FIELD OF THE INVENTION

[0001] The present invention relates to safe and improved processes for the preparation of substantially pure intermediates and their use in the synthesis of Ripretinib and salts thereof.

BACKGROUND OF THE INVENTION

[0002] Ripretinib has the chemical name N-[4-Bromo-5-[l-ethyl-l,2-dihydro-7- (methylamino)-2-oxo-l,6-naphthyridin-3-yl]-2-fluorophenyl]-N ' -phenylurea (compound formula-I). Ripretinib has the following chemical structure:

[0003] Ripretinib (Quinlock) is approved by U.S. Food and Drug Administration for the treatment of gastrointestinal stromal tumors (GIST).

[0004] Ripretinib and its synthesis are disclosed in U.S. Patent No. 8,461,179.

SUMMARY OF THE DISCLOSURE

[0005] The present disclosure comprises an improved process for the synthesis of Ripretinib or salts thereof.

[0006] In particular, the present disclosure provides a process for the preparation of Ripretinib (I), comprising reacting a Compound-Va: wherein A is selected from the group consisting of an inorganic acid (preferably hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid), or an organic acid (preferably citric acid, succinic acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, and methanesulfonic acid), and n is i for a dibasic acid or 2 for a monobasic acid; with phenylisocyanate, optionally isolating Ripretinib; and optionally purifying the Ripretinib.

[0007] The disclosure further comprises substantially pure intermediates, process for the synthesis thereof, and use thereof in the synthesis of Ripretinib or salts thereof. Also disclosed are impurities in the preparation of Ripretinib.

[0008] In another aspect, the present disclosure comprises Ripretinib or salts thereof produced by the processes of the present disclosure.

[0009] The present disclosure also encompasses the use of Ripretinib or salts thereof prepared by the processes of the present disclosure for the preparation of pharmaceutical compositions of Ripretinib and salts thereof.

[0010] The present disclosure comprises processes for preparing the above-mentioned pharmaceutical compositions. The processes include combining Ripretinib or salts thereof prepared by the processes of the present disclosure with at least one pharmaceutically acceptable excipient.

[0011] Ripretinib or salts thereof prepared by the processes of the present disclosure and the pharmaceutical compositions of Ripretinib or salts thereof prepared by the processes of the present disclosure can be used as medicaments, in embodiments, for the treatment of Gastrointestinal Stromal Tumors (GIST).

[0012] The present disclosure also comprises methods for the treatment of Gastrointestinal Stromal Tumors (GIST), by administering a therapeutically effective amount of Ripretinib or salts thereof prepared by the processes of the present disclosure, or at least one of the above pharmaceutical compositions, to a subject in need of the treatment.

BRIEF DESCRIPTION OF THE FIGURES

[0013] Figure 1 shows a powder X-ray diffraction pattern ("powder XRD" or "PXRD") of Compound formula IV.

[0014] Figure 2 shows PXRD of Compound formula V.

[0015] Figure 3 shows PXRD of Compound formula Va. [0016] Figure 4 shows PXRD of Ripretinib Form 1.

[0017] Figure 5 shows PXRD of Ripretinib Form 1.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0018] The present disclosure comprises an improved process for the synthesis of Ripretinib or salt thereof.

[0019] The disclosure further comprises substantially pure intermediates and process for the synthesis thereof. Disclosed intermediates can be advantageously used for preparation of Ripretinib or salts thereof.

[0020] Known processes for preparation of Ripretinib involve multiple purification steps in the active pharmaceutical ingredient (API) stage. The disclosed process in U.S. Patent No. 8,461,179 results in the formation of many impurities during the synthesis of intermediates as well as the final product. In view of this, it is necessary to develop an industrially viable process having highly pure intermediates resulting in a product, which is complying with the ICH requirements of quality parameters.

[0021] As used herein, and unless indicated otherwise, the term "isolated" corresponds to compounds that are physically separated from the reaction mixture in which they are formed. [0022] As used herein, and unless indicated otherwise, the term "reduced pressure" refers to a pressure of about 10 mbar to about 500 mbar, or about 50 mbar.

[0023] Ripretinib or intermediates thereof may be referred to herein as substantially pure or substantially free of impurities. As used herein in this context, unless indicated otherwise, the expressions "substantially pure" and "substantially free of impurities" will be understood to mean that the compound contains about 1% or less, about 0.5% or less, about 0.2% or less, about 0.1% or less or an undetectable amount, or about 0% of impurities, of the subject compound as measured, for example, by HPLC (i.e. area%). Thus, Ripretinib and salts thereof or intermediates thereof described herein as substantially pure would be understood to contain greater than about 99% (w/w), greater than about 99.5 % (w/w), greater than about 99.8% (w/w), greater than about 99.9% (w/w) or about 100% (w/w) of Ripretinib and salts thereof or intermediates thereof.

Accordingly, in some embodiments of the disclosure, the described compound may contain from about 0.2% to about 1% (w/w), from about 0.5% to about 1% (w/w), or from about 0.2% to about 0.5% (w/w) of one or more impurities. [0024] As used herein, unless otherwise indicated, Form 1 of Ripretinib refers to a crystalline form as disclosed in WO2020/185812. Accordingly, Form 1 of Ripretinib may be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 9.3, 11.8, 17.2, 24.4 and 27.0 degrees 2-theta ± 0.2 degrees 2-theta; a PXRD pattern as depicted in Figure 4 or Figure 5. Form 1 of Ripretinib may be alternatively characterized by the PXRD pattern having peaks at 9.3, 11.8, 17.2, 24.4 and 27.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks at 7.4, 10.8, 18.6, 20.5 and 23.7 degrees 2- theta ± 0.2 degrees 2-theta. Alternatively, Form 1 of Ripretinib may be characterized by a PXRD pattern having peaks at 7.4, 9.3, 10.8, 11.8, 17.2, 18.6, 20.5, 23.7, 24.4 and 27.0 degrees 2-theta ± 0.2 degrees 2-theta. Form 1 of Ripretinib may alternatively or additionally be characterized by a solid state ¹³ C NMR spectrum having peaks at 162.9, 160.0, 139.5, 128.9, 121.6 ± 0.2 ppm. Form 1 of Ripretinib may alternatively or additionally be characterized by a solid state ¹³ C NMR spectrum having the following chemical shift absolute differences from a reference peak at 87.4 ppm ± 0.2 ppm of 75.5, 72.6, 52.1, 41.5, 34.2± 0.1 ppm. Form I may be anhydrous form.

[0025] The modifier "about" should be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression "from about 2 to about 4" also discloses the range "from 2 to 4." When used to modify a single number, the term “about” may refer to plus or minus 10% of the indicated number and includes the indicated number. For example, "about 10%" may indicate a range of 9% to 11%, and "about 1" means from 0.9-1.1. [0026] As used herein, unless stated otherwise, XRPD measurements are measured using copper Ka radiation wavelength 1.5418 A. Preferably, XRPD peaks reported herein are measured using CuK a radiation, = 1.5418 A, typically at a temperature of 25 ± 3 °C.

[0027] As used herein, unless stated otherwise, ¹³ C NMR ( ¹³ C CP/MAS NMR) reported herein employ cross-polarization acquired using the standard pulse scheme at spinning frequency of 12 kHz, with a recycle delay of 8s and cross-polarization contact time of 2 ms. The strength of spin-locking fields BI( ¹³ C) expressed in frequency units co 1/2K = yBl was 64 kHz, preferably at a temperature of at 293 K ± 3°C.

[0028] A thing, e.g., a reaction mixture, may be characterized herein as being at, or allowed to come to "room temperature" or "ambient temperature", often abbreviated as "RT". This means that the temperature of the thing is close to, or the same as that of the space, e.g., the room or fume hood, in which the thing is located. Typically, room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.

[0029] The amount of solvent employed in chemical processes, e.g., reactions or crystallizations, may be referred to herein as a number of "volumes" or "vol" or "V." For example, a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent. In this context, this expression would be understood to mean milliliters of the solvent per gram of the material being suspended, such that suspending a 5 grams of a material in 10 volumes of a solvent means that the solvent is used in an amount of 10 milliliters of the solvent per gram of the material that is being suspended or, in this example, 50 mL of the solvent. In another context, the term "v/v" may be used to indicate the number of volumes of a solvent that are added to a liquid mixture based on the volume.

[0030] The present invention comprises a process for the preparation of Ripretinib of compound formula-I:

Ripretinib (I) comprising reacting a Compound-Va: wherein A is selected from the group consisting of an inorganic acid (preferably hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid), or an organic acid (preferably citric acid, succinic acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, and methanesulfonic acid), and n is i for a dibasic acid or 2 for a monobasic acid; with phenylisocyanate, optionally isolating Ripretinib; and optionally purifying the Ripretinib. [0031] The Compound-Va can be prepared by reaction of Compound-V: with an acid selected from the group consisting of an inorganic acid (preferably hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid), or an organic acid (preferably citric acid, succinic acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, and methanesulfonic acid), and isolating Compound-Va.

