FIELD OF THE INVENTION
The present invention relates to an improved, efficient, and industrially advantageous process for the preparation of Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib of formula I and its key intermediates.

Particularly, the present invention provides a novel intermediates and process for the purification.

More particularly, the present invention relates to novel intermediate of formula III

wherein, R is a C1-C5 straight and branched chain alkyl group.

More particularly, the present invention also relates to process for the purification to obtain substantially pure compound of formula IX.


BACKGROUND OF THE INVENTION
Ibrutinib of formula I, marketed under the trade name IMBRUVICA®, an orally administered drug is a Bruton’s tyrosine kinase (BTK) inhibitor. Ibrutinib has been indicated for the treatment of Mantle cell lymphoma (MCL), Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL), Small lymphocytic lymphoma (SLL) with 17p deletion, Waldenstrom’s macroglobulinemia (WM), Marginal zone lymphoma (MZL), and Chronic graft versus host disease (cGVHD).
Ibrutinib (CAS No. 936563-96-1) is chemically known as 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one.
Ibrutinib, its pharmaceutically acceptable salts and process for the preparation thereof were first disclosed in US Patent 7,514,444 (US’444).
US’444 has described a process for the preparation of Ibrutinib by involving use of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine. The process is schematically represented as follows:

The above process involves the isolation of intermediates, which ultimately makes the whole process is lengthy and industrially inefficient. The process also involves polymer-linked triphenyl phosphate in the Mitsunobu reaction, which is more expensive in comparison to ordinary triphenyl phosphate, reduce yield of reaction, and increases the cost of industrial production. Further, no purification is described for the Boc-protected intermediate.
1,1-Dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene and its process for the preparation from 4-Phenoxybenzoic acid were first described in PCT Publication No. 2001/019829 (WO’829).
WO’829 has also described 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine intermediate, and its preparation from 3-amino-4-cyano-5-(4-phenoxyphenyl) pyrazole. The process is schematically represented as follows:

The above process involves use of thionyl chloride which is very toxic corrosive reagent causing damage to lungs and skin. It is also not safe for handling on large scale. Further, it involves isolation of intermediates, which is very time-consuming process.
PCT Publication No. 2016/066673 discloses a process for preparation of ibrutinib and its synthesis intermediates. The process is schematically represented as follows:

The US Patent No. 9,834,561 also describes process for the preparation of Ibrutinib and intermediates thereof. The process is schematically represented as follows:

The above process does not involve purification of intermediate III and IIIa to remove impurities which are formed during Mitsunobu reaction due to side reactions of active amino groups present in Intermediate III.
A Chinese patent application 106279284 also describes process for the preparation of Ibrutinib. It involves column chromatography method for purification of intermediates, which is suitable at large scale production. The process is schematically represented as follows:

Apart from the above-mentioned patent applications, there are several patent applications which are also disclosing Ibrutinib, intermediates and process for the purification thereof.
In view of the discussions in above paragraphs, most of the prior art processes involve purification methods not conducive to industrial production involving chromatography; highly expensive catalysts which are highly moisture sensitive for N-arylation; more expensive polymer-linked triphenyl phosphate instead of ordinary triphenyl phosphate in the Mitsunobu reaction; which ultimately reduce yield of reaction and increases the cost of industrial production.
The purpose of the present invention is to overcome the disadvantages of complex reaction operation, low yield, difficult removal of by-products, and to provide suitable route for industrial production of Ibrutinib.
OBJECT OF THE INVENTION
The main object of the present invention is to provide an improved, efficient, and industrially advantageous process for the preparation of Bruton’s tyrosine kinase (BTK) inhibitor, ibrutinib of formula I and its key intermediates.

Another object of the present invention is to provide a novel intermediates and process for the purification.
Another object of the present invention is to provide a novel intermediate of formula III

wherein, R is a C1-C5 straight and branched chain alkyl group.
Another object of the present invention is to provide a process for the purification to obtain substantially pure compound of formula IX.

Yet another object of the present invention is to provide purification technique for removal of triphenylphosphine impurities formed in the process for the conversion of 3-(p-phenoxyphenyl)-1,2,5,7-tetraza-1H-inden-4-ylamine into pure (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of ibrutinib of formula I and intermediates thereof.

In an embodiment, the present invention provides a novel intermediates and process for the purification.
In an embodiment, the present invention provides an intermediate of formula III

wherein, R is a C1-C5 straight and branched chain alkyl group.
In an embodiment, the present invention provides a process for the preparation of 2-[Hydroxy(4-phenoxyphenyl) methylene] propanedinitrile compound of the formula IV.

