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WO2024257116A1 - Novel polymorphic forms of asciminib and its pharmaceutical salts thereof - Google Patents

Novel polymorphic forms of asciminib and its pharmaceutical salts thereof Download PDF

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Publication number
WO2024257116A1
WO2024257116A1 PCT/IN2024/050651 IN2024050651W WO2024257116A1 WO 2024257116 A1 WO2024257116 A1 WO 2024257116A1 IN 2024050651 W IN2024050651 W IN 2024050651W WO 2024257116 A1 WO2024257116 A1 WO 2024257116A1
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formula
asciminib
compound
treating
solvent
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French (fr)
Inventor
Shyam Sunder Reddy TALASANI
Venkateshwar Rao CIRUSANAGANDLA
Rushyarao YAJJUVARAPU
Rajashekar KOTTE
Jayakrishna KASUGANTI
Srinivasan ABAYEE KALIYAPERUMAL
Sriram RAMPALLI
Pulla Reddy Muddasani
Venkaiah Chowdary Nannapaneni
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Natco Pharma Ltd
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Natco Pharma Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
    • C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/29—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings
    • C07C309/30—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of non-condensed six-membered aromatic rings of six-membered aromatic rings substituted by alkyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/34—Esters of acyclic saturated polycarboxylic acids having an esterified carboxyl group bound to an acyclic carbon atom
    • C07C69/36—Oxalic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to an improved process for the preparation of Asciminib HC1 comprising novel process intermediates.
  • the invention also described the novel polymorphic forms of Asciminib and its pharmaceutical salts.
  • the W02020230099 described crystalline forms of Asciminib hydrochloride and Asciminib.
  • 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.
  • 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 HC1.
  • the third aspect of the present invention provides amorphous solid dispersions comprising Asciminib HC1 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 HC1 of formula- 1 from acid addition salts of Asciminib.
  • 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 HC1 of Formula- 1.
  • FIG-6 Illustrates the X-ray powder diffractogram of amorphous solid dispersion comprising Asciminib HC1 and Hydroxypropylcellulose (HPC).
  • suitable solvent 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- dimethoxy ethane, 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
  • anti-solvent refers to a solvent which is used to precipitate the solid from a solution.
  • 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, diisopropylethyl
  • 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 HC1.
  • the acid is preferably selected from oxalic acid, monomethyl oxalic acid, Para toluenesulfonic acid & Nitric acid.
  • Form-N 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.
  • 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.
  • 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.
  • step-b) the suitable temperature used is ranging from 30°C to the reflux temperature of the solvent used;
  • 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 HC1 of formula- 1 using novel acid addition salts of Asciminib.
  • a process for the preparation of amorphous Asciminib HC1 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 HC1 in methanol, c) distilled off the solvent and spray dried the filtrate obtained in step-b) to get amorphous Asciminib HC1 of Formula- 1.
  • 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.
  • amorphous Asciminib HC1 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 HC1 in methanol, c) distilled off the solvent and spray dried the filtrate obtained in step-b) to get amorphous Asciminib HC1 of Formula- 1.
