SAJJA ESWARAIAH (IN)
MATHAD VIJAYAVITTHAL T (IN)
ISMAIL (IN)
SUBUDDHI PRAVEEN (IN)
SALADI VENKATA NARASAYYA (IN)
KAMMARI BAL RAJU (IN)
SRINIVASAN THIRUMALAI RAJAN (IN)
| WO2018154131A1 | 2018-08-30 |
| We Claim: 1. A solid dispersion of Evobrutinib and one or more pharmaceutically acceptable excipients. Formula- 1 2. The solid dispersion as claimed in claim 1 is storage stable at 2°C to 8°C temperature condition. 3. A process for the preparation of amorphous 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. 4. The process as claimed in claim 3 wherein, providing a solution of Evobrutinib in methanol is carried out by heating the solution to a temperature ranging from 35-55°C. 5. A process for the preparation of solid dispersion of Evobrutinib with one or more pharmaceutically acceptable excipients, which comprises: a) providing a solution of Evobrutinib of formula- 1 and at least one pharmaceutically acceptable excipient in a solvent selected from methanol, dichloromethane or mixture thereof, b) isolating the solid dispersion of Evobrutinib with one or more pharmaceutically acceptable excipients. 6. The solid dispersion as claimed in claim 1 and 5 wherein, the pharmaceutically acceptable excipient is selected from but not limited to polyvinylpyrrolidone (povidone or PVP), polyvinylpolypyrrolidone, PVP-K30, polysorbate, cross linked polyvinyl pyrrolidone (crospovidone), polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose-ES (HPMC-ES), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), syloid, eudragit, copovidone. A process for the preparation of solid dispersion of Evobrutinib with one or more pharmaceutically acceptable excipients, which comprises: a) providing a solution of Evobrutinib of formula- 1 and at least one pharmaceutically acceptable excipient in methanol, b) isolating the solid dispersion of Evobrutinib with one or more pharmaceutically acceptable excipients. The solid dispersion as claimed in claim 7 wherein, the pharmaceutically acceptable excipient is selected from syloid, eudragit, copovidone, PVP K-30, hydroxypropyl methylcellulose-ES (HPMC-ES). A process for the preparation of solid dispersion of Evobrutinib of formula- 1 in combination with hydroxypropyl methylcellulose acetate succinate (HPMC-AS), which comprises: a) providing a solution of Evobrutinib of formula- 1 with hydroxypropyl methylcellulose acetate succinate (HPMC-AS) in methanol and dichloromethane solvent mixture, b) isolating the solid dispersion of Evobrutinib with hydroxypropyl methylcellulose acetate succinate (HPMC-AS). The process as claimed in any of preceding claims 5 to 9 wherein, providing a solution of Evobrutinib in step a) is carried out by dissolving Evobrutinib and an excipient in a solvent. The process as claimed in claim 3 to 9 wherein, providing a solution of Evobrutinib is carried out optionally by heating the mixture to temperature ranging from about 25 °C to the reflux temperature of the solvent. An improved process for the preparation of pure Evobrutinib of formula- 1, which comprises: a) reacting the compound of general formula-2 with compound of general formula-3 in presence of nitrogen bicyclic base in a solvent to provide compound of general formula- Formula - 2 Formula - 4 b) reacting the compound of general formula-4 with compound of formula-5 in presence of a palladium catalyst, phosphine ligand and a base in a solvent to provide compound of general formula- 6, c) deprotecting the compound of general formula-6 with an acid in a solvent to provide compound of formula-7 or its salt, d) reacting the compound of formula-7 with a compound of general formula- 8 in presence of a base in a solvent to provide Evobrutinib of formula- 1, e) optionally purifying the compound of formula- 1 in a solvent to provide pure Evobrutinib. wherein, ‘PG’ is H or N-protecting group; X is F, Cl, Br or I The process as claimed in claim 12 wherein, 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); the palladium catalyst used in step-b) is selected from l,l'-bis(diphenylphosphino) ferrocene] dichloropalladium (II) (Pd(dppf)Ch), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), palladium(II)acetate (Pd(OAc)2), palladium(II)chloride (PdCh), bis(benzo nitrile)palladium(II)dichloride (Pd(PhCN)2C12), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Ch), and allyl palladium(II) chloride dimer (PdCl(C3Hs)]2); the acid used in step-c) is organic acid or inorganic acid; the base used in step-b) and step-d) is selected from organic base or inorganic base; the 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 process as claimed claim 12 wherein, 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. An improved process for the preparation of pure Evobrutinib of formula- 1, which comprises: a) reacting the tert-butyl-4-(((6-amino-5-chloropyrimidin-4-yl)amino)methyl)piperidine- 1 -carboxylate of formula-4a with 4-phenoxyphenyl)boronic acid in presence of palladium (Il)acetate and 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl to provide tert-butyl-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidine- 1 -carboxylate of formula-6a, b) converting the compound of formula-6a to Evobrutinib of forumula-1. An improved process for the preparation of Evobrutinib of formula- 1 with high yields and purity, which comprises: a) deprotecting the compound of formula-6a into 5-(4-phenoxyphenyl)-N4-(piperidin-4- ylmethyl)pyrimidine-4,6-diamine of formula-7 by using a hydrochloric acid in ester solvent. b) converting the compound of formula-7 to Evobrutinib of forumula- 1. The process as claimed in claim 16 wherein, the ester solvent is selected from methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate. The pharmaceutical composition comprising Evobrutinib obtained according to any of preceding claims and a pharmaceutically acceptable carrier. |
Related Application:
This application claims the benefit of priority of our Indian patent applications number 202241009108 filed on 21 st February 2022 and 202241013239 filed on 11 th March 2022 which are incorporated herein by reference.
