DESC:PROCESS FOR PREPARATION OF ACALABRUTINIB
INTRODUCTION
The present application relates to a process for the preparation Acalabrutinib of formula (I) or pharmaceutically acceptable salts thereof. The present application relates to amorphous acalabrutinib and solid dispersion of acalabrutinib. Also the present application relates to process for the preparation amorphous acalabrutinib and solid dispersion of acalabrutinib by suitable methods.
Acalabrutinib (ACP-196) is an experimental anti-cancer drug and a second generation BTK inhibitor developed by Acerta Pharma. It is designed to be more selective than ibrutinib. Acalabrutinib or its salts is used for the treatment of Chronic Lympholytic Leukemia (CLL). 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-(pyridin-2-yl)benzamide.
US9290504B2 (hereinafter the US’504 patent) assigned to Merck Sharp & Dohme, covers acalabrutinib or a pharmaceutically acceptable salts thereof. The process disclosed in US’504 patent involves the use of expensive Pd(dppf)Cl2 and (4-(pyridin-2-ylcarbamoyl)phenyl)boronic acid for the preparation of aclabrutinib. Hence the process disclosed in the US’504 patent is not a cost-effective process and not suitable for commercial manufacture of acalabrutinib.
Therefore, there remains a need for an improved process for the commercial production of Acalabrutinib of formula (I) or pharmaceutically acceptable salts thereof.

SUMMARY
First aspect of the present application relates to a process for the preparation of acalabrutinib of formula (I) or pharmaceutically acceptable salts thereof, comprising the steps of:
a) Reacting compound of formula (VII) with compound of formula (X) to provide compound of formula (VI)
;
b) Hydrolysis of compound of formula (VI) to provide compound of formula (V)
;
c) Conversion of compound of formula (V) to compound of formula (IV)
;
d) Reacting compound of formula (IV) with compound of formula (XI) to provide compound of formula (III)
;
e) Conversion of compound of formula (III) to compound of formula (II)
;
f) Reaction of compound of formula (II) with 2-butynoic acid or 2-butynoyl chloride to provide acalabrutinib of formula (I) or a pharmaceutically acceptable salts thereof
;
wherein, R1 is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms; R2 and R3 are independently hydrogen, a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, optionally substituted with an alkyl group having 1-6 carbon atoms or an aryl group having 6-12 carbon atoms or an alkoxy group having 1-6 carbon atoms, or halogen, an aryl-alkyl group having 7-12 carbon atoms optionally substituted with an alkyl group having 1-6 carbon atoms or an aryl group having 6-12 carbon atoms or an alkoxy group having 1-6 carbon atoms or halogen, trialkyl silyl group having 3-12 carbon atoms and an amino protecting group; X is a leaving group; P is an amino protecting group.
Second aspect of the present application relates to a process for the preparation of compound of formula (VI) comprising reacting compound of formula (VII) with compound of formula (X)

wherein, R1 is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms; P is an amino protecting group and X is a leaving group.
Third aspect of the present application relates to a process for the preparation of compound of formula (V) comprising hydrolysis of compound of formula (VI)

wherein, R1 is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms; P is an amino protecting group and X is a leaving group.
Fourth aspect of the present application relates to a process for the preparation of compound of formula (IV) comprising converting compound of formula (V) to compound of formula (IV)

wherein, P is an amino protecting group and X is a leaving group.
Fifth aspect of the present application relates to a process for the preparation of compound of formula (III), comprising reacting compound of formula (IV) with compound of formula (XI)

wherein, P is an amino protecting group; R2 and R3 are independently hydrogen, a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, optionally substituted with an alkyl group having 1-6 carbon atoms or an aryl group having 6-12 carbon atoms or an alkoxy group having 1-6 carbon atoms, or halogen, an aryl-alkyl group having 7-12 carbon atoms optionally substituted with an alkyl group having 1-6 carbon atoms or an aryl group having 6-12 carbon atoms or an alkoxy group having 1-6 carbon atoms or halogen, trialkyl silyl group having 3-12 carbon atoms and an amino protecting group; X is a leaving group.
Sixth aspect of the present application relates to a process for the preparation of compound of formula (II), comprising converting compound of formula (III) to compound of formula (II) in presence of a suitable reagent

wherein, P is an amino protecting group; R2 and R3 are independently hydrogen, a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, optionally substituted with an alkyl group having 1-6 carbon atoms or an aryl group having 6-12 carbon atoms or an alkoxy group having 1-6 carbon atoms, or halogen, an aryl-alkyl group having 7-12 carbon atoms optionally substituted with an alkyl group having 1-6 carbon atoms or an aryl group having 6-12 carbon atoms or an alkoxy group having 1-6 carbon atoms or halogen, trialkyl silyl group having 3-12 carbon atoms and an amino protecting group.
Seventh aspect of the present application relates to the process for the preparation of compound of formula (IV), comprising steps of:
a) Conversion of compound of formula (VI) to a compound of formula (XII) in presence of a suitable reagent
;
b) Hydrolysis of compound of formula (XII) to a compound of formula (XIII)
;
c) Conversion of compound of formula (XIII) to compound of formula (IV)

wherein, R1 is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms; P is an amino protecting group and X is a leaving group;
Eighth aspect of the present application relates to a process for the preparation of acalabrutinib of formula (I) or pharmaceutically acceptable salts thereof comprising the steps of:
a) Reacting compound of formula (IV) with compound of formula (XI) to provide compound of formula (III)

b) Conversion of compound of formula (III) to compound of formula (II)

c) Reacting compound of formula (II) with 2-butynoic acid or 2-butynoyl chloride to provide acalabrutinib of formula (I) or a pharmaceutically acceptable salt thereof
;
wherein, P is an amino protecting group; R2 and R3 are independently hydrogen, a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, optionally substituted with an alkyl group having 1-6 carbon atoms or an aryl group having 6-12 carbon atoms or an alkoxy group having 1-6 carbon atoms, or halogen, an aryl-alkyl group having 7-12 carbon atoms optionally substituted with an alkyl group having 1-6 carbon atoms or an aryl group having 6-12 carbon atoms or an alkoxy group having 1-6 carbon atoms or halogen, trialkyl silyl group having 3-12 carbon atoms and an amino protecting group; X is a leaving group.
Ninth aspect of the present application relates to amorphous solid dispersion of acalabrutinib with one or more pharmaceutically acceptable carrier.
Tenth aspect of the present application relates to a process for preparation of amorphous solid dispersion of acalabrutinib with one or more pharmaceutically acceptable carrier comprising
(a) dissolving acalabrutinib and one or more pharmaceutically acceptable carrier in suitable solvent or mixture thereof;
(b) isolating amorphous solid dispersion of acalabrutinib;
(c) optionally drying the amorphous solid dispersion of acalabrutinib.
Eleventh aspect of the present application relates to a process for preparation of amorphous solid dispersion of acalabrutinib with one or more pharmaceutically acceptable carrier comprising mixing amorphous acalabrutinib with one or more pharmaceutically acceptable carrier.
Twelfth aspect of the present application relates to a pharmaceutical composition comprising amorphous solid dispersion of acalabrutinib and one or more pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1: The PXRD pattern of amorphous form of acalabrutinib obtained by the process of example 15.
Figure 2: The PXRD pattern of amorphous acalabrutinib obtained by the process of example 17.
Figure 3: The PXRD pattern of amorphous solid dispersion of acalabrutinib and co-povidone (1:1 w/w), obtained by the process of example 19.
Figure 4: The PXRD pattern of amorphous solid dispersion of acalabrutinib, co-povidone and syloid (1:1:1 w/w), obtained by the process of example 23.

