DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Ibrutinib and its amorphous form thereof. Ibrutinib is represented by the following structural formula (I).

BACKGROUND OF THE INVENTION
Ibrutinib is marketed by Pharmacyclics in US under the trade name Imbruvica® for the treatment of Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia, Waldenstrom's Macroglobulinernia, Small lymphocytic lymphoma.

Ibrutinib is chemically known as 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1Hpyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinyl]-2-propen-1-one and structurally
represented as below.

US7514444B2 discloses a process for preparing Ibrutinib which is shown schematically by below Scheme.

In this reaction scheme, a process for preparing ibrutinib by coupling compound 9 with compound 10 under Mitsunobu reaction conditions to obtain compound 7a, deprotecting compound 7a (i.e. removal of the Boc group) to form compound 8a, and acylating the nitrogen of the 3-piperidine moiety of compound 8a with acryloyl chloride using standard acylation conditions to form Ibrutinib. According to this process, compound 9 is coupled with compound 10 in the presence of polymer-bound triphenylphosphine (TPP) and Ibrutinib is formed by acylating compound 8a using organic solvent (dichloromethane, DCM) and organic base (triethylamine, Et3N). To perform acylation reaction using organic base very low temperature is required. In order to isolate Ibrutinib from the acylation reaction mixture column chromatography is required.

WO2017074265A1 discloses a process for preparing Ibrutinib which is shown schematically by below Scheme.

In this reaction scheme, compounds of formula 12 & 12a is prepared by reacting compound 9 with 11. Compound of formula 8 is prepared by deprotecting compounds of formula 12 & 12a. Ibrutinib is obtained by acylating the nitrogen of the 3-piperidine moiety of compound 8 with acryloyl chloride using inorganic base in biphasic reaction condition. In order to isolate Ibrutinib from the acylation reaction mixture column chromatography is required and reaction carried out in biphasic reaction condition.

However, the process described in the above patents for the preparation of Ibrutinib is tedious and suffers from many disadvantages like poor yield, low purity and not feasible to economical large-scale production. To overcome this problem, it is necessary to develop a new and cost-effective process for the preparation of large scale production of Ibrutinib with high purity.

Thus, the present invention fulfills the need of the art and provides an improved and industrially applicable process for preparation of Ibrutinib which are reproducible and provides Ibrutinib having pharmaceutical grade purity.

The present inventors use inorganic base and phase transfer catalyst for the acylation reaction. By using inorganic base and phase transfer catalyst present inventors found that rate of reaction is fast and need not to perform reaction below -5°C. Further this process is reproducible and provide Ibrutinib having Pharmaceutical grade purity.

WO2013184572A1 application discloses crystalline, solvates and amorphous
form of Ibrutinib. In particular, the application discloses polymorphic Forms A, B, C, D, E and F characterized by PXRD, IR, DSC and TGA. WO '572 application discloses a solvent such as dichloromethane is used to prepare Ibrutinib solution, and then the amorphous Ibrutinib is obtained through rapid evaporation of the solvent. This method requires high equipment conditions and easy to be mixed with other crystal forms of Ibrutinib during the production process. Therefore, Ibrutinib obtained with low purity.

WO2016088074A1 application discloses process for the preparation of amorphous form of Ibrutinib by dissolving Ibrutinib in DMSO/DMF solvent and added this Ibrutinib solution into the water to provide amorphous Ibrutinib.

The solvents used in this method have higher biological toxicity, and the solvent residues in the prepared amorphous products lead to higher biological toxicity.

WO2016088074A1 discloses a method for obtaining amorphous Ibrutinib through long-term high-temperature heating with other crystal forms. Due to the long-term heating of drug molecules, the resulting product has a high impurity content and low practical value.

WO2017085628A1 discloses two processes for preparing amorphous Ibrutinib. One is to use ethylene glycol dimethyl ether and ethanol as a benign solvent, water as a poor solvent, and a reverse addition method to prepare amorphous Ibrutinib.

In addition, the polarity of ethylene glycol dimethyl ether is insufficient and the oil solubility of ethanol is low, resulting in a low concentration of the saturated solution of Ibrutinib, which cannot effectively improve the production efficiency of amorphous Ibrutinib.