  • the third aspect of the present invention provides amorphous solid dispersions comprising Asciminib HC1 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
  • the ratio of the weight of Asciminib HC1 to the weight of the excipient(s) within the solid dispersion ranges from but not limited to about 1:0.05 to 1:5.
  • amorphous solid dispersion comprising Asciminib HC1 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 HC1 in methanol, c) providing a solution of Asciminib HC1 and one or more excipients in a solvent, d) obtaining amorphous solid dispersion comprising Asciminib HC1 and the corresponding excipient(s).
  • 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.
  • HPC Hydroxypropyl cellulose
  • a preferred embodiment of the present invention provides a process for the preparation of amorphous solid dispersion comprising Asciminib HC1 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 HC1 in methanol, c) providing a solution of Asciminib HC1 and Hydroxypropyl cellulose (HPC) in methanol, d) obtaining amorphous solid dispersion comprising Asciminib HC1 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 HC1 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.
  • a process for the preparation of crystalline form-A of Asciminib HC1 of formula- 1, comprising of: a) Treating the monomethyl oxalate salt of Asciminib of formula-9 with cone. HC1 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 HC1 of Formula- 1.
  • the fifth aspect of the present invention provides an improved process for the preparation of Asciminib HC1 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
  • 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 (PPhs Ch.
  • DIPNA diisopropyl-N-nitrosamine
  • the process of the present invention does not require chromatographic purification techniques, which are commercially not viable.
  • the present invention involves the usage of low cost reagents & solvents which reduce the cost of production and provides Asciminib HC1 with high yield & purity which is best suitable for commercial scale process.
  • Example-1 Process for the preparation of 4-(Chlorodifluoromethoxy)aniline, p-Toluenesulfonic add (Formula-2)
  • Example-4 Process for the preparation of N-[4-(chlorodifluoromethoxy) phenyl]-6-[(3R)-3-hydroxy-l-pyrrolidinyl]-5-[l-(tetrahydro-2H-pyran-2-yl)- lH-pyrazol-5-yl]-3-pyridinecarboxamide (Formula-8)
  • Pd Pd (PPhs Ch (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.
  • 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.
  • 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.
  • Example-5 Process for the preparation of N-[4-(chlorodifluoro methoxy)phenyl]-6-[(3R)-3-hydroxy-l-pyrrolidinyl]-5-(lH-pyrazol-3-yl)-3- pyridinecarboxamide, 2-methoxy-2-oxo-acetic add (Formula-9)
  • Example-6 Process for the preparation of N-[4-(chlorodifluoromethoxy) phenyl]-6-[(3R)-3-hydroxypyrrolidin-l-yl]-5-(lH-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-l- pyrrolidinyl]-5-(lH-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.
  • Example-7 Preparation of amorphous solid dispersion comprising Asciminib HC1 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).
  • Example-8 Preparation of amorphous solid dispersion comprising Asciminib HC1 of formula-1 and Povidone.
  • Example-9 Preparation of amorphous solid dispersion comprising Asciminib HC1 of formula-1 and Copovidone.
  • Example-11 Process for the preparation of N- [4- (chlorodifluoro methoxy)phenyl]-6-[(3R)-3-hydroxy-l-pyrrolidinyl]-5-(lH-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 Y-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy-l-pyrrolidinyl]-5-(lH- 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-l-pyrrolidinyl]-5-(lH-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-l-pyrrolidinyl]-5-[l-(tetrahydro-2H-pyran- 2-yl)-lH-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.

