DESC:Field of invention
The present invention relates to an improved process for the preparation of Asciminib HCl comprising novel process intermediates. The invention also described the novel polymorphic forms of Asciminib and its pharmaceutical salts.

Background of invention
The N-[4­(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-3-yl)pyridine-3-carboxamide hydrogen chloride is commonly known as Asciminib HCl, which has the following chemical structure of compound 1:

Compound-1
Asciminib HCl is marketed under brand name Scemblix, which is indicated for the treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase (Ph+ CML-CP) previously treated with two or more tyrosine kinase inhibitors.
The WO2020230099 described crystalline forms of Asciminib hydrochloride and Asciminib.
The WO 2021154980 described the amorphous and crystalline forms of Asciminib and its salts.
The WO2022206937 described the crystalline forms of Asciminib Hydrochloride Form-L, Form-F and Form-J.
There is still a need to develop further solid-state forms of Asciminib salts to meet the pharmaceuticals requirements.
Since the development of new polymorphic forms of an active pharmaceutical ingredient provides new opportunity to improve the performance characteristics of pharmaceutical finished product, the development of new polymorphic form is always encouraged.
The present inventors have developed novel polymorphs of Asciminib salts, which are useful for the preparation of pure Asciminib HCl and also in various pharmaceutical compositions.
Summary of invention:
The first aspect of the present invention provides novel crystalline forms of Asciminib acid addition salts, which are useful in the preparation of pure Asciminib HCl.
The second aspect of the present invention provides a process for the preparation of amorphous Asciminib HCl of formula-1 using novel acid addition salts of Asciminib.
The third aspect of the present invention provides amorphous solid dispersions comprising Asciminib HCl of formula-1 and one or more pharmaceutically acceptable excipients as well as its process for the preparation using novel acid addition salts of Asciminib.
The fourth aspect of the present invention provides a process for the preparation of crystalline form-A of Asciminib HCl of formula-1 from acid addition salts of Asciminib.
The fifth aspect of the present invention provides an improved process for the preparation of Asciminib HCl of Formula-1.

Description of Diagrams:

FIG-1: Illustrates the X-ray powder diffractogram of crystalline Asciminib nitric
acid.
FIG-2: Illustrates the X-ray powder diffractogram of crystalline Asciminib
monomethyl oxalic acid.
FIG-3: Illustrates the differential scanning calorimetry of crystalline Asciminib
nitric acid.
FIG-4: Illustrates the differential scanning calorimetry of crystalline Asciminib
monomethyl oxalic acid.
FIG-5: Illustrates the X-ray powder diffractogram of amorphous form of Asciminib
HCl of Formula-1.
FIG-6: Illustrates the X-ray powder diffractogram of amorphous solid dispersion
comprising Asciminib HCl and Hydroxypropylcellulose (HPC).
FIG-7: Illustrates the X-ray powder diffractogram of amorphous solid dispersion
comprising Asciminib HCl and Povidone.
FIG-8: Illustrates the X-ray powder diffractogram of amorphous solid dispersion
comprising Asciminib HCl and Copovidone.

Detail description of invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" selected from aliphatic hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, petroleum ether and the like; and aromatic hydrocarbon solvents such as toluene, xylene and the like; "ether solvents" such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, monoxime, dioxime and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as N, N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone (NMP) and the like; "chlorinated solvents" such as dichloromethane/ methylene chloride, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone 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, tert.amyl alcohol, t-butanol and the like; "polar solvents" such as water or mixtures thereof.
As used herein the present invention, the term "anti-solvent" refers to a solvent which is used to precipitate the solid from a solution.
As used herein the present invention the term “suitable base” refers to “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 and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; Ammonia; and organic bases like dimethylamine, diethylamine, diisopropylamine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or mixtures thereof.

The first aspect of the present invention provides novel crystalline forms of Asciminib acid addition salts, which are useful in the preparation of pure Asciminib HCl. Wherein, the acid is preferably selected from oxalic acid, monomethyl oxalic acid, Para toluenesulfonic acid & Nitric acid.
In a preferred embodiment of the present invention provides novel crystalline form of Asciminib monomethyl oxalic acid of formula-9 hereinafter designated as “Form-N”, which is characterized by:
i) Its powder X-ray diffractogram having peaks at about 7.6, 10.2, 13.7, 15.7, 16.3, 19.9, 20.6, 22.0, 22.5, 23.8, 24.4 and 26.4 ± 0.2 degrees 2-theta.
ii) powdered X-ray diffraction pattern as shown in Figure-2.

