DESC:FIELD OF THE INVENTION
The present invention relates to amorphous acalabrutinib maleate and process for preparation thereof. Acalabrutinib maleate is represented by following structural formula (IA).

BACKGROUND OF THE INVENTION
Acalabrutinib is a second generation Bruton's tyrosine kinase inhibitor. It blocks an enzyme called Bruton's tyrosine kinase, which helps B cells to survive and grow. By blocking this enzyme, acalabrutinib is expected to slow down the build-up of cancerous B cells in CLL, thereby delaying progression of the cancer.

Acalabrutinib is approved by USFDA as CALQUENCE® capsule for the treatment of Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma.

Acalabrutinib is chemically known as 4-{8-amino-3- [(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl)}-N-(pyridine-2-yl)benzamide and structurally represented as below.

Acalabrutinib maleate is approved by USFDA as CALQUENCE® tablet for the treatment of Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma.

Acalabrutinib maleate is chemically known as 4-{8-Amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide (2Z)-2-butenedioic acid hydrate and structurally represented as below.

WO2013010868 discloses acalabrutinib and process for the preparation thereof.

WO2017002095 discloses various crystalline forms I, II, III, IV, V, VI, VII VIII and amorphous form of acalabrutinib. WO’095 also discloses various salt forms fumarate, gentisate, maleate, phosphate, L-tartrate, citrate, oxalate, and sulfate of Acalabrutinib. Amongst the various salts, acalabrutinib maleate crystalline Form A is disclosed in WO’095 and it is characterized by 1H NMR, PXRD, TG-FTIR, DSC and DVS.

WO2018064797 discloses crystalline forms 1, 2, 3 and 4 of Acalabrutinib.

WO2018229613 discloses crystalline forms RSV1, RSV2, RSV3, RSV4 and RSV5 of Acalabrutinib.

WO2021239893A1 discloses amorphous solid dispersion of Acalabrutinib.

WO2018148961A1 discloses crystalline form I of Acalabrutinib Malate and its preparation.

It is a well-known fact that different polymorphic forms of the same drug may have substantial differences in certain pharmaceutically important properties such as dissolution characteristics, bioavailability patterns, handling properties, solubility, flow characteristics and stability.

Further, different physical forms may have different particle size, hardness and glass transition temperatures. Since polymorphic forms can vary in their properties, regulatory authorities require that efforts be made to identify all polymorphic forms.

The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product.

There remains a continuing need, for different polymorphic forms of acalabrutinib and its salts to be explored and developed.

An amorphous form of some of the drugs exhibit much higher bioavailability than the crystalline forms, which leads to the selection of the amorphous form as the final drug substance for pharmaceutical dosage from development. Additionally, the aqueous solubility of crystalline form is lower than its amorphous form in some of the drugs, which may result in the difference in their in vivo bioavailability.

Thus, the present invention provides amorphous form of acalabrutinib maleate and its process for the preparation.

OBJECTS OF THE INVENTION
The main object of the present invention is to provide amorphous acalabrutinib maleate of formula (IA).

Another object of the present invention is to provide process for preparation of amorphous acalabrutinib maleate of formula (1A) which comprises;
(a) Reacting Acalabrutinib with maleic acid in suitable solvent to obtain Acalabrutinib maleate.
(b) Dissolving Acalabrutinib maleate in suitable solvent and isolating amorphous Acalabrutinib maleate.

Yet another object of the present invention is to provide process for preparation of amorphous acalabrutinib maleate of formula (1A) directly from Acalabrutinib without isolation of Acalabrutinib maleate.

Yet another object of the present invention is to provide process for preparation of acalabrutinib of formula (I) which comprises;
(a) Reacting compound of formula (VI) with compound of formula (V) in the presence of catalyst in suitable base in suitable solvent to obtain compound of formula (IV).

(b) Deprotecting compound of formula (IV) using acid in suitable solvent to obtain compound of formula (III).

(c) Reacting compound of formula (III) with 2-Butynoic acid (II) in the presence of condensing agent in suitable base in suitable solvent to obtain Acalabrutinib of formula (I).

SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide amorphous acalabrutinib maleate of formula (IA)

Another aspect of the present invention is to provide process for preparation of amorphous acalabrutinib maleate of formula (1A) which comprises;
(a) Reacting Acalabrutinib with maleic acid in suitable solvent to obtain Acalabrutinib maleate.
(b) Dissolving Acalabrutinib maleate in suitable solvent and isolating amorphous Acalabrutinib maleate.

Yet another aspect of the present invention is to provide process for preparation of amorphous acalabrutinib maleate of formula (1A) directly from Acalabrutinib without isolation of Acalabrutinib maleate.

Yet another aspect of the present invention is to provide process for preparation of acalabrutinib of formula (I) which comprises;
(a) Reacting compound of formula (VI) with compound of formula (V) in the presence of catalyst in suitable base in suitable solvent to obtain compound of formula (IV).

(b) Deprotecting compound of formula (IV) using acid in suitable solvent to obtain compound of formula (III).

(c) Reacting compound of formula (III) with 2-Butynoic acid (II) in the presence of condensing agent in suitable base in suitable solvent to obtain Acalabrutinib of formula (I).

DETAILED DESCRIPTION OF THE DRAWINGS
Fig.1 shows an XRPD pattern of amorphous acalabrutinib maleate of formula (IA).

DETAILED DESCRIPTION OF THE INVENTION
The main embodiment of the present invention is to provide amorphous acalabrutinib maleate of formula (IA).

Another embodiment of the present invention is to provide process for preparation of amorphous acalabrutinib maleate of formula (1A) which comprises;
(a) Reacting Acalabrutinib with maleic acid in suitable solvent to obtain Acalabrutinib maleate.
(b) Dissolving Acalabrutinib maleate in suitable solvent and isolating amorphous Acalabrutinib maleate.

Yet another embodiment of the present invention is to provide process for preparation of amorphous acalabrutinib maleate of formula (1A) directly from Acalabrutinib without isolation of Acalabrutinib maleate.

Isolation of amorphous Acalabrutinib maleate is carried out by employing any of the techniques, but not limited to cooling, decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, solvent evaporation, solvent-anti solvent system, rotational distillation using a device such as buchi rotavapor, distillation under vacuum, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization), rotary cone vacuum dryer (RVPD), melt crystallization, sieving, grinding, milling and the like.

Yet another embodiment of the present invention is to provide process for preparation of acalabrutinib of formula (I) which comprises;
(a) Reacting compound of formula (VI) with compound of formula (V) in the presence of catalyst in suitable base in suitable solvent to obtain compound of formula (IV).

(b) Deprotecting compound of formula (IV) using acid in suitable solvent to obtain compound of formula (III).

(c) Reacting compound of formula (III) with 2-Butynoic acid (II) in the presence of condensing agent in suitable base in suitable solvent to obtain Acalabrutinib.

In above embodiment, wherein the suitable catalyst which could be employed in step (a) may be selected from group comprising of phase transfer catalyst such as tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium chloride, tetrabutylammonium bisulfate, tricaprylmethylammonium chloride, tri-n-butylmethylammonium chloride, tetrabutylammonium hydroxide, benzyl triethylammonium chloride, tetrabutyl phosphonium bromide; palladium catalyst such as 1,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(dppf)Cl2), tetrakis(triphenylphosphine)palladium(0)(Pd(PPh3)4), palladium(II)acetate
(Pd(OAc)2), palladium(II)chloride(PdCl2), bis(benzonitrile)palladium(II) dichloride (Pd(PhCN)2Cl2), bis(triphenylphosphine) palladium (II) dichloride (Pd(PPh3)2Cl2), and allylpalladium(II)chloride dimer (PdCl(C3H5)]2) or mixture thereof.
Step (a) is carried out in the presence of catalyst and base in suitable solvent at 100-110°C.

In above embodiment, wherein the suitable acid which could be employed in step (b) may be selected from group comprising of trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, hydrogen chloride, hydrogen bromide, acetic acid or mixtures thereof.

Step (b) is carried out in the presence of acid in suitable solvent at 25-35°C.