Thus, the present invention fulfills the need of the art and provides an improved and industrially applicable process for preparation of Ibrutinib amorphous form which are reproducible and provides Ibrutinib having pharmaceutical grade purity.

OBJECTS OF THE INVENTION
The main object of the present invention is to provide an improved process for the preparation of Ibrutinib of formula (I) which comprises;

(a) Reacting compound of formula (III) with acryloyl chloride of formula (II) in the presence of base and phase transfer catalyst in suitable solvent to obtain Ibrutinib of formula (I).

Another object of the present invention is to provide an improved process for the preparation of Ibrutinib amorphous form of formula (I) which comprises;

(a) Reacting compound of formula (III) with acryloyl chloride of formula (II) in the presence of base and phase transfer catalyst in suitable solvent to obtain Ibrutinib of formula (I).

(b) Treating in-situ Ibrutinib of formula (I) with toluene to obtain Ibrutinib toluene solvate of formula (I).
(c) Reacting Ibrutinib toluene solvate compound of formula (I) with acid followed by base in suitable solvent to obtain Ibrutinib of formula (I).
(d) Dissolving in-situ Ibrutinib of formula (I) in suitable solvent and carrying-out spray-drying to obtain Ibrutinib amorphous form of formula (I).

In yet another object of the present invention is to provide an improved process for the preparation of Ibrutinib amorphous form of formula (I) which comprises;

(a) Reacting Ibrutinib toluene solvate compound of formula (I) with acid followed by base in suitable solvent to obtain Ibrutinib of formula (I).
(b) Dissolving in-situ Ibrutinib of formula (I) in suitable solvent and carrying-out spray-drying to obtain Ibrutinib amorphous form of formula (I).

SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide an improved process for the preparation of Ibrutinib of formula (I) which comprises;

(a) Reacting compound of formula (III) with acryloyl chloride of formula (II) in the presence of base and phase transfer catalyst in suitable solvent to obtain Ibrutinib of formula (I).

Another aspect of the present invention is to provide an improved process for the preparation of Ibrutinib amorphous form of formula (I) which comprises;
(a) Reacting compound of formula (III) with acryloyl chloride of formula (II) in the presence of base and phase transfer catalyst in suitable solvent to obtain Ibrutinib of formula (I).

(b) Treating in-situ Ibrutinib of formula (I) with toluene to obtain Ibrutinib toluene solvate of formula (I).
(c) Reacting Ibrutinib toluene solvate compound of formula (I) with acid followed by base in suitable solvent to obtain Ibrutinib of formula (I).
(d) Dissolving in-situ Ibrutinib of formula (I) in suitable solvent and carrying-out spray-drying to obtain Ibrutinib amorphous form of formula (I).

In yet another aspect of the present invention is to provide an improved process for the preparation of Ibrutinib amorphous form of formula (I) which comprises;

(a) Reacting Ibrutinib toluene solvate compound of formula (I) with acid followed by base in suitable solvent to obtain Ibrutinib of formula (I).
(b) Dissolving in-situ Ibrutinib of formula (I) in suitable solvent and carrying-out spray-drying to obtain Ibrutinib amorphous form of formula (I).

DETAILED DESCRIPTION OF THE DRAWINGS
Fig.1 shows an XRPD pattern of Ibrutinib amorphous form as prepared by Example 3.
Fig.2 shows an XRPD pattern of Ibrutinib toluene solvate as prepared by Example 2.
DETAILED DESCRIPTION OF THE INVENTION
The main embodiment of the present invention is to provide an improved process for the preparation of Ibrutinib of formula (I) which comprises;

(a) Reacting compound of formula (III) with acryloyl chloride of formula (II) in the presence of base and phase transfer catalyst in suitable solvent to obtain Ibrutinib of formula (I).

Another embodiment of the present invention is to provide an improved process for the preparation of Ibrutinib amorphous form of formula (I) which comprises;

(a) Reacting compound of formula (III) with acryloyl chloride of formula (II) in the presence of base and phase transfer catalyst in suitable solvent to obtain Ibrutinib of formula (I).