[0032] The compound-V can be prepared by reacting Compound-IV: with aqueous methylamine under pressure; and optionally isolating Compound-V.

[0033] The Compound-IV can be prepared by reacting Compound-II:

Compound-II with Compound-Ill:

Compound-Ill in the presence of an alkali metal or alkaline earth metal base, or an organic amine base; and optionally isolating Compound-IV. [0034] A further aspect of the disclosure provides a process for preparing Ripretinib (I): comprising:

(a) reacting Compound-II: in the presence of an alkali metal or alkaline earth metal base, or an organic amine base; to form Compound-IV:

(b) reacting Compound-IV with aqueous methylamine under pressure to form

(c) reacting Compound-V with an acid selected from the group consisting of an inorganic acid (preferably hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid), or an organic acid (preferably citric acid, succinic acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, and methanesulfonic acid), and n is i for a dibasic acid or 2 for a monobasic acid; to form Compound-Va: wherein A is selected from the group consisting of an inorganic acid (preferably hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid), or an organic acid (preferably citric acid, succinic acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, and methanesulfonic acid), and n is 1 for a dibasic acid or 2 for a monobasic acid, preferably wherein

(d) reacting Compound-Va with phenylisocyanate : in a polar solvent, to form Ripretinib, optionally isolating Ripretinib and optionally purifying Ripretinib.

[0035] Optionally, the compound formula IV may be crystallized.

[0036] In another aspect, the present invention comprises a process for the preparation of

Ripretinib (I):

Ripretinib (I) comprising the steps of a) reacting compound formula -II with Compound formula-III to form a compound formula-IV; b) reacting compound formula-IV with methylamine to form compound formula-V, preferably in crystalline form;

Compound-V c) purifying compound formula-V using acid to prepare substantially pure compound formula-

Va, preferably in crystalline form;

Compound-Va d) reacting compound formula-Va with compound formula- VI to obtain Ripretinib, preferably substantially pure Ripretinib;

e) Optionally, further purifying Ripretinib using a solvent and/or mixture of solvents.

[0037] In another aspect, the process can be performed according to scheme-2 herein below:

Compound-ll Compound-Ill Compound-IV Compound-V

Ripretinib(l) Compound-Va [0038] Compound formula-IV can be prepared in presence of inorganic and organic bases. Inorganic bases include for example potassium carbonate, potassium bicarbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, sodium hydroxide, potassium hydroxide and lithium hydroxide. In any embodiment of the processes disclosed herein, the base is cesium carbonate, potassium carbonate or sodium hydroxide. Alternatively, in any embodiments of the processes disclosed herein, the base is potassium carbonate.

[0039] Compound formula-IV can be prepared in presence of solvent selected from alcohols (particularly Cl -3 alcohols, more particularly methanol, ethanol, propanol, isopropanol or butanol), ketones (particularly C3-6 ketones, more particularly acetone, methyl isobutyl ketone, butanone, or acetophenone), dipolar aprotic solvents [particularly dimethyl formamide (DMF), dimethylacetamide, hexamethyl phosphoramide (HMPA), N,N-dimethylacetamide (DMA), N- methyl-2-pyrrolidone (NMP)], halogenated hydrocarbons (particularly halogenated Cl -6 alkanes, more particularly methylene dichloride, or ethylene dichloride), ethers [particularly C4-8 ethers, more particularly methyl tertiary butyl ether, diisopropyl ethyl ether, tetrahydrofuran (THF), dioxane, methyl-THF], dialkyl sulfoxides [particularly di(Cl-6 alkyl)sulfoxides, more particularly dimethyl sulfoxide], esters (particularly C4-8 alkyl esters, more particularly ethyl acetate, benzyl acetate, or isoamyl acetate), aliphatic hydrocarbons (particularly C6-12 hydrocarbons, more particularly heptane, hexanes, cyclohexane, or cyclohexenes), aromatic hydrocarbons (particularly C6-12 aromatic hydrocarbons, more particularly toluene or xylenes), water, or mixtures thereof. In any embodiment of the processes described herein, the solvent is a dipolar aprotic solvent. Alternatively, according to any embodiment of the processes described herein, the solvent is dimethylacetamide or dimethylformamide. Particularly according to any embodiment of the processes described herein, the solvent is dimethylacetamide.

[0040] Compound formula-IV can be prepared in different conditions, for example temperature in the range of 20°C to 120°C, 40°C to 100°C, and 70 °C to 90°C.

[0041] Compound formula-IV can be isolated by extraction, precipitation or by any known process in the art. In embodiments the isolation process is quenching in water at different temperature, for example quenching in water at 0-30°C. Compound formula-IV may be further crystallized. [0042] Compound formula-V can be prepared in presence of solution of methylamine. The methylamine solutions may be prepared in alcohol, ethers, alkyl or aryl solvents or in aqueous solution. In embodiments the methylamine solution is in methanol or aqueous solution. In embodiments the methylamine solution is an aqueous solution.

[0043] Compound formula-V can be prepared in presence of solvent selected from alcohol (Cl-3), ketones (C3-6), organic solvents (CI-8 alkanes, for example dimethyl formamide, dimethylacetamide), halogenated organic solvents (for example methylene dichloride, ethylene dichloride), ethers (for example methyl tertiary butyl ether, tetrahydrofuran, dioxane , methyl THF), sulphoxides (e.g. dimethyl sulphoxide), esters (for example ethyl acetate, benzyl acetate, isoamyl acetate), alkyl hydrocarbon (for example heptane, hexanes, cyclohexenes), arylated hydrocarbon (for example toluene, xylenes), water or mixtures thereof. In embodiments the solvent is selected from methanol, dioxane, water or mixture thereof. In embodiments the solvent is water.

[0044] Compound formula-V can be prepared in different condition for example temperature in the range of 60°C tol40°C, 80°C tol20°C, and 100°C tol lO°C.

[0045] Compound formula-V can be isolated by extraction, precipitation or by any know process in the art. In embodiments the isolation process is quenching in water at different temperature or the direct filtration of reaction mixture. In embodiments the isolation process is quenching in water and filtration of reaction mixture at 0-30°C.

[0046] Compound formula-V contains 3-(5-amino-2-bromo-4-fluorophenyl)-7- (dimethylamino)-l-ethyl-l,6-naphthyridin-2(lH)-one (Compound formula- VII) in an amount between about 0.10% to 5.0%, about 1.0% to 3.0% and about 2.0% by area of Compound formula-V.

[0047] Compound formula-V can be purified by treatment with different organic and inorganic acids. Suitable acid may be selected from the list comprising hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, methane sulphonic acid, trifluoro- methanesulphonic acid, difluoromethanesulphonic acid, di chloroacetic acid, glucuronic acid, gluconic acid, tartaric acid, citric acid, fumaric acid and any known acid which may form a salt of compound formula-V which may further precipitates from the mixture. In embodiments the acid is hydrochloric acid, tartaric acid, succinic acid, sulphuric acid, oxalic acid or citric acid. In embodiments the acid is hydrochloric acid to obtain compound formula-Va. [0048] Compound formula-V can be purified in different temperature in the range of 0°C to 100°C. In embodiments the temperature is 30°C to 80°C, and 50-70°C.

[0049] Compound formula-V can be purified in solvent selected from alcohol (Cl -3), ketones (C3-6), organic solvents (Cl -8 alkanes, for example dimethyl formamide), halogenated organic solvents (for example methylene dichloride, ethylene dichloride), ethers ( for example methyl tertiary butyl ether, tetrahydrofuran), sulphoxides (e.g. dimethyl sulphoxide), esters (ethyl acetate, benzyl acetate, isoamyl acetate), alkyl hydrocarbon (for example heptane, hexanes, cyclohexenes), arylated hydrocarbon (for example toluene, xylenes), water or mixtures thereof. In embodiments the solvent is methanol, ethanol, isopropyl alcohol or water. In embodiments the solvent is water.

[0050] Compound formula-Va is substantially free from 3-(5-amino-2-bromo-4- fluorophenyl)-7-(dimethylamino)-l -ethyl- l,6-naphthyridin-2(lH)-one impurity (compound formula- VII). Compound formula-Va comprises about 0.10% to about 5.0%, about 0.10% to about 1.0%, about 0.20% to about 0.30% by weight of compound formula -VII. In embodiments the substantially pure Compound formula-Va is crystalline. Substantially pure Compound formula-Va may be used for the preparation of Ripretinib or salts thereof.

