WO2025146653A1

WO2025146653A1 - Process for the preparation of n- [4(chlorodifluoromethoxy)phenyl]-6-[(3r)-3-hydroxy pyrrolidin-l-yl]-5-(lh-pyrazol-3-yl) pyridine-3- carboxamide and pharmaceutically acceptable salts thereof

Info

Publication number: WO2025146653A1
Application number: PCT/IB2025/050064
Authority: WO
Inventors: Manik Reddy Pullagurla; Kiran Kumar Kothakonda; Bhaskar Reddy Pitta; Jagadeesh Babu Rangisetty
Original assignee: Biophore India Pharmaceuticals Pvt Ltd
Current assignee: Biophore India Pharmaceuticals Pvt Ltd
Priority date: 2024-01-04
Filing date: 2025-01-03
Publication date: 2025-07-10
Anticipated expiration: 2026-07-04

Abstract

The present invention provides a process for the preparation of N- [4(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H- pyrazol-3-yl) pyridine-3-carboxamide represented by compound of formula (1) and pharmaceutically acceptable salts thereof.

Description

PROCESS FOR THE PREPARATION OF N-

[4(CHLORODIFLUOROMETHOXY)PHENYL]-6-[(3R)-3-HYDROXY

PYRROLIDIN-l-YL]-5-(lH-PYRAZOL-3-YL) PYRIDINE-3-

CARBOXAMIDE AND PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

FIELD OF THE INVENTION

The present invention provides a process for the preparation of N- [4(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-l-yl]-5-(lH- pyrazol-3-yl) pyridine-3-carboxamide represented by compound of formula (1) and pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

N-[4(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-l-yl]-5-(lH- pyrazol-3-yl) pyridine-3-carboxami dehydrogen chloride (1/1) is commonly known as Asciminib hydrochloride. It is having a molecular formula of C20H18CIF2N5O3.HCI. Asciminib hydrochloride is a white to slightly yellow powder.

US8829195 discloses preparation of Asciminib free base and isolation using silica gel column chromatography which is not feasible at industrial scale.

W02020230100 Al discloses a process for the reparation of compound N-[4- (Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-l-yl]-5-(lH-pyrazol- 5-yl)pyridine-3-carboxamide (Asciminib) or its salt comprising reaction of (R)-methyl 5-bromo-6-(3-hydroxypyrrolidin-l-yl)nicotinate (D2) with 1-1 - (tetrahydro-2H- pyran-2-yl)-l H-pyrazole-5-boronic acid, pinacol ester (D3) using K2CO3 in toluene in the presence of PdCl2(dtbpf) to provide methyl 6-((R)-3- hydroxypyrrolidin-1 -yl)-5- (1 -(tetrahydro-2H-pyran-2-yl)-l H-pyrazol-5-yl)nicotinate (D4). Then, reaction of obtained compound (D4) with 4-(chloro difluoromethoxy) aniline HCI (D5) in methyl tetrahydrofuran, using potassium tert-butoxide to afford N-(4-(Chloro difluoromethoxy) phenyl)-6-((R)-3-hvdroxypyrrolidin-l-yl)-5- (l-(tetrahvdro-2H- pyran-2-yl)-l H-pyrazol-5-yl) nicotinamide (D6). Converted N-(4-(Chloro difluoromethoxy)phenyl)-6-((R)-3-hvdroxypyrrolidin-l-yl)-5-(l-(tetrahvdro-2H- pyran-2-yl)-l H-pyrazol-5-yl)nicotinamide (D6) using HCI solution in the presence of methanol to obtain N-(4-(Chloro difluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-l- yl)-5-(l H-pyrazol-5-yl)nicotinamide (Al) further converted to compound (Al a) as illustrated in scheme- 1.

Scheme-1

As can be seen from the above, the disadvantages of the prior art process for the preparation Asciminib or its salts thereof involves usage of expensive solvents, reaction conditions and further purification, which leads to decreases in the yield of the final product. The prior art methods are not industrially viable at plant level.

Thus, there is a need to develop alternative, simple, cost effective, robust, and industrially viable process for the preparation of Asciminib Hydrochloride to sort out issues associated with prior art methods. Accordingly, our inventors have developed a process with simple and mild reaction conditions, low amount of metal complex catalyst involved, industrially viable process with high purity and good yield in large scale production.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide a process for the preparation of Asciminib and its pharmaceutically acceptable salts.

Another objective of the present invention is to provide a process for the purification of Asciminib and its pharmaceutically acceptable salts.

Another objective of the present invention is to provide a process for the purification of Asciminib and its pharmaceutically acceptable salts from its salt form with (+)- Dibenzoyl-D-tartaric acid (DBTA).

A further objective of the present invention is to provide a process for the preparation of a solid dispersion of Asciminib hydrochloride with pharmaceutically acceptable excipient.

Yet another objective of the present invention is to provide a process for the preparation of Asciminib and its pharmaceutically acceptable salts with a purity greater than 99.0%, preferably greater than 99.5%, and more preferably greater than 99.9%, as determined by High-Performance Liquid Chromatography (HPLC).

