WO2020208592A1

WO2020208592A1 - Process for preparation of erdafitinib, its purification and amorphous solid dispersion

Info

Publication number: WO2020208592A1
Application number: PCT/IB2020/053431
Authority: WO
Inventors: Srinivas ORUGANTI; Saikat Sen; Mohan Kumar KOTTUR; Vishnu Vardhana Vema Reddy EDA; Magesh SAMPATH; Rehani Rajeev Budhdev; Khushi Ram; Shirshendu Das Gupta
Original assignee: Dr. Reddy’S Laboratories Limited
Priority date: 2019-04-12
Filing date: 2020-04-10
Publication date: 2020-10-15

Abstract

An aspect of the present application provides a process for the preparation of Erdafitinib and its pharmaceutically acceptable salts. Another aspect of the present application relates to amorphous solid dispersions of Erdafitinib, process for the preparation thereof and pharmaceutical composition comprising amorphous solid dispersions of Erdafitinib. Another aspect of the present application provides process for purification of Erdafitinib.

Description

PROCESS FOR PREPARATION OF ERDAFITINIB, ITS

PURIFICATION AND AMORPHOUS SOLID DISPERSION

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application claims benefit of Indian provisional Patent Application No. 201941014776 filed on 12 April 2019 and 201941050183 filed on 5 December 2019 which are hereby incorporated by reference in its entirety.

INTRODUCTION

Erdafitinib is a Pan-Fibroblast Growth Factor Receptor (FGFR) Tyrosine Kinase Inhibitor. The drug compound having the adopted name “Erdafitinib” has chemical name N-(3,5-dimethoxyphenyl)-N’-(l-methylethyl)- N-[3-(l-methyl-lH-pyrazol-4-yl)quinoxalin-6-yl]ethane-l, 2-diamine having the following structure:

Erdafitinib (Balversa™) has been approved by USFDA on 12 April 2019 for the treatment of patients with Metastatic Urothelial Cancer.

US8895601 discloses Erdafitinib, its process of preparation. The process described in US8895601 having many drawbacks such as 1) more number of steps, 2) use of a potentially genotoxic compound N-(2-chloroethyl)-2- propanamine HC1 in the last step of synthesis, and 3) low yield in final step of API synthesis. In view of these drawbacks the process described in the literature is neither cost effective nor suitable for manufacturing at commercial scale.

Further US9902714 discloses a benzodiazepine compound having the following structure represented as compound A:

Compound A

US9902714 also discloses process for preparation of benzodiazepine compound A by reacting Erdafitinib with formaldehyde. This benzodiazepine compound A is referred as impurity A in this application.

Therefore, there remains a need to provide a cost effective and commercially viable process for the preparation Erdafitinib. Also there remains a need to provide a process for purification of Erdafitinib contaminated with impurity A to provide pure Erdafitinib which is pharmaceutically acceptable for administration.

SUMMARY OF THE INVENTION

In the first embodiment, the present application provides a process for preparation of Erdafitinib and its salts comprising;

a) reacting 3,5-dimethoxyaniline with compound of formula (I) to provide compound of formula (II)

b) reducing the compound of formula (II) to obtain compound of formula (III) or its salts

c) reacting compound of formula (III) with compound of formula (IV) to obtain Erdafitinib and its salts

In the second embodiment, the present application provides a novel compound of Formula III and its salts and its use in preparation of Erdafitinib.

Formula (III)

In the third embodiment, the present application provides amorphous solid dispersion of Erdafitinib together with at least one pharmaceutically acceptable excipient.

In the fourth embodiment, the present application provides a process for the preparation of amorphous solid dispersion of Erdafitinib, comprising the steps of;

a) providing a solution of Erdafitinib and at least one pharmaceutically acceptable excipient in a suitable solvent or a mixture thereof;

b) removing the solvent from the solution obtained in step a); and c) isolating the amorphous solid dispersion of Erdafitinib;

In the fifth embodiment, the present application provides a pharmaceutical composition comprising amorphous solid dispersion of Erdafitinib together with at least one pharmaceutically acceptable excipient.

In the sixth embodiment, the present application provides use of acid addition salts of Erdafitinib formed with organic acids for the purification of Erdafitinib specifically for reducing the content of impurity A.

In the seventh embodiment, the present application provides a process for purification of Erdafitinib specifically for reducing the content of impurity A comprising;

a) reacting crude Erdafitinib having impurity A with an organic acid in a suitable solvent to provide acid addition salt of Erdafitinib;

b) converting acid addition salt of Erdafitinib obtained from step a) to Erdafitinib by conventional methods.

BRIEF DESCRIPTION OF THE DRAWING

Figure 1 illustrates a characteristic PXRD pattern of crystalline Erdafitinib obtained from example 4.

Figure 2 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Erdafitinib with polyvinylpyrrolidone-K 30 prepared by the method of Example No 5.

Figure 3 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Erdafitinib with copovidone prepared by the method of Example No 6.

Figure 4 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Erdafitinib with HPMC prepared by the method of Example No 7.

Figure 5 is an illustrative X-ray powder diffraction pattern of amorphous solid dispersion of Erdafitinib with HPC prepared by the method of Example No 8. DETAILED DESCRIPTION

In embodiments, step a) involves the preparation of compound of Formula II by reaction of 3,5-dimethoxyaniline with compound of formula (I) in the presence of a suitable base, a catalyst and a suitable solvent.

