Improved process for the preparation of 4-l8-amino-3-r -l-(but-2-vnoyl)nyrrolidin-2-yll

imidazofl ,5-alpyrazin- 1 -yl > }-N-(pyridine-2-yl ibenzamide

Related Application:

This application claims the benefit of priority of our Indian patent application numbers 201941018549 filed on 09 May 2019 and 201941032599 12 August 2019 which is incorporated herein by reference.

Field of the Invention:

The present invention relates to improved process for the preparation of 4-{8-amino-3- [(2S)- 1 -(but-2-ynoyl)pyrrolidin-2-yl]imidazo[ 1 ,5-a]pyrazin- 1 -yl) } -N-(pyridine-2-yl)benzamide, which is referred to as Acalabrutinib.

The present invention relates to acid addition salts of Acalabmtinib intermediate compound of general formula-4, which is represented by the following structural formula

Formula-4

and process for its preparation thereof.

The present invention also relates to Acalabrutinib ethylene glycol and process for its preparation thereof.

Background of the Invention:

Acalabrutinib is an orally bioavailable and a small chiral molecule inhibiter of Bruton tyrosine kinase (BTK). Acalabrutinib is classified as BCS class 2 that exhibits BCS class 1 characteristics under in vivo conditions.

Acalabrutinib is approved by USFDA as CALQUENCE capsule for oral administration for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Acalabrutinib is chemically known as 4-{8-amino-3-[(2S)-l-(but-2-ynoyl)pyrrolidin-2-yl] imidazo[l,5-a]pyrazin-l-yl)}-N-(pyridine-2-yl)benzamide represented by the following structural formula- 1.

U.S patent 7459554 B2 discloses Acalabrutinib or a pharmaceutically acceptable salt.

U.S patent 9290504 B2 discloses Acalabrutinib and process for the preparation of Acalabrutinib thereof.

International PCT publication W02017/002095 A1 (herein after referred as WO‘095) describes various crystalline forms I, II, III, IV, V, VI, VII, VIII and amorphous forms of Acalabrutinib.

WO ‘095 also describes various salt forms fumarate, maleate, phosphate, L-tartrate, citrate, oxalate and sulfate of Acalabrutinib.

International PCT publication of WO2018/064797 A1 describes crystalline forms 1, 2, 3 and 4 of Acalabrutinib.

International PCT publication W02013/010868 A1 discloses a process for the preparation of Acalabrutinib from (S)-benzyl 2-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl) pyrrolidine- 1 -carboxylate by Suzuki coupling with 4-(pyridin-2-yl-aminocarbonyl)benzene boronic acid followed by deprotection to provide (S)-4-(8-Amino-3-(pyrrolidin-2-yl)imidazo[l,5 -a]pyrazin-l-yl)-N-(pyridin-2-yl)benzamide then coupling with 2-butynoic acid to provide Acalabrutinib is low yield.

Thus, there is a need for development of a process for the preparation of Acalabrutinib, which is efficient, economical and feasible at commercial scale. Brief description of the Invention:

In one aspect, the present invention provides an improved process for the preparation of Acalabrutinib of formula- 1.

Formula- 1

In another aspect, the present invention provides acid addition salts of formula-I.

Wherein, R is selected from amino protecting group with the proviso that amino protecting group is not tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz).

In another aspect, the present invention provides a process for the preparation of Acalabrutinib of formula- 1 comprising aminating compound of formula-2 with aminating agent in sodium iodide to provide compound of formula-3 and converting compound of formula-3 to Acalabrutinib of formula- 1.

Formula-2 Formula-3

In another aspect, the present invention provides acid addition salt of compound of formula-4. Acid

Wherein, R is selected from amino protecting group.

Brief description of Drawings:

Figure-1: Illustrates the PXRD pattern of crystalline form-M of compound of formula-7

Figure-2: Illustrates the PXRD pattern of crystalline form-S of Acalabrutinib ethylene glycol Figure-3: Illustrates the PXRD pattern of crystalline form-M of compound of formula-4b

Figure-4: Illustrates the PXRD pattern of crystalline form-S of (S)-benzyl 2-(8-amino-l-bromo imidazo[l,5-a]pyrazin-3-yl)pyrrolidine-l-carboxylate obtained according to example- 12

Figure-5: Illustrates the PXRD pattern of amorphous Acalabrutinib

Figure-6: Illustrates the PXRD pattern of crystalline form-M of compound of formula-7

Figure-7: Illustrates the PXRD pattern of crystalline Form-S 1 of Acalabrutinib

Figure-8: Illustrates the PXRD pattern of crystalline Form-S2 of Acalabrutinib

Figure-9: Illustrates the PXRD pattern of crystalline Form-S of Acalabrutinib

Detailed description of the Invention:

The term“suitable solvent” used in the present invention refers to“hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, n-pentane, cycloheptane, methylcyclohexane, m-, o-, or p-xylene and the like;“ether solvents” such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1 ,2-dimethoxy ethane and the like;“ester solvents” such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like;“polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like;“chloro solvents” such as dichlorome thane, dichloroethane, chloroform, carbontetrachloride and the like;“ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutylketone, acetyl acetone and the like;“nitrile solvents” such as acetonitrile, propionitrile, isobutyronitrile and the like;“alcoholic solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2- nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 1,2- ethoxy ethanol, diethylene glycol, 1,2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like;“polar solvents” such as water or mixtures thereof.

The“suitable base” as used in the present invention is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like;“alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like;“alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; ammonia; and organic bases such as“alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like; triethylamine, methyl amine, ethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo(4.3.0)non-5-ene (DBN), lithium diisopropylamide (LDA), n-butyllithium, tribenzylamine, isopropylamine, diisopropylamine, diisopropylethylamine, N-methyl-2-pyrrolidone (NMP), N-methylmorpholine, N-ethylmorpholine, piperidine, 4-dimethylaminopyridine (DMAP), morpholine, pyridine, 2,6- lutidine, 2,4,6-collidine, imidazole, 1 -methyl imidazole, 1,2,4-triazole, l,4-diazabicyclo[2.2.2] octane (DABCO) or mixtures thereof.

The “suitable acid” is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid or phosphoric acid; and organic acids such as oxalic acid, maleic acid, malonic acid, tartaric acid, fumaric acid, citric acid, malic acid, succinic acid, mandelic acid, lactic acid, acetic acid, propionic acid, 2-chloromandelate, paratoluenesulfonic acid, ethane- 1 ,2-disulfonic acid, camphorsulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-2-sulfonic acid, benzene sulfonic acid, adipic acid, glutaric acid, glutamic acid, palmitic acid or aspartic acid.

The first embodiment, of the present invention provides a process for the preparation of Acalabrutinib of formula- 1, which comprises:

a) aminating compound of formula-2 with a suitable aminating agent in the presence of sodium iodide to provide compound of formula-3,

Formula-2 Formula-3

Wherein, R is selected from amino protecting group as defined above b) converting compound of formula-3 to provide Acalabrutinib of formula- 1.