SUMMARY OF THE INVENTION

Accordingly, in the first aspect, the present invention provides a process for the preparation of Asciminib and its pharmaceutically acceptable salts, with purity greater than 99.5% by HPLC, wherein the process comprises the following steps: a) reacting methyl 5-bromo-6-chloronicotinate (10) with (R)-pyrrolidin-3-ol (9) to provide (R)-methyl 5-bromo-6-(3-hydroxypyrrolidin-l-yl) nicotinate (8); b) reacting the compound of formula (8) with l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazole-5-boronic acid, pinacol ester (7) in the presence of a base and a metal complex catalyst to provide methyl 6-((R)-3-hydroxypyrrolidin-l-yl)-5-(l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl) nicotinate (6); c) converting the compound of formula (6) to 6-((R)-3-hydroxypyrrolidin-l-yl)-5- (l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl) nicotinic acid (5); d) reacting the compound of formula (5) with 4-(chloro difluoromethoxy)aniline (4) or a salt thereof to provide N-(4-(chlorodifhioromethoxy)phenyl)-6-((R)-3- hydroxypyrrolidin-l-yl)-5-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5- yl)nicotinamide (3); or optionally reacting the compound of formula (6) with 4- (chloro difluoromethoxy)aniline (4) or a salt thereof to provide the compound of formula (3); e) converting the compound of formula (3) to Asciminib as (+) DBTA salt of formula (2a); f) converting Asciminib as (+) DBTA salt of formula (2a) to Asciminib of formula (2); and g) optionally, converting the Asciminib of formula (2) or Asciminib salt (1) to an amorphous solid dispersion with pharmaceutically acceptable excipient in presence of hydrochloric acid.

In another aspect, the compounds of formula (6), (5) and (2a) may be prepared in situ and proceed to subsequent steps without further purification.

In the second aspect, the present invention provides a process for purifying Asciminib (2) or its salts (1), comprising the following steps: a) dissolving Asciminib (2) or its salts (1) in a suitable solvent; b) cooling the solution to an appropriate temperature; and c) isolating the purified Asciminib (2) or its salts (1). In the third aspect, the present invention provides a process for preparing solid dispersion of Asciminib hydrochloride with at least one pharmaceutically acceptable excipient from Asciminib salt, comprising the following steps: i. dissolving Asciminib salt in a suitable solvent; ii. adjusting the pH of the solution using a suitable base; iii. adding a suitable solvent to the reaction mixture; iv. adding hydrochloric acid to the reaction mixture; v. adding at least one pharmaceutically acceptable excipient to the reaction mixture; and vi. isolating the solid dispersion of Asciminib hydrochloride.

In the fourth aspect, the present invention provides a process for preparing solid dispersion of Asciminib hydrochloride from Asciminib (2), comprising the following steps:

A. dissolving Asciminib (2) in a suitable solvent;

B. adding hydrochloric acid to the reaction mixture;

C. adding at least one pharmaceutically acceptable excipient to the reaction mixture; and

D. isolating the solid dispersion of Asciminib hydrochloride.

In this aspect, the preparation of solid dispersion of Asciminib hydrochloride does not require isolation of Asciminib hydrochloride salt.

In the fifth aspect, the present invention provides a process for preparing Asciminib (2) or its salts (1) is having a purity greater than 99.0%, preferably greater than 99.5%, and more preferably greater than 99.9%, as determined by High-Performance Liquid Chromatography (HPLC).

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 : Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous solid dispersion of Asciminib hydrochloride (1) with HPMC-E3 Figure 2: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous form of Asciminib free base of formula (2).

Figure 3: Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous form of Asciminib as DBTA salt of formula (2a).

DETAILED DESCRIPTION OF THE INVENTION

The term “suitable solvent” used in the present invention until unless specified is selected from, but are not limited to “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; “ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 2-m ethyl tetrahydrofuran, 1,4-di oxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, n-pentane, petroleum ether and the like; “chloro solvents” such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like; “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethyl ketone and the like; and water and/or mixtures thereof.

The term “suitable base” used herein the present invention until unless specified is selected from inorganic bases like “alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tert- butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine (DIPEA), di isobutyl amine, trimethylamine, triethylamine, tri isopropylamine, tributylamine, tert-butyl amine, pyridine, piperidine, 4-dimethylamino pyridine (DMAP) or mixtures thereof.

The term “coupling agent” used herein the present invention until unless specified is selected from the group consisting of carbonyl-diimidazole (CDI), carbonyl-di (1,2,4- triazole), 1 -(3 -dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride (EDC-HC1), di cyclohexyl carbodiimide (DCC) and propane phosphonic acid cyclic anhydride (PPA).

The term “additive” used herein the present invention until unless specified is selected from the group consisting of 1 -hydroxy benzotriazole (HOBt), l-hydroxy-7- azabenzotriazole (HOAt), 6-chloro-l-hydroxy-lH-benzotriazole (Cl-HOBt), hydroxy pyridines (HOPy), Imidazole or its salts, 1,8-Diazabicyclo [5.4.0]undec-7-en (DBU); tertiary amines or its hydro halide salts thereof selected from the group consisting of triethyl amine hydrochloride or diisopropylethyl amine hydrochloride or mixtures thereof.

The term “acid” herein the present invention is selected from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like; organic acids such as methane sulfonic acid, 2, 5 -dihydroxy benzoic acid, ethane di sulfonic acid, p-toluene sulfonic acid (PTSA), benzene sulfonic acid, ethane di sulfonic acid, ethane sulfonic acid, naphthalene di sulfonic acid, naphthalene-2- sulfonic acid, camphor sulfonic acid, acetic acid, oxalic acid, fumaric acid, maleic acid, oleic acid, malic acid, adipic acid, stearic acid, cinnamic acid, succinic acid, malonic acid, mandelic acid, palmitic acid, lactic acid, citric acid, tartaric acid, gentisic acid, cyclamic acid, D-glucuronic acid, glycolic acid, isethionic acid, saccharine, salicylic acid, naphthal ene-l,5-disulfonic acid and the like.

Accordingly, in the first embodiment, the present invention provides a process for the preparation of Asciminib salts (1), is having a purity greater than 99.5% by HPLC, as illustrated in Scheme 2.