Compound-VII

[0051] The present disclosure provides a process for preparing Ripretinib (I), comprising:

(a) reacting Compound-II:

Compound-II with Compound-Ill: Compound-Ill in the presence of an alkali metal or alkaline earth metal base, or an organic amine base; to form Compound-IV:

(b) reacting Compound-IV with aqueous methylamine under pressure to form Compound- V :

(c) reacting Compound-V with an acid selected from the group consisting of an inorganic acid (preferably hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid), or an organic acid (preferably citric acid, succinic acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, and methanesulfonic acid), and n is i for a dibasic acid or 2 for a monobasic acid; to form Compound- Va: wherein A is selected from the group consisting of an inorganic acid (preferably hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid), or an organic acid (preferably citric acid, succinic acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, and methanesulfonic acid), and n is 1 for a dibasic acid or 2 for a monobasic acid, preferably wherein

Compound Va is:

(d) reacting Compound-Va with phenylisocyanate : in a polar solvent, to form Ripretinib, optionally isolating Ripretinib and optionally purifying Ripretinib.

[0052] Preferably, the process for preparing Ripretinib (I) comprises:

(a) reacting Compound-II: in the presence of potassium carbonate, to form Compound-IV: (b) reacting Compound-IV with aqueous methylamine under pressure to form

(c) reacting Compound-V with hydrochloric acid; to form Compound-Va:

(d) reacting Compound-Va with phenylisocyanate : in a polar solvent, preferably dimethylacetamide to form Ripretinib, optionally isolating Ripretinib and optionally purifying Ripretinib.

[0053] The steps (a)-(d) may be conducted as described in any of the aspects and embodiments disclosed herein.

[0054] Compound formula-I can be prepared in presence of organic and inorganic bases. The organic bases may be selected from the list comprising triethylamine, disopropyl amine, pyridine, DBU (l,8-Diazabicyclo(5.4.0)undec-7-ene) and the inorganic bases may be selected from the list comprising potassium carbonate, potassium bicarbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide and other bases known in prior art. In embodiments the base may be selected from triethylamine, disopropyl amine and pyridine. In embodiments the base is triethylamine. [0055] In any aspect or embodiment of the present invention, Compound formula-I is prepared in the absence of a base, i.e. Compound-Va may be reacted with phenylisocyanate in a polar solvent, preferably dimethylacetamide, in the absence of a base. [0056] Compound formula-I can be prepared in presence of a solvent selected from the list comprising: ethers [particularly C4-8 ethers, more particularly methyl tertiary butyl ether, disopropyl ethyl ether, tetrahydrofuran (THF), dioxane, and methyl THF], ketones (particularly C3-6 ketones, more particularly acetone, methyl isobutyl ketone, butanone, or acetophenone), dipolar aprotic solvents [particularly dimethyl formamide, dimethylacetamide, hexamethyl phosphoramide (HMPA), N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP)], halogenated hydrocarbons (particularly halogenated Cl -6 alkanes, more particularly methylene di chloride or ethylene di chloride), sulfoxides ([particularly di(Cl-6 alkyl)sulfoxides, more particularly dimethyl sulphoxide), esters ((particularly C4-8 alkyl esters, more particularly ethyl acetate, benzyl acetate or isoamyl acetate), aliphatic hydrocarbons (particularly C6-12 hydrocarbons, more particularly heptane, hexanes, cyclohexane, or cyclohexenes), aromatic hydrocarbons (particularly C6-12 aromatic hydrocarbons, more particularly toluene or xylenes), water, or mixtures thereof. In any embodiment of the processes described herein, the solvent in this step is selected from tetrahydrofuran, dimethylacetamide, dimethylformamide and DMSO, and particularly dimethylacetamide.

[0057] Compound formula-I can be prepared in different condition, for example temperature in the range of (-10)°C to 60°C, 0°C to 50°C and 10°C to 50°C.

[0058] Compound formula-I can be isolated by extraction, precipitation or by any known isolation process in the art. In embodiments the isolation process is quenching in water or in aq. Sodium carbonate solution at different temperature. In embodiments the isolation process is quenching the reaction mass in aqueous sodium carbonate solution at about 0°C to 30°C.

[0059] In another embodiment, Ripretinib (Compound formula-I) may be purified by solvent selected from the list comprising alcohol (Cl-5), ketones (C3-6), organic solvents (Cl-8 alkanes, e.g. dimethyl formamide), halogenated organic solvents (for example methylene dichloride, ethylene dichloride), or ethers (for example methyl tertiary butyl ether, tetrahydrofuran), sulphoxides (e.g. dimethyl sulphoxide), esters (for example ethyl acetate, benzyl acetate, isoamyl acetate), alkyl hydrocarbon (for example heptane, hexanes, cyclohexenes), arylated hydrocarbon (for example toluene, xylenes), water or mixtures thereof.

[0060] In another embodiment, the present invention comprises substantially pure Ripretinib having a purity of greater than about 99.50 %, greater than about 99.85 % wherein substantially pure Ripretinib is having an impurity profile meeting the ICH guidelines. Substantially pure Ripretinib may comprises not more than 0.15% of known impurity.

[0061] The process related impurities that appear in the impurity profile of the Ripretinib may be substantially removed by the process of the present invention resulting in the formation of substantially pure Ripretinib, which meets the ICH guidelines.

[0062] In another aspect, the present disclosure comprises 3-(5-amino-2-bromo-4- fluorophenyl)-7-(dimethylamino)-l -ethyl- l,6-naphthyridin-2(lH)-one (compound Formula VII) or salt thereof

Compound-VII

[0063] Compound Formula- VII may be an impurity obtained in the preparation of Ripretinib and salts thereof.

[0064] In another aspect, the present disclosure comprises 3-(5-amino-2-bromo-4- fluorophenyl)-7-(dimethylamino)- 1 -ethyl- 1 ,6-naphthyridin-2(lH)-one (compound Formula- VII) in an amount of about 0.1% to 5.0% in compound formula V, about 0.10% to 1.0% in compound

Va, about 0.20 to 0.30% in compound Va. Ripretinib API may comprise not more than about

0.15 of compound Formula- VII. Ripretinib API may comprise about 0.05% to about 0.15% of compound Formula- VII.

[0065] In another aspect, there is provided a crystalline compound selected from: or

[0066] The crystalline form of Compound formula IV can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 11.6; 13.0; 14.6; 24.7 and 26.3 degrees 2-theta ± 0.2 degrees 2-theta; a PXRD pattern as depicted in Figure 1, and combinations of these data.

[0067] Crystalline form of Compound formula IV may be further characterized by a PXRD pattern having peaks at 11.6; 13.0; 14.6; 24.7 and 26.3 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks at 9.6; 15.5; 18.6; 19.5 and 21.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0068] Crystalline form of Compound formula IV may be characterized by each of the above characteristics alone or by all possible combinations, e.g., by a PXRD pattern having peaks at 11.6; 13.0; 14.6; 24.7 and 26.3 degrees 2-theta ± 0.2 degrees 2-theta and a PXRD pattern as depicted in Figure 1.

[0069] Crystalline form of Compound formula IV may alternatively be characterized by a PXRD pattern having peaks at 9.6; 11.6; 13.0; 14.6; 15.5; 18.6; 19.5; 21.5 24.7 and 26.3 degrees 2-theta ± 0.2 degrees 2-theta.

[0070] The present disclosure includes a crystalline form of Compound formula V. The crystalline form of Compound formula V can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 15.0; 16.1; 19.9; 24.6 and 25.6 degrees 2-theta ± 0.2 degrees 2-theta; a PXRD pattern as depicted in Figure 2, and combinations of these data. [0071] Crystalline form of Compound formula V may be further characterized by a PXRD pattern having peaks at 15.0; 16.1; 19.9; 24.6 and 25.6 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks at 8.2; 14.1; 20.4; 23.0 and 30.5 degrees 2-theta ± 0.2 degrees 2-theta. [0072] Crystalline form of Compound formula V may be characterized by each of the above characteristics alone or by all possible combinations, e.g., by a PXRD pattern having peaks at 15.0; 16.1; 19.9; 24.6 and 25.6degrees 2-theta ± 0.2 degrees 2-theta and a PXRD pattern as depicted in Figure 2.

[0073] Crystalline form of Compound formula V may alternatively be characterized by a PXRD pattern having peaks at 8.2; 14.1;15.0; 16.1; 19.9; 20.4; 23.0; 24.6; 25.6 and 30.5 degrees 2-theta ± 0.2 degrees 2-theta.