DETAILED DESCRIPTION
First aspect of the present application relates to a process for the preparation of acalabrutinib of formula (I) or pharmaceutically acceptable salts thereof, comprising the steps of:
a) Reacting compound of formula (VII) with compound of formula (X) to provide compound of formula (VI)
;
b) Hydrolysis of compound of formula (VI) to provide compound of formula (V)
;
c) Conversion of compound of formula (V) to compound of formula (IV)
;
d) Reacting compound of formula (IV) with compound of formula (XI) to provide compound of formula (III)
;
e) Conversion of compound of formula (III) to compound of formula (II)
;
f) Reaction of compound of formula (II) with 2-butynoic acid or 2-butynoyl chloride to provide acalabrutinib of formula (I) or a pharmaceutically acceptable salts thereof
;
wherein, R1 is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms; R2 and R3 are independently hydrogen, a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, optionally substituted with an alkyl group having 1-6 carbon atoms or an aryl group having 6-12 carbon atoms or an alkoxy group having 1-6 carbon atoms, or halogen, an aryl-alkyl group having 7-12 carbon atoms optionally substituted with an alkyl group having 1-6 carbon atoms or an aryl group having 6-12 carbon atoms or an alkoxy group having 1-6 carbon atoms or halogen, trialkyl silyl group having 3-12 carbon atoms and an amino protecting group; X is a leaving group; P is an amino protecting group.
In embodiments of step a), reaction between compound of formula (VII) and compound of formula (X) is carried out in an inert organic solvent including but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, isopropanol and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, proprionitrile and the like; chlorinated solvents such as dichloromethane, chloroform and the like and mixtures thereof. Specifically, the solvent may be an ether solvent. More specifically, the ether solvent may be tetrahydrofuran. In one embodiment, the reaction between compound of formula (VII) and compound of formula (X) is carried out in presence of a suitable coupling agent including but not limited to carbodiimides such as dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and the like; phosphonium reagents such as benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate (PyBOP), bromo-tripyrrolidino-phosphonium hexafluorophosphate (PyBrOP) and the like; immonium reagents such as benzotriazol-1-yloxy-N,N-dimethyl-methaniminium hexachloroantimonate (BOMI), 5-(1H-benzotriazol-1-yloxy)-3,4-dihydro- 1-methyl 2H-pyrrolium hexachloroantimonate (BDMP) and the like; ammonium/uronium reagents such as such as 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxid-hexafluorophosphate (HATU), 3-[bis(dimethyl-amino)methyliumyl]-3H-benzotriazol-1-oxid-hexa?uorophosphate (HBTU), 1-[bis(dimethyl-amino)methylen]-5-chlorbenzotriazolium-3-oxid-hexafluorophosphat (HCTU) and the like; imidazolium reagents such as carbonyldiimidazole (CDI), 2-chloro-1,3-dimethyl 1H-benzimidazolium hexafluorophosphate (CBMI), 2-(benzotriazol-1-yl)oxy-1,3-dimethylimidazolidinium hexafluorophosphate (BOI) and the like; pyridinium reagents such as 2-bromo-1-methylpyridinium iodide (BMPI), 2-chloro-1-methylpyridinium iodide (CMPI) and the like. Specifically, the suitable coupling agent may be HATU. In another embodiment, the reaction between compound of formula (VII) and compound of formula (X) may be carried out in presence of a suitable base including but not limited to triethyl amine, diisopropyl ethyl amine (DIPEA), pyridine, dimethyl aminopyridine (DMAP) and the like. Specifically, the base may be DIPEA. The reaction of step a) may be carried out at a temperature of about -20 °C to about boiling point of the solvent. Specifically, the reaction of step a) may be carried out at a temperature about -5 °C to about 30 °C.
In embodiments of step b), hydrolysis reaction of compound of formula (VI) was carried out in an inert organic solvent including but not limited to aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, ethanol isopropanol and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether, terahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; water; and mixtures thereof. Specifically, the solvent may be an ether solvent. More specifically, the ether solvent may be tetrahydrofuran. The reaction may be carried out in presence of a base including but not limited to metal alkoxide base such as sodium methoxide, sodium tert-butoxide and the like; metal carbonate bases such as potassium carbonate, sodium carbonate and the like; metal hydroxide bases such as lithium hydroxide, sodium hydroxide and the like. Specifically, the base may be lithium hydroxide. The reaction may be carried out at a temperature of about -10 °C to about boiling point of the solvent. Specifically, the reaction may be carried out at a temperature about -5 °C to about 30 °C.
In embodiments of step c), conversion of compound of formula (V) to compound of formula (IV), comprising reacting compound of formula (V) with a suitable condensation reagent followed by reacting with 2-amino pyridine. The reaction may be carried out in an inert organic solvent including but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, isopropanol and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as methyl t-butyl ether, tetrahydrofuran and the like; chlorinated solvents such as dichloromethane, chloroform and the like and mixtures thereof. Specifically, the solvent may be a chlorinated solvent. More specifically, the chlorinated solvent may be dichloromethane. The reaction may be carried out in presence of a suitable condensation reagent including but not limited to triflic anhydride, phosphorous oxychloride, thionyl chloride, oxalyl chloride, phosphorous pentoxide, triphenoxyphosphene, zinc chloride, poly phosphoric acid and the like; mixtures thereof. Specifically, the suitable condensation reagent may be oxalyl chloride, phosphorous oxychloride, thionyl chloride and the like. More specifically, the suitable condensation reagent may be oxalyl chloride. The reaction may be carried out at a temperature of about -10 °C to about the boiling point of the solvent. Specifically, the reaction carried out at a temperature about -5 °C to about 30 °C.
In embodiments of step d), the reaction between compound of formula (IV) and compound of formula (XI) may be carried out in an inert organic solvent including but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; ether solvents such as methyl t-butyl ether, 1,4-dioxane and the like; chlorinated solvents such as dichloromethane, chloroform and the like and mixtures thereof. Specifically, the solvent may be an ether solvent. More specifically, the ether solvent may be 1, 4-dioxane. The reaction may be carried out at a temperature of about 20 °C to about boiling point of the solvent. More specifically, the reaction may be carried out at a temperature of about 80 °C to about boiling point of the solvent.
In embodiments of step e), conversion of compound of formula (III) to a compound of formula (II) may be carried out in a suitable solvent in presence of an acid reagent. The suitable solvent may include but not limited to water; alcoholic solvent such as, methanol, isopropanol and the like; ketones such as acetone, methyl ethyl ketone and the like; ethers such as 1,4-dioxane, tetrahydrofuran and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, dichloroethane and the like. Specifically, the solvent may be a chlorinated solvent. More specifically, the chlorinated solvent may be dichloroethane. The acid reagent may include but not limited to mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid and the like; organic acids such as formic acid, acetic acid, trifluoroacetic acid and the like; sulfonic acids such as methanesulfonic acid, triflic acid and the like. Specifically, the acid reagent may be sulfonic acid. More specifically, the acid reagent may be triflic acid. The reaction may be carried out at a temperature of about 20 °C to about boiling point of the solvent.
In embodiments of step f), reaction of compound of formula (II) with 2-butynoic acid is carried out in presence of a suitable coupling agent in a suitable solvent. The suitable solvent may include but not limited to a polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, isopropanol and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvents such as diethyl ether, methyl t-butyl ether and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvents such as dichloromethane, chloroform and the like and mixtures thereof. Specifically, the solvent may be a chlorinated solvent. More specifically, the chlorinated solvent may be dichloromethane. The suitable coupling agent may include but not limited to carbodiimides; phosphonium reagents; immonium reagents; ammonium/uronium reagents; imidazolium reagents; pyridinium reagents. Specifically, the suitable coupling agent may be HATU. In embodiment, reaction of compound of formula (II) with 2-butynoic acid may be carried out in presence of a suitable base including but not limited to triethyl amine, diisopropyl ethyl amine, pyridine, dimethyl aminopyridine (DMAP) and the like. Specifically, the base may be diisopropyl ethyl amine (DIPEA). The reaction may be carried out at a temperature of about -20 °C to about boiling point of the solvent. Specifically, the reaction may be carried out at a temperature about -5 °C to about 30 °C.
In embodiments of step f), reaction of compound of formula (II) with 2-butynoyl chloride is carried out in presence of a suitable base.
Second aspect of the present application relates to a process for the preparation of compound of formula (VI) comprising reacting compound of formula (VII) with compound of formula (X)