Scheme-2

In another embodiment, the steps involved in the preparation of Asciminib salts (1) as shown in scheme 2 are as follows:

Step a) of the foregoing process involves reacting methyl 5-bromo-6-chloronicotinate (10) with (R)-pyrrolidin-3-ol (9) in the presence of a base selected from organic bases, such as dimethylamine, diethylamine, diisopropylamine, diisopropylethylamine (DIPEA), di isobutyl amine, trimethylamine, triethylamine, tri isopropyl amine, tributylamine, tert-butylamine, pyridine, piperidine, 4-dimethylamino pyridine (DMAP), or mixtures thereof, with Diisopropylethylamine (DIPEA) being particularly preferred. The reaction is carried out in a suitable solvent, such as ester solvents including ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec butyl acetate, isopropyl acetate, and the like, with ethyl acetate being most preferred. The reaction is performed under appropriate conditions, at a temperature from about 70°C to about 80°C, and maintained for a sufficient period of time to ensure the completion of the reaction, yielding the compound of formula (8).

The step b) of the forgoing process involves reacting the compound of formula (8) with l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-5-boronic acid, pinacol ester of formula (7) in the presence of metal complex catalyst selected from from [(o- tol)₃P]₂PdC12, [t-Bu3PPdBr]2/Pd-113, (dtbpf)PdC12/Pd-118, PEPPSI, PdCl₂(PPh₃)₂, Pd(tBu₂PhP)₂, Pd(dppf)C12.CH₂C12, [(t-Bu)₃P]Pd(0), CataCXium C, Pd(tBu₂PhP)₂(Pd-122), Pd(dppf)Cl₂— CH₂C1₂ (Pd-106), (2-MeOPh)₃P/Pd₂(dba)₃, and PdC12(Amphos)2/Pd-132, preferably PdC12(Amphos)2; and a base selected from "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like, preferably sodium bicarbonate; in a solvent selected from “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 2-methyl tetrahydrofuran, 1,4-di oxane and the like; and water and/or mixtures thereof, preferably 1,4-di oxane and water to provide methyl 6-((R)-3- hydroxypyrrolidin-l-yl)-5-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl)nicotinate (6). The step b) reaction is carried out at a suitable temperature from about 85°C to about 100°C temperature of the solvent used and maintain for a sufficient period till completion of the reaction.

The step c) of the forgoing process involves reacting the compound the compound of formula (6) with a base selected from "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and the like; preferably sodium hydroxide; in a suitable solvent selected from “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; preferably methanol; followed by isolation using suitable solvent selected from “ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, secbutyl acetate, isopropyl acetate and the like, preferably ethyl acetate under appropriate reaction conditions to provide 6-((R)-3-hydroxypyrrolidin-l-yl)-5-(l-(tetrahydro-2H- pyran-2-yl)-lH-pyrazol-5-yl)nicotinic acid (5). The step c) reaction is carried out at a suitable temperature from about 25°C to about reflux temperature of the solvent used and maintain for a sufficient period till completion of the reaction.

The step d) of the forgoing process involves coupling compound of formula (5) with 4-(chloro difluoromethoxy)aniline (4) or its salt thereof in the presence of coupling agent selected from carbonyl-diimidazole (CDI), carbonyl-di(l,2,4-triazole), l-(3- dimethylaminopropyl)-3 -ethylcarbodiimide hydrochloride (EDC-HC1), di cyclohexyl carbodiimide (DCC) and propane phosphonic acid cyclic anhydride (PPA); additive selected from 1 -hydroxy benzotriazole (HOBt), l-hydroxy-7-azabenzotriazole (HO At), 6-chloro-l-hydroxy-lH-benzotriazole (Cl-HOBt), hydroxy pyridines (HOPy), Imidazole or its salts; a base selected from organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine (DIPEA), di isobutyl amine, trimethylamine, triethylamine, tri isopropylamine, tributylamine, tert-butyl amine, pyridine, piperidine, 4-dimethylamino pyridine (DMAP) or mixtures thereof, preferably Diisopropylethylamine (DIPEA); in a solvent selected from “polar aprotic solvents” such as dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like; preferably N, N-dimethylformamide to provide N-(4- (chlorodifluoromethoxy)phenyl)-6-((R)-3-hydroxypyrrolidin-l-yl)-5-(l-(tetrahydro- 2H-pyran-2-yl)-lH-pyrazol-5-yl) nicotinamide (3). The step d) reaction is carried out at a suitable temperature from about 40°C to about 70°C temperature of the solvent used and maintain for a sufficient period till completion of the reaction.

The step d) of the forgoing process also involves reacting the compound of formula (6) with 4-(chloro difluoromethoxy)aniline (4) or its salt thereof in the presence of a base selected from "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and the like, preferably potassium tert-butoxide; in a solvent selected from “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 2-methyl tetrahydrofuran, 1,4-di oxane and the like; preferably 2-methyl tetrahydrofuran to provide N-(4-(chlorodifluoromethoxy)phenyl)-6-((R)-3-hydroxypyrrolidin-l-yl)-5- (l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl)nicotinamide (3). The step d) reaction is carried out at a suitable temperature from about 25°C to about 35°C temperature of the solvent used and maintain for a sufficient period till completion of the reaction.

The step d) of the forgoing process also involves reacting the compound of formula (8) with l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-5-boronic acid, pinacol ester of formula (7) in the presence of metal complex catalyst selected from [(o-tol)₃P]2PdC12, [t-Bu3PPdBr]2/Pd-113, (dtbpf)PdC12/Pd-118, PEPPSI, PdCl₂(PPh₃)₂, Pd(tBu₂PhP)₂, Pd(dppf)C12.CH₂C12, [(t-Bu)₃P]Pd(0), CataCXium C, Pd(tBu₂PhP)₂(Pd-122), Pd(dppf)C12 — CH2CI2 (Pd-106), (2-MeOPh)₃P/Pd2(dba)₃, and PdC12(Amphos)2/Pd- 132, preferably PdC12(Amphos)2; and a base selected from "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like, preferably sodium bicarbonate; in a solvent selected from “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 2- methyl tetrahydrofuran, 1,4-di oxane and the like; and water and/or mixtures thereof, preferably 1,4-di oxane and water, followed by reacting with 4-(chloro difluoromethoxy)aniline (4) or its salt thereof in the presence of a base selected from "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tert- butoxide, potassium tert-butoxide, lithium tert-butoxide and the like, preferably potassium tert-butoxide; in a solvent selected from “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, 2-methyl tetrahydrofuran, 1,4- dioxane and the like; preferably 2-methyl tetrahydrofuran, which on further isolation to provide compound of formula (3).