[0074] The present disclosure includes Compound formula Va: wherein A is selected from the group consisting of an inorganic acid (preferably hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid), or an organic acid (preferably citric acid, succinic acid, oxalic acid, -(+)-tartaric acid, maleic acid, benzoic acid, and methanesulfonic acid), and n is i for a dibasic acid or 2 for a monobasic acid; preferably wherein A is an inorganic acid, particularly hydrochloric acid or hydrobromic acid, and more particularly wherein Compound -Va is:

Compound-Va and crystalline form thereof. Compound formula Va and crystalline form thereof may be substantially pure. Compound formula Va may comprise 3-(5-amino-2-bromo-4-fluorophenyl)- 7-(dimethylamino)-l-ethyl-l,6-naphthyridin-2(lH)-one (Compound formula- VII) in an amount about 0.30% area or less. Compound formula Va may comprise about 0.10% to 1.0%, 0.10% to 0.30%, and about 0.20% to 0.30% area of 3-(5-amino-2-bromo-4-fluorophenyl)-7- (dimethylamino)-l-ethyl-l,6-naphthyridin-2(lH)-one.

[0075] The present disclosure includes a crystalline form of Compound formula Va. The crystalline form of Compound formula Va can be characterized by data selected from one or more of the following: a PXRD pattern having peaks at 8.3; 19.6; 22.0; 22.4 and 25.7 degrees 2- theta ± 0.2 degrees 2-theta; a PXRD pattern as depicted in Figure 3, and combinations of these data.

[0076] Crystalline form of Compound formula Va may be further characterized by a PXRD pattern having peaks at 8.3; 19.6; 22.0; 22.4 and 25.7 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks at 9.7; 13.1; 23.2; 26.3 and 27.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0077] Crystalline form of Compound formula Va may be characterized by each of the above characteristics alone or by all possible combinations, e.g., by a PXRD pattern having peaks at 8.3; 19.6; 22.0; 22.4 and 25.7 degrees 2-theta ± 0.2 degrees 2-theta and a PXRD pattern as depicted in Figure 3.

[0078] Crystalline form of Compound formula Va may alternatively be characterized by a PXRD pattern having peaks at 8.3; 9.7; 13.1; 19.6; 22.0; 22.4; 23.2; 25.7; 26.3 and 27.1 degrees 2-theta ± 0.2 degrees 2-theta.

[0079] In another aspect, the present disclosure provides the use of any one of the intermediates for the preparation of Ripretinib or salts thereof. Compound formula (Va) and solid state form thereof, may be used for the preparation of Ripretinib or salts thereof.

[0080] In another aspect, the present disclosure comprises Ripretinib or salts thereof produced by the processes of the present disclosure.

[0081] The present disclosure also comprises the use of Ripretinib or salts thereof prepared by the processes of the present disclosure for the preparation of pharmaceutical compositions or formulations of Ripretinib and salts thereof. [0082] The present disclosure comprises pharmaceutical formulations comprising Ripretinib or salts thereof prepared according to the present disclosure and at least one pharmaceutically acceptable excipient.

[0083] The present disclosure comprises processes for preparing the above mentioned pharmaceutical formulations. The processes include combining Ripretinib or salts thereof prepared by the processes of the present disclosure with at least one pharmaceutically acceptable excipient.

[0084] Ripretinib or salts thereof prepared by the processes of the present disclosure and the pharmaceutical compositions or formulations of Ripretinib or salts thereof prepared by the processes of the present disclosure can be used as medicaments, in embodiments, for the treatment of Gastrointestinal stromal tumors (GIST).

[0085] The present disclosure also comprises methods for the treatment of Gastrointestinal stromal tumors (GIST), by administering a therapeutically effective amount of Ripretinib or salts thereof prepared by the processes of the present disclosure, or at least one of the above pharmaceutical compositions or formulations, to a subject in need of the treatment.

[0086] Having described the disclosure with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification.

Analytical Methods

[0087] HPLC Method: Column: Ascentis Express 90 A C18 (15 cm X 4.6) mm, 2.7 pm;

(Cat#53829-U); Column temperature: 30°C; Mobile Phase: Eluent A: Buffer: Methanol (95:05), Eluent B: Acetonitrile : Water (90: 10) Buffer: lOmM Ammonium acetate in Water, Diluent: Acetonitrile: DMSO (80:20); Flow rate: 0.7 mL/minute; Detection: 240 nm; Injection Volume : 5 pL; Elution: Gradient

2, Powder X-ray Diffraction (XRD) method

X-ray diffraction was performed on X-Ray powder diffractometer:

[0088] Bruker D8 Advance; Copper Ka radiation ( = 1.5418 A); Lynx eye detector; laboratory temperature 22-25 °C; PMMA specimen holder ring. Prior to analysis, the samples were gently ground by means of mortar and pestle in order to obtain a fine powder. The ground sample was adjusted into a cavity of the sample holder and the surface of the sample was smoothed by means of a cover glass.

Measurement parameters:

Scan range: 2 - 40 degrees 2-theta;

Scan mode: continuous;

Step size: 0.05 degrees;

Time per step: 0.5 s;

Sample spin: 30 rpm;

Sample holder: PMMA specimen holder ring with silicon background.

[0089] The disclosure is further illustrated by reference to the following examples describing in detail the preparation of the composition and methods of use of the disclosure.

3. Particle size distribution method:

[0090] Instrumentation: Malvern Laser Diffraction Mastersizer 3000.

[0091] Accessory name: Aero S

Experimental Parameters

Measuring range: 0.01 - 3000 mcm

Analysis model: General purpose

Fine powder mode: use fine powder mode

Particle type: non-spherical

Powder RI: 1.714

Density (g/cm3): 1.5

Absorption index: 0

Measurement obscuration limits: obscuration lower limit (%): 0.5

Obscuration higher limit (%): 6

Measurement obscuration filtering: Enable filtering

Time out (seconds): 5

Sample measuring duration (seconds): 5

Background measuring duration (seconds): 5

Number of Measurements: 1 Pressure: 2 Bar

Feed rate of the flow cell: 50%

Venturi type: standard venture disperser

Tray type: General purpose tray (with hopper)

Hopper gap: 2mm (hopper with standard ball bearing)

Example- 1 : Preparation of 3-(5-amino-2-bromo-4-fluorophenyl)-7-chloro-l-ethyl-l,6- naphthyridin-2(lH)-one (Compound formula-IV)

[0092] Ethyl 2-(5-amino-2-bromo-4-fluorophenyl)acetate (150 grams, 0.543 mol, Compound formula-II) was reacted with 6-chloro-4-(ethylamino)nicotinaldehyde (102.3 grams, 0.554 mol, Compound formula III) in the presence of potassium carbonate (97.6 grams, 0.706 mol.) at 80- 90°C in Dimethylacetamide (DMAc, 450 mL) for 4-6 hours. After completion of the reaction, the mass is cooled to 20-35°C and water (1800 mL) is added and filtered to afford 3-(5-amino-2- bromo-4-fluorophenyl)-7-chloro-l-ethyl-l,6-naphthyridin-2(lH )-one (Compound formula-IV) , 215 grams (0.54 mol, >99% yield on dry basis) with >97% HPLC purity The obtained material was analyzed by XRPD and found crystalline form of Compound formula IV.

Example -2: Preparation of 3-(5-amino-2-bromo-4-fluorophenyl)-l-ethyl-7-(methylamino)-l ,6- naphthyridin-2(lH)-one (Compound formula- V)

[0093] 3-(5-Amino-2-bromo-4-fluorophenyl)-7-chloro-l-ethyl-l,6-naph thyridin-2(lH)-one (150 grams , 0.378 mol, crystalline Compound-IV) was reacted with methylamine (-40% in water) (3000 mL, 20 V) at 100°C-l 10°C for 5 hrs in a pressure reactor and pressure observed is 5-10 kg/cm2, the reaction mass is cooled and product was filtered at 0-5°C to afford 3-(5-amino- 2-bromo-4-fluorophenyl)-l-ethyl-7-(methylamino)-l,6-naphthyr idin-2(lH)-one (Compound formula- V) with yield 131 grams (0.335 mol, Yield 88.6% on dry basis ) having >97% HPLC purity. The obtained material was analyzed by XRPD and found crystalline form of Compound formula V.

Example-3: Preparation of 3-(5-amino-2-bromo-4-fluorophenyl)-l-ethyl-7-(methylamino)-l ,6- naphthyridin-2(lH)-one di-hydrochloride (Compound formula-Va) [0094] 3-(5-amino-2-bromo-4-fluorophenyl)-l-ethyl-7-(methylamino)-l ,6-naphthyridin- 2(lH)-one (6.1kg, crystalline Compound formula V) is charged in 19.5 L water at 20-30°C and heated to 60-70°C. Cone, hydrochloric acid (26 L) is added in 60-90 min and stirred for 60-90 min at 60-70°C followed by cooling and filtration at 0-5°C to obtain crystalline 3-(5-amino-2- bromo-4-fluorophenyl)- 1 -ethyl -N-methyl-2-(m ethylimino)- 1 ,2-dihydro- 1 ,6-naphthyridin-7- amine dihydrochloride (5.9k g, having >99.3% HPLC purity (Compound formula-Va). The product was observed to be substantially free from 3-(5-amino-2-bromo-4-fluorophenyl)-7- (dimethylamino)-l-ethyl-l,6-naphthyridin-2(lH)-one (Compound formula- VII) impurity. The obtained material was analyzed by XRPD and was found to be crystalline form of Compound formula Va.

