WO2016207172A1 - Préparation d'ibrutinib amorphe pur - Google Patents

Préparation d'ibrutinib amorphe pur Download PDF

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Publication number
WO2016207172A1
WO2016207172A1 PCT/EP2016/064332 EP2016064332W WO2016207172A1 WO 2016207172 A1 WO2016207172 A1 WO 2016207172A1 EP 2016064332 W EP2016064332 W EP 2016064332W WO 2016207172 A1 WO2016207172 A1 WO 2016207172A1
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ibrutinib
solution
amorphous
salt
solvent
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PCT/EP2016/064332
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English (en)
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Christopher Rose
Herbert Silberberger
Ludwig FELZMANN
Stefanie BRUNNER
Kathrin HÖFERL-PRANTZ
Hannes Lengauer
Andreas Berger
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Sandoz Gmbh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention refers to the preparation of the amorphous form of the Bruton's tyrosine kinase (Btk) inhibitor l-((R)-3-(4-arrdno-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- ⁇ pyrimidin-l - yl)piperidin-l-yl)prop-2-en-l-one (ibrutinib).
  • Btk Bruton's tyrosine kinase
  • ibrutinib Bruton's tyrosine kinase
  • the invention refers to a process for the preparation of substantially pure amorphous ibrutinib, which uses a salt of ibrutinib as starting material.
  • Btk Bruton's tyrosine kinase
  • BCR cell surface B-cell receptor
  • Ibrutinib is a selective, irreversible inhibitor of BTK first disclosed in WO 2008/039218, which has been shown to be highly clinically efficacious in relapsed/refractory CLL and mantle cell lymphoma (see e.g. Burger et. Leukemia & Lymphoma (2013), 54(11), 2385-91).
  • Amorphous ibrutinib is moisture stable. It is therefore a good alternative to crystalline ibrutinib as amorphous material has a higher solubility, which is connected with better bioavailability, than corresponding crystalline forms.
  • amorphous ibrutinib is the preferred physical form for the preparation of pharmaceutical compositions.
  • CN 103121999 A discloses ibrutinib of undisclosed form with an HPLC purity of 98.6% and >98% ee by crystallization from toluene.
  • CN 103923084 A discloses anhydrous, hydrous as well as solvate crystal forms of ibrutinib, the solvate forms of ibrutinib being solvates of oxolane and trichloromethane.
  • solvates with methanol and MIBK suffer from low solubility of ibrutinib in those solvents (about 1 wt% or less), thereby limiting their use for purification and subsequent preparation of amorphous ibrutinib on industrial scale as this would require very large amounts of solvent.
  • the solvates from methanol and methylisobutylketone are not suitable for the preparation of amorphous ibrutinib for use in the manufacture of a medicament.
  • amorphous ibrutinib can be obtained from material that has been purified by chromatography on silica gel using dichloromethane/alcohol mixtures.
  • This approach bears the disadvantage that the eluent in the final purification step generally may contain unspecified amounts of silica gel leaking from the column. Because such impurities might affect chemical stability in an uncontrolled manner, such a material is not appropriate for use in a medicament.
  • use of ICH class ⁇ solvents such as dichloromethane and methanol is not preferred for API synthesis.
  • amorphous ibrutinib material prepared by fast rotary evaporation as described in WO 2008/039218 features a solid state best described as honey -like, gum, or foam, depending on the amount of residual dichloromethane still present. Such a material is difficult or even impossible to handle and process on a large scale.
  • IPCOM000238881D describes the preparation of the hydrochloride salt of ibrutinib, which is obtained by reaction of tert-butyl-(R)-3-(4-aniino-3-iodo-lH-pyrazolo[3,4-(3 ⁇ 4pyrimidin-l- yl)piperidin-l-carboxylate with (4-phenoxyphenyl)boronic acid and treating the resulting tert- butyl-(R)-3 -(4-amino-3 -(4-phenoxyphenyl)-lH-pyrazolo [3 ,4- ⁇ pyrinudin- 1 -yl)piperidin-l - carboxylate with ethanolic HC1.
  • ibrutinib as obtained by dissolving the starting material in acetone or 2-methyl THF and concentrating to dryness following the procedures described in US 7,514,444, in which the resulting material is purified by chromatography on silica gel, and thus the approach bears the disadvantage that the eluent in the final purification step contains unspecified amounts of silica gel leaking from the column.