In an embodiment, the present invention provides a process for the preparation of substantially pure (R)-3-(4-Phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine compound of formula IX.

In another aspect, the present invention provides a process for the purification to obtain substantially pure compound of formula IX.

DETAILED DESCRIPTION OF THE INVENTION
The present disclosure encompasses an improved process for the preparation of ibrutinib of formula I and intermediates thereof.

As discussed above, the processes described in the literature have significant disadvantages. More particularly, the process described in prior art have disadvantages of complex reaction operation, low yield, difficult removal of by-products, and to provide suitable route of for industrial production of Ibrutinib.
Therefore, the reported processes may not be considered suitable for large scale production.
As used herein, the modifier term "about" should be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression "from about 5 to about 10" also discloses the range "from 5 to 10." When used to modify a single number, the term "about" may refer to plus or minus 10% of the indicated number and includes the indicated number e.g., "about 10%" may indicate a range from 9% to 11%, and "about 1" may be from 0.9-1.1.
As used herein, and unless otherwise specified, the term "Alkyl" refers to a mono-radical of a branched or unbranched saturated hydrocarbon chain that can be substituted or unsubstituted. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isopropyl, tert-butyl, isobutyl, and like.
As used herein, and unless otherwise indicated, the term "polar aprotic solvent" has a higher dielectric constant, generally greater than 15 and is at least one selected from the group consisting of amide-based organic solvents, such as N,N-dimethylformamide (DMF), ?,?-dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), formamide, acetamide, propanamide, hexamethyl phosphoramide (HMPA), and hexamethyl phosphorus triamide (HMPT); nitrile solvents, such as acetonitrile, propionitrile, C2-C6 nitriles, or the like; nitro- based organic solvents, such as nitromethane, nitroethane, nitropropane, and nitrobenzene; pyridine-based organic solvents, such as pyridine and picoline; sulfone-based solvents, such as dimethyl sulfone, diethylsulfone, diisopropylsulfone, 2-methylsulfolane, 3-methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethy sulfolane, 3-sulfolene, and sulfolane; and sulfoxide-based solvents such as dimethylsulfoxide (DMSO).
As used herein, and unless specified otherwise, the term "chlorinated solvent" refers to a C1-C6 chlorinated hydrocarbon. In some aspects, the chlorinated solvents are selected from the group consisting of carbon tetrachloride, dichloromethane (DCM), dichloroethane, chlorobenzene, and chloroform.
As used herein, and unless specified otherwise, the term "hydrocarbon solvent" refers to a saturated hydrocarbon, which may be linear, branched, or cyclic. Examples of a hydrocarbon solvent include, such as, C5-C8 aliphatic hydrocarbons, n-pentane, isopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3- dimethylpentane, 3-ethylpentane, 2,2,3 -trimethylbutane, n-octane, isooctane, 3- methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, or the like.
As used herein, and unless specified otherwise, the term "alcohol solvents" include, but are not limited to, substituted or unsubstituted C1-C6 alcohols, methanol, ethanol, 1-propanol, isopropyl alcohol (IPA), 2-nitroethanol, 2-fluoroethanol, ethylene glycol, 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, tert-butyl alcohol, 2-ethoxyethanol, di-ethylene glycol, pentanol, neo-pentyl alcohol, tert-pentyl alcohol, cyclohexanol, benzyl alcohol, phenol, glycerol, or the like.
As used herein, and unless otherwise specified, the term "isolated" in reference to the compounds of the present invention, their salts or solid-state forms thereof corresponds to compounds that are physically separated from the reaction mixture in which they are formed.
As used herein, the term “protecting group” refers to a moiety that is formed to render a functional moiety unreactive. The protecting group can be removed to restore the functional moiety to its original state.

As used herein, and unless otherwise specified, the term "substantially free" is meant that the Ibrutinib of formula I or any other intermediate thereof of the present invention contain about 2% (w/w) or less, about 1% (w/w) or less, about 0.5% (w/w) or less, or about 0.2% (w/w) or, or about 0.1% (w/w) less of a specified or unspecified impurity.
As used herein, and unless otherwise specified, the term "substantially pure" relates to compounds having a purity of about 95% or more. In other words, the term relates a compound, having a purity, measured as % area normalization by HPLC, of about 95% or more. In other aspects, the term relates to compounds having a purity of about more than 97% area normalization by HPLC. In preferred embodiments, the term relates to compounds having a purity of about more than 98% (by HPLC; area normalization).