In embodiments of step a), the reaction may be carried out by using a suitable base such as, for example, alkali metal carbonates, such as, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkali metal bicarbonates, such as, for example, sodium bicarbonate, potassium bicarbonate, or the like, alkali metal hydroxides, such as, lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like; alkaline earth metal hydroxides, such as, barium hydroxide, strontium hydroxide, magnesium hydroxide, calcium hydroxide, or the like; alkali metal hydrides, such as, sodium hydride, lithium hydride, potassium hydride or the like; metal alkoxides, such as, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide, or the like; organic bases, such as, triethylamine, diisopropyl ethylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 2,6-dimethylpyridine, N,N- dimethylaminopyridine or the like; organometallic bases, such as, lithium di isopropyl amide, butyllithium, lithium bis(trimethylsilyl)amide, or the like; organic hydroxides such as benzyltrimethylammonium hydroxide, tetraethylammonium hydroxide, tetramethylammonium hydroxide, tetra-n- butylammonium hydroxide, or the like.

In embodiments of step a), the reaction may be carried out by using a suitable catalyst such as, for example, alkali metal halides, such as, potassium iodide, sodium iodide or the like; ammonium salts such as tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, tetra-n-butylammonium iodide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium iodide, (2-chloroethyl)trimethylammonium chloride, trioctylmethylammonium chloride, or the like; heterocyclic ammonium chlorides such as 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride, l,3-didecyl-2- methylimidazolium chloride, or the like; phosphonium salts such as methyltriphenoxyphosphonium iodide, tetrabutylphosphonium chloride, tetrabutylphosphonium bromide, or the like; phase transfer reagents, such as, 18- crown-6 or the like.

In embodiments of step a), the reaction may be carried out in the presence of a suitable solvent. Examples of such solvents include, but are not limited to: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, MTBE, dioxane, and dimethoxyethane; alcohols, such as methanol, ethanol, ethylene glycol, 1- propanol, 2-propanol, 2-methoxyethanol, 1 -butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, glycerol, and C1-C6 alcohols; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, and chlorobenzene; aromatic hydrocarbons, such as toluene; aliphatic hydrocarbons, nitriles, esters and polar aprotic solvents such as DMF, DMSO, DMAc; water; any mixtures of two or more thereof. In a preferred embodiment, the reaction may be carried out in presence of DMF.

In embodiments of step a), the reaction may be carried out at a temperature ranging from about 0°C to about boiling temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, under the conditions outlined above, the reaction is effected for a period of about 30 minutes to about 24 hours or longer.

In embodiments of step a), the compound of formula II may be isolated directly from the reaction mixture itself after the reaction is complete, by filtration or after conventional work up with techniques such as quenching with a suitable reagent, extraction, evaporation of solvent or the like.

In embodiments of step a), the compound of Formula II is optionally isolated by extracting in a solvent followed by removal of the solvent by evaporation. In embodiments of step a), the compound of Formula II is optionally purified by using suitable technique known in the literature. The compound of Formula II may be isolated or may be used directly in the next step without isolation.

In embodiments, step b) involves the preparation of compound of Formula III by reducing the compound of Formula II by using a suitable reducing agent and a suitable solvent.

In embodiments of step b), the reduction may be carried out by using a suitable reducing agent. The suitable reducing agents that may be used are but not limited to lithium borohydride, sodium Borohydride (NaBH₄), lithium aluminum hydride (L1AIH₄), Red-Al, sodium triacetoxyborohydride, sodium cyanoborohydride, borane either employed as such in form of, as for example, BH_3*THF and B¾*DMS, or produced in situ in form of, as for example, NaBH₄ in combination with reagents such as, BF_3*Et₂0, BF_3*THF, iodine, or the like. In embodiments the amount of reducing agent required may vary depending on the nature of reducing agent, reaction conditions etc.

In embodiments of step b), the reduction reaction may be carried out in the presence of a suitable solvent. Examples of such solvents include, but are not limited to: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, MTBE, dioxane, and dimethoxyethane; alcohols, such as methanol, ethanol, ethylene glycol, 1 -propanol, 2-propanol, 2-methoxyethanol, 1 -butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, glycerol, and C1-C6 alcohols; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, and chlorobenzene; aromatic hydrocarbons, such as toluene; aliphatic hydrocarbons, nitriles, esters and polar aprotic solvents such as DMF, DMSO, DMAc, any mixtures of two or more thereof. In a preferred embodiment, the reduction reaction may be carried out in tetrahydrofuran.

In embodiments of step b), the reaction may be carried out at a temperature ranging from about 0 °C to about boiling temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, under the conditions outlined above, the reaction is effected for a period of about 30 minutes to about 24 hours or longer.

In embodiments of step b), the compound of formula III may be isolated directly from the reaction mixture itself after the reaction is complete, by filtration or after conventional work up with techniques such as quenching with a suitable reagent, extraction, evaporation of solvent or the like.

In embodiments of step b), the compound of Formula III is optionally isolated by extracting in a solvent followed by removal of the solvent by evaporation. Optionally the compound of Formula III may be isolated or may be used directly in the next step without isolation.

In embodiments of step b), the compound of Formula III is optionally converted into a suitable salt by using conventional techniques known in literature for salt preparation. In embodiments of step b), if the compound of Formula III is isolated as its salt in that case if required it may again converted in to free form by using conventional techniques known in literature.

