Process for the preparation of crystalline form of resmetirom

Abstract

The present invention relates to a process for the preparation of crystalline Form CSI of resmetirom. The present invention also relates to a process for the preparation of highly pure crystalline Form CSI of resmetirom. The Form CSI obtained by the processes of the present invention is characterized by X-ray powder diffraction pattern containing peaks at 5.8°±0.2°, 11.7°±0.2°, and 26.5°±0.2° 2 theta.

Description

RESME-2026PROCESS FOR THE PREPARATION OF CRYSTALLINE FORM OF RESMETIROMPRIORITY

[0001] This application claims the benefit of Indian Provisional Application No.20251004136 filed on January 17, 2025, entitled “PROCESS FOR THE PREPARATION OF CRYSTALLINE FORM OF RESMETIROM”, the contents of which are incorporated herein by reference.BACKGROUND OF THE INVENTIONTechnical Field

[0002] The present invention relates to a process for the preparation of crystalline Form CSI of resmetirom. The invention also relates to a process for the preparation of highly pure crystalline Form CSI of resmetirom.Description of the Related Art

[0003] Resmetirom, also known by its chemical name 2-[3,5-dichloro-4-((6-oxo-5-(propan-2-yl)-l,6-dihydropyridazin-3-yl)oxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-l,2,4-triazine-6-carbonitrile, is represented by the following compound of formula I,I

[0004] Resmetirom, a thyroid hormone receptor-beta (THR-beta) agonist, is approved by the US Food and Drug Administration (the USFDA) under the tradename of REZDIFFRA® for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis, in conjunction with diet and exercise. Resmetirom is the first drug for the treatment of non-alcoholic steatohepatitis (NASH) with fibrosis that is approved by the USFDA, and this drug is considered as a major breakthrough in the treatment of NASH.RESME-2026

[0005] Resmetirom is covered in a published International Application No. WO W02007 / 009913 (the WO’913 publication), which describes a process for the preparation of resmetirom. Further, a process for the preparation of resmetirom is described in the published International Application No. W02014 / 043706 (the WO’706 publication), and WO’706 publication also discloses a crystalline form of resmetirom named as Form I.

[0006] Resmetirom is known to exhibit polymorphism, and numerous polymorphic forms and processes for their preparation are reported in the literature. For instance, the published International Application No. WO2021063367 (the WO’367 publication) relates to a crystalline Form CSI of resmetirom, the published International Application No. WO2021129465 (the WO’465 publication) relates to a crystalline Form CSIV of resmetirom, the published International Application No. WO2022052822 (the WO’ 822 publication) relates to a crystalline Form CSVI of resmetirom, the published International Application No. W02022171200 (the WO ’200 publication) relates to a crystal Form 3 of resmetirom, and the published International Application No WO2022194073 (the WO’073 publication) relates to a crystal Form A of resmetirom.

[0007] Further, a Chinese Published Patent Application, CN115124515 relates to crystalline Form 3 and Form 4 of resmetirom.

[0008] It is a known fact that manufacture of a polymorphic form of a therapeutically active compound having the desired purity is a challenging task. The present invention fulfills such a requirement by providing a simple, and effective process for the manufacture of a crystalline form of resmetirom namely the crystalline Form CSI having the desired purity.SUMMARY OF THE INVENTION

[0009] The present invention relates to a process for the preparation of crystalline Form CSI of resmetirom (hereinafter, it may be referred to as the “crystalline Form CSF’ or the “Form CSF’), wherein the process comprises reacting ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l, 6-dihydropyridazin-3-yl) oxy) phenyl) hydrazono) acetyl) carbamate (the compound II) with a base, followed by treatmentRESME-2026with an acid, and isolating the Form CSI from the reaction mass; wherein the conversion of the compound II to the Form CSI is carried out in the presence of a solvent system, and wherein the Form CSI is characterized by X-ray powder diffraction pattern containing peaks at 5.8°±0.2°, 11.7°±0.2°, and 26.5°±0.2° 2 theta.

[0010] The present invention also relates to a process for the preparation of crystalline Form CSI of resmetirom, wherein the process comprises the steps of: (a) providing a mixture containing ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5- isopropyl-6-oxo- 1 ,6-dihydropyridazin-3-yl)oxy) phenyl) hydrazono) acetyl)carbamate (the compound II) in a first solvent;(b) treating the mixture obtained in the step (a) with a base to obtain a reaction mixture;(c) heating the reaction mixture of the step (b) to obtain a suspension or a solution;(d) cooling the suspension or the solution of the step (c);(e) treating the suspension or the solution of step (d) with an acid;(f) combining the resulting reaction mixture obtained in the step (e) with a second solvent to obtain a solid; and(g) optionally, isolating the solid to obtain Form CSI, and wherein the Form CSI is characterized by X-ray powder diffraction pattern containing peaks at 5.8°±0.2°, 11.7°±0.2°, and 26.5°±0.2° 2 theta.

[0011] The present invention relates to the process for the preparation of crystalline form CSI of resmetirom further comprising the steps of:(h) combining the solid obtained in the step (f) with a second solvent to obtain a suspension;(i) treating the suspension obtained in the step (h) with a base or a buffer to obtain a reaction mass, and optionally, filtering it to obtain a filtrate; (j) combining the reaction mass or the filtrate of step (i) with the first solvent;RESME-2026(k) treating the reaction mass of the step (j) with an acid to obtain a solid;and(l) isolating the solid to obtain highly pure Form CSI, and wherein the Form CSI is characterized by X-ray powder diffraction pattern containing peaks at 5.8°±0.2°, 11.7°±0.2°, and 26.5°±0.2° 2 theta.

