DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
INTRODUCTION
The present invention provides process for the preparation of Ibrutinib and its intermediates.
BACKGROUND OF THE INVENTION
The drug compound having the adopted name “Ibrutinib” has a chemical name l-((R)-3-(4-amino-3-(4-phenoxyphenyl)-lH-pyrazolo[3,4-d]pyrimidin-l-yl)piperidin-l-yl)prop-2-en-l-one, and is structurally represented below.

Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK) and is approved in US for the treatment of patients with mantle cell lymphoma and chronic lymphocytic leukemia who have received at least one prior therapy.
US patent 7,514,444 discloses process for the preparation of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1). The process disclosed in the patent is outlined below and it involves four key steps: (a) isolation of the enol intermediate (3) form the base mediated reaction of the acid chloride, generated from 4-phenoxybenzoic acid (2), with malononitrile; (b) Trimethylsilyldiazomethane mediated methylation of the enol intermediate (3) to furnish (4); (c) condensation of (4) with hydrazine hydrate to afford the pyrazole (5); and (d) construction of the pyrimidine (1) by reacting (5) with formamide.

The above route requires the isolation of individual synthetic intermediate and a particularly laborious purification protocol for intermediate (4). The above process also requires the use of potentially hazardous and expensive Trimethylsilyldiazomethane.
US ‘444 also discloses process for the preparation of Ibrutinib from the compound of formula (1). The schematic representation of the process is depicted below.

Chinese patent application CN103121999A discloses process for the preparation of Ibrutinib by coupling 3-bromo-pyrazolo[3,4-d]pyrimidin-4-amine with 4-phenoxyphenylboronic acid, followed by reaction with (S)-N-Boc-3-piperidinol, protection of the primary amino group with trifluoroacetyl chloride, reaction of the formed product with propenoyl chloride, and deprotection of the amino group to afford Ibrutinib. The schematic representation of the process is depicted below.

Chinese patent application CN103965201A discloses process for the preparation of 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine by condensation of 5-amino-4-cyanopyrazole with formamide to obtain 4-amino-1H-pyrazolo[3,4-d]pyrimidine, followed by bromination and reaction with trimethyl(4-phenoxyphenyl)stannane to obtain 4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine. The schematic representation of the process is depicted below.
Despite the existence of processes for the preparation of Ibrutinib and its intermediates, there remains a need for providing novel solution that would decrease the consumption of time and labor and it is of particular importance to develop methods that would allow for the increase in yields of particular steps, which in turn would favor an increase of the yield of the whole technology.
The inventors of the present invention have developed an improved route in which the formation of the undesirable by-products in the reaction steps is kept down to acceptable levels, thereby eliminating expensive and time-consuming column chromatography.
SUMMARY OF THE INVENTION
In a first aspect, the present invention provides a process for the preparation of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine of formula II,

Formula II,
which comprises:
(a) reacting 4,6-dichloropyrimidine-5-carbaldehyde with (4-phenoxyphenyl)magnesium bromide to give (4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methanol (Formula IIa),

(b) oxidizing (4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methanol (Formula IIa) to (4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methanone (Formula IIb),

(c) reacting (4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methanone with hydrazine to give 4-chloro-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine,

(d) aminating the compound of formula IIc to obtain 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Formula II),

In a second aspect, the compound of formula II is reacted with a piperidine compound of formula V to give tert-butyl (R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- carboxylate of formula III, a key intermediate in the preparation of Ibrutinib.

Suitable leaving groups are, for example, methanesulfonate, benzenesulfonate, trifluoromethanesulfonate or p-toluenesulfonate of hydroxy compounds and halogen.
In an embodiment, the compound of formula III is converted to Ibrutinib by methods known in the art, for example as per the method disclosed in US patent 7,514,444 B2.
In a third aspect, the present invention provides an improved process for the preparation of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine of formula II,

Formula II
by reacting 4-phenoxybenzoic acid with thionyl chloride and malononitrile in presence of base, followed by reaction with dimethyl sulfate and hydrazine to obtain 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile in a one-pot reaction. The compound 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile is converted to compound of formula II by reacting with formamide. The reaction scheme is outlined below.

