WO2016132383A1 - Procédé pour la préparation d'ibrutinib - Google Patents

Procédé pour la préparation d'ibrutinib Download PDF

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WO2016132383A1
WO2016132383A1 PCT/IN2016/050057 IN2016050057W WO2016132383A1 WO 2016132383 A1 WO2016132383 A1 WO 2016132383A1 IN 2016050057 W IN2016050057 W IN 2016050057W WO 2016132383 A1 WO2016132383 A1 WO 2016132383A1
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formula
process according
group
alkali metal
base
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PCT/IN2016/050057
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English (en)
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Sureshbabu JAYACHANDRA
Sonny SEBASTAIAN
Jagadeeshwar Rao
Himaprasad NAIDU
Mallareddy Adla
Srinivasa Rao Mannava
Suresh Reddy SABBELLA
Ramesh Dandala
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Mylan Laboratories Limited
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Publication of WO2016132383A1 publication Critical patent/WO2016132383A1/fr

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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 relates generally to the chemical and pharmaceutical arts and more specifically to a process for the preparation of ibrutinib or pharmaceutically acceptable salts thereof.
  • Ibrutinib is chemically known as l-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4- d]pyrimidin-l-yl]-l-piperidinyl]-2-propen-l-one and is structurally represented in Formula I below.
  • Ibrutinib is an inhibitor of Bruton's tyrosine kinase.
  • Ibrutinib is currently marketed in the United States as IMBRUVICA® by Janssen Pharmaceuticals for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy, chronic lymphocytic leukemia who have received at least one prior therapy, chronic lymphocytic leukemia with 17p deletion, and Waldenstrom's macroglobulinemia.
  • U.S. Patent No. 7,514,444 discloses inhibitors of Bruton's tyrosine kinase, including ibrutinib.
  • Some processes disclose lengthy or complex procedures for purification of ibrutinib, for example, that employ use of column chromatography.
  • the presently disclosed invention overcomes such limitations of the prior providing processes whereby, ibrutinib may be prepared on an industrial scale with high purity without the use of complex or lengthy purification procedures.
  • One aspect of the present invention provides process for the preparation of ibrutinib.
  • ibrutinib may be prepared by the following steps:
  • X is a halogen selected from the group consisting of - F, -CI, -Br, and -I and R is hydroxy or halogen.
  • Formula VI may be reacted with (4-phenoxyphenyl)boronic acid in the presence of a metal catalyst, a base, and a solvent.
  • the metal catalyst may be, for example, tetrakis(triphenylphosphine)palladium, palladium (II) acetate, bis(triphenylphosphine)palladium(II) dichloride, bis(acetonitrile)dichloro palladium, bis(benzonitrile)palladium chloride, [l,l'-bis(diphenylphosphino) ferrocine]dichloropalladium(II) complex with dichloromethane, tris(dibenzylideneacetone)dipalladium(0), or bis(dibenzylideneacetone) palladium.
  • the base may be an organic base or an inorganic base.
  • suitable inorganic bases include alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali metal alkoxides, alkali metal phosphates, and alkali metal acetates.
  • suitable solvents include 1,4- dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, t-amyl alcohol, dichloromethane, tetrahydrofuran, toluene, ethanol, methanol, isopropyl alcohol, acetone, dimethyl formamide, water, and mixtures thereof.
  • the conversion of Formula A to ibrutinib may be carried out by reacting with compound of Formula VII:
  • R is -OH or a halogen selected from the group consisting of -F, -CI, -Br, and -I.
  • this step may be carried out in the presence of a solvent, which may be, for example, an ethereal solvent, a chlorinated solvent, a hydrocarbon solvent, water, or mixtures thereof.
  • a base which may be organic or inorganic.
  • suitable inorganic bases include alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, and alkali alkoxides.
  • suitable organic bases include pyridine, triethylamine, and N,N-diisopropylethylamine.
  • this step may be carried out in the presence of condensing agent.
  • suitable condensing agents include di-2-pyridyl carbonate, 1, 1'- carbonyldiimidazole, or a carbodiimide selected from the group consisting of ⁇ , ⁇ '- dicyclohexylcarbodiimide, diisopropyl carbodiimide, and N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide.
  • a compound of Formula VI may be prepared by the following steps: a. reacting a compound of Formula III with a compound of Formula IV to get a compound of Formula V; and
  • X is a halogen selected from the group consisting of -F, -CI, -Br, and -I;
  • P is an amine protecting group; and
  • L is hydrogen, an alkylsulfonyl group, or an arylsulfonyl group.
