WO2016132383A1

WO2016132383A1 - Process for the preparation of ibrutinib

Info

Publication number: WO2016132383A1
Application number: PCT/IN2016/050057
Authority: WO
Inventors: Sureshbabu JAYACHANDRA; Sonny SEBASTAIAN; Jagadeeshwar Rao; Himaprasad NAIDU; Mallareddy Adla; Srinivasa Rao Mannava; Suresh Reddy SABBELLA; Ramesh Dandala
Original assignee: Mylan Laboratories Limited
Priority date: 2015-02-18
Filing date: 2016-02-17
Publication date: 2016-08-25

Abstract

A processes for the preparation of 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4- d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one (ibrutinib). The disclosed process may be useful for preparing ibrutinib that may be included in pharmaceutical dosage forms.

Description

PROCESS FOR THE PREPARATION OF IBRUTINIB

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of Indian provisional patent applications No. 777/CHE/2015 filed on February 18, 2015 and 2560/CHE/2015 filed on May 22, 2015, which are hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION

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.

BACKGROUND OF THE INVENTION

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.

Formula I 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.

SUMMARY OF THE INVENTION

One aspect of the present invention provides process for the preparation of ibrutinib.

In one embodiment, ibrutinib may be prepared by the following steps:

a. reacting a compound of Formula VI or a salt thereof with (4-phenoxyphenyl)boronic acid to get a compound of Formula A; and

Formula A b. converting the compound of Formula A to ibrutinib;

Formula I

Within the context of this embodiment, "X" is a halogen selected from the group consisting of - F, -CI, -Br, and -I and R is hydroxy or halogen. According to this embodiment, 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. Examples of suitable inorganic bases include alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali metal alkoxides, alkali metal phosphates, and alkali metal acetates. Examples of 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.

According to the present embodiment, the conversion of Formula A to ibrutinib may be carried out by reacting with compound of Formula VII:

Formula VII Within the context of this embodiment, R is -OH or a halogen selected from the group consisting of -F, -CI, -Br, and -I.

In some embodiments, when R is a halogen, 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. This step may be further carried out in the presence of a base which may be organic or inorganic. Examples of suitable inorganic bases include alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, and alkali alkoxides. Examples of suitable organic bases include pyridine, triethylamine, and N,N-diisopropylethylamine.

In some embodiments, when R is -OH, this step may be carried out in the presence of condensing agent. Examples of suitable condensing agents include di-2-pyridyl carbonate, 1, 1'- carbonyldiimidazole, or a carbodiimide selected from the group consisting of Ν,Ν'- dicyclohexylcarbodiimide, diisopropyl carbodiimide, and N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide.

In another embodiment of the present invention, 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

Formula V b. deprotecting the compound of Formula V to get a compound of Formula VI;

Formula V Formula VI

In this embodiment, 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.

In some embodiments, where L is hydrogen, Formula III may be reacted with Formula IV in the presence of a reagent, for example, diisopropyl azodicarboxylate, triphenylphosphine, diethyl azodicarboxylate, a triphenylphosphine, a C₂-C8 trialkylphosphine, or mixtures thereof.

In some embodiments, where L is an alkylsulfonyl group or an arylsulfonyl group, the reacting step may be carried out in the presence of a base and a solvent. Within the context of this embodiment, the base may be an organic base or an inorganic base. Examples of suitable inorganic bases include alkali metal hydroxides, alkali metal hydrides, alkali metal bicarbonates, alkali metal carbonates, and alkali alkoxides. Examples of suitable organic bases include pyridine, triethylamine, and Ν,Ν-diisopropylethylamine. The solvent may be, for example, a polar aprotic solvents or a crown ether solvent. Examples of 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. Examples of 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:

O

Formula VI Formula II

According to the present embodiment, compound of formula VI may be converted into compound of formula II by reacting compound of formula VI with compound of formula VII.

Formula VII

Within the context of this embodiment, R is -OH or a halogen selected from the group consisting of -F, -CI, -Br, and -I.

In some embodiments, when R is -OH, this reaction may be carried out in the presence of a condensing agent which may be, for example, diphenyl carbonate, Ι, Γ-carbonyldiimidazole, and carbodiimides selected from the group consisting of NN'-dicyclohexylcarbodiimide, Ν,Ν'- diisopropylcarbodiimide, or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide.