In a preferred embodiment of the present invention provides a process for the preparation of crystalline form-N of Asciminib monomethyl oxalic acid of formula-9, comprising of:
a) Treating the compound of formula-8 with oxalic acid dihydrate in a suitable solvent,
b) heating the reaction mixture to a suitable temperature,
c) stirring the reaction mixture,
d) cooling the reaction mixture to a suitable temperature,
e) filtering the obtained solid and washed with a solvent to get the crystalline form-N of Asciminib monomethyl oxalic acid of formula-9.

Wherein in step-a) & e), the suitable solvent is selected from ether solvents, chloro solvents, ester solvents, alcohol solvents, ketone solvents, polar aprotic solvents, hydrocarbon solvents, nitrile solvents and polar solvents such as water or mixtures thereof.
In step-b), the suitable temperature used is ranging from 30°C to the reflux temperature of the solvent used;

In a preferred embodiment of the present invention provides a process for the preparation of crystalline form-N of Asciminib monomethyl oxalic acid of formula-9, comprising of:
a) Treating the compound of formula-8 with oxalic acid dihydrate in methanol,
b) heating the reaction mixture to 40-45°C,
c) stirring the reaction mixture,
d) cooling the reaction mixture to 0-5°C,
e) filtering the obtained solid and washed with methanol to get the crystalline form-N of Asciminib monomethyl oxalic acid of formula-9.

The second aspect of the present invention provides a process for the preparation of amorphous Asciminib HCl of formula-1 using novel acid addition salts of Asciminib.
In a preferred embodiment of the present invention provides a process for the preparation of amorphous Asciminib HCl of Formula-1, comprising of:
a) Treating the monomethyl oxalate salt of Asciminib of formula-9 with a suitable base and a solvent,
b) treating the compound obtained in step-a) with HCl in methanol,
c) distilled off the solvent and spray dried the filtrate obtained in step-b) to get amorphous Asciminib HCl of Formula-1.
Wherein,
The base used in above step-a) is selected from organic or inorganic base, preferably inorganic base.
The solvent used in step-a) & b) are selected from ester solvent and alcoholic solvents.

In a preferred embodiment of the present invention provides a process for the preparation of amorphous Asciminib HCl of Formula-1, comprising of:
a) Treating the monomethyl oxalate salt of Asciminib of formula-9 with sodium carbonate in Ethyl acetate,
b) treating the compound obtained in step-a) with HCl in methanol,
c) distilled off the solvent and spray dried the filtrate obtained in step-b) to get amorphous Asciminib HCl of Formula-1.

The third aspect of the present invention provides amorphous solid dispersions comprising Asciminib HCl of formula-1 and one or more pharmaceutically acceptable excipients as well as its process for the preparation using novel acid addition salts of Asciminib.
The “excipient “used herein is selected from but not limited to polyvinylpyrrolidone(povidone or PVP), polyvinylpolypyrrolidone, polysorbate, copovidone, crosslinked polyvinylpyrrolidone (crospovidone), polyethylene glycol (macrogol or PEG), polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, propylene glycol, cellulose, cellulose acetate phthalate (CAP), methyl cellulose, carboxymethyl cellulose (CMC, its sodium and calcium salts), carboxymethylethyl cellulose (CMEC), ethyl cellulose, hydroxymethyl cellulose, ethyl hydroxyethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropyl cellulose acetate succinate, hydroxypropyl methyl cellulose (hypromellose or HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxyethyl methyl cellulose succinate (HEMCS), hydroxypropyl cellulose acetate succinate (HPCAS), hydroxypropyl methylcellulose phthalate (HPMC-P), hydroxypropyl methylcellulose acetate phthalate, microcrystalline cellulose (MCC), crosslinked sodium carboxymethyl cellulose (croscarmellose sodium), crosslinked calciumcarboxymethyl cellulose and the like.
In the present invention, the ratio of the weight of Asciminib HCl to the weight of the excipient(s) within the solid dispersion ranges from but not limited to about 1:0.05 to 1:5.
In a preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising Asciminib HCl and one
or more pharmaceutically acceptable excipients, comprising of:
a) Treating the monomethyl oxalate salt of Asciminib of formula-9 with a suitable base and a solvent,
b) treating the compound obtained in step-a) with HCl in methanol,
c) providing a solution of Asciminib HCl and one or more excipients in a
solvent,
d) obtaining amorphous solid dispersion comprising Asciminib HCl and the corresponding excipient(s).
Wherein,
The base used in above step-a) is selected from organic or inorganic base, preferably inorganic base.
The solvent used in step-a) & c) are selected from ester solvent and alcoholic solvents.
The excipients used in above step-c) are preferably selected from Hydroxypropyl cellulose (HPC), Povidone and Copovidone.