In one aspect, the present invention provides an intermediate of formula III

wherein, R is a C1-C5 straight and branched chain alkyl group. Preferably R is methyl, ethyl and propyl.
In yet another aspect, the present invention provides intermediates of formula IIIa and IIIb.

In an embodiment, the present invention provides a novel intermediates and process for the purification.

In another aspect, the present invention provides a process for the preparation of 2-[Hydroxy(4-phenoxyphenyl)methylene] propanedinitrile compound of the formula IV

comprising the steps of:
(a) reacting p-Phenoxybenzoic acid compound of formula II

with an alkyl propiolate of the formula X

in a suitable solvent in the presence of a suitable base to obtain alkyl (E)-1-(p-phenoxybenzoyloxy)ethene-2-carboxylate compound of formula III

wherein, R is a C1-C5 straight and branched chain alkyl group;
(b) reacting compound of formula III with malononitrile to obtain compound of formula IV.
(c) Optionally, purifying the compound of formula IV.
Preferably, the alkyl propiolate of formula X in step (a) is selected from ethyl propiolate, and methyl propiolate. Most preferably, the alkyl propiolate is ethyl propiolate.
The suitable base in step (a) is preferably an organic base, selected from, but not limited to, triethylamine (TEA), N, N-diisopropylethylamine (DIPEA), tetramethylethylenediamine (TMEDA), pyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 4-dimethylaminopyridine (DMAP), potassium tert-butoxide, and the like Most preferably, the base is triethylamine.
The suitable solvent in step (a) may include, but are not limited to polar aprotic solvent, chlorinated solvent, or the like.
Preferably, the solvent is selected from, but not limited to, acetonitrile, tetrahydrofuran, DMF, DMSO, or the mixture thereof. Most preferably, the solvent is acetonitrile.
The process of step (a) may be carried out for about 30-60 minutes at a temperature from about 0°C to about 100°C, preferably at about 0°C to about 50°C, and most preferably at about 20°C to about 30°C.
The reaction of compound of formula III with malononitrile in step (b) to obtain compound of formula IV is carried out for about 30-60 minutes at a temperature from about 0°C to about 100°C, preferably at about 0°C to about 50°C, and most preferably at about 20°C to about 30°C.
The above process for the preparation of compound of formula IV can be done either as a one pot reaction; meaning, compound of formula IV can be prepared from p-phenoxybenzoic acid compound of formula II without isolating compound of formula III. Alternatively, the compound of formula III can be isolated prior to its conversion to compound of formula IV.

In another aspect, the present invention provides a process for the preparation of substantially pure (R)-3-(4-Phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine compound of formula IX,

comprising the steps of:
(a) reacting 3-(p-phenoxyphenyl)-1,2,5,7-tetraza-1H-inden-4-ylamine compound of formula VII

with 1-tert-butyloxycarbonyl-3-(S)-hydroxypiperidine; and subjecting the resulting reaction mixture to Mitsunobu reaction conditions in the presence of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (TPP) to obtain a mixture of compounds of formula VIII, VIIIa, VIIIb & VIIIc




(b) purifying the reaction mixture of step (a) with a suitable hydrocarbon solvent to remove the impurity of formula VIII & VIIIc;
(c) deprotecting the resulting mixture of compounds of formula VIIIa, and VIIIb to obtain substantially pure (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine compound of formula IX; and
(d) optionally, converting compound of formula IX to Ibrutinib or a pharmaceutically acceptable salt or a solid state form thereof.
During Mitsunobu coupling reaction it has observed that along with desired product triphenylphosphine complex of formula VIII & VIIIc are also formed as impurities, which after deprotection reaction convert back to starting reactant.
Preferably, the suitable hydrocarbon solvent in step (b) is selected from, but not limited to, cyclohexane, n-heptane, hexane, and the like, or the mixture thereof. Most preferably, the hydrocarbon solvent is cyclohexane.
The residue containing compounds of formula VIIIa, and VIIIb obtained after purification step (b) may be dissolved in a suitable solvent before deprotection step. Preferably, the solvent selected is a polar solvent, selected from a suitable alcohol, ketone, ester, ether, or the like. Most preferably, the solvent is selected from, but not limited to THF, methanol, iso-propyl alcohol, or the like, or mixture thereof.
De-deprotection in step (c) can be accomplished with any suitable inorganic or organic acid as a de-protecting agent known in the prior-art. Preferably, the deprotecting agent is an inorganic acid. Most preferably, the inorganic acid is HCl and HBr.
The purification with hydrocarbon solvent in step (b) is carried out for about 30-60 minutes at a temperature from about 0°C to about 100°C, preferably at about 0°C to about 50°C, and most preferably at about 20°C to about 30°C.
In another aspect, the present invention provides a process for the purification to obtain substantially pure compound of formula IX.
In another aspect, the present invention provides a process for the purification of (R)-3-(4-Phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine compound of formula IX,