In embodiments, step c) involves the preparation of Erdafitinib or its salts by reacting compound of formula (III) with a compound of formula (IV) by using a suitable reagent and a suitable solvent. In embodiments of step c) the preparation of Erdafitinib or its salts may be carried out by using standard conditions of Buchwald-Hartwig coupling reaction.

In embodiments of step c) the reaction may be carried out in presence of a metal catalyst, such as tris(dibenzylideneacetone)dipalladium(0), bis(dibenzylideneacetone)palladium(0), palladium(II) chloride, palladium(II) acetate, dichloro[ 1 , 1 '-bis(diphenylphosphino)ferrocene]palladium(II), [1,1'- bis(diphenylphosphino)fenOcene]dichloropalladium(II),

tetrakis(triphenylphosphine)palladium(0), bis(tri-/c/7- butylphosphine)palladium(O), bis(triphenylphosphine)palladium(II) dichloride, (dppf)Ni(o-tolyl)Cl, bis(l,5-cyclooctadiene)nickel(0), or the like; and optionally in presence of a suitable ligand such as Xantphos, PPI13, (o-tolyl)3P, /-BU3P, BINAP, dppf, dppb, SPhos, XPhos, BrettPhos, CyJohnPhos, or the like.

In embodiments of step c), the reaction may be carried out by using a suitable base such as, for example, alkali metal carbonates, such as, for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkali metal bicarbonates, such as, for example, sodium bicarbonate, potassium bicarbonate, or the like, alkali metal hydroxides, such as, lithium hydroxide, sodium hydroxide, potassium hydroxide, or the like; alkaline earth metal hydroxides, such as, barium hydroxide, strontium hydroxide, magnesium hydroxide, calcium hydroxide, or the like; alkali metal hydrides, such as, sodium hydride, lithium hydride, potassium hydride or the like; metal alkoxides, such as, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert- butoxide, lithium tert-butoxide, or the like; organic bases, such as, triethylamine, diisopropyl ethylamine, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, 2,6- dimethylpyridine, N,N-dimethylaminopyridine or the like; organometallic bases, such as, lithium diisopropylamide, butyllithium, lithium bis(trimethylsilyl)amide, or the like; organic hydroxides such as benzyl trimethyl ammonium hydroxide, tetraethylammonium hydroxide, tetramethylammonium hydroxide, tetra-n- butylammonium hydroxide, or the like; alkali metal phosphates, such as, sodium phosphate, potassium phosphate, lithium phosphate, or the like.

In embodiments of step c), the reaction may be carried out in the presence of a suitable solvent. Examples of such solvents include, but are not limited to: ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, MTBE, dioxane, and dimethoxyethane; alcohols, such as methanol, ethanol, ethylene glycol, 1- propanol, 2-propanol, 2-methoxyethanol, 1 -butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, glycerol, and C1-C6 alcohols; halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, and chlorobenzene; aromatic hydrocarbons, such as toluene; aliphatic hydrocarbons, nitriles, esters and polar aprotic solvents such as DMF, DMSO, DMAc, any mixtures of two or more thereof. In a preferred embodiment, the reaction may be carried out in presence of toluene.

In embodiments of step c), the reaction may be carried out at a temperature ranging from about 0°C to about boiling temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, under the conditions outlined above, the reaction is effected for a period of about 30 minutes to about 24 hours or longer.

In embodiments of step c), Erdafitinib may be isolated directly from the reaction mixture itself after the reaction is complete, by filtration or after conventional work up with techniques such as quenching with a suitable reagent, extraction, evaporation of solvent or the like.

In embodiments of step c), Erdafitinib obtained may be optionally further dried at suitable temperatures, and atmospheric or reduced pressures, for about 1- 50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like.

In embodiments of step c), the Erdafitinib obtained may be optionally further purified by recrystallization or by slurrying in a suitable solvent or by column chromatography or any other suitable technique.

In an aspect of the present application, Erdafitinib may be obtained as a salt which may be further treated with suitable base by conventional methods known in the literature. In embodiments, Erdafitinib may be purified by making suitable salts of Erdafitinib and then converting those salts to Erdafitinib by using suitable base by conventional methods known in the literature.

In an aspect of the present application, Erdafitinib obtained from the first embodiment of the present application is crystalline solid. In an aspect of the present application, Erdafitinib obtained from the first embodiment of the present application can be characterized by PXRD pattern substantially as illustrated in Figure- 1. In an aspect of the present application, Erdafitinib obtained from the first embodiment of the present application having the following characteristic 2- theta peaks at about 6.56, 12.21, 13.86, 14.87, 16.60, 18.38, 19.15, 19.52, 19.88, 23.40, 24.37 and 25.25° 20± 0.2° 20.

Erdafitinib obtained according to the process of the present application can be milled or micronized by any process known in the art, such as ball milling, jet milling, wet milling etc., to produce a desired particle size distribution.

In embodiments the compound of formula (IV) used in the present application for preparation of Erdafitinib may be prepared according to the procedures known in US8895601 or in any other literature.

In embodiments the compound of formula (I) used in the present application for preparation of Erdafitinib may be prepared according to the procedures known in the literature.

Formula (III)

In embodiments the compound of Formula III and its salts may be prepared and isolated according to the procedures as described in step b) of the first embodiment of the present application. In embodiments the compound of Formula III and its salts are novel compounds. In embodiments the compound of Formula III and its salts can be used as an intermediate in the synthesis of Erdafitinib. In embodiments, the compound of Formula III and its salts may be used according to the procedures as described in the step c) of first embodiment of the present application.