The step e) of the forgoing process involves reacting the compound of formula (3) with an acid selected from sulfuric acid, hydrochloric acid, phosphoric acid, and the like; preferably hydrochloric acid; in a solvent selected from “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; preferably methanol, followed by treated with (+)-Dibenzoyl-D-tartaric acid (DBTA) to provide Asciminib as DBTA salt of formula (2a). Wherein Asciminib as DBTA salt of formula (2a) obtained in step e) is amorphous in nature.

The step f) of the forgoing process involves converting the compound of formula (2a) to Asciminib of formula (2) by treating with a base selected from alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like, preferably sodium carbonate. Wherein Asciminib free base obtained in step f) is amorphous in nature.

The step g) of the forgoing process involves optionally converting the Asciminib of formula (2) to Asciminib salt (1) in presence of hydrochloric acid in a suitable solvent, to the reaction mixture, pharmaceutically acceptable excipient was added. The pharmaceutically acceptable excipient selected from polyvinylpyrrolidone (PVP), polyvinylpyrrolidone K-30, (PVP K-30), Copovidone, povidone, magnesium stearate, polyvinyl acetate hydroxyethyl cellulose (HEC), hydroxy propyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxy propyl methyl cellulose acetate succinate (HPMC-AS), hydroxy propyl methyl cellulose -E3, (HPMC-E3), Soluplus, Neusilin, Salcaprozate sodium, Sodium caprylate, Eudragit, Eudragit-EPO, Dicalcium phosphate (DCP), croscarmellose, sodium croscarmellose, a-cyclodextrin, P-Cyclodextrin, y-cyclodextrin, hydroxypropyl beta cyclodextrin (HPBCD), Sulfobutylether-P-cyclodextrin (SBCED) or the like, preferably Hydroxypropyl methylcellulose; in a solvent selected from “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; preferably methanol.

In another embodiment, the compound of formula (6), (5), and (2a) can be prepared in-situ and proceeds to next steps without further purification. wherein the preparation of solid dispersion of Asciminib hydrochloride does not involves isolation of Asciminib hydrochloric acid salt. In another embodiment, wherein the solid dispersion of Asciminib hydrochloride so obtained according to the present invention could be amorphous or crystalline.

In the second embodiment, the present invention provides a process for the purification of Asciminib (2) and its salts (1), which involves dissolving Asciminib (1) and its salts in a suitable solvent, followed by cooling the solution to a suitable temperature. The final step of the process is the isolation of pure Asciminib (1) and its salts. In one embodiment, the suitable solvent used in the first step is selected from alcohol solvents or hydrocarbon solvents, with methanol or n-heptane being particularly preferred.

In the third embodiment, the present invention provides a process for preparing solid dispersion of Asciminib hydrochloride with at least one pharmaceutically acceptable excipient from Asciminib salt, comprising the following steps: i. dissolving Asciminib salt in a suitable solvent; ii. adjusting the pH of the solution using a suitable base; iii. adding a suitable solvent to the reaction mixture; iv. adding hydrochloric acid to the reaction mixture; v. adding at least one pharmaceutically acceptable excipient to the reaction mixture; and vi. isolating the solid dispersion of Asciminib hydrochloride.

In another embodiment, the suitable solvent used in the first step is selected from ester solvents and water and/or mixture thereof, with ethyl acetate and water being particularly preferred.

In another embodiment, the salt used in step i. is selected from oxalic acid, succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, tartaric acid, lactic acid, acetic acid, ‘fumaric acid, benzoic acid, benzenesulfonic acid, citric acid, camphor sulfoicacid, ethane sulfonic acid, gluconic acid, glutamic acid, methanesulfonic acid, para toluene sulfonic acid, with (+)-dibenzoyl-D-tartaric acid being used. In another embodiment, Asciminib (+) DBTA salt used in step i) is amorphous in nature and X-Ray powder diffractogram as shown in figure-3.

In another embodiment, the suitable base used in the second step is selected from "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and the like, with sodium hydroxide being particularly preferred.

In another embodiment, pharmaceutically acceptable excipient selected from polyvinylpyrrolidone (PVP), polyvinylpyrrolidone K-30, (PVP K-30), Copovidone, povidone, magnesium stearate, polyvinyl acetate hydroxyethyl cellulose (HEC), hydroxy propyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxy propyl methyl cellulose acetate succinate (HPMC-AS), hydroxy propyl methyl cellulose -E3, (HPMC-E3), Soluplus, Neusilin, Salcaprozate sodium, Sodium caprylate, Eudragit, Eudragit-EPO, Dicalcium phosphate (DCP), croscarmellose, sodium croscarmellose, a-cyclodextrin, P-Cyclodextrin, y-cyclodextrin, hydroxypropyl beta cyclodextrin (HPBCD), Sulfobutylether-P-cyclodextrin (SBCED) or the like, preferably Hydroxypropyl methylcellulose-E3.