In some embodiment, 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. Examples of suitable inorganic bases include selected from the group consisting of alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, and alkali alkoxides. Examples of organic bases include pyridine, triethylamine, and Ν,Ν-diisopropylethylamine. Examples of suitable solvents include ethereal solvents, chlorinated solvents, hydrocarbon solvents, water, and mixtures thereof.

In another embodiment, ibrutinib may be prepared by reacting a compound of Formula II with (4-phenoxyphenyl)boronic acid to get ibrutinib of Formula I;

Formula II Formula I

Within the context of this embodiment, 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. Examples of 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.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that the description of the present invention has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known.

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:

a) reacting a compound of Formula III with a compound of Formula IV to get a compound of

Formula V

b) deprotecting the c Formula VI.

Formula V Formula VI

According to this embodiment, 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. The term "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. 15/1, Georg Thieme Verlag, Stuttgart 1974; H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine", Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982; and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate", Georg Thieme Verlag, Stuttgart 1974. Amine protecting groups include, for example, -R^p, =R^Q, -C(0)R°, -C(O)OR⁰,-S(O)₂R°, and 2- nitrophenylsulfenyl, wherein

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^Q is =C(H)-R°; and

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_₃alkyl)silyl (e.g., trimethylsilyl).

Particular examples of 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-dimethyoxybenzyl (Dmpm), p- methoxybenzyl (PMB), p-methoxyphenyl (PMP), acetyl (Ac), formyl, trifluoroacetyl (Tfa), benzoyl (Bz), or 2-nitrophenylsulfenyl (Nps).

The term "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. Representative examples of 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.

The term "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.

The term "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.

The term "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. Examples of aryl groups include phenyl, napthyl, anthracenyl, and fluorenyl.

The term "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.

The term "halo" or "halogen" as used herein means fluoro, chloro, bromo, or iodo.

The term "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.

The term "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. Representative examples of 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.

The term "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 term "oxo" as used herein means a =0 group. The term "thia" as used herein means a =S group.

In particularly useful embodiments, the protecting group is a tert-butyloxycarbonyl (BOC) protecting group.

In the context of this embodiment, L may be hydrogen, an alkylsulfonyl group, or an arylsulfonyl group.

As a first step in this embodiment, a compound of Formula III may be reacted with a compound of Formula IV to get a compound of Formula V.

According to some embodiments of the present invention, when L is hydrogen, 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. For example, in some embodiments, 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. In other embodiments, this reaction is performed in the presence of diethyl azodicarboxylate (DEAD) and a triphenylphosphine or C₂-C8 trialkylphosphine. In particular embodiments, 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. Examples of 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. Examples of suitable crown ether solvents include 18- crown-6 and diaza-18-crown-6, and mixtures thereof. In particularly useful embodiments, N- methylpyrrolidone, dimethyl formamide, or tetrahydrofuran is used as a solvent.

According to some embodiments of the present invention, 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. This may be performed in the presence of a base and a suitable solvent. The base may be an inorganic base or an organic base. Examples of suitable inorganic bases include alkali metal hydroxides, alkali metal hydrides, alkali metal bicarbonates, alkali metal carbonates, and alkali alkoxides. Examples of suitable alkali metal hydroxides include sodium hydroxide and potassium hydroxide. Examples of suitable alkali metal include sodium hydride and potassium hydride. Examples of suitable alkali metal bicarbonates include sodium bicarbonate and potassium bicarbonate. Examples of suitable alkali metal carbonates include sodium carbonate, potassium carbonate, and cesium carbonate. Examples of suitable alkali alkoxides include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, and potassium tert-butoxide. Examples of suitable organic bases include pyridine, triethylamine, and Ν,Ν-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. Examples of 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. Examples of suitable crown ether solvents include 18-crown-6 and diaza-18-crown-6, and mixtures thereof. In particularly useful embodiments, N-methylpyrrolidone, dimethyl formamide, or tetrahydrofuran is used as a solvent. According to the present embodiment, a compound of Formula V may be deprotected to get a compound of Formula VI. Again, one of skill in the art will be familiar with and knowledgeable regarding suitable deprotection conditions for the variety of protecting groups that may be used in the context of the present invention. For example, many 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. In certain embodiments, when the protecting group is a tert-butyloxycarbonyl moiety, use of trifluoroacetic acid is useful for deprotection.