  • Formula III may be reacted with Formula IV in the presence of a reagent, for example, diisopropyl azodicarboxylate, triphenylphosphine, diethyl azodicarboxylate, a triphenylphosphine, a C 2 -C8 trialkylphosphine, or mixtures thereof.
  • a reagent for example, diisopropyl azodicarboxylate, triphenylphosphine, diethyl azodicarboxylate, a triphenylphosphine, a C 2 -C8 trialkylphosphine, or mixtures thereof.
  • the reacting step may be carried out in the presence of a base and a solvent.
  • the base may be an organic base or an inorganic base.
  • suitable inorganic bases include alkali metal hydroxides, alkali metal hydrides, alkali metal bicarbonates, alkali metal carbonates, and alkali alkoxides.
  • suitable organic bases include pyridine, triethylamine, and ⁇ , ⁇ -diisopropylethylamine.
  • the solvent may be, for example, a polar aprotic solvents or a crown ether solvent.
  • polar aprotic solvents examples include acetone, dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, monoglyme, diglyme, xylene, toluene, methyl isobutyl ketone, methyl ethyl ketone, cyclohexane, and mixtures thereof.
  • crown ether solvents include 18-crown-6, diaza-18-crown-6, and a mixture thereof.
  • Another embodiment of the present invention provides a process for the preparation of compound of formula II, which may be carried out by converting the compound of formula VI to compound of formula II:
  • compound of formula VI may be converted into compound of formula II by reacting compound of formula VI with compound of formula VII.
  • R is -OH or a halogen selected from the group consisting of -F, -CI, -Br, and -I.
  • this reaction may be carried out in the presence of a condensing agent which may be, for example, diphenyl carbonate, ⁇ , ⁇ -carbonyldiimidazole, and carbodiimides selected from the group consisting of NN'-dicyclohexylcarbodiimide, ⁇ , ⁇ '- diisopropylcarbodiimide, or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide.
  • a condensing agent which may be, for example, diphenyl carbonate, ⁇ , ⁇ -carbonyldiimidazole, and carbodiimides selected from the group consisting of NN'-dicyclohexylcarbodiimide, ⁇ , ⁇ '- diisopropylcarbodiimide, or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide.
  • R when R is a halogen, this reaction may be carried out in the presence of a base and a solvent.
  • the base may be, for example, an organic base or an inorganic base.
  • suitable inorganic bases include selected from the group consisting of alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, and alkali alkoxides.
  • organic bases include pyridine, triethylamine, and ⁇ , ⁇ -diisopropylethylamine.
  • suitable solvents include ethereal solvents, chlorinated solvents, hydrocarbon solvents, water, and mixtures thereof.
  • ibrutinib may be prepared by reacting a compound of Formula II with (4-phenoxyphenyl)boronic acid to get ibrutinib of Formula I;
  • X is a halogen selected from the group consisting of -F, -CI, -Br, and -I.
  • This reaction may be carried out in the presence of a metal catalyst, a base, and a solvent.
  • the metal catalyst may be, for example, tetrakis(triphenylphosphine)palladium, palladium (II) acetate, bis(triphenylphosphine)palladium(II) dichloride, bis(acetonitrile)dichloro palladium, bis(benzonitrile)palladium chloride, [l,l'-bis(diphenylphosphino) ferrocine]dichloropalladium(II) complex with dichloromethane, tris(dibenzylideneacetone)dipalladium(0), or bis(dibenzylideneacetone) palladium.
  • the base may be an organic base or an inorganic base.
  • Example of inorganic bases include alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali metal alkoxides, alkali metal phosphates, and alkali metal acetates.
  • suitable solvents include 1,4-dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, t-amyl alcohol, dichloromethane, tetrahydrofuran, toluene, ethanol, methanol, isopropyl alcohol, acetone, dimethyl formamide, water, and mixtures thereof.
  • One aspect of the present invention provides a processes for the preparation of ibrutinib.
  • One embodiment of the present invention provides a process for the preparation of a compound of Formula VI, which may include the following steps:
  • the "X" moiety is a halogen, for example, fluoro, chloro, bromo, or iodo. In some particularly useful embodiments, X is an iodo moiety.
  • P is an amine protecting group.
  • amine protecting group is well known and understood in the art. Examples of suitable amine protecting groups, as well as suitable conditions for protecting and deprotecting, can be found in prior art, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999; “The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981; in “Methoden der organischen Chemie", Houben-Weyl, 4th edition, Vol.