In the process of the first embodiment, the suitable aminating agent used in step-a) is selected from the group consisting of ammonia, formamide, ammonia gas, ammonium carbamate, ammonium formate, ammonium phosphate, ammonium acetate, ammonium fluoride, ammonium bromide, ammonium chloride, ammonium iodide, ammonium iodate, ammonium carbonate, ammonium citrate, ammonium chromate, ammonium dichromate, ammonium hydroxide, ammonium lactate, ammonium molybdate, ammonium nitrate, ammonium oxalate, ammonium sulfate, ammonium sulfide, ammonium tartrate, ammonium triflate, ammonium thiocyanate, ammonium dihydrogen phosphate, urea, methyl carbamate, ethyl carbamate, propyl carbamate or t-butyl carbamate and alkyl or aryl amines.

In the process of the first embodiment, wherein sodium iodide used in step-a) is in the amount of less than 1 equivalent, or 1 equivalent, or 1 to 4.0 equivalents, with respect to the compound of formula-2.

In the process of the first embodiment, the suitable solvent is selected from alcohol solvent, ester solvents, chloro solvents, nitrile solvents, ether solvents, ketone solvents, polar aprotic solvents, hydrocarbon solvents, water or mixture thereof.

According to the prior art processes, amination of compound of formula-2 is carried out under high pressure and high temperature conditions i.e. more than 100°C. These conditions are not recommended on commercial scale. Further, the said prior art processes provided the compound of formula-3 with low yield and high level of impurities. In order to overcome these problems associated with the prior art processes, inventors of the present invention have altered the process. The present invention involves process for the preparation of compound of formula-3 comprising reacting compound of general formula-2 in the presence of suitable ammonia source in sodium iodide. By using sodium iodide, inventors of the present invention were able to reduce the high pressure and high temperature conditions. Further compound of formula-3 is obtained with good yield and purity.

In the process of the first embodiment, the compound of formula-3 obtained according to the present invention is having a purity of about 97% by HPLC or purity of about 99.0% by HPLC or purity of about 99.5% or purity of about 99.9% by HPLC.

In the process of the first embodiment, a process for the preparation of Acalabrutinib of formula- 1 further comprising:

a) reacting the compound of formula-3 or its acid addition salts compound of formula-4

with the compound of formula-5

Formula-5

Re and Rd are each independently H or Ci- ₆ alkyl; or Re and Rd, together with the oxygen atoms to which they are attached and the boron atom to which the oxygen atoms are attached, form a 5 to 6-membered heterocyclic ring, which is optionally substituted with 1, 2, 3 or 4 Ci - ₄ alkyl groups

in the presence of palladium catalyst in a suitable base in a suitable solvent to provide compound of formula-6,

b) treating the compound of formula-6 with a suitable acid or Lewis’ acid in a suitable solvent to provide compound of formula-7,

c) optionally purifying the compound of formula-7 using a suitable solvent to provide pure compound of frmula-7,

d) reacting the compound of formula-7 with 2-butynoic acid in the presence of suitable condensing agent in the presence or absence of suitable base in a suitable solvent to provide Acalabrutinib of formula- 1 ,

e) treating Acalabrutinib of formula- 1 with ethylene glycol in a suitable solvent to provide Acalabrutinib ethylene glycol,

f) treating Acalabrutinib ethylene glycol with a suitable solvent to provide Acalabrutinib of formula- 1.

In the process of the first embodiment, the suitable palladium catalyst used in step-a) is selected from l,r-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (Pd(dppf)Cl ₂ ), tetra kis(triphenylphosphine) palladium (0) (Pd(PPli ₃ ) ₄ ), palladium(II)acetate (Pd(OAc) ₂ ), palladium (II) chloride (PdCb), bis(benzonitrile)palladium(II)dichloride (Pd(PhCN) ₂ Cl ₂ ), bis(triphenyl phosphine) palladium (II) dichloride (Pd(PPli ₃ ) ₂ Cl ₂ ), and allylpalladium(II)chloride dimer (PdCl(C ₃ H ₅ )] ₂ ); the suitable base is selected from organic base or inorganic base;

the suitable Lewi’s acid used in step-b) is selected from aluminium chloride, aluminium bromide, Iron chloride, tin tetrachloride, tintetrabromide, stannous chloride, titanium tetra chloride, calcium chloride and zinc chloride, lithium tetrafluoroborate (L1BF ₄ ) or trifluoroborate; the suitable acid is selected from organic acid or inorganic acid;

the suitable condensing agent used in step-d) is selected from phosphonium reagents such as benzotriazol-l-yloxy-tris(dimethylamino)-phosphoniumhexafluo rophosphate (BOP), benzo triazol- 1 -yloxy-tripyrrolidino-phosphoniumhexafluorophosphate (PyBOP) , bromo-tripyrrolidino phosphoniumhexafluorophosphate (PyBrOP) and the like; immonium reagents such as benzo triazol- 1 -yloxy-N,N-dimethyl-methaniminiumhexachloroantimonate (B OMI) , 5 -( 1 H-benzotri azol-l-yloxy)-3,4-dihydro-l-methyl-2H-pyrroliumhexachloroant imonate (BDMP) and the like; ammonium/uronium reagents such as such as l-[bis(dimethylamino)methylene]-lH-l,2,3- triazolo[4,5-b]pyridinium-3-oxid-hexafluorophosphate (HATU), 3-[bis(dimethyl-amino)methyl iumyl] -3H-benzotriazol- 1 -oxid-hexafluorophosphate (HBTU), 1 - [bis(dimethyl-amino)methylen] -5-chlorobenzotriazolium-3-oxid-hexafluorophosphate (HCTU) and the like; imidazolium reagents such as carbonyldiimidazole (CDI), 2-chloro-l, 3-dimethyl- lH-benzimidazoliumhexa fluorophosphate (CBMI), 2-(benzotriazol- l-yl)oxy- 1 ,3-dimethylimidazolidiniumhexafluoro phosphate (BOI) and the like; pyridinium reagents such as 2-bromo- 1 -methylpyridiniumiodide (BMPI), 2-chloro- 1 -methylpyridinium iodide (CMPI) and the like with the proviso that the condensing agent is not carbodiimides;

the suitable solvent used in step-a) to step-f) is selected from alcohol solvents, ester solvents, hydrocarbon solvents, chloro solvents, ketone solvents, ether solvents, nitrile solvents, polar aprotic solvents and water or mixture thereof.

In the process for the first embodiment, wherein Acalabrutinib obtained according to the present invention is amorphous in nature.

The second embodiment, of the present invention provides (S)-benzyl 2-(8-amino-l- bromoimidazo[l,5-a]pyrazin-3-yl)pyrrolidine-l-carboxylate tartrate of compound of formula-4a.

In the second embodiment, the compound of formula-4a obtained according to the present invention is useful in the preparation of Acalabrutinib.

The third embodiment, of the present invention provides (S)-benzyl 2-(8-amino-l-bromo imidazo[l,5-a]pyrazin-3-yl)pyrrolidine-l-carboxylate oxalate of compound of formula-4b.

In the third embodiment, the compound of formula-4b obtained according to the present invention is useful in the preparation of Acalabrutinib.

The fourth embodiment, of the present invention provides a crystalline form of (S)-benzyl 2-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl)pyrrolidine-l-c arboxylate oxalate of formula-4b, which is herein after designated as form-M.

The crystalline form-M of (S)-benzyl 2-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl) pyrrolidine- 1 -carboxylate oxalate obtained according to the present invention is characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure-3.