According to the present embodiment, deprotection of compound of Formula V to give Formula VI may be carried out in the presence of a solvent. Again, one of skill in the art will be familiar with appropriate and useful conditions for removal of protecting groups. Examples of suitable solvents include alcohol solvents, chlorinated solvents, water, and mixtures thereof. Examples of suitable alcohol solvents include methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, t-butanol, pentanol, and mixtures thereof. Examples of 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.

Within the context of the present invention, Formula VI may be optionally converted into its acid salt form. In some embodiments, 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.

Methods for converting compounds into their acid salt forms are well known in the art. For example, 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.

Within the context of this embodiment, a free base moiety on formula VI may be optionally reacted with a suitable acid to obtain a salt of formula VI. Examples of suitable acids include, for example, inorganic acids and organic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid. Suitable organic acids include, for example, oxalic acid, and tartaric acid. In certain embodiments, the acid is hydrochloric acid and the dihydrochloride salt of Formula VI is formed.

Within the context of the present invention, Formula VI, or a salt thereof, 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.

Formula VI Formula II

According to the present embodiment, the compound of Formula VI may be in free base form or in a salt form.

According to the present embodiment, 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

VII.

Formula VII In one embodiment, the "R" moiety is OH.

According to this embodiment, where "R" is OH, the compound of Formula VI may be reacted with the compound of Formula VII using condensing agent. Examples of suitable condensing agents include diphenyl carbonate (DPC), 1 , l'-carbonyldiimidazole (CD I), and carbodiimides. Examples of suitable carbodiimides include Ν,Ν'-dicyclohexylcarbodiimide (DCC), Ν,Ν'- diisopropylcarbodiimide (DIPC), and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC). In some embodiments, NN'-dicyclohexylcarbodiimide is used as a condensing agent.

In other embodiments, the "R" moiety is a halo group, for example, fluoro, chloro, bromo, or iodo.

According to this embodiment, where R is a halo group, 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. Examples of suitable inorganic base include alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, and alkali alkoxides. Examples of suitable alkali metal hydroxides include sodium hydroxide and potassium hydroxide. Examples of suitable alkali metal bicarbonates include sodium bicarbonate and potassium bicarbonate. Examples of suitable alkali metal carbonates include sodium carbonate, potassium carbonate, and cesium carbonate. Examples of suitable alkali alkoxides may be used but not limited to sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, and potassium tert-butoxide. Examples of suitable organic bases include pyridine, triethylamine, and Ν,Ν-diisopropylethylamine. In particularly useful embodiments, sodium carbonate is used as a base.

Within the context of this embodiment, the solvent may be an ethereal solvent, a chlorinated solvent, a hydrocarbon solvent, water, or a mixture thereof. Examples of suitable chlorinated solvents include dichlorome thane, dichloroethane, chloroform, and mixtures thereof. Examples of suitable ethereal solvents include 1 ,4-dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert- butyl ether, tetrahydrofuran, and mixtures thereof. Examples of 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. Within the context of the present invention, 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.

Formula II Formula 1

Within the context of this embodiment, the "X" moiety is a halo group, for example, fluoro, chloro, bromo, or iodo.

According to the present embodiment, 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.

Examples of 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. In particularly useful embodiments, tetrakis(triphenylphosphine)palladium is used as a catalyst.

The base used in this embodiment may be an inorganic base or an organic base. Examples of inorganic bases include alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali alkoxides, alkali metal phosphates, and alkali metal acetates. Examples of alkali metal hydroxides include sodium hydroxide and potassium hydroxide. Examples of alkali metal bicarbonates include sodium bicarbonate and potassium bicarbonate. Examples of alkali metal carbonates include sodium carbonate, potassium carbonate, and cesium carbonate. Examples of alkali alkoxides include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, and potassium tert-butoxide. Examples of alkali metal phosphates include sodium phosphate and potassium phosphate. Examples of alkali metal acetates include sodium acetate and potassium acetate. Examples of organic bases include pyridine, triethylamine, and Ν,Ν-diisopropylethylamine. In particularly useful embodiments, potassium phosphate is used as a base.

Examples of 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, isopropanol, acetone, dimethyl formamide, water, and mixtures thereof. In particularly useful embodiments, 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

Formula VI

Formula A

b) converting the compound of Formula A to ibrutinib of Formula I.

Formula A

Formula I

Within the context of this embodiment, 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.

According to the present embodiment, a compound of Formula VI, or a salt thereof, 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.

Examples of suitable metal catalyst 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. In certain useful embodiments, bis(triphenylphosphine)palladium(II) dichloride is used as a metal catalyst.