In the fourth embodiment, the present invention provides a process for preparing solid dispersion of Asciminib hydrochloride from Asciminib (2), comprising the following steps:

A. dissolving Asciminib (2) in a suitable solvent;

B. adding hydrochloric acid to the reaction mixture;

D. isolating the solid dispersion of Asciminib hydrochloride.

Wherein Asciminib free base used in step A is amorphous in nature. In another embodiment, the suitable solvent used in the first step is selected from “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like, with methanol being particularly preferred.

In another embodiment, the pharmaceutically acceptable excipient is selected from the list as defined above, preferably Hydroxypropyl methylcellulose-E3.

In another embodiment, isolating involve removal of solvent is carrying out by suitable techniques which includes but not limited to decantation, evaporation under reduced pressure, flash evaporation, vacuum drying, concentrating the reaction mixture, atmospheric distillation, distillation under reduced pressure, distillation by using a rotational distillation device such as Buchi rotavapor, agitated thin film drying (ATFD), melt extrusion, spray drying, freeze drying (lyophilization), spray-freeze drying, cooling the clear solution to lower temperatures to precipitate the solid followed by filtration by gravity or suction, thin film drying, centrifugation or any other suitable techniques known in the art.

In another embodiment, drying solid dispersion of Asciminib hydrochloride by a 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 can be carried out at atmospheric pressure or under reduced pressures at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures. The drying can be carried out for any period required to obtain the desired quality, such as from about 15 minutes to 10 hours or longer.

In the fifth embodiment, the present invention provides a process for the preparation of (R)-pyrrolidin-3-ol (8). The process involves dissolving (2R, 4R)-4- hydroxypyrrolidine-2-carboxylic acid in cyclohexanone, resulting in the formation of (R)-pyrrolidin-3-ol (8). In the sixth embodiment, the present invention provides a process for the preparation of l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-5-boronic acid, pinacol ester of formula (6). The process comprises two key steps: (a) converting IH-pyrazole to l-(tetrahydro- 2H-pyran-2-yl)-lH-pyrazole, and (b) further converting l-(tetrahydro-2H-pyran-2- yl)-lH-pyrazole to l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-5-boronic acid, pinacol ester of formula (6).

In the seventh embodiment, the present invention provides a process for the preparation of methyl 5-bromo-6-chloronicotinate (9). The process comprises three steps: (a) brominating 6-hydroxynicotinic acid with bromine in acetic acid to obtain 5-bromo-6-hydroxynicotinic acid; (b) chlorinating 5-bromo-6-hydroxynicotinic acid with phosphorus chloride in the presence of tetramethylammonium chloride in toluene to produce 5-bromo-6-chloronicotinic acid; and (c) esterifying 5-bromo-6- chloronicotinic acid to yield methyl 5-bromo-6-chloronicotinate (9).

In the eighth embodiment, the present invention is to provide a process for the preparation of 4-(chloro difluoromethoxy) aniline (3), which is illustrated in scheme

Scheme-3

In the nineth embodiment, the present invention provides Asciminib hydrochloride (1) is purity greater than 99% by HPLC, preferably greater than 99.5% by HPLC, more preferably greater than 99.9% by HPLC with total impurities less than 1.0%, more preferably less than 0.5%.

In the tenth embodiment, the present invention provides Asciminib hydrochloride (1) obtained according to the present invention is having loss on drying less than 5.0% (w/w), preferably less than 3.0% (w/w). In the eleventh embodiment, the present invention provides Asciminib hydrochloride (1) obtained in the present invention is free of any degradation impurities preferably less than 0.15% and more preferably less than 0.10%(w/w).

In the twelfth embodiment, the present invention provides Asciminib hydrochloride (1) obtained in the present invention have Acid impurity and THP impurity are less than

0.15% and more preferably less than 0.10% (w/w)

Acid impurity THP impurity

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.

EXAMPLES

Example 1: Preparation of (R)-methyl 5-bromo-6-(3-hydroxypyrrolidin-l-yl) nicotinate (8)

Methyl 5-bromo-6-chloronicotinate (10) (100 g) was dissolved in ethyl acetate (500 mL) with (R)-pyrrolidin-3-ol (9) (45 g) and diisopropylethylamine (110 g) at room temperature. The mixture was heated to 70-85°C and stirred. Upon completion, the reaction was cooled to room temperature, and IN hydrochloric acid (500 mL) was added. The organic layer was separated, and additional ethyl acetate was added to the aqueous layer, stirred, and separated again. The combined organic layers were washed with water and sodium chloride solution and the solvent was distilled off. Methyl tertbutyl ether (200 mL) was added, and n-heptane (500 mL) was then added and stirred. The solid was filtered, washed with heptane, and dried to yield the title compound. Yield: 90%; Purity: >95%.

Example 2: Preparation of methyl 6-((R)-3-hydroxypyrrolidin-l-yl)-5-(l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl) nicotinate (6)

A mixture of Sodium bicarbonate (42 gm), water (90 ml) and 1,4-di oxane (180 ml) was added to l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazole-5-boronic acid, pinacol ester (7) (34 gm). To this, (R)-methyl 5-bromo-6-(3-hydroxypyrrolidin-l-yl) nicotinate (8) (30 gm) was added under nitrogen pressure. [Bis(di-tert-butyl(4- dimethylaminophenyl) phosphine) dichloro palladium (II)] (Pd(amphos)C12) (150 mg) was added to the reaction mass and stirred. Then, the reaction mass was heated to 90- 95°C. On completion of the reaction, the reaction mass was cooled to room temperature. Filtered the reaction mass and washed with ethyl acetate. Ethyl acetate and water (1 : 1) ratio was added and stirred for 5-10 min. Layers were separated. The aqueous layer was extracted with ethyl acetate. The organic layer was combined and washed with 10% sodium chloride and distilled off the organic layer under vacuum to get the titled compound. Purity: >95%