The fifth embodiment, of the present invention provides a process for the preparation of crystalline form-M of (S)-benzyl 2-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl)pyrrolidine-l- carboxylate oxalate of formula-4b, comprising:

a) treating (S)-benzyl 2-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl)pyrrolidine-l- carboxylate with oxalic acid in a suitable solvent,

b) isolating crystalline form-M of (S)-benzyl 2-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3- yl)pyrrolidine- 1 -carboxylate oxalate of formula-4b.

In the process of the fifth embodiment, the suitable solvent used in step-a) is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

In the process of the fifth embodiment, isolating compound of formula-4b is carried out by any of the methods known in the art or isolation 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, or other techniques specific to the equipment used and the like, and optionally washing with a solvent. The sixth embodiment, of the present invention provides a process for the preparation of Acalabrutinib of formula- 1 , comprising:

a) treating the compound of formula-3

Formula-3

wherein R is selected from amino protecting group as described above

with a suitable acid in a suitable solvent to provide its corresponding acid addition salt of formula-4

Formula-4

b) treating the compound of formula-4 with a suitable base in a suitable solvent to provide compound of formula-3,

c) converting compound of formula-3 to Acalabrutinib of formula- 1.

In the process of the sixth embodiment, the suitable acid used in step-a) is selected from organic acid or inorganic acid; the suitable solvent used in step-a) and step-b) is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof; the suitable base used in step-b) is selected from organic base or inorganic base.

According to prior art process, compound of formua-3 is obtained with a purity of less than 90% and contaminated with impurities.

Inventors of the present invention were able to prepare the pure compound of formula-3 with a purity of greater than 99.9%. This is achieved by treating compound of formula-3 with a suitable acid to provide its corresponding acid addition salt of compound of formula-4 and further treating acid addition salt of compound of formula-4 with a suitable base selected from organic base or inorganic base to provide pure compound of formula-3.

In the process of the sixth embodiment, the compound of formula-3 obtained according to the present invention is having a purity of about 97% by HPLC or purity of about 99.0% by HPLC or purity of about 99.5% or purity of about 99.9% by HPLC.

In the process of the sixth embodiment, the compound of formula-3 obtained according to the present invention is having“Hydroxy impurity” less than about 0.1%; less than about 0.01% as measured by HPLC.

Hydroxy Impurity

In the process of the sixth embodiment, the compound of formula-3 obtained according to the present invention having the following one or more impurities less than about 0.1% as measured by HPLC.

Cyclized impurity Bromo impurity Dichloro impurity Enantiomer impurity

The seventh embodiment, of the present invention provides crystalline form of (R)-4-(8- amino-3-(pyrrolidin-2-yl)imidazo[ 1 ,5-a]pyrazin- 1 -yl)-N-(pyridin-2-yl)benzamide of formula-7 which is herein after designated as Form-M. The crystalline form-M of (R)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l- yl)-N-(pyridin-2-yl)benzamide of formula-7 obtained according to the present invention is characterized by its X-ray powder diffraction (XRD) pattern having peaks at about 4.7, 5.7, 7.7, 9.5, 11.5, 12.2, 12.7, 13.1, 15.4, 17.4, 17.9, 18.8, 19.3, 19.6, 20.4, 22.8, 23.9, 24.6, 25.1, 27.1 and 30.0 ± 0.2 degrees 2-theta.

The crystalline form-M of (R)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l- yl)-N-(pyridin-2-yl)benzamide of formula-7 obtained according to the present invention is further characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure- 1.

The crystalline form-M of (R)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l- yl)-N-(pyridin-2-yl)benzamide of formula-7 obtained according to the present invention is useful in the preparation of Acalabrutinib of formula- 1.

The eighth embodiment, of the present invention provides a process for the preparation of crystalline form-M of (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl )-N-(pyridin-

2-yl)benzamide of formula-7, comprising:

a) adding a suitable solvent to (R)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l- yl)-N-(pyridin-2-yl)benzamide compound of formula-7,

b) isolating crystalline form-M of (R)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[l,5-a]pyrazin- l-yl)-N-(pyridin-2-yl)benzamide compound of formula-7.

In the process of the eighth embodiment, the suitable solvent used in step-a) is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof to compound of formula-7.

In the process of the eighth embodiment, heating a mixture of compound of formula-7 and a suitable solvent at a suitable temperature ranging from 35°C to reflux temperature of the solvent used.

In the process of the eighth embodiment, isolating crystalline form-M of (R)-4-(8-amino-

3-(pyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl)-N-(pyridin -2-yl)benzamide of formula-7 by any of the methods known in the art or isolation 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, or other techniques specific to the equipment used and the like, and optionally washing with a solvent..

The ninth embodiment, of the present invention provides crystalline form of Acalabrutinib ethylene glycol, which is herein after designated as Form-S.

The crystalline form-S of Acalabrutinib ethylene glycol obtained according to the present invention is characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure -

2.

The crystalline form-S of Acalabrutinib ethylene glycol obtained according to the present invention is useful in the preparation of Acalabrutinib compound of formula- 1.

The tenth embodiment, of the present invention provides a process for the preparation of crystalline form-S of Acalabrutinib ethylene glycol, comprising:

a) reacting compound of formula-7 with 2-butynoic acid,

b) treating the mixture with ethylene glycol to provide crystalline form-S of Acalabrutinib ethylene glycol.

In the process of the tenth embodiment, reacting compound of formula-7 with 2-butynoic acid in step-a) is carried out in the presence of suitable condensing agent in the presence or absence of suitable base in a solvent.

the suitable condensing agent used in step-a) is selected from phosphonium reagents such as benzotriazol-l-yloxy-tris(dimethylamino)-phosphoniumhexafluo rophosphate (BOP), benzo triazol- 1 -yloxy-tripyrrolidino-phosphoniumhexafluorophosphate (PyBOP), bromo-tri pyrrolidino-phosphoniumhexafluorophosphate (PyBr OP) and the like; immonium reagents such as benzotriazol-l-yloxy-N,N-dimethyl-methaniminiumhexachloroant imonate (BOMI), 5-(lH- benzotriazol- l-yloxy)-3, 4-dihydro- 1 -methyl-2H-pyrroliumhexachloroantimonate (BDMP) and the like; ammonium/uronium reagents such as such as l-[bis(dimethylamino)methylene]-lH- 1 ,2,3-triazolo[4,5-b]pyridinium-3-oxid-hexafluorophosphate (HATU), 3-[bis(dimethyl-amino) methyliumyl]-3H-benzotriazol- 1 -oxid-hexafluorophosphate (HBTU), 1 -[bis(dimethyl-amino) methylen]-5-chlorobenzotriazolium-3-oxid-hexa fluorophosphate (HCTU) and the like; imidazolium reagents such as carbonyl diimidazole (CD I), 2-chloro-l, 3-dimethyl- lH-benzi midazoliumhexafluorophosphate (CBMI), 2-(benzotriazol-l-yl)oxy-l,3-dimethylimidazo lidiniumhexafluorophosphate (BOI) and the like; pyridinium reagents such as 2-bromo-l- methylpyridiniumiodide (BMPI), 2-chloro-l-methylpyridinium iodide (CMPI) and the like with the proviso that the condensing agent is not carbodiimides.

In the process of the tenth embodiment, reacting a mixture obtained in step-a) with ethylene glycol in a suitable solvent to provide crystalline form-S of Acalabrutinib ethylene glycol.