  • R p is a -C(R P1 ) 3 , wherein each R P1 is hydrogen or optionally substituted aryl, provided that at least one R P1 is not hydrogen;
  • R° is hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 1-10 haloalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein each alkyl, aryl, and heteroaryl group is optionally substituted.
  • Optionally substituted as used herein means the reference group may be substituted by one or more groups (e.g., 1 to 5, or 1 to 3, or 1 to 2 groups or 1 group) that are each independently halo, alkyl, alkoxy, nitro, cyano, tri(Ci_ 3 alkyl)silyl (e.g., trimethylsilyl).
  • groups e.g., 1 to 5, or 1 to 3, or 1 to 2 groups or 1 group
  • amine protecting groups include, carbonyls (e.g., methyl carbamate, 9- fluorenylmethyoxycarbonyl (Fmoc), trichloroethoxycarbonyl (Troc), tert-butyloxycarbonyl (BOC), 2-trimethylsilylethyloxycarbonyl (Teoc), allyloxycarbonyl (Alloc), p-methoxybenzyl carbonyl (Moz), and carboxybenzyl (Cbz)), sulfonyls (e.g., p-toluenesufonyl (Ts), trimethylsilylethanesulfoyl (Ses), tert-butylsulfonyl (Bus), 4-methoxyphenylsulfonyl, 4- nitrobenzenesulfonyl (nosyl)), trityl (trt), benzyl (Bn), 3,4-
  • alkenyl as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons, unless otherwise specified, and containing at least one carbon-carbon double bond.
  • alkenyl include, but are not limited to, ethenyl, 2- propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-l- heptenyl, 3-decenyl, and 3,7-dimethylocta-2,6-dienyl.
  • alkoxy as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • alkyl as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, unless otherwise specified.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • aryl as used herein, means a monocyclic (i.e., phenyl), bicyclic, or tricyclic ring fused or bridged system containing at least one phenyl ring.
  • Non-phenyl rings that are part of a bicyclic or tricyclic ring system may be fully or partially saturated, may contain one or more heteroatoms, each selected from N, S, and O, and may be optionally substituted with one or two oxo and/or thia groups.
  • aryl groups include phenyl, napthyl, anthracenyl, and fluorenyl.
  • arylalkyl as used herein, means an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of arylalkyl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, fluorenylmethyl and 2-naphth-2-ylethyl.
  • halo or halogen as used herein means fluoro, chloro, bromo, or iodo.
  • haloalkyl as used herein, means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, perfluorononyl, and 2-chloro-3-fluoropentyl.
  • heteroaryl as used herein, means a monocyclic, bicyclic, or tricyclic ring system containing at least one heteroaromatic ring. Any additional rings that are part of a bicyclic or tricyclic ring system may be fully or partially saturated or may be aromatic rings, and each may optionally contain one or more heteroatoms, each selected from N, S, and O.
  • monocyclic and bicyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, triazinyl.
  • benzimidazolyl benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, dihydroquinolinyl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl, and tetrahydroquinolin-yl.
  • heteroarylalkyl as used herein, means a heteroaryl, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of heteroarylalkyl include, but are not limited to, furylmethyl, imidazolylmethyl, pyridinylethyl, pyridinylmethyl, pyrimidinylmethyl, and thienylmethyl.
  • the protecting group is a tert-butyloxycarbonyl (BOC) protecting group.
  • L may be hydrogen, an alkylsulfonyl group, or an arylsulfonyl group.
  • a compound of Formula III may be reacted with a compound of Formula IV to get a compound of Formula V.
  • the reaction of a compound of Formula III with a compound of Formula IV to may occur under Mitsunobu reaction conditions, which are well known to one of skill in the art.
  • the compound of Formula III may be reacted with a compound of Formula IV in the presence of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine to give a compound of Formula V.
  • this reaction is performed in the presence of diethyl azodicarboxylate (DEAD) and a triphenylphosphine or C 2 -C8 trialkylphosphine.
  • diethyl azodicarboxylate (DEAD) and triethylphopshine are used for carrying out this reaction.
  • This reaction may be performed in the presence of a solvent.
  • the solvent may be a polar aprotic solvent or a crown ether.
  • suitable polar aprotic solvents include acetone, dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, monoglyme, diglyme, xylene, toluene, methyl isobutyl ketone, methyl ethyl ketone, cyclohexane, and mixtures thereof.