Example 3: Preparation of 6-((R)-3-hydroxypyrrolidin-l-yl)-5-(l-(tetrahydro- 2H-pyran-2-yl)-lH-pyrazol-5-yl) nicotinic acid (5)

Methyl 6-((R)-3 -hydroxypyrrolidin- 1 -y l)-5 -( 1 -(tetrahydro-2H-pyran-2-yl)- 1H- pyrazol-5-yl) nicotinate (6) (34 gm) was dissolved in methanol (102 ml) at room temperature. The reaction mass was cooled to 15 to 5°C, then 15% sodium hydroxide was slowly added to the reaction mass and stirred to room temperature. After completion of the reaction, distilled out the solvent completely under vacuum below 50°C.10% sodium chloride was added to the residue and the reaction mass was washed with toluene. The toluene layer was washed with water. To the aqueous layer 2-methyl tetrahydrofuran (5 volumes) was added and the pH of the reaction mass was adjusted to 4-4.5 by adding hydrochloric acid and stirred. Layers were separated. Aqueous layer back extracted with 2-methyl tetrahydrofuran. The organic layer was combined and washed with 10% sodium chloride and distilled the organic layer under vacuum at 40- 50°C to get the crude compound. Ethyl acetate (2 volumes) was added to the crude at room temperature and heated to 50-55°C. The reaction mass was stirred and cooled to room temperature, further cooled to 0-5°C. Filtered the reaction mass and dried to get the title compound. Yield: >98%. Purity: >95%

Example 4: Preparation of N-(4-(chloro difluoromethoxy) phenyl)-6-((R)-3- hydroxypyrrolidin-l-yl)-5-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl) nicotinamide (3)

6-((R)-3-hydroxypyrrolidin-l-yl)-5-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl) nicotinic acid (5.0 g) (5) was dissolved in DMF (50ml) at room temperature. To this 4-(chloro difluoromethoxy) aniline (1.88 gm) (4), HOBt (0.75 g) and EDC.HC1 (4.52 g) was added to the reaction mass, then DIPEA (4.0 ml) was added and stirred for 60- 90 minutes. The reaction mass was heated to 50-60°C. On completion of the reaction, the reaction mass was cooled to room temperature, then chilled water (5 volume) and ethyl acetate (5 volume) was added and stirred. Layers were separated. Aqueous layer was extracted with ethyl acetate. Neutral carbon (2 gm) was added to the organic layer at 60-65°C. Filtered the reaction mass and the total filtrate was distilled off under vacuum at 50°C to get the title compound. Purity: >95%

Example 5: Alternative preparation of N-(4-(chloro difluoromethoxy) phenyl)-6- ((R)-3-hydroxypyrrolidin-l-yl)-5-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5- yl) nicotinamide (2)

Methyl 6-((R)-3 -hydroxypyrrolidin- 1 -yl)-5-(l -(tetrahydro-2H-pyran-2-yl)- 1H- pyrazol-5-yl) nicotinate (6) (6 gm) and 2-methyl tetrahydrofuran (30 ml) were added under nitrogen pressure at room temperature, then 4-(chloro difluoromethoxy) aniline (1.88 gm) (4) and potassium tert-butoxide (5 gm) were added. The reaction mass was stirred for 1-2 hours. After completion of the reaction, 10% sodium chloride was added to the reaction mass. Layers were separated. The aqueous layer was back extracted with tetrahydrofuran (3 volumes). The organic layer was combined and washed with sodium chloride solution. The organic layer was treated with activated carbon and stirred. Distilled off the filtrate under vacuum to get the residue. Isopropyl alcohol (3.5 ml) was added the residue, then heptane was added and stirred. The reaction mass was cooled to 0-5°C and stirred. Filtered the solid and washed with heptane to get the title compound. Purity: >95% Example 6: Alternative preparation of N-(4-(chloro difluoromethoxy) phenyl)-6- ((R)-3-hydroxypyrrolidin-l-yl)-5-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5- yl) nicotinamide (3)

(R)-Methyl 5-bromo-6-(3-hydroxypyrrolidin-l-yl) nicotinate (8) (100 g) was added to water (300 mL), sodium bicarbonate (140 g), 1,4-di oxane (600 mL), and 1- (tetrahydro-2H-pyran-2-yl)-lH-pyrazole-5-boronic acid pinacol ester (7) (110 g) at room temperature under nitrogen. Pd(amphos)C12 (500 mg) was added, and the mixture was stirred. The reaction mass was heated to 75-85°C until completion, then cooled to room temperature. The mixture was filtered, and the solid was washed with 1,4-dioxane. Toluene (500 mL) and water (500 mL) were added to the filtrate and stirred. The organic layer was separated, and toluene was added to the aqueous layer and stirred. The combined toluene layers were washed with sodium chloride solution. The organic layer was treated with L-cysteine (15 g) and Ultra-DX carbon (10 g), heated to 60-70°C, then cooled to room temperature, filtered, and washed with toluene. The filtrate was co-distilled with 2-methyl tetrahydrofuran to obtain compound (5).

To this compound, 2-methyl tetrahydrofuran (300 mL) was added under nitrogen, and the reaction was cooled to 0-5°C. 4-(Chloro difluoromethoxy) aniline (4) (64 g) in tetrahydrofuran and 20% potassium tertiary butoxide (578 g) in THF were added, and the mixture was stirred. Upon completion, 10% ammonium chloride solution (1000 mL) was added and stirred. The organic layer was separated, and 2-methyl tetrahydrofuran (300 mL) was added to the aqueous layer and stirred. The organic layers were washed with sodium chloride solution (300 mL). The organic layer was treated with Ultra-DX carbon (10 g), stirred, filtered, and washed with tetrahydrofuran. The filtrate was distilled under vacuum.