Example -4: l-(4-Bromo-5-(l-ethyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6- naphthyridin-3-yl)- 2-fluorophenyl)-3 -phenylurea (Ripretinib Form-1)

[0095] l-(4-Bromo-5-(l-ethyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6- naphthyridin-3-yl)-2- fluorophenyl)-3 -phenylurea (4g, Ripretinib,) was charged into DMSO (40 mL) and heated to 60- 70°C to get clear solution and charcoalized at same temperature. In another flask charged (80 mL) purified water and charged l-(4-bromo-5-(l-ethyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6- naphthyridin-3-yl)-2-fluorophenyl)-3 -phenylurea Form-1 (4 mg) seed in it and heated to 60-70°C and slowly added DMSO solution to it at 60-70°C. Gradually cool the slurry at 20-30°C, filtered and dried at 50-60°C to get l-(4-bromo-5-(l-ethyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6- naphthyri din-3 -yl)-2-fluorophenyl)-3 -phenylurea (form- 1 ) .

[0096] Form-1 seed preparation : l-(4-Bromo-5-(l-ethyl-7-(methylamino)-2-oxo-l,2- dihydro-l,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea (1 g, Ripretinib) was charged into DMSO (137.7 mL) and water (15.36 ml) and heated to 60-65°C to get clear solution. Slowly added water (153 ml) to get precipitate which is stirred for 1 hr. and water (43 ml) is added ,stir for 15 min, cool to 30-35°C, filter and dry at 50-60°C to get 0.8 grams Ripretinib Form-1.

Example-5: Preparation of l-(4-bromo-5-(l-ethyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6- naphthyri din-3 -yl)-2-fluorophenyl)-3 -phenylurea (Compound formula-I)

[0097] 3-(5-Amino-2-bromo-4-fluorophenyl)-l-ethyl-7-(methylamino)-l ,6-naphthyridin- 2(lH)-one di-hydrochloride (18grams, 0.0388 mol. crystalline Compound formula-Va) was reacted with phenyl isocyanate (18.48 grams, 0.155 mol. Compound formula- VI) in a DMAc (90 mL) at 30-35°C for 4 hr. The reaction mass is quenched in aq. sodium carbonate solution (4.7grams in 360 mL water) at 20-30°C and filtered to afford wet 69.5 grams wet Ripretinib Crude (moisture 51.23%) having 70.96% HPLC purity.

[0098] Ripretinib crude wet (57.9 grams, moisture 51.23% ) was heated in mixture of toluene (375 mL) and methanol (375 mL) at 60-70°C for 2hr, cooled to 20-30°C and filtered to get wet Ripretinib Pure (16.5 grams) with >94.48% HPLC purity.

[0099] Ripretinib Pure (16.0 grams) was purified by heating in THF (750 mL) at 60-70°C for 4 hr , cooled to 20-30°C and filtered to get Ripretinib Cryst (13.5 grams) with >99.76 HPLC purity with all known and unknown impurities <0.1%.

[0100] Ripretinib Cryst (13 grams) was dissolved in DMSO (117 mL) at 25-30°C to get clear solution, filtered and washed with DMSO (13 ml). In another flask charged purified water (260 ml) and add Ripretinib form-1 seed (13 mg) and stir for Ihr at 60-70°C, cool top 25-30°C, stir for 1 hour, filtered and dried at 50-60°C to get Ripretinib Form-1 (11.5 grams).

Example-6: Preparation of l-(4-bromo-5-(l-ethyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6- naphthyri din-3 -yl)-2-fluorophenyl)-3 -phenylurea (Compound formula-I)

[0101] 3-(5-Amino-2-bromo-4-fluorophenyl)-l-ethyl-7-(methylamino)-l ,6-naphthyridin- 2(lH)-one di-hydrochloride (70g, 0.151 mol. crystalline Compound formula-Va) was reacted with phenyl isocyanate (71.86g, 0.603 mol. Compound formula- VI) in a DMAc (350 ml) at 25- 30° for 5 hr. The reaction mass is quenched in aq. sodium carbonate solution (18.54g in 1400 ml water) at 20-30°C, filtered and washed with water (350 ml) to afford wet Ripretinib Crude (271 grams, moisture -53.74%) with 72.05% HPLC purity.

Ripretinib crude wet (192.9 grams, moisture 53.74%) was heated in mixture of toluene (1250 ml) and methanol (1250 ml) at 60-70°C for 2 hr, cooled to 20-30°C , stir for 60 min, filtered and washed with methanol (50 ml) to get wet Ripretinib Pure (54 grams, LOD-3.42%) with >99.66% HPLC purity with all known and unknown impurities <0.12%.

Example-7: Preparation of l-(4-bromo-5-(l-ethyl-7-(methylamino)-2-oxo-l,2-dihydro-l,6- naphthyri din-3 -yl)-2-fluorophenyl)-3 -phenylurea (Compound formula-I) [0102] Ripretinib crude wet (77.4 grams, KF 53.74%) from example-6 was slurried in methanol (100 ml) at 20-30°C for 60 min, filtered and washed with methanol (20 ml) to get Ripretinib crude (wet 36.1 grams, moisture 8.46%) with 73.17% HPLC purity.

[0103] Ripretinib crude wet (36.1 grams, KF 8.46%) was heated in mixture of toluene (500 mL) and methanol (500 mL) at 60-70°C for 2 hr, cooled to 20-30°C , stir for 60 min, filtered and washed with methanol (20 mL) to get Ripretinib Pure (wet 21.5 grams) with >99.72% HPLC purity and all known and unknown impurities <0.10%.

[0105] Further aspects and embodiments of the present disclosure are set out in the following numbered clauses:

1. A process for the preparation of Ripretinib (I), comprising reacting a Compound-Va: wherein A is selected from the group consisting of an inorganic acid (preferably hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid), or an organic acid (preferably citric acid, succinic acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, and methanesulfonic acid), and n is 1 for a dibasic acid or 2 for a monobasic acid; with phenylisocyanate, optionally isolating Ripretinib; and optionally purifying the Ripretinib.

2. A process according to Clause 1, wherein the Compound-Va is substantially free from 3-(5- amino-2-bromo-4-fluorophenyl)-7-(dimethylamino)-l -ethyl- l,6-naphthyridin-2(lH)-one (compound formula- VII), optionally wherein the Compound-Va contains: 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, about 0.5% or less, about 0.2% or less, about 0.1% or less, about 0.05% or less, about 0.02% or less, about 0.01% or less, or about 0% of the compound VII, preferably as measured by HPLC (i.e. area %), optionally wherein Compound-Va contains undetectable amounts of Compound VII.

3. A process according to Clause 1 or Clause 2, wherein the polar solvent is selected from one or more of: ethers, particularly C4-8 ethers [more particularly methyl tertiary butyl ether, disopropyl ethyl ether, tetrahydrofuran (THF), dioxane or methyl THF]; ketones [particularly C3-6 ketones, more particularly acetone, methyl isobutyl ketone, butanone, or acetophenone]; dipolar aprotic solvents [particularly N,N-dimethylacetamide (DMA), dimethyl formamide (DMF), or hexamethyl phosphoramide (HMPA), or N-methyl-2- pyrrolidone (NMP)]; halogenated hydrocarbons [particularly halogenated C1-6 alkanes, more particularly methylene di chloride or ethylene di chloride]; sulfoxides particularly di(Ci-6 alkyl)sulfoxides [more particularly dimethyl sulfoxide]; esters, particularly C4-8 alkyl esters [more particularly ethyl acetate, benzyl acetate or isoamyl acetate]; aliphatic hydrocarbons, particularly C6-12 hydrocarbons [more particularly heptane, hexanes, cyclohexane, or cyclohexenes]; aromatic hydrocarbons, particularly C6-12 aromatic hydrocarbons [more particularly toluene or xylenes]; water; or mixtures thereof. A process according to any of Clauses 1, 2 or 3, wherein the polar solvent comprises, consists essentially of, or consists of a polar solvent selected from: a dipolar aprotic solvent [more particularly dimethyl formamide, dimethylacetamide, or hexamethyl phosphoramide (HMPA), N,N-dimethylacetamide (DMA), or N-methyl-2-pyrrolidone (NMP)]; or a C4-8 ether, more particularly methyl tertiary butyl ether, diisopropyl ethyl ether, tetrahydrofuran (THF), dioxane or methyl THF; particularly wherein the polar solvent is selected from the group consisting of: tetrahydrofuran, dimethylacetamide, dimethylformamide and DMSO. A process according to any of Clauses 1, 2 or 3, wherein the solvent is dimethylacetamide. A process according to any of Clauses 1, 2, 3, 4, or 5, wherein the reaction is carried out at a temperature of: about -10°C to about 100°C, about 0°C to about 90°C, about 10°C to about 80°C, about 15°C to about 70°C, about 18°C to about 65°C, about 20°C to about