In an embodiment, suitable solvent at step a) may be selected from halogenated hydrocarbons, C₁-C₆ alcohols, C₃-C₆ ketones, Cs-Cx aliphatic or aromatic hydrocarbons, C3-C₆ esters, C2-C₆ aliphatic or cyclic ethers, C2-C₆ nitriles, water or mixtures thereof

In preferred embodiment, the suitable solvent may be selected from the group consisting of dichloromethane, methanol, ethanol, 2-propanol, 1 -butanol, 2- butanol, 1-pentanol, 2-pentanol, 3-pentanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl acetate, ethyl acetate, isopropyl acetate, tetrahydrofuran, water and mixtures thereof.

In addition to the pharmaceutically acceptable excipients provided in the examples described in this application, any other suitable excipient can also be used for preparation of amorphous solid dispersion.

In an embodiment, the other suitable pharmaceutically acceptable excipient of this aspect may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-60, hydroxypropyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxypropylmethyl cellulose, methyl cellulose 15 cps, prosolv HD 40, syloid, syloid 244 NF, polyvinylpyrrolidone vinylacetate, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene-polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-P VAc-PEG)), gelucire 44/14, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxym ethyl ethylcelluloseand the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like; homopolymers and copolymers of N- vinyl lactams, cellulose esters, cellulose ethers, high molecular weight polyalkylene oxides, polyacrylamides, vinyl acetate polymers, graft copolymers of polyethylene glycol, polyvinyl caprolactam and polyvinyl acetate, oligo- and polysaccharides and mixtures thereof organic amines such as alkyl amines (primary, secondary, and tertiary), aromatic amines, alicyclic amines, cyclic amines, aralkyl amines, hydroxylamine or its derivatives, hydrazine or its derivatives, and guanidine or its derivatives, or any other excipient at any aspect of present application. The use of mixtures of more than one of the pharmaceutical excipients to provide desired release profiles or for the enhancement of stability is within the scope of this invention. Also, all viscosity grades, molecular weights, commercially available products, their copolymers, and mixtures are all within the scope of this invention without limitation.

Any physical form of Erdafitinib may be utilized for providing the solution of Erdafitinib in step a). Erdafitinib that may be used as the input for the process of the present invention may be obtained by the process as described in the present application or the processes described in the art.

In an embodiment, providing a solution at step a) may be carried out by taking the reaction mixture containing Erdafitinib directly or by dissolving Erdafitinib and at least one pharmaceutically acceptable excipient in a suitable solvent simultaneously or by dissolving components in a suitable solvent separately to form individual solutions and combining those solutions later.

In an embodiment, a solution of Erdafitinib and the excipient may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.

In an embodiment, a solution of Erdafitinib and the excipient may be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and/or hydrose, to remove colored components, etc., before filtration.

In an embodiment, removal of solvent at step b) may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using buchi rotavapor, spray drying, freeze drying, agitated thin film drying, filtration and the like.

In preferred embodiment, the solvent may be removed 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.

In an embodiment, the isolation of an amorphous solid dispersion of Erdafitinib and excipient at step c) involves recovering the solid obtained in step b). The solid obtained from step b) may be recovered using techniques such as by scraping, or by shaking the container, or adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used.

In an embodiment, amorphous solid dispersion of Erdafitinib may be combined with additional excipient using a technique known in art or by the procedures disclosed in the present application.

In preferred embodiment, amorphous solid dispersion of the present application may be combined with additional excipient either by physical blending of both the solid components or by suspending both the components in a suitable solvent and conditions, such that both the components remain unaffected. Blending may be carried out using techniques known in art such as rotatory cone dryer, fluidized bed dryer or the like optionally under reduced pressure / vacuum or inert atmosphere such nitrogen at suitable temperature and sufficient time to obtain uniform composition of amorphous solid dispersion of Erdafitinib with pharmaceutically acceptable excipient and at least one additional pharmaceutically acceptable excipient.

In an embodiment, amorphous solid dispersion of the present application may be combined with additional excipient by evaporating the suspension or solution of amorphous solid dispersion of Erdafitinib and additional excipient.

In an embodiment, pharmaceutically acceptable additional excipient may be same or different from the excipient used in the preparation of amorphous solid dispersion of Erdafitinib. Additional excipient may include, but not limited to an inorganic oxide such as S1O2, T1O2, ZnCk, ZnO, AI2O3 and zeolite; a water insoluble polymer is selected from the group consisting of cross- polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross- linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross-linked styrene divinyl benzene or any other excipient at any aspect of present application.

Amorphous solid dispersion of Erdafitinib isolated at step c) may be dried 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 may be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In embodiments, the present application provides adsorbates, wherein Erdafitinib is associated with a suitable substrate. Suitable substrate may be a particulate and/or porous substrate, wherein this substrate has an outer and/or inner surface onto which the API may be adsorbed. This means that if the substrate has pores, these pores are filled by the Erdafitinib and the substrate remains unaffected, it does not, at least not essentially, change during and / or after the adsorption. In embodiments, the suitable substrate is selected from the excipients provided in the present application.

Amorphous solid dispersion of Erdafitinib may be obtained alternatively either by employing a melt-extrusion technique.

US8895601 discloses isolation of Erdafitinib by converting Erdafitinib hydrochloride salt with ammonium hydroxide solution in a mixture of DCM and water.

