WO2023122322A1 - Procédés améliorés pour la préparation de ripretinib - Google Patents

Procédés améliorés pour la préparation de ripretinib Download PDF

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Publication number
WO2023122322A1
WO2023122322A1 PCT/US2022/053916 US2022053916W WO2023122322A1 WO 2023122322 A1 WO2023122322 A1 WO 2023122322A1 US 2022053916 W US2022053916 W US 2022053916W WO 2023122322 A1 WO2023122322 A1 WO 2023122322A1
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Prior art keywords
acid
compound
ripretinib
process according
inorganic
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PCT/US2022/053916
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English (en)
Inventor
Parven Kumar Luthra
Chandrasekhar Sinha
Nitin Dnyaneshwar Arote
Anand Kumar Pandey
Bhupendra Prakash TYAGI
Jitendra Kamalakar SONAR
Sanjay Jaiswal
Maulik Dipakbhai MISTRY
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Teva Pharmaceuticals International Gmbh
Teva Pharmaceuticals Usa, Inc.
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Publication of WO2023122322A1 publication Critical patent/WO2023122322A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • 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.
  • 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:
  • Ripretinib (Quinlock) is approved by U.S. Food and Drug Administration for the treatment of gastrointestinal stromal tumors (GIST).
  • the present disclosure comprises an improved process for the synthesis of Ripretinib or salts thereof.
  • 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.
  • 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 methan
  • 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.
  • the present disclosure comprises Ripretinib or salts thereof produced by the processes of the present disclosure.
  • 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.
  • 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.
  • 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).
  • GIST Gastrointestinal Stromal Tumors
  • 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.
  • GIST Gastrointestinal Stromal Tumors
  • Figure 1 shows a powder X-ray diffraction pattern ("powder XRD” or "PXRD”) of Compound formula IV.
  • Figure 2 shows PXRD of Compound formula V.
  • Figure 3 shows PXRD of Compound formula Va.
  • Figure 4 shows PXRD of Ripretinib Form 1.
  • Figure 5 shows PXRD of Ripretinib Form 1.
  • the present disclosure comprises an improved process for the synthesis of Ripretinib or salt thereof.
  • 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.
  • the term “isolated” corresponds to compounds that are physically separated from the reaction mixture in which they are formed.
  • reduced pressure refers to a pressure of about 10 mbar to about 500 mbar, or about 50 mbar.
  • Ripretinib or intermediates thereof may be referred to herein as substantially pure or substantially free of impurities.
  • 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%).
  • 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.
  • 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.
  • 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.
  • 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.
  • 13 C NMR 13 C CP/MAS NMR
  • 13 C NMR 13 C CP/MAS NMR
  • 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.
  • a thing e.g., a reaction mixture
  • room temperature or “ambient temperature”, often abbreviated as "RT”.
  • RT room temperature
  • room temperature is from about 20°C to about 30°C, or about 22°C to about 27°C, or about 25°C.
  • 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.”
  • a material may be referred to as being suspended in 10 volumes (or 10 vol or 10V) of a solvent.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • an inorganic acid preferably hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid
  • organic acid preferably citric acid, succinic acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, and methanesulfonic acid
  • the compound-V can be prepared by reacting Compound-IV: with aqueous methylamine under pressure; and optionally isolating Compound-V.
  • the Compound-IV can be prepared by reacting Compound-II:
  • a further aspect of the disclosure provides a process for preparing Ripretinib (I): comprising:
  • Compound-V 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
  • the compound formula IV may be crystallized.
  • the present invention comprises a process for the preparation of
  • 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;
  • Va preferably in crystalline form
  • 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.
  • the base is cesium carbonate, potassium carbonate or sodium hydroxide.
  • the base is potassium carbonate.
  • 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,
  • solvent selected
  • the solvent is a dipolar aprotic solvent.
  • the solvent is dimethylacetamide or dimethylformamide.
  • the solvent is dimethylacetamide.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 the solvent is selected from methanol, dioxane, water or mixture thereof. In embodiments the solvent is water.
  • 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.
  • Compound formula-V can be isolated by extraction, precipitation or by any know process in the art.
  • the isolation process is quenching in water at different temperature or the direct filtration of reaction mixture.
  • the isolation process is quenching in water and filtration of reaction mixture at 0-30°C.
  • 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.
  • 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.
  • the acid is hydrochloric acid, tartaric acid, succinic acid, sulphuric acid, oxalic acid or citric acid.
  • the acid is hydrochloric acid to obtain compound formula-Va.
  • 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.
  • 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.
  • esters ethyl acetate, benzyl acetate, isoamyl acetate
  • alkyl hydrocarbon for example heptane, hexanes, cyclohexenes
  • arylated hydrocarbon for example toluene, xylenes
  • water or mixtures thereof e.g. methanol, ethanol, isopropyl alcohol or water. In embodiments the solvent is water.
  • 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.
  • the substantially pure Compound formula-Va is crystalline.
  • Substantially pure Compound formula-Va may be used for the preparation of Ripretinib or salts thereof.
  • the present disclosure provides a process for preparing Ripretinib (I), comprising:
  • 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:
  • Compound-V 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:
  • the process for preparing Ripretinib (I) comprises:
  • 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.
  • the base may be selected from triethylamine, disopropyl amine and pyridine.
  • the base is triethylamine.
  • 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.
  • a polar solvent preferably dimethylacetamide
  • 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 sulphoxid
  • 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.
  • Compound formula-I can be isolated by extraction, precipitation or by any known isolation process in the art.
