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WO2022162690A1 - Procédé de préparation de riprétinib et de formes à l'état solide de celui-ci - Google Patents

Procédé de préparation de riprétinib et de formes à l'état solide de celui-ci Download PDF

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Publication number
WO2022162690A1
WO2022162690A1 PCT/IN2022/050059 IN2022050059W WO2022162690A1 WO 2022162690 A1 WO2022162690 A1 WO 2022162690A1 IN 2022050059 W IN2022050059 W IN 2022050059W WO 2022162690 A1 WO2022162690 A1 WO 2022162690A1
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Prior art keywords
ripretinib
crystalline form
formula
preparation
present
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Inventor
Srinivas ORUGANTI
J. Sembian RUSO
Vishnu Vardhana Vema Reddy EDA
Saikat Sen
Barla RAJU
Sharmistha Pal DATTA
Srinivasulu Rangineni
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Dr Reddys Laboratories Ltd
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Dr Reddys Laboratories Ltd
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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 process for the preparation of Ripretinib and intermediates thereof.
  • the present invention also relates to solid state forms of Ripretinib and their processes for the preparation thereof.
  • Ripretinib is the adopted name for a drug chemically described as l-(4-bromo-5-[l-ethyl- 7-(methylamino)-2-oxo-l,2-dihydro-l,6-naphthyridin-3-yl]-2-fluoro-phenyl)-3-phenylurea and is represented by structural Formula I.
  • Ripretinib is a kinase inhibitor and is marketed in USA under the brand name as QINLOCK® tablets in 50 mg strength for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with 3 or more kinase inhibitors, including imatinib.
  • U.S. patent no. 8,461,179 discloses general procedure for the preparation of Ripretinib.
  • PCT publication no WO2021138483A1 discloses amorphous solid dispersion of Ripretinib with HPMC-AS.
  • Polymorphism is an important aspect of pharmaceutical drug in terms of its solubility and bioavailability.
  • One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in the gastric juices of a patient.
  • Different crystalline forms of polymorphs of the same pharmaceutical compounds can and reportedly do have different aqueous solubility.
  • the different solubility of the drug compound affects the bioavailability of drug at target site.
  • the prior art process for the preparation of Ripretinib have major drawbacks such as difficulties with respect to removal of process related impurities; poor commercial viability due to use of hazardous reactants; use of column chromatography and/ or low yields and purity of intermediates and final product. Therefore, there remains a need to develop such a process, which overcomes one or more of the above drawbacks associated with prior art process for preparation of Ripretinib.
  • the inventors of present invention have found out an improved process for the preparation of Ripretinib and intermediates thereof and solid state forms thereof.
  • the present invention provides a process for the preparation of Ripretinib of Formula I, comprising reacting a compound of Formula IF with a compound of formula III’ in presence of a base to obtain Ripretinib of formula I.
  • the present invention provides a process for the preparation of Ripretinib of Formula I, comprising reacting a compound of Formula II with a compound of Formula III in presence of a base to obtain Ripretinib of Formula I.
  • the present invention provides a process for the preparation of Ripretinib intermediate of Formula IV, comprising reacting a compound of Formula V with a compound of Formula VI in presence of a base to obtain Ripretinib intermediate of Formula IV.
  • the present invention provides a process for the preparation of Ripretinib intermediate of Formula VII, comprising treating a compound of Formula VIII with a reducing agent to obtain Ripretinib intermediate of Formula VII.
  • the present invention provides a process for the preparation of Ripretinib of Formula I, comprising converting compound of formula XI to Ripretinib of Formula
  • the present invention provides a process for the preparation of Ripretinib intermediate of Formula XV, comprising treating a compound of formula XIV with an oxidizing agent to obtain Ripretinib intermediate of Formula XV.
  • the present invention provides a crystalline form R1 of Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at about 6.7°, 7.5°, 13.3°, 14.2°, 15.9°, 19.1°, 19.5°, 19.9°, 23.0°, 23.4°, 25.2°, 25.6°, 27.6°, 28.7° and 32.1° ⁇ 0.2° 26.
  • the present invention provides a crystalline form R1 of Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 1.
  • the present invention provides a crystalline form R1 of Ripretinib characterized by TGDTA graph as depicted in Figure 2.
  • the present invention provides a process for the preparation of crystalline form R1 of Ripretinib, comprising steps of: i) providing Ripretinib in one or more suitable organic solvents; ii) isolating crystalline form R1 of Ripretinib.
  • the present invention provides a crystalline form R2 of Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at about 7.08°, 8.10°, 11.2°, 12.0°, 14.3°, 15.0°, 16.5°, 18.18°, 19.5°, 21.71°, 22.39° and 23.96° ⁇ 0.2° 20.
  • the present invention provides a crystalline form R2 of Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 4.
  • the present invention provides a process for the preparation of crystalline form R2 of Ripretinib, comprising steps of: i) providing Ripretinib in one or more suitable organic solvents; ii) optionally, adding one or more suitable anti-solvents; iii) isolating crystalline form R2 of Ripretinib.
  • the present invention provides a crystalline form R3 of Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at about 7.6°, 10.9°, 11.3°, 14.1°, 19.5°, 22.0° and 27.5° ⁇ 0.2° 20.
  • the present invention provides a crystalline form R3 of Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 5.
  • the present invention provides a process for the preparation of crystalline form R3 of Ripretinib, comprising steps of: i) providing Ripretinib in one or more suitable organic solvents; ii) optionally, adding one or more suitable anti-solvents; iii) isolating crystalline form R3 of Ripretinib.
  • the present invention provides a crystalline form R4 of Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at about 7.04, 12.34 and 22.67 ⁇ 0.2° 20.
  • the application provides a crystalline form R4 of Ripretinib characterized by X-ray diffraction pattern having additional characteristic peaks at about 14.14°, 15.60° and 26.94° ⁇ 0.2° 20.
  • the present invention provides a crystalline form R4 of Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 6.
