity greater than about 99.0% by weight. Which is substantially free from ‘dimer impurity’ less than about 1.0% or less than about 0.5% or less than about 0.1% or less than about 0.05% as measured by HPLC (High performance liquid chromatography) method.

[0072] The third aspect of the fifth embodiment provides a pure Remibrutinib of formula- 1 having a purity greater than about 99.0% by weight. Which is substantially free from ‘acetyl impurity’ less than about 1.0% or less than about 0.5% or less than about 0.1% or less than about 0.05% as measured by HPLC (High performance liquid chromatography) method.

[0073] The fourth aspect of the fifth embodiment provides a pure Remibrutinib of formula- 1 having a purity greater than about 99.0% by weight. Which is substantially free from ‘chloro impurity’ less than about 1.0% or less than about 0.5% or less than about 0.1% or less than about 0.05% as measured by HPLC (High performance liquid chromatography) method.

[0074] The fifth aspect of the fifth embodiment provides a pure Remibrutinib of formula- 1 or a pharmaceutically acceptable acid salt thereof, having a purity greater than about 99.5%. Which is substantially free from acetyl impurity and / or chloro impurity present in an amount lower than about 0.2% or lower than about 0.15% or lower than about 0.1 % or lower than about 0.05% as measured by High-Performance Liquid Chromatography (HPLC).In an embodiment, the present invention provides a pure Remibrutinib of formula- 1 or a pharmaceutically acceptable acid salt thereof, having one or more impurities of acetyl impurity and chloro impurity present in an amount lower than about 0.2% or lower than about 0.15% or lower than about 0.1% or lower than about 0.05% as measured by High-Performance Liquid Chromatography (HPLC).

[0075] In an embodiment, the present invention provides a pharmaceutical composition comprising Remibrutinib having one or more impurities selected from acetyl impurity and chloro impurity in an amount of less than about 0.5%, less than about 0.3%, less than about 0.1%, or less than about 0.05%, as measured by HPLC.

[0076] In the sixth embodiment, the present invention provides acetyl impurity and chloro impurity represented by the following structural formulae.

[0077]

[0078] Acetyl Impurity Chloro Impurity

[0079] In the seventh embodiment, the present invention provides novel compounds represented by the following structural formula.

[0080]

[0081] Formula-4

[0082] Wherein ‘PG’ is H or N-protecting group;

[0083] In an embodiment, the present invention provides Remibrutinib having a purity of greater than about 99.5%, preferably greater than about 99.7%, more preferably greater thanabout 99.8% as measured by HPLC.

[0084] In the eighth embodiment, the present invention provides a solid dispersion comprising Remibrutinib and one or more pharmaceutically acceptable excipients.

[0085] In the eighth embodiment, the suitable pharmaceutically acceptable excipient is selected from but not limited to syloid, eudragit, 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, crospolyvinylpolypyrrolidone, 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, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropylmethyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose K100 (HPMC-K100), hydroxypropyl methylcellulose-E5 (EUDRAGIT), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropylcellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropylmethylcellulose acetate phthalate, microcrystalline cellulose (MCC), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, magnesium stearate, aluminium stearate, calcium stearate, magnesium carbonate, talc, iron oxide (red, yellow, black), stearic acid, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches such as maize starch or corn starch, sodium starch glycolate, sodium carboxymethyl starch, pregelatinized starch, gelatin, sodium dodecyl sulfate, edetate disodium, sodium phosphate, sodium lauryl sulfate, triacetin, sucralose, calcium phosphate, polydextrose, a-, P-, y-cyclodex trins, sulfobutylether beta-cyclodextrin, sodium stearyl fumarate, fumaric acid, alginic acid, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, docusate sodium, glyceryl behenate, glyceryl stearate, meglumine, arginine, polyethylene oxide, polyvinyl acetatephthalates and the like.

[0086] In the ninth embodiment, the present invention provides a process for the preparation of solid dispersion of Remibrutinib with one or more pharmaceutically acceptable excipients, which comprises:

[0087] a) providing a solution comprising Remibrutinib and at least one pharmaceutically acceptable excipient; and

[0088] b) isolating the solid dispersion of Remibrutinib.