The base may be an inorganic base or an organic base. Examples of suitable inorganic bases include alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali alkoxides, alkali metal phosphates, and alkali metal acetates. Examples of suitable alkali metal hydroxides include sodium hydroxide and potassium hydroxide. Examples of suitable alkali metal bicarbonates include sodium bicarbonate and potassium bicarbonate. Examples of suitable alkali metal carbonates include sodium carbonate, potassium carbonate, and cesium carbonate. Examples of suitable alkali alkoxides include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, and potassium tert-butoxide. Examples of suitable alkali metal phosphates include sodium phosphate and potassium phosphate. Examples of suitable alkali metal acetates include sodium acetate or potassium acetate. Examples of suitable organic bases include pyridine, triethylamine, and Ν,Ν-diisopropylethylamine. In particularly useful embodiments, sodium carbonate or potassium phosphate is used as a base.

Examples of 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, isopropanol, acetone, dimethyl formamide, water, and mixtures thereof. In particularly useful embodiments, a mixture of ethanol and water is used as a solvent.

Next, Formula A may be converted into ibrutinib.

Within the context of this embodiment, 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.

Formula VII

In some embodiments, the "R" moiety is -OH.

According to this embodiment, where "R" is -OH, the compound of Formula A may be reacted with the compound of Formula VII in the presence of a condensing agent. Examples of suitable condensing agents include diphenyl carbonate (DPC), 1 , l'-carbonyldiimidazole (CDI), and carbodiimides. Examples of suitable carbodiimides include N,N'-dicyclohexylcarbodiimide (DCC), Ν,Ν'-diisopropylcarbodiimide (DIPC), and N-(3-dimethylaminopropyl)-N'- ethylcarbodiimide (EDC). In some embodiments, NN'-dicyclohexylcarbodiimide is used as a condensing agent.

According to this embodiment, where R is a halo group, the compound of Formula A may be reacted with compound of Formula VII in the presence of a suitable solvent. Within the context of this embodiment, the solvent may be an ethereal solvent, a chlorinated solvent, a hydrocarbon solvent, water, or a mixture thereof. Examples of suitable chlorinated solvents include dichlorome thane, dichloroethane, chloroform, and mixtures thereof. Examples of suitable ethereal solvents include 1 ,4-dioxane, diethyl ether, ethyl tert-butyl ether, methyl tert- butyl ether, tetrahydrofuran, and mixtures thereof. Examples of suitable hydrocarbon solvents include heptane, hexane, toluene, and mixtures thereof. In particularly useful embodiments, dichloromethane is used as a solvent.

This reaction may be carried out optionally in the presence of a base. The base may be an inorganic base or an organic base. Examples of suitable inorganic base include alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, and alkali alkoxides. Examples of suitable alkali metal hydroxides include sodium hydroxide and potassium hydroxide. Examples of suitable alkali metal bicarbonates include sodium bicarbonate and potassium bicarbonate. Examples of suitable alkali metal carbonates include sodium carbonate, potassium carbonate, and cesium carbonate. Examples of suitable alkali alkoxides may be used but not limited to sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert- butoxide, and potassium tert-butoxide. Examples of suitable organic bases include pyridine, triethylamine, and N,N-diisopropylethylamine.

By practicing the processes disclosed herein, 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. In some embodiments of the present invention, a solid may simply be precipitated out of solution and dried to obtain a high-quality ibrutinib product. In this manner, 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. For example, the coating may contain gelatin, titanium dioxide, blank ink, or mixtures thereof.

Within the context of the present invention, dosage forms containing ibrutinib as disclosed herein may have about 140 mg to about 540 mg of ibrutinib per dosage form. In particularly useful embodiments of the present invention, the dosage form contains 140 mg of ibrutinib.

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

EXAMPLES

Example 1: Process for the preparation of (S)-tert-butyl 3-((methylsulfonyl)oxy)piperidine- 1-carboxylate (Formula IV, P=BOC, L=methylsulfonyl)

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.

Example 3: Process for the preparation of 3-iodo-lH-pyrazolo[3,4-d]pyrimidine-4-amine (Formula III, X=I)

A mixture of lH-pyrazolo[3,4-d]pyrimidine-4-amine (150 g), N-iodo succinamide (375 g) and N,N-dimethylformamide (2.5 L) was stirred at 80 °C for 5 h. The reaction mixture was cooled to room temperature and then diluted with water (10 L). The solid was collected by filtration, washed with statured aqueous sodium sulfite (2 X 1 L) and dried under vacuum to give 3-iodo-l- H-pyrazolo[3,4-d]pyrimidine-4-amine (Formula III, where X=I).