Field of the invention:
The present invention relates to an improved process for the preparation of l-(4-(((6- amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperid in-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
Background of the invention:
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.
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)meth yl) piperidin-l-yl)prop-2-en-l-one and pharmaceutically acceptable salts, solvates and pharmaceutical compositions thereof.
U.S. Patent No. 9073947 and ‘Journal of Medicinal Chemistry 2019, 62(17), 7643- 7655’ discloses process for the preparation of Evobrutinib which involves column purifications and lyophilisation methods to provide Evobrutinib with low yield, which is not viable at large scale production.
In order to overcome the aforementioned problems, 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.
Brief description of the invention:
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.
Brief description of the Drawings:
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.
Detailed description of the Invention:
As used herein the term 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, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N- methylpyrrolidone (NMP) and the like; “chloro solvents” such as dichloromethane, di chloroethane, chloroform, carbon tetrachloride and the like; “ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutylketone 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, 2 -methoxyethanol, 1,2-ethoxy ethanol, diethylene glycol, 1,2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol, monoethyl ether, cyclohexanol, benzyl alcohol or glycerol and the like; “polar solvents” such as water or mixtures thereof.
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(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.
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.
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), 2-(trimethylsilyl)ethoxycarbonyl (Teoc), 2-(4-6-trifluoromethylphenylsulfonyl)ethoxy carbonyl (Tsc), t-butoxycarbonyl (BOC), 1-adamantyloxycarbonyl (Adoc), 2-adamantyl carbonyl (2-Adoc), 2,4-dimethylpent-3-yloxycarbonyl (Doc), cyclohexyloxycarbonyl (Hoc), l,l-dimethyl-2,2,2-trichloroethoxy carbonyl (TcBOC), vinyl, 2-chloroethyl, 2-phenylsulfonyl ethyl, allyl, benzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenyl-4-pyridylmethyl, N',N'-dimethyl hydrazinyl, methoxymethyl, t-butoxymethyl (Bum), benzyloxymethyl (BOM), or 2-tetra hydropyranyl (THP), l-(ethoxy)ethyl,pmethoxybenzyl, triphenylmethyl, diphenylmethyl, hydroxyl methyl, methoxymethyl, and t-butyldimethylsilylmethyl, N-pivaloyloxymethyl (POM), 1,1 -diethoxymethyl, tri(Cl-4-alkyl)silyl, p-methoxybenzylcarbonyl (Moz or MeOZ) group, 9-fluorenylmethyloxycarbonyl (FMOC) group, acetyl (Ac) group, methanesulfonyl (Ms) group, benzoyl (Bz) group, Benzyl (Bn) group, p-methoxybenzyl (PMB), 3,4- dimethoxybenzyl.
The term“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 s(dii sopropylphosphino) ethane, l,2-bis(dibutylphosphino)ethane, l,2-bis(dicyclohexylphosphino)ethane, 1,3-bis
(dicyclohexylphosphino)propane, l,3-bis(diiso-propylphosphino)propane, l,4-bis(diisopropyl phosphino)-butane, 2,4-bis(dicyclohexylphosphino)pentane, 2-Dicyclohexylphosphino-2,6 ' -dimethoxybiphenyl (S Phos), and 2-dicyclohexylphosphino-2', 4',6'-triisopropylbiphenyl (XPhos) and like.