DETAILED DESCRIPTION
In a first aspect, the present invention provides a process for the preparation of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine of formula II,

Formula II,
which comprises:
(a) reacting 4,6-dichloropyrimidine-5-carbaldehyde with (4-phenoxyphenyl)magnesium bromide to give (4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methanol (Formula IIa),

(b) oxidizing (4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methanol (Formula IIa) to (4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methanone (Formula IIb),

(c) reacting (4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methanone with hydrazine to give 4-chloro-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine,

(d) aminating the compound of formula IIc to obtain 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Formula II),

The step a) of synthesis of Formula IIa may be carried out by the addition of either 4-phenoxyphenylmagnesium chloride or 4-phenoxyphenylmagnesium bromide in a suitable solvent.
Suitable solvents that may be used include, but are not limited to: diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1, 2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, dioxane or the like; aliphatic or alicyclic hydrocarbons, such as for example, hexane, heptane, pentane, cyclohexane, methylcyclohexane, or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, tetralin, or the like; or any mixtures thereof.
In step b), oxidation of hydroxyl group of formula IIa may be carried out using any method known to a person skilled in the art. Suitable reagents or methods that may be used for oxidation include not limited to Swern oxidation, Oppenauer oxidation, sodium hypochlorite, manganese (IV) oxide, pyridinium chlorochromate, pyridinium dichromate, Jones reagent, 2-iodoxybenzoic acid and Dess-Martin periodinane.
In step c), the compound of formula IIc can be prepared by using either hydrazine (as hydrate or anhydrous) or a suitable hydrazinium salt in presence of base and a suitable solvent. Suitable bases that may be used include, but are not limited to: organic bases, such as for example, triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, or the like; inorganic bases, such as for example, alkali metal hydrides, such as for example, lithium hydride, sodium hydride, potassium hydride, or the like; sodamide; n-butyl lithium; lithium diisopropylamide; alkoxides such as sodium methoxide, potassium teritary butoxide or the like; alkali metal carbonates, such as for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkaline earth metal carbonates, such as for example, magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as for example, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or the like;
Suitable solvents that may be used include but not limited to acetone, butanone, pentanone, methyl isobutyl ketone, or the like; esters, such as for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, or the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, methyl tetrahydrofuran 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, sulpholane, formamide, acetamide, propanamide, or the like; nitromethane; or any mixtures thereof.
In step d), amination can be carried out in presence of suitable ammonia source such as a solution of ammonia in alcoholic or ethereal solvents, or ammonium salts (e.g. ammonium acetate). Typically this reaction requires heating and can be carried out under either sealed tube or microwave conditions.
In a second aspect, the compound of formula II is reacted with a piperidine compound of formula V to give tert-butyl (R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- carboxylate of formula III, a key intermediate in the preparation of Ibrutinib.

The term “leaving group”, as used herein, has the same meaning to the skilled artisan (Advanced Organic Chemistry: reactions, mechanisms and structure –Fourth Edition by Jerry March, John Wiley and Sons Ed.; 1992 pages 351 – 357) and represents a group which is part of and attached to a substrate molecule; in a reaction where the substrate molecule undergoes a displacement reaction (with for example a nucleophile), the leaving group is then displaced. Example of leaving groups include, but are not limited to: halogen (F, Cl, Br and I), preferably Cl, Br, or I; tosylate, mesylate, triflate, acetate, camphorsulfonate, aryoxide, and aryoxide substituted with at least one electron withdrawing. The preferred leaving groups are mesylate and tosylate.
Suitable leaving groups are, for example, methanesulfonate, benzenesulfonate, trifluoromethanesulfonate or p-toluenesulfonate of hydroxy compounds and halogen.
Suitable solvents that may be used in the above reaction include but not limited to N, N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, acetonitrile, sulpholane, formamide, acetamide, propanamide, or the like; or any mixtures thereof. In a preferred embodiment, acetonitrile - N, N-dimethylformamide mixture is used.
Suitable bases that may be used in the above reaction include, but are not limited to: organic bases, such as for example, triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, or the like; inorganic bases, such as for example, alkali metal hydrides, such as for example, lithium hydride, sodium hydride, potassium hydride, or the like; sodamide; n-butyl lithium; lithium diisopropylamide; alkoxides such as sodium methoxide, potassium teritary butoxide or the like; alkali metal carbonates, such as for example, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, or the like; alkaline earth metal carbonates, such as for example, magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as for example, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, or the like;
Suitable temperatures that may be employed may be less than about 150°C, less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures. More preferably, the reaction is carried out between 80 0C to 90 0C.
HPLC method of analysis:
Chromatographic conditions
A liquid chromatograph equipped with variable wavelength UV-detector.
Column : Symmetry C-18 (75x4.6mm, 3.5µm)
Flow rate : 1.0mL/min
Injection Volume : 5µL
Column Temperature : Ambient
Wavelength : 210 nm
Diluents : Acetonitrile: Water (80:20)
Mobile Phase A : 0.1%TFA in Water
Mobile Phase B : Acetonitrile
Gradient Program :
Time (min) % of Mobile Phase A % of Mobile Phase B
00.00 90 10
02.00 90 10
10.00 05 95
20.00 05 95
22.00 90 10
25.00 90 10