  • the processes should be scalable and lead to amorphous ibrutinib in high yield. Further, process-specific byproducts should be efficiently depleted.
  • FIGURES Figure 1 shows an X-ray powder diffraction (XRPD) spectrum of amorphous ibrutinib obtained in Example 2 by the process of the present invention.
  • XRPD X-ray powder diffraction
  • Figure 2 shows an X-ray powder diffraction (XRPD) spectrum of amorphous ibrutinib obtained in Example 3 by the process of the present invention.
  • Figure 3 shows an XRPD spectrum of ibrutinib hydrochloride obtained in Example 7 by the process of the present invention.
  • the present invention refers to a process for the preparation of amorphous 1 -((R)-3-(4-ann ⁇ o-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- ⁇ ]pyrimidin-l - yl)piperidin-l -yl)prop-2-en-l -one (ibrutinib), comprising the steps of:
  • the present invention provides a process for the preparation of a salt of ibrutinib, the process comprising the steps of:
  • the invention relates to a process for preparing amorphous ibrutinib.
  • the process comprises the steps of:
  • amorphous ibrutinib can be prepared by the process of the present invention in substantially pure form, and in particular can be prepared in pure form.
  • the terms "pure” and “substantially pure” in the context of the present invention refer to phase- purity and chemical purity of the amorphous ibrutinib. Phase purity of amorphous ibrutinib is characterized by the absence of any peaks in the XRPD pattern. Chemical purity of the amorphous ibrutinib can for example be determined by HPLC analysis.
  • the amorphous ibrutinib obtained by the process described herewith thus preferably has a chemical purity of 98.0 wt.% or more, preferably of 99.0 wt.% or more, more preferably of 99.5 wt.%, most preferably of 99.9 wt.%, based on the total weight of the amorphous ibrutinib.
  • amorphous ibrutinib can be prepared according to the process of the present invention without using column chromatography. As a consequence, any possible product contamination with silica, such as silica gel, can be avoided.
  • the amorphous ibrutinib thus preferably has a content of silica, which is less than 1.0 wt.%, preferably is less than 0.3 wt.%, more preferably is less than 0.1 wt.%, further more preferably is less than 0.03 wt.%, most preferably is less than 0.01 wt%, based on the total weight of the amorphous ibrutinib.
  • amorphous ibrutinib which is substantially free from any crystal form of ibrutinib, such as crystal form A of ibrutinib.
  • substantially free in the context of the present invention means that no crystalline form, such as crystalline form A can be detected by XRPD measurement, i.e. no peaks of a crystalline form can be observed in an XRPD measurement.
  • the invention is directed to the amorphous form of ibrutinib having no noticeable peak in a powder X-ray diffraction.
  • a salt of ibrutinib is provided, such as a crystalline salt.
  • the salt provided in step (i) is not particularly limited but is typically a pharmaceutically acceptable salt, including, but not limited to, acid addition salts formed by reacting the free base form of ibrutinib with an organic or inorganic acid, such as salts of
  • an organic acid comprising aliphatic and aromatic sulfonic acid, trifluoroacetic acid, pyruvic acid, oxalic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, naphthyl disulfonic acid, and formic acid, or
  • an inorganic acid comprising hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, and phosphorous acid.
  • the salt in step (i) includes solvent addition forms, hydrates, alcoholates or any other (co)crystal forms thereof, particularly solvates or polymorphs.
  • Solvates can contain either stoichiometric or non-stoichiometric amounts of a solvent.
  • the solvate may be any solvate of ibrutinib and an organic solvent use for cocrystallization, including ibrutinib solvates of methanol,
  • MIBK methylisobutylketone
  • anisole dichloromethane
  • chlorobenzene 1 ,4-dioxane
  • isopropanol and pyridine preferably solvates of ibrutinib and a solvent selected from chlorobenzene, 1,4-dioxane, isopropanol and pyridine.
  • Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is an alcohol.
  • the salt is in crystalline form.
  • the salt is ibrutinib hydrochloride or ibrutinib nitrate, most preferably, the salt is crystalline ibrutinib hydrochloride.
  • Step (ii) of the process of the present invention includes adding an organic solvent and an alkaline component to obtain a solution of ibrutinib.
  • the organic solvent is not particularly limited as long as ibrutinib can be completely dissolved therein and can subsequently be isolated from the organic solvent, such as by the addition of an anti-solvent such as water or an aqueous salt solution.