In a preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising Asciminib HCl and Hydroxypropyl cellulose (HPC), comprising of:
a) Treating the monomethyl oxalate salt of Asciminib of formula-9 with sodium carbonate in Ethyl acetate,
b) treating the compound obtained in step-a) with HCl in methanol,
c) providing a solution of Asciminib HCl and Hydroxypropyl cellulose (HPC) in methanol,
d) obtaining amorphous solid dispersion comprising Asciminib HCl and Hydroxypropyl cellulose (HPC).

The amorphous solid dispersions obtained from the present invention are useful for the preparation of various pharmaceutical compositions.

The fourth aspect of the present invention provides a process for the preparation of crystalline form-A of Asciminib HCl of formula-1 from acid addition salts of Asciminib, wherein the acid addition salt is selected from oxalic acid or monomethyl oxalate, preferably monomethyl oxalate of Asciminib.
In a preferred embodiment of the present invention provides a process for the preparation of crystalline form-A of Asciminib HCl of formula-1, comprising of:
a) Treating the monomethyl oxalate salt of Asciminib of formula-9 with conc. HCl in methanol,
b) heating the reaction mixture to 40-45°C,
c) stirring the reaction mixture,
d) cooling the reaction mixture,
e) distilled off the solvent and dried to get crystalline form-A of Asciminib HCl of Formula-1.

The fifth aspect of the present invention provides an improved process for the preparation of Asciminib HCl of Formula-1, comprising of:
a) Treating 4-(Chlorodifluoromethoxy)aniline p-Toluenesulfonic acid salt of formula-2 with a suitable base in a suitable solvent to provide free base compound of formula-2,
b) treating 5-Bromo-6-chloro-pyridine-3-carboxylic acid compound of formula-3 with thionyl chloride in a suitable solvent to provide acid chloride compound of formula-3,
c) reacting the free base compound of formula-2 with acid chloride compound of formula-3 in presence of a suitable base in a suitable solvent to provide 5-bromo-6-chloro-N-[4-[chloro(difluoro)methoxy]phenyl]pyridine-3-carboxamide of formula-4,
d) reacting the compound of formula-4 with (R)-Pyrrolidin-3-ol of formula-5 in presence of a suitable base in a suitable solvent to provide 5-bromo-N-[4-[chloro(difluoro)methoxy]-6-[(3R)-3-hydroxypyrrolodin-1yl]pyridine-3-carboxamide of formula-6,
e) reacting the compound of formula-6 with 1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester of formula-7 in presence of a suitable base and catalyst in a suitable solvent to provide N-[4-(chlorodifluoromethoxy) phenyl]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-3-pyridine carboxamide of formula-8, optionally purifying the obtained compound with a suitable solvent,
f) treating the compound of formula-8 with oxalic acid dihydrate in a suitable solvent to provide N-[4-(chlorodifluoro methoxy)phenyl]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-(1H-pyrazol-3-yl)-3-pyridinecarboxamide, 2-methoxy-2-oxo-acetic acid of formula-9,
g) treating the compound of formula-9 with a suitable base in a suitable solvent, followed by treating the obtained compound with HCl in methanol to provide Asciminib HCl of Formula-1.
Wherein,
The base used in above step-a, c, d, e & g) is selected from organic or inorganic base, preferably inorganic base.
The solvent used in step-a) to g) is selected from ether solvents, chloro solvents, ester solvents, alcohol solvents, ketone solvents, polar aprotic solvents, hydrocarbon solvents, nitrile solvents and polar solvents or mixtures thereof.
The catalyst used in step-e) is Pd (PPh3)2Cl2.
In a preferred embodiment of the present invention provides an improved process for the preparation of Asciminib HCl of Formula-1, comprising of:
a) Treating 4-(Chlorodifluoromethoxy)aniline, p-Toluenesulfonic acid salt of formula-2 with sodium hydroxide in water to provide free base compound of formula-2,
b) treating 5-Bromo-6-chloro-pyridine-3-carboxylic acid compound of formula-3 with thionyl chloride in dimethyl formamaide and toluene to provide acid chloride compound of formula-3,
c) reacting the free base compound of formula-2 with acid chloride compound of formula-3 in presence of sodium carbonate in water to provide 5-bromo-6-chloro-N-[4-[chloro(difluoro)methoxy]phenyl]pyridine-3-carboxamide of formula-4,
d) reacting the compound of formula-4 with (R)-Pyrrolidin-3-ol of formula-5 in presence of potassium carbonate in isopropyl alcohol to provide 5-bromo-N-[4-[chloro(difluoro)methoxy]-6-[(3R)-3-hydroxypyrrolodin-1yl]pyridine-3-carboxamide of formula-6,
e) reacting the compound of formula-6 with 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester of formula-7 in presence of potassium carbonate and Pd(PPh3)2Cl2 in acetonitrile to provide N-[4-(chlorodifluoro methoxy)phenyl]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-3-pyridine carboxamide of formula-8, purifying the obtained compound with methanol,
f) treating the compound of formula-8 with oxalic acid dihydrate in methanol to provide N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-(1H-pyrazol-3-yl)-3-pyridine carboxamide, 2-methoxy-2-oxo-acetic acid of formula-9,
g) treating the compound of formula-9 with sodium carbonate in ethyl acetate, followed by treating the obtained compound with HCl in methanol to provide Asciminib HCl of Formula-1.