Mobile Phase A preparation:
1 mL of trifluoroacetic acid was added into 1000 mL of water. The solution obtained was filtered through a 0.45 µm membrane and then sonicated to degas.
Sample Preparation:
About 2 mg of sample was weighed into a 5 mL volumetric flask and dissolved in the diluent combination. The solution obtained was then made up to 5 mL with the diluent combination.

Examples
Example 1: One-pot preparation of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile
Toluene (40 mL) and 4-Phenoxy benzoic acid (20g) were charged into the 250 mL single neck RBF at room temperature under inert atmosphere. The contents were cooled to 5-10 0C. SOCl2 (20 mL) and DMF (0.2 mL) were charged into the reaction mass at 5-10 0C . The reaction mixture was stirred and heated to 80-85 0C for 3-3.5 hour. After the completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mass was concentrated under reduced pressure at 50- 55 0C in presence of nitrogen atmosphere. Toluene (40 mL) was charged to the above reaction mass and the reaction mass was concentrated under reduced pressure at 50-55 0C to remove traces of SOCl2 to obtain the concentrated mass. Sodium hydride (11.2g) was charged into the fresh 500 mL RBF under inert atmosphere at room temperature and cooled to 0-5 0C. THF (100 mL) was added to the above RBF at 0-5 0C. Malononitrile (6.16g) was diluted in THF (40 mL) and then this solution was added to the above reaction mixture at 5-10 0C over a period of 10-15 min. The concentrated mass which was obtained above (21.7g) was diluted in THF (60 mL) and this solution was added to the reaction mixture at 5-10 0C over a period of 10-15 min. Reaction mass temperature was raised to room temperature and stirred for 1 hour at room temperature. Dimethyl sulfate (21.7 mL) was charged into the reaction mass at room temperature and the reaction mixture was stirred and heated to 60 - 65 0C. After the completion of the reaction, the resulting reaction mixture was cooled to room temperature. Triethylamine (32.3 mL) and hydrazine sulfate (12.15g,) were charged into the reaction mass at room temperature and the reaction mixture was stirred and heated to 60 - 65 0C for 1 hour. After completion of the reaction, the reaction mass was quenched with ice cold water (100 mL) at room temperature. The reaction mixture was stirred for 20-30 min at room temperature and concentrated under reduced pressure at 45-50 0C. Ethyl acetate (100 mL) was charged into the reaction mass and stirred for 10-15 min at room temperature. Reaction mass was transferred in to a separating funnel and separated both aqueous and organic layers. Organic layer was washed with water (100 mL). Reaction mass was transferred in to a separating funnel and separated both aqueous and organic layers. Organic layer was dried over Na2SO4 and filtered. The organic layer was concentrated under reduced pressure at 45-50 0C. The concentrated mass was triturated with DCM (40 mL) and MTBE (150 mL) for 30 min at room temperature. The solid was filtered and the wet cake was washed with MTBE (20 mL). The wet cake was dried under vacuum at room temperature for 3-4 hour to obtain the title compound.
Yield: 48.5%
Analytical Data:
1H NMR (400 MHz, DMSO-d6): d 12.11 (s, 1H), 7.80 (d, J = 8.7 Hz, 2H), 7.42 (t, J = 8.0 Hz, 2H), 7.18 (t, J = 7.4 Hz, 1H), 7.10 (d, J = 7.6 Hz, 2H), 7.08 (d, J = 7.5 Hz, 2H), 6.42 (s, 2H).
Mass: m/z = 277 [M+H] +
HPLC purity (% Area Method): 96%
Example 2: One-pot preparation of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile
Toluene (100 mL) and 4-Phenoxy benzoic acid (50g) were charged into the 500 mL single neck RBF at room temperature under inert atmosphere. The contents were cooled to 5-10 0C. SOCl2 (50 mL) and DMF (0.5 mL) were charged into the reaction mass at 5-10 0C. The reaction mixture was stirred and heated to 80-85 0C for 3-3.5 hour. After the completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mass was concentrated under reduced pressure at 50- 55 0C in presence of nitrogen atmosphere. Toluene (50 mL) was charged to the above reaction mass and the reaction mass concentrated was under reduced pressure at 50-55 0C to remove traces of SOCl2 to obtain the concentrated mass. THF (200 ml) and DIPEA (116.4g) were charged into the fresh 1000 mL RBF under inert atmosphere at room temperature and cooled to 0-5 0C. Malononitrile (15.4 g) was diluted in THF (50 mL) and then this solution was added to the above reaction mixture at 5-10 0C over a period of 10-15 min. The concentrated mass which was obtained above was diluted with THF (50 mL) and this solution was added to the reaction mixture at 5-10 0C over a period of 20-30 min. Reaction mass temperature was raised to room temperature and stirred the reaction mass for 1h at room temperature. The reaction mixture was cooled to 0-5 0C and dimethyl sulfate (54.2 mL) was charged into the reaction mixture at 0-5 0C and the reaction mixture was stirred and heated to 60 - 65 0C. After the completion of the reaction, the resulting reaction mixture was cooled to 0-5 0C. Triethylamine (65.2 mL) and Hydrazine hydrate (9.9 mL) were charged into the reaction mass at 0-5 0C and the reaction mixture was heated and stirred at 60 - 65 0C for 1 hour. After completion of the reaction, the reaction mass was concentrated under reduced pressure at 50-55 0C. Water was charged to the reaction mass at room temperature. Ethyl acetate (250 mL) was charged into the reaction mass and stirred for 10-15 min at room temperature. Reaction mass was transferred in to a separating funnel and separated both aqueous and organic layers. Organic layer was washed with water (100 mL). Reaction mass was transferred into a separating funnel and separated both aqueous and organic layers. Organic layer was dried over Na2SO4 and filtered. The organic layer was concentrated under reduced pressure at 45-50 0C. The concentrated mass was triturated with DCM (100 mL) and MTBE (100 mL) for 30 min at room temperature. The solid was filtered and the wet cake was washed with MTBE (100 mL) and DCM (25 mL). The wet cake was dried under vacuum at room temperature for 3-4 hour to obtain the desired compound.
Yield: 60 %
Analytical Data:
1H NMR (400 MHz, DMSO-d6): d 12.11 (s, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.42 (t, J = 7.8 Hz, 2H), 7.18 (t, J = 7.3 Hz, 1H), 7.09 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 7.6 Hz, 2H), 6.46 (s, 1H).
Mass: m/z = 277 [M+H]+
HPLC (% Area Method): 98.3%
Example 3: preparation of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile (12g) and Formamide solution (97%, 180 mL) were charged into a 500 ml RBF at 25-30 0C under nitrogen atmosphere. The reaction mixture was heated to 180 0C and maintained for 19 hours at 180 0C. After completion of the reaction, the reaction mass was cooled to room temperature. Ice cold water (180 mL) was charged into the reaction mixture and stirred the resulting reaction mixture for 25-30 min at 25-30 0C. The reaction mass was filtered and wet cake was washed with water (60 mL). Wet cake was dried under vacuum at 25-30 0C for 10-12 hours to give the title compound.
Yield: 91%
Analytical Data:
1H NMR (400 MHz, DMSO-d6): d 13.55 (s, 1H), 8.21 (s, 1H), 7.66 (d, J = 8.6 Hz, 2H), 7.43 (t, J = 8.0 Hz, 2H), 7.22-7.06 (m, 5H), 6.79 (brs, 2H).
Mass: m/z = 304; [M+H]+
HPLC (% Area Method): 98.3%