  • the organic solvent is preferably selected from acetone, methanol, ethyl acetate, isopropyl acetate, isopropyl alcohol, methyl isobutyl ketone (MIBK), methyl ethyl ketone (MEK), tetrahydrofuran (THF), dichloromethane (DCM), dioxane, toluene, anisole, 2-methyl tetrahydrofuran or combinations thereof.
  • Particularly preferred solvents include acetone, isopropanol, methanol, and 2-methyl tetrahydrofuran, most preferably the solvent is acetone or isopropanol.
  • the alkaline component may be an organic or inorganic alkaline component.
  • the alkaline component is typically selected from one or more of triethylamine (TEA), sodium hydroxide (NaOH), potassium carbonate (K2CO3), sodium carbonate (Na2CC>3), potassium hydroxide (KOH), sodium bicarbonate (NaHC0 3 ).
  • Preferred alkaline components are selected from NaOH or TEA.
  • Step (iii) of the process of the present invention includes isolating ibrutinib from the solution obtained in step (ii). Isolating ibrutinib from the solution is not particularly limited as long as ibrutinib can be obtained in high purity.
  • ibrutinib is directly obtained in amorphous form.
  • amorphous ibrutinib may be obtained from the reaction mixture by the addition of a suitable anti-solvent, such as water, leading to precipitation of amorphous ibrutinib.
  • a suitable anti-solvent such as water
  • an amorphous product may be obtained in case the solution of ibrutinib is added to the anti-solvent rapidly, i.e. typically in one portion. Further, obtaining an amorphous product is typically achieved when the solution of ibrutinib is added in a small volume to a large volume of the anti-solvent.
  • the ratio of the volume of the ibrutinib solution to the volume of the anti-solvent is typically between 1 :5 and 1:50, preferably between 1:10 and 1:40, more preferably between 1:15 and 1:30.
  • the temperature of the anti- solvent is preferably below 30°C, more preferably about room temperature, i.e. 20°C to 25 °C.
  • a combination of two or more of the above features such as adding the solution of ibrutinib in one portion to the anti-solvent, wherein the ratio of ibrutinib solution to the anti-solvent is (v/v) 1:10 or less typically leads to the formation of a pure amorphous ibrutinib product.
  • the process variables relevant for obtaining an amorphous ibrutinib product from a solution are for example described in "S.L. Morissette et al., Advanced Drug Delivery Reviews, 56 (2004) 275-300".
  • amorphous ibrutinib can then be isolated by processes known in the art, such as filtration or centrifugation, preferably by filtration. Additionally, isolation of ibrutinib by optional extraction and removal of organic solvent typically leads to substantially pure amorphous ibrutinib. Therefore, amorphous ibrutinib can be obtained in step (iii) in substantially pure form, preferably in pure form. Thus, it is typically not necessary to perform any further purification steps. In particular, further purification by column chromatography can be avoided.
  • ibrutinib is obtained in non-amorphous form, such as crystalline form A, form B or form C of ibrutinib, preferably in crystalline form A. Isolation of crystalline ibrutinib is typically achieved by the addition of a suitable anti-solvent, such as water and isolation of crystalline ibrutinib.
  • a crystalline product is typically achieved if the anti-solvent is added in more than one portion to the solution of ibrutinib, preferably in three or more portions, and most preferably the anti-solvent is added in multiple small portions, such as dropwise, to the ibrutinib solution.
  • addition of the anti-solvent to the ibrutinib solution is slow enough to allow the formation of ibrutinib crystals and inhibiting precipitation of amorphous ibrutinib.
  • the ratio of the volume of the ibrutinib solution to the volume of the anti-solvent is typically between 2:1 and 1 :5, more preferably is between 1 : 1 and 1:4, most preferably about 1:3.
  • the temperature of the solvent is preferably 30°C or more, more preferably 40°C or more, and most preferably 50°C or more, wherein the upper limit of the temperature of the solvent is defined by the boiling point of the anti-solvent and the organic solvent.
  • the anti-solvent having about room temperature i.e. about 20 to 25°C is added to the ibrutinib solution having a temperature as described above, such as 40°C or more, most preferably about 50°C, while maintaining the temperature of the resulting mixture at a temperature corresponding to the temperature of the ibrutinib solution.
  • One or more of the above features will ensure the formation of ibrutinib crystals, thereby inhibiting precipitation of amorphous ibrutinib.