Advantages of the present invention:
1. Avoids the formation of diisopropyl-N-nitrosamine (DIPNA) impurity by using sodium carbonate base instead of diisopropylethylamine (DIPEA) base.
2. Controls the desbromo impurity from ~25% to below 5%.
3. Controls the impurity-A (migrated impurity) from ~8% to below 0.15% by using monomethyl oxalic acid instead of aqueous HCl.
4. Avoids the use of multiple solvents in the reactions and also avoids multiple unit operations such as extractions, water washings and distillations.
5. The process of the present invention does not require chromatographic purification techniques, which are commercially not viable.
6. The present invention involves the usage of low cost reagents & solvents which reduce the cost of production and provides Asciminib HCl with high yield & purity which is best suitable for commercial scale process.

PXRD method of analysis:

PXRD analysis of the Asciminib salts were carried out using Panlytical Expert Pro DY3248 X-ray powder diffractometer using Cu-Ka radiation of 10 wavelength 1.5406 A° and at continuous scan speed of 0.03°/min.

The best mode of carrying out the present invention was 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: Process for the preparation of 4-(Chlorodifluoromethoxy)aniline, p-Toluenesulfonic acid (Formula-2)
4-[Chloro(difluoro)methoxy]aniline (200g) and ethyl acetate (2400 ml) were charged into a 5.0L 4N RBF and stirred for 10 min at 25-30°C. p-Toluenesulfonic acid monohydrate (196.5g) was added to the reaction mixture and stirred for 3.5 hrs at the same temperature. Filtered the product and washed with ethyl acetate and dried to afford the title compound. Yield: 366.75 g (97.0%).

Example-2: Process for the preparation of 5-bromo-6-chloro-N-[4-[chloro (difluoro)methoxy]phenyl]pyridine-3-carboxamide (Formula-4)
5-Bromo-6-chloro-pyridine-3-carboxylic acid of formula-3 (177.8 g) and Toluene (625 ml) were charged into a 1.0L 4N RBF and stirred for 10 min at 25-30°C. Dimethyl formamaide (4.9g) was added to the reaction mixture and stirred for 10 min at the same temperature. Thionyl chloride (121.9 g) was added to the reaction mass dropwise at above 25°C for about 30 minutes. Heated the reaction mass to 50-55°C and stirred for 3.5 hours. After completion of reaction by HPLC, reaction mixture was cooled to 25-30°C, to get acid chloride compound of formula-3.
Simultaneously 4-(Chlorodifluoromethoxy)aniline, p-Toluenesulfonic acid salt of formula-2 (250 g), DM water (1500 ml) and NaOH (41.0 g) were charged into another RB flask and stirred for 10 min at 25-30°C. Extracted the aqueous layer twice with toluene, combined the organic layers and washed with water. Separated the top organic layer containing compound of formula-2 free base solution.
Sodium carbonate (144.9g) and DM water (625 ml) were charged into another RB flask and and stirred for 10 min at 25-30°C for dissolution. Charged above compound of formula-2 free base solution into the aqueous sodium carbonate solution. Heated the reaction mass to 80-85°C. The above acid chloride solution of formula-3 was added dropwise for about 1.5 hrs and maintained for 2.5 hrs at the same temperature. Cooled reaction mixture to 25-30°C and maintained for 3.5 hrs. Filtered the product and washed with DM water and dried to afford the title compound.
Yield: 264.0g (93.6%); Purity by HPLC is 99.29%

Example-3: Process for the preparation of 5-bromo-N-[4-[chloro(difluoro) methoxy]-6-[(3R)-3-hydroxypyrrolodin-1yl]pyridine-3-carboxamide (Formula-6)
5-bromo-6-chloro-N-[4-[chloro(difluoro)methoxy]phenyl]pyridine-3-carboxamide of formula-4 (225.0 g), Isopropyl alcohol (675 ml), (R)-Pyrrolidin-3-ol of formula-5 (52.3 g) and K2CO3 (150.9 g) were charged into RB flask at 25-30°C. Heated the reaction mixture to 75-80°C and stirred for 4.5 hrs at the same temperature. After completion of reaction by HPLC, DM water (1350 ml) was added to the reaction mixtures then cooled to 25-30°C and further stirred for 2.5 hrs. Filtered the product and washed with DM water and dried to afford the title compound. Yield: 247.3g (97.9%); Purity by HPLC is 99.42%