Example 4: preparation of tert-butyl (R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate
3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (20g) and DMF (200 mL) were charged into the 500 mL 2 neck RBF at 25 0C- 30 0C under inert atmosphere. Tert-butyl (S)-3-((methylsulfonyl)oxy)piperidine-1-carboxylate (22.12g) and cesium carbonate (53.7g) were charged into the reaction mass at 25-30 0C. The reaction mass was heated to 85-90 0C and stirred for 40-44h at 85-90 0C. After the completion of the reaction, the reaction mass was cooled to 25-30 0C. Ice cold water (300 mL) and DCM (200 mL) were charged into the reaction mixture at 25-30 0C and stirred the resulting reaction mixture for 25-30 minutes. The organic and aqueous layers were separated and the aqueous layer was extracted with DCM (100 mL). The organic layers were combined and washed with washed with ice cold water (200 mL). Organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure 45-50 0C to obtain the title compound. The obtained compound was purified by column chromatography (50% EtOAc: Hexane). The obtained fractions from the column chromatography were concentrated under reduced pressure at 30°C-40 0C. To the concentrated mass was added ice cold water (100 mL) and stirred for 1 hour at 20-30 0C. The obtained solid was filtered and washed with water (50 mL). The Wet cake was dried under reduced pressure at 20-30 0C to obtain the titled compound.
Yield: 36.4 %
Analytical Data:
1H NMR (400 MHz, DMSO-d6): 8.26 (s, 1H), 7.66 (td, J = 8.6, 2.2 Hz, 2H), 7.43 (tdd, J = 8.4, 7.5, 2.1 Hz, 2H), 7.21 – 7.08 (m, 5H), 6.83 (brs, 2H), 4.71 – 4.64 (m, 1H), 4.18 – 3.64 (two brm, 2H), 3.61 – 3.41 (brm, 1H), 3.09 – 2.90 (brm, 1H), 2.25 – 2.16 (m, 1H), 2.12 – 2.04 (m, 1H), 2.01 – 1.82 (brm, 1H), 1.61 – 1.50 (m, 1H), 1.32 ((brs, 9H).
Mass: m/z = 487.3; [M+H] +
HPLC (% Area Method): 95.6%

Example 5: preparation of 3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
Tert-butyl (R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (11.5 g) and DCM (23 mL) were charged into the 100 mL RBF at 25-30 0C under inert atmosphere. The reaction mass was cooled to 0-5 0C.Trifluoro acetic acid (15 mL) was added into the reaction mass at 0-5 °C. The reaction mixture temperature was raised to 25-30 0C. The reaction mixture was stirred for 24hours at 25-30 0C. After completion of the reaction, the reaction mass was concentrated under reduced pressure at 50-55 °C. The concentrated mass was dissolved in DCM (115 mL) at 25-30 0C. pH of the reaction mass was adjusted to ~8-9 by adding saturated sodium bicarbonate solution at25-30 0C. The reaction mass was transferred into a separating funnel and separated both aqueous and organic layers. The combined organic extracts were washed with brine solution (57.5 mL). Organic layer was dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure at 45-50 0C to obtain the title compound. The title compound was triturated with MTBE (20 mL) for 30 min at 25-30 0C. The solid was filtered and wet cake was washed with MTBE (5 mL). Wet cake was dried under reduced pressure at 25-30 0Cfor 2-3h to furnish the title compound (Purity: 96.6 %).
Yield: 99%
Analytical Data:
1H NMR (400 MHz, DMSO-d6): d 8.24 (s, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.43 (m, 2H), 7.18 (t, 1H), 7.14-7.10 (m, 4H), 6.85 (brs, 2H), 4.81 (m, 1H), 3.23 (m, 1H), 3.13 (m, 1H), 3.04 (m, 1H), 2.65 (m, 1H), 2.14-2.02 (m, 2H), 1.83 (m, 1H), 1.67 (m, 1H).
Mass: m/z = 387; [M+H] +
HPLC (% Area Method): 96.6%
Example 6: preparation of Ibrutinib
3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (9g) and DCM (180 mL) were charged into the 500 ml RBF at 25-30 0C under inert atmosphere. The reaction mixture was cooled to -10 to 0 0C.Triethylamine (3.2 mL) was added into the reaction mass at -10 to 0 0C. Acryloyl chloride (1.7 mL, 0.020 moles) was added to the reaction mass at -10 to 0 0C. The reaction mixture was stirred for 1h at -10 to 0 0C. After completion of the reaction, water (90 mL) was charged to the reaction mass at 5-10 0C. The reaction mixture was stirred for 10-15 minutes at 25-30 0C and was transferred in to the separating funnel to separate aqueous and organic layer. Organic extracts were combined and washed with water (45 mL).The organic layer was dried over anhydrous sodium sulfate and filtered. The organic layer was concentrated under reduced pressure at 45-50 0C to obtain the title compound. The title compound was purified by column chromatography by using 60-120 mesh silica gel (eluted with 90-95% EtOAc / Hexane). All the pure fractions were concentrated under reduced pressure at 50-55 0C to obtain the title compound.
Yield: 49.7 %
Analytical Data:
1H NMR (400 MHz, DMSO-d6): d 8.26 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.44 (m, 2H), 7.19 (t, 1H), 7.14-7.11 (m, 4H), 6.90 (dd, 0.5H), 6.71 (dd, 0.5H), 6.10 (dd, 1H), 5.72 (d, 0.5H), 5.58 (d, 0.5H), 4.69 (m, 1H), 4.55 (d, 0.5H), 4.21 (m, 1H), 4.09 (d, 0.5H), 3.73 (m, 0.5H), 3.19 (m, 1H), 2.98 (t, 0.5H), 2.25 (m, 1H), 2.13 (m, 1H), 1.19 (m, 1H), 1.58 (m, 1H).
Mass: m/z = 441; [M+H] +
HPLC (% Area Method): 96.5%