wherein, R1 is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms; P is an amino protecting group and X is a leaving group.
Third aspect of the present application relates to a process for the preparation of compound of formula (V) comprising hydrolysis of compound of formula (VI)

wherein, R1 is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms; P is an amino protecting group and X is a leaving group.
Fourth aspect of the present application relates to a process for the preparation of compound of formula (IV) comprising converting compound of formula (V) to compound of formula (IV)

wherein, P is an amino protecting group and X is a leaving group.
Fifth aspect of the present application relates to a process for the preparation of compound of formula (III), comprising reacting compound of formula (IV) with compound of formula (XI)

wherein, P is an amino protecting group; R2 and R3 are independently hydrogen, a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, optionally substituted with an alkyl group having 1-6 carbon atoms or an aryl group having 6-12 carbon atoms or an alkoxy group having 1-6 carbon atoms, or halogen, an aryl-alkyl group having 7-12 carbon atoms optionally substituted with an alkyl group having 1-6 carbon atoms or an aryl group having 6-12 carbon atoms or an alkoxy group having 1-6 carbon atoms or halogen, trialkyl silyl group having 3-12 carbon atoms and an amino protecting group; X is a leaving group.
Sixth aspect of the present application relates to a process for the preparation of compound of formula (II), comprising converting compound of formula (III) to compound of formula (II) in presence of a suitable reagent

wherein, P is an amino protecting group; R2 and R3 are independently hydrogen, a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, optionally substituted with an alkyl group having 1-6 carbon atoms or an aryl group having 6-12 carbon atoms or an alkoxy group having 1-6 carbon atoms, or halogen, an aryl-alkyl group having 7-12 carbon atoms optionally substituted with an alkyl group having 1-6 carbon atoms or an aryl group having 6-12 carbon atoms or an alkoxy group having 1-6 carbon atoms or halogen, trialkyl silyl group having 3-12 carbon atoms and an amino protecting group.
Seventh aspect of the present application relates to a process for the preparation of compound of formula (IV), comprising steps of:
a) Conversion of compound of formula (VI) to a compound of formula (XII) in presence of a suitable reagent
;
b) Hydrolysis of compound of formula (XII) to a compound of formula (XIII)

c) Conversion of compound of formula (XIII) to compound of formula (IV)
;
wherein, R1 is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms; P is an amino protecting group and X is a leaving group.
In embodiments of the step a), conversion of compound of formula (VI) to a compound of formula (XII) may be carried out in an inert organic solvent including but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvent such as methyl t-butyl ether, 1,4-dioxane and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvent such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like and mixtures thereof. Specifically, the solvent may be chlorinated solvent. More specifically, the chlorinated solvent may be dichloromethane. The reaction of step a) may be carried out in presence of a suitable condensation reagent may include but not limited to triflic anhydride, phosphorous oxychloride, thionyl chloride, oxalyl chloride, phosphorous pentoxide, triphenoxyphosphene, zinc chloride and the like. Specifically, the reaction may be carried out in presence of oxalyl chloride. The reaction may be carried out at a temperature of about -10 °C to about boiling point of the solvent. Specifically, the reaction may be carried out at a temperature about -5 °C to about 30 °C.
In embodiments of step b), hydrolysis reaction of compound of formula (XII) may be carried out in an inert organic solvent including but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; alcoholic solvent such as methanol, isopropanol and the like; ketone solvent such as acetone, ethyl methyl ketone and the like; ether solvent such as methyl t-butyl ether, tetrahydrofuran and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvent such as dichloromethane, chloroform and the like; water and mixtures thereof. Specifically, the solvent may be an ether solvent. More specifically, the ether solvent may be tetrahydrofuran. The reaction may be carried out in presence of a base including but not limited to metal alkoxide base such as sodium methoxide, sodium tert-butoxide and the like; metal carbonate bases such as potassium carbonate, sodium carbonate and the like; metal hydroxide bases such as lithium hydroxide, sodium hydroxide and the like; Specifically the base may be lithium hydroxide. The reaction may be carried out at a temperature of about -10 °C to about boiling point of the solvent. Specifically, the reaction carried out at a temperature about -5 °C to about 30 °C.
In embodiments of the step c), reaction of compound of formula (XIII) with 2-amino pyridine was carried out in an inert organic solvent including but not limited to polar aprotic solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO) and the like; ether such as tetrahydrofuran and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; ketone solvent such as acetone, methyl isobutyl ketone and the like; ether solvent such as diethyl ether, methyl t-butyl ether and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; nitrile solvents such as acetonitrile, propionitrile and the like; chlorinated solvents such as dichloromethane, chloroform and the like; and mixtures thereof. Specifically, the solvent may be chlorinated solvent. More specifically, the chlorinated solvent may be dichloromethane. The reaction of step c) may be carried out in presence of a suitable condensation reagent may include but not limited to triflic anhydride, phosphorous oxychloride, thionyl chloride, oxalyl chloride, phosphorous pentoxide and the like. Specifically, the suitable condensation reagent may be oxalyl chloride. The reaction may be carried out at a temperature of about -10 °C to about boiling point of the solvent. Specifically, the reaction may be carried out at a temperature about -5 °C to about 30 °C.
Eighth aspect of the present application relates to a process for the preparation of acalabrutinib of formula (I) or pharmaceutically acceptable salts thereof comprising the steps of:
a) Reacting compound of formula (IV) with compound of formula (XI) to provide compound of formula (III)
;
b) Conversion of compound of formula (III) to compound of formula (II)
;
c) Reacting compound of formula (II) with 2-butynoic acid or 2-butynoyl chloride to provide acalabrutinib of formula (I) or a pharmaceutically acceptable salt thereof
;
wherein, P is an amino protecting group; R2 and R3 are independently hydrogen, a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, optionally substituted with an alkyl group having 1-6 carbon atoms or an aryl group having 6-12 carbon atoms or an alkoxy group having 1-6 carbon atoms, or halogen, an aryl-alkyl group having 7-12 carbon atoms optionally substituted with an alkyl group having 1-6 carbon atoms or an aryl group having 6-12 carbon atoms or an alkoxy group having 1-6 carbon atoms or halogen, trialkyl silyl group having 3-12 carbon atoms and an amino protecting group; X is a leaving group.
Another aspect of the present application relates to a compound of formula (VI)