  • Suitable crown ether solvents include 18- crown-6 and diaza-18-crown-6, and mixtures thereof.
  • N- methylpyrrolidone, dimethyl formamide, or tetrahydrofuran is used as a solvent.
  • the compound of Formula III when L is an alkylsulfonyl or an arylsulfonyl group, the compound of Formula III may be reacted with a compound of Formula IV to get a compound of Formula V.
  • the base may be an inorganic base or an organic base.
  • suitable inorganic bases include alkali metal hydroxides, alkali metal hydrides, alkali metal bicarbonates, alkali metal carbonates, and alkali alkoxides.
  • suitable alkali metal hydroxides include sodium hydroxide and potassium hydroxide.
  • suitable alkali metal include sodium hydride and potassium hydride.
  • suitable alkali metal bicarbonates include sodium bicarbonate and potassium bicarbonate.
  • suitable alkali metal carbonates include sodium carbonate, potassium carbonate, and cesium carbonate.
  • suitable alkali alkoxides include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.
  • suitable organic bases include pyridine, triethylamine, and ⁇ , ⁇ -diisopropylethylamine. In particularly useful embodiments, potassium carbonate or cesium carbonate is used as a base.
  • the solvent may be a polar aprotic solvent or a crown ether.
  • suitable polar aprotic solvents include acetone, dimethyl formamide, dimethyl sulfoxide, dimethyl acetamide, N- methylpyrrolidone, tetrahydrofuran, acetonitrile, monoglyme, diglyme, xylene, toluene, methyl isobutylketone, methyl ethyl ketone, cyclohexane, and mixtures thereof.
  • suitable crown ether solvents include 18-crown-6 and diaza-18-crown-6, and mixtures thereof.
  • N-methylpyrrolidone, dimethyl formamide, or tetrahydrofuran is used as a solvent.
  • a compound of Formula V may be deprotected to get a compound of Formula VI.
  • protecting groups may be removed by hydrogenolysis or through the use of an acid or a base.
  • the acid may be, for example, an organic or an inorganic acid. Suitable organic acids include, for example, acetic acid, trifluoroacetic acid, trifluoromethanesulfuric acid, formic acid, and mixtures thereof.
  • Suitable inorganic acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, hydrofluoric acid, boric acid, tetrafluoroboric acid, orthophosphoric acid, and mixtures thereof.
  • the protecting group is a tert-butyloxycarbonyl moiety
  • use of trifluoroacetic acid is useful for deprotection.
  • deprotection of compound of Formula V to give Formula VI may be carried out in the presence of a solvent.
  • suitable solvents include alcohol solvents, chlorinated solvents, water, and mixtures thereof.
  • suitable alcohol solvents include methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, t-butanol, pentanol, and mixtures thereof.
  • suitable chlorinated solvents include dichloromethane, dichloroe thane, chloroform, and mixtures thereof. In particularly useful embodiments, where a tert-butyloxycarbonyl group is removed by trifluoroacetic acid, dichloromethane is used as a solvent.
  • Formula VI may be optionally converted into its acid salt form.
  • conversion of Formula VI to its salt form may improve purity and yield of Formula VI as well as yield and purity of products of subsequent steps, including of the final ibrutinib product. While not wishing to be bound by theory, it is currently believed that converting Formula VI to salt form changes the solubility of the compound in solution such that it enhances precipitation and isolation of Formula VI. The increased yield and purity of Formula VI may then, consequently, enhance the yield and purity of products of subsequent steps.
  • a free base moiety on a compound may be reacted with a suitable acidic reagent.
  • a pharmaceutically acceptable salt may alternatively be prepared by other methods well-known in the art, for example, ion exchange.
  • a free base moiety on formula VI may be optionally reacted with a suitable acid to obtain a salt of formula VI.
  • suitable acids include, for example, inorganic acids and organic acids.
  • suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid.
  • Suitable organic acids include, for example, oxalic acid, and tartaric acid.
  • the acid is hydrochloric acid and the dihydrochloride salt of Formula VI is formed.
  • Formula VI may be useful as an intermediate for synthesizing ibrutinib.
  • Another embodiment of the present invention provides a process for the preparation of a compound of Formula II, which may be carried out by converting the compound of Formula VI to the compound of Formula II.
  • the compound of Formula VI may be in free base form or in a salt form.