  • the present invention provides a process for the preparation of crystalline form R4 of Ripretinib, comprising steps of: i) providing Ripretinib in one or more suitable organic solvents; ii) optionally, adding one or more suitable anti-solvents; iii) isolating crystalline form R4 of Ripretinib.
  • the present invention provides a crystalline form R5 of Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at about 6.95, 8.00, 13.63, 14.35 and 20.02 ⁇ 0.2° 20.
  • the application provides a crystalline form R5 of Ripretinib characterized by X-ray diffraction pattern having additional characteristic peaks at about 15.96, 18.80 and 23.34 ⁇ 0.2° 20.
  • the present invention provides a crystalline form R5 of Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 7.
  • the present invention provides a process for the preparation of crystalline form R5 of Ripretinib, comprising steps of: i) providing Ripretinib in one or more suitable organic solvents; ii) optionally, adding one or more suitable anti-solvents; iii) isolating crystalline form R5 of Ripretinib.
  • the present invention provides a crystalline form R6 of Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at about 6.7, 14.5, 24.8 and 25.76 ⁇ 0.2° 20.
  • the application provides a crystalline form R6 of Ripretinib characterized by X-ray diffraction pattern having additional characteristic peaks at about 13.98, 18.32, 19.83 22.18 and 27.4 ⁇ 0.2° 26.
  • the present invention provides a crystalline form R6 of Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 8.
  • the present invention provides a crystalline form R6 of Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 9.
  • the present invention provides a process for the preparation of crystalline form R6 of Ripretinib, comprising steps of: i) providing Ripretinib in one or more suitable organic solvents; ii) optionally, adding one or more suitable anti-solvents; iii) isolating crystalline form R6 of Ripretinib.
  • the present invention provides a crystalline form R7 of Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at about 7.11, 7.95 18.36 and 20.26 ⁇ 0.2° 26.
  • the application provides a crystalline form R7 of Ripretinib characterized by X-ray diffraction pattern having additional characteristic peaks at about 13.28, 14.33, 23.4 and 25.68 ⁇ 0.2° 26.
  • the present invention provides a crystalline form R7 of Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 10.
  • the present invention provides a process for the preparation of crystalline form R7 of Ripretinib, comprising steps of: i) providing Ripretinib form R6 in one or more suitable organic solvents; ii) optionally, adding one or more suitable anti-solvents; iii) isolating crystalline form R7 of Ripretinib.
  • the present application relates to amorphous solid dispersion of Ripretinib with a suitable pharmaceutically acceptable excipient.
  • the present application relates to amorphous solid dispersion of Ripretinib with Eudragit.
  • the present invention provides amorphous solid dispersion of Ripretinib with Eudragit (1: 3 w/w) characterized by X-ray diffraction pattern as depicted in Figure 11. In another embodiment, the present invention provides amorphous solid dispersion of Ripretinib with Eudragit (1: 5 w/w) characterized by X-ray diffraction pattern as depicted in Figure 12.
  • the present application relates to a process for preparing amorphous solid dispersion of Ripretinib comprising: i) dissolving a mixture of Ripretinib and Eudragit in a suitable solvent and ii) isolating amorphous solid dispersion of Ripretinib.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising crystalline form R1 of Ripretinib or crystalline form
  • R2 of Ripretinib or crystalline form R3 of Ripretinib or crystalline form
  • R5 of Ripretinib or crystalline form R6 of Ripretinib or crystalline form
  • R7 of Ripretinib or amorphous solid dispersion and at least one pharmaceutically acceptable excipient.
  • Figure 1 is an illustration of a PXRD pattern of crystalline form R1 of Ripretinib.
  • Figure 2 is an illustration of TGDTA graph of crystalline form R1 of Ripretinib.
  • Figure 3 is an illustration of a PXRD pattern of crystalline form R1 of Ripretinib by Example-11.
  • Figure 4 is an illustration of a PXRD pattern of crystalline form R2 of Ripretinib by Example- 12.
  • Figure 5 is an illustration of a PXRD pattern of crystalline form R3 of Ripretinib by Example- 18.
  • Figure 6 is an illustration of a PXRD pattern of crystalline form R4 of Ripretinib by Example- 19.
  • Figure 7 is an illustration of a PXRD pattern of crystalline form R5 of Ripretinib by Example-21.
  • Figure 8 is an illustration of a PXRD pattern of crystalline form R6 of Ripretinib by Example-22.
  • Figure 9 is an illustration of a PXRD pattern of crystalline form R6 of Ripretinib by Example-23.
  • Figure 10 is an illustration of PXRD pattern of crystalline form R7 of Ripretinib by Example-24.
  • Figure 11 is an illustration of a PXRD pattern of amorphous solid dispersion of Ripretinib with Eudragit (1: 3 w/w) obtained as per Example-25.
  • Figure 12 is an illustration of a PXRD pattern of amorphous solid dispersion of Ripretinib with Eudragit (1: 5 w/w) obtained as per Example-26.
  • ethyl 4, 6-dichloronico tinate and ethyl 2-(5- amino-2-bromo-4-fluorophenyl)acetate may be obtained according to any method known in the art or may be procured from the commercially available sources.
  • the present invention provides a process for the preparation of Ripretinib of Formula I, comprising reacting a compound of Formula IF with a compound of formula III’ in presence of a base to obtain Ripretinib of formula I.
  • X is phenoxy.
  • both Pi and P2 are each independently selected from group consisting of
  • the suitable protecting group may be selected from the group consisting of acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, phenylacetyl, phthalyl, o- nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4 -chlorobenzoyl, 4-bromobenzoyl, 4- nitrobenzoyl, and the like; sulfonyl groups such as phenylsulfonyl, benzenesulfonyl, 4- nitrobenzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyl-oxycarbonyl, 2-nitrobenzyloxycarbonyl,
  • Protecting groups are known to those skilled in the art and can be added or removed using well-known procedures such as those set forth in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, N.Y., (3rd Edition, 1999).
  • the present invention provides a process for the preparation of Ripretinib of Formula I, comprising reacting a compound of Formula II with a compound of Formula III in presence of a base to obtain Ripretinib of Formula I.