wherein, R1 is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms; P is an amino protecting group and X is a leaving group.
A specific aspect of the present application relates to a compound of formula (VIa)
.
Another specific aspect of the present application relates to a compound of formula (VIb)

wherein, X is a leaving group.
Yet another specific aspect of the present application relates to a compound of formula (VIc)

wherein, P is an amino protecting group and X is a leaving group.
Still another specific aspect of the present application relates to a compound of formula (VId)

wherein, R1 is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms and X is a leaving group.
Further aspect of the present application relates to the use of compound of formula (VI) or (VIa) or (VIb) or (VIc) or (VId) for the preparation of acalabrutinib of formula (I) or pharmaceutically acceptable salts thereof.
Still further aspect of the present application relates to conversion of compound of formula (VI) or (VIa) or (VIb) or (VIc) or (VId) to acalabrutinib of formula (I) or a pharmaceutically acceptable salts thereof.
Another aspect of the present application relates to a compound of formula (V)

wherein, P is an amino protecting group and X is a leaving group.
A specific aspect of the present application relates to a compound of formula (Va)
.
Another Specific aspect of the present application relates to a compound of formula (Vb)

wherein, X is a leaving group.
Yet another Specific aspect of the present application relates to a compound of formula (Vc)

wherein, p is an amino protecting group.
Further aspect of the present application relates to the use of compound of formula (V) or (Va) or (Vb) or (Vc) for the preparation of acalabrutinib of formula (I) or pharmaceutically acceptable salts thereof.
Still further aspect of the present application relates to the conversion of compound of formula (V) or (Va) or (Vb) or (Vc) to acalabrutinib of formula (I) or a pharmaceutically acceptable salts thereof.
Another aspect of the present application relates to a compound of formula (IV)

wherein, P is an amino protecting group and X is a leaving group.
A specific aspect of the present application relates to a compound of formula (IVa)
.
Another specific aspect of the present application relates to a compound of formula (IVb)

wherein, X is a leaving group.
Still another specific aspect of the present application relates to a compound of formula (IVc)

wherein, P is an amino protecting group.
Another aspect of the present application relates to the use of compound of formula (IV) or (IVa) or (IVb) or (IVc) for the preparation of acalabrutinib of formula (I) or pharmaceutically acceptable salts thereof.
Yet another aspect of the present application relates to the conversion of compound of formula (IV) or (IVa) or (IVb) or (IVc) to acalabrutinib of formula (I) or a pharmaceutically acceptable salts thereof.
Another aspect of the present application relates to a compound of formula (IIIa)
.
Yet another aspect of the present application relates to a compound of formula (IIIb)

wherein, P is an amino protecting group.
Still another aspect of the present application relates to a compound of formula (IIIc)

Further aspect of the present application relates to the use of compound of formula (IIIa) or (IIIb) or (IIIc) for the preparation of acalabrutinib of formula (I) or pharmaceutically acceptable salts thereof.
Still further aspect of the present application relates to the conversion of compound of formula (IIIa) or (IIIb) or (IIIc) to acalabrutinib of formula (I) or a pharmaceutically acceptable salts thereof.
Another aspect of the present application relates to a compound of formula (XII)

wherein, R1 is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms; P is an amino protecting group and X is a leaving group.
A specific aspect of the present application relates to a compound of formula (XIIa)
.
Another aspect of the present application relates to a compound of formula (XIIb)

wherein, P is an amino protecting group and X is a leaving group.
Yet another aspect of the present application relates to a compound of formula (XIIc)

wherein, X is a leaving group.
Still another aspect of the present application relates to a compound of formula (XIId)

wherein, R1 is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms and P is an amino protecting group.
Further aspect of the present application relates to the use of compound of formula (XII) or (XIIa) or (XIIb) or (XIIc) or (XIId) for the preparation of acalabrutinib of formula (I) or pharmaceutically acceptable salts thereof.
Still further another aspect of the present application relates to the conversion of compound of formula (XII) or (XIIa) or (XIIb) or (XIIc) or (XIId) to acalabrutinib of formula (I) or a pharmaceutically acceptable salts thereof.
Another aspect of the present application relates to a compound of formula (XIII)

wherein, P is an amino protecting group and X is a leaving group.
A specific aspect of the present application relates to a compound of formula (XIIIa)
.
Another aspect of the present application relates to a compound of formula (XIIb)

wherein X is a leaving group.
Yet specific aspect of the present application relates to a compound of formula (XIIc)