Ethyl acetate (700 mL) and heptane (300 mL) were added to the residue at room temperature, heated to 70-80°C, then cooled to room temperature. The solid was filtered, washed with heptane (100 mL), and dried to yield the title compound with an 85% yield.

Example 7: Preparation of N-[4(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3- hydroxypyrrolidin-l-yl]-5-(lH-pyrazol-3-yl) pyridine-3-carboxamide (2) N-(4-(chloro difluoromethoxy) phenyl)-6-((R)-3-hydroxypyrrolidin-l-yl)-5-(l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl) nicotinamide (3) (100 g) was dissolved in methanol (1500 mL) at room temperature. The reaction mixture was cooled to 10- 15°C, and concentrated hydrochloric acid (25 mL) in methanol (500 mL) was added. After stirring, the pH was adjusted to 4.0-5.0 with sodium hydroxide solution at 0- 5°C, then further adjusted to 7.5-8.5 with 1% sodium hydroxide solution. The solvent was distilled off, and the mixture was cooled to 25-35°C. Ethyl acetate (1000 mL) and water (1000 mL) were added and stirred. The organic layer was separated, and the aqueous layer was extracted with additional ethyl acetate. The combined ethyl acetate layers were washed with 10% sodium chloride solution (300 mL), treated with Ultra- DX carbon (10 g), filtered, and the solvent distilled off under vacuum. (+)-Dibenzoyl- D-tartaric acid (68 g) was added, and the mixture was heated to 70-80°C, then cooled to 25-35°C and filtered. The solid was washed with ethyl acetate (100 mL) and further treated with ethyl acetate (800 mL), heated, cooled, filtered, and washed again. The wet solid was added to ethyl acetate (1000 mL), treated with 10% sodium carbonate solution (500 mL), and stirred. The organic layer was separated, washed with sodium chloride solution, distilled under vacuum, and degassed. Heptane (400 mL) was added, and the solid was filtered, washed with heptane, and dried to yield the title compound (86%). Purity: >99%. The PXRD pattern of the obtained compound is illustrated in figure-2.

Example 8: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3)

N-[4-(Chloro difluoromethoxy )phenyl]-6-[(3 R)-3-hy droxypyrrolidin- 1 -yl]-5-(lH- pyrazol-3-yl)pyridine-3 -carboxamide (2) was dissolved in methanol (3000 mL) at 25- 35°C. Concentrated hydrochloric acid (30 mL) was added, and the mixture was stirred. Hydroxypropyl methylcellulose-E3 (150 g) was then added, and the reaction mass was heated to 60-65°C while stirring. The reaction mixture was filtered, and the resulting solution was spray-dried to obtain an amorphous solid dispersion of Asciminib hydrochloride (1) with Hydroxypropyl methylcellulose-E3. Yield: 80%. Purity: >99.95. The PXRD pattern of the obtained compound is illustrated in figure-1.

Example 9: Preparation of Asciminib hydrochloride (la) N-(4-(chloro difluoromethoxy) phenyl)-6-((R)-3-hydroxypyrrolidin-l-yl)-5-(l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl) nicotinamide (3) (2 gm) was dissolved in methanol (16 ml) at room temperature. To this 37% hydrochloric acid was added at the same temperature for 1-2 hours. On completion of the reaction, 30% sodium hydroxide (2 ml) solution and neutral carbon was added to the reaction mass at 50°C and stirred for 30 minutes. The pH of the filtrate was adjusted to 3-3.5 using 30% sodium hydroxide solution, then the seeding compound was added and stirred for 10 minutes. Cooled the reaction mass to 0-5°C. The pH of the reaction mass was adjusted to 7.5-9.0 using aqueous 1% sodium hydroxide solution and stirred the reaction mass at 5-10°C for 2-3 hours. Filtered the solid and washed with water. To the obtained wet solid, methanol (5 volumes) and 37% hydrochloric acid (1.5 equivalent) was added and stirred at room temperature. The reaction mass was cooled to 0-5°C. Filtered the solid and dried under vacuum to get the title compound. Purity: >99%.

Example 10: Preparation of amorphous solid dispersion of Asciminib hydrochloride (1) with Hydroxypropyl methylcellulose-E3 (HPMC-E3)

A mixture of ethyl acetate (5 volume), water (5 volume) and 100 g of Asciminib (+)- dibenzoyl tartaric acid salt were added at room temperature. pH of the reaction mass was adjusted to 9-10 using 10% sodium carbonate solution. The reaction mass was extracted with ethyl acetate. Distilled the ethyl acetate layer. The crude compound was dissolved in methanol (150 mL) at room temperature and stirred. To this 18-20% methanolic hydrochloric acid was added at the same temperature. The obtained solution was added to Hydroxypropyl methylcellulose (12.5 g) and stirred for 15 to 30 minutes at the same temperature. The reaction mixture was spray dried to obtain amorphous solid dispersion of Asciminib hydrochloride (1) with Hydroxypropyl methylcellulose-E3.