The inventors of the present application have observed that the impurity A was not reduced in a significant content while using hydrochloride salt of Erdafitinib. However, the impurity A was reduced significantly when acid addition salt of Erdafitinib formed with organic acids was used for the purification process.

In the seventh embodiment, the present application provides a process for purification of Erdafitinib specifically for reducing the content of impurity A comprising; a) reacting crude Erdafitinib having impurity A with an organic acid in a suitable solvent to provide acid addition salt of Erdafitinib;

Step a) involves preparation of acid addition salt of Erdafitinib comprising dissolving crude Erdafitinib having impurity A in a suitable solvent and adding an organic acid to the solution.

The crude Erdafitinib can be obtained directly from the reaction mass during the synthesis of Erdafitinib.

Acid addition salts may be formed with a wide variety of organic acids such as those listed, for example, in Asian Journal of Pharmaceutical Sciences, 2016, 11, pp. 722-734. Examples of acid addition salts include salts formed with an organic acid selected from the group lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulphonic, para-toluenesulphonic, methanesulphonic (mesylate), ethanesulphonic, naphthalenesulphonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic, adipic, ascorbic, aspartic, citric, gluconic, hippuric, glutamic, sebacic, stearic, tartaric, mandelic, salicylic, glutamic, trifluoroacetic, camphoric, cypionic, caproic, enanthic, lauric, nicotinic, pivalic acids, or the like. Preferably the organic acid are para toluenesulphonic acid (PTSA), Benzoic acid and succinic acid.

The suitable solvent of step a) may be selected from a group of solvents in which Erdafitinib and/or the selected organic acid are soluble. Examples of solvents include but are not limited to alcohols such as ethanol, ethylene glycol, 1- propanol, 2-propanol, 2-methoxyethanol, 1 -butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol and glycerol; nitriles such as acetonitrile and propionitrile; aprotic polar solvents such as DMF, DMSO and DMAc; hydrocarbons such as toluene, hexane, heptane and xylene; halogenated solvents such as chlorobenzene; esters such as ethyl acetate, methyl acetate, benzyl benzoate, butyl acetate, sec-butyl acetate and tert-butyl acetate; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl amyl ketone, methyl propyl ketone and diisobutyl ketone; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, MTBE, dioxane, and dimethoxyethane; water or mixture of solvents thereof.

The precipitated salt of Erdafitinib formed with organic acid may be isolated and dried by common techniques known in the literature.

The obtained acid addition salt of Erdafitinib with organic acid may be characterized with ¹HNMR, mass and other techniques.

Step b) involves conversion of acid addition salt of Erdafitinib, as obtained from step a), to Erdafitinib by using a suitable base and a suitable solvent.

The reaction can be carried out in the presence of aqueous base. Bases that are useful in the reaction include, but are not limited to: inorganic bases such as alkali metal or alkaline earth metal carbonates, hydrogen carbonates, hydroxides, e.g. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, ammonium hydroxide or the like.

The suitable solvent of step b) is water in which the acid addition salt of Erdafitinib may be dissolved or suspended. Optionally step b) may be carried out in the mixture of water and a suitable solvent. Examples of solvents include but are not limited to alcohols such as ethanol, ethylene glycol, 1 -propanol, 2- propanol, 2-methoxyethanol, 1 -butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol and glycerol; nitriles such as acetonitrile and propionitrile; aprotic polar solvents such as DMF, DMSO and DMAc; hydrocarbons such as toluene, hexane, heptane and xylene; halogenated solvents such as chlorobenzene; esters such as ethyl acetate, methyl acetate, benzyl benzoate, butyl acetate, sec-butyl acetate and tert-butyl acetate; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl amyl ketone, methyl propyl ketone and diisobutyl ketone; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, MTBE, dioxane, and dimethoxyethane; or mixture of solvents thereof.

The obtained Erdafitinib may be isolated and dried by common techniques known in the art.

The Erdafitinib salts obtained by the process of the present application may be mono salt, hemi salt, di salt, etc. In the present application the PTSA salt is obtained as monotosylate, benzoate as monobenzoate salt and succinate salt as hemi succinate salt.

The content of impurity A is found to be same for Erdafitinib salt and Erdafitinib free base obtained after converting Erdafitinib salt to Erdafitinib.

The following table summarizes the results obtained from the purification of Erdafitinib and the relative content of impurity A by using acid addition salts of Erdafitinib formed with organic acids as an intermediate for purification of Erdafitinib.

Table 1:

By comparing the results, as provided in Table 1, it is evident that the organic acid salts are more than 13 times superior in comparison to hydrochloride salt for purification of Erdafitinib. The acid addition of salts of Erdafitinib formed with organic acids have an advantage over acid addition of salts of Erdafitinib formed with inorganic acid like hydrochloric acid.

Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

General description of the PXRD equipment

X-ray diffraction was measured using Rigaku Desktop X-ray diffractometer, Model: MiniFlex600. System description: CuK- Alpha 1 wavelength= 1.54060, voltage 40k V, current 15 mA, divergence slit = 1.25°; Sample stage=Reflection. Scan type: Continuous; Detector - Scintillator Nal (Tl); Measurement parameters: Start Position [°2Th.]: 3; End Position [°2Th.]: 40; Step Size [°2Th.]: 0.02; Scan Speed [°/min]: 1.