As used herein, the term “solid dispersion” refers to dispersion of drug in a solid matrix where the matrix is either a small molecule or polymer. Preferably 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. In other words, in a solid dispersion, the two or more components (polymer and API) form a homogeneous one-phase system, where the particle size of the API in the solid dispersion is reduced to its molecular size.
As used herein, the term “excipient” refers to play a significant role in stabilizing solid dispersions, maximizing bioavailability, and overcoming absorption issues associated with poorly soluble drugs.
In the present application, solid dispersion and premix are used interchangeably to describe solid states disclosed herein.
In the first embodiment, 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.
In the process of the first embodiment, 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).
In the process of the first embodiment, 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 ).
In the process of the first embodiment, 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.
In the process of the first embodiment, the reaction temperature in step-b) is 100°C or less than 100°C.
In the process of the first embodiment, the suitable acid used in step-c) is organic or inorganic acid.
In the process of the first embodiment, the suitable base used in step-b) and step-d) is selected from organic base or inorganic base. In the process of the first embodiment, 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.
In an aspect of the first embodiment, 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, e) optionally purifying the compound of formula- 1 in isopropyl ether to provide pure form of Evobrutinib.
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. Below are the comparative data between demerits of prior art process and merits of present invention.
• Prior art process for the preparation of tert-butyl 4-(((6-amino-5-(4-phenoxyphenyl) pyrimidin-4-yl)amino)methyl)piperidine-l -carboxylate compound of formula-6 or formula-6a involves microwave assisted reaction method, which is not feasible at large scale production. The said process involves high temperatures upto 150°C and high mole ratio of palladium acetate. Also uses column purification to get desired product with low yield (48%). The said process did not disclose purity of formula-6.
Whereas, 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. Further, compound of formula-6 produced by the present invention is having HPLC purity of at least 97.66% with high yield of 86%.
• Prior art process involves deprotection of compound of formula-6 using hydrochloric acid in diethyl-ether (low boiling solvent) and uses lyophilization technique, which are not feasible at large-scale production.
Whereas, 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%.
• Prior art process for the preparation of Evobrutinib uses column chromatography to provide Evobrutinib with low yield.
Whereas, 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%.
In the second embodiment, 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,
Formula - 2
Formula - 4 wherein, ‘PG’ is H or N-protecting group; X is F, Cl, Br or I. Nitrogen bicyclic base is same as defined above b) converting the compound of general formula-4 to provide Evobrutinib of formula- 1.
In the third embodiment, 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.
In the fourth embodiment, 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.
In an aspect of the fourth embodiment, 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.
In an aspect of the fourth embodiment, 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.
In the fifth embodiment, 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
Evobrutinib of formula- 1.
In the sixth embodiment, 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.
In the seventh embodiment, 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.
In the process of seventh embodiment, 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.
In the process of the seventh embodiment, treating Evobrutinib of formula- 1 in a solvent at a temperature of about 30°C and above. Optionally, the resulting solution can be filtered to make it particle free.
In the first aspect of the seventh embodiment, 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.
In the second aspect of the seventh embodiment, 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.
In the eighth embodiment, the present invention provides a solid dispersion of Evobrutinib comprising Evobrutinib and one or more pharmaceutically acceptable excipients.
In the eighth embodiment, 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, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropylmethyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose-ES (HPMC-ES), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methyl cellulose 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-cyclodextrins, 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 acetate phthalates and the like.
In the ninth embodiment, 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.
In the process of ninth embodiment, 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.
In the process of ninth embodiment, the suitable pharmaceutically acceptable excipient used in step-a) is same as defined above.
In the first aspect of the ninth embodiment, 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.
In the process of first aspect of the ninth embodiment, the suitable alcohol solvent used in step-a) is methanol.
In the process of first aspect of the ninth embodiment, the suitable pharmaceutically acceptable one or more excipients used in step-a) is PVP-K30, Copovodone, HPMC-ES, Eudragit, Syloid.
In the second aspect of the ninth embodiment, 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. In the process of second aspect of the ninth embodiment, the suitable alcohol solvent used in step-a) is methanol; the suitable chloro solvent used in step-a) is dichloromethane.
In the process of second aspect of the ninth embodiment, the suitable pharmaceutically acceptable excipient used in step-a) is HPMC-AS.
In the process of the present invention, providing a solution of Evobrutinib of formula- 1 is carried out by dissolving Evobrutinib and an excipient in a solvent. Optionally by heating the mixture to suitable temperature ranging from about 25°C to the reflux temperature of the solvent used in the reaction. Optionally, the resulting solution can be filtered to make it particle free.
In the process of the present invention, 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.
In the process of the present invention, 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.
In the present invention, pharmaceutically acceptable excipient used for the preparation of solid dispersion can be amorphous, crystalline or any other physical form.