[0089] In the process of the ninth embodiment, providing a solution in step-a) comprises dissolving Remibrutinib and / or ‘at least one pharmaceutically acceptable excipient’ in a suitable solvent at a suitable temperature of about 25°C and above. Optionally, the solution can be filtered to make it particle free.

[0090] In the process of the ninth embodiment, further ‘adding Remibrutinib to the obtained solution of excipient’ or ‘adding excipient to the obtained solution of Remibrutinib’ ata suitable temperature of about 25°C and above.

[0091] In the process of ninth embodiment, the suitable solvent used in step-a) is selected from alcohol solvents.

[0092] In the process of ninth embodiment, the suitable pharmaceutically acceptable excipient used in step-a) is same as defined in the eighth embodiment.

[0093] In the first aspect of the ninth embodiment, the present invention provides a process for the preparation of solid dispersion of Remibrutinib with HPMC-klOO, which comprises:

[0094] a) providing a solution comprising Remibrutinib and HPMC-klOO; and

[0095] b) isolating the solid dispersion of Remibrutinib with HPMC-klOO.

[0096] In the process of the first aspect of ninth embodiment, providing a solution in step-a) comprises dissolving Remibrutinib or HPMC-klOO in an alcohol solvent at a suitable temperature of about 25 °C and above. Optionally, the solution can be filtered to make it particle free.In the process of the first aspect of ninth embodiment, further ‘adding Remibrutinib to the obtained solution of HPMC-klOO’ or ‘adding HPMC-klOO to the obtained solution of Remibrutinib’ at a suitable temperature of about 25°C and above.

[0097] In the second aspect of the ninth embodiment, the present invention provides a process for the preparation of solid dispersion of Remibrutinib with Eudragit, which comprises:

[0098] a) providing a solution comprising Remibrutinib and Eudragit and

[0099] b) isolating the solid dispersion of Remibrutinib with Eudragit.

[0100] In the process of the ninth embodiment, providing a solution of Remibrutinib or Eudragit in step-a) comprises dissolving Remibrutinib or Eudragit in an alcohol solvent at a suitable temperature of about 25 °C and above. Optionally, the solution can be filtered to make it particle free.

[0101] In the process of the second aspect of the ninth embodiment, further ‘adding Eudragit to the obtained solution of Remibrutinib’ or ‘adding Remibrutinib to the obtained solution of Eudragit’ at a suitable temperature of about 25°C and above.

[0102] In an embodiment, wherein the weight ratio of solid dispersion of Remibrutinib to the excipient ranges from about 1:0.05 to about 1:5. Preferably, the ratio is about 1:1.

[0103] In the present invention, the starting material of Remibrutinib to prepare a solid dispersion, can be used in the form of amorphous or crystalline or any other physical form with the process prepared from the present invention or any of the processes known in the art.

[0104] In the present invention, pharmaceutically acceptable excipient used for the preparation of solid dispersion can be amorphous, crystalline or any other physical form.

[0105] In the process of the present invention the resulting, solid dispersion of Remibrutinib can be amorphous, crystalline or a mixture thereof.

[0106] In an embodiment, pharmaceutical composition comprising solid dispersion ofRemibrutinib and one or more pharmaceutically acceptable excipient is formulated in a manner suitable for the route of administration to be used.

[0107] As used herein, the term "pharmaceutical compositions" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

[0108] The excipients can be selected from Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems 2006.

[0109] In the process of present invention, isolation or isolating involves the removal of solvent, which is carried out using 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, isolation by column chromatographic purification, drying, filtration, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration of the reaction mixture or by any other suitable techniques known in the art.

[0110] In the process of the present invention, Remibrutinib or its solid dispersions.can be dried in 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 pressure at temperature of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperature. The drying can be carried out for any time required for obtaining a desired quality such as from about 15 minutes to about 10 hours or longer.