(b) Treating in-situ Ibrutinib of formula (I) with toluene to obtain Ibrutinib toluene solvate of formula (I).
(c) Reacting Ibrutinib toluene solvate compound of formula (I) with acid followed by base in suitable solvent to obtain Ibrutinib of formula (I).
(d) Dissolving in-situ Ibrutinib of formula (I) in suitable solvent and carrying-out spray-drying to obtain Ibrutinib amorphous form of formula (I).

Step (a) is carried out in the presence of base and phase transfer catalyst in suitable solvent at -5-0°C. Addition of acryloyl chloride solution in reaction mass dropwise at -5-0°C in 20 to 30 min. under nitrogen atmosphere.

In step (b) in-situ dissolving residue obtained from step (a) in toluene at 25-35°C. Heat the reaction mass at 45-50°C for 60 to 70 min and seeded with Ibrutinib toluene solvate at 45-50°C.

Step (c) is carried out by dissolving toluene solvate in suitable solvent at 25-35°C and wash organic layer with acid followed by base at 25-35°C. Distill out solvent under vacuum below 35°C to obtain residue. Dissolving residue in mixture of methylene chloride and methanol at 30-35°C and add charcoal to reaction mass. Filter the reaction mass and stir the filtrate for 3 hr at -5-0°C. Filter the reaction mass to obtain Ibrutinib.

Step (d) is carried out in-situ by dissolving Ibrutinib in suitable solvent at 25-30°C and filter the reaction mass through micron filter and filtrate subjected to spray dryer to obtain amorphous form.

In yet another embodiment of the present invention is to provide an improved process for the preparation of Ibrutinib amorphous form of formula (I) which comprises;

(a) Reacting Ibrutinib toluene solvate compound of formula (I) with acid followed by base in suitable solvent to obtain Ibrutinib of formula (I).
(b) Dissolving in-situ Ibrutinib of formula (I) in suitable solvent and carrying-out spray-drying to obtain Ibrutinib amorphous form of formula (I).

In above embodiments, wherein the suitable base which could be employed in step (a) & (c) may be selected from group comprising of inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and organic bases such as triethyl amine, methyl amine, ethyl amine, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), isopropyl amine, diisopropylamine, diisopropylethylamine, N-methylmorpholine, N-ethylmorpholine, piperidine, dimethylaminopyridine, morpholine, pyridine or mixtures thereof.

In above embodiments, wherein the suitable phase transfer catalyst which could be employed in step (a) may be selected from group comprising of tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium chloride, tetrabutylammonium bisulfate, tricaprylmethylammonium chloride, tri-n-butylmethylammonium chloride, tetrabutylammonium hydroxide, benzyl triethylammonium chloride, tetrabutyl phosphonium bromide and the like.

In above embodiments, wherein the suitable acid which could be employed in step (a) & (c) may be selected from group comprising of inorganic acid selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, sulfamic acid and organic acid such as formic acid, acetic acid, trifluoro acetic acid, methanesulfonic acid, ethane sulfonic acid, benzene sulfonic acid, trifluoromethane sulfonic acid, p-toluenesulfonic acid, tartaric acid, mandelic acid, malic acid, maleic acid, succinic acid, malonic acid, oxalic acid, dibenzoyl tararic acid, lactic acid, cinnamic acid and the like.

In above embodiments, wherein the suitable solvents which could be employed in step (a), (b), (c) and (d) may be selected from group comprising of alcohols such as methanol, ethanol, 1-propanol, 2-propanol, butanol, ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, esters such as ethyl acetate, methyl acetate, propyl acetate, ethers such as diethyl ether, tetrahydrofuran, dioxane, diisopropyl ether, dimethyl ether, 1,2-dimethoxyethane, aromatic hydrocarbon such as benzene, toluene, xylene, chlorobenzene, nitrobenzene, aliphatic hydrocarbons hexane, heptane, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dialkylformamides selected from dimethyl formamide, dialkylsulfoxides selected from dimethyl sulfoxide, dialkylacetamides selected from N, N-dimethyl acetamide; nitriles selected from acetonitrile and propionitrile; water or mixtures thereof.