In the process of the tenth embodiment, the suitable solvent used in step-a) and step-b) is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar- aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof;

The crystalline form-S of Acalabrutinib ethylene glycol obtained according to the present invention is having a purity of about 97% by HPLC or purity of about 99.0% by HPLC or purity of about 99.5% or purity of about 99.9% by HPLC.

The eleventh embodiment, of the present invention provides a process for the preparation of Acalabrutinib of formula- 1, which comprises:

a) Reacting (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl )-N-(pyridin-2-yl) benzamide of formula-7

with 2-butynoic acid in the presence of suitable condensing agent in the presence or absence of suitable base in a suitable solvent to provide Acalabrutinib,

b) optionally purifying the Acalabrutinib to provide pure Acalabrutinib. In the process of the eleventh embodiment, the suitable condensing agent used in step-a) is same as defined above; the suitable base used in step-a) is selected form inorganic base or organic base with the proviso that the base in not triethyl amine.

US9290504 B2 discloses process for the preparation of Acalabrutinib by reacting compound of formula-7 with 2-butynoic acid in the presence of HATU and triethyl amine to provide Acalabrutinib with 18% yield.

The present invention involves process for the preparation of Acalabrutinib by reacting compound of formula-7 with 2-butynoic acid in the presence of HATU and catalytic amount of DMAP to provide Acalabrutinib with 80% yield. By replacing the base from triethyl amine to 4- dimethylaminopyridine [DMAP] inventors of the present invention have surprisingly found that the yield of Acalabrutinib has increased from 18% to 80%.

In an embodiment, Acalabrutinib obtained according to the present invention is having one or more of the following impurities less than about 0.1% as measured by HPLC.

6- Amide impurity Pyrrolidine impurity Benzyl impurity

In an embodiment, Acalabrutinib of formula- 1 obtained according to the present invention is having a purity of about 97% by HPLC or purity of about 99.0% by HPLC or purity of about 99.5% or purity of about 99.9% by HPLC.

The twelfth embodiment, of the present invention provides a process for the preparation of Acalabrutinib, comprising:

a) treating Acalabrutinib with a suitable acid in a suitable solvent to provide its corresponding acid addition salt of Acalabrutinib,

b) treating the acid addition salt of Acalabrutinib with a suitable base,

c) isolating to provide pure Acalabrutinib.

In the process of the twelfth embodiment, the suitable acid used in step-a) is organic acid or inorganic acid; the suitable base used in step-b) is organic base or inorganic base; the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

isolating Acalabrutinib obtained in step-c) is carried out by any methods known in the art or is isolated 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, or other techniques specific to the equipment used and the like, and optionally washing with a solvent to provide pure Acalabrutinib.

The thirteenth embodiment, of the present invention provides a process for the preparation of Acalabrutinib, which comprises:

a) Reacting 2-butynoic acid with 4-aminophenol in the presence or absence of base selected from organic base or inorganic base in a solvent to provide 4-aminophenylbut-2-ynoate compound of formula-8,

Formula-8

b) reacting compound of formula-8 with (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[l,5-a] pyrazin-l-yl)-N-(pyridin-2-yl)benzamide of formula-7 in the presence or absence of a suitable base in a suitable solvent to provide Acalabrutinib of formula- 1.

In the process of the thirteenth embodiment, the suitable solvent used in step-a) and step- b) is selected form alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar- aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

The fourteenth embodiment, of the present invention provides acid addition salts of compound of formula-I.

Formula-I

wherein, R is selected from amino protecting group is same as defined above with the proviso that amino protecting group is not tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz); the acid is same as defined above.

The compound of formula-I obtained according to the present invention is useful in the preparation of Acalabrutinib of formula- 1. The fifteenth embodiment, of the present invention relates to novel intermediate compounds which are useful in the preparation of Acalabrutinib.

Formula- 11 Formula-6

wherein, R is selected from amino protecting group same as defined above with the proviso that amino protecting group is not tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz).

The sixteenth embodiment, of the present invention provides crystalline form of (S)- benzyl 2-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl)pyrrolidine-l-c arboxylate, which is herein after designated as form-S.

The crystalline form-S of (S)-benzyl 2-(8-amino-l-bromoimidazo[l,5-a] pyrazin-3- yl)pyrrolidine- 1 -carboxylate obtained according to the present invention is characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure-4.

The crystalline form-S of (S)-benzyl 2-(8-amino-l-bromoimidazo[l,5-a] pyrazin-3-yl) pyrrolidine- 1 -carboxylate obtained according to the present invention is useful in the preparation of Acalabrutinib of formula- 1. The seventeenth embodiment, of the present invention provides a process for the preparation of (S)-benzyl 2-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl)pyrrolidine-l- carboxylate, comprising:

a) treating (S)-benzyl 2-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl)pyrrolidine-l- carboxylate oxalate salt of formula-4b with a suitable base in a suitable solvent, b) isolating crystalline form-S of (S)-benzyl 2-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3- yl)pyrrolidine- 1 -carboxylate.

In the process of the seventeenth embodiment, the suitable base used in the step-a) is selected from organic base or inorganic base; the suitable solvent is selected from alcohol solvents, ester solvents, hydrocarbon solvents, nitrile solvents, polar-aprotic solvents, ketone solvents, ether solvents, chloro solvents, and water or mixture thereof.

The eighteenth embodiment, of the present invention provides a process for the purification of (4-(pyridin-2-ylcarbamoyl)phenyl)boronic acid compound of formula-5a, comprising:

a) treating (4-(pyridin-2-ylcarbamoyl)phenyl)boronic acid with orthophosphoric acid in a suitable solvent,

b) isolating to provide pure (4-(pyridin-2-ylcarbamoyl)phenyl)boronic acid compound of formula-5a.

In the process of the eighteenth embodiment, the compound of formula-5 a obtained according to the present invention is having a purity of about 97% by HPLC or a purity of about 99.0% by HPLC or a purity of about 99.5% or a purity of about 99.9% by HPLC.

Formula-5 a In the process of the eighteenth embodiment, the compound of formula-5a obtained according to the present invention is having desbromo impurity

Desbromo impurity

less than about 0.1% as measured by HPLC.

The nineteenth embodiment, of the present invention provides acid addition salts of compound of formula-4.

Formula-4

wherein, R is selected from amino protecting group same as defined above and acid is same as defined above.

The twentieth embodiment, of the present invention provides solid state form of compound of formula-4.

Acid addition salts of compound of formula-4 obtained according to the present invention are useful in the preparation of Acalabrutinib.

In an embodiment, the compounds of formula-2 and formula-5 used as starting materials in the present invention can be prepared according to the prior known processes or is synthesized according to the present invention.

The twenty-first embodiment, of the present invention provides a crystalline Form-S of Acalabrutinib of formula- 1. The crystalline Form-S of Acalabrutinib obtained according to the present invention is characterized by powdered X-Ray Diffraction (PXRD) pattern having peaks at about 8.4, 9.9, 12.0 and 16.8 ± 0.2 degrees 2-theta.

The crystalline Form-S of Acalabrutinib obtained according to the present invention is further characterized by its PXRD pattern having peaks at about 7.6, 15.4, 15.8, 16.7, 17.6 and 19.9 ± 0.2 degrees 2-theta.

The crystalline Form-S of Acalabrutinib obtained according to the present invention is further characterized by its PXRD pattern as illustrated in Figure-9.