  • a compound of Formula VI may be converted into a compound of Formula II by reacting the compound of Formula VI with a compound of Formula
  • the compound of Formula VI may be reacted with the compound of Formula VII using condensing agent.
  • suitable condensing agents include diphenyl carbonate (DPC), 1 , l'-carbonyldiimidazole (CD I), and carbodiimides.
  • suitable carbodiimides include ⁇ , ⁇ '-dicyclohexylcarbodiimide (DCC), ⁇ , ⁇ '- diisopropylcarbodiimide (DIPC), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC).
  • NN'-dicyclohexylcarbodiimide is used as a condensing agent.
  • the "R" moiety is a halo group, for example, fluoro, chloro, bromo, or iodo.
  • the compound of Formula VI may be reacted with compound of Formula VII in the presence of a base and a suitable solvent.
  • the base may be an inorganic base or an organic base.
  • suitable inorganic base include alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, and alkali alkoxides.
  • suitable alkali metal hydroxides include sodium hydroxide and potassium hydroxide.
  • suitable alkali metal bicarbonates include sodium bicarbonate and potassium bicarbonate.
  • suitable alkali metal carbonates include sodium carbonate, potassium carbonate, and cesium carbonate.
  • alkali alkoxides may be used but not limited to sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.
  • suitable organic bases include pyridine, triethylamine, and ⁇ , ⁇ -diisopropylethylamine.
  • sodium carbonate is used as a base.
  • the solvent may be an ethereal solvent, a chlorinated solvent, a hydrocarbon solvent, water, or a mixture thereof.
  • suitable chlorinated solvents include dichlorome thane, dichloroethane, chloroform, and mixtures thereof.
  • suitable ethereal solvents include 1 ,4-dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert- butyl ether, tetrahydrofuran, and mixtures thereof.
  • suitable hydrocarbon solvents include heptane, hexane, toluene, and mixtures thereof. In particularly useful embodiments, a mixture of water and tetrahydrofuran is used as a solvent.
  • Formula II may be useful as an intermediate for synthesizing ibrutinib.
  • Another embodiment of the present invention provides a process for the preparation of ibrutinib which may be carried out by reacting a compound of Formula II with (4-phenoxyphenyl)boronic acid to obtain ibrutinib of Formula I.
  • the "X" moiety is a halo group, for example, fluoro, chloro, bromo, or iodo.
  • the compound of Formula II may be reacted with (4- phenoxyphenyl)boronic acid. This may be carried out in the presence of metal catalyst and a base in a suitable solvent.
  • Suitable metal catalysts include tetrakis(triphenylphosphine)palladium, palladium (II) acetate, bis(triphenylphosphine) palladium(II) dichloride, bis(acetonitrile)dichloro palladium, bis(benzonitrile)palladium chloride, [1,1 - bis(diphenylphosphino)ferrocine]dichloropalladium(II) complex with dichloromethane, tris(dibenzylideneacetone)dipalladium(0), and bis(dibenzylideneacetone) palladium.
  • tetrakis(triphenylphosphine)palladium is used as a catalyst.
  • the base used in this embodiment may be an inorganic base or an organic base.
  • inorganic bases include alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali alkoxides, alkali metal phosphates, and alkali metal acetates.
  • alkali metal hydroxides include sodium hydroxide and potassium hydroxide.
  • alkali metal bicarbonates include sodium bicarbonate and potassium bicarbonate.
  • alkali metal carbonates include sodium carbonate, potassium carbonate, and cesium carbonate.
  • alkali alkoxides include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.
  • alkali metal phosphates include sodium phosphate and potassium phosphate.
  • alkali metal acetates include sodium acetate and potassium acetate.
  • organic bases include pyridine, triethylamine, and ⁇ , ⁇ -diisopropylethylamine. In particularly useful embodiments, potassium phosphate is used as a base.
  • solvents examples include 1,4-dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, t-amyl alcohol, dichloromethane, tetrahydrofuran, toluene, ethanol, methanol, isopropanol, acetone, dimethyl formamide, water, and mixtures thereof.
  • a mixture of 1,4-dioxane and water is used as a solvent.
  • Another aspect of the present invention provides an additional process for the preparation of ibrutinib.
  • One embodiment of the present invention provides a process for the preparation of ibrutinib which may include the following steps: a) reacting a compound of Formula VI with (4-phenoxyphenyl)boronic acid to get a compound of Formula A; and
  • the "X" moiety is a halo group, for example, fluoro, chloro, bromo, or iodo and Formula VI may be in a free base form or in a salt form.