The following examples illustrate the present invention but should not be construed as limiting the scope of the invention.

EXAMPLES
Example 1: Preparation of (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (Formula III)
To a solution of 1,4-dioxane (500 ml) add 3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Formula VI) (50 gm), (S)-1-Boc-3-hydroxypiperidine (Formula V) (58.04 gm) under nitrogen atmosphere at 25-35°C and stir for 10 to 15 min. Add Triphenyl phosphine (151.28 gm) at 25-35°C. Heat reaction mass at 45-55°C and add solution of Diisopropyl azodicarboxylate in 1,4-dioxane(117 gm Diisopropyl azodicarboxylate in 50 ml 1,4-dioxane) dropwise at 45-55°C. Sit the reaction mass at 50-55°C for 3 hrs. Add IPA HCl (350 ml) to the reaction mass at 45-55°C and stir the reaction mass at 60-70°C for 6 hrs. Add ethyl acetate (1250 ml) to the reaction mass at 60-70°C in 50 to 60 min. Stir the reaction mass 10-15 min at 60-70°C. Cool the reaction mass at 35-40°C and stir it for 2 hrs. Filter the solid and wash wet cake with ethyl acetate (50 ml). Take this wet material and add IPA (450 ml), Purified water (50 ml). Heat reaction mass at 75-80°C and stir it for 15 to 20 min. Cool the reaction mass at 10-15°C and stir it for 50 to 60 min. Filter the reaction mass and wash with chilled IPA (50 ml). Dry the wet product in Vacuum tray dryer at 60-65°C for 12 hrs.
Dry Weight: 45 to 55 gm.

Example 2: Preparation of Ibrutinib toluene solvate (Formula I)
To as solution of Methylene chloride (2000 ml) add (R)-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (Formula III) (100 gm), Sodium sulphate (61.65 gm), Sodium bicarbonate (60.34 gm) and Tetrabutyl ammonium bromide (1.0 gm) at 25-35°C under nitrogen atmosphere. Add Acryloyl chloride solution (21 gm mixed with methylene chloride 200 ml) (Formula II) in reaction mass dropwise at -5-0°C in 20 to 30 min under nitrogen atmosphere. Stir the reaction mass at -5-0°C for 6 hrs. Add hydrochloric acid solution (1000 ml) (Conc, HCl 50 gm in 1000 ml purified water) in it dropwise at -5-5°C. Sir the reaction mass at 25-35°C for 20 to 30 min. Separate organic layer and add sodium bicarbonate solution (500 ml) (25 gm Sodium bicarbonate in 500 ml purified water) at 25-35°C. Stir reaction mass for 20-30 min at 25-35°C. Separate organic layer and add purified water (500 ml) at 25-35°C. Stir reaction mass for 20-30 min at 25-35°C. Separate organic layer and add Brine solution (500 ml) (50 gm Sodium chloride in 500 ml purified water) at 25-35°C. Stir reaction mass for 20-30 min at 25-35°C. Separate organic layer. Distill out organic layer under vacuum below 35°C and degas for 30 to 40 min below 35°C. Add toluene (800 ml) to the residue at 25-35°C. Heat reaction mass at 65-70°C and stir for 10 to 15 min. Cool the reaction mass at 45-50°C in 60 to 70 min. Reaction mass seeded with Ibrutinib toluene solvate (1.0 gm) at 45-50°C. Stir the reaction mass for 50 to 60 min at 45-50°C. Reaction mass cool to 25-30°C and stir for 10 hrs. Filter the reaction mass and wash with toluene (100 ml).
Dry the wet product in Vacuum tray dryer at 30-35°C for 6 hrs.
Dry Weight: 70 to 90 gm.