Example-4: Process for the preparation of N-[4-(chlorodifluoromethoxy) phenyl]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-3-pyridinecarboxamide (Formula-8)
Acetonitrile (2000 ml) was charged into 5.0 L RB flask and degassing using nitrogen at 25-30°C. Charged 5-bromo-N-[4-[chloro(difluoro)methoxy]-6-[(3R)-3-hydroxypyrrolodin-1yl]pyridine-3-carboxamide of formula-6 (200.0 g), 1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester of formula-7 (144.3 g), K2CO3 (89.6g) into the reactor at 25-30°C under nitrogen atmosphere. Pd (PPh3)2Cl2 (1.52g) was added to the reaction mixture and raised the temperature to 80-85°C and stirred for 12 hrs at the same temperature. After completion of reaction by HPLC, the aqueous N-Acetyl cysteine solution (3.5g in 1000 ml water) was added to the reaction mass and maintained for 3 hrs at 60-65°C. And then water (1000 ml) was added to the reaction mass and cooled the slurry to 25-30°C and maintain for 4 hrs. Filtered the solid and washed with acetonitrile:DM water (1:1) followed by DM water and dried to get the title compound as crude.
The above crude compound of formula-8 (218.9 g) and methanol (2000 ml) were charged into RB flask and heated to 60-65°C and stirred for 2 hrs for complete dissolution. Charcoal (10 g) was added to reaction mass and stirred form 30 min at 60-65°C. Filtered the reaction mass and washed with pre-heated methanol (200 ml) and cooled the obtained filtrate to 0-5°C and stirred for 1 hr. Filtered the solid and washed with pre-cooled methanol and dried to get the title compound. Yield: 186.6 g (80.8 %); Purity by HPLC is >99.0 %

Example-5: Process for the preparation of N-[4-(chlorodifluoro methoxy)phenyl]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-(1H-pyrazol-3-yl)-3-pyridinecarboxamide, 2-methoxy-2-oxo-acetic acid (Formula-9)
Oxalic acid dihydrate (103.9 g) and methanol (1080 ml) were charged into 2.0L RB flask at 25-30°C. Heated the reaction mass to 40-45°C and stirred for 3.5 hrs at the same temperature. N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-3-pyridinecarboxamide of formula-8 (220.0 g) and methanol (20 ml) were added to the reaction mass and stirred 14.5 hrs at 40-45°C. After completion of the reaction by HPLC, cooled the reaction mixture to 25-30°C fallowed to 0-5°C and maintain for 2.5 hrs. Filtered the product and washed with pre-cooled methanol and dried to get the title compound. Yield: 203.7 g (89.2 %); Purity by HPLC is 99.74 %
The PXRD of the obtained compound of formula-9 is illustrated in figure-2 and DSC thermogram is illustrated in figure-4.

Example-6: Process for the preparation of N-[4¬-(chlorodifluoromethoxy) phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-5-(1H-pyrazol-3-yl)pyridine-3-carboxamide hydrogen chloride (Formula-1)
DM water (3000 ml) and sodium chloride (1000 ml) were charged into 10.0 L 4N RB flask and stirred for 10 min at 25-30°C. Sodium carbonate (114.8 g), ethyl acetate (4500 ml) and N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-(1H-pyrazol-3-yl)-3-pyridinecarboxamide, 2-methoxy-2-oxo-acetic acid of formula-9 (300 g) were added to the reaction mass and stirred for 30 min. Separated both the layers, extracted aqueous layer with ethyl acetate (1500 ml). Combined the organic layers and washed with aqueous sodium chloride solution. Charcoal (3.0 g) was added to the organic layer and heated to 40-45°C and stirred for 10 min at the same temperature. Filtered the reaction mass through hyflo bed and washed with ethyl acetate (300 mL). Concentrated the organic layer under reduced pressure at 45-50°C and co-distilled with methanol (300 mL). Methanol (1500 mL) was added to the reaction mass followed by HCl in methanol solution (162.2 g, 12.8% w/w) then stirred for 10 minutes. Filtered the reaction mass and washed with methanol and spray dried the above filtrate to get the title compound. Yield: 150.4 g (57.1 %); Purity by HPLC is 99.75 %; Impurity-A: 0.02% by HPLC.
The PXRD of the obtained compound of formula-1 is illustrated in figure-5