  • the reaction may be carried out in the presence of suitable organic solvent.
  • the reaction is carried out in the presence of tetrahydrofuran.
  • the reaction may be carried out in the presence of a suitable base. In a preferred embodiment the reaction is carried out in the presence of 1 -methylpyrrolidine.
  • the present invention provides a process for the preparation of Ripretinib intermediate of Formula IV, comprising reacting a compound of Formula V with a compound of Formula VI in presence of a base to obtain Ripretinib intermediate of Formula IV.
  • the reaction may be carried out in the presence of a suitable base.
  • the reaction is carried out in the presence of lithium hydroxide or lithium hydroxide on alumina.
  • the present invention relates to use of Ripretinib intermediate of Formula IV prepared according to the methods disclosed herein for the preparation of Ripretinib.
  • the present invention provides a process for the preparation of Ripretinib intermediate of Formula VII, comprising treating a compound of Formula VIII with a reducing agent to obtain Ripretinib intermediate of Formula VII.
  • the reaction may be carried out in the presence of a suitable reducing agent.
  • the reducing agents may be selected from the group consisting of that can potentially be employed for this transformation are: lithium aluminium hydride (LiAlH4), lithium tri-tert-butoxyaluminum hydride (LiAlH(0t-Bu)3) diisobutylaluminium hydride (DIBAL-H), Lithium borohydride
  • LiBH4 Lithium triethylborohydride
  • LiBHEts Lithium triethylborohydride
  • the present invention relates to use of Ripretinib intermediate of Formula VII prepared according to the methods disclosed herein in the preparation of Ripretinib.
  • the present invention provides Ripretinib, obtained according the processes of above aspects.
  • the suitable protecting group may be selected from the group consisting of acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, phenylacetyl, phthalyl, o- nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4- nitrobenzoyl, and the like; sulfonyl groups such as phenylsulfonyl, benzenesulfonyl, 4- nitrobenzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyl-oxycarbonyl, 2-nitrobenzyloxycarbonyl, p
  • the present invention provides a process for the preparation of Ripretinib of Formula I, comprising: a) reacting a compound of Formula IX with a compound of Formula III in presence of a base to obtain a compound of Formula XI; b) reacting a compound of Formula XI with a compound of formula XII in presence of a base of obtain compound of formula XIII; c) converting compound of formula XIII to Ripretinib of formula I.
  • the present invention provides a process for the preparation of Ripretinib of Formula I, comprising converting compound of formula XI to Ripretinib of Formula I; wherein Xi is as defined above.
  • the reaction of step-a) may be carried out in the presence of a suitable base. In a preferred embodiment the reaction is carried out in the presence of 1 -methylpyrrolidine.
  • the reaction of step-a) may be carried out in the presence of suitable organic solvent. In a preferred embodiment the reaction is carried out in the presence of tetrahydrofuran.
  • the reaction of step-b) may be carried out in the presence of a suitable base. In a preferred embodiment the reaction is carried out in the presence of Lithium hydroxide monohydrate (LiOH.FLO).
  • the reaction of step-b) may be carried out in the presence of suitable organic solvent. In a preferred embodiment the reaction is carried out in the presence of N,N-Dimethylacetamide (DMAc).
  • the present invention provides a process for the preparation of Ripretinib intermediate of Formula XV, comprising treating a compound of formula XIV with an oxidizing agent to obtain Ripretinib intermediate of Formula XV.
  • the reaction may be carried out in the presence of a suitable oxidizing agent.
  • the oxidizing agents may be selected from the group consisting of general oxidizing agents such as hydrogen peroxide, urea hydrogen peroxide, percarbonates, benzoyl peroxide, peracetic acid, di-t-butyl peroxide, persulfate, sodium peroxide, periodic acid, periodate, perboric acid, perborates, permanganic acid, permanganates, iodic acid, iodates, molecular iodine, cerium ammonium nitrate, ferric nitrate, 2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO) or the like, or mixtures thereof.
  • the reaction is carried out in the presence of mixture of 2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO) and molecular iodine.
  • the present invention relates to use of Ripretinib intermediate of Formula XV prepared according to the methods disclosed herein in the preparation of Ripretinib.
  • the present invention provides a crystalline form R1 of Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at about 6.7°, 7.5°, 13.3°, 14.2°, 15.9°, 19.1°, 19.5°, 19.9°, 23.0°, 23.4°, 25.2°, 25.6°, 27.6°, 28.7° and 32.1° ⁇ 0.2° 26.
  • the crystalline form R1 of Ripretinib may be further characterized by X-ray diffraction pattern having characteristic peaks at about 6.7°, 7.5°, 11.4°, 12.3°, 13.3°, 13.7°, 14.2°, 14.7°, 15.4°, 15.9°, 16.5°, 17.2°, 18.0°, 19.1°, 19.5°, 19.9°, 20.2°, 22.0°, 22.2°, 23.0°, 23.4°, 24.0°, 24.3°, 25.2°, 25.6°, 26.2°, 26.7°, 27.6°, 28.7°, 29.1°, 30.6°, 32.1°, 33.1°, 34.0°, 35.8°, 36.9° and 38.6° ⁇ 0.2° 20.
  • the present invention provides a crystalline form R1 of Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 1.
  • the present invention provides a crystalline form R1 of Ripretinib characterized by TGDTA graph as depicted in Figure 2.
  • the present invention provides a process for the preparation of crystalline form R1 of Ripretinib, comprising steps of: i) providing Ripretinib in one or more suitable organic solvents; ii) isolating crystalline form R1 of Ripretinib.
  • the suitable organic solvent may be selected from the group consisting of N,N-dimethylformamide (DMF), dimethylacetamide (DMA), methanol, ethanol, isopropyl alcohol, water or mixtures thereof.
  • the crystalline form R1 of Ripretinib is stable and has excellent physico-chemical properties.
  • the crystalline form R1 of Ripretinib of the present application may be easily formulated into a pharmaceutical composition along with suitable pharmaceutically acceptable excipients.