substantially free from impurities of formula VIII & VIIIc

comprising treating mixture of compounds of formula VIII, VIIIa, VIIIb & VIIIc with a suitable hydrocarbon solvent to remove the impurities of formula VIII & VIIIc.
In another aspect, the present invention provides a process for the preparation of substantially pure Ibrutinib.
In another aspect, the present invention provides a process for the preparation of ibrutinib of formula I as depicted in following Scheme 1.

The progress of the reaction can be monitored by suitable chromatographic techniques such as high-pressure liquid chromatography (HPLC), gas chromatography (GC), ultra-pressure liquid chromatography (UPLC), thin layer chromatography (TLC) and the like.

The following examples are provided to describe the invention in further detail.
Although, the following examples illustrate the present invention in more detail but should not be construed as limiting the scope of the invention.

While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES:
Example 1: Preparation of 2-[hydroxy(4-phenoxyphenyl) methylene] propanedinitrile (IV)
Thionyl chloride (67.6 ml, 0.933 mole) was added slowly to 4-Phenoxybenzoic acid (100.0 g, 0.467 mole) at 20-30°C. The resulting reaction mixture was heated under stirring at temperature 60-65°C for 4-5 hours. After completion of reaction by HPLC, thionyl chloride was distilled off under vacuum below 70°C. Toluene (100 ml) was added to the oily residue and distilled off under vacuum below 70°C to remove traces of thionyl chloride to obtained 4-phenoxybenzoyl chloride as a viscous oil. Thus, the obtained viscous oil of 4-phenoxybenzoyl chloride was dissolved in toluene (200 ml) and added to a solution of malononitrile (40 g, 0.60 mole) and diisopropylethylamine (203 ml, 1.16 mole) in THF (200 ml) maintaining temperature of reaction mass 0-10°C. The reaction mass was stirred for 60 minutes at 20-30°C. After completion of reaction by HPLC, the reaction mass was quenched with demineralized water (500 ml) and extracted with ethyl acetate (2 x 500 ml). The organic layer was successively washed with 1N aqueous HCl solution and aqueous sodium chloride solution. The organic layer then distilled off completely under vacuum. Isopropyl alcohol (200 ml) was added to the crude mass, slowly added concentrated HCl (300 ml) and then stirred for 30-60 minutes at 20-30°C. Demineralized water (500 ml) was added to the reaction mass, stirred 30-60 minutes, filtered, and washed with demineralized water (1000 ml) to obtained crude mass. To the crude material dissolved in methanol (300 ml), demineralized water (500 ml) was added slowly, and the precipitated material was filtered and washed with demineralized water (100 ml). The wet material dried to obtained 2-[hydroxy(4-phenoxyphenyl) methylene] propanedinitrile as brownish to yellow colored solid (109.0 g, 89%) with HPLC purity >97%.