wherein, wherein, P is an amino protecting group.
Further aspect of the present application relates to the use of compound of formula (XIII) or (XIIIa) or (XIIIb) or (XIIIc) for the preparation of acalabrutinib of formula (I) or pharmaceutically acceptable salts thereof.
Still further aspect of the present application relates to the conversion of compound of formula (XIII) or (XIIIa) or (XIIIb) or (XIIIc) to acalabrutinib of formula (I) or a pharmaceutically acceptable salts thereof.
Yet another aspect of the present application relates to amorphous form of acalabrutinib.
One of the embodiments of the present application relates to amorphous form of acalabrutinib characterized by a PXRD pattern substantially as illustrated in the pattern of Figure 1 or Figure 2.
Another aspect of the present application relates to a process for preparing amorphous form of acalabrutinib comprising
(a) dissolving acalabrutinib in a suitable solvent or mixture thereof,
(b) removing the solvent of step (a) by any suitable technique, and
(c) optionally drying amorphous acalabrutinib.
Any crystalline form of acalabrutinib or mixture thereof may be used as starting material for preparing amorphous form of acalabrutinib.
In embodiments of step (a), suitable solvents include, but are not limited to ketone solvent such as acetone, ethyl methyl ketone, 2-butanone, methyl isobutyl ketone and the like; ether solvent such as tetrahydrofuran, dioxane and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbon solvent such as dichloromethane, chloroform and the like; alcohol solvent such as methanol, ethanol, propanol, isopropanol and the like; water; mixtures thereof. Specifically, the solvent may be selected from a group of ketone solvent such as acetone, ethyl methyl ketone, 2-butanone, methyl isobutyl ketone and the like. Specifically, the solvent may be acetone. In another embodiment, the solvent may be a halogenated hydrocarbon solvent, such as dichloromethane, chloroform and the like. Specifically, the solvent may be dichloromethane. In another embodiment, the solvent is a mixture of an alcohol solvent and a halogenated hydrocarbon solvent. Specifically, the solvent is a mixture of methanol and dichloromethane.
In one embodiment of step (a), the dissolving of acalabrutinib and a suitable solvent may be performed at a temperature of about 5°C to about the boiling point of the solvent. In another embodiment, acalabrutinib may be dissolved in a suitable solvent at a temperature of about 5 °C to about boiling point of the solvent. In a specific embodiment, acalabrutinib may be dissolved in a suitable solvent at a temperature of about 20 °C to about 30 °C.
In another embodiment of step (a), the solution of acalabrutinib may be filtered to remove any un-dissolved particles or extraneous matter.
In one embodiment of step (b), suitable techniques that may be used for the removal of solvent include but are not limited to rotational distillation using a device such as Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization), Rotary cone vacuum dryer (RVPD), melt crystallization and the like, optionally under reduced pressure. One specific embodiment of the present application relates to spray-drying or freeze-drying technique, to provide amorphous form of acalabrutinib. Another specific embodiment of the present application relates to using Buchi Rotavapor to provide amorphous form of acalabrutinib. Alternatively, an anti-solvent may be added to the solution of acalabrutinib of step (a) to precipitate amorphous form of acalabrutinib and the precipitated solid may be isolated by any methods known in the art, such as filtration. The suitable anti-solvent may be any organic solvent known in the art in which acalabrutinib is insoluble or slightly soluble.
The resulting solid may be collected by using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used.
The isolated solid may be optionally further dried to afford amorphous form of acalabrutinib. Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80 °C and more specifically less than about 60 °C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer.
The dried product may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the product. Equipment that may be used for particle size reduction includes but not limited to ball mill, roller mill, hammer mill, and jet mill.
It was found that the amorphous acalabrutinib is stable and has excellent physico-chemical properties. The amorphous form of acalabrutinib of the present application may be easily formulated into a pharmaceutical composition along with suitable pharmaceutically acceptable excipients.
Another aspect of the present application provides pharmaceutical composition comprising amorphous form of acalabrutinib with one or more pharmaceutically acceptable excipients.
Ninth aspect of the present application relates to amorphous solid dispersion of acalabrutinib with one or more pharmaceutically acceptable carrier.
Another aspect of the present application relates to amorphous form of Acalabrutinib characterized by a PXRD pattern substantially as illustrated in the pattern of Figure 3 or Figure 4.
Tenth aspect of the present application relates to process for preparation of amorphous solid dispersion of acalabrutinib with one or more pharmaceutically acceptable carrier comprising
(a) dissolving acalabrutinib and one or more pharmaceutically acceptable carrier in suitable solvent or mixture thereof;
(b) isolating amorphous solid dispersion of acalabrutinib;
(c) optionally drying the amorphous solid dispersion of acalabrutinib.
Any crystalline form of acalabrutinib or mixture thereof may be used as starting material for preparing amorphous solid dispersion of acalabrutinib.
In embodiments of step (a), suitable solvents include, but are not limited to ketone solvent such as acetone, ethyl methyl ketone, 2-butanone, methyl isobutyl ketone and the like; ether solvent such as tetrahydrofuran, dioxane and the like; ester solvent such as ethyl acetate, isopropyl acetate and the like; aromatic hydrocarbon solvent such as toluene, xylene and the like; halogenated hydrocarbon solvent such as dichloromethane, chloroform and the like; alcohol solvent such as methanol, ethanol, propanol, isopropanol and the like; mixtures thereof. In one embodiment, the solvent may be an alcohol solvent such as methanol, ethanol, propanol, isopropanol, tert-butanol and the like. In another embodiment, the solvent is methanol. In still another embodiment, the solvent may be a halogenated hydrocarbon solvent such as dichloromethane, chloroform and the like. In yet another embodiment, the solvent may be dichloromethane.
In one embodiment of step (a), dissolving acalabrutinib in suitable solvent may be performed at a temperature of about 5°C to about the boiling point of the solvent. In another embodiment, Acalabrutinib may be dissolved in a suitable solvent at a temperature of about 20 °C to about 30 °C.
In another embodiment of step (a), the solution of acalabrutinib may be filtered to remove any un-dissolved particles or extraneous matter.
The pharmaceutically acceptable carrier may be any suitable carrier reported in the literature. Specifically, the pharmaceutically acceptable carrier includes, but not restricted to methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl cellulose, polysaccharides, heteropolysaccharides (pectins), poloxamers, poloxamines, ethylene vinyl acetates, polyethylene glycols, dextrans, polyvinyl alcohols, propylene glycols, polyvinylacetates, phosphatidylcholines (lecithins), miglyols, polylactic acid, polyhydroxybutyric acid, polyvinylpyrrolidones (PVP), silicon dioxide (syloid), copovidone, methacrylic acid, polymethacrylate, mixtures of two or more thereof, copolymers thereof and derivatives thereof. More specifically, the pharmaceutically acceptable carrier may be selected from a group of hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate, co-povidone, polyvinylpyrrolidones (PVP), Eudragit, syloid and mixtures thereof.
The ratio (weight/weight) of acalabrutinib and pharmaceutically acceptable carrier in amorphous solid dispersion of the present application may be about 5:95, or about 10:90, or about 15:85, or about 20:80, or about 25:75, or about 30:70, or about 35:65, or about 40:60, or about 45:55, or about 50:50 and vice versa.
Isolation of amorphous solid dispersion of acalabrutinib may involve one or more methods including removal of solvent by techniques known in the art e.g. evaporation, distillation, filtration of precipitated solid and the like, cooling, concentrating the reaction mass, and the like. Stirring or other alternate methods such as shaking, agitation, and the like, may also be employed for the isolation. One of the embodiments relate to addition of an anti-solvent to the solution of step (a) to precipitate amorphous solid dispersion of acalabrutinib with one or more pharmaceutically acceptable carrier. Distillation of the solvent may be conducted at atmospheric pressure or above, or under reduced pressures and at a temperatures less than about 120°C, less than about 100°C, less than about 90°C, or any other suitable temperatures. Any temperature and vacuum conditions can be used as long as there is no increase in the impurity levels of the product due to decomposition.
Suitable techniques which can be used for the distillation include, but not limited to, distillation using a rotary evaporator device such as a Buchi Rotavapor, spray drying, agitated thin film drying ("ATFD"), and the like. Specifically, techniques providing a rapid solvent removal may be utilized to provide the desired amorphous solid dispersion of acalabrutinib with one or more pharmaceutically acceptable carrier. More specifically, distillation using a rota-vapor device such as a Buchi Rotavapor or a spray drying technique may be used for the isolation of amorphous solid dispersion of acalabrutinib with one or more pharmaceutically acceptable carrier.
The solid may be collected using techniques such as by scraping, or by shaking the container, or other techniques specific to the equipment used.
The isolated solid may be optionally further dried to afford amorphous solid dispersion of acalabrutinib. Drying may be suitably carried out using any of an air tray dryer, vacuum tray dryer, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, at temperatures less than about 120°C, less than about 100°C, less than about 80°C, or any other suitable temperatures. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 30 minutes to about 24 hours, or longer.
Eleventh aspect of the present application relates to process for preparation of amorphous solid dispersion of acalabrutinib with one or more pharmaceutically acceptable carrier comprising mixing amorphous acalabrutinib with one or more pharmaceutically acceptable carrier.
The mixing may be carried out by any known methods in the art. Specifically, the mixing may be carried out by blending. Blending of amorphous Acalabrutinib and one or more pharmaceutically acceptable carrier may be carried out in a suitable equipment known in the art. Specifically, blending may be carried out in a V-blender, double cone blender, rotatory cone vacuum drier (RCVD). The blending may further comprise unit operations such as Rapid Mix Granulation (RMG), milling, co-milling, grinding and the like. Alternatively, the mixing of amorphous Acalabrutinib with one or more pharmaceutically acceptable carrier may be carried out by physical blending. Physical blending may be carried out by blending amorphous Acalabrutinib with one or more pharmaceutically acceptable carrier in a petri-dish or mortar pestle.
The obtained amorphous solid dispersion of Acalabrutinib may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the amorphous solid dispersions. Equipment that may be used for particle size reduction include, but not limited to, ball, roller, and hammer mills, jet mills and the like.
It was found that the amorphous solid dispersion of Acalabrutinib of the present application is stable and has excellent physico-chemical properties. The amorphous solid dispersion of Acalabrutinib of the present application may be easily formulated into a pharmaceutical composition comprising Acalabrutinib along with one or more pharmaceutically acceptable excipients.
Twelfth aspect of the present application relates to a pharmaceutical composition comprising amorphous solid dispersion of acalabrutinib and one or more pharmaceutically acceptable excipient.
Pharmaceutical composition comprising amorphous acalabrutinib/ amorphous solid dispersion of acalabrutinib of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Pharmaceutical composition may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations; and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.