[0111] Remibrutinib or its solid dispersions 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 may be performed before drying, or after the completion of drying of the product.P-XRD Method of Analysis:

[0112] PXRD analysis of compound of formula- 1 was carried out by using BRUKER Bench Top D2-phaser (D2-210150) diffractometer using Cu Ka radiation of wavelength 1.5406 A° and Generator kV is 30.0 kV; Generator mA is 10.0 mA; Detector Name SSD16O(1D mode).

[0113] (OR)

[0114] The PXRD analysis of compound of formula- 1 of the present invention was carried out by using BRUKER / D8 ADVANCE diffractometer or BRUKER / D8 ADVANCE DAVINCI diffractometer using CuKa radiation of wavelength 1.5406A0.

[0115] The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

[0116] Examples:

[0117] Reference Example-1: Preparation of Remibrutinib using the process described in W02024069507A1.

[0118] Sodium carbonate (140 mg / 1.2 equivalents) was added to the mixture of N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (500 mg) in ethyl-acetate (10 ml). The suspension was heated to 50°C. A solution of acrylic anhydride (146 mg / 1.05 equivalents) in ethyl-acetate was slowly added to the mixture at 50°C. Stirred the mixture for 30 minutes at 50°C.

[0119] No significant reaction progress was observed.

[0120] Extending the reaction under similar conditions led to a substantial formation of dimer impurity along with other impurities and Remibrutinib.

[0121] Example-1: Preparation of Remibrutinib

[0122] Sodium bicarbonate (3.7 g) was added to the mixture of N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (10 g) in tetrahydrofuran (300 ml) and water (50 ml) at 25-30°C. Cooled the mixture to -5 to 0°C and acryloyl chloride in tetrahydrofuran (2 g in 100 ml) was slowly addedto the mixture and stirred for 2 hours at the same temperature. Water (50 ml) and isopropyl acetate (200 ml) were added to the mixture at 0-5°C. Heated the mixture to 25-30°C and stirred for 15 minutes. Separated the organic layer from the mixture. Treated the organic layer with 0.05M Sulfuric acid (100 ml) at 25-30°C. Organic layer treated with sodium chloride solution and sodium bicarbonate solution at 25-30°C. Distilled-off the organic layer to obtain titled product. Yield: 10.51 g

[0123] Example-2: Purification of Remibrutinib

[0124] 10% methanol in dichloromethane (100 ml) was added to the product obtained in example- 1. Silica (2 g) and activated carbon (1 g) were added to the mixture at 25-30°C. Heated the mixture to 40-45 °C and stirred for one hour. Filtered the mixture through hy-flow bed at 40-45°. Distilled-off the filtrate. Co-distilled the mixture in ethanol. Ethanol (100 ml) was added to the mixture. Heated the mixture to 75-80°C and stirred for 60 minutes. Cooled the mixture to 25-30°C and stirred for 3 hours. Filtered the mixture and dried to get titled product.

[0125] Yield 7.2 g; HPLC Purity: 99.34%,

[0126] Dimer impurity: 0.03%; Acetyl impurity: 0.09%; Propinoyl impurity: 0.07%; Chloro impurity: 0.19%.

[0127] Example-3: Preparation of solid dispersion of Remibrutinib with HPMC-K100

[0128] HPMC-K100 (1 g) was added to the mixture of Remibrutinib (1 g) in Methanol (40 ml) at 25-30°C. Heated the mixture to 60-65°C and stirred for 30 minutes. Cooled the mixture to 25-30°C and stirred for 30 minutes. Distilled off the solvent completely from the mixture to get titled compound.

[0129] Yield: 2 g

[0130] The PXRD pattern of the obtained compound is illustrated in figure- 1.

[0131] Example-4: Preparation of solid dispersion of Remibrutinib with Eudragit Eudragit (1 g) was added to the mixture of Remibrutinib (1 g) and Methanol (40 ml) at 25-30°C. Heated the mixture to 60-65°C and stirred for 30 minutes. Cooled the mixture to 25-30°C and stirred for 30 minutes. Filter the mixture through filter paper. Distilled-off the solvent completely from the filtrate to get titled compound.Yield: 2 g

[0132] The PXRD pattern of the obtained compound is illustrated in figure-2.