The twenty-second embodiment, of the present invention provides a process for the preparation of crystalline Form-S of Acalabrutinib, comprising:

a) adding crystalline Form-I of Acalabrutinib in a mixture of methanol and water;

b) cooling the mixture obtained in step-a) to 0-5°C;

c) stirring the mixture for 9 to 10 hours;

d) filtering the compound obtained in step-c); and

e) drying the compound obtained in step-d) to provide crystalline Form-S of Acalabrutinib.

The twenty-third embodiment, the present invention provides a process for the preparation of crystalline Form-S of Acalabrutinib, comprising:

a) adding crystalline Form- III of Acalabrutinib in a mixture of methanol and water;

b) cooling the mixture obtained in step-a) to 0-5°C;

c) stirring the mixture for 9 to 10 hours;

d) filtering the compound obtained in step-c); and

e) drying the compound obtained in step-d) to provide crystalline Form-S of Acalabrutinib.

In step-d) of twenty-second and twenty-third embodiments provides a crystalline form of Acalabrutinib (hereinafter referred as“Form-S 1”).

The twenty-fourth embodiment, of the present invention provides a process for the preparation of crystalline Form-S of Acalabrutinib, comprising:

a) adding crystalline Form-Ill of Acalabrutinib in a mixture of methanol, water and n- heptane; b) cooling the mixture obtained in step-a) to 0-5°C;

c) stirring the mixture for 9 to 10 hours;

d) filtering the compound obtained in step-c); and

e) drying the compound obtained in step-d) to provide crystalline Form-S of Acalabrutinib.

In step-d) of the twenty-fourth embodiment provides a crystalline form of Acalabrutinib (hereinafter referred as“Form-S2”).

In the process of the present invention, the crystalline forms of Acalabrutinib produced according to the present invention may be dried in suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at atmospheric pressure or under reduced pressure at temperature of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperature. The drying may be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.

In another embodiment, the present invention provides pharmaceutical composition comprising crystalline Form-S of Acalabrutinib and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention provides pharmaceutical composition comprising crystalline Form-S 1 of Acalabrutinib and one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention provides pharmaceutical composition comprising crystalline Form- S2 of Acalabrutinib and one or more pharmaceutically acceptable excipients.

Wherein, the excipient can be selected from Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems 2006.

In yet another embodiment, pharmaceutical composition comprising crystalline Form-S, SI and S2 of Acalabrutinib and one or more pharmaceutically acceptable excipients is formulated in a manner suitable for the route of administration to be used. As used herein, the term "pharmaceutical compositions" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

The starting materials crystalline Forms I & III of Acalabrutinib used in the present invention can be prepared by methods reported in US9796721 B2 or any other methods known in the art.

The twenty-fifth embodiment, of the present invention provides a process for the preparation of Acalabrutinib of fomrula-1, comprising:

a) treating compound of formula-6 with Lewi’s acid to provide (S)-4-(8-amino-3-

(pyrrolidin-2-yl)imidazo[ 1 ,5-a]pyrazin- 1 -yl)-N-(pyridin-2-yl)benzamide of formula-7, b) converting compound of formula-7 to provide Acalabrutinib of formula- 1.

In the process of the twenty-fifth embodiment, the suitable Lewi’s acid used in step-a) is selected from aluminium chloride, aluminium bromide, Iron chloride, tin tetrachloride, tintetrabromide, stannous chloride, titanium tetrachloride, calcium chloride and zinc chloride, lithium tetrafluoroborate (L1BF ₄ ) or trifluoroborate.

Acalabrutinib prepared according to the present invention is micronized or milled in conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that are used for particle size reduction include, but not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or micronization is performed before drying, or after the completion of drying of the product.

In embodiment of the present invention, Acalabrutinib obtained has a particle size distribution of D ₉₀ less than about 150 pm, or less than about 100 pm; or less than about 50 pm.

The present invention also encompasses pharmaceutical composition comprising Acalabrutinib and its pharmaceutical acceptable salts one or more pharmaceutically acceptable excipients. As used herein, the term "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.

P-XRD Method of Analysis: PXRD analyses of compounds produced by the present invention were carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A°.

PSD method of Analysis: Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 2000 instrument.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

Example-1: Preparation of (S)-benzyl 2-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl) pyrrolidine-l-carboxylate [Formula-3]

Isopropanol (350 ml) was added to (S)-benzyl 2-(l-bromo-8-chloroimidazo[l,5-a] pyrazin-3-yl)pyrrolidine-l-carboxylate (70 gms) at 25-30°C in an autoclave vessel. Ammonia (350.0 ml) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 80-85°C and stirred for 4 hours. Cooled the reaction mixture to 25-30°C. Distilled off the solvent completely from the filtrate under reduced pressure. Water and ethyl acetate were added to the obtained compound at 25-30°C and stirred for 30 minutes at the same temperature. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. Combined the organic layers and washed with sodium chloride. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.

Purity by HPLC: 28.95%.

Example-2: Preparation of (S)-benzyl 2-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl) pyrrolidine-l-carboxylate tartrate [Formula-4a]

Ethyl acetate was added to the obtained compound in example- 1 at 60-65°C and stirred for 30 minutes. A mixture of Tartaric acid (24.25 gms), isopropanol (75.0 ml) and water (3.75 ml) were added to the reaction mixture at 0-5°C and stirred for 2 hours. Filtered the solid, washed with ethyl acetate and dried to get the title compound.

Yield: 70.0 gms; Purity by HPLC: 97.48%.

Example-3: Preparation of (S)-benzyl 2-(8-amino-l-(4-(pyridin-2-ylcarbamoyl)phenyl) imidazo[l,5-a]pyrazin-3-yl)pyrrolidine-l-carboxylate [Formula-6]

Dichloromethane (300 ml) was added to the compound obtained in example-2 (60.0 gms) at 25-30°C. Aqueous sodium hydroxide solution was added to the mixture and stirred for 30 minutes. Layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and distilled off the solvent completely from the organic layer under reduced pressure. Dimethyl formamide (480.0 ml) was added to the obtained compound at 25-30°C. Pd(dppf>2Cl2 (4.27 gms) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 90-95°C and stirred for 1 hour. Compound of formula-5a (41.21 gms), dimethyl formamide (120.0 ml) and sodium carbonate (30.0 gms) were slowly added to the reaction mixture at 90-95°C and stirred for 3 hours. Cooled the reaction mixture to 0-5°C. Water was slowly added to the reaction mixture at 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 45.0 gms.

Example-4: Preparation of (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl )- N-(pyridin-2-yl)benzamide [Formula-7]

33% HBr in acetic acid (760.0 ml) was added to the compound obtained in example-3 (100 gms) at 25-30°C and stirred for 4 hours. Cooled the reaction mixture to 0-5°C. Acetone (900.0 ml) was slowly added to the reaction mixture at 0-5°C and stirred for 2 hours. Filtered the precipitated solid, washed with acetone at 0-5°C. Water (300.0 ml) was added to the obtained solid at 0-5°C. The pH of the reaction mixture was adjusted using aqueous sodium hydroxide solution at 0-5°C. Dichloromethane was added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with sodium chloride solution at 25- 30°C. Distilled off the solvent completely from the organic layer under reduced pressure. Methyl tert-butyl ether (300.0 ml) was added to the obtained compound at 45-50°C and stirred for 30-60 minutes. Cooled the temperature of the reaction mixture to 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with methyl tert-butyl ether and dried to get the title compound.