Example 2: Preparation of 3-(p-phenoxyphenyl)-1H-1,2,5,7-tetraazainden-4-ylamine (VII)
Dimethyl sulfate (54.3 ml,0.572 mole) and sodium bicarbonate (48 g,0.572 mole) were added to a solution of 2-[hydroxy(4-phenoxyphenyl) methylene] propanedinitrile (100 g,0.381 mole) in acetone (1000 ml) at 20-30°C. Thereafter, temperature of reaction mass was raised to 50-55°C and stirred for 24 hours. After completion of reaction by HPLC, the reaction mass was cooled to 20-30°C and filtered to remove inorganic salts. The filtrate then concentrated under vacuum to afford [Methoxy(p-phenoxyphenyl)methylidene]propanedinitrile as an oily mass. To the concentrated oily mass, added toluene (100 ml) and again concentrated to remove traces of acetone. To the concentrated oily mass added 80% hydrazine hydrate (60 ml) at 0-10°C and stirred for 1-2 hours at 25-35°C. After completion of reaction by HPLC, the reaction mass was filtered and washed with toluene (200 ml) to get 3-Amino-5-(p-phenoxyphenyl)-2H-pyrazole-4-carbonitrile with wet purity by HPLC >96%.
The above wet material 3-Amino-5-(p-phenoxyphenyl)-2H-pyrazole-4-carbonitrile (197 g) was suspended in Formamide (1000 ml) and heated at l40°C-150°C. After completion of reaction by HPLC, the reaction mixture was cooled to 50-60°C followed by addition of demineralized water (1000 ml), then cooled to 20-30°C and stirred for 60 minutes at 20-30°C. The resulting solid was filtered, washed with demineralized water (1000 ml) and then slurry washed with acetone (200 ml) to get crude wet solid. To the crude wet solid was added N-methyl-2-pyrrolidone (400 ml) and heated to 60-65°C for dissolution. The reaction mass cooled to 20-30°C, then added isopropyl alcohol (1200 ml) slowly. The precipitated material was filtered, washed with isopropyl alcohol (100 ml) and dried to afford pure 3-(p-phenoxyphenyl)-1H-1,2,5,7-tetraazainden-4-ylamine compound (85.5g, 73%) as a light yellow to dark brown solid with purity by HPLC >98%.
Example 3: Preparation of (R)-3-(4-Phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (IX)
Diisopropyl azodicarboxylate (166.82 g, 0.825 mole) and triphenylphosphine (216.4 g, 0.825 mole) were added lot wise to a solution of l-tert­butyloxycarbonyl-3-(S)-hydroxypiperidine (99.6 g, 0.495 mole), and 3-(p-phenoxyphenyl)-1 ,2,5,7-tetraza-lH-inden-4-ylamine (50.0 g, 0.165 mole) in ethyl acetate (500 ml) and stirred for 4-5 hrs. at 25-35°C. After completion of reaction by HPLC, the solvent was distilled off completely under vacuum. Cyclohexane (500 ml) was added to a concentrated mass, stirred, and then filtered at 20-30°C. To the resulting solid material, added Methanol (250.0 ml) and cooled to 0-5°C followed by addition of concentrated HCl (200 ml) and then stirred for 2-4 h at 25-35°C. After completion of reaction by HPLC, added water (500 ml) and the reaction mass washed thrice with MDC (300 ml x 3) and layers were separated followed by pH adjustment ~10-12 of aqueous layer by using 30% aqueous NaOH solution maintaining at 0-10°C. The reaction mass was further stirred for 1-2 h at 20-30°C, filtered and washed with demineralized water (50 ml). To the resulting solid was then added methanol (300 ml) and heated to reflux temperature for dissolution followed by slow addition of demineralized water (300 ml). The resulting solid material then cooled to 20-30°C and stirred for 30-60 minutes, filtered and washed with a mixture of methanol and demineralized water (1:9), wet material dried to afford (45 g,70%) (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a light yellow to cream colored solid with HPLC purity =99.0%.
Example 4: Preparation of 1-[(3R)-3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]prop-2-en-1-one (Ibrutinib)
(R)-3-(4-Phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50.0 g, 0.129 mole ) was taken in a mixture of methanol (250 ml) and MDC (400 ml) then cooled to -80°C to -70 °C followed by addition of N,N-diisopropylethylamine (33.6 ml,0.194 mole). Distilled acryloyl chloride (12.6 ml, 0.156 mole) solution in MDC (100 ml) was added to the reaction mass slowly at -80°C to -70 °C and stirred for 30-60 minutes at -80 to -70 °C. After completion of reaction by HPLC, demineralized water (250 ml) was added and then layers were separated. Aqueous layer was re-extracted with MDC (250 ml). Combined organic layer was washed with 1% aqueous citric acid solution (250 ml) and washed with demineralized water (250 ml). To the organic layer activated carbon 10% by weight was added, stirred for 20-30 minutes at 20-30°C, filtered through hyflo and concentrated under atmospheric pressure to get oily mass. To the oily mass toluene (500 ml) was added and then concentrated under vacuum until the distilled volume (100 ml) of toluene was attained. The reaction mass was cooled to 20-30°C and stirred for 2h, filtered and washed with toluene (100 ml) to get crude ~ 60 g off white to white solid with HPLC purity >98%.
The above crude wet material (~60.0 g) was dissolved in MDC (200 ml), activated carbon 10% by weight was added and stirred for 20-30 minutes at 20-30°C followed by filtration through hyflo bed, then washing of bed with MDC (150 ml). The filtrate was then concentrated at atmospheric pressure to get oily mass. To the oily mass toluene (500 ml) was added and then concentrated under vacuum until attained the distilled volume (100 ml). The reaction mass was cooled to 20-30°C and stirred for 2h, then filtered and washed with toluene (100 ml) to get white to off white solid ~ 55 g with HPLC purity >99.0%.
The above wet material (~55.0 g) was dissolved in MDC (200 ml), activated carbon 10% by weight was added and stirred for 20-30 minutes at 20-30°C followed by filtration through hyflo bed, then washing of bed with MDC (150 ml). The filtrate was then concentrated at atmospheric pressure to get oily mass. To the oily mass toluene (500 ml) was added and then concentrated under vacuum until attained the distilled volume (100 ml). The reaction mass was cooled to 20-30°C and stirred for 2h, then filtered and washed with toluene (100 ml) to get white to off white solid ~ 50 g with HPLC purity >99.5%.