DEFINITION
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms "about," "general, ‘generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms “comprising” and “comprises” mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
The term “optional” or “optionally” is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner. The following definitions are used in connection with the present disclosure unless the context indicates otherwise.
“Halogen” is defined as non-metallic elements found in group VII of the periodic table and is selected from fluorine, bromine, chlorine and iodine.
“Hydroxy” is defined as the group –OH.
“Alkyl group having 1-6 carbon atoms” is defined as straight or branched chain alkyl having 1-6 carbon atoms. Examples may be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like.
“Aryl group having 6-12 carbon atoms” is defined as monocyclic, bicyclic, and tricyclic ring systems having a total of six to twelve ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term "aryl group having 6-12 carbon atoms" also refers to “heteroaryl” ring systems. The term “heteroaryl” refers to monocyclic, bicyclic, and tricyclic ring systems having a total of six to twelve ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members.
“Alkoxy having 1-6 carbon atoms” is defined as straight or branched chain alkyl group, attached to the principal carbon chain through oxygen. Examples may be methoxy, ethoxy, isopropoxy, tert-butoxy and the like.
“Aryl-alkyl group having 7-12 carbon atoms” is defined as an aryl group, as previously defined, attached to the principal carbon chain through an alkyl group, as previously defined. “Substitution” on an “Aryl-alkyl group having 7-12 carbon atoms” is defined by a substitution over the aryl group. Examples may be benzyl, 4-methoxy-benzyl and the like.
Amino protecting group is defined as any amino protecting group as known in Greene et al., Protecting groups in organic chemistry, Third Edition, 1999. Examples include benzyloxycarbonyl (Cbz) and tert-Butyloxycarbonyl (Boc), acetyl and the like. Specifically, the amino protecting group may be benzyloxycarbonyl (Cbz).
Leaving group is defined as any group known in the art. Examples include halide, triflate, sulfonate, mesylate, tosylate and the like.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.