Yield: 60.0 gms.

Example-5: Preparation of amorphous form of Acalabrutinib

Dichloromethane (20 ml) was added to the compound obtained in example-4 (4.0 gms) at 25-30°C. Cooled the temperature of the reaction mixture to 0-5°C. 2-Butynoic acid (1.26 gms) and 4-dimethylaminopyridine (0.122 gms) were slowly added to the reaction mixture at 0-5°C and stirred for 4 hours at the same temperature. Water (4.0 ml) was added to the reaction mixture at 0-5°C. The pH of the reaction mixture was adjusted using aqueous sodium bicarbonate solution and stirred for 30 minutes at 25-30°C. Layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with water at 25-30°C. Distilled off the solvent completely from the organic layer under reduced pressure. Methyl tert- butyl ether (20 ml) was added to the obtained compound at 40-45°C and stirred for 30 minutes at the same temperature. Filtered the precipitated solid, washed with methyl tert-butyl ether and dried to get the title compound. Yield: 2.6 gms.

Example-6: Preparation of (3-chloropyrazin-2-yl)methanamine hydrochloride

Acetic acid (120.0 ml) was added to 3-chloropyrazine-2-carbonitrile (30.0 gms) at 25- 30°C in an autoclave vessel. Raney Ni (12.0 gms) and acetic acid (120 ml) slurry were added to the mixture. 4.5-5 kg/cm hydrogen gas pressure was applied to the mixture at 25-30°C. Raised the temperature of the mixture to 40-45°C and stirred for 3 hours. Cooled the mixture to 25-30°C. Water was added to the mixture at 25-30°C. Filtered the mixture through hyflow bed and washed the hyflow bed with water. Acidic carbon (3.0 gms) was added to the filtrate at 25-30°C. Raised the temperature of the mixture to 50-55°C and stirred for 1 hour. Cooled the mixture to 25-30°C. Filtered the mixture through hyflow bed and washed the hyflow bed with water. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with toluene (75.0 ml). Ethyl acetate (300.0 ml) was added to the mixture at 25-30°C. Cooled the mixture to 10- 15°C. Isopropanol hydrochloride (45.0 ml) was added to the mixture at 10-15°C. Raised the temperature of the mixture to 25-30°C and stirred for 5 hours. Filtered the precipitated solid, washed with ethyl acetate and dried. A mixture of methanol (30.0 ml) and isopropanol (210.0 ml) were added to the obtained compound. Raised the temperature of the mixture to 50-55°C and stirred for 1 hour. Cooled the mixture to 5-10°C and stirred for 2 hours. Filtered the solid, washed with isopropanol and dried to get the title compound.

Yield: 25.9 gms; M.R : 175-180°C; Purity by HPLC: 97.58%.

Example 7: Preparation of ((S)-benzyl 2-(((3-chloropyrazin-2-yl)methyl)carbamoyl) pyrrolidine-l-carboxylate

Step-1):

Water (100.0 ml) was added to (3-chloropyrazin-2-yl)methanamine hydrochloride (100.0 gms) at 25-30°C. Cooled the mixture to 5-10°C. Aqueous sodium hydroxide solution was added to the mixture at 5-10°C and stirred for 1 hour. Toluene (300.0 ml) and TBAB (17.7 gms) were added to the mixture at 5-10°C.

Step-2):

Dichloromethane (300.0 ml) and dimethyl form amide (1.0 ml) were added to (S)-l- ((benzyloxy)carbonyl)pyrrolidine-2-carboxylic acid (114.54 gms) at 25-30°C. Cooled the mixture to 10-15°C. Oxalyl chloride (40.0 ml) was added to mixture at 10-15°C. Raised the temperature of the mixture to 25-30°C under nitrogen atmosphere and stirred for 2 hours. Toluene (800.0 ml) was added to mixture at 25-30°C. The mixture was added to the mixture obtained in step-1 at 5- 10°C. Raised the temperature of the mixture to 25-30°C and stirred for 2 hours. Water and hydrochloric acid were added to mixture at 25-30°C. Ethyl acetate was added to mixture at 25- 30°C and stirred for 1 hour. Filtered the mixture through hyflow bed and washed the hyflow bed with ethyl acetate. Layers were separated and extracted the aqueous layer with ethyl acetate. Combined the organic layers, washed with water and sodium bicarbonate and stirred for 1 hour at 25-30°C. Layers were separated. Basic carbon was added to organic layer at 25-30°C and stirred for 45 minutes at the same temperature. Filtered the mixture through hyflow bed and washed the hyflow bed with ethyl acetate. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with methyl tert-butyl ether. To the obtained compound, methyl tert- butyl ether (300 ml) was added at 25-30°C. Raised the temperature of the mixture to 50-55°C and stirred for 45 minutes. Cooled the mixture to 25-30°C and stirred for 45 minutes. Further cooled the mixture to 5-10°C and stirred for 3 hours. Filtered the solid, washed with MTBE and dried to get the title compound. Yield: 90.0 gms; M.R : 90-95°C: Purity by HPLC: 98.42%.

Example 8: Preparation of (S)-benzyl 2-(l-bromo-8-chloroimidazo[l,5-a]pyrazin-3-yl) pyrrolidine-l-carboxylate

Acetonitrile (500 ml) was added to ((S)-benzyl 2-(((3-chloropyrazin-2-yl)methyl) carbamoyl )pyrrolidine- 1 -carboxylate (100 gms) at 25-30°C. Cooled the mixture to 10-15°C. Phosphorus oxychloride (163.9 gms) was added to mixture at 10-15°C. Raised the temperature of the mixture to 70-75°C and stirred for 5 hours. Distilled off the mixture 60°C under vacuum. Cooled the mixture to 50-55°C. Tetrahydrofuran (500.0 ml) was added to the mixture at 50-55°C. Cooled the mixture to 5-10°C. Water and ammonia were added to the mixture at 5-10°C. Ammonia was added to the mixture at 5-10°C and stirred for 30 minutes. Raised the temperature of mixture to 25-30°C. Layers were separated and extracted the aqueous layer with methyl tert- butyl ether. Combined the organic layers and washed with water. Layers were separated and organic layers washed with sodium chloride solution. Distilled off the organic layer below 50°C under vacuum. Dimethylformamide (150.0 ml) and N-Bromosuccinimide (50.1 gms) were added to the obtained compound at 5-10°C and stirred for 2 hours. Water was added to the mixture at 5- 10°C and stirred for 2 hours. Filtered the solid, washed with water and dried to get the title compound. Isopropanol (300.0 ml) and water (100.0 ml) were added to the obtained compound at 25-30°C and stirred for 1 hour. Cooled the mixture to 5-10°C and stirred for 2 hours. Filtered the solid, washed with water and dried to get the title compound. Yield: 78.0 gms.