In above embodiment, wherein the suitable condensing agent used in step (c) is selected from phosphonium reagents such as benzotriazol-1-yloxy-tris(dimethyl amino)-phosphoniumhexafluorophosphate (BOP), benzotriazol-1-yloxy-tripyrrolidino-phosphoniumhexafluorophosphate (PyBOP), bromo-tripyrrolidino-phosphoniumhexafluorophosphate (PyBrOP) and the like; ammonium/uronium reagents such as such as 1-[bis(dimethylamino)methylene]-lH-1,2,3-triazolo[4,5-b]pyridinium-3-oxid-hexafluorophosphate (HATU), 3-[bis(dimethyl-amino) methyliumyl]-3H-benzotriazol-l-oxid-hexafluorophosphate (HBTU),
1-[bis(dimethylamino)methylene]-5-chlorobenzotriazolium-3-oxid-hexafluoro phosphate (HCTU) and the like; imidazolium reagents such as carbonyl diimidazole (CDI), 2-chloro-1,3-dimethyl-lH-benzimidazolium hexa fluoro phosphate (CBMI), 2-(benzotriazol-l-yl)oxy-1,3-dimethyl imidazolidinium hexafluorophosphate (BOI) and the like; pyridinium reagents such as 2-bromo-1-methylpyridiniumiodide (BMPI), 2-chloro-1methylpyridinium iodide (CMPI) and the like;

Step (c) is carried out in the presence of condensing agent and suitable base in solvent at 25-35°C.

In above embodiment, 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 solvents which could be employed in step (a), (b) and (c) may be selected from group comprising of alcohols such as methanol, ethanol, 1-propanol, 2-propanol, n-butanol, ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone, esters such as ethyl acetate, methyl acetate, propyl acetate, isopropyl acetate, ethers such as diethyl ether, tetrahydrofuran, dioxane, diisopropyl ether, dimethyl ether, methyl tertiary butyl ether, 1,2-dimethoxyethane, aromatic hydrocarbon such as benzene, toluene, xylene, chlorobenzene, nitrobenzene, aliphatic hydrocarbons such as hexane, cyclohexane, heptane, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dialkylformamides such as dimethyl formamide, dialkylsulfoxides such as dimethyl sulfoxide, dialkylacetamides such as N, N-dimethyl acetamide, alkylpyrrolidone such as N-methyl pyrrolidone, nitriles such as acetonitrile, 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 Benzyl (S)-2-(8-amino-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Formula IV)
To a solution of n-butanol (750 ml) add benzyl (S)-2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (Formula VI) (100 gm), (4-(pyridine-2-ylcarbamoyl)phenyl)boronic acid (Formula V) (64 gm), tetrabutyl ammonium bromide (10 gm), potassium carbonate solution (potassium carbonate (49.8 gm) in purified water (250 ml)) and stir at 25-35°C for 20-30 min. Add Pd(dppf)Cl2 (6.3 gm) at 25-35°C and stir for 20-30 min. Heat reaction mass to 100-110°C and stir for 90-120 min. Add purified water (250 ml) at 25-35°C and stir for 20-30 min. Separate the organic layer and add purified water (300 ml) and stir for 20-30 min. Separate the organic layer and filter through hyflow bed and wash with n-butanol (50 ml). Distill out organic layer under vacuum at 60-70°C and degas for 30-40 min. Add acetonitrile (800 ml) and heat reaction mass at 75-85°C and stir for 20-30 min. Cool the reaction mass to 25-35°C and stir for 60-90 min. Filter the reaction mass and wash with acetonitrile (100 ml). Dry the material at 50-55°C in vacuum oven for 8-10 hrs.
Dry weight: 90-115 gm.