EXAMPLES
Example 1: Preparation of methyl 4-(amino(3-chloropyrazin-2-yl)methyl)-benzoate (VIIa)
To a solution of methyl (E)-4-((benzhydrylimino)methyl)benzoate (IXa) (40 g) in tetrahydrofuran (400 mL) was cooled to 0 °C and potassium bis(trimethylsilyl)amide (146 mL, 1 M) was added to the reaction mass at the same temperature. The reaction mass was stirred at this temperature for 30 minutes at 0 °C. A solution of 2,3-dichloropyrazine (VIIIa) (15.2 mL) in tetrahydrofuran (40 mL) was added to the reaction mass in a drop wise manner for 30 minutes. The reaction mass was further stirred for 1 hour at 25-30 °C and poured in an ice-cold water (300 mL). The reaction mass was extracted with ethyl acetate (300 mL). The organic layer was evaporated to give crude product. Ethyl acetate (1 L) and dilute hydrochloric acid (3 M, 1 L) was added to the crude product and stirred for 30 minutes. The phases were separated and the organic layer was extracted with dilute hydrochloric acid (3 M, 2 × 250 mL). The aqueous layer was washed with ethyl acetate (200 mL) and alkalified with solid sodium carbonate to pH=8. The aqueous layer was then extracted with ethyl acetate (3 × 300 mL) and the combined organic layers were dried and concentrated under vacuum to provide title compound.
Yield: 28 g; Purity (by HPLC): 89.80%
Example 2: Preparation of benzyl (2S)-2-(((3-chloropyrazin-2-yl)(4-(methoxycarbonyl)phenyl)methyl)carbamoyl)pyrrolidine-1-carboxylate (VIa)
To a pre-cooled solution of methyl 4-(amino(3-chloropyrazin-2-yl)methyl)benzoate (VIIa) (5.1 g) in dry tetrahydrofuran (51 mL) at 0 °C was added N-benzyloxycarbonyl-L-proline (Xa) (5.5 g), diisopropylethyl amine (8.0 mL) and HATU (8.39 g) at the same temperature. The reaction mass was stirred for 1 hour at 25-30 °C. The reaction mass was poured in ice-cold water (100 mL) and extracted with ethyl acetate (2 × 100 mL). Combined organic layers were washed with brine solution, separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The product was purified by silica gel chromatography (ethyl acetate: hexane = 1:1) to provide the title compound.
Yield: 6.5 g; Purity by HPLC: 93.02%
Example 3: Preparation of 4-(((S)-1-((benzyloxy)carbonyl)pyrrolidine-2-carboxamido)(3-chloropyrazin-2-yl)methyl)benzoic acid (Va)
To a 0 °C pre-cooled solution of benzyl (2S)-2-(((3-chloropyrazin-2-yl)(4-(methoxycarbonyl)phenyl)methyl)carbamoyl)pyrrolidine-1-carboxylate (VIa) (2.0 g) in tetrahydrofuran (15 mL) was added a solution of lithium hydroxide (496 mg) in water (15 mL). The reaction mass was then stirred for 5 hour at 25-30 °C. The pH of the reaction mixture was adjusted to 3 with dilute hydrochloric acid (3 M) and extracted with ethyl acetate (2 × 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, evaporated under reduced pressure to afford the desired compound.
Yield: 1.80 g; Purity by HPLC: 95.99%
Example 4: Preparation of benzyl (S)-2-(8-chloro-1-(4-(pyridin-2-ylcarba-moyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (IVa)
A Solution of 4-(((S)-1-((benzyloxy)carbonyl)pyrrolidine-2-carboxamido)(3-chloropyrazin-2-yl)methyl)benzoic acid (Va) (1.8 g) in dichloromethane (20 mL) was cooled to 0 °C and dimethyl formaminde (26.6 mg), oxalyl chloride (1.56 mL) were added. The reaction mass was stirred for 24 hours at 25-30 °C. Volatiles were evaporated from the reaction mass under reduced pressure and the obtained residue was diluted with dichloromethane (15 mL). A solution of 2-amino pyridine (1.02 g) in dichloromethane (15 mL) was added to the above solution at 0° C and the resulting reaction mass was stirred for 24 hours at 25-30 °C. The reaction mass was quenched with aqueous saturated solution of sodium bicarbonate (50 mL) and extracted with dichloromethane (2 ×100 mL). The combined organic layers were evaporated under reduced pressure to get crude product. The crude product was washed with water to remove the excess 2-amino pyridine. The obtained product was purified by silica gel chromatography (ethyl acetate: hexane = 7:3) to provide a gummy material and which was agitated with water to obtain a pale yellow suspension. The precipitated solid was filtered and dried under reduced pressure at 25-30 °C to afford the title compound.
Yield: 650 mg; Purity by HPLC: 94.35%
Example 5: Process for the preparation of benzyl (S)-2-(8-chloro-1-(4-(methoxycarbonylphenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (XIIa)
To a pre-cooled solution of benzyl (2S)-2-(((3-chloropyrazin-2-yl)(4-(methoxycarbonyl)-phenyl)methyl)carbamoyl)pyrrolidine-1-carboxylate (VIa) (200 mg) in dry dichloromethane (5 mL); pyridine (187 mg) followed by phosphorous oxychloride (287.2 mg) was added at 0 °C under nitrogen atmosphere and the reaction mass was allowed to stir for 24 hours at 25-30 °C. A second lot of pyridine (187 mg) followed by phosphorous oxychloride (287.2 mg) was added to the reaction mass and allowed to stir further for 24 hours at 25-30 °C. The reaction mass was poured in to saturated sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (2 × 10 mL). Combined organic layers were concentrated under reduced pressure. The product was purified by silica gel chromatography (ethyl acetate: hexane = 1:1) to provide the desired compound.
Yield: 40 mg
Example 6: Process for the preparation of benzyl (S)-2-(8-chloro-1-(4-(methoxycarbonyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (XIIa)
To a pre-cooled solution of benzyl (2S)-2-(((3-chloropyrazin-2-yl)(4-(methoxycarbonyl)phenyl)-methyl)carbamoyl)pyrrolidine-1-carboxylate (VIa) (500 mg) in dry dichloromethane (5 mL); a solution of dimethyl formamide (7.2 mg) in dichloromethane (5 mL) followed by oxalyl chloride (0.25 mL) was added under nitrogen atmosphere at 0 °C and resulting reaction mass was allowed to stir for 24 hours at 25-30 °C. The reaction mixture was poured in to saturated sodium bicarbonate solution (10 mL) and extracted with dichloromethane (2 × 50 mL). Organic layer was concentrated under reduced pressure to get the crude product which was taken as such to the next step without any further purification.
Yield: 430 mg
Example 7: Process for the preparation of (S)-4-(3-(1-((benzyloxy)carbonyl)-pyrrolidin-2-yl)-8-chloroimidazo[1,5-a]pyrazin-1-yl)benzoic acid (XIIIa)
To a pre-cooled solution of benzyl (S)-2-(8-chloro-1-(4-(methoxycarbonyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (XIIa) (100 mg) in tetrahydrofuran (3 mL) and water (3 mL) was added lithium hydroxide (25.6 mg) at 0 °C and allowed to stir for 3 hours at 25-30 °C. The reaction mass was acidified with dilute hydrochloric acid (1 M, 3 mL) to pH=4 and extracted with ethyl acetate (2 × 50 mL). Combined organic layers were dried over anhydrous sodium sulfate, evaporated under reduced pressure to get crude title compound, which was then taken up to the next step without any further purification
Yield: 90 mg
Example 8: Process for the preparation of benzyl (S)-2-(8-chloro-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (IVa)
To a solution of (S)-4-(3-(1-((benzyloxy)carbonyl)pyrrolidin-2-yl)-8-chloroimidazo[1,5-a]pyrazin-1-yl)benzoic acid (XIIIa) (40 mg) in dichloromethane (1.2 mL) under nitrogen atmosphere at 0 °C was added a solution of dimethyl formamide (0.62 mg) in dichloromethane (0.5 mL) followed by a solution of oxalyl chloride (53.3 mg) in dichloromethane (0.5 mL) and the resulting reaction mass was allowed to stir for 20 hours at 25-30 °C. Volatiles were evaporated from the reaction mass under reduced pressure. The residue obtained was dissolved in dichloromethane (2 mL) and added a solution of 2- amino pyridine (23.7 mg) in dichloromethane (2 mL) was added at 0 °C and allowed to stir for 24 hours at 25-30 °C. The reaction mixture was concentrated under vacuum. The residue, thus obtained, was purified by silica gel chromatography (ethyl acetate: hexane = 3:2) to afford the desired compound.
Yield: 25.9 mg
Example 9: Preparation of benzyl (S)-2-(8-((4-methoxybenzyl)amino)-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (IIIa)
To a solution of benzyl (S)-2-(8-chloro-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (IVa) (300 mg) in 1, 4-dioxane (3 mL) was added p-methoxybenzylamine (447 mg) at 25-30 °C. The resulting reaction mass was stirred for 48 hours at 110 °C. The reaction mass was concentrated under vacuum. The residue, obtained thus, was then purified by silica gel chromatography (ethyl acetate: hexane = 3:2). The gummy material, obtained by evaporation of required solvent fractions, was agitated in water to give a pale yellow suspension. The solid was filtered and dried under reduced vacuum to obtain the title compound.
Yield: 300 mg; Purity by HPLC: 95.34%
Example 10: Preparation of benzyl-(S)-2-(8-((2,4-dimethoxybenzyl)amino)-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (IIIc)
To a solution of benzyl (S)-2-(8-chloro-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (IVa) (200 mg) in 1, 4-dioxane (3 mL) was added 2,4-dimethoxybenzylamine (363 mg) at 25-30 °C. The resulting reaction mass was stirred for 48 hours at 110 °C. The reaction mass was concentrated under vacuum. The residue, obtained thus, was then purified by silica gel chromatography (ethyl acetate: hexane = 3:2) to obtain the title compound.
Yield: 196 mg; Purity by HPLC: 86.43%
Example 11: Preparation of (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (II)
To a solution of benzyl (S)-2-(8-((4-methoxybenzyl)amino)-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (IIIa) (100 mg) in 1,2- dichloroethane (2 mL) under nitrogen atmosphere triflic acid (230 mg) was added and the reaction mass was stirred for 16 hours at 90 °C. The reaction mass was quenched with water (20 mL) and extracted with ethyl acetate (2 × 10 mL). Aqueous layer was alkalified (pH ~ 9) with saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (2 × 10 mL). Combined organic layers were concentrated under reduced pressure to provide crude product. The obtained crude product was stirred in a mixture of dichloromethane (20 mL) and an aqueous solution of sodium hydroxide (3 M, 5 mL) for 30 minutes. Organic layer was separated and evaporated under reduced pressure to get the crude free base. The crude product was purified by preparative thin layer chromatography using 5 % methanol in dichloromethane as eluent to obtain the pure title compound.
Yield: 35 mg; Purity by HPLC: 98.10%