  • a combination of two or more of the above features such as adding the anti-solvent slowly, such as dropwise, to the ibrutinib solution, wherein the ratio of ibrutinib solution to the anti-solvent is (v/v) about 1:3, typically leads to the formation of ibrutinib crystals, i.e. a crystalline ibrutinib product.
  • the addition of seeding crystals to the ibrutinib solution after addition of the anti-solvent is preferred for obtaining a crystalline product.
  • the process variables relevant for obtaining a crystalline ibrutinib product from a solution are for example described in "S.L. Morissette et al., Advanced Drug Delivery Reviews, 56 (2004) 275-300".
  • the crystalline ibrutinib can be isolated by processes known in the art, such as filtration or centrifugation, preferably by filtration.
  • step (iv) described in the following may optionally be performed. Further, step (iv) is essentially performed in the embodiment in which ibrutinib is obtained in step (iii-1) in crystalline form. Step (iv) includes adding an organic solvent to obtain a solution of ibrutinib.
  • the solvent used in step (iv) is not particularly limited as long as ibrutinib can be completely dissolved therein, and the solvent can easily be removed, for example by evaporation.
  • the organic solvent used in step (iv) has a boiling point at ambient conditions of 1013 mbar, 25°C of 101°C or below, preferably of 80°C or below most preferably of 66°C or below.
  • the organic solvent used in step (iv) is selected from methanol, dichloromethane, tetrahydrofuran, acetone, dioxane or combinations thereof, most preferably methanol.
  • Step (iv) further includes isolating amorphous ibrutinib from the solution.
  • Isolating amorphous ibrutinib thus requires removal of the organic solvent to obtain substantially pure amorphous ibrutinib, preferably pure amorphous ibrutinib.
  • Isolating is typically performed by precipitation of ibrutinib by anti-solvent addition as described above, such as addition of water to the solution of ibrutinib obtained in step (iv) and isolation of the precipitate by e.g. filtration or fast evaporation of solvent, preferably by filtration.
  • anti-solvent addition includes addition of a suitable organic solvent to affect precipitation of ibrutinib from the solution.
  • Typical anti-solvents include, but are not limited to methyltertbutylether (MTBE), acetonitrile, heptane and water, preferably water.
  • isolating of ibrutinib in step (iv) may be performed by processes conventionally known in the art, such as spray drying, lyophilisation, thermal desolvation, or hot melt- extrusion.
  • isolating of ibrutinib in step (iv) is not limited as long as crystallization of ibrutinib from the solution is substantially inhibited.
  • a salt of ibrutinib is obtained by a process comprising the steps of:
  • the compound of formula (1) may be provided in its base form, or may alternatively be provided as salt and/or solvate thereof, including hydrates, alcoholates or any other typical (co)crystals.
  • the salt may be any typical acid addition salt, such as those described in step (i) of the process for preparing amorphous ibrutinib.
  • the salt is the monohydrochloride or the dihydrochloride salt.
  • specific salts such as the monohydrochloride are preferred for the purpose of enantiomeric purification
  • Solvates may contain either stoichiometric or non-stoichiometric amounts of a solvent.
  • the solvate may be any solvate of compound (1) and an organic solvent use for cocrystallization, including solvates of methanol, methylisobutylketone (MIBK), toluene, anisole, dichloromethane, chlorobenzene, 1 ,4-dioxane, isopropanol and pyridine, preferably solvates of chlorobenzene, 1,4-dioxane, isopropanol and pyridine.
  • the salt obtained by the process of this embodiment is typically a salt as described above for step (i) of the process for preparing amorphous ibrutinib, and is preferably obtained in crystalline form.
  • the preferred embodiments described above for the salt provided in step (i) of the process for preparing amorphous ibrutinib equally apply to the salt obtained by the process of this embodiment.
  • the inorganic alkaline component in step (a) is typically selected from one or more of sodium hydroxide (NaOH), potassium carbonate (K2CO3), sodium carbonate (Na 2 C0 3 ), potassium hydroxide (KOH), sodium bicarbonate (NaHC0 3 ), preferably is selected from NaOH, Na 2 CC>3, KOH and NaHC0 3 , most preferably is NaOH.
  • NaOH sodium hydroxide
  • K2CO3 sodium carbonate
  • KOH potassium hydroxide
  • NaHC0 3 sodium bicarbonate
  • reaction efficiency i.e. increased yield and higher purity of the compound of formula (2)
  • reaction efficiency could be further increased by firstly adding an aqueous solution of the inorganic alkaline component to the compound of formula (1) and subsequently removing water before the addition of acryloyl chloride.