  • the crystalline form R1 of Ripretinib of the present invention or the pharmaceutical compositions thereof comprises Ripretinib with a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
  • Crystalline form R1 of Ripretinib was found to be stable in 25 ⁇ 2°C and 2-8°C conditions for three months.
  • the data presented below substantiate that the Crystalline form R1 of Ripretinib has a high storage stability.
  • the present invention provides a crystalline form R2 of Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at about 7.08°, 8.10°, 11.2°, 12.0°, 14.3°, 15.0°, 16.5°, 18.18°, 19.5°, 21.71°, 22.39° and 23.96° ⁇ 0.2° 20.
  • the present invention provides a crystalline form R2 of Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 4.
  • the present invention provides a process for the preparation of crystalline form R2 of Ripretinib, comprising steps of: i) providing Ripretinib in one or more suitable organic solvents; ii) optionally, adding one or more suitable anti-solvents; iii) isolating crystalline form R2 of Ripretinib.
  • suitable organic solvent or anti-solvent may be selected from the group consisting of methanol, ethanol, isopropyl alcohol, water or mixtures thereof.
  • the starting material is any crystalline form of Ripretinib, known in the literature or in this present application. In one embodiment, the starting material is crystalline form R1 of Ripretinib.
  • the present invention provides a process for the preparation of crystalline form R2 of Ripretinib, comprising steps of: i) providing Ripretinib in one or more suitable organic solvents; ii) optionally, adding one or more suitable anti-solvents; iii) optionally, adding seed crystals of crystalline form of Ripretinib; iv) isolating crystalline form R2 of Ripretinib.
  • the crystals of Form R2 of Ripretinib may be used as the nucleating agent or “seed” crystals for subsequent crystallizations from solutions.
  • the crystalline form R2 of Ripretinib is an anhydrous form.
  • the crystalline form R1 of Ripretinib is stable and has excellent physico-chemical properties.
  • the crystalline form R1 of Ripretinib of the present application may be easily formulated into a pharmaceutical composition along with suitable pharmaceutically acceptable excipients.
  • the crystalline form R2 of Ripretinib of the present invention or the pharmaceutical compositions thereof comprises Ripretinib with a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
  • Crystalline form R2 of Ripretinib was found to be stable at 25 ⁇ 2°C and 2-8°C conditions for three months.
  • the data presented below substantiate that the Crystalline form R2 of Ripretinib has a high storage stability.
  • the present invention provides a crystalline form R3 of Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at about 7.6°, 10.9°, 11.3°, 14.1°, 19.5°, 22.0° and 27.5° ⁇ 0.2° 26.
  • the crystalline form R3 of Ripretinib may be further characterized by X-ray diffraction pattern having characteristic peaks at about 5.7°, 7.6°, 10.9°, 11.3°, 12.7°, 13.6°, 14.1°, 15.09°, 17.6°, 19.5°, 20.05°, 21.5°, 22.06°, 23.09°, 24.6°, 26.4°, 27.5°, 30.3°, 30.6°, 32.2°, 35.2° and 39.0° ⁇ 0.2° 20.
  • the present invention provides a crystalline form R3 of Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 5.
  • the present invention provides a process for the preparation of crystalline form R3 of Ripretinib, comprising steps of: i) providing Ripretinib in one or more suitable organic solvents; ii) optionally, adding one or more suitable anti-solvents; iii) isolating crystalline form R3 of Ripretinib.
  • the suitable organic solvent or anti-solvent may be selected from the group consisting of ethyl acetate and hexane.
  • the crystalline form R3 of Ripretinib of the present invention is stable under thermal, humid and stress conditions. Further, the crystalline form R3 of Ripretinib of the present invention exhibits superior solubility in solvents such as water, as compared to reported crystalline forms of Ripretinib.
  • Ripretinib obtained according the processes of present invention and the crystalline form R3 of Ripretinib of the present invention or the pharmaceutical compositions thereof, comprises Ripretinib with a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
  • Ripretinib may be obtained according to any method known in the art.
  • the present invention provides a crystalline form R4 of Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at about 7.04, 12.34 and 22.67 ⁇ 0.2° 26.
  • the application provides a crystalline form R4 of Ripretinib characterized by X-ray diffraction pattern having additional characteristic peaks at about 14.14°, 15.60° and 26.94° ⁇ 0.2° 20.
  • the present invention provides a crystalline form R4 of Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 6.
  • the present invention provides a process for the preparation of crystalline form R4 of Ripretinib, comprising steps of: i) providing Ripretinib in one or more suitable organic solvents; ii) optionally, adding one or more suitable anti-solvents; iii) isolating crystalline form R4 of Ripretinib.
  • the suitable organic solvent may be selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl 2-pyrrolidone or mixtures thereof.
  • the starting material Ripretinib is in any crystalline form or amorphous form as known in the literature.
  • the crystals of Form R4 of Ripretinib may be used as the nucleating agent or “seed” crystals for subsequent crystallizations from solutions.
  • the crystalline form R4 of Ripretinib is stable and has excellent physico-chemical properties.
  • the crystalline form R4 of Ripretinib of the present application may be easily formulated into a pharmaceutical composition along with suitable pharmaceutically acceptable excipients.
  • the crystalline form R4 of Ripretinib of the present invention or the pharmaceutical compositions thereof comprises Ripretinib with a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
  • the present invention provides a crystalline form R5 of Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at about 6.95, 8.00, 13.63, 14.35 and 20.02 ⁇ 0.2° 20.
  • the application provides a crystalline form R5 of Ripretinib characterized by X-ray diffraction pattern having additional characteristic peaks at about 15.96, 18.80 and 23.34 ⁇ 0.2° 20.
  • the present invention provides a crystalline form R5 of Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 7.
  • the present invention provides a process for the preparation of crystalline form R5 of Ripretinib, comprising steps of: i) providing Ripretinib in one or more suitable organic solvents; ii) optionally, adding one or more suitable anti-solvents; iii) isolating crystalline form R5 of Ripretinib.