Example 4: Process for the preparation of (R)-tert-butyl-3-(4-amino-3-iodo-lH- pyrazolo[3,4-d]pyrimidine-l-yl)piperidine-l-carboxylate (Formula V, X=I, P=BOC)

A solution of diisopropyl azodicarboxylate in tetrahydrofuran (30 mL) was added drop wise to a stirred solution of 3-iodo-lH-pyrazolo[3,4-d]pyrimidine-4-amine (Formula III, 5.9 g), (S)-tert- butyl-3-hydroxypiperidine-l-carboxylate (Formula IV, L=H; 10 g), triethylphosphine (11.8 g), and tetrahydrofuran (300 mL) at 5-10 °C over 30 min. The resulting mixture was stirred at room temperature for 12 h and then concentrated under vacuum. The residue was purified on silica gel column then eluted with dichloromethane and methanol (10: 1) to give (R)-tert-butyl-3-(4-amino- 3-iodo-lH-pyrazolo[3,4-d]pyrimidine-l-yl)piperidine-l-carboxylate (Formula V, where X=I and P=BOC group).

Example 5: Process for the preparation of (R)-tert-butyl-3-(4-amino-3-iodo-lH- pyrazolo[3,4-d]pyrimidine-l-yl)piperidine-l-carboxylate (Formula V, X=I, P=BOC)

(S)-tert-butyl-3-((methylsulfonyl)oxy)piperidine-l-carboxylate (Formula IV, L=methylsulfonyl; 3.06 g), dimethyl formamide (26 mL), and cesium carbonate (4.88 g) were added to a solution of 3-iodo-lH-pyrazolo[3,4-d]pyrimidine-4-amine (Formula III, 2.61g). The reaction mass was heated to 90-100 °C for 6 h and then another lot of (S)-tert-butyl-3-hydroxypiperidine-l- carboxylate (3.06 g) and cesium carbonate (4.88 g) was added and maintained at same temperature for another 10 h. The reaction mass was cooled to room temperature and water (260 mL) was added. The product was extracted with ethyl acetate (3 x 50 mL). The organic layer was concentrated to give (R)-tert-butyl-3-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidine-l- yl)piperidine- 1 -carboxylate (Formula VI, where X=I).

Example 6: Process for the preparation of 3-(4-iodo)-l-(piperidine-3-yl)-lH-pyrazolo[3,4- d]pyrimidine-4-amine (Formula VI, where X=I)

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). The aqueous layer was saturated with sodium chloride (10 g) and extracted with dichloromethane (100 mL). Both organic layers were concentrated to get 3-(4-iodo)-l-(piperidine-3-yl)-lH-pyrazolo[3,4-d]pyrimidine-4-amine (Formula VI, where X=I).

Example 7: Process for the preparation of l-(3-(4-amino-3-iodo-lH-pyrazolo[3,4- d]pyrimidin-l-yl)piperidine-l-yl)prop-2-en-l-one (Formula II, X=I)

Dichloromethane (10 mL), tetrahydrofuran (5 mL), sodium carbonate (0.6 g), and water (1.0 mL) were added to a suspension of 3-(4-iodo)l-(piperidine-3-yl)-lH-pyrazolo[3,4-d]pyrimidine-4- amine (Formula VI, 1 g). The reaction mass was cooled to 0-10 °C and acryloyl chloride (Formula VII, R=C1; 260 mg) was added. The mass was slowly allowed to warm to room temperature and stirred for 2 h until the reaction was complete. The reaction mass was concentrated, diluted with dichloromethane (10 mL), and filtered to remove insoluble solids. The filtrate was concentrated and purified by silica gel column chromatography to get l-(3-(4- amino-3-iodo- lH-pyrazolo[3 ,4-d]pyrimidin- 1 -yl)piperidine- 1 -yl)prop-2-en- 1 -one (Formula II, where X=I).

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. The reaction mixture cooled to room temperature and then water (50 mL) was added. The product was extracted with ethyl acetate (2 x 50 mL) and concentrated to get a residue. The residue was purified by silica gel column chromatography with dichloromethane and methanol 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 (ibrutinib).