Preparation of (R)-3-(4-Phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (IX):
Example 5: Purification with Cyclohexane
Diisopropyl azodicarboxylate (486.9 ml, 2.48 mole) and triphenylphosphine (650.4 g, 2.48 mole) were added lot wise to a solution of l-tert­butyloxycarbonyl-3-(S)-hydroxypiperidine (300 g, 0.84 mole) and 3-(p-phenoxyphenyl)-1 ,2,5,7-tetraza-lH-inden-4-ylamine (150 g, 0.495 mole) in ethyl acetate (1500 ml) and stirred for 4-5 hrs. at 25-35°C. After completion of reaction by HPLC, the solvent was distilled off completely under vacuum. Cyclohexane (1500 ml) was added to a concentrated mass, stirred, and then filtered at 20-30°C. To the resulting solid material, added THF (750 ml) and demineralized water (1500 ml), the reaction mass was cooled to 0-5°C followed by addition of concentrated HCl (600 ml) and then stirred overnight at 25-35°C. After completion of reaction by HPLC, the reaction mass washed thrice with MDC (900 ml x 3) and layers were separated followed by pH adjustment ~10-12 of aqueous layer by using 30% aqueous NaOH solution maintaining at 0-10°C. The reaction mass was further stirred for 1-2 h at 20-30°C, filtered and washed with demineralized water (150 ml). To the resulting solid was then added methanol (750 ml) and heated to reflux temperature for dissolution followed by slow addition of demineralized water (750 ml). The resulting solid material then cooled to 20-30°C and stirred for 30-60 minutes, filtered and washed with a mixture of methanol and demineralized water (1:9), wet material dried to afford (126 g,66%) (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as an off white to cream colored solid with HPLC purity =99.8%.
Example 6: Purification with Cyclohexane
Diisopropyl azodicarboxylate (290.5 ml, 1.48 mole) and triphenylphosphine (388.2 g, 1.48 mole) were added lot wise to a solution of l-tert­butyloxycarbonyl-3-(S)-hydroxypiperidine (198.64 g, 0.987 mole) and 3-(p-phenoxyphenyl)-1 ,2,5,7-tetraza-lH-inden-4-ylamine (100.0g, 0.329 mole) in ethyl acetate (1000 ml) and stirred for 4-5 hrs. at 25-35°C. After completion of reaction by HPLC, the solvent was distilled off completely under vacuum. Cyclohexane (1000 ml) was added to a concentrated mass, stirred and then filtered at 20-30°C. To the resulting solid material, added THF (500 ml) and demineralized water (1000 ml), the reaction mass was cooled to 0-5°C followed by addition of concentrated HCl (400 ml) and then stirred overnight at 25-35°C. After completion of reaction by HPLC, the reaction mass washed thrice with MDC (600 ml x 3) and layers were separated followed by pH adjustment ~10-12 of aqueous layer by using 30% aqueous NaOH solution maintaining at 0-10°C. The reaction mass was further stirred for 1-2 h at 20-30°C, filtered and washed with demineralized water (100.0 ml). The crude mass then given slurry wash with acetone (100 ml) at 0-10°C.To the resulting solid was then added methanol (500 ml) and heated to reflux temperature for dissolution followed by slow addition of demineralized water (1000 ml). The resulting solid material then cooled to 20-30°C and stirred for 30-60 minutes, filtered and washed with a mixture of methanol and demineralized water (1:9), wet material dried to afford (86 g, 68%) (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as an off white to cream colored solid with HPLC purity 99.96%.
Example 7: Purification with n-Heptane
Diisopropyl azodicarboxylate (32.4 ml, 0.165 mole) and triphenylphosphine (43.27 g, 0.165 mole) were added lot wise to a solution of l-tert­butyloxycarbonyl-3-(S)-hydroxypiperidine (20 g, 0.099 mole) and 3-(p-phenoxyphenyl)-1 ,2,5,7-tetraza-lH-inden-4-ylamine (10.0g, 0.033 mole) in ethyl acetate (1000 ml) and stirred for 4-5 hrs. at 25-35°C. After completion of reaction by HPLC, the solvent was distilled off completely under vacuum. n-Heptane (100 ml) was added to a concentrated mass, stirred and then filtered at 20-30°C. To the resulting solid material, added THF (50 ml) and demineralized water (100 ml), the reaction mass was cooled to 0-5°C followed by addition of concentrated HCl (40 ml) and then stirred overnight at 25-35°C. After completion of reaction by HPLC, the reaction mass washed thrice with MDC (60 ml x 3) and layers were separated followed by pH adjustment ~10-12 of aqueous layer by using 30% aqueous NaOH solution maintaining at 0-10°C. The reaction mass was further stirred for 1-2 h at 20-30°C, filtered and washed with demineralized water (10 ml). To the resulting solid was then added methanol (50 ml) and heated to reflux temperature for dissolution followed by slow addition of demineralized water (50 ml). The resulting solid material then cooled to 20-30°C and stirred for 30-60 minutes, filtered and washed with a mixture of methanol and demineralized water (1:9), wet material dried to afford (8.2 g, 65%) (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as an off white to cream colored solid with HPLC purity 99.8%.
Example 8: Purification with n-Hexane
Diisopropyl azodicarboxylate (32.4 ml, 0.165 mole) and triphenylphosphine (43.27 g, 0.165 mole) were added lot wise to a solution of l-tert­butyloxycarbonyl-3-(S)-hydroxypiperidine (20 g, 0.099 mole) and 3-(p-phenoxyphenyl)-1 ,2,5,7-tetraza-lH-inden-4-ylamine (10.0g, 0.033 mole) in ethyl acetate (1000 ml) and stirred for 4-5 hrs. at 25-35°C. After completion of reaction by HPLC, the solvent was distilled off completely under vacuum. n-Hexane (100 ml) was added to a concentrated mass, stirred, and then filtered at 20-30°C. To the resulting solid material, added THF (50 ml) and demineralized water (100 ml), the reaction mass was cooled to 0-5°C followed by addition of concentrated HCl (40 ml) and then stirred overnight at 20-30°C. After completion of reaction by HPLC, the reaction mass washed thrice with MDC (60 ml x 3) and layers were separated followed by pH adjustment ~10-12 of aqueous layer by using 30% aqueous NaOH solution maintaining at 0-10°C. The reaction mass was further stirred for 1-2 h at 20-30°C, filtered and washed with demineralized water (10.0 ml). To the resulting solid was then added methanol (50 ml) and heated to reflux temperature for dissolution followed by slow addition of demineralized water (50 ml). The resulting solid material then cooled to 20-30°C and stirred for 30-60 minutes, filtered and washed with a mixture of methanol and demineralized water (1:9), wet material dried to afford (8.5 g, 67%) (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine as an off white to cream colored solid with HPLC purity 99.9%.