  • This essentially water-free solution may then be cooled and added to the substrate, concomitant with a further addition of an aqueous solution of the inorganic alkaline component.
  • removal of water is preferably performed by azeotropic drying, such as azeotropic drying by use of a Dean-Stark trap.
  • the water content is preferably reduced to 0.1 wt% or less, based on the amount of organic solvent.
  • organic solvent in step (a) is preferably selected from one or more of
  • dichloromethane isopropanol, isobutanol, anisole, n-butanol, t-butanol, n-propanol, tetrahydrofuran, methyl tetrahydrofuran, methyltertbutylether (MTBE), diisopropylethylether (DIPET), methylisobutylketone (MIBK), methylethylketone (MEK), and acetone (ACT), preferably is selected from isopropanol and dichloromethane.
  • DCM dichloromethane
  • isopropanol isobutanol, anisole, n-butanol, t-butanol, n-propanol, tetrahydrofuran, methyl tetrahydrofuran, methyltertbutylether (MTBE), diisopropylethylether (DIPET), methylisobutylketone (MIB
  • step (a) of the process of the present invention are conventionally designated as "Schotten-Baumanri" reaction conditions, using an amine and an aqueous solution of an alkaline component as starting compounds for the formation of the amide.
  • the reaction as described herein leads to the formation of the salt of ibrutinib in high yield and high purity, i.e. without the formation of byproducts in step (a).
  • the reaction allows for an easy purification of the salt obtained in step (d) even without isolating the intermediate compound (2) from the reaction mixture.
  • step (b) the compound of formula (2) may optionally be isolated from the reaction mixture.
  • Isolating may be achieved by washing the reaction mixture with a suitable aqueous salt solution, such as a NaCl or (NH 4 ) 2 S0 4 salt solution, preferably an (NH ⁇ SC ⁇ salt solution.
  • a suitable aqueous salt solution such as a NaCl or (NH 4 ) 2 S0 4 salt solution, preferably an (NH ⁇ SC ⁇ salt solution.
  • the organic and inorganic layers are separated and the organic layer dried by azeotropic drying, which is preferably performed by use of a Dean-Stark trap.
  • the residual water content of the organic layer is reduced to 1.5 wt% water or less, based on the amount of the organic layer.
  • step (c) is directly performed after step (a), thus without isolating the compound of formula (2) from the reaction mixture of step (a).
  • the acid used in step (c) is not particularly limited and typically includes the organic and morganic acids described above for the formation of pharmaceutically acceptable acid addition salts provided in step (i) of the process for preparing amorphous ibrutinib.
  • the acid in step (c) is hydrochloric acid.
  • Step (d) of isolating the salt of ibrutinib from the reaction mixture may be performed by processes known in the art, such as extraction, precipitation or addition of seed crystals, which may be followed by filtration of the solid form of ibrutinib from the reaction mixture, centrifugation, or evaporation of solvent.
  • the isolated crystals may optionally be dried, e.g.
  • step (d) may optionally be further purified, such as by dissolving ibrutinib in a suitable solvent following crystallization from the solution.
  • the process of preparing a salt of ibrutinib comprises the steps of:
  • the invention is directed to a process for preparing the hydrochloride salt of ibrutinib, as represented by formula (3) below, and which is further preferably obtained in crystalline form.
  • the invention as described herein therefore allows access to amorphous ibrutinib in very high purity without the requirement of chromatography, such as silica chromatography. Moreover, the processes of the invention have the following advantages:
  • the process of the present invention has the further advantage that the amorphous ibratinib can be obtained in powder form, and therefore has beneficial properties making it especially suitable for use in the preparation of a medicament and preparing same on industrial scale.
  • the amorphous ibrutinib obtained in powder form is typically free flowing, and its particle size and particle size distribution can be controlled by processes known in the art, such as by milling and/or sieving the amorphous ibrutinib in powder form.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the amorphous form of ibrutinib as described above, such as tablets or capsules, preferably for use in the treatment of cancer.