Example 9: Process for the preparation of (R)-tert-butyl-3-(4-amino-3-iodo-lH- pyrazolo[3,4-d]pyrimidine-l-yl)piperidine-l-carboxylate (Formula V; X=I, P=BOC)

Potassium carbonate (118.9 g, 1.5 eq) was added to a solution of 3-iodo-lH-pyrazolo[3,4- d]pyrimidine-4-amine (Formula III, 150 g, 1.0 eq) and (S)-tert-butyl-3- ((methylsulfonyl)oxy)piperidine-l-carboxylate (Formula IV, L=methylsulfonyl; 80.1 g, 0.5 eq) in N-methylpyrrolidone (1350 mL). The 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. A fourth lot of (S)-tert-butyl-3-((methylsulfonyl)oxy)piperidine-l-carboxylate (40.5 g, 0.25 eq) was then added and the reaction mixture was maintained at temperature for 12 hours. The reaction mass was then cooled to room temperature and poured into water (13.5 L). The product was filtered and washed with water (3 x 50 mL). The wet material was dried at 50-60 °C for 8-10 hours and dried powdered material was washed with hexane (750 mL) at 50 °C and purified in methanol (1500 mL) to give (R)-tert-butyl-3-(4-amino-3-iodo-lH-pyrazolo[3,4- d]pyrimidine-l-yl)piperidine-l-carboxylate (Formula V, where X=I and P=BOC group).

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)

Hydrochloric acid (15% in 15 mL isopropyl alcohol) 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 (ibrutinib, 5 g) in acetone (50 mL) and stirred for 6 hours at 40-50 °C. The reaction mass was cooled to room temperature, filtered, and washed with acetone (10 mL). The wet material was dried under vacuum at 50 °C to get 3-(4-iodo)-l-(piperidine-3-yl)-lH-pyrazolo[3,4-d]pyrimidine-4-amine dihydrochloride (the dihydrochloride 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)

A mixture of 3-(4-iodo)-l-(piperidine-3-yl)-lH-pyrazolo[3,4-d]pyrimidine-4-amine dihydrochloride (dihydrochloride salt form of Formula VI, 75 g, 1.0 eq), (4- phenoxyphenyl)boronic acid (42.3 g, 1.1 eq), potassium phosphate (228.9 g, 6.0 eq), and bis(triphenylphosphine)palladium(II) dichloride (5 g, 0.04 eq) in a mixture of ethanol (1125 mL) and water (525 mL) was stirred at 80-90 °C for 5 hours under nitrogen atmosphere. 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). The combined ethyl acetate layers were concentrated and the obtained crude product was crystalized in ethyl acetate to get 3-(4- phenoxyphenyl)-l-(piperidine-3-yl)-lH-pyrazolo[3,4-d]pyrimidine-4-amine (Formula A).

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)

A solution of acryloyl chloride (Formula VII, R=C1; 8.35 mL, 1.0 eq) in dichloromethane (800 mL) was added to a solution of 3-(4-phenoxyphenyl)-l-(piperidine-3-yl)-lH-pyrazolo[3,4- d]pyrimidine-4-amine (Formula A, 40 g, 1.0 eq) in dichloromethane (2000 mL) at 0-5 °C and stirred for 60 min at 0-5 °C. Water (400 mL) was added to the reaction mass and the layers were separated. The organic layer was washed with 5% aqueous sodium bicarbonate solution (400 mL) followed by water (400 mL). The organic layer was concentrated under vacuum at 40 °C followed recrystallization in toluene (400 mL) to get l-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)- lH-pyrazolo[3,4-d]pyrimidin-l-yl]-l-piperidinyl]-2-propen-l-one (ibrutinib, Formula I). Example 13: Process for the preparation of (R)-tert-butyl-3-(4-amino-3-iodo-lH- pyrazolo[3,4-d]pyrimidine-l-yl)piperidine-l-carboxylate (Formula V, X=I, P=BOC)

Potassium carbonate (132.3 g, 2.5 eq) was added to a solution of 3-iodo-lH-pyrazolo[3,4- d]pyrimidine-4-amine (Formula III, 100 g, 1.0 eq) and (S)-tert-butyl-3- ((methylsulfonyl)oxy)piperidine-l-carboxylate (Formula IV, L=mefhylsulfonyl; 160.5 g, 1.5 eq) in N-methylpyrrolidone (900 mL). The reaction mass was maintained to 65-75 °C for 96 hours. The reaction mass was cooled to room temperature, poured into water (9 L), and stirred for 2-3 h. The product was filtered and washed with water (2 x 200 mL). The wet material was purified using methanol to get (R)-tert-butyl-3-(4-amino-3-iodo-lH-pyrazolo[3,4-d]pyrimidine-l- yl)piperidine-l-carboxylate (Formula V, where X=I and P=BOC group).