  • the suitable organic solvent may be selected from the group consisting of methanol, ethanol, 2-propanol, n-propanol, n-butanol, isoamyl alcohol, octanol, 1,2-propanediol, S-(+)-l,2-propanediol and ethylene glycol or mixtures thereof.
  • the starting material Ripretinib is in any crystalline form or amorphous form as known in the literature.
  • the crystals of Form R5 of Ripretinib may be used as the nucleating agent or “seed” crystals for subsequent crystallizations from solutions.
  • the crystalline form R5 of Ripretinib is stable and has excellent physico-chemical properties.
  • the crystalline form R5 of Ripretinib of the present application may be easily formulated into a pharmaceutical composition along with suitable pharmaceutically acceptable excipients.
  • the crystalline form R5 of Ripretinib of the present invention or the pharmaceutical compositions thereof comprises Ripretinib with a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
  • the present invention provides a crystalline form R6 of Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at about 6.7, 14.5, 24.8 and 25.76 ⁇ 0.2° 20.
  • the application provides a crystalline form R6 of Ripretinib characterized by X-ray diffraction pattern having additional characteristic peaks at about 13.98, 18.32, 19.83 22.18 and 27.4 ⁇ 0.2° 20.
  • the present invention provides a crystalline form R6 of Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 8.
  • the present invention provides a crystalline form R6 of Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 9.
  • the present invention provides a process for the preparation of crystalline form R6 of Ripretinib, comprising steps of: i) providing Ripretinib in one or more suitable organic solvents; ii) optionally, adding one or more suitable anti-solvents; iii) isolating crystalline form R6 of Ripretinib.
  • the suitable organic solvent may be selected from the group consisting of diisopropyl ether, dibutyl ether, cyclopentyl methyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF) and methyl THF or mixtures thereof.
  • the starting material Ripretinib is in any crystalline form or amorphous form as known in the literature.
  • the crystals of Form R6 of Ripretinib may be used as the nucleating agent or “seed” crystals for subsequent crystallizations from solutions.
  • the crystalline form R6 of Ripretinib is stable and has excellent physico-chemical properties.
  • the crystalline form R6 of Ripretinib of the present application may be easily formulated into a pharmaceutical composition along with suitable pharmaceutically acceptable excipients.
  • the crystalline form R6 of Ripretinib of the present invention or the pharmaceutical compositions thereof comprises Ripretinib with a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
  • the present invention provides a crystalline form R7 of Ripretinib characterized by X-ray diffraction pattern having characteristic peaks at about 7.11, 7.95, 18.36 and 20.26 ⁇ 0.2° 20.
  • the application provides a crystalline form R7 of Ripretinib characterized by X-ray diffraction pattern having additional characteristic peaks at about 13.28, 14.33, 23.4 and 25.68 ⁇ 0.2° 20.
  • the present invention provides a crystalline form R7 of Ripretinib characterized by X-ray diffraction pattern as depicted in Figure 10.
  • the present invention provides a process for the preparation of crystalline form R7 of Ripretinib, comprising steps of: i) providing Ripretinib form R6 in one or more suitable organic solvents; ii) optionally, adding one or more suitable anti-solvents; iii) isolating crystalline form R7 of Ripretinib.
  • the suitable organic solvent may be selected from the group consisting of methanol, ethanol, 2-propanol, n-propanol, n-butanol, isoamyl alcohol, octanol, 1,2-propanediol, S-(+)-l,2-propanediol and ethylene glycol or mixtures thereof.
  • the starting material Ripretinib is crystalline form R6 of Ripretinib.
  • the crystals of Form R7 of Ripretinib may be used as the nucleating agent or “seed” crystals for subsequent crystallizations from solutions.
  • the crystalline form R7 of Ripretinib is stable and has excellent physico-chemical properties.
  • the crystalline form R7 of Ripretinib of the present application may be easily formulated into a pharmaceutical composition along with suitable pharmaceutically acceptable excipients.
  • Crystalline form R7 of Ripretinib may be a purer form of crystalline form R2 Ripretinib.
  • the crystalline form R7 of Ripretinib of the present invention or the pharmaceutical compositions thereof comprises Ripretinib with a chemical purity of at least 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.
  • the present application relates to amorphous solid dispersion of Ripretinib with a suitable pharmaceutically acceptable excipient.
  • the present application relates to amorphous solid dispersion of Ripretinib with Eudragit.
  • the amount of Ripretinib in amorphous solid dispersion with Eudragit may be about 2% w/w to about 98% w/w, or about 5% w/w to about 95% w/w, or about 10% w/w to about 90% w/w, or about 20% w/w to about 80% w/w, or about 30% w/w to about 70% w/w, or about 40% w/w to about 60% w/w, or about 50% w/w.
  • the present application relates to a process for preparing amorphous solid dispersion of Ripretinib comprising: i) dissolving a mixture of Ripretinib and Eudragit in a suitable solvent and ii) isolating amorphous solid dispersion of Ripretinib.
  • Ripretinib Any physical form of Ripretinib may be used for the preparation of solid dispersion of Ripretinib of the present invention.
  • the suitable solvent for dissolving Ripretinib in step a) include, but are not limited to ketones such as acetone, ethyl methyl ketone, 2-butanone, methyl isobutyl ketone; ethers such as tetrahydrofuran; esters such as ethyl acetate, isopropyl acetate; nitriles such as acetonitrile, propionitrile; halogenated hydrocarbons such as dichloromethane, chloroform; alcohols such as methanol, ethanol, propanol, isopropanol; water; mixtures thereof.
  • the solvent for dissolving Ripretinib may be a mixture of THF and water.
  • the step a) may be performed at a temperature of about 0 °C to about the boiling point of the solvent.
  • the solution comprising a suitable pharmaceutically acceptable excipient and Ripretinib in a suitable solvent is stirred for a sufficient time.
  • Eudragit may be mixed with Ripretinib and the mixture may be dissolved in a suitable solvent. Alternatively, Eudragit may be added to a solution of Ripretinib in a suitable solvent.