  • X-Ray Powder Diffraction (XRPD) XRPD diffractograms were obtained with an X'Pert PRO diffractometer (PANalytical, Almelo, The Netherlands) equipped with a theta/theta coupled goniometer in transmission geometry, programmable XYZ stage with well plate holder, Cu-Kalpha ⁇ radiation source (wavelength 0.1541 nm) with a focusing mirror, a 0.5° divergence slit, a 0.02° soller slit collimator and a 0.5° anti-scattering slit on the incident beam side, a 2 mm anti-scattering slit, a 0.02° soller slit collimator, a Ni-filter and a solid state PlXcel detector on the diffracted beam side.
  • X'Pert PRO diffractometer PANalytical, Almelo, The Netherlands
  • the diffractogram was recorded at room temperature at a tube voltage of 40 kV, tube current of 40 mA, applying a step size of 0.013° 2-theta with 40 sec per step in the angular range of 2 ° to 40 0 2-theta.
  • a typical precision of the 2-theta values is in the range of ⁇ 0.2° 2-theta.
  • a diffraction peak that appears for example at 9.4° 2-theta can appear between 9.2 and 9.6° 2-theta on most X-ray diffractometers under standard conditions.
  • UV wavelength 245 nm
  • Amorphous ibrutinib was stable under these conditions, as determined by the absence of XRPD peaks, in partiqular the absence of characteristic XRPD peaks of form A of ibrutinib after 8 weeks at 40°C / 75% RH.
  • Example 4 Crystalline ibrutinib (form A) was obtained in the same way as described in Example 3. 18 g of the crystalline ibrutinib were dissolved in 300 mL dichloromethane resulting in a turbid solution. After filtration of the solids, the solvent was removed under reduced pressure yielding amorphous ibrutinib as a foamy solid. The material was homogenized using a mortar and pestle resulting in a white powder (16.8 g, 93% yield).
  • Example 5 Example 5
  • Amorphous ibrutinib was obtained in the same way as described in Example 4 except that after filtration of the solids, the ibrutinib solution was subjected to spray drying, yielding amorphous ibrutinib as a white powder.
  • Amorphous ibrutinib was obtained in the same way as described in Example 4 except that after filtration of the solids, the ibrutinib solution was subjected to lyophilisation, yielding amorphous ibrutinib as a white powder.
  • the reaction according to the above reaction scheme is carried out as follows: Amine-hydrochloride (4) (1.0 g, 1 eq.) is suspended in 2-propanol (20 mL), followed by the addition of an aqueous K 2 C0 3 -solution (50% w/w, 2.7 g, 5 eq.). The mixture is cooled with an ice/acetone bath. Acryloyl chloride (148 ⁇ , 0.97 eq.) is added and the mixture is stirred for 15 min. Another portion of acryloyl chloride (152 ⁇ ⁇ , 1.0 eq.) is added, followed by stirring for 35 min.
  • Ibrutinib hydrochloride was prepared by the procedures basically as set forth in Example 7 with the use of different alkaline components as shown below in Table 2.
  • Example 12 Reproduction of Example lb of US 7,514,444 according to the above reaction scheme gave amorphous ibrutinib with a purity of only ⁇ 60 area% (HPLC) after performing the reported chromatographic purification in silica gel.
  • the product obtained contained high amounts of residual silicate and starting materials. Therefore, the obtained product would not be suitable for pharmaceutical applications, such as the preparation of pharmaceutical compositions.
  • Example 12
  • Amine-hydrochloride (4) (5 g, 1 eq.) is suspended in 2-propanol (85 mL), followed by the addition of 2M NaOH (4.9 mL, 1 eq.). Then the water is removed by azeotropic drying using a Dean-Stark trap to a limit ⁇ 0.1 % 3 ⁇ 40 in 2-propanol. Then the mixture is cooled to -5°C. In the meantime, acryloyl chloride (1,0 mL, 1.3 eq.) is dissolved in 3 mL 2-propanol cooled to -15°C and stirred for lh at this temperature.
  • the reaction mixture is warmed to r.t. and quenched by the addition of 42% (NH ⁇ SC solution (15 mL), then water (30 mL) and 2-propanol (10 mL) is added.
  • the layers were separated at 50°C and the organic layer was dried by azeotropic drying using a Dean-Stark trap to a limit ⁇ 1.5 % 3 ⁇ 40 in 2-propanol.
  • the resulting solution is filtered and then concentrated HCl (1.2 mL, 1.5 eq.) and seeding crystals were added.
  • ibrutinib hydrochloride (3) (4.01 g) in a purity of more than 99 area% as determined by HPLC measurement.