Example 14: Process for the preparation of 3-(4-phenoxyphenyl)-l-(piperidine-3-yl)-lH- pyrazolo[3,4-d]pyrimidine-4-amine (Formula A)

A mixture of 3-(4-iodo)-l-(piperidine-3-yl)-lH-pyrazolo[3,4-d]pyrimidine-4-amine dihydrochloride (dihydrochloride salt of Formula VI, 10 g, 1.0 eq), (4-phenoxyphenyl)boronic acid (5.62 g, 1.1 eq), sodium carbonate (7.6 g, 3.0 eq) and bis(triphenylphosphine)palladium(II) dichloride (0.05 g) in a mixture of ethanol (150 mL) and water (70 mL) was stirred at 75-80 °C for 5 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through HYFLO. 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)

A mixture of 3-(4-iodo)-l-(piperidine-3-yl)-lH-pyrazolo[3,4-d]pyrimidine-4-amine dihydrochloride (10 g, 1.0 eq), (4-phenoxyphenyl)boronic acid (5.62 g, 1.1 eq), sodium carbonate (7.6 g, 3.0 eq), and bis(triphenylphosphine)palladium(II) dichloride (0.05 g) in a mixture of efhanol (150 mL) and water (70 mL) was stirred at 75-80 °C for 5 hours under nitrogen atmosphere. 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). The combined methylene chloride layers were treated with aqueous solution of N-acetyl-L-cysteine (2.5 g in 30 mL water) for 10-12 h and 10% aqueous NaOH solution was added to raise the reaction mass pH to 9.0. The layers were separated, the organic layer was washed with water (50 mL) and concentrated to obtain a crude product, which 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 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)

A solution of acryloyl chloride (Formula VII, R=C1; 2.21 g, 0.95 eq) in dichloromethane (30 mL) was added to a solution of 3-(4-phenoxyphenyl)-l-(piperidine-3-yl)-lH-pyrazolo[3,4- d]pyrimidine-4-amine (Formula A, 10 g, 1.0 eq) in dichloromethane (120 mL) at 32-37 °C and stirred for 60 min at 30-35 °C. The reaction mass was washed with 10% aqueous HC1 (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 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. 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)-lH-pyrazolo [3,4-d]pyrimidin-l-yl]- 1 -piperidinyl] -2-propen- 1 -one (ibrutinib).

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) A solution of acryloyl chloride (Formula VII, R=C1; 2.21 g, 0.95 eq) in dichloromethane (30 mL) was added to a solution of 3-(4-phenoxyphenyl)-l-(piperidine-3-yl)-lH-pyrazolo[3,4- d]pyrimidine-4-amine (10 g, 1.0 eq) in dichloromethane (120 mL) at 30-35 °C and stirred for 60 min at 30-35 °C. 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

(ibrutinib).

Claims

We claim:

1. A process for the preparation of ibrutinib, comprising the steps of:

a. reacting a compound of Formula VI or a salt thereof with (4- phenoxyphenyl)boronic acid to get a compound of Formula A; and

b. converting the compound of Formula A to ibrutinib;

wherein X is a halogen selected from the group consisting of -F, -CI, -Br, and -I and R is hydroxy or halogen.

2. The process according to claim 1, wherein the step-a, is carried out in the presence of a metal catalyst, a base, and a solvent.

3. The process according to claim 2, wherein the metal catalyst is selected from the group consisting of 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.

4. The process according to claim 2, wherein the base is an organic base or an inorganic base.

5. The process according to claim 4, wherein the inorganic base is selected from the group consisting of alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali metal alkoxides, alkali metal phosphates, and alkali metal acetates.

6. The process according to claim 2, wherein the solvent is selected from the group consisting of 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.

7. The process according to claim 1, wherein the step-b is carried out using a reagent of a compound of Formula VII;

Formula VII wherein R is -OH or a halogen selected from the group consisting of -F, -CI, -Br, and -I.

8. The process according to claim 7, wherein R is a halogen selected from the group consisting of -F, -CI, -Br, and -I.

9. The process according to claim 7, which is further carried out in the presence of a solvent.

10. The process according to claim 9, wherein the solvent is selected from the group consisting of an ethereal solvent, a chlorinated solvent, a hydrocarbon solvent, water, and mixtures thereof.