Example 7: preparation of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
Step-1: preparation of (4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methanol
Magnesium turnings (0.205 g) was taken in a dry 100 mL 2-necked RBF, equipped with an efficient stir bar, condenser and Nitrogen inlet. THF (10 mL) was added into the reaction flask, and stirred at room temperature under nitrogen. 4-Bromodiphenyl ether (1.23 mL) was added into the reaction mass at room temperature. The reaction mass was allowed to reflux for 3 hour. The reaction mass was cooled to 0 0C. 4, 6-dichloropyrimidine-5-carbaldehyde (1g) in THF (10 mL) was added drop wise over 10 minutes at 0 0C. The reaction mass was warmed to room temperature and stirred at room temperature for 3 hr. After the completion of the reaction, the reaction mass was cooled to 0 0C and was quenched with 10 ml saturated ammonium chloride solution and extracted into ethyl acetate. The organic layers were combined and dried over sodium sulfate, evaporated under reduced pressure to obtain the titled compound.
Yield: 77 %
Analytical Data:
1H NMR (400 MHz, CDCl3): d 8.76 (s, 1H), 7.35 (dd, J = 8.4, 7.6 Hz, 2H), 7.27 (d, J = 8.2 Hz, 2H), 7.13 (t, J = 7.4 Hz, 1H), 7.04 – 6.96 (m, 4H), 6.55 (d, J = 8.7 Hz, 1H), 3.08 (d, J = 9.5 Hz, 1H).
13C NMR (400 MHz, CDCl3): d 161.43 (2C), 157.32, 156.89, 156.66, 133.66, 132.99, 129.82 (2C), 126.91 (2C), 123.66, 119.17 (2C), 118.65 (2C), 70.75.
HPLC (% Area Method): 99%
Step-2: preparation of 4, 6-dichloropyrimidin-5-yl-4-phenoxyphenyl-methanone
4, 6-dichloropyrimidin-5-yl-4-phenoxyphenyl methanol (1 g) was taken in a dry 100 mL single-necked RBF, equipped with an efficient stir bar, nitrogen inlet. Dichloromethane (20 mL) was added into the reaction flask, and stirred at room temperature for 15 minutes. Dess–Martin periodinane (1.84 g) and sodium bicarbonate (0.244 g) was added into the reaction mass at room temperature. The reaction mass was allowed to stir at room temperature for 3 hour under nitrogen. After the completion of the reaction, the reaction mass was diluted with 10 ml water and 20 mL DCM and stirred for 10 minutes. The reaction mass was filtered through a celite pad. The DCM layer was separated from the filtrate and the aqueous layer was extracted with DCM (2x 65 mL). The organic layers were combined, dried over sodium sulfate (5g) and evaporated under reduced pressure to obtain the titled compound.
Yield: 83 %
Analytical Data:
1H NMR (400 MHz, CDCl3): d 8.90 (s, 1H), 7.78 (d, J = 8.8 Hz, 2H), 7.43 (t, J = 7.9 Hz, 2H), 7.25 (t, J = 7.4 Hz, 1H), 7.11 (d, J = 7.7 Hz, 2H), 7.04 (d, J = 8.9 Hz, 2H).
13C NMR (400 MHz, CDCl3): d 187.10, 164.08 (2C), 158.56, 158.15, 154.51, 132.06 (2C), 132.00, 130.23 (2C), 128.62, 125.35, 120.70 (2C), 117.47 (2C).
HPLC (% Area Method): 99%
Step-3: 4-chloro-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine
4, 6-dichloropyrimidin-5-yl-4-phenoxyphenyl-methanone (0.1 g) was taken in a dry 25 mL two-necked RBF, equipped with an efficient stir bar, and a nitrogen inlet. Dioxane (2 mL) was added into the reaction flask, and stirred at room temperature. The reaction mass was cooled to 0 0C. Hydrazine hydrate (0.022 g in 0.5 mL dioxane) was added into the reaction mass at 0 0C. The reaction mass was allowed to stir at room temperature for 5 hour. Sodium bicarbonate (0.024 g) was added into the reaction mass at room temperature. The reaction mixture was allowed to stir at room temperature for 18 hours. After the completion of the reaction, the reaction mass was diluted with ice cold water (10 mL) and extracted into ethyl acetate (2x10 mL). The organic layers were combined and washed with 10 ml 2N HCl solution. The organic layer was separated, dried over sodium sulfate and evaporated under reduced pressure to obtain the titled compound.