In a result of the present inventions process, solid dispersion of Evobrutinib can be amorphous, crystalline or a mixture thereof.
It is an object of the present invention to provide storage stable solid dispersions of Evobrutinib.
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.
After storage, the PXRD diffractograms of solid dispersions of Evobrutinib were found to be similar when compared with initial PXRD’s of figure- 1 to figure-6.
Therefore, the objective of the present invention was achieved through the preparation of storage stable solid dispersions of Evobrutinib.
In an embodiment, the present invention provides pharmaceutical composition comprising solid dispersion of Evobrutinib or amorphous Evobrutinib of formula- 1 and one or more pharmaceutically acceptable excipients.
Wherein the excipient can be selected from those reported in Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems 2006.
In yet another embodiment, pharmaceutical 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. As used herein, the term "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.
The process described in the present invention is 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.
Examples:
Example-1: Preparation of tert-butyl 4-(((6-amino-5-chloropyrimidin-4-yl)amino) met hy 1 jpiperid ine- 1 -carboxylate
Tert-butyl-4-(aminomethyl)piperidine-l -carboxylate (81 ml) and 1,8-diazabicyclo [5.4.0]undec-7-ene (60.34 g) were added to a mixture of 5,6-dichloropyrimidin-4-amine (50 g) in N,N-dimethylformamide (500 ml) at 25-35°C. Heated the mixture to 90-95°C and stirred for 22 hrs. Cooled the mixture to 25-30°C. Water was added to the mixture at 25-35°C and stirred for 5 hrs. Filtered the precipitated solid, washed with water and n-heptane and dried to get the title compound. Yield: 73.0 gms; Purity by HPLC: 98.7%
Example-2: Preparation of tert-butyl 4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl) amino)methyl)piperidine-l-carboxylate
(4-Phenoxyphenyl)boronic acid (75.12 g) was added to a mixture of tert-butyl 4-(((6- amino-5-chloropyrimidin-4-yl)amino)methyl)piperidine-l-carbo xylate(100 g), 2-di cyclo hexylphosphino-2',6'-dimethoxybiphenyl (12 g) and potassium carbonate (121.28 g) in 1,4- di oxane (1000 ml) at 25-30°C and stirred for 30 minutes under nitrogen atmosphere. Palladium acetate (1.96 g) was added to the mixture at 25-30°C. Heated the mixture to 100- 105°C and stirred for 3 hrs. Cooled the mixture to 25-30°C. Water and ethyl acetate were added to the mixture at 25-35°C and stirred for 30 minutes. Filtered the mixture by using hyflow bed. Organic layer was separated from the filtrate. Organic layer was treated with carbon powder and distilled-off the solvent under reduced pressure, n-heptane (800 ml) was added to the obtained compound. Heated the mixture to 60-65°C and stirred for 90 minutes. Cooled the mixture to 25-30°C and stirred for 2 hrs. Filtered the precipitated solid, washed with n-heptane and dried to get the title compound. Yield: 120 gms, Purity by HPEC: 97.6% Example-3: Preparation of 5-(4-phenoxyphenyl)-N4-(piperidin-4-ylmethyl)pyrimidine- 4,6-diamine
Tert-butyl-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl )amino)methyl) piperidine- 1 -carboxylate (200 g) in methanol (600 ml) was cooled to 0-5°C. Hydrochloric acid in ethyl acetate (500 ml) was slowly added to the mixture at 0-5°C. Mixture allowed to warm to 25-30°C and stirred for 20 hours. Water was added to the mixture and treated the mixture with aqueous ammonia solution. Dichloromethane was added to the mixture at 25- 30°C and stirred for 10 minutes. Layers were separated and distilled-off the organic layer under reduce pressure. Obtained compound was treated with isopropyl ether and dried to get the title compound. Yield: 150 gms, Purity by HPLC: 76.4%
Example-4: Preparation of Evobrutinib
Sodium bicarbonate (23.86 g) and water (301 ml) were added to the mixture of 5-(4- phenoxyphenyl)-N4-(piperidin-4-ylmethyl)pyrimidine-4,6-diami ne (70 g) in tetrahydrofuran (2800 ml). Cooled the mixture to 0-5°C. Acryloyl chloride (23.62 g) was slowly added to the mixture. Mixture allowed to warm to 25-30°C and stirred for 20 hrs. Distilled-off the solvent from the mixture under reduced pressure. Ethyl acetate and water were added to the mixture and stirred for 10 minutes. Both the layers were separated. Organic layer was treated with aqueous hydrochloric acid solution and carbon powder. Distilled-off the organic layer under reduced pressure. Isopropyl ether was added to the mixture at 25-30°C and stirred for 14 hrs. Filtered the mixture and washed with isopropyl ether. Dried to get the title compound.