Preparation of 2-[hydroxy(4-phenoxyphenyl) methylene] propanedinitrile (IV)

Example 9: Ethyl propiolate (2.7 g, 0.0276 mole) was added slowly to a reaction mixture of 4-Phenoxybenzoic acid (5.0 g, 0.023 mole) and triethylamine (4.65 g, 0.046 mole) in Acetonitrile at 20-30°C. The resulting reaction mixture was stirred at temperature 20-30°C for 60 minutes. The completion of reaction was monitored by TLC, and compound of formula IIIa was confirmed by LCMS showing m/z value at 313.76 (M+1). Malononitrile (1.82 g, 0.027 mole) was added to reaction mixture and stirred for 60 minutes at 20-30°C.After reaction completion by TLC, reaction mass was quenched with water extracted with ethyl acetate and then concentrated under vacuum. Isopropyl alcohol (10 ml) was added to the crude mass, slowly added concentrated HCl (15 ml) and then stirred for 30-60 minutes at 20-30°C. Demineralized water (25 ml) was added to the reaction mass, stirred 30-60 minutes, filtered and washed with demineralized water (50 ml) to obtained crude mass. To the crude material dissolved in methanol (15 ml), demineralized water (25 ml) was added slowly, and the precipitated material was filtered and washed with demineralized water (10 ml). The wet material dried to obtained 2-[Hydroxy(4-phenoxyphenyl) methylene] propanedinitrile as brownish to yellow colored solid (5.0 g, 81%) with HPLC purity >95%.