  • a compound of Formula VI may be reacted with (4-phenoxyphenyl)boronic acid to obtain a compound of formula A.
  • This reaction may occur in the presence of a metal catalyst and a base in a suitable solvent.
  • suitable metal catalyst examples include tetrakis(triphenylphosphine)palladium, palladium (II) acetate, bis(triphenylphosphine)palladium(II) dichloride, bis(acetonitrile)dichloro palladium, bis(benzonitrile)palladium chloride, [1,1 - bis(diphenylphosphino)ferrocine]dichloropalladium(II) complex with dichloromethane, tris(dibenzylideneacetone)dipalladium(0), and bis(dibenzylideneacetone) palladium.
  • bis(triphenylphosphine)palladium(II) dichloride is used as a metal catalyst.
  • the base may be an inorganic base or an organic base.
  • suitable inorganic bases include alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali alkoxides, alkali metal phosphates, and alkali metal acetates.
  • suitable alkali metal hydroxides include sodium hydroxide and potassium hydroxide.
  • suitable alkali metal bicarbonates include sodium bicarbonate and potassium bicarbonate.
  • suitable alkali metal carbonates include sodium carbonate, potassium carbonate, and cesium carbonate.
  • suitable alkali alkoxides include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, and potassium tert-butoxide.
  • suitable alkali metal phosphates include sodium phosphate and potassium phosphate.
  • suitable alkali metal acetates include sodium acetate or potassium acetate.
  • suitable organic bases include pyridine, triethylamine, and ⁇ , ⁇ -diisopropylethylamine. In particularly useful embodiments, sodium carbonate or potassium phosphate is used as a base.
  • solvents examples include 1,4-dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert-butyl ether, tetrahydrofuran, t-amyl alcohol, dichloromethane, tetrahydrofuran, toluene, ethanol, methanol, isopropanol, acetone, dimethyl formamide, water, and mixtures thereof. In particularly useful embodiments, a mixture of ethanol and water is used as a solvent.
  • Formula A may be converted into ibrutinib.
  • the conversion of the compound of Formula A into ibrutinib may occur by reacting the compound of Formula A with a compound of Formula VII.
  • the "R" moiety is -OH.
  • the compound of Formula A may be reacted with the compound of Formula VII in the presence of a condensing agent.
  • suitable condensing agents include diphenyl carbonate (DPC), 1 , l'-carbonyldiimidazole (CDI), and carbodiimides.
  • suitable carbodiimides include N,N'-dicyclohexylcarbodiimide (DCC), ⁇ , ⁇ '-diisopropylcarbodiimide (DIPC), and N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide (EDC).
  • NN'-dicyclohexylcarbodiimide is used as a condensing agent.
  • the "R" moiety is a halo group, for example, fluoro, chloro, bromo, or iodo.
  • the compound of Formula A may be reacted with compound of Formula VII in the presence of a suitable solvent.
  • the solvent may be an ethereal solvent, a chlorinated solvent, a hydrocarbon solvent, water, or a mixture thereof.
  • suitable chlorinated solvents include dichlorome thane, dichloroethane, chloroform, and mixtures thereof.
  • suitable ethereal solvents include 1 ,4-dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert- butyl ether, tetrahydrofuran, and mixtures thereof.
  • suitable hydrocarbon solvents include heptane, hexane, toluene, and mixtures thereof. In particularly useful embodiments, dichloromethane is used as a solvent.
  • the base may be an inorganic base or an organic base.
  • suitable inorganic base include alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, and alkali alkoxides.
  • suitable alkali metal hydroxides include sodium hydroxide and potassium hydroxide.
  • suitable alkali metal bicarbonates include sodium bicarbonate and potassium bicarbonate.
  • suitable alkali metal carbonates include sodium carbonate, potassium carbonate, and cesium carbonate.
  • alkali alkoxides may be used but not limited to sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert- butoxide, and potassium tert-butoxide.
  • suitable organic bases include pyridine, triethylamine, and N,N-diisopropylethylamine.
  • ibrutinib may be prepared on an industrial scale with high purity (> 99.5%) without the use of complex or lengthy purification procedures, such as column chromatography, which requires optimization and can often take a great deal of time, depending on the properties of the product as well as the amount of product being purified.
  • a solid may simply be precipitated out of solution and dried to obtain a high-quality ibrutinib product.
  • the methods disclosed herein provide a simple and industrially scalable process for preparing ibrutinib.