  • isolating amorphous solid dispersion of Ripretinib may involve one or more methods including removal of solvent (by techniques known in the art e.g. evaporation, distillation, filtration of precipitated solid and the like), cooling, concentrating the reaction mass, adding seed crystals to induce precipitation, and the like. Stirring or other alternate methods such as shaking, agitation, and the like, may also be employed for the isolation. Distillation of the solvent may be conducted at atmospheric pressure or above, or under reduced pressures and at a temperatures less than about 120°C, less than about 100°C, less than about 90°C, or any other suitable temperatures. Any temperature and vacuum conditions can be used as long as there is no increase in the impurity levels of the product due to decomposition.
  • Suitable techniques which can be used for the distillation include, but not limited to, distillation using a rotary evaporator device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), and the like.
  • a rotary evaporator device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), and the like.
  • techniques providing a rapid solvent removal may be utilized to provide the desired amorphous solid dispersion of Ripretinib.
  • distillation using a rota-vapor device such as a Buchi Rotavapor or a spray drying technique may be used for the isolation of amorphous solid dispersion of Ripretinib with a suitable pharmaceutically acceptable excipient.
  • the solid obtained from step b) may be collected using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used.
  • the isolated solid may be optionally further dried to afford amorphous solid dispersion of Ripretinib.
  • Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer and the like.
  • the drying may be carried out at atmospheric pressure or above, or under reduced pressures, at temperatures less than about 120°C, less than about 100°C, less than about 80°C, or any other suitable temperatures.
  • the drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer.
  • the obtained amorphous solid dispersions may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the amorphous solid dispersions.
  • Equipment that may be used for particle size reduction include, but not limited to, ball, roller, and hammer mills, jet mills and the like.
  • the amorphous solid dispersion of Ripretinib with Eudragit is stable and has excellent physico-chemical properties.
  • the amorphous solid dispersion of the present application may be easily formulated into a pharmaceutical composition comprising Ripretinib.
  • the amorphous solid dispersion of Ripretinib with Eudragit may have no more than about 5% w/w of any crystalline form of Ripretinib.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising crystalline form R1 of Ripretinib or crystalline form
  • R2 of Ripretinib or crystalline form R3 of Ripretinib or crystalline form
  • R5 of Ripretinib or crystalline form R6 of Ripretinib or crystalline form
  • R7 of Ripretinib or amorphous solid dispersion and at least one pharmaceutically acceptable excipient.
  • Suitable temperatures for the reaction at any stage of the process of the present invention may be less than about 150°C, less than about 100°C, less than about 80°C, less than about 60°C, or any other suitable temperatures.
  • removal of solvent at any stage of the process of the present invention may be carried out by methods known in the art or any procedure disclosed in the present application.
  • removal of solvent may include, but not limited to: solvent evaporation or sublimation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Biichi® Rotavapor®, spray drying, freeze drying (Lyophilization), agitated thin film drying and the like.
  • the compounds at any stage of the process of the present invention may be isolated using conventional techniques known in the art.
  • useful techniques include but are not limited to, decantation, centrifugation, gravity filtration, suction filtration, concentrating, cooling, stirring, shaking, combining with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, or the like.
  • the isolation may be optionally carried out at atmospheric pressure or under reduced pressure.
  • the solid that is obtained may carry a small proportion of occluded mother liquor containing a higher percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor.
  • the compounds at any stage of the process of the present invention may be recovered from a suspension/solution using any of techniques such as decantation, filtration by gravity or by suction, centrifugation, slow evaporation, or the like, or any other suitable techniques.
  • the reaction can be efficiently completed at room temperature or ambient temperature or if required reaction mass can be heated to elevated temperatures or up to about the reflux temperatures, and maintained for about 10 minutes to about 5 hours or longer.
  • the resulting solid may be optionally further dried. Drying may be suitably carried out using equipment such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures, at atmospheric pressure or under reduced pressure, and in the presence or absence of an inert atmosphere such as nitrogen, argon, neon, or helium. The drying may be carried out for any desired time periods to achieve a desired purity of the product, such as, for example, about 1 to about 15 hours, or longer.
  • Ripretinib of present invention has average particle size of particles between 1 to 100 pm, less than 90 pm, less than 80 pm, less than 60 pm, less than 50 pm, less than 40 pm, less than 30 pm, less than 20 pm, less than 10 pm, less than 5 pm or any other suitable particle sizes.
  • Ripretinib of present invention may have particle size distribution: D10 of particles smaller than 20 pm, smaller than 15 pm, smaller than 10 pm, or smaller than 5 pm; D50 of particles smaller than 100 pm, smaller than 90 pm, smaller than 80 pm, smaller than 70 pm, smaller than 60 pm, smaller than 50 pm, smaller than 40 pm, smaller than 30 pm, smaller than 20 pm, smaller than 10 pm; D90 of particles smaller than 200 pm, smaller than 175 pm, smaller than 150 pm, smaller than 140 pm, smaller than 130 pm, smaller than 120 pm, smaller than 110 pm, smaller than 100 pm, smaller than 90 pm, smaller than 80 pm, smaller than 70 pm, smaller than 60 pm, smaller than 50 pm, smaller than 40 pm, smaller than 30 pm, smaller than 20 pm, smaller than 10 pm.
  • Particle size distributions of Ripretinib particles may be measured using any techniques known in the art.
  • particle size distributions of Ripretinib particles may be measured using microscopy or light scattering equipment, such as, for example, a Malvern Master Size 2000 from Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom.
  • D10 in the context of the present invention is 10% of the particles by volume are smaller than the D10 value and 90% particles by volume are larger than the D10 value.
  • D50 in the context of the present invention is 50% of the particles by volume are smaller than the D50 value and 50% particles by volume are larger than the D50 value.
  • D90 in the context of the present invention is 90% of the particles by volume are smaller than the D90 value and 10% particles by volume are larger than the D90 value.