EXAMPLES

Example-1: Preparation of Compound of Formula I

Isopropylamine (5.0 g) and anhydrous CFhCh were added into a 250 mL flask at 25-30 °C under nitrogen atmosphere. Triethylamine (23.6 mL) was added into the reaction flask and the reaction mixture was cooled to 0 °C. 2-chloroacetyl chloride (8.7 mL) was added slowly into the reaction mixture at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 4 h at 5-10°C. The progress of the reaction was monitored by TLC. Water (100 mL) was added into the reaction mixture at 10 °C and-which was then stirred. The organic layer was separated and washed with saturated aqueous solution of sodium bicarbonate (70 mL), then brine solution (100 mL) and finally dried over sodium sulfate. The obtained organic layer was evaporated under reduced pressure below 45 °C to obtain the crude product. The crude product was purified by column chromatography using silica gel (60-120 mesh) and 30-40% EtO Ac/Hexane as eluent to obtain the title compound as yellow solid.

Yield: 9.01 g Yield (%): 78.5% Example-2: Preparation of 2-[(3,5-dimethoxyphenyl)amino]-N-(propan-2- yl)acetamide (Compound of Formula II)

Compound of Formula I (8.37 g) obtained from example-1 and DMF (84 mL) were added at room temperature into a 250 mL flask fitted with a magnetic stir bar and nitrogen inlet. 3,5-dimethoxyaniline (9.49 g), potassium carbonate (25.6 g) and potassium iodide (0.99 g) were added into the reaction flask at room temperature under nitrogen atmosphere. The reaction mixture was heated to 80-85 °C and maintained at that temperature for 17 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature. Water and MTBE (100 mL) were added into the reaction mixture at room temperature and stirred for 1 h. The organic layer was separated, washed with brine and dried over sodium sulfate. The obtained organic layer was evaporated under reduced pressure below 45 °C to obtain crude product. The crude product was purified by column chromatography using silica gel (100- 200 mesh) and 30% ethyl acetate in hexane as eluent to obtain the title compound as light brown liquid.

Yield: 11.74 g; Yield (%): 75%

Example-3: Preparation of Compound of Formula III

LiAlFL (3.0 g) was added at room temperature and under nitrogen atmosphere into a 250 mL flask, equipped with a reflux condenser, and then cooled to 0 °C. Anhydrous THF (50 mL) was added into the reaction flask over 15 min under nitrogen atmosphere at 0 °C. Compound of Formula II (5.2 g) obtained from example-2 (dissolved in 10 mL THF) was added into the reaction mixture over 30 min at 0 °C. The reaction mixture was refluxed at 70-75 °C for 17 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to 0 °C after completion of the reaction. Excess L1AIH4 was quenched by drop-wise addition of 2M aqueous NaOH solution at 0 °C. Ethyl acetate (200 mL) was added into the reaction mixture and stirred for 20 min at room temperature. The reaction mixture was filtered through a pad of Celite. The obtained organic layer was evaporated under reduced pressure below 40 °C to obtain the crude product. The crude product was purified by column chromatography using silica gel (100- 200 mesh) and 2% MeOH in ethyl acetate as eluent to obtain the title compound as light brown liquid.

Yield: 3.43 g; Yield (%): 70 %

Example-4: Preparation of Erdafitinib

Compound of Formula III (1.0 g, 4.20 mmoles) obtained from example-3 and toluene (20 mL) were added at room temperature into a 100 mL flask equipped with a magnetic stir bar and reflux condenser. Compound of Formula IV (1.82 g) and CS2CO3 (4.0 g) were added into the reaction flask under N2 atmosphere. The reaction mass was purged with argon gas for 15 minutes. Pd₂(dba)₃ (0.384 g) and Xantphos (0.239 g) were added into the reaction mixture under N2 atmosphere. The reaction mass was again purged with argon gas for 15 minutes. The reaction mixture was refluxed at 110 °C for 17 h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature after completion of the reaction and filtered through a pad of Celite. The Celite pad was washed with ethyl acetate (25 mL). The combined organic layers were dried over sodium sulphate and evaporated under reduced pressure below 40 °C to obtain crude product. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 10% MeOH in ethyl acetate as eluent to obtain Erdafitinib as a yellow solid.

Yield: 1.6 g, Yield (%): 85%

The PXRD pattern of the isolated material is represented as Figure- 1.

Example-5: Preparation of amorphous solid dispersion of Erdafitinib with polyvinylpyrrolidone-K30

Erdafitinib (250 mg) and PVP K-30 (250 mg) were added at 25 °C into mixture of a methanol (1 ml) and dichloromethane (9 mL) taken in a flask. The reaction mass was stirred for 5 minutes at 25 °C and then filtered to obtain a particle free solution. The clear solution was evaporated under vacuum at 45°C and the solid obtained was dried under reduced pressure at 45 °C for 30 min.

Yield: 425 mg

The PXRD pattern of the isolated material is represented as Figure-2.

Example-6: Preparation of amorphous solid dispersion of Erdafitinib with Copovidone.

Erdafitinib (250 mg) and Copovidone (250 mg) were added at 25°C into a mixture of methanol (1 ml) and dichloromethane (9 mL) taken in a flask. The reaction mass was stirred for 5 minutes at 25 °C and then filtered to obtain a particle free solution. The clear solution was evaporated under vacuum at 45 °C and the solid obtained was dried under reduced pressure at 45 °C for 30 min.

Yield: 430 mg

The PXRD pattern of the isolated material is represented as Figure-3.