Example-7: Preparation of amorphous solid dispersion comprising Asciminib HCl of formula-1 and Hydroxypropyl cellulose (HPC)
DM Water (2500 mL) and NaCl (125 g) were charged into 4N RBF and then charged sodium carbonate (95.7 g) and stirred the rection mixture at 25-35°C for 10 minutes. Ethyl acetate (3750 mL) and Asciminib monomethyl oxalate of formula-9 (250 g) were added to the rection mixture and stirred for 30 minutes. Separated the organic layer and extracted the aqueous layer with ethyl acetate (1250 mL). Combined the organic layers containing the product and washed with 5% sodium chloride (1250 mL) and DM water (2500 mL). Charcoal (2.5 g) was added to the organic layer and stirred at 25-35°C for 10 minutes. Filtered the reaction mass through hyflo bed and washed with ethyl acetate (250 mL). Concentrated the organic layer under reduced pressure at 45-50°C and co-distilled with methanol (300 mL). Methanol (2500 mL) was added to the reaction mass followed by HCl in methanol solution (46.1 g, 15% w/w) and Hydroxypropyl cellulose (HPC) (62.5 g) then stirred for 30 minutes. Filtered the reaction mass and washed with methanol and spray dried the above filtrate to get the title compound. Yield: 156.5 g (55.9 %); Purity by HPLC is >99.5 %
The PXRD of the obtained compound of formula-1 is illustrated in figure-6

Example-8: Preparation of amorphous solid dispersion comprising Asciminib HCl of formula-1 and Povidone.
NaCl solution (10 mL of 5% w/v) and sodium carbonate (3.8 g) were charged into 4N RBF and stirred the rection mixture at 25-35°C for 10 minutes. Ethyl acetate (150 mL) and Asciminib monomethyl oxalate of formula-9 (10 g) were added to the rection mixture and stirred for 30 minutes. Separated the organic layer and extracted the aqueous layer with ethyl acetate (50 mL). Combined the organic layers containing the product and washed with DM water (100 mL). Concentrated the organic layer under reduced pressure at 45-50°C and co-distilled with methanol (30 mL). Methanol (90 mL) was added to the reaction mass followed by HCl in methanol solution (5.3 g, 13% w/w) and Povidone (2.5 g) then stirred for 10 minutes. Filtered the reaction mass and washed with methanol and spray dried the above filtrate to get the title compound. Yield: 5.5 g
The PXRD of the obtained compound of formula-1 is illustrated in figure-7

Example-9: Preparation of amorphous solid dispersion comprising Asciminib HCl of formula-1 and Copovidone.
NaCl solution (10 mL of 5% w/v) and Na2CO3 (3.8 g) were charged into 4N RBF and stirred the rection mixture at 25-35°C for 10 minutes. Ethyl acetate (150 mL) and Asciminib monomethyl oxalate of formula-9 (10 g) were added to the rection mixture and stirred for 30 minutes. Separated the organic layer and extracted the aqueous layer with ethyl acetate (50 mL). Combined the organic layers containing the product and washed with DM water (100 mL). Concentrated the organic layer under reduced pressure at 45-50°C and co-distilled with methanol (30 mL). Methanol (90 mL) was added to the reaction mass followed by HCl in methanol solution (5.3 g, 13% w/w) and Copovidone (2.5 g) then stirred for 10 minutes. Filtered the reaction mass and washed with methanol and spray dried the above filtrate to get the title compound. Yield: 5.7 g
The PXRD of the obtained compound of formula-1 is illustrated in figure-8

Example-10: Preparation of crystalline Form-A of Asciminib HCl(Formula-1).
Methanol (490 mL) and Asciminib monomethyl oxalate of formula-9 (70 g) were charged into 4N RBF and stirred the rection mixture at 25-35°C for 10 minutes. Heated the reaction mixture to 40-45°C and added 35% w/w conc. HCl (15.7 g) then stirred for 30 minutes. Filtered the reaction mass and washed with methanol (35 mL). Distilled off the methanol from the reaction mixture under vacuum at 50-55°C and then cooled the reaction mixture to 40-45°C. Ethyl acetate (1400 mL) was added to the reaction mixture at 40-45°C, then cooled to 25-35°C and maintained for 2 hours. Filtered the solid and washed with ethyl acetate and dried to get the title compound. Yield: 55.7 g; Purity by HPLC is >99.5%.