Example 10: Ethyl propiolate (5.4 g, 0.055 mole) was added slowly to a reaction mixture of 4-Phenoxybenzoic acid (10.0 g, 0.046 mole) and triethylamine (9.3 g, 0.092 mole) in Acetonitrile at 20-30°C. The resulting reaction mixture was stirred at temperature 20-30°C for 60 minutes. The completion of reaction was monitored by TLC, and compound of formula IIIa was confirmed by LCMS showing m/z value at 313.76 (M+1). Malononitrile (3.94 g, 0.059 mole) was added to reaction mixture and stirred for 60 minutes at 20-30°C. After reaction completion by TLC, reaction mass was quenched with water extracted with ethyl acetate and then concentrated under vacuum. Isopropyl alcohol (20 ml) was added to the crude mass, slowly added concentrated HCl (30 ml) and then stirred for 30-60 minutes at 20-30°C. Demineralized water (50 ml) was added to the reaction mass, stirred 30-60 minutes, filtered and washed with demineralized water (100 ml) to obtained crude mass. To the crude material dissolved in methanol (30 ml), demineralized water (50 ml) was added slowly, and the precipitated material was filtered and washed with demineralized water (20 ml). The wet material dried to obtained 2-[Hydroxy(4-phenoxyphenyl) methylene] propanedinitrile as brownish to yellow colored solid (10.5 g, 86%) with HPLC purity >95%.

CLAIMS:

WE CLAIM

Claim 1. A process for the preparation of 2-[hydroxy(4-phenoxyphenyl)methylene] propanedinitrile compound of the formula IV,

comprising the steps of:
a) reacting p-phenoxybenzoic acid compound of formula II,

with an alkyl propiolate of the formula X,

in a solvent in the presence of a base to obtain alkyl (E)-1-(p-phenoxybenzoyloxy)ethene-2-carboxylate compound of formula III,

wherein, R is a C1-C5 straight and branched chain alkyl group;
b) reacting compound of formula III with malononitrile to obtain compound of formula IV, and
c) Optionally, purifying the compound of formula IV.
Claim 2. The process as claimed in claim 1, wherein in the step (a) the alkyl propiolate of formula X is selected from ethyl propiolate and methyl propiolate.
Claim 3. The process as claimed in claim 1, wherein in step (a) base is selected from an organic base; wherein organic base is selected from triethylamine (TEA), N, N-diisopropylethylamine (DIPEA), tetramethylethylenediamine (TMEDA), pyridine, 1,4-diazabicyclo[2.2.2]octane (DABCO), 4-dimethylaminopyridine (DMAP) and potassium tert-butoxide.
Claim 4. The process as claimed in claim 1, wherein in step (a) solvent is selected from polar aprotic solvent and chlorinated solvent.
Claim 5. The process as claimed in claim 4, wherein the polar aprotic solvent and chlorinated solvent are selected from acetonitrile, tetrahydrofuran, DMF, DMSO or the mixture thereof.
Claim 6. The process as claimed in claim 1, wherein in the step (a) the compound of formula IV is optionally isolated.
Claim 7. A process for the preparation of substantially pure (R)-3-(4-Phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine compound of formula IX,

comprising the steps of:
a) reacting 3-(p-phenoxyphenyl)-1,2,5,7-tetraza-1H-inden-4-ylamine compound of formula VII,

with 1-tert-butyloxycarbonyl-3-(S)-hydroxypiperidine in the presence of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine (TPP) to obtain a mixture of compounds of formula VIII, VIIIa, VIIIb and VIIIc


(b) purifying the reaction mixture of step (a) with a hydrocarbon solvent to remove the impurity of formula VIII and VIIIc;
(c) deprotecting the resulting mixture of compounds of formula VIIIa, and VIIIb to obtain substantially pure (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine compound of formula IX; and
(d) optionally, converting compound of formula IX to Ibrutinib or a pharmaceutically acceptable salt or a solid state form thereof.
Claim 8. A process for the preparation of substantially pure (R)-3-(4-Phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine compound of formula IX,

substantially free from impurities of formula VIII and VIIIc,

comprising treating mixture of compounds of formula VIII, VIIIa, VIIIb and VIIIc

with a suitable hydrocarbon solvent to remove the impurities of formula VIII and VIIIc.
Claim 9. The process as claimed in claims 7 and 8, wherein hydrocarbon solvent is selected from cyclohexane, n-heptane and hexane.
Claim 10. An intermediate of formula III

wherein, R is a C1-C5 straight and branched chain alkyl group.