Yield: 75 %
Analytical Data:
1H NMR (400 MHz, CDCl3): d 11.62 (s, 1H), 8.86 (s, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.40 (t, J = 7.9 Hz, 2H), 7.22 – 7.06 (m, 5H).
13C NMR (400 MHz, CDCl3): d 158.84, 156.34, 155.82, 155.56, 154.89, 146.26, 131.56 (2C), 129.91 (2C), 125.42, 123.97, 119.64 (2C), 118.02 (2C), 110.94.
Mass: m/z = 323; [M+H] +
HPLC (% Area Method): 99.9%
Step-4: preparation of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine
4-chloro-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (0.050 g) was taken in a dry 50 mL sealed tube, equipped with an efficient stir bar. Isopropanol (5 mL) was added into the sealed tube, and the reaction mixture was stirred at room temperature. The obtained reaction mixture was cooled to 0 0C. A saturated solution of ammonia in isopropanol (5 mL) was added to the reaction mixture at 0 0C. The seal tube was closed properly and the reaction mixture was warmed to room temperature. The reaction mixture was refluxed for 23 hours. After the completion of the reaction, the reaction mass was cooled to room temperature and the solvent was evaporated under reduced pressure to obtain the titled compound. The obtained compound was purified by column chromatography (15% methanol/dichloromethane).
Yield: 63 %
Analytical Data:
1H NMR (400 MHz, DMSO-d6): d 13.54 (s, 1H), 8.21 (s, 1H), 7.66 (d, J = 8.5 Hz, 2H), 7.44 (t, J = 7.8 Hz, 2H), 7.24 – 7.05 (m, 5H), 6.80 (brs, 2H).
13C NMR (400 MHz, DMSO-d6): d 158.51, 157.45, 156.74, 156.49, 156.21, 144.36, 130.56 (2C), 130.46 (2C), 128.90, 124.21, 119.45 (2C), 119.35 (2C), 97.36.
,CLAIMS:1. A process for the preparation of 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, represented by formula II,

Formula II,
comprising the steps of :
(a) reacting 4,6-dichloropyrimidine-5-carbaldehyde with (4-phenoxyphenyl)magnesium halide in a suitable solvent to give (4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methanol (Formula IIa);

(b) oxidizing (4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methanol (Formula IIa) with an oxidizing agent to give (4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methanone (Formula IIb);

(c) reacting (4,6-dichloropyrimidin-5-yl)(4-phenoxyphenyl)methanone (Formula IIb) with hydrazine or hydrazinium salts to give 4-chloro-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine;

(d) aminating the compound of formula IIc to obtain 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Formula II),

2. The (4-phenoxyphenyl)magnesium halide as per claim 1 is selected from 4-phenoxyphenylmagnesium chloride and 4-phenoxyphenylmagnesium bromide.
3. A process for the preparation of tert-butyl (R)-3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1- carboxylate by reacting 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine with

where L is a leaving group selected from halogens, tosylate, mesylate, triflate, acetate and camphorsulfonate.