Example 9: Preparation of (S)-benzyl 2-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl) pyrrolidine-l-carboxylate

Isopropanol (500 ml) was added to (S)-benzyl 2-(l-bromo-8-chloroimidazo[l,5-a] pyrazin-3-yl)pyrrolidine-l -carboxylate (100 gms) at 25-30°C in an autoclave vessel. Ammonia (500.0 ml) and sodium iodide (34.5 gms) were added to mixture at 25-30°C. Raised the temperature of the mixture to 90-95°C and stirred for 8 hours. Cooled the mixture to 25-30°C. Distilled off the solvent completely from the filtrate under reduced pressure. Water and dichloromethane were added to the obtained compound at 25-30°C and stirred for 45 minutes. Layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with aqueous sodium chloride solution. Layer were separated and distilled off the organic layer under reduced pressure and co-distilled with isopropanol. To the obtained compound, isopropanol (300 ml) and water (100 ml) was at 25-30°C. Raised the temperature of the mixture to 50-55 °C and stirred for 45 minutes. Cooled the mixture to 25-30°C and further cooled to 0-5 °C and stirred for 8 hours at the same temperature. Filtered the precipitated solid, washed with water and dried. N-Butanol (300 ml) was added to the obtained compound at 25-30°C. Raised the temperature of the mixture to 50-55°C and stirred for 45 minutes. Cooled the mixture to 0-5°C and stirred for 4 hours. Filtered the precipitated solid, washed with water and dried to get the title compound.

Yield: 65.0 gms; Purity by HPLC: 99.51%.

Example-10: Preparation of (S)-benzyl 2-(8-amino-l-bromoimidazo[l,5-a]pyrazin-3-yl) pyrrolidine-l-carboxylate [Formula-3]

Isopropanol (500 ml) was added to (S)-benzyl 2-(l-bromo-8-chloroimidazo[l,5-a] pyrazin-3-yl)pyrrolidine-l-carboxylate (100 gms) at 25-30°C in an autoclave vessel. Ammonia (500.0 ml) and sodium iodide (34.5 gms) were added to mixture at 25-30°C. Raised the temperature of the mixture to 90-95°C and stirred for 10 hours. Cooled the mixture to 25-30°C. Distilled off the solvent completely from the filtrate under reduced pressure. Water and dichloromethane were added to the obtained compound at 25-30°C and stirred for 45 minutes. Layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and washed with aqueous sodium chloride solution. Layer were separated and distilled off the organic layer under reduced pressure to get the title compound.

Purity by HPLC: 90.81%.

Example-11: Preparation of crystalline form-M of (S)-benzyl 2-(8-amino-l- bromoimidazo[l,5-a]pyrazin-3-yl) pyrrolidine-l-carboxylate oxalate salt [Formula-4b]

Acetone (500 ml) was added to the compound obtained in example- 10 at 25-30°C. Oxalic acid (43.2 gms) was added mixture at 25-30°C. Raised the temperature of the mixture to 50-55°C and stirred for 45 minutes. Cooled the mixture to 25-30°C. Further cooled the mixture to 0-5°C and stirred for 2 hours. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 110 gms; Purity by HPLC: 99.47%.

The PXRD of the obtained compound is depicted in Figure-3.

Example-12: Preparation of crystalline form-S of (S)-benzyl 2-(8-amino-l-bromo imidazo[l,5-a]pyrazin-3-yl) pyrrolidine-l-carboxylate [Formula-3]

Ethyl acetate (500 ml) was added to the obtained compound in example- 11 at 25-30°C. Aqueous potassium hydroxide solution was added to the mixture and stirred for 30 minutes. Layers were separated and extracted the aqueous layer with ethyl acetate. Distilled off the solvent completely under reduced pressure. Isopropanol (50 ml) and water (300 ml) was added to the obtained compound at 50-55°C and stirred for 45 minutes. Cooled the mixture to 0-5°C and stirred for 8 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 65 gms; Purity by HPLC: 99.77%.

The PXRD of the obtained compound is depicted in Figure-4.

Example-13: Preparation of (4-(pyridin-2-ylcarbamoyl)phenyl)boronic acid [Formula-5a]

Tetrahydrofuran (500 ml) was added to 4-bromo-N-(pyridin-2-yl)benzamide (50 gms) at 25-30°C. Triisopropyl borate (120 ml) was added to the mixture. Cooled the mixture to -75°C to -70°C. n-butyl lithium (69.12 gms) was added to the mixture at -75°C to -70°C and stirred for 2 hours. Methanol was added to the mixture and stirred for 30 minutes. Aqueous hydrochloric acid solution was added to the mixture at -75 to -70°C and stirred for 45 minutes. Raised the temperature to 25-30°C. Filtered the solid, washed with water and dried.

Purity by HPLC: 87.51%; Des bromo impurity: 6.76%

Example-14: Purification of (4-(pyridin-2-ylcarbamoyl)phenyl)boronic acid [Formula-5a]

Acetone (500 ml), orthophosphoric acid (100 ml) and water (300 ml) was added to the compound obtained in example- 13. Raised the temperature of the mixture to 50-55 °C and stirred for 1 hour. Cooled he mixture to 25-30°C and stirred for 1 hour. Further cooled to 5-10°C and stirred for 1 hour. Filtered the solid and washed with water. Purity by HPLC: 93.9%; Des bromo impurity: 2.96%.

Example-15: Purification of (4-(pyridin-2-ylcarbamoyl)phenyl)boronic acid [Formula-5a]

Ethanol (200 ml) and water (500 ml) was added to the obtained compound in example- 14 at 25-30°C. Raised the temperature of the mixture to 50-55°C and stirred for 1 hour. Cooled the mixture to 5-10°C and stirred for 2 hours. Filtered the solid, washed with water and dried to get the title compound. Yield: 28.0 gms.

M.P: 200°C; Purity by HPLC: 98.56%; Des bromo impurity 0.2%.

Example-16: Preparation of crystalline form-M of (S)-4-(8-amino-3-(pyrrolidin-2-yl) imidazo[l,5-a]pyrazin-l-yl)-N-(pyridin-2-yl)benzamide [Formula-7]

Water (50.0 ml) was added to (S)-benzyl 2-(8-amino-l-(4-(pyridin-2-ylcarbamoyl) phenyl)imidazo[l,5-a]pyrazin-3-yl)pyrrolidine-l-carboxylate (100.0 gms) at 25-30°C. Aqueous hydrobromide solution was added to mixture at 25-30°C. Raised the temperature of the mi ture to 60-65°C and stirred for 3 hours. Cooled the mixture to 25-30°C. Water and dichloromethane were added to mixture at 25-30°C and stirred for 25 minutes. Filtered the mixture through hyflow bed and washed the hyflow bed with water. Layers were separated. Methyl tert-butyl ether was added to aqueous layers at 25-30°C and stirred for 25 minutes. Layers were separated. Activated carbon was added to aqueous layers at 25-30°C and stirred for 45 minutes. Filtered the mixture through hyflow bed and washed the hyflow bed with water. Layers were separated. Dichloromethane and methanol were added to aqueous layers at 25-30°C. Cooled the mixture to 5-10°C. Ammonia was added to the mixture at 5-10°C and stirred for 30 minutes. Layers were separated. Dichloromethane and methanol were added to aqueous layers at 5-10°C and stirred for 15 minutes. Layers were separated. Combined the total organic layers at 5-10°C. Aqueous sodium chloride solution was added to organic layer at 5-10°C and stirred for 15 minutes. Layers were separated. Distilled off the organic layer under reduced pressure. Methyl tert-butyl ether (300.0 ml) was added to the obtained compound at 45-50°C and stirred for 2 hours. Distilled off the solvent from the mixture under reduced pressure. Methyl tert-butyl ether was added to the obtained compound at 45-50°C. Raised the temperature of the mixture to 55-60°C and stirred for 2 hours. Cooled the mixture to 5-10°C and stirred for 3 hours. Filtered the solid, washed with methyl tert-butyl ether and dried to get the title compound. Yield: 58.0 gms; M.R = 150-170°C. The PXRD of the obtained compound is depicted in Figure- 1.