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Abstract

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

Description

NOVEL POLYMORPHIC FORMS OF ASCIMINIB AND ITS
PHARMACEUTICAL SALTS THEREOF
Field of invention
The present invention relates to an improved process for the preparation of Asciminib HC1 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- l-yl]-5-(lH-pyrazol-3-yl)pyridine-3-carboxamide hydrogen chloride is commonly known as Asciminib HC1, which has the following chemical structure of compound 1:
Figure imgf000003_0001
Compound- 1
Asciminib HC1 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 W02020230099 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 HC1 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 HC1.
The second aspect of the present invention provides a process for the preparation of amorphous Asciminib HC1 of formula- 1 using novel acid addition salts of Asciminib.
The third aspect of the present invention provides amorphous solid dispersions comprising Asciminib HC1 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 HC1 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 HC1 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 HC1 of Formula- 1.
FIG-6: Illustrates the X-ray powder diffractogram of amorphous solid dispersion comprising Asciminib HC1 and Hydroxypropylcellulose (HPC).
FIG-7: Illustrates the X-ray powder diffractogram of amorphous solid dispersion comprising Asciminib HC1 and Povidone.
FIG-8: Illustrates the X-ray powder diffractogram of amorphous solid dispersion comprising Asciminib HC1 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- dimethoxy ethane, 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 HC1. 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 HC1 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 HC1 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 HC1 in methanol, c) distilled off the solvent and spray dried the filtrate obtained in step-b) to get amorphous Asciminib HC1 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 HC1 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 HC1 in methanol, c) distilled off the solvent and spray dried the filtrate obtained in step-b) to get amorphous Asciminib HC1 of Formula- 1.
The third aspect of the present invention provides amorphous solid dispersions comprising Asciminib HC1 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 HC1 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 HC1 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 HC1 in methanol, c) providing a solution of Asciminib HC1 and one or more excipients in a solvent, d) obtaining amorphous solid dispersion comprising Asciminib HC1 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 HC1 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 HC1 in methanol, c) providing a solution of Asciminib HC1 and Hydroxypropyl cellulose (HPC) in methanol, d) obtaining amorphous solid dispersion comprising Asciminib HC1 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 HC1 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 HC1 of formula- 1, comprising of: a) Treating the monomethyl oxalate salt of Asciminib of formula-9 with cone. HC1 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 HC1 of Formula- 1.
The fifth aspect of the present invention provides an improved process for the preparation of Asciminib HC1 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-lyl]pyridine-3- carboxamide of formula-6, e) reacting the compound of formula-6 with l-(Tctrahydro-2/7-pyran-2-yl)-//7- 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-l-pyrrolidinyl]-5-[l-(tetrahydro-2H-pyran-2-yl)- lH-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-( 1 H-pyrazol-3 -y 1) -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 HC1 in methanol to provide Asciminib HC1 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 (PPhs Ch.
In a preferred embodiment of the present invention provides an improved process for the preparation of Asciminib HC1 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-lyl]pyridine-3- carboxamide of formula-6, e) reacting the compound of formula-6 with l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazole-5-boronic acid pinacol ester of formula-7 in presence of potassium carbonate and Pd(PPh3)2C12 in acetonitrile to provide N-[4-(chlorodifluoro methoxy )phenyl] -6- [(3R)-3-hydroxy- 1 -pyrrolidinyl] -5- [ 1 -(tetrahydro-2H- pyran-2-yl)-lH-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-l- pyrrolidinyl]-5-(lH-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 HC1 in methanol to provide Asciminib HC1 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 HC1.
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 HC1 with high yield & purity which is best suitable for commercial scale process.
Figure imgf000013_0001
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 A0 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 add (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 (F ormula-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(difhioro) methoxy]-6-[(3R)-3-hydroxypyrrolodin-lyl]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-l-pyrrolidinyl]-5-[l-(tetrahydro-2H-pyran-2-yl)- lH-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-lyl]pyridine-3-carboxamide of formula-6 (200.0 g), 1- (Tctrahydro-2/7-pyran-2-yl)-//7-pyrazolc-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 (PPhs Ch (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-l-pyrrolidinyl]-5-(lH-pyrazol-3-yl)-3- pyridinecarboxamide, 2-methoxy-2-oxo-acetic add (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-l-pyrrolidinyl]-5-[l-(tetrahydro-2H-pyran-2-yl)-lH-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-l-yl]-5-(lH-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-l- pyrrolidinyl]-5-(lH-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 HC1 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 HC1 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 HC1 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 HC1 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 HC1 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 HC1 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 HC1 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-Aof Asciminib HCl(Formula-l).