Yield: 41.8 gms, Purity by HPLC: 97.6%
Example-5: Preparation of solid dispersion of Evobrutinib with PVP-K30
Evobrutinib (250 mg) and PVP-K30 (250 mg) were added to methanol (25 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: 440 mg.
The P-XRD pattern of the obtained compound is illustrated in figure-1.
Example-6: Preparation of solid dispersion of Evobrutinib with Copovidone
Evobrutinib (250 mg) and Copovidone (250 mg) were added to methanol (25 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: 432 mg.
The P-XRD pattern of the obtained compound is illustrated in figure-2.
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.
The P-XRD pattern of the obtained compound is illustrated in figure-3.
Example-8: Preparation of solid dispersion of Evobrutinib with HPMC-AS
Particle free solution of Evobrutinib (250 mg) in methanol (10 ml) was added to the mixture of HPMC-AS (250 mg) in dichloromethane (2.5 ml) and methanol (2.5 ml) at 25- 30°C. Heated the mixture to 55-60°C and stirred for 15 minutes. Distilled off the mixture completely and dried to get the title compound. Yield: 410 mg;
The P-XRD pattern of the obtained compound is illustrated in figure-4.
Example-9: Preparation of solid dispersion of Evobrutinib with eudragit
Evobrutinib (250 mg) and Eudragit (250 mg) were added to methanol (25 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: 435 mg;
The P-XRD pattern of the obtained compound is illustrated in figure-5.
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.
Example-11: Preparation of amorphous Evobrutinib
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.
Yield: 500 mg. The P-XRD pattern of the obtained compound is illustrated in figure-7.
Comparative Example-1: Preparation of tert-butyl 4-(((6-amino-5-(4-phenoxyphenyl) pyrimidin-4-yl)amino)methyl)piperidine-l-carboxylate
Into a 20-mL microwave vial was placed tert-butyl 4-[(6-amino-5-Chloropyrimidin-4- yl) amino]methylpiperidine-l-carboxylate (797.30 mg; 2.33 mmol), (4-phenoxyphenyl) boronic acid (748.79 mg; 3.50 mmol), palladium(ii) acetate (26.18 mg; 0.12mmol), 2- dicyclohexyl phosphino-2',6'-dimethoxybiphenyl (95.75 mg; 0.23 mmol), potassium carbonate (967.03 mg; 7.00 mmol), dioxane (9.00 mL) and water (0.90 mL). The reaction was then heated in the microwave for 2 h at 150 °C. The reaction mixture was then filtered, then concentrated to dryness. The resulting residue was dissolved with DCM (2mL) then purified by silica gel chromatography (50 g, 80-100% EtOAc/Hexanes, then 0-40% MeOH/EtOAc) to give tert-butyl 4-({ [6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino} methyl)piperidine-l -Carboxylate (534.6 mg, 48.2% yield).
Comparative Example-2: Preparation of 5-(4-phenoxyphenyl)-N4-(piperidin-4-yl methyl)pyrimidine-4,6-diamine
Into a 20-mL vial containing 4-([6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl] amino methyl)piperidine-l -carboxylate (534.60 mg; 1.12 mmol; 1.00 eq.) methanol (4.00 mL)was added hydrogen chloride (5.62 mL, 11.24 mmol) (2.0 M solution in Et20). The reaction was stirred at room temperature for 18 h. The reaction was then concentrated to dryness to give 5- (4-phenoxyphenyl)-N-(piperidin-4-ylmethyl)pyrimidine-4,6-dia mine.
Comparative Example-3: Preparation of Evobrutinib
To a 20-mL vial was added 5-(4-phenoxyphenyl)-N-(piperidin-4-ylmethyl) pyrimidine-4,6-diamine (210.00 mg; 0.56 mmol; 1.00 eq.), sodium bicarbonate(70.48 mg; 0.84 mmol; 1.50 eq.), THF (8.00 mL; 98.74 mmol; 176.55 eq.) and water (0.80 mL; 44.41 mmol; 79.40 eq.). The mixture was cooled to 0 °C on an ice bath. Acryloyl chloride (0.15 mL, 1.83 mmol) was then added dropwise. The ice bath was removed and the reaction was stirred at room temperature for 12 h before it was purified by silica gel chromatography (25 g KPNH Silica, 0-100% methanol/ethyl acetate) to afford the title compound (A18) (21 mg, 8.7% yield).