  • Ripretinib of present invention can be micronized or milled using conventional techniques to get the desired particle size to achieve desired solubility profile to suit to pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction include, but not limited to ball milling, roller milling and hammer milling. Milling or micronization may be performed before drying, or after the completion of drying of the product.
  • the compound of this application is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art.
  • X-ray diffraction was measured using Rigaku Desktop X-ray diffractometer, Model: MiniFlex600.
  • Scan type Continuous; Detector - Scintillator Nal (Tl); Measurement parameters: Start Position [°2Th.]: 3 ; End Position [°2Th.]: 40; Step Size [°2Th.]: 0.02; Scan Speed [7min]: 1
  • Thermogravimetry-differential thermal analysis was performed on a Rigaku Thermo plus EVO2 TG-DTA8122 instrument. The measurement was carried out under a dry nitrogen stream (a flow rate of 320 mL/min) and a normal pressure at a temperature rising rate of 10 °C/min.
  • Ethyl 4,6-dichloronicotinate (10 g) and acetonitrile (80mL) were charged into a reactor at 25-35 °C under nitrogen atmosphere.
  • Ethylamine 70% in water solution (11 g) was added to the reactor at 25-35 °C and the reaction mixture was stirred for 22-24 h at 25-35 °C.
  • After completion of the reaction the reaction mass was concentrated under reduced pressure below 50 °C. Water (40 mL) was charged into the obtained residue and the reaction mixture was stirred for 30-40 min at room temperature. The solid was filtered and washed with water (10 mL). The solid was dried under reduced pressure at room temperature.
  • Ethyl 6-chloro-4-(ethylamino)nicotinate (Formula VIII, 4.5 g) and dichloromethane (110 mL) were charged into a reactor at -55 °C to -45 °C under nitrogen atmosphere.
  • Diisobutylaluminium hydride (DIBAL-H) in toluene 39 mL, 1.5M in toluene was gradually added to the reactor at - 50°C to -25°C and the reaction mixture was stirred for 1-2 h at -50°C to -40°C. After completion of the reaction, the reaction mass was allowed to warm to -10°C to -5 °C. 10% aq.
  • Example 5 Preparation of 3-(5-amino-2-bromo-4-fluorophenyl)-7-chloro-l-ethyl-l,6- naphthyridin-2(lH)-one (Formula IV).
  • Ethyl 2-(5-amino-2-bromo-4-fluorophenyl)acetate (Formula V, 10 g) and N, N-dimethylacetamide (80 mL) were charged into the reactor under nitrogen atmosphere at room temperature.
  • 6-chloro- 4-(ethylamino)nicotinaldehyde (Formula VI, 6.6 g) was charged into the reaction mixture at room temperature.
  • Example 7 Preparation of 3-(5-amino-2-bromo-4-fluorophenyl)-l-ethyl-7-(methylamino)- l,6-naphthyridin-2(lH)-one (Formula II).
  • Ripretinib (Formula I, 7.3 g) was charged into reactor. DMF (29 mL) was charged at room temperature and the reaction mass was heated at 120 °C till a clear solution is obtained. The reaction mixture was stirred and allowed to cool to 25-35 °C over a period of 30-40 min. The reaction mixture was filtered and the solid was washed with methanol (21 mL). The solid was charged into reactor and DMF (20 mL) was added and the reaction mass was heated at 120 °C till a clear solution is obtained. The reaction mixture was stirred and allowed to cool to 25-35 °C over a period of 30-40 min. The reaction mixture was filtered and the solid was washed with methanol (20 mL).
  • Ripretinib (Formula I, 7.3 g) was charged into reactor. DMF (29 mL) was charged at room temperature and the reaction mass was heated at 120 °C till a clear solution is obtained. The reaction mixture was stirred and allowed to cool to 25-35 °C over a period of 30-40 min. The reaction mixture was filtered and the solid was washed with methanol (21 mL). The solid was charged into reactor and water (24 mL) was added at 25-35°C and the reaction mass was stirred for 30-40 min. The solid was filtered under suction and the solid was washed with water (6 mL). The solid was dried under vacuum at 45-50° C for 1-2 h to obtain crystalline form R1 of Ripretinib (Formula I). [Purity by HPLC analysis 99.5%].
  • Example 11 Preparation of crystalline form R1 of Ripretinib.
  • Ripretinib (Formula I, 7.3 g) was charged into reactor. DMF (29 mL) was charged at room temperature and the reaction mass was heated at 120 °C till a clear solution is obtained. The reaction mixture was stirred and allowed to cool to 25-35 °C over a period of 30-40 min. The reaction mixture was filtered and the solid was washed with methanol (21 mL). The solid was charged into reactor and DMF (20 mL) was added and the reaction mass was heated at 120 °C till a clear solution is obtained. The reaction mixture was stirred and allowed to cool to 25-35 °C over a period of 30-40 min. The reaction mixture was filtered and the solid was washed with methanol (20 mL).
  • Example 12 Preparation of crystalline form R2 of Ripretinib.
  • Ripretinib (1 g) was suspended in ethanol (10 mL). The reaction mass was stirred at 25°C for about 3-4 hours. The reaction mass was filtered under vacuum and dried in VTD at 80°C about 4-5 hours to obtain crystalline form R2 of Ripretinib (Formula I).
  • the combined DCM layer was washed with 10% aqueous ammonium chloride solution (100 mL), followed by brine (100 mL).
  • the DCM layer was dried over sodium sulfate and concentrated under vacuum below 50 °C to obtain a solid.
  • Hexane 60 mL was charged into the solid thus obtained at RT. The suspension was stirred for 30 min at RT. The solid was filtered and washed with hexane (50 mL). The solid was dried in a hot air oven at 40 °C for 2 h to obtain to obtain the title compound of Formula VII (6.2 g).
  • the filtrate and washings were concentrated under vacuum below 50 °C to obtain the crude product.