Example-7: Preparation of amorphous solid dispersion of Erdafitinib with HPMC.

Erdafitinib (250 mg) and HPMC (250 mg) were added at 25°C into a mixture methanol (10 ml) and dichloromethane (40 mL) taken in a flask. The reaction mass was stirred for 5 minutes at 25 °C and then filtered to obtain a particle free solution. The clear solution was evaporated under vacuum at 45 °C and the solid obtained was dried under reduced pressure at 45 °C for 30 min.

Yield: 430 mg

The PXRD pattern of the isolated material is represented as Figure-4.

Example-8: Preparation of amorphous solid dispersion of Erdafitinib with HPC.

Erdafitinib (250 mg) and HPC (250 mg) were added at 25°C into a mixture of Methanol (10 ml) and dichloromethane (40 mL) taken in a flask. The reaction mass was stirred for 5 minutes at 25 °C and then filtered to obtain a particle free solution. The clear solution was evaporated under vacuum at 45 °C and the solid obtained was dried under reduced pressure at 45 °C for 30 min. Yield: 428 mg

The PXRD pattern of the isolated material is represented as Figure-5.

Example-9: Preparation of crude Erdafitinib

Erdafitinib (5 g) and impurity A (0.1 g) were taken in methanol (15 mL) and stirred for 10 minutes at room temperature. The solution was concentrated under reduced pressure to obtain the impure Erdafitinib as yellow solid.

HPLC purity: 98.08% Impurity A: 1.92%

Example-10: Preparation of Erdafitinib PTSA salt

Impure Erdafitinib (500 mg) obtained from example 9 and acetonitrile (6 mL) were added into a flask and the mixture was heated to 50-55 °C to get a solution. A solution of i-toluene sulfonic acid (190 mg) in acetonitrile (3 mL) was added drop wise at 50-55°C to the above solution and stirred for 3 h. The slurry containing precipitated solid was stirred for 12 h at 25-30°C. The solid, obtained by filtration, was washed with THF (15 mL) and dried under reduced pressure below 45°C to obtain the PTSA salt as a yellow solid.

Yield: 0.625 g (90%)

HPLC purity: 99.98%; Impurity A: 0.02%

¾ NMR (400 MHz, DMSO-7₆) S 9.01 (s, 1H), 8.53 (s, 1H), 8.31 (brs, 2H), 8.20 (d, 7 = 0.4 Hz, 1H), 7.82 (d, 7= 9.1 Hz, 1H), 7.47 (d, 7= 8.1 Hz, 2H), 7.28 (d, 7 = 2.6 Hz, 1H), 7.24 (dd, 7 = 9.1, 2.7 Hz, 1H), 7.10 (d, 7 = 7.8 Hz, 2H), 6.50 (d, 7 = 2.2 Hz, 2H), 6.47 (t, 7 = 2.1 Hz, 1H), 4.09 (t, 7 = 7.5 Hz, 2H), 3.94 (s, 3H), 3.76 (s, 6H), 3.46 - 3.33 (m, 1H), 3.25 - 3.10 (m, 2H), 2.28 (s, 3H), 1.22 (d, 7 = 6.5 Hz, 6H)

Example-11: Preparation of Erdafitinib from Erdafitinib PTSA salt.

Erdafitinib PTSA salt (600 mg) obtained from example 10 and water (14 mL) were added into a flask at 25-30°C. The pH was adjusted to 7-8 by adding 10 % aqueous sodium bicarbonate solution to the reaction mixture which was then stirred for 30 min at 25-35 °C. The reaction mass was extracted with ethyl acetate (2 x 18 mL) and washed with brine solution. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain Erdafitinib.

HPLC purity: 99.98 % Impurity A: 0.02%

Example-12: Preparation of Erdafitinib benzoate salt

Impure Erdafitinib (500 mg) obtained from example 9 and acetonitrile (7 mL) were added into a flask and the mixture was heated to 50-55 °C to get a solution. Benzoic acid (136 mg) was added at 50-55°C to the above solution and stirred for 4 h. The slurry containing precipitated solid was stirred for 12 h at 25-30°C. The solid, obtained by filtration, washed with THF. The solid was stirred in THF (10 mL) for 16 h, filtered and dried under reduced pressure below 45°C to obtain the benzoate salt as yellow solid.

Yield: 85 %

HPLC purity: 99.97% Impurity A: 0.03%

¾ NMR (400 MHz, DMSO) d 8.96 (s, 1H), 8.53 (s, 1H), 8.19 (s, 1H), 8.02 - 7.87 (m, 2H), 7.76 (d, J= 9.2 Hz, 1H), 7.61 - 7.50 (m, 1H), 7.49 - 7.39 (m, 2H), 7.29 (d, J = 9.2 Hz, 1H), 7.18 (s, 1H), 6.47 (d, J = 2.2 Hz, 2H), 6.44 - 6.36 (m, 1H), 4.06 - 3.85 (m, 5H), 3.74 (s, 6H), 3.00 - 2.75 (m, 3H), 1.04 (d, J= 5.9 Hz, 6H).

Example-13: Preparation of Erdafitinib succinate salt

Impure Erdafitinib (500 mg) obtained from example 9 and acetonitrile (7 mL) were added into a flask and the mixture was heated to 50-55 °C to get a solution. Succinic acid (132 mg) was added at 50-55°C to the above solution and stirred for 4 h. The slurry containing precipitated solid was stirred for 12 h at 25-30°C. The solid, obtained by filtration, was washed with THF. The solid was stirred in THF (10 mL) for 16 h, filtered and dried under reduced pressure below 45°C to obtain the benzoate salt as a yellow solid.