[0133] Example-5: Process for the preparation of tert-butyl (2-((4-amino-6-(3-amino-5-fluoro-2-methylphenyl) pyrimidin-5-yl)oxy)ethyl)(methyl)carbamate

[0134] aq. Sodium bicarbonate solution (105 g) was added to the mixture of 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)aniline (99.52 g) and tert-butyl (2-((4-amino-6-chloropyrimidin-5-yl)oxy)ethyl)(methyl)carbamate (100 g) in 1,2-dimethoxyetane (2 L) at 25-30°C. To the mixture bis(triphenylphosphine)palladium (Il)dichloride (23.18 g) was added at 25-30°C. Heated the mixture to 85-90°C and stirred for 11 hours. Mixture allowed to cool to 25-30°C. Treated the mixture with aq. sodium bicarbonate solution. Ethyl acetate (1 L) was added to the mixture at 25-30°. Separated the organic layer form the mixture. Organic layer treated with aq. Sodium chloride solution, activated carbon and silica gel. Distilled -off the mixture. Ethyl acetate (500 ml) and n-Hexane (I L) were added to the mixture at 25-30°C and stirred for 18 h. Filtered the mixture and dried to obtain title compound. Yield: 102 g.

[0135] Example-6: Process for the preparation of tert-butyl (2-((4-amino-6-(3-(4-cyclopropyl-2-fluorobenzamido)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)oxy)ethyl)(methyl) carbamate

[0136] Pure acid chloride of 4-cyclopropyl-2-fluorobenzoyl chloride (53.6 g) in isopropyl acetate (225 ml) was added to the pre-cooled mixture of tert-butyl (2-((4-amino-6-(3-amino-5-fluoro-2-methylphenyl) pyrimidin-5-yl)oxy)ethyl)(methyl)carbamate (98 g), N,N-diisopropylethylamine (38.73 g) in isopropyl acetate (135 ml) at 0-5°C and stirred for 2 hours. Filtered the mixture. Water was added to the obtained solid at 25-30°C and stirred for 45 minutes. Filtered the mixture. Isopropyl acetate was added to the obtained solid at 25-30°C. Heated the mixture to 60-65°C and stirred for 2 hours. Cooled the mixture to 25-30°C and stirred for 4 hours. Filtered the solid and dried to obtain title compound. Yield: 105 g

[0137] Example-7: Process for the preparation of N-(3-(6-amino-5-(2-(methylamino)ethoxy) pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide.

[0138] Trifluoroacetic acid (138 ml) was added to the mixture of tert-butyl(2-((4-amino-6-(3-(4-cyclopropyl-2-fluorobenzamido)-5-fluoro-2-methylphenyl)pyrimidin-5-yl)oxy)ethyl) (methyl) carbamate (100 g) in dichloromethane (1 L) at 25-30°C and stirred the mixture for 12 hours. Distilled - off the mixture to obtain residue. Methyl tert-butyl ether (300 mL) and 2N aq. HC1 (1750 mL) were added to the residue at 25-30°C and stirred for 10 minutes. Distilled-off the organic layer from the biphasic system. The obtained aqueous layer washed with Methyl tert-butyl ether and ethylacetate separately. Adjusted the aqueous layer pH to 9.0-10.0 by using aq. NaOH solution. Filtered the precipitated solid, methanol (I L) was added to the filtered solid and heated the mixture to 60-65 °C and stirred for 1 hour. Allowed to cool the mixture to 25-30°C and stirred for 1 hour. Filtered the precipitated solid and dried to get titled product. Yield: 67.5 g; HPLC Purity: 99.83%.