Example 3: Preparation Ibrutinib amorphous form (Formula I)
To a solution of Methylene chloride (1500 ml) add Ibrutinib toluene solvate (Formula I) (100 gm) at 25-35°C. Stir it for 10-15 min at 25-35°C. Add aqueous sulphuric acid solution (1000 ml) (30 gm Sulphuric acid in 1000 ml purified water) at 25-35°C. Stir it for 20-30 min at 25-35°C. Separate organic layer and add sulphuric acid solution (1000 ml) (30 gm Sulphuric acid in 1000 ml purified water) at 25-35°C. Stir it for 20-30 min at 25-35°C. Separate organic layer. Combined organic layer and add Sodium bicarbonate solution (1000 ml) (50 gm Sodium bicarbonate in 1000 ml purified water) at 25-35°C. Stir it for 20-30 min at 25-35°C. Separate organic layer and add purified water (1000 ml) at 25-35°C. Stir it for 20-30 min at 25-35°C. Separate organic layer and add Brine solution (1000 ml) (100 gm sodium chloride in 1000 ml purified water) at 25-35°C. Stir it for 20-30 min at 25-35°C. Separate organic layer. Distill out solvent under vacuum below 35°C and degas for 30 to 45 min below 35°C. Add methylene chloride: Methanol mixture (1:9, 750 ml). Stir reaction mass for 20-30 min at 30-35°C. Add neutral activated charcoal (5 gm) at 30-35°C. Stir reaction mass for 20-30 min at 30-35°C. Filter the reaction mass through Hyflow bed and wash with methylene chloride: Methanol mixture (1:9, 50 ml). Take clear filtrate and cool to 0-5°C and stir for 3 hrs at -5-0°C. Filter the reaction mass and wash with chilled methanol (100 ml). Suck dry material for 60 to 90 min.
Dissolve above semi dry Ibrutinib in methylene chloride (1000 ml) at 25-30°C. Filter the reaction mass through micron filter. Take clear filter and subject for spray dryer. Collect the amorphous material from product collector.
Dry the wet product in Vacuum tray dryer at 30-35°C for 36 hrs.
Dry Weight: 50 to 70 gm.

The process of present invention is depicted in following scheme. ,CLAIMS:We claim:
1. A process for preparation of Ibrutinib of formula (I) which comprises;

(a) Reacting compound of formula (III) with acryloyl chloride of formula (II) in presence of base and phase transfer catalyst in solvent to obtain Ibrutinib of formula (I).

2. A process for preparation of Ibrutinib amorphous form of formula (I) which comprises;

(a) Reacting compound of formula (III) with acryloyl chloride of formula (II) in presence of base and phase transfer catalyst in solvent to obtain Ibrutinib of formula (I).

(b) Treating in-situ Ibrutinib of formula (I) with toluene to obtain Ibrutinib toluene solvate of formula (I).
(c) Reacting Ibrutinib toluene solvate compound of formula (I) with acid followed by base in solvent to obtain Ibrutinib of formula (I).
(d) Dissolving in-situ Ibrutinib of formula (I) in solvent and carrying-out spray-drying to obtain Ibrutinib amorphous form of formula (I).

3. The process as claimed in claim 1 or claim 2, wherein phase transfer catalyst for step (a) is selected from tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium chloride, tetrabutylammonium bisulfate, tricaprylmethylammonium chloride, tri-n-butylmethylammonium chloride, tetrabutylammonium hydroxide, benzyl triethylammonium chloride, and tetrabutyl phosphonium bromide.

4. The process as claimed in claim 1 or claim 2, wherein base for step (a) and (c) is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and cesium bicarbonate.

5. The process as claimed in claim 2, wherein acid for step (c) is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and sulfamic acid.

6. The process as claimed in claim 1 or claim 2, wherein solvent for step (a), (b), (c) and (d) is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, ethyl methyl ketone, methyl isobutyl ketone, ethyl acetate, methyl acetate, propyl acetate, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethyl formamide, dimethyl sulfoxide, N, N-dimethyl acetamide, water or mixtures thereof.

7. A process for preparation of Ibrutinib amorphous form of formula (I) which comprises;
(a) Reacting Ibrutinib toluene solvate compound of formula (I) with sulphuric acid in methylene chloride followed by sodium bicarbonate in water to obtain Ibrutinib of formula (I).
(b) Dissolving in-situ Ibrutinib of formula (I) in methylene chloride and carrying-out spray-drying to obtain Ibrutinib amorphous form of formula (I).