Yield: 89 %

HPLC purity: 99.98% Impurity A: 0.02%

¾ NMR (400 MHz, D₂0) d 8.62 (s, 1H), 8.15 (s, 1H), 8.03 (s, 1H), 7.57 (d, J = 9.2 Hz, 1H), 7.11 (d, J= 9.6 Hz, 1H), 7.02 (s, 1H), 6.49 (s, 1H), 6.45 (s, 2H), 4.16 (t, J= 7.1 Hz, 2H), 3.96 (s, 3H), 3.78 (s, 6H), 3.50 - 3.41 (m, 1H), 3.33 (t, J= 6.8 Hz, 2H), 2.44 (s, 2H), 1.32 (d, J= 6.5 Hz, 6H).

Comparative Example:

Example-14: Preparation of Erdafitinib HC1 salt

Impure Erdafitinib (500 mg) obtained from example 9 and IPA (2 mL) were added into a flask and the mixture was heated to 60 °C to get a solution. Isopropanolic hydrochloride (IPA.HC1) was added slowly to the reaction mixture at 60 °C to adjust pH to 2. The precipitated product slurry was cooled to 25-30°C. Erdafitinib hydrochloride salt was obtained by filtration as a solid. The solid was stirred in THF (2.5 mL) for 18 h and filtered under vacuum. Yield:

HPLC purity: 99.73% Impurity A: 0.27%

¹H NMR (400 MHz, DMSO-i¾) S 9.10 (s, 2H), 9.02 (s, 1H), 8.57 (s, 1H), 8.22 (s, 1H), 7.83 (d, J = 9.2 Hz, 1H), 7.38 (d, J = 9.2 Hz, 1H), 7.26 (d, J = 2.7 Hz, 1H), 6.94 (brs, 2H), 6.51 (d, J = 2.2 Hz, 2H), 6.45 (t, J = 2.1 Hz, 1H), 4.21 (t, J = 7.3 Hz, 2H), 3.94 (s, 3H), 3.76 (s, 6H), 3.42 - 3.27 (m, 1H), 3.24 - 3.03 (m, 2H), 1.25 (d, J = 6.5 Hz, 6H).

Claims

Claims:

1 A process for preparation of Erdafitinib and its salts comprising;

2. The process as claimed in claim 1, wherein reaction in step a) is carried out in presence of base and solvent.

3. The process as claimed in claim 2, wherein reaction in step a) is carried out in presence of solvent selected from ethers, alcohols, halogenated hydrocarbons, aromatic hydrocarbons, aliphatic hydrocarbons, nitriles, esters, and polar aprotic solvents such as DMF, DMSO, DMAc; water; any mixtures.

4. The process as claimed in claim 3, wherein reaction in step a) is carried out in DMF.

5. The process as claimed in claim 1, wherein reaction in step a) is carried out in presence of a catalyst selected from alkali metal halides, ammonium salts, heterocyclic ammonium chlorides, phosphonium salts and ; phase transfer reagents.

6. The process as claimed in claim 5, wherein reaction in step a) is carried out in presence of potassium Iodide.

7. The process as claimed in claim 1, wherein the reduction in step b) is carried out in presence of a reducing agent selected from lithium borohydride, sodium Borohydride (NaBFB), lithium aluminum hydride (LiAlFB), Red-Al, sodium triacetoxyborohydride, sodium cyanoborohydride, borane.

8. The process as claimed in claim 1, wherein the reduction in step b) is carried out in presence of a solvent selected from ethers, alcohols, halogenated hydrocarbons, aromatic hydrocarbons, aliphatic hydrocarbons, nitriles, esters, and polar aprotic solvents such as DMF, DMSO, DMAc; or any mixtures.

9. The process as claimed in claim 8, wherein the reduction in step b) is carried out in tetrahydrofuran.

10. The process as claimed in claim 1, wherein the coupling in step c) is carried out in presence of palladium metal catalyst.

11. The process as claimed in claim 1, wherein the coupling in step c) is carried out in presence of a solvent selected from ethers, alcohols, halogenated hydrocarbons, aromatic hydrocarbons, aliphatic hydrocarbons, nitriles, esters, and polar aprotic solvents such as DMF, DMSO, DMAc; or any mixtures.

12. The process as claimed in claim 11, wherein the coupling in step c) is carried out in toluene.

13. A compound of formula III and its salts

14. Use of compound of formula III and its salts for preparation of Erdafitinib

15. Use of acid addition salts of Erdafitinib formed with organic acids for the purification of Erdafitinib specifically for reducing the content of impurity A

16. A process for purification of Erdafitinib specifically for reducing the content of impurity A comprising;

17. The process as claimed in claim 16, wherein the organic acid is selected from the group of lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulphonic, para-toluenesulphonic, methanesulphonic (mesylate), ethanesulphonic, naphthalenesulphonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic, adipic, ascorbic, aspartic, citric, gluconic, hippuric, glutamic, sebacic, stearic, tartaric, mandelic, salicylic, glutamic, trifluoroacetic, camphoric, cypionic, caproic, enanthic, lauric, nicotinic, pivalic acids.

18. The process as claimed in claim 16, wherein the organic acid is selected from para toluenesulphonic acid (PTSA), Benzoic acid and succinic acid.