[0139] Example-8: Process for the preparation of Remibrutinib

[0140] Aq. Sodium bicarbonate solution (24 g) was added to the mixture of N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide (65 g) in tetrahydrofuran (1950 ml) at 25-30°. Cooled the mixture to 0-5°C. Pure acryloyl chloride (15.56 g) in tetrahydrofuran (650 ml) was slowly added to the mixture at 0-5°C and stirred the mixture for 2 hours, isopropyl acetate (1350 ml) and water (325 mL) were added to the mixture. Separated the organic layer from the mixture. 1,8-Diazabicycloundec-7-ene (43.6 g) was added to the organic layer at 25-30°C and stirred the mixture for 2 hours. Treated the mixture with 0.05 M sulfuric acid and aq. sodium bicarbonate solution. Further treated the mixture with sodium chloride solution at 25-30°. Separated the organic layer and distilled-off the same. 1,4-di oxane (520 ml) was added to the obtained mixture at 25-30°C. Heated the mixture to 75-80 °C and stirred for 30 minutes. Allowed to cool the mixture to 25-30°C and stirred for 5 hours. Filtered the obtained solid and dried to get titled product. Yield 49.5g

[0141] HPLC Purity: 99.43%, Dimer impurity: 0.03%; Acetyl impurity: 0.07%; Chloro impurity: 0.20%.

[0142] Example-9: Process for the purification of Remibrutinib

[0143] Silica gel (4.0 g) and charcoal (2.0g) were added to the mixture of Remibrutinib (20.0 g) in methanol and Dichloromethane at 1:9 ratios (600 ml) at 25-30°C and stirred the mixturefor 1 hour. Filtered the mixture and distilled - off the filtrate. 1,4-dioxane (160 mL) was added to the obtained solid and heated the mixture to 80-85°C and stirred for 1 hour. Cooled the mixture to 35-40°C and stirred for 4 hours. Filtered the mixture and dried to get titled compound Yield: 18 g

[0144] HPLC Purity: 99.86%, Acetyl impurity: 0.03%; Propinoyl impurity: 0.02%.

Claims

We Claim:

1. A process for the preparation of Remibrutinib of formula- 1, comprising;a) reacting N-(3-(6-amino-5-(2-(methylamino)ethoxy)pyrimidin-4-yl)-5-fluoro-2- methylphenyl)-4-cyclopropyl-2-fluorobenzamide of formula-2 with acryloyl chloride in the presence of a base and a solvent to obtain Remibrutinib;Formula-2 Formula-1b) optionally treating the obtained Remibrutinib with an acid followed by treatment with a base; andc) optionally purifying the Remibrutinib of step a) or b) in a solvent or mixture of solvents to obtain pure Remibrutinib.

2. The process according to claim 1, wherein the acryloyl chloride is in a pure form having a purity greater than about 99.5% by weight and / or contains one or more impurities selected from acetyl chloride and propionyl chloride in an amount of less than about 0.5%, less than about 0.1%, or less than about 0.05%, as measured by Gas Chromatography.

3. A process for the purification of Remibrutinib of formula- 1 comprises;a) providing a solution of Remibrutinib in a solvent or a mixture of solvents; b) treating the solution obtained in step a) with a charcoal and / or silica;c) filtering the solution obtained in step b) to obtain a filtrate;d) concentrating the filtrate to obtain Remibrutinib;e) treating the obtained Remibrutinib with a solvent or a mixture of solvents; and f) isolating pure Remibrutinib.

4. The process according to claim 1, wherein the acid is selected from inorganic acid or organic acid; the base is selected from an organic base or an inorganic base.

5. The process according to claim 1 or 3, wherein the solvent is selected from an alcohol solvent, an ester solvent, a chlorinated solvent, an ether solvent, a ketone solvent, a nitrile solvent, a polar aprotic solvent, water, or mixtures thereof.

6. A process for the preparation of Remibrutinib of formula- 1 comprising:a) reacting a compound of formula-6 with a compound of formula-5 in the presence of a palladium catalyst and a base to obtain a compound of formula-4,Formula-4b) reacting the compound of formula-4 with a compound of formula-7 in the presencec) deprotecting the compound of formula-3 with an acid in a solvent to obtain a compound of formula-2,d) reacting the compound of formula-2 with acryloyl chloride to obtain Remibrutinib of formula- 1,e) optionally purifying the Remibrutinib in a solvent to obtain pure Remibrutinib.