Example 12: Preparation of (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (II)
To a stirred solution of benzyl (S)-2-(8-((4-methoxybenzyl)amino)-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (IIIa) (200 mg) in water (5.5 mL) and 1,2- dichloroethane (2 mL), triflic acid (460 mg) was added and the reaction mass was stirred for 16 hours at 90 °C. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 × 10 mL). Aqueous layer was alkalified (pH ~ 9) with saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (2 × 10 mL). Combined organic layers were concentrated under reduced pressure to provide crude product. The obtained crude product was stirred in a mixture of dichloromethane (20 mL) and aqueous solution of sodium hydroxide (3 M, 5 mL) for 30 minutes. Organic layer was then separated and evaporated under reduced pressure to provide the crude title compound and which was taken forward to the next step without further purification.
Yield: 90 mg
Example 13: Preparation of (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (II)
A solution of benzyl-(S)-2-(8-((2,4-dimethoxybenzyl)amino)-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (IIIc) (100 mg) in trifluoroacetic acid (0.9 mL) and water (0.1 mL) under nitrogen atmosphere was stirred for 24 hours at 100 °C. The reaction mass was quenched with water (20 mL) and extracted with ethyl acetate (2 × 10 mL). Aqueous layer was alkalified (pH ~ 9) with saturated aqueous sodium hydroxide (3M, 2 mL) and extracted with ethyl acetate (2 × 10 mL). Combined organic layers were concentrated under reduced pressure to provide crude product.
Yield: 45 mg; Purity by HPLC: 93.49%
Example 14: Preparation of 4-{8-amino-3-[(2S)-1-(but-2-ynoyl)pyrrolidin-2-yl]imidazo[1,5-a]pyrazin-1-yl}-N-(pyridin-2-yl)benzamide (I)
To a stirred solution of (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(pyridin-2-yl)benzamide (II) (90 mg) in dichloromethane (3 mL); triethylamine (68.5 mg), 1-HATU (102.8 mg) and 2-butynoic acid (19 mg) were added and the reaction mass was stirred for 16 hours. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (2 × 10 mL). The organic layer was separated and evaporated under reduced pressure. The crude product, obtained thus, was purified by preparative thin-layer chromatography using 2 % methanol in dichloromethane as eluent to obtain the title compound.
Yield: 48.37 mg; Purity by HPLC: 98.28%
Example 15: Preparation of amorphous form of acalabrutinib
Acalabrutinib (500 mg) was dissolved in acetone (20 mL) at 30 °C. The solution was filtered to make it particle-free. The solvent was evaporated under vacuum at 50 °C to provide the desired compound.
Example 16: Preparation of amorphous form of acalabrutinib
Acalabrutinib (500 mg) was dissolved in dichloromethane (20 mL) at 30 °C. The solution was filtered to make it particle-free. The solvent was evaporated under vacuum at 45 °C to provide the desired compound.
Example 17: Preparation of amorphous acalabrutinib
Acalabrutinib (500 mg) was dissolved in a mixture of methanol-dichloromethane (10%, 20 mL) at 30 °C. The solution was filtered to make it particle-free. The filtrate was evaporated vacuum at 45 °C to provide the title compound.
Example 18: Preparation of amorphous solid dispersion of acalabrutinib and syloid (1:1 w/w)
Amorphous acalabrutinib (150 mg) and syloid (150 mg) was grinded in a mortar-pestle for 5 minutes to provide the title compound.
Example 19: Preparation of amorphous solid dispersion of acalabrutinib and co-povidone (1:1 w/w)
Acalabrutinib (0.5 g) and co-povidone (0.5 g) was dissolved in dichloromethane (25 mL) at 28 °C. The solution was filtered to make it particle-free. The solvent was evaporated in a rotavapor under the following conditions to provide the desired compound
RPM: 200, Temperature: 45 °C, Vacuum Set Point: 2 torr.
Example 20: Preparation of amorphous solid dispersion of Acalabrutinib and PVPK 90 (1:1 w/w)
Acalabrutinib (0.5 g) and PVPK 90 (0.5 g) was mixed with dichloromethane (25 mL) at 28 °C and stirred for 5 minutes to provide a solution. The solution was filtered to make it particle-free. The filtrate was evaporated in a rotavapor under the following conditions to afford the title compound.
RPM: 200, Temperature: 45 °C, Vacuum Set Point: 2 torr.
Example 21: Preparation of amorphous solid dispersion of acalabrutinib and hydroxyl propyl cellulose (1:1 w/w)
Acalabrutinib (0.5 g) and hydroxyl propyl cellulose (0.5 g) was mixed with dichloromethane (40 mL) at 28 °C and stirred for 5 minutes to provide a solution. The solution was filtered to make it particle-free. The filtrate was evaporated in a rotavapor under the following conditions to afford the title compound
RPM: 200, Temperature: 45 °C, Vacuum Set Point: 2 torr.
Example 22: Preparation of amorphous solid dispersion of acalabrutinib and hydroxyl propyl methyl cellulose (1:1 w/w)
Acalabrutinib (0.5 g) and hydroxyl propyl methyl cellulose 90 (0.5 g) was mixed with dichloromethane (40 mL) at 28 °C and stirred for 5 minutes to provide a solution. The solution was filtered to make it particle-free. The filtrate was evaporated in a rotavapor under the following conditions to afford the title compound
RPM: 200, Temperature: 45 °C, Vacuum Set Point: 2 torr.
Example 23: Preparation of amorphous solid dispersion of acalabrutinib, co-povidone and syloid (1:1:1 w/w)
Amorphous solid dispersion of acalabrutinib and co-povidone (200 mg), as prepared in Example 5, was mixed with syloid (100 mg) in a mortar pestle and grinded for 10 minutes to provide the title compound.

,CLAIMS:We claim:
1. A process for the preparation of acalabrutinib of formula (I) or pharmaceutically acceptable salts thereof, comprising the steps of:
a) Reacting compound of formula (VII) with compound of formula (X) to provide compound of formula (VI)
;
b) Hydrolysis of compound of formula (VI) to provide compound of formula (V)
;
c) Conversion of compound of formula (V) to compound of formula (IV)
;
d) Reacting compound of formula (IV) with compound of formula (XI) to provide compound of formula (III)
;
e) Conversion of compound of formula (III) to compound of formula (II)
;
f) Reaction of compound of formula (II) with 2-butynoic acid or 2-butynoyl chloride to provide acalabrutinib of formula (I) or a pharmaceutically acceptable salts thereof
;
wherein, R1 is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms; R2 and R3 are independently hydrogen, a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, optionally substituted with an alkyl group having 1-6 carbon atoms or an aryl group having 6-12 carbon atoms or an alkoxy group having 1-6 carbon atoms, or halogen, an aryl-alkyl group having 7-12 carbon atoms optionally substituted with an alkyl group having 1-6 carbon atoms or an aryl group having 6-12 carbon atoms or an alkoxy group having 1-6 carbon atoms or halogen, trialkyl silyl group having 3-12 carbon atoms and an amino protecting group; X is a leaving group; P is an amino protecting group.
2. The process of claim 1, wherein step a) is carried out in presence of a coupling agent and base.
3. The process of claim 2, wherein coupling agent is HATU and base is DIPEA.
4. The process of claim 1, wherein step c) is carried out in presence of a condensation reagent.
5. The process of claim 4, wherein the condensation reagent is oxalyl chloride.
6. A process for the preparation of compound of formula (IV), comprising steps of:
a) Conversion of compound of formula (VI) to a compound of formula (XII) in presence of a suitable reagent
;
b) Hydrolysis of compound of formula (XII) to a compound of formula (XIII)
;
c) Conversion of compound of formula (XIII) to compound of formula (IV) comprising reacting compound of formula (XIII) with amino pyridine in presence of a suitable reagent

wherein, R1 is a linear or branched alkyl group having 1-6 carbon atoms, an aryl group having 6-12 carbon atoms, an aryl-alkyl group having 7-12 carbon atoms; P is an amino protecting group and X is a leaving group;
7. The process of claim 6, further comprising conversion of compound of formula (IV) to acalabrutinib.
8. The process of claim 6, wherein suitable reagent of step a) is oxalyl chloride or phosphorous oxychloride.