  • the isolation process is quenching in water or in aq. Sodium carbonate solution at different temperature.
  • the isolation process is quenching the reaction mass in aqueous sodium carbonate solution at about 0°C to 30°C.
  • Ripretinib 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.
  • esters for example ethyl acetate, benzyl acetate, isoamyl acetate
  • alkyl hydrocarbon for example heptane, hexanes, cyclohexenes
  • arylated hydrocarbon for example toluene, xylenes
  • 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.
  • 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.
  • 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 Formula- VII may be an impurity obtained in the preparation of Ripretinib and salts thereof.
  • 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
  • Ripretinib API may comprise not more than about
  • Ripretinib API may comprise about 0.05% to about 0.15% of compound Formula- VII.
  • a crystalline compound selected from: or
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present disclosure comprises Ripretinib or salts thereof produced by the processes of the present disclosure.
  • 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.
  • the present disclosure comprises pharmaceutical formulations comprising Ripretinib or salts thereof prepared according to the present disclosure and at least one pharmaceutically acceptable excipient.
  • 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.
  • 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).
  • GIST Gastrointestinal stromal tumors
  • 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.
  • GIST Gastrointestinal stromal tumors
  • Scan range 2 - 40 degrees 2-theta
  • Step size 0.05 degrees
  • Sample holder PMMA specimen holder ring with silicon background.
  • Fine powder mode use fine powder mode
  • Particle type non-spherical
  • 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 -2 Preparation of 3-(5-amino-2-bromo-4-fluorophenyl)-l-ethyl-7-(methylamino)-l,6- naphthyridin-2(lH)-one (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.
  • 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).
  • 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)
  • 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.
  • 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.
  • 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%.
  • 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)
  • 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.
  • 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%.
  • 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.
  • 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
  • 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 sul
  • 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 dipolar aprotic solvent more particularly dimethyl formamide, dimethylacetamide, or hexamethyl phosphoramide (HMPA), N,N-dimethylacetamide (DMA), or N-methyl-2-pyrroli
  • 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 Clause 21, wherein the further purification comprises slurrying Ripretinib in the solvent at a temperature of at least 35°C, and cooling.
  • the solvent is a polar aprotic solvent, preferably selected from acetonitrile and THF, and more preferably THF.
  • 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.
  • 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
  • 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.
  • step (vi) optionally drying.
  • 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.
  • 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.
  • step (iii) comprises adding the solution in step (i) to the water or water containing Ripretinib form-1 seeds.
  • 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 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.
  • 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.
  • 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.
  • 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 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 1, for preparing Ripretinib (I) comprising:
  • 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 :
  • Compound-V 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:
  • step (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.
  • step (b) is carried out according to any of Clauses 52, 53, 54, 55, or 56.
  • step (d) reacting Compound-Va with phenylisocyanate : in a polar solvent, preferably dimethylacetamide to form Ripretinib, optionally isolating Ripretinib and optionally purifying Ripretinib.
  • a polar solvent preferably dimethylacetamide
  • step (b) is carried out according to any of Clauses 54, 55, or 56.
  • step (c) is carried out according to Clause 44, 45, 46, 47, 48, 49, 50, or 51.
  • 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.
  • 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.).
  • 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.
  • an inorganic acid preferably hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid
  • an organic acid preferably citric acid, succinic acid, oxalic acid, tartaric acid, maleic acid, benzoic acid, and methanesulfonic acid
  • 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 for preparing Ripretinib comprising preparing a compound according to any of Clauses 85, 86, 87, 88, or 89, and converting the compound to Ripretinib.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des procédés sûrs et améliorés pour la préparation d'intermédiaires sensiblement purs de formule Va et leur utilisation dans la synthèse de Ripretinib et de sels de celui-ci.
PCT/US2022/053916 2021-12-24 2022-12-23 Procédés améliorés pour la préparation de ripretinib WO2023122322A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8461179B1 (en) 2012-06-07 2013-06-11 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
WO2013184119A1 (fr) * 2012-06-07 2013-12-12 Flynn Daniel L Dihydronaphtyridines et composés apparentés utiles comme inhibiteurs de kinases pour le traitement de maladies prolifératives
WO2020185812A1 (fr) 2019-03-11 2020-09-17 Teva Pharmaceuticals International Gmbh Formes à l'état solide de riprétinib
CN112625038A (zh) * 2020-12-31 2021-04-09 武汉九州钰民医药科技有限公司 制备瑞普替尼的方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8461179B1 (en) 2012-06-07 2013-06-11 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
WO2013184119A1 (fr) * 2012-06-07 2013-12-12 Flynn Daniel L Dihydronaphtyridines et composés apparentés utiles comme inhibiteurs de kinases pour le traitement de maladies prolifératives
WO2020185812A1 (fr) 2019-03-11 2020-09-17 Teva Pharmaceuticals International Gmbh Formes à l'état solide de riprétinib
CN112625038A (zh) * 2020-12-31 2021-04-09 武汉九州钰民医药科技有限公司 制备瑞普替尼的方法

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Title
MCDONALD MATTHEW A ET AL: "Reactive crystallization: a review", REACTION CHEMISTRY & ENGINEERING, vol. 6, no. 3, 16 November 2020 (2020-11-16), pages 357 - 574, XP055951360, ISSN: 2058-9883, Retrieved from the Internet <URL:https://pubs.rsc.org/en/content/articlepdf/2021/re/d0re00272k> DOI: 10.1039/D0RE00272K *

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