Example-11: Process for the preparation of N-[4-(chlorodifluoro methoxy)phenyl]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-(1H-pyrazol-3-yl)-3-pyridinecarboxamide, Oxalic acid
Oxalic acid dihydrate (3.1 g) and acetonitrile (200 ml) were charged into 2.0L RB flask at 25-30°C. Heated the reaction mass to 40-45°C and then added N-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-(1H-pyrazol-3-yl)-3-pyridinecarboxamide (10 g) and stirred for 2 hrs at 40-45°C. After completion of the reaction by HPLC, cooled the reaction mixture to 25-30°C and maintained for 2 hrs. Filtered the product and washed with acetonitrile and dried to get the title compound. Yield: 11.0 g.

Example-12: Process for the preparation of N-[4-(chlorodifluoro methoxy)phenyl]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-(1H-pyrazol-3-yl)-3-pyridinecarboxamide, Nitric acid
Nitric acid (1.88 g) was added to a suspension of N-[4-(Chlorodifluoro methoxy)phenyl]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-3-pyridinecarboxamide of formula-8 (10g) in methanol (100 ml) at 25-30°C and stirred for 5 hrs at the same temperature. After completion of reaction by TLC, resulting solution was concentrated under reduced pressure at 35°C. Then resulting residue was triturated with ethyl acetate (200ml) for one hr at 25-30°C. Filtered the solid, washed with ethyl acetate and dried the wet compound to obtain the title compound. Yield: 8.7 g.
The PXRD of the obtained compound is illustrated in figure-1 and DSC thermogram is illustrated in figure-3.
,CLAIMS:We Claim:

1. An improved process for the preparation of Asciminib HCl of Formula-1, comprising of:
a) Treating 4-(Chlorodifluoromethoxy)aniline p-Toluenesulfonic acid salt of formula-2 with a suitable base in a suitable solvent to provide free base compound of formula-2,

b) treating 5-Bromo-6-chloro-pyridine-3-carboxylic acid compound of formula-3 with thionyl chloride in a suitable solvent to provide acid chloride compound of formula-3,

c) reacting the free base compound of formula-2 with acid chloride compound of formula-3 in presence of a suitable base in a suitable solvent to provide 5-bromo-6-chloro-N-[4-[chloro(difluoro)methoxy]phenyl]pyridine-3-carboxamide of formula-4,

d) reacting the compound of formula-4 with (R)-Pyrrolidin-3-ol of formula-5

in presence of a suitable base in as suitable solvent to provide 5-bromo-N-[4-[chloro(difluoro)methoxy]-6-[(3R)-3-hydroxypyrrolodin-1yl]pyridine-3-carboxamide of formula-6,

e) reacting the compound of formula-6 with 1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester of formula-7

in presence of a suitable base and catalyst in a suitable solvent to provide N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-3-pyridine carboxamide of formula-8, optionally purifying the obtained compound with a suitable solvent,

f) treating the compound of formula-8 with oxalic acid dihydrate in a suitable solvent to provide N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-(1H-pyrazol-3-yl)-3-pyridinecarboxamide, 2-methoxy-2-oxo-acetic acid of formula-9,

g) treating the compound of formula-9 with a suitable base in a suitable solvent, followed by treating the obtained compound with HCl in methanol to provide Asciminib HCl of Formula-1.

2. The process as claimed in claim-1, wherein,
In step-a, c, d, e & g) the base used is is selected from organic or inorganic base,
preferably inorganic base.
In step-a) to g) the solvent used is selected from ether solvents, chloro solvents,
ester solvents, alcohol solvents, ketone solvents, polar aprotic solvents, hydrocarbon solvents, nitrile solvents and polar solvents or mixtures thereof.
In step-e) the catalyst used is Pd (PPh3)2Cl2.

3. An improved process for the preparation of Asciminib HCl of Formula-1, comprising of:
a) Treating 4-(Chlorodifluoromethoxy)aniline, p-Toluenesulfonic acid salt of formula-2 with sodium hydroxide in water to provide free base compound of formula-2,
b) treating 5-Bromo-6-chloro-pyridine-3-carboxylic acid compound of formula-3 with thionyl chloride in dimethyl formamaide and toluene to provide acid chloride compound of formula-3,
c) reacting the free base compound of formula-2 with acid chloride compound of formula-3 in presence of sodium carbonate in water to provide 5-bromo-6-chloro-N-[4-[chloro(difluoro)methoxy]phenyl]pyridine-3-carboxamide of formula-4,
d) reacting the compound of formula-4 with (R)-Pyrrolidin-3-ol of formula-5 in presence of potassium carbonate in isopropyl alcohol to provide 5-bromo-N-[4-[chloro(difluoro)methoxy]-6-[(3R)-3-hydroxypyrrolodin-1yl]pyridine-3-carboxamide of formula-6,
e) reacting the compound of formula-6 with 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester of formula-7 in presence of potassium carbonate and Pd(PPh3)2Cl2 in acetonitrile to provide N-[4-(chlorodifluoro methoxy)phenyl]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl]-3-pyridine carboxamide of formula-8, purifying the obtained compound with methanol,
f) treating the compound of formula-8 with oxalic acid dihydrate in methanol to provide N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-(1H-pyrazol-3-yl)-3-pyridine carboxamide, 2-methoxy-2-oxo-acetic acid of formula-9,
g) treating the compound of formula-9 with sodium carbonate in ethyl acetate, followed by treating the obtained compound with HCl in methanol to provide Asciminib HCl of Formula-1.