  • Example 13 Preparation of ibrutinib form A including ibrutinib hydrochloride as intermediate
  • Amine-hydrochloride (4) (4.0 g, 1 eq.) is suspended in 2-propanol (76 mL), followed by the addition of a 2M NaOH solution (17.7 mL) whilst stirring at ambient temperature. The solution is cooled to -1° C and acryloylchloride (810 ⁇ , 1.3 eq.) is added, followed by stirring for 35 min. The reaction mixture is quenched by the addition of a 42% aqueous (NH 4 ) 2 S0 4 -solution ( ⁇ 42 mL) and the phases were separated. To the organic layer was added 2-propanol (310 mL). The mixture was concentrated to a total weight of 53.75 g followed by filtration.
  • Ibrutinib hydrochloride (1 g, 1 eq.) (3) was suspended in acetone (16.7 mL) at ambient temperature, 2M NaOH - solution (1.2 mL) were added and the solution was stirred for 15 min. Activated charcoal (0.2 g) was added and the mixture was stirred for 30 min at ambient temperature. The solids were filtered off, rinsed with 10 mL acetone and the solution was concentrated to a total weight of 15 g. Concentrated HCl (37%, 17 ⁇ ) was added followed by stirring for 15 minutes. The solution was warmed to 50 °C and 25 mL of water were added dropwise. Seeding crystals were added, followed by stirring for 30 minutes upon which a white suspension is obtained.
  • Ibrutinib form A was then converted to amorphous ibrutinib in accordance with the procedures described in Example 3.
  • Amine-hydrochloride (4) (10 g, 1 eq.) is suspended in 2-propanol (190 mL) and cooled to 0° C to 5° C. After addition of 2M NaOH - solution (38.4 mL), a clear solution was obtained. The mixture was cooled to -12° C and acryloyl chloride (1.82 mL) was added in two portions. The reaction mixture was stirred for 15 minutes upon which consumption of 4 was judged to be greater than 99% by HPLC.

Abstract

L'invention concerne la préparation de la forme amorphe de l'inhibiteur de la Bruton tyrosine kinase (BTK) l-((R)-3-(4-amino-3-(4-phénoxyphényl)-1H-pyrazolo[3,4-d]pyrimidine-1-yl)pipéridine-1-yl)prop-2-en-1-one (ibrutinib). L'invention concerne en particulier un procédé de préparation de l'ibrutinib amorphe sensiblement pur. Dans un autre aspect, l'invention concerne un procédé de préparation d'un sel d'ibrutinib.
PCT/EP2016/064332 2015-06-26 2016-06-22 Préparation d'ibrutinib amorphe pur WO2016207172A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP15173984 2015-06-26
EP15173984.4 2015-06-26

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WO2017137446A1 (fr) * 2016-02-09 2017-08-17 Azad Pharmaceutical Ingredients Ag Procédé de synthèse d'ibrutinib amorphe stable
WO2019070698A1 (fr) 2017-10-02 2019-04-11 Johnson Matthey Public Limited Company Nouvelles formes d'ibrutinib
EP3501609A1 (fr) 2017-12-08 2019-06-26 Zentiva K.S. Compositions pharmaceutiques comprenant de l'ibrutinib
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CN113135917A (zh) * 2020-01-16 2021-07-20 北京赛思源生物医药技术有限公司 一种依鲁替尼的无定型物及其药用组合物

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017137446A1 (fr) * 2016-02-09 2017-08-17 Azad Pharmaceutical Ingredients Ag Procédé de synthèse d'ibrutinib amorphe stable
WO2019070698A1 (fr) 2017-10-02 2019-04-11 Johnson Matthey Public Limited Company Nouvelles formes d'ibrutinib
EP3501609A1 (fr) 2017-12-08 2019-06-26 Zentiva K.S. Compositions pharmaceutiques comprenant de l'ibrutinib
WO2019195827A1 (fr) 2018-04-06 2019-10-10 Johnson Matthey Public Limited Company Nouvelle forme d'ibrutinib
WO2020170270A1 (fr) * 2019-02-19 2020-08-27 Msn Laboratories Private Limited, R&D Center Nouveaux polymorphes cristallins de 1-[(3r)-3-[4-amino-3-(4-phénoxyphényl)-1h-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pipéridinyl]-2-propène-1-one et leur procédé de préparation
CN113135917A (zh) * 2020-01-16 2021-07-20 北京赛思源生物医药技术有限公司 一种依鲁替尼的无定型物及其药用组合物

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