Example 17: Preparation of crystalline form-S of Acalabrutinib ethylene glycol

Acetonitrile (250.0 ml) was added to (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[l,5-a] pyrazin-l-yl)-N-(pyridin-2-yl)benzamide (50.0 gms) at 25-30°C. 2-Butynoic acid (11.34 gms) and HATU (47.5 gms) were added to the mixture at 25-30°C and stirred for 6 hours. Dichloromethane and water were added to the mixture at 25-30°C. Cooled the mixture to 5-10°C. aqueous sodium bicarbonate solution was added to mixture at 5-10°C and stirred for 15 minutes. Layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and distilled off the solvent completely from the organic layer under reduced pressure. Water was added to the obtained compound at 25-30°C. Cooled the mixture to 0-5°C. Aqueous hydrochloric acid was added to the mixture at 0-5°C and stirred for 20 minutes. Methyl tert-butyl ether was added to the mixture at 25-30°C and stirred for 20 minutes. Layers were separated. Ethyl acetate was added to aqueous layer and stirred for 20 minutes. Layers were separated. Combined the aqueous layers and dichloromethane was added to it. Cooled the mixture to 0-5 °C. Aqueous sodium bicarbonate solution was added to the mixture at 0-5 °C and stirred for 20 minutes. Layers were separated and aqueous layer was extracted with dichloromethane. Combined the total organic layers and washed with water. Distilled off the solvent from the mixture under reduced pressure and co-distilled with ethyl acetate.

Purity by HPLC: 81.59%.

To the obtained compound ethyl acetate (150 ml) and ethylene glycol (15 ml) was added at 25-30°C. Raised the temperature of the mixture to 40-45°C and stirred for 40 minutes. Cooled the mixture to 25-30°C and stirred for 2 hours. Liltered the precipitated solid, washed with ethyl acetate and dried to get the title compound.

Yield: 50 gms; M.R: 108-110°C; Purity by HPLC: 99.51%.

The PXRD of the obtained compound is depicted in Ligure-2.

Example 18: Preparation of amorphous form of Acalabrutinib

Dichloromethane (250 ml) was added to Acalabrutinib ethylene glycol (50 gms) at 25- 30°C and stirred for 30 minutes. Water (250 ml) was added to the mixture at 25-30°C and stirred for 45 minutes. Layers were separated and aqueous layer was extracted with dichloromethane. Combined the organic layers. Water was added to the organic layer at 25-30°C and stirred for 45 minutes. Layers were separated. Distilled off the solvent from the mixture under reduced pressure. Methanol (250 ml) was added to the obtained compound at 25-30°C. Carbon (5.0 gms) was added to the mixture and stirred for 40 minutes. Liltered the mixture through hyflow bed and washed the bed with methanol. Distilled off the solvent completely under reduced pressure. Methyl tert -butyl ether (150 ml) was added to the obtained compound at 25-30°C and stirred for 2 hours at the same temperature. Liltered the solid, washed with methyl tert -butyl ether and dried to get the title compound. Yield: 65 gms; M.R: 123-128°C. Purity by HPLC: 99.90%; Dimer impurity: 0.08%; Acetyl impurity: 0.09%; Piperidine impurity: 0.11%.

The PXRD pattern of the obtained compound is illustrated in Ligure-5.

Particle Size Distribution (PSD): D(10) is 7.2 pm; D(50) is 41.6 pm; D(90) is 100.3 pm.

Example-19: Preparation of crystalline Form-Si of Acalabrutinib.

Crystalline Form-Ill of Acalabrutinib (5 gms) was added to mixture of methanol (95 ml) and water (5 ml) at 25-30°C. Cooled the slurry to 0-5°C and stirred for 9-10 hours at the same temperature. Filtered the solid to get the title compound. Yield: 4.2 gms.

The P-XRD pattern of the obtained compound is illustrated in figure-7.

Example-20: Preparation of crystalline Form-Si of Acalabrutinib.

Crystalline Form-I of Acalabrutinib (0.5 gms) was added to mixture of methanol (9.5 ml) and water (0.5 ml) at 25-30°C. Cooled the slurry to 0-5°C and stirred for 9-10 hours at the same temperature. Filtered the solid to get the title compound. Yield: 390 mg. The P-XRD pattern of the obtained compound was similar to the PXRD pattern which is illustrated in figure-7.

Example-21: Preparation of crystalline Form-S2 of Acalabrutinib.

Crystalline Form-Ill of Acalabrutinib (0.5 gms) was added to a mixture of methanol (9.4 ml), water (0.5 ml) and n-heptane (0.1 ml) at 25-30°C. Cooled the slurry to 0-5°C and stirred for 9-10 hours at the same temperature. Filtered the solid to get the title compound.

Yield: 390 mg. The P-XRD pattern of the obtained compound is illustrated in figure-8.

Example-22: Preparation of crystalline Form-S of Acalabrutinib.

Dried the solid obtained in examples 1 and 2 at 40°C for 7-8 hours to get the title compound. Yield: 4.15 gms.

The P-XRD pattern of the obtained compound is illustrated in figure-9.

Example-23: Preparation of crystalline Form-S of Acalabrutinib.

Dried the solid obtained in example-3 at 25-30°C for 3 days to get the title compound. Yield: 360 mg.

Example 24: Preparation of (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[l,5-a]pyrazin-l-yl )- N-(pyridin-2-yl)benzamide [Formula-7]

Dichloromethane (80.0 ml) was added to S)-benzyl 2-(8-amino-l-(4-(pyridin-2-yl carbamoyl)phenyl)imidazo[l,5-a]pyrazin-3-yl)pyrrolidine-l-ca rboxylate (10 gms) at 25-30°C. Cooled the mixture to 0-5°C. Titanium tetrachloride (28 gms) was slowly added to the mixture at 0-5°C and stirred for 25 minutes. Raised the temperature of the mixture to 25-30°C. Titanium tetrachloride (7.1 gms) was slowly added to mixture at 25-30°C and stirred for 10 minutes. Cooled the mixture to 5-10°C. Water (20 ml) was added to mixture at 5-10°C. Aqueous ammonia solution (100 ml) was slowly added to mixture at 5-10°C and stirred for 45 minutes. Methanol was added to mixture at 25-30°C. Filtered the mixture through hyflow bed and washed the hyflow bed with water. Layers were separated and extracted the aqueous layer with dichlorome thane. Combined the organic layers and distilled off the solvent completely from the organic layer under reduced pressure. Methyl tert -butyl ether (20 ml) was added to the obtained residue and co-distilled at 45°C. Methyl tert-butyl ether was added to the obtained residue at 45°C. Cooled the mixture to 10-15°C and stirred for 30 minutes. Filtered the solid, washed with methyl tert-butyl ether and dried to get the title compound.

Yield: 5.0 gms; The PXRD pattern of the obtained compound is illustrated in Figure-6.