4. Novel crystalline Form-N of Asciminib monomethyl oxalic acid of formula-9, which is characterized by:
i) Its powder X-ray diffractogram having peaks at about 7.6, 10.2, 13.7, 15.7, 16.3, 19.9, 20.6, 22.0, 22.5, 23.8, 24.4 and 26.4 ± 0.2 degrees 2-theta.
ii) powdered X-ray diffraction pattern as shown in Figure-2.

5. A process for the preparation of crystalline form-N of Asciminib monomethyl oxalic acid of formula-9, comprising of:
a) Treating the compound of formula-8 with oxalic acid dihydrate in a suitable solvent,
b) heating, stirring and cooling the reaction mixture,
c) filtering the obtained solid and washed with a solvent to get the crystalline form-N of Asciminib monomethyl oxalic acid of formula-9.

6. A process for the preparation of crystalline form-N of Asciminib monomethyl oxalic acid of formula-9 as claimed in claim-5, comprising of:
a) Treating the compound of formula-8 with oxalic acid dihydrate in methanol,
b) heating, stirring and cooling the reaction mixture,
c) filtering the obtained solid and washed with methanol to get the crystalline form-N of Asciminib monomethyl oxalic acid of formula-9.

7. A process for the preparation of amorphous Asciminib HCl of Formula-1, comprising of:
a) Treating the monomethyl oxalate salt of Asciminib of formula-9 with a suitable base and a solvent,
b) treating the compound obtained in step-a) with HCl in methanol,
c) distilled off the solvent and spray dried the filtrate obtained in step-b) to get amorphous Asciminib HCl of Formula-1.

8. The process as claimed in claim-7, wherein,
In step-a) the base used is selected from organic or inorganic base, preferably
inorganic base.
In step-a) & b) the solvent used is selected from ester solvent and alcoholic solvents.

9. The process for the preparation of amorphous Asciminib HCl of Formula-1 as claimed in claim-7, comprising of:
a) Treating the monomethyl oxalate salt of Asciminib of formula-9 with sodium carbonate in Ethyl acetate,
b) treating the compound obtained in step-a) with HCl in methanol,
c) distilled off the solvent and spray dried the filtrate obtained in step-b) to get amorphous Asciminib HCl of Formula-1.

10. A process for the preparation of amorphous solid dispersion comprising Asciminib HCl and one or more pharmaceutically acceptable excipients, comprising of:
a) Treating the monomethyl oxalate salt of Asciminib of formula-9 with a suitable base and a solvent,
b) treating the compound obtained in step-a) with HCl in methanol,
c) providing a solution of Asciminib HCl and one or more excipients in a solvent,
d) obtaining amorphous solid dispersion comprising Asciminib HCl and the corresponding excipient(s).

11. The process as claimed in claim-10, wherein,
In step-a) the base used is selected from organic or inorganic base, preferably
inorganic base.
In step-a) & c) the solvent used is selected from ester solvent and alcoholic solvents.
In step-c) the excipient used is preferably selected from Hydroxypropyl cellulose
(HPC), Povidone and Copovidone.

12. The process for the preparation of amorphous solid dispersion comprising Asciminib HCl and Hydroxypropyl cellulose (HPC) as claimed in claim-10, comprising of:
a) Treating the monomethyl oxalate salt of Asciminib of formula-9 with sodium carbonate in Ethyl acetate,
b) treating the compound obtained in step-a) with HCl in methanol,
c) providing a solution of Asciminib HCl and Hydroxypropyl cellulose (HPC) in methanol,
d) obtaining amorphous solid dispersion comprising Asciminib HCl and Hydroxypropyl cellulose (HPC).

13. N-[4-(chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy-1-pyrrolidinyl]-5-(1H-pyrazol-3-yl)-3-pyridinecarboxamide, 2-methoxy-2-oxo-acetic acid of formula-9 and 4-(Chlorodifluoromethoxy)aniline p-Toluenesulfonic acid salt of formula-2 and Impurity-A having the following structural formulae:

14. The process for the preparation of Asciminib HCl of Formula-1 of the present invention is having impurity-A not more than 0.15%, preferably not more than 0.10%, more preferably not more than 0.05% by HPLC.