Claims

We claim:

1. A process for the preparation of Asciminib hydrochloride of formula (1)

which comprises: a) reacting the methyl 5-bromo-6-chloronicotinate of formula (10)

with (R)-pyrroli din-3 -ol (9)

HN V"^OH

(9) in the presence of a base to provide (R)-methyl 5-bromo-6-(3- hydroxypyrrolidin-l-yl) nicotinate (8);

b) reacting the compound of formula (8) and l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazole-5-boronic acid, pinacol ester of formula (7)

in the presence of a base and a metal complex catalyst to provide methyl 6-((R)- 3-hydroxypyrrolidin-l-yl)-5-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl) nicotinate (6);

c) reacting the compound of formula (6) with a base to provide to 6-((R)-3- hydroxypyrrolidin-l-yl)-5-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl) nicotinic acid (5);

d) reacting the compound of formula (5) with 4-(chloro difluoromethoxy) aniline

(4) or a salt thereof

in the presence of a coupling agent, an additive and a base to provide N-(4- (chloro difluoromethoxy) phenyl)-6-((R)-3 -hydroxypyrrolidin- 1 -yl)-5-( 1 - (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl) nicotinamide (3);

(or) reacting the compound of formula (6) with 4-(chloro difluoromethoxy) aniline (4) or a salt thereof in the presence a base to provide compound of formula (3); (or) reacting the compound of formula (8) with the compound of formula (7) in the presence of a base and a metal complex catalyst to provide methyl 6-((R)-3- hydroxypyrrolidin-l-yl)-5-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl) nicotinate (6), followed by reacting with a 4-(chloro difluoromethoxy)aniline (4) or a salt thereof in the presence a base to provide compound of formula (3);

e) converting the compound of formula (3) to Asciminib as (+) DBTA salt of formula (2a);

Asciminib (+) DBTA Salt (2a) f) converting Asciminib (+) DBTA salt of formula (2a) to Asciminib of formula (2) using a base. g) converting Asciminib of formula (2) to Asciminib hydrochloride (1) and subsequently to an amorphous solid dispersion with pharmaceutically acceptable excipient.

2. The process as claimed in claim 1, wherein the base is selected from “alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tert-butoxide, potassium tert- butoxide, lithium tert-butoxide and the like; organic bases like dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine (DIPEA), di isobutyl amine, trimethylamine, triethylamine, tri isopropyl amine, tributylamine, tert-butyl amine, pyridine, piperidine, 4-dimethylamino pyridine (DMAP) or mixtures thereof;

3. The process as claimed in claim 1, wherein the metal complex catalyst is selected from [(o-tol)₃P]₂PdC12, [t-Bu3PPdBr]2/Pd-113, (dtbpf)PdC12/Pd-118, PEPPSI, PdCl₂(PPh₃)₂, Pd(tBu₂PhP)₂, Pd(dppf)C12.CH₂C12, [(t-Bu)₃P]Pd(0), CataCXium C, Pd(tBu₂PhP)₂(Pd-122), Pd(dppf)Cl₂— CH₂C1₂ (Pd-106), (2-MeOPh)₃P/Pd₂(dba)₃, and PdC12(Amphos)2/Pd-132.

4. The process as claimed in claim 1, wherein the suitable coupling agent comprises carbonyl-diimidazole (CDI), carbonyl-di(l,2,4-triazole), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HC1), dicyclo hexyl carbodiimide (DCC), propane phosphonic acid cyclic anhydride (PPA) and/or mixtures thereof; and the suitable additive comprises 1 -hydroxy benzotriazole (HOBt), l-hydroxy-7-azabenzotriazole (HOAt), 6-chloro-l -hydroxy - IH-benzotriazole (Cl-HOBt), hydroxy pyridines (HOPy), Imidazole or its salts, 1,8- Diazabicyclo[5.4.0]undec-7-en (DBU) and/or mixtures thereof.

5. The process as claimed in claim 1, wherein the reaction of step e) is carried out in the presence of acid selected from sulfuric acid, hydrochloric acid, phosphoric acid, and the like.

6. The process as claimed in claim 1, wherein the solvent in each step is carried out in the presence of a suitable solvents selected from water, alcoholic solvent, ethers, polar aprotic solvents, esters and/or mixtures thereof.

7. A process for preparing solid dispersion of Asciminib hydrochloride from Asciminib salt, comprising the following steps: i. dissolving Asciminib salt in a suitable solvent; ii. adjusting the pH of the solution using a suitable base; iii. adding a suitable solvent to the reaction mixture; iv. adding hydrochloric acid to the reaction mixture; v. adding a suitable excipient to the reaction mixture; and vi. isolating the solid dispersion of Asciminib hydrochloride.

8. The process as claimed in claim 7, wherein the salt is selected from oxalic acid, succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, tartaric acid, lactic acid, acetic acid, ‘fumaric acid, benzoic acid, benzenesulfonic acid, citric acid, ethane sulfonic acid, gluconic acid, glutamic acid, methanesulfonic acid, para toluene sulfonic acid and (+)-dibenzoyl-D-tartaric acid.

9. A process for preparing solid dispersion of Asciminib hydrochloride from Asciminib (2), comprising the following steps:

A. dissolving Asciminib (2) in a suitable solvent;

B. adding hydrochloric acid to the reaction mixture;

C. adding a suitable excipient to the reaction mixture; and

D. isolating the amorphous solid dispersion of Asciminib hydrochloride.

Wherein Asciminib used in step A is amorphous.

10. The process as claimed in claim 7 and 9, wherein the solvent is selected from alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; “ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; water or its mixture thereof.

11. The process as claimed in any of the proceeding claims, wherein the pharmaceutically acceptable excipient is selected from but not limited to polyvinylpyrrolidone (povidone or PVP), polyvinylpolypyrrolidone, Polyvinylpyrrolidone-K-30 (PVP-K-30), cross linked polyvinyl pyrrolidone (crospovidone), polyethylene glycol (macrogol or PEG), propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), , hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl beta cyclodextrin (HPpCD), Salcaprozate sodium, sodium caprylate, Soluplus, hydroxypropyl methyl cellulose-E3 (hypromellose or HPMC-E3), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose-ES (HPMC-ES), hydroxyethyl methyl cellulose succinate (HEMCS), sulfobutylether-P-cyclodextrin (SBCED), Hydroxypropyl methylcellulose-E3 (HPMC-E3), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), syloid, eudragit, copovidone, maltodextrin, mannitol or isomalt.

12. Compound of Asciminib (+) DBTA salt of formula (2a) with purity at least 99.0% (w/w) by HPLC.