  • the ibrutinib prepared by the methods disclosed herein may be useful in the treatment of individuals with mantle cell lymphoma who have received at least one prior therapy, chronic lymphocytic leukemia who have received at least one prior therapy, chronic lymphocytic leukemia with 17p deletion, or Waldenstrom's macroglobulinemia.
  • the ibrutinib disclosed herein may be incorporated into oral pharmaceutical dosage forms, for example, a capsule or tablet.
  • the tablet or capsule may include additional pharmaceutically acceptable excipients, for example, croscarmellose sodium, magnesium stearate, sodium lauryl sulfate, and mixtures thereof.
  • the tablet may, in some embodiments, be coated with a film that includes additional excipients, artificial flavorings, artificial colorings, and mixtures thereof.
  • the coating may contain gelatin, titanium dioxide, blank ink, or mixtures thereof.
  • dosage forms containing ibrutinib as disclosed herein may have about 140 mg to about 540 mg of ibrutinib per dosage form.
  • the dosage form contains 140 mg of ibrutinib.
  • Triethylamine (15.1 g) and methane sulfonyl chloride (6.26 g) was slowly added to a solution of N-Boc-3 -hydroxy piperidine (10 g) in dichloromethane (200 mL) at 0-5 °C. The mixture was stirred for 60 min at 0-5 °C and water (200 mL) was added. The layers were separated and the organic layer was washed with water (200 mL) and concentrated to give tert-butyl-(S)-3- ((methylsulfonyl)oxy)piperidine- 1 -carboxylate.
  • Example 2 Process for the preparation of lH-pyrazolo[3,4-d]pyrimidine-4-amine (precursor to Formula III)
  • a solution of 5-amino-lH-pyrazole-4-carbonitrile (10 g) in formamide (80 mL) was stirred at 165 °C for 5 h.
  • the reaction mixture was cooled to room temperature and diluted with water (120 mL).
  • the crude product was filtered.
  • the filtered cake was washed with water (20 mL) and followed by methanol (20 mL).
  • the product was dried to get lH-pyrazolo[3,4- d]pyrimidine-4-amine.
  • Trifluoroacetic acid (3.0 mL) was added to a solution of (R)-tert-butyl-3-(4-amino-3-iodo-lH- pyrazolo[3,4-d]pyrimidine-l-yl)piperidine-l-carboxylate (Formula V, 2.8 g) in dichloromethane (300 mL) at 0-10 °C. The reaction mass was heated to room temperature and stirred for 6 h. The mass was concentrated and the residue was dissolved in dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution (100 mL).
  • Example 8 Process for the preparation of l-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo[3,4-d]pyrimidin-l-yl]-l-piperidinyl]-2-propen-l-one (ibrutinib)
  • a mixture of l-(3-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidine-l-yl)prop-2-en- 1-one (Formula II, 200 mg), (4-phenoxyphenyl)boronic acid (160 mg), potassium phosphate (0.32 g), tetrakis(triphenylphosphine)palladium (87 mg), 1,4-dioxane (5 mL), and water (1 mL) was stirred at 100 °C for 5 h under nitrogen atmosphere.
  • reaction mass temperature was raised to 60-80 °C for 6 hours and then second lot of (S)-tert-butyl-3-((methylsulfonyl)oxy)piperidine-l-carboxylate (80.1 g, 0.5 eq) was added. The reaction mixture was maintained at same temperature for another 6 hours. A third lot of (S)-tert-butyl-3-((methylsulfonyl)oxy)piperidine-l-carboxylate (40.5 g, 0.25 eq) was then added and the reaction mass was maintained at temperature for 6 hours.
  • Example 10 process for the preparation of 3-(4-iodo)-l-(piperidine-3-yl)-lH-pyrazolo[3,4- d]pyrimidine-4-amine dihydrochloride (dihydrochloride salt form of Formula VI)
  • Example 11 Process for the preparation of 3-(4-phenoxyphenyl)-l-(piperidine-3-yl)-lH- pyrazolo[3,4-d]pyrimidine-4-amine (Formula A)
  • the reaction mixture cooled to room temperature and filtered through HYFLO and the obtained filtrate was concentrated under reduced pressure at 50 °C.
  • the obtained product was dissolved in aqueous hydrochloric acid (300 mL) and washed with methylene chloride (1 x 750 mL, 3 x 375 mL).
  • the aqueous layer was neutralized with aqueous sodium carbonate (900 mL) and extracted the product with ethyl acetate (1 x 1125 mL, 2 x 750 mL).