Example 2: Preparation of (S)-4-(8-amino-3-(pyrrolidine-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (Formula III)
To a solution of hydrobromic acid in acetic acid (600 gm) add Benzyl (S)-2-(8-amino-1-(4-(pyridine-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl) pyrrolidine-1-carboxylate (Formula IV) (100 gm) at 25-35°C and stir for 90-120 min. Add purified water (2000 ml), methylene chloride (1000 ml) and stir at 25-35°C for 20-30 min. Separate aqueous layer and add methylene chloride (1000 ml) and stir at 25-35°C for 15-20 min. Separate aqueous layer and add activated charcoal (5 gm) and stir at 25-35°C for 30-40 min. Filter the reaction mass and wash with purified water (100 ml). Add 30% sodium hydroxide solution (sodium hydroxide (300 gm) in purified water (1000 ml)) to filtrate at 15-25°C and stir for 5-10 min. Add mixture of methylene chloride:methanol (4000 ml) and stir for 15-20 min. Separate organic layer and add purified water (500 ml) and stir for 15-20 min. Separate organic layer and add 10% brine solution (sodium chloride 50 gm in purified water (500 ml)) and stir for 15-20 min. Separate organic layer and distill out under vacuum below 45-50°C and degas it for 40-60 min. Add Isopropyl alcohol (100 ml) and distill out under vacuum below 45-55°C. Add Isopropyl alcohol (1000 ml) and heat the reaction mass at 80-85°C and stir for 30-40 min. Cool the reaction mass to 25-35°C and stir for 50-60 min. Filter the reaction mass and wash with Isopropyl alcohol (100 ml). Dry the material at 50-55°C in vacuum oven for 10-12 hrs.
Dry weight: 50-60 gm.

Example 3: Preparation of Acalabrutinib (Formula I)
To a solution of methylene chloride (2000 ml) add (S)-4-(8-amino-3-(pyrrolidine-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridine-2-yl)benzamide (Formula III) (100 gm), 2-butynoic acid (Formula II) (22.11 gm) at 25-35°C and stir for 10-15 min. Cool the reaction mass and add HATU (100 gm) at 0-5°C. Add pyridine solution (pyridine (79.2 gm) in methylene chloride (500 ml)) at 0-5°C and stir for 40-50 min. Stir the reaction mass at 25-35°C for 4-5 hrs. Filter the reaction mass and wash with methylene chloride (100 ml). Add water (1000 ml) to wet cake and stir at 25-35°C for 50-60 min. Filter the solid and wash with water (100 ml). Add methylene chloride (2500 ml) to wet cake. Add 5% sodium bicarbonate solution (sodium bicarbonate (75 gm) in purified water (1500 ml)) and stir at 25-35°C for 50-60 min. Separate organic layer and add 5% acetic acid solution (acetic acid (50 gm) in purified water (1000 ml)) and stir at 25-35°C for 15-20 min. Separate organic layer and add 8% hydrochloric acid solution (hydrochloric acid (50 gm) in purified water (500 ml)) and stir at 25-35°C for 20-30 min. Separate aqueous layer add activated charcoal (5 gm) and stir at 25-35°C for 30-40 min. Filter the reaction mass through hyflow bed and wash with water (100 ml). Add methylene chloride (2000 ml) and 10% NaOH solution (450 ml) and stir for 15-20 min. Separate organic layer and distill out under vacuum below 45°C. Add acetone (600 ml) to reaction mass and stir at 50-55°C for 30-40 min. Cool the reaction mass and stir at 25-35°C for 3-4 hrs. Filter the reaction mass and wash with acetone (100 ml). Dry the material at 40-45°C in vacuum oven for 5-6 hrs.
Dry weight: 60-80 gm.

Example 4: Preparation of amorphous Acalabrutinib maleate (Formula IA)
To a solution of acetone (2150 ml) and purified water (220 ml) add acalabrutinib free base (Formula I) (100 gm) at 25-35°C and stir the reaction mass for 10-15 minutes. Heat reaction mass to 50-55°C and stir for 10 minutes and add maleic acid solution (maleic acid (24.93 gm) in purified water (130 ml)) in it dropwise. Stir reaction mass at 50-55°C for 20-30 minutes. Cool the reaction mass to 20-25°C and stir for 20-24 hours. Filter the reaction mass and wash it with acetone (100 ml). To a solution of methanol (3375 ml) and methylene chloride (375 ml) add acalabrutinib maleate (75 gm) and stir the reaction mass at 25-35°C for 30-40 min. Distill out reaction mass under vacuum at 45-50°C and degas to obtain amorphous material.
Weight: 72 gm

The process of present invention is depicted in following scheme.