11. The process according to claim 9, which is further carried out in the presence of a base.

12. The process according to claim 11, wherein the base is an organic base or an inorganic base.

13. The process according to claim 12, wherein the inorganic base is selected from the group consisting of alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, and alkali alkoxides.

14. The process according to claim 12, wherein the organic base is selected from the group consisting of pyridine, triethylamine, and N,N-diisopropylethylamine

15. The process according to claim 7, wherein R is -OH.

16. The process according to claim 15, which is further carried out in the presence of condensing agent.

17. The process according to claim 16, wherein condensing agent is selected from the group consisting of di-2-pyridyl carbonate, Ι, Γ-carbonyldiimidazole, or a carbodiimide selected from the group consisting of NN'-dicyclohexylcarbodiimide, diisopropyl carbodiimide, and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide.

18. A process for the preparation of a compound of Formula VI, comprising the steps of: a. reacting a compound of Formula III with a compound of Formula IV to get a compound of Formula V; and

Formula V Formula VI wherein 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.

19. The process according to claim 18, wherein when L is hydrogen and the step-a is carried out in the presence of a reagent selected from diisopropyl azodicarboxylate, triphenylphosphine, diethyl azodicarboxylate, a triphenylphosphine, a C₂-C8 trialkylphosphine, and mixtures thereof.

20. The process according to claim 18, wherein L is an alkylsulfonyl group or an arylsulfonyl group and the step-b is carried out in the presence of a base and a solvent.

21. The process according to claim 20, wherein the base is an organic base or an inorganic base.

22. The process according to claim 21, wherein the inorganic base is selected from the group consisting of alkali metal hydroxides, alkali metal hydrides, alkali metal bicarbonates, alkali metal carbonates, and alkali alkoxides.

23. The process according to claim 21, wherein the organic base is selected from the group consisting of pyridine, triethylamine, and N,N-diisopropylethylamine.

24. The process according to claim 20, wherein the solvent is a polar aprotic solvents or a crown ether solvent.

25. The process according to claim 24, wherein the polar aprotic solvent is selected from the group consisting of 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.

26. The process according to claim 24, wherein the crown ether solvent is selected from the group consisting of 18-crown-6, diaza-18-crown-6, and a mixture thereof.

27. A process for the preparation of ibrutinib, comprising reacting a compound of Formula II with (4-phenoxyphenyl)boronic acid to get ibrutinib of Formula I;

Formula II Formula 1 wherein X is a halogen selected from the group consisting of -F, -CI, -Br, and -I.

28. The process according to claim 26, further carried out in presence of a metal catalyst, a base, and a solvent.

29. The process according to claim 28, wherein the metal catalyst is selected from the group consisting of 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.

30. The process according to claim 28, wherein the base is an organic base or an inorganic base.

31. The process according to claim 30, wherein the inorganic base is selected from the group consisting of alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, alkali metal alkoxides, alkali metal phosphates, and alkali metal acetates.

32. The process according to claim 28, wherein the solvent is selected from the group consisting of 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.

33. The process of claim 18, further comprising the step of reacting formula VI with a compound of Formula VII to form a compound of formula II;

Formula VI Formula II wherein R is -OH or a halogen selected from the group consisting of -F, -CI, -Br, and - I.

34. The process according to claim 33, wherein when R is -OH further carried out in the presence of a condensing agent.

35. The process according to claim 34, wherein the condensing agent is selected from the group consisting of diphenyl carbonate, 1, 1 ' -carbon yldiimidazole, and carbodiimides selected from the group consisting of NN'-dicyclohexylcarbodiimide, Ν,Ν'- diisopropylcarbodiimide, and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide.

36. The process according to claim 33, wherein R is a halogen selected from the group consisting of -F, -CI, -Br, and -I further carried out in the presence of a base and a solvent.

37. The process according to claim 36, wherein the base is an organic base or an inorganic base.

38. The process according to claim 37, wherein the inorganic base is selected from the group consisting of alkali metal hydroxides, alkali metal bicarbonates, alkali metal carbonates, and alkali alkoxides.

39. The process according to claim 37, wherein the organic base is selected from the group consisting of pyridine, triethylamine, and N,N-diisopropylethylamine.

40. The process according to claim 36, wherein the solvent is selected from the group consisting of ethereal solvents, chlorinated solvents, hydrocarbon solvents, water, and mixtures thereof.