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 cone. HC1 (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-l-pyrrolidinyl]-5-(lH-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 Y-[4-(Chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy-l-pyrrolidinyl]-5-(lH- 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-l-pyrrolidinyl]-5-(lH-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-l-pyrrolidinyl]-5-[l-(tetrahydro-2H-pyran- 2-yl)-lH-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 HC1 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,
Figure imgf000021_0001
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,
Figure imgf000021_0002
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,
Figure imgf000021_0003
Formula-4 d) reacting the compound of formula-4 with (R)-Pyrrolidin-3-ol of formula-5
Figure imgf000022_0001
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-lyl]pyridine-3- carboxamide of formula-6,
Figure imgf000022_0002
Formula-6 e) reacting the compound of formula-6 with l-(Tctrahydro-2/7-pyran-2-yl)-//7- pyrazole-5-boronic acid pinacol ester of formula-7
Figure imgf000022_0003
Formula-7 in presence of a suitable base and catalyst in a suitable solvent to provide N-[4- (chlorodifluoromethoxy)phenyl]-6-[(3R)-3-hydroxy-l-pyrrolidinyl]-5-[l- (tetrahydro-2H-pyran-2-yl)-lH-pyrazol-5-yl]-3-pyridine carboxamide of formula-8, optionally purifying the obtained compound with a suitable solvent,
Figure imgf000022_0004
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-(lH-pyrazol-3-yl)-3-pyridinecarboxamide, 2-methoxy-2-oxo- acetic acid of formula- 9,
Figure imgf000023_0001
Formula-9 g) treating the compound of formula-9 with a suitable base in a suitable solvent, followed by treating the obtained compound with HC1 in methanol to provide Asciminib HC1 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 (PPhs Ch.
3. An improved process for the preparation of Asciminib HC1 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-lyl]pyridine-3- carboxamide of formula-6, e) reacting the compound of formula-6 with l-(tetrahydro-2H-pyran-2-yl)-lH- pyrazole-5-boronic acid pinacol ester of formula-7 in presence of potassium carbonate and Pd(PPh3)2C12 in acetonitrile to provide N-[4-(chlorodifluoro methoxy )phenyl] -6- [(3R)-3-hydroxy- 1 -pyrrolidinyl] -5- [ 1 -(tetrahydro-2H- pyran-2-yl)-lH-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-l- pyrrolidinyl]-5-(lH-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 HC1 in methanol to provide Asciminib HC1 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 HC1 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 HC1 in methanol, c) distilled off the solvent and spray dried the filtrate obtained in step-b) to get amorphous Asciminib HC1 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 HC1 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 HC1 in methanol, c) distilled off the solvent and spray dried the filtrate obtained in step-b) to get amorphous Asciminib HC1 of Formula- 1.
10. A process for the preparation of amorphous solid dispersion comprising Asciminib HC1 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 HC1 in methanol, c) providing a solution of Asciminib HC1 and one or more excipients in a solvent, d) obtaining amorphous solid dispersion comprising Asciminib HC1 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 HC1 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 HC1 in methanol, c) providing a solution of Asciminib HC1 and Hydroxypropyl cellulose (HPC) in methanol, d) obtaining amorphous solid dispersion comprising Asciminib HC1 and Hydroxypropyl cellulose (HPC).
13. N- [4-(chlorodifluoromethoxy)phenyl] -6- [(3R)-3 -hydroxy- 1 -pyrrolidinyl] -5- (lH-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:
Figure imgf000027_0001
14. The process for the preparation of Asciminib HC1 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.
PCT/IN2024/050651 2023-06-13 2024-05-31 Novel polymorphic forms of asciminib and its pharmaceutical salts thereof Pending WO2024257116A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013171639A1 (en) * 2012-05-15 2013-11-21 Novartis Ag Benzamide derivatives for inhibiting the activity of abl1, abl2 and bcr-abl1
WO2020230099A1 (en) * 2019-05-16 2020-11-19 Novartis Ag Crystalline forms of n-[4-(chlorodifluoromethoxy)phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide
WO2021154980A1 (en) * 2020-01-28 2021-08-05 Teva Pharmaceuticals International Gmbh Solid state forms of asciminib and processes for the preparation thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013171639A1 (en) * 2012-05-15 2013-11-21 Novartis Ag Benzamide derivatives for inhibiting the activity of abl1, abl2 and bcr-abl1
WO2020230099A1 (en) * 2019-05-16 2020-11-19 Novartis Ag Crystalline forms of n-[4-(chlorodifluoromethoxy)phenyl]-6-[(3r)-3-hydroxypyrrolidin-1-yl]-5-(1h-pyrazol-5-yl)pyridine-3-carboxamide
WO2021154980A1 (en) * 2020-01-28 2021-08-05 Teva Pharmaceuticals International Gmbh Solid state forms of asciminib and processes for the preparation thereof

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