50°C, about 20°C to about 40°C, about 20°C to about 35°C. A process according to Clause 5 wherein the reaction is carried out at a temperature of about 15°C to about 45°C, about 20°C to about 40°C, or about 30°C to about 35°C. A process according to any of Clauses 1, 2, 3, 4, 5, 6, or 7, wherein the reaction mixture is quenched with an aqueous inorganic base, preferably potassium carbonate, potassium bicarbonate, sodium carbonate, or sodium bicarbonate, more preferably sodium carbonate. A process according to any of Clauses 1, 2, 3, 4, 5, 6, or 7, wherein Compound-Va is crystalline, optionally wherein Compound-Va is characterized by an XRPD pattern substantially as depicted in Figure 3. A process according to any of Clauses 1, 2, 3, 4, 5, 6, 7, or 8, wherein Ripretinib is isolated by filtration or extraction, optionally by filtration. A process according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, or 9, wherein the Ripretinib is slurried with a Ci-Ce alcohol, preferably methanol or ethanol, preferably methanol, and filtered. A process according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, wherein Ripretinib is purified, optionally from a solvent and antisolvent. A process according to Clause 10 or Clause 11, wherein Ripretinib is purified by a process comprising slurrying Ripretinib in a mixture of a sol vent/ anti solvent, cooling, and optionally isolating. A process according to any of Clauses 10, 11, or 12, wherein Ripretinib is purified by a process comprising slurrying Ripretinib in a mixture of a solvent/anti solvent at a temperature of at least 35°C, and cooling. A process according to any of Clauses 10, 11, 12 or 13, wherein the solvent is selected from the group consisting of a Ci-Ce alcohol, preferably methanol or ethanol, and most preferably wherein the solvent is methanol. A process according to any of Clauses 10, 11, 12, 13, or 14, wherein the antisolvent is selected from the group consisting of a C5-C10 aliphatic or aromatic hydrocarbon, preferably toluene or a xylene, and most preferably wherein the antisolvent is toluene. A process according to any of Clauses 11, 12, 13, 14, or 15, wherein the Ripretinib is slurried in a mixture of a solvent/antisolvent at a temperature of: about 45°C to about 85°C, about 40°C to about 80°C, about 50°C to about 75°C, about 55°C to about 75°C, or about 60°C to about 70°C. A process according to any of Clauses 10, 11, 12, 13, 14, 15, or 16, wherein the mixture is slurried for: about 10 minute to about 4 hours, about 20 minutes to about 2 hours, about 30 minutes to about 90 minutes, or about 60 minutes. A process according to any of Clauses 11, 12, 13, 14, 15, 16, or 17, wherein the mixture is cooled to a temperature of: about 5°C to about 35°C, about 10°C to about 30°C, about 15°C to about 30°C, or about 20°C to about 30°C. A process according to any of Clauses 10, 11, 12, 13, 14, 15, 16, 17, or 18, wherein Ripretinib is purified by slurrying in a mixture of toluene and methanol, preferably at a temperature of about 50°C to about 75°C, about 55°C to about 75°C, or about 60°C to about 70°C. A process according to any of Clauses 10, 11, 12, 13, 14, 15, 16, 17, 18, or 19, wherein the Ripretinib is isolated by filtration, centrifuge or decantation, preferably by filtration. A process according to any of Clauses 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, wherein the Ripretinib is subjected to a further purification from another solvent, preferably comprising slurrying Ripretinib in the solvent, cooling, and optionally isolating. A process according to Clause 21, wherein the further purification comprises slurrying Ripretinib in the solvent at a temperature of at least 35°C, and cooling. A process according to Clause 21 or Clause 22, wherein the solvent is a polar aprotic solvent, preferably selected from acetonitrile and THF, and more preferably THF. A process according to any of Clauses 21, 22 or 23, wherein the Ripretinib is slurried in the solvent at a temperature of: about 45°C to about 100°C, about 50°C to about 95°C, about 60°C to about 90°C, or about 70°C to about 85°C. A process according to any of Clauses 21, 22, 23, or 24, wherein the mixture is stirred for: about 10 minute to about 4 hours, about 20 minutes to about 2 hours, about 30 minutes to about 90 minutes, or about 60 minutes. A process according to any of Clauses 21, 22, 23, 24, or 25, wherein the cooling is to a temperature of: about 5°C to about 35°C, about 10°C to about 30°C, about 15°C to about 30°C, or about 20°C to about 30°C. A process according to any of Clauses 20, 21, 22, 23, 24, 25, or 26, wherein the Ripretinib is purified by slurrying in acetonitrile, preferably at reflux. A process according to any of Clauses 20, 21, 22, 23, 24, 25, 26, or 27, wherein the Ripretinib is isolated by filtration, centrifuge or decantation, preferably by filtration. A process according to any of Clauses 10-28, further comprising drying the Ripretinib, preferably under reduced pressure, and/or at a temperature of: about 30°C about 80°C, about 40°C to about 70°C, about 45°C to about 65°C, or about 50°C to about 60°C. A process according to any of Clauses 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 further comprising converting the Ripretinib to crystalline Form-1. A process according to Clause 30, wherein the Ripretinib is converted to crystalline Form 1, preferably wherein Form I is characterized by data selected from the following:

(a) a PXRD pattern having peaks at 9.3, 11.8, 17.2, 24.4 and 27.0 degrees 2-theta ± 0.2 degrees 2-theta;

(b) a PXRD pattern as depicted in Figure 4 or Figure 5;

(c) a PXRD pattern having peaks at 9.3, 11.8, 17.2, 24.4 and 27.0 degrees 2-theta ± 0.2 degrees 2-theta, and also having one, two, three, four or five additional peaks at 7.4, 10.8, 18.6, 20.5 and 23.7 degrees 2-theta ± 0.2 degrees 2-theta;

(d) a PXRD pattern having peaks at 7.4, 9.3, 10.8, 11.8, 17.2, 18.6, 20.5, 23.7, 24.4 and 27.0 degrees 2-theta ± 0.2 degrees 2-theta;

(e) a solid state ¹³ C NMR spectrum having peaks at 162.9, 160.0, 139.5, 128.9, 121.6 ± 0.2 ppm;

(f) a solid state ¹³ C NMR spectrum having the following chemical shift absolute differences from a reference peak at 87.4 ppm ± 0.2 ppm of 75.5, 72.6, 52.1, 41.5, 34.2± 0.1 ppm; and

(g) a combination of any one of (a), (b), (c), or (d), with any of (e) or (f). A process according to Clause 31, wherein Ripretinib is converted to crystalline Form I by crystallising from a solvent selected from the group consisting of: water, DMSO, THF, toluene, methanol, acetonitrile, triethylamine, amyl acetate, amyl alcohol, iso-butanol, isobutyl acetate, n-butyl acetate, sec-butyl acetate, tert-butyl acetate, cumene, 1,2- di chloroethane, cyclomethylethyl ether, diethyl malonate, diethoxymethane, diisopropyl ether, ethyl acetoacetate, ethylbenzene, 1 -propanol, iso-propyl acetate, n-propyl acetate, 1,2-propylene carbonate, 3 -pentanone, o-xylene, m-xylene, p-xylene, or a combination thereof. A process according to Clause 32, wherein the solvent comprises DMSO and water, preferably in a volume ratio of about 6: 1 to about 1 :6, about 4: 1 to about 1 :4, about 2: 1 to about 1 :4, about 1 : 1 to about 1 : 1 :3, about 1 : 1.5 to about 1 :3.5, or about 1 :2. A process according to Clause 32 or Clause 33, comprising dissolving Ripretinib in the solvent or solvent mixture at a temperature of at least 35°C to the reflux temperature, optionally in the presence of Ripretinib Form-1 seeds, and cooling. A process according to any of Clauses 32, 33 or 34, wherein the Ripretinib is dissolved in the solvent at a temperature of: about 45°C to about 85°C, about 40°C to about 80°C, about 50°C to about 75°C, about 55°C to about 75°C, or about 60°C to about 70°C. A process according to any of Clauses 34 or 35, wherein the cooling is to a temperature of: about 5°C to about 35°C, about 10°C to about 30°C, about 15°C to about 30°C, or about 20°C to about 30°C. A process according to Clause 31, wherein the Ripretinib is converted to Form-1 by a process comprising:

(i) providing a solution of Ripretinib in DMSO, optionally at an elevated temperature;

(ii) optionally treating the solution with decolourising charcoal and filtering;

(iii) combining the solution with water, optionally wherein the water is at an elevated temperature and/or wherein the water contains seeds of Form- 1 Ripretinib;

(iv) cooling the mixture; and

(v) optionally isolating the Ripretinib form-1; and

(vi) optionally drying. A process according to Clause 37, wherein the temperature in step (i) is: about 40°C to about 90°C, about 50°C to about 80°C, about 55°C to about 75°C, or about 60°C to about 70°C. A process according to any of Clauses 37 or 38, wherein the temperature in step (ii) is: about 40°C to about 90°C, about 50°C to about 80°C, about 55°C to about 75°C, or about 60°C to about 70°C. A process according to any of Clauses 37, 38 or 39, wherein step (iii) comprises adding the solution in step (i) to the water or water containing Ripretinib form-1 seeds. A process according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 36, 37, 38, 39, or 40, wherein the Compound-Va : wherein A is selected from the group consisting of an inorganic acid (preferably hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid), or an organic acid (preferably citric acid, succinic acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, and methanesulfonic acid), and n is 1 for a dibasic acid or 2 for a monobasic acid; is prepared by reaction of Compound-V: with an acid selected from the group consisting of an inorganic acid (preferably hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid), or an organic acid (preferably citric acid, succinic acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, and methanesulfonic acid), and isolating Compound-Va. A process according to Clause 41, wherein the acid is an inorganic acid, preferably selected from the group consisting of: hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid. A process according to Clause 41 or Clause 42, wherein the acid is hydrochloric acid. A process according to any of Clauses41, 42 or 43, comprising combining the compound of Formula V with hydrochloric acid, at an elevated temperature, preferably at a temperature of: about 40°C to about 90°C, about 50°C to about 80°C, about 55°C to about 75°C, or about 60°C to about 70°C, to form a reaction mixture. A process according to Clause 44, wherein the compound of Formula V is provided as a mixture in water, preferably at an elevated temperature, more preferably at a temperature of: about 40°C to about 90°C, about 50°C to about 80°C, about 55°C to about 75°C, or more preferably about 60°C to about 70°C. A process according to Clause 45, wherein the hydrochloric acid is concentrated. A process according to any of Clauses 44, 45 or 46, wherein the hydrochloric acid is added portionwise, preferably over a period of: about 20 minutes to about 200 minutes, about 30 minutes to about 150 minutes, about 40 minutes to about 100 minutes, or about 60 to about 90 minutes. A process according to any of Clauses 41, 42, 43, 44, 45, 46, or 47, wherein the reaction mixture is stirred at an elevated temperature, preferably at a temperature of: about 40°C to about 90°C, about 50°C to about 80°C, about 55°C to about 75°C, or more preferably about 60°C to about 70°C. A process according to Clause 48, wherein the reaction mixture is stirred at the elevated temperature for a period of: about 20 minutes to about 200 minutes, about 30 minutes to about 150 minutes, about 40 minutes to about 100 minutes, or about 60 to about 90 minutes. A process according to any of Clauses 48 or 49, wherein the reaction mixture is cooled, preferably to a temperature of -5°C to about 10°C or about 0°C to about 5°C. A process according to any of Clauses 41, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, wherein the Compound Va is isolated, preferably by filtration, centrifuge, or decantation, more preferably by filtration. A process according to any of Clauses, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or 51, wherein the compound Va is: A process according to any of Clauses, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52, wherein the compound-V is prepared by reacting Compound-IV: with aqueous methylamine under pressure; and optionally isolating Compound-V. A process according to Clause 53, wherein Compound-IV is heated with the aqueous methylamine in a sealed vessel, preferably wherein the heating is to a temperature of about 60°C to about 130°C, about 80°C-120°C, or about 100°C-110°C. A process according to Clause 54, wherein Compound-V is isolated by filtration, optionally by filtration at: about 0°C to about 25°C, about 0°C to about 20°C, about 0°C to about 15°C, about 2°C to about 12°C, or about 3°C to about 10°C. A process according to any of Clauses 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, or 54, wherein Compound-V is crystalline, optionally wherein the Compound-V is characterized by an XRPD pattern substantially as depicted in Figure 2. A process according to any of Clauses 52, 53, 54, 55, or 56, wherein Compound-IV is prepared by reacting Compound-II: with Compound-Ill:

Compound-Ill in the presence of an alkali metal or alkaline earth metal base, or an organic amine base; and optionally a solvent, and optionally isolating Compound-IV. A process according to Clause 57, wherein the base is selected from the group consisting of: potassium carbonate, potassium bicarbonate, cesium carbonate, cesium hydroxide, sodium carbonate, sodium bicarbonate, potassium phosphate, sodium phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide, optionally wherein the base is cesium carbonate, potassium carbonate or sodium carbonate; or optionally wherein the base is cesium carbonate or potassium carbonate, and most preferably potassium carbonate. A process according to Clause 57, wherein the base is an amine selected from the group an alkyl amine, a cyclic amine or an arylamine, optionally a C2-10 mono-, di-, or tri-alkylamine, a C4-8 cyclic amine, or a Ce-io aromatic amine, optionally wherein the base is selected from trimethylamine, triethylamine, disopropyl amine, pyrrolidine, pyrrole, pyridine, or DBU [l,8-Diazabicyclo(5.4.0)undec-7-ene], or wherein the base is selected from triethylamine, disopropyl amine, pyridine, DBU (l,8-Diazabicyclo(5.4.0)undec-7-ene). A process according to any of Clauses 57, 58, or 59, wherein the reaction is carried out in a solvent, optionally selected from the group consisting of: alcohols, particularly C1-3 alcohols, more particularly methanol, ethanol, propanol, isopropanol or butanol; ketones, particularly C3-6 ketones, more particularly acetone, methyl isobutyl ketone, butanone, or acetophenone; dipolar aprotic solvents, particularly dimethyl formamide (DMF), dimethylacetamide, hexamethyl phosphoramide (HMPA), N,N-dimethylacetamide (DMA), N-methyl-2- pyrrolidone (NMP); halogenated hydrocarbons, particularly halogenated Ci-6 alkanes, more particularly methylene dichloride, or ethylene dichloride; ethers, particularly C4-8 ethers, more particularly methyl tertiary butyl ether, diisopropyl ethyl ether, tetrahydrofuran (THF), dioxane , methyl-THF]; dialkyl sulfoxides, particularly di(Ci-6 alkyl)sulfoxides, more particularly dimethyl sulfoxide; esters, particularly C4-8 alkyl esters, more particularly ethyl acetate, benzyl acetate, or isoamyl acetate; aliphatic hydrocarbons, particularly C6-12 hydrocarbons, more particularly heptane, hexanes, cyclohexane, or cyclohexenes; aromatic hydrocarbons, particularly C6-12 aromatic hydrocarbons, more particularly toluene or xylenes; water; or mixtures thereof. A process according to Clause 60, wherein the reaction is carried out in a dipolar aprotic solvent, optionally wherein the solvent is dimethylacetamide or dimethylformamide. A process according to Clause 61, wherein the solvent is dimethylacetamide. A process according to any of Clauses 57, 58, 59, 60, 61, or 62, wherein the reaction is carried out at a temperature of: about 10°C to about 120°C, about 15°C to about 80°C, about 40°C to about 120°C, about 50°C to about 110°C, about 60°C to about 100°C, about 70°C to about 95°C, or about 80°C to about 90°C. A process according to any of Clauses 57, 58, 59, 60, 61, 62, or 63, wherein Compound-IV is isolated by extraction, precipitation or filtration, and preferably by filtration. A process according to any of Clauses 57, 58, 59, 60, 61, 62, 63, or 64, wherein Compound- IV is crystalline, optionally wherein Compound-IV is characterized by an XRPD pattern substantially as depicted in Figure 1. A process according to Clause 1, for preparing Ripretinib (I), comprising:

(a) reacting Compound-II:

Compound-II with Compound-Ill: Compound-Ill in the presence of an alkali metal or alkaline earth metal base, or an organic amine base; to form Compound-IV :

(b) reacting Compound-IV with aqueous methylamine under pressure to form Compound- V :

(c) reacting Compound-V with an acid selected from the group consisting of an inorganic acid (preferably hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid), or an organic acid (preferably citric acid, succinic acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, and methanesulfonic acid), and n is i for a dibasic acid or 2 for a monobasic acid; to form Compound-Va: wherein A is selected from the group consisting of an inorganic acid (preferably hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid), or an organic acid (preferably citric acid, succinic acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, and methanesulfonic acid), and n is i for a dibasic acid or 2 for a monobasic acid, preferably wherein Compound Va is:

(d)reacting Compound-Va with phenylisocyanate : in a polar solvent, to form Ripretinib, optionally isolating Ripretinib and optionally purifying Ripretinib. A process according to Clause 66 wherein step (a) is carried out according to any of Clauses 57, 58, 59, 60, 61, 62, 63, 64, or 65. A process according to Clause 66 or Clause 67, wherein step (b) is carried out according to any of Clauses 52, 53, 54, 55, or 56. A process according to any of Clauses 66, 67 or 68, wherein step (c) is carried out according to Clause 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, or 51. A process according to any of Clauses, 66, 67, 68, or 69, wherein step (d) is carried out according to any of Clauses 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40. A process according to Clause 1, for preparing Ripretinib (I), comprising: (a) reacting Compound-II: in the presence of potassium carbonate, to form Compound-IV:

(b) reacting Compound-IV with aqueous methylamine under pressure to form

Compound-V :

(c) reacting Compound-V with hydrochloric acid; to form Compound-Va:

(d)reacting Compound-Va with phenylisocyanate : in a polar solvent, preferably dimethylacetamide to form Ripretinib, optionally isolating Ripretinib and optionally purifying Ripretinib. A process according to Clause 71 wherein step (a) is carried out according to any of Clauses 63, 64, or 65. A process according to Clause 71 or Clause 72, wherein step (b) is carried out according to any of Clauses 54, 55, or 56. A process according to any of Clauses 71, 72 or 73, wherein step (c) is carried out according to Clause 44, 45, 46, 47, 48, 49, 50, or 51. A process according to any of Clauses, 71. 72, 73, or 74, wherein step (d) is carried out according to any of Clauses 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40. A process for preparing Compound-IV comprising by reacting Compound-II: in the presence of an alkali metal or alkaline earth metal base, or an organic amine base; and optionally isolating Compound-IV. A process according to Clause 76, wherein the base is selected from the group consisting of: potassium carbonate, potassium bicarbonate, cesium carbonate, cesium hydroxide, sodium carbonate, sodium bicarbonate, potassium phosphate, sodium phosphate, sodium hydroxide, potassium hydroxide, lithium hydroxide, optionally wherein the base is cesium carbonate, potassium carbonate or sodium carbonate; or optionally wherein the base is cesium carbonate or potassium carbonate, and most preferably potassium carbonate. A process according to Clause 76, wherein the base is an amine selected from the group an alkyl amine, a cyclic amine or an arylamine, optionally a C2-10 mono-, di-, or tri-alkylamine, a C4-8 cyclic amine, or a Ce-io aromatic amine, optionally wherein the base is selected from trimethylamine, triethylamine, disopropyl amine, pyrrolidine, pyrrole, pyridine, or DBU [l,8-Diazabicyclo(5.4.0)undec-7-ene], or wherein the base is selected from triethylamine, disopropyl amine, pyridine, and DBU (l,8-Diazabicyclo(5.4.0)undec-7-ene.). A process according to any of Clauses 76, 77 or 78, wherein the reaction is carried out in a solvent, optionally selected from the group consisting of: alcohols, particularly C1-3 alcohols, more particularly methanol, ethanol, propanol, isopropanol or butanol; ketones, particularly C3-6 ketones, more particularly acetone, methyl isobutyl ketone, butanone, or acetophenone; dipolar aprotic solvents, particularly dimethyl formamide (DMF), dimethylacetamide, hexamethyl phosphoramide (HMPA), N,N-dimethylacetamide (DMA), N-methyl-2- pyrrolidone (NMP); halogenated hydrocarbons, particularly halogenated C1-6 alkanes, more particularly methylene dichloride, or ethylene dichloride; ethers, particularly C4-8 ethers, more particularly methyl tertiary butyl ether, diisopropyl ethyl ether, tetrahydrofuran (THF), dioxane , methyl-THF]; dialkyl sulfoxides, particularly di(Ci-6 alkyl)sulfoxides, more particularly dimethyl sulfoxide; esters, particularly C4-8 alkyl esters, more particularly ethyl acetate, benzyl acetate, or isoamyl acetate; aliphatic hydrocarbons, particularly C6-12 hydrocarbons, more particularly heptane, hexanes, cyclohexane, or cyclohexenes; aromatic hydrocarbons, particularly C6-12 aromatic hydrocarbons, more particularly toluene or xylenes; water; or mixtures thereof. A process according to Clause 79, wherein the reaction is carried out in a dipolar aprotic solvent, optionally wherein the solvent is dimethylacetamide or dimethylformamide; or optionally dimethylacetamide. A process according to any of Clauses 76, 77, 78, 79, or 80, wherein the reaction is carried out at a temperature of: about 10°C to about 120°C, about 15°C to about 80°C, about 40°C to about 120°C, about 50°C to about 110°C, about 60°C to about 100°C, about 70°C to about 95°C, or about 80°C to about 90°C . A process according to any of Clauses 76, 77, 78, 79, 80, or 81, wherein Compound-IV is isolated by extraction, precipitation or filtration. A process according to Clause 82 wherein Compound-IV is isolated by filtration. A process according to any of76, 77, 78, 79, 80, 81, 82, or 83, wherein Compound-IV is crystalline, optionally wherein Compound-IV is characterized by an XRPD pattern substantially as depicted in Figure 1. A crystalline compound selected from: Crystalline Compound-IV according to Clause 85, characterized by an XRPD pattern substantially as depicted in Figure 1. Crystalline Compound-V according to Clause 85, characterized by an XRPD pattern substantially as depicted in Figure 2. Compound- Va: wherein A is selected from the group consisting of an inorganic acid (preferably hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid), or an organic acid (preferably citric acid, succinic acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, and methanesulfonic acid), and n is 1 for a dibasic acid or 2 for a monobasic acid; preferably wherein A is an inorganic acid, particularly hydrochloric acid or hydrobromic acid, and more particularly wherein Compound -Va is: Compound-Va according to Clause 88, optionally in crystalline form, and optionally in crystalline form characterized by an XRPD pattern substantially as depicted in Figure 3. A process for preparing Compound-Va as defined in Clause 89 comprising reaction of Compound- V : with an acid selected from the group consisting of an inorganic acid (preferably hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid), or an organic acid (preferably citric acid, succinic acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, and methanesulfonic acid), and isolating Compound-Va. A process according to Clause 90, wherein the acid is an inorganic acid, preferably selected from the group consisting of: hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid. A process according to Clause 90 or Clause 91, wherein the acid is hydrochloric acid. A process according to any of Clauses 90, 91 or 92, comprising combining the compound of Formula V with hydrochloric acid, at an elevated temperature, preferably at a temperature of: about 40°C to about 90°C, about 50°C to about 80°C, about 55°C to about 75°C, or about 60°C to about 70°C, to form a reaction mixture. A process according to Clause 93, wherein the compound of Formula V is provided as a mixture in water, preferably at an elevated temperature, more preferably at a temperature of : about 40°C to about 90°C, about 50°C to about 80°C, about 55°C to about 75°C, or more preferably about 60°C to about 70°C. A process according to any of Clauses 93 or 94, wherein the hydrochloric acid is concentrated. A process according to any of Clauses 93, 94 or 95, wherein the hydrochloric acid is added portionwise, preferably over a period of: about 20 minutes to about 200 minutes, about 30 minutes to about 150 minutes, about 40 minutes to about 100 minutes, or about 60 to about 90 minutes. A process according to any of Clauses 93, 94, 95, or 96, wherein the reaction mixture is stirred at an elevated temperature, preferably at a temperature of: about 40°C to about 90°C, about 50°C to about 80°C, about 55°C to about 75°C, or more preferably about 60°C to about 70°C. A process according to Clause 97, wherein the reaction mixture is stirred at the elevated temperature for a period of: about 20 minutes to about 200 minutes, about 30 minutes to about 150 minutes, about 40 minutes to about 100 minutes, or about 60 to about 90 minutes. A process according to any of Clauses97 or 98, wherein the reaction mixture is cooled, preferably to a temperature of -5°C to about 10°C or about 0°C to about 5°C. A process according to any of Clauses 85, 86, 87, 88, 89, 90, 91, 92, 93, or 94, wherein the Compound Va is isolated, preferably by filtration, centrifuge, or decantation, more preferably by filtration. Use of a compound according to any of Clauses 85, 86, 87, 88, or 89, for the preparation of Ripretinib. A process for preparing Ripretinib comprising preparing a compound according to any of Clauses 85, 86, 87, 88, or 89, and converting the compound to Ripretinib. A process according to any of Clauses 1 to 84, further comprising combining the Ripretinib with at least one pharmaceutically acceptable excipient to form a pharmaceutical composition.