7. The process according to claim 6, wherein PG represents H or an N-protecting group and X represents F, Cl, Br, or I.

8. A compounds represented by the following structural formulae.Acetyl Impurity Chloro Impurity9. A compound represented by the following general formula.Formula-4Wherein ‘PG’ is H or an N-protecting group.

10. A Pure Remibrutinib or a pharmaceutically acceptable acid salt thereof, having one or more impurities selected from acetyl impurity and chloro impurity present in an amount lower than about 0.2% or lower than about 0.15% or lower than about 0.1% or lower than about 0.05% as measured by High-Performance Liquid Chromatography (HPLC).

11. The Remibrutinib or pharmaceutically acceptable acid salt thereof according to claim 10, having a purity greater than about 99.5% or greater than about 99.7% or greater than about 99.9% as measured by HPLC.

12. A pharmaceutical composition comprising Remibrutinib having one or more impurities selected from acetyl impurity and chloro impurity in an amount of less than about 0.5%, less than about 0.3%, less than about 0.1%, or less than about 0.05%, as measured by HPLC.

13. A solid dispersion comprising Remibrutinib and one or more pharmaceutically acceptable excipients.

14. A process for the preparation of a solid dispersion of Remibrutinib comprising:a) providing a solution or suspension of Remibrutinib and one or more pharmaceutically acceptable excipients in a solvent or a mixture of solvents; and b) isolating the solid dispersion comprising Remibrutinib and the excipient.

15. The solid dispersion according to claim 13 or 14, wherein the pharmaceutically acceptable excipient is selected from syloid, eudragit, polyvinylpyrrolidone (povidone or PVP; PVP of different grades like K-15, K-30, K-60, K-90 and K-120 may be used), copovidone, crospolyvinylpolypyrrolidone, 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), hydroxymethylcellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropylmethyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose K-100, hydroxypropyl methylcellulose-E5 (HPMC-E5), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropylcellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropylmethylcellulose acetate phthalate, microcrystalline cellulose (MCC), cross linked sodium carboxymethyl cellulose (croscarmellose sodium), cross linked calcium carboxymethyl cellulose, dextrates, dextrin, dextrose, sucrose, glucose, xylitol, lactitol, sorbitol, mannitol, maltitol, maltose, raffinose, fructose, maltodextrin, anhydrous lactose, lactose monohydrate, starches suchas maize starch or com starch, sodium starch glycolate, sodium carboxymethyl starch, pregelatinized starch, sodium alginate, propylene glycol alginate, citric acid, succinic acid, carbomer, meglumine, arginine, polyethylene oxide, polyvinyl acetate phthalates.

16. The solid dispersion according to claim 13 or 14, wherein the pharmaceutically acceptable excipient is ‘hydroxypropyl methylcellulose K-100’ or eudragit.

17. The solid dispersion according to claim 13 or 14, wherein the weight ratio of Remibrutinib to the excipient ranges from about 1:0.05 to about 1:5.

18. The process according to claim 14, wherein step (a) is carried out at a temperature ranging from about 25 °C to the reflux temperature of the solvent.

19. A process for the preparation of a solid dispersion of Remibrutinib with hydroxypropyl methylcellulose K-100 comprising:a) providing a solution or suspension of Remibrutinib and hydroxypropyl methylcellulose K-100 in an alcohol solvent; andb) isolating the solid dispersion.

20. A process for the preparation of a solid dispersion of Remibrutinib with Eudragit comprising;a) providing a solution or suspension of Remibrutinib and Eudragit in an alcohol solvent; andb) isolating the solid dispersion.

21. The process according to any one of the preceding claims, wherein the isolation technique is selected from decantation, evaporation under reduced pressure, flash evaporation, vacuum drying, atmospheric distillation, distillation under reduced pressure, rotary evaporation, agitated thin-film drying, melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, filtration or combinations thereof.

22. A pharmaceutical composition comprising a solid dispersion of Remibrutinib and at least one pharmaceutically acceptable excipient.

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