  • Example 12 Process for the preparation of l-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo [3,4-d]pyrimidin-l-yl]-l-piperidinyl]-2-propen-l-one (ibrutinib)
  • Example 14 Process for the preparation of 3-(4-phenoxyphenyl)-l-(piperidine-3-yl)-lH- pyrazolo[3,4-d]pyrimidine-4-amine (Formula A)
  • the obtained filtrate was concentrated under reduced pressure at 50 °C.
  • the obtained product was dissolved in aqueous hydrochloric acid (20 mL) and washed with methyl isobutyl ketone (3 x 30 mL).
  • the aqueous layer was neutralized with 10% sodium hydroxide (80 mL) and extracted the product with methylene chloride (1 x 200 mL, 1 x 100 mL).
  • the combined methylene chloride layers were concentrated and the obtained crude product was crystalized in methanol and water to get 3-(4-phenoxyphenyl)-l-(piperidine-3-yl)-lH- pyrazolo[3,4-d]pyrimidine-4-amine (Formula A).
  • Example 15 Process for the preparation of 3-(4-phenoxyphenyl)-l-(piperidine-3-yl)-lH- pyrazolo[3,4-d]pyrimidine-4-amine (Formula A)
  • the reaction mixture was cooled to room temperature, filtered through HYFLO, and the obtained filtrate was concentrated under reduced pressure at 50 °C.
  • the obtained product was dissolved in aqueous hydrochloric acid (20 mL) and washed with methyl isobutyl ketone (3 x 30 mL).
  • the aqueous layer was neutralized with 10% sodium hydroxide (80 mL) and the product was extracted with methylene chloride (1 x 200 mL, 1 x lOOmL).
  • Example 16 process for the preparation of l-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo [3,4-d]pyrimidin-l-yl]-l-piperidinyl]-2-propen-l-one (ibrutinib)
  • the organic layer was washed with 5% aqueous sodium bicarbonate solution (50 mL) and followed by water (50 mL).
  • the organic layer was concentrated under vacuum at 40 °C and recrystallized in toluene (100 mL).
  • the obtained wet material was dried and dissolved in methanol (50 mL) at 40-45 °C, cooled to 0-5°C, and filtered.
  • the wet material was dissolved in dimethyl sulfoxide (30 mL), water (500 mL) was added, and the solution was stirred for lh.
  • Example 17 process for the preparation of l-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-lH- pyrazolo [3,4-d]pyrimidin-l-yl]-l-piperidinyl]-2-propen-l-one (ibrutinib)
  • the reaction mass was washed with 10% aqueous HCl (3 X 100 mL) followed by water (50 mL).
  • the organic layer was washed with 5% aqueous sodium bicarbonate solution (50 mL) and followed by water (50 mL).
  • the organic layer was treated with 1,8- diazabicyclo[5.4.0]undec-7-ene (0.72 g) for 6-8 h.
  • the organic layer was then washed with 10% aqueous HCl solution (50 mL) followed by sodium bicarbonate solution (50 mL) and water (50 mL).
  • the organic layer was concentrated under vacuum below 40 °C and recrystallized in toluene (100 mL).
  • the obtained wet material was dried, dissolved in methanol (50 mL) at 40- 45 °C, and cooled to 0-5 °C.
  • the filtered wet material was dissolved in dimethyl sulfoxide (30 mL), water (500 mL) was added, and the reaction mixture was stirred for 1 h.
  • the wet material was washed with water (2 x 100 mL) and dried at 30-35 °C to get l-[(3R)-3-[4-amino-3- (4-phenoxyphenyl)- 1 H-pyrazolo- [3 ,4-d]pyrimidin- 1 -yl] - 1 -piperidinyl] -2-propen- 1 -one

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Abstract

L'invention concerne des procédés pour la préparation de 1-[(3R)-3-[4-amino-3-(4-phénoxyphényl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pipéridinyl]-2-propène-1-one (ibrutinib). Le procédé de l'invention peut être utile pour la préparation d'ibrutinib qui peut être inclus dans des formes galéniques pharmaceutiques.
PCT/IN2016/050057 2015-02-18 2016-02-17 Procédé pour la préparation d'ibrutinib WO2016132383A1 (fr)

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CN109206426B (zh) * 2017-07-06 2021-10-08 上海复星星泰医药科技有限公司 吡唑并嘧啶类化合物的制备方法

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