,CLAIMS:We claim:
1. Amorphous acalabrutinib maleate of formula (IA).

2. Process for preparation of amorphous acalabrutinib maleate of formula (1A) which comprises;
(a) Reacting Acalabrutinib with maleic acid in suitable solvent to obtain Acalabrutinib maleate.
(b) Optionally isolating Acalabrutinib maleate.
(c) Dissolving Acalabrutinib maleate in suitable solvent and isolating amorphous Acalabrutinib maleate.

3. The process as claimed in claim 2, wherein suitable solvent for step (a) and (c) is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, acetone, ethyl methyl ketone, methyl isobutyl ketone, ethyl acetate, methyl acetate, propyl acetate, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, dioxane, diisopropyl ether, methyl tertiary butyl ether, dimethyl formamide, dimethyl sulfoxide, N, N-dimethyl acetamide, N-methyl pyrrolidone, hexane, cyclohexane, heptane, acetonitrile, water or mixtures thereof.

4. The process as claimed in claim 2, wherein isolation of amorphous Acalabrutinib maleate is carried out by employing technique is selected from solvent evaporation, solvent-anti solvent system, rotational distillation using a device such as buchi rotavapor, distillation under vacuum, spray drying, freeze drying (lyophilization), crystallization.

5. Process for preparation of acalabrutinib of formula (I) which comprises;
(a) Reacting compound of formula (VI) with compound of formula (V) in the presence of catalyst in suitable base in suitable solvent to obtain compound of formula (IV).

(b) Deprotecting compound of formula (IV) using acid in suitable solvent to obtain compound of formula (III).

(c) Reacting compound of formula (III) with 2-Butynoic acid (II) in the presence of condensing agent in suitable base in suitable solvent to obtain Acalabrutinib of formula (I).

6. The process as claimed in claim 5, wherein suitable catalyst for step (a) is selected from phase transfer catalyst such as tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium chloride, tetrabutylammonium bisulfate, tetrabutylammonium hydroxide and palladium catalyst such as 1,l'-bis(diphenylphosphino) ferrocene]dichloropalladium(II)(Pd(dppf)Cl2),
tetrakis(triphenylphosphine)palladium(0)(Pd(PPh3)4),palladium(II)acetate(Pd(OAc)2), palladium(II)chloride (PdCl2), bis(triphenylphosphine) palladium (II) dichloride (Pd(PPh3)2Cl2), or mixture thereof.

7. The process as claimed in claim 5, wherein suitable base for step (a) & step (c) is selected from 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.

8. The process as claimed in claim 5, wherein suitable acid for step (b) is selected from trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, hydrogen chloride, hydrogen bromide, acetic acid or mixtures thereof.

9. The process as claimed in claim 5, wherein suitable condensing agent for step (c) is selected from benzotriazol-1-yloxy-tris(dimethyl amino)-phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate (PyBOP), 1-[bis(dimethylamino)methylene]-lH-1,2,3-
triazolo[4,5-b]pyridinium-3-oxid-hexafluorophosphate (HATU), 3-[bis(dimethyl-amino) methyliumyl]-3H-benzotriazol-l-oxid-hexafluorophosphate (HBTU), 1-[bis(dimethylamino)methylene]-5-chlorobenzotriazolium-3-oxid-hexafluoro phosphate (HCTU), carbonyl diimidazole (CDI).

10. The process as claimed in claim 5, wherein suitable solvent for step (a), (b) & (c) is selected from methanol, ethanol, 1-propanol, 2-propanol, butanol, acetone, ethyl methyl ketone, methyl isobutyl ketone, ethyl acetate, methyl acetate, propyl acetate, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, dioxane, diisopropyl ether, methyl tertiary butyl ether, dimethyl formamide, dimethyl sulfoxide, N, N-dimethyl acetamide, N-methyl pyrrolidone, hexane, cyclohexane, heptane, acetonitrile, water or mixtures thereof.