  • the crude product was purified by column chromatography using 100-200 mesh silica gel and 18- 20% EtO Ac -hexane as eluent. The fractions containing the pure product were combined and concentrated under reduced pressure below 50 °C to obtain the title compound of Formula XI (2.3 g) as an off white solid.
  • 6-chloro-4-(ethylamino)nicotinaldehyde (compound of formula XII, 0.9 g) was charged under nitrogen atmosphere to a solution of compound of Formula XI (2.1 g) in A,A-di ethyl acetamide (21 mF) at 25-35 °C.
  • Eithium hydroxide monohydrate (0.33 g) was charged into the reaction mixture at 25-35 °C.
  • the reaction mixture was stirred at RT for 4-5 h.
  • water (61 mF) was charged into the reaction mixture at 25-35 °C.
  • the suspension obtained was stirred for 1 h at 25-35 °C.
  • the solid was filtered under suction and washed with water (21 mF).
  • the wet solid was unloaded and suspended in methanol (21 mF).
  • the suspension was stirred for 10 min at 25-35 °C.
  • the solid was filtered under suction and washed with methanol (5.5 mF).
  • the solid was dried in a hot air oven at 45 °C for 8 h to obtain the title compound of Formula XIII (2.01 g) as a pale yellow colored solid.
  • Example 18 Preparation of crystalline form R3 of Ripretinib.
  • Ripretinib (1 g) was provided in 70-80% ethyl acetate in hexane (10 mF). The reaction mass was stirred at RT for about 3-4 hours. The reaction mass was filtered under vacuum and dried in VTD at 80°C about 4-5 hours to obtain crystalline form R3 of Ripretinib of compound of formula I.
  • Ripretinib (2 g) was suspended in DMF (10 mF). The resulting slurry was stirred at 20-25°C for about 4-5 hours. The material was filtered under vacuum to obtain the title compound.
  • Example 20 Preparation of crystalline form R4 of Ripretinib.
  • Ripretinib (10 g) was suspended in DMF (50 mL). The resulting slurry was stirred at 55-60°C for about 2 hours. Then reaction mass was cooled to Room temperature and maintained about 45min. The material was filtered under vacuum to obtained the title compound.
  • Example 21 Preparation of crystalline form R5 of Ripretinib.
  • Ripretinib (6 g) was suspended in Ethanol (60 mL), the resulting slurry was stirred at 20-25°C for about 4-5 hours. The material was filtered under vacuum to obtain the title compound.
  • Ripretinib (1 g) was suspended in THF (10 mL), the resulting slurry was stirred at 20-25°C for about 4-5 hours. The material was filtered under vacuum and air dried the material to obtain the title compound.
  • Ripretinib (1 g) was suspended in THF (10 mL), the resulting slurry was stirred at 20-25°C for about 4-5 hours. The material was filtered under vacuum and dried in VTD at 70-75°C for about 5-8 hours to obtain the title compound.
  • Ripretinib Form R6 (0.5 g) was suspended in Methanol (5 mL), the resulting slurry was stirred at 20-25°C for about 48-72 hours. The material was filtered under vacuum and air dry the material to obtain the title compound.
  • Example-25 Preparation of amorphous solid dispersion of Ripretinib with Eudragit L100.
  • Ripretinib (0.1 g) and Eudragit LI 00 (0.3 g) was subjected to milling in ball mill (Agate jar, frequency: 25Hz time: 2 hrs). The obtained solid corresponds to amorphous Ripretinib as confirmed by PXRD.
  • Example-26 Preparation of amorphous solid dispersion of Ripretinib with Eudragit L100.
  • Ripretinib (0.1 g) and Eudragit LI 00 (0.5 g) was dissolved in mixture of THF (7.2 mL) and water (0.8 mL) at 55-60 °C and subjected to dry distillation over rotavapour under vacuum at 55-60°C.
  • the obtained solid corresponds to amorphous ripretinib as confirmed by PXRD.

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Abstract

La présente invention concerne un procédé de préparation de riprétinib et d'intermédiaires de celui-ci. L'invention concerne également un procédé de préparation d'intermédiaires de riprétinib. La présente invention concerne des formes à l'état solide de riprétinib et leur procédé de préparation. Plus particulièrement, la présente invention concerne la forme cristalline R1 du riprétinib, la forme cristalline R2 du riprétinib, la forme cristalline R3 du riprétinib, la forme cristalline R4 du riprétinib, la forme cristalline R5 du riprétinib, la forme cristalline R6, la forme cristalline R7, une dispersion solide amorphe de riprétinib et leurs procédés de préparation. Ces formes cristallines (forme R1, forme R2, forme R3, forme R4, forme R5, forme R6 et forme R7) et la dispersion solide amorphe de riprétinib sont stables et peuvent être facilement formulées dans des formes posologiques pharmaceutiquement acceptables.
PCT/IN2022/050059 2021-01-28 2022-01-25 Procédé de préparation de riprétinib et de formes à l'état solide de celui-ci Ceased WO2022162690A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2020143424A1 (fr) * 2019-01-08 2020-07-16 中国科学院上海营养与健康研究所 Cible de tumeur stromale gastro-intestinale depdc5 et son application au diagnostic et au traitement
WO2020185812A1 (fr) * 2019-03-11 2020-09-17 Teva Pharmaceuticals International Gmbh Formes à l'état solide de riprétinib

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2020143424A1 (fr) * 2019-01-08 2020-07-16 中国科学院上海营养与健康研究所 Cible de tumeur stromale gastro-intestinale depdc5 et son application au diagnostic et au traitement
WO2020185812A1 (fr) * 2019-03-11 2020-09-17 Teva Pharmaceuticals International Gmbh Formes à l'état solide de riprétinib

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MINO R. CAIRA: "CRYSTALLINE POLYMORPHISM OF ORGANIC COMPOUNDS", TOPICS IN CURRENT CHEMISTRY., SPRINGER, BERLIN., DE, vol. 198, 1 January 1998 (1998-01-01), DE , pages 163 - 208, XP001156954, ISSN: 0340-1022, DOI: 10.1007/3-540-69178-2_5 *

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