[0012] The present invention relates to the process for the preparation of crystalline form CSI of resmetirom further comprising the steps of:(h-i) combining the solid obtained in the step (f) with a second solvent to obtain a suspension;(i-i) treating the suspension obtained in the step (h-i) with a base or a buffer to obtain a reaction mass; and optionally, separating the formed aqueous layer from the organic layer;(j-i) combining the reaction mass or the aqueous layer of the step (i-i) with the first solvent;(k-i) treating the reaction mass, or the aqueous layer of the step (j-i) with an acid to obtain a solid; and(1-i) isolating the solid to obtain highly pure Form CSI, and wherein the Form CSI is characterized by X-ray powder diffraction pattern containing peaks at 5.8°±0.2°, 11.7°±0.2°, and 26.5°±0.2° 2 theta.

[0013] The present invention further relates to a process for the preparation of crystalline Form CSI of resmetirom comprising the steps of:(a-i) providing a mixture containing resmetirom and first solvent;(a-ii) heating the mixture of the step (a-i) to obtain a suspension or a solution; (a-iii) cooling the suspension or the solution obtained in the step (a-ii);(a-iv) adding a second solvent to the solution of the step (a-iii) to obtain a mixture; and(a-v) isolating resmetirom crystalline Form CSI from the mixture of the step (a-iv), and wherein the Form CSI is characterized by X-ray powderRESME-2026diffraction pattern containing peaks at 5.8°±0.2°, H.7o±0.2°, and 26.5°±0.2° 2 theta.

[0014] The present invention further relates to a process for the preparation of highly pure crystalline Form CSI of resmetirom, wherein the process comprises the steps of:(b-i) providing a mixture containing ethyl (2-cyano-2-(2-(3,5-dichloro-4- ((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl) oxy) phenyl) hydrazono) acetyl) carbamate (the compound II) in first solvent;(b-ii) treating the mixture obtained in the step (b-i) with a base to obtain a reaction mixture;b-(iii) heating the reaction mixture of the step (b-ii) to obtain a suspension or a solution;(b-iv) cooling the suspension or the solution of the step (b-iii);(b-v) treating the suspension or the solution of step (b-iv) with an acid; (b-vi) combining the resulting reaction mixture obtained in the step (b-v) with second solvent to obtain a solid;(b-vii) the solid obtained in the step (b-vi) is combined with the second solvent to obtain a suspension or a solution;(b-viii) treating the suspension obtained in the step (b-vii) with a base or a buffer to obtain a reaction mass, and optionally, filtering it to obtain a filtrate;(b-ix) combining the reaction mass or the filtrate of step (b-viii) with the first solvent;(b-x) treating the reaction mass of the step (b-ix) with an acid to obtain a solid; and(b-xi) isolating the solid of step (b-x) to obtain the highly pure Form CSI, and wherein the Form CSI is characterized by X-ray powder diffraction pattern containing peaks at 5.8°±0.2°, 11.7°±0.2°, and 26.5°±0.2° 2 theta.RESME-2026

[0015] The present invention further relates to a process for the preparation of highly pure crystalline Form CSI of resmetirom, wherein the process comprises the steps of:(c-i) providing a mixture containing ethyl (2-cyano-2-(2-(3,5-dichloro-4- ((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl) oxy) phenyl) hydrazono) acetyl) carbamate (the compound II) in first solvent; (c-ii) treating the mixture obtained in the step (c-i) with a base to obtain a reaction mixture;(c-iii) heating the reaction mixture of the step (c-ii) to obtain a suspension or a solution;(c-iv) cooling the suspension or the solution of the step (c-iii);(c-v) treating the suspension or the solution of step (c-iv) with an acid; (c-vi) combining the resulting reaction mixture obtained in the step (c-v) with second solvent to obtain a solid;(c-vii) the solid obtained in the step (c-vi) is combined with the second solvent to obtain a suspension or a solution;(c-viii) treating the suspension obtained in the step (c-vii) with a base or a buffer to obtain a reaction mass, and optionally, separating the formed aqueous layer from the organic layer;(c-ix) combining the reaction mass or the aqueous layer of step (c-viii) with the first solvent;(c-x) treating the reaction mass or the aqueous layer of the step (c-ix) with an acid to obtain a solid; and(c-xi) isolating the solid of step (c-x) to obtain the highly pure Form CSI, and wherein the Form CSI is characterized by X-ray powder diffraction pattern containing peaks at 5.8°±0.2°, 11.7°±0.2°, and 26.5°±0.2° 2 theta.

[0016] These and other aspects of the present invention are described in more detail in the following detailed description of the invention.BRIEF DESCRIPTION OF THE DRAWINGRESME-2026

[0017] Figure 1 illustrates a characteristic powder X-ray diffraction (PXRD) pattern of crystalline Form CSI of resmetirom as obtained in example 3.

[0018] Figure 2 illustrates a characteristic powder X-ray diffraction (PXRD) pattern of crystalline Form CSI of resmetirom as obtained in example 18.DETAIEED DESCRIPTION OF THE INVENTION

[0019] In an aspect, the present invention provides a process for the preparation of crystalline Form CSI of resmetirom (hereinafter, it may be referred to as the “Form CSI”), wherein the process comprises reacting ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl) oxy) phenyl) hydrazono) acetyl) carbamate (the compound II) with a base, followed by treatment with an acid, and isolating the Form CSI from the reaction mass; wherein the conversion of the compound II to the Form CSI is carried out in the presence of a solvent system, and wherein the Form CSI is characterized by X-ray powder diffraction pattern containing peaks at 5.8°±0.2°, 11.7°±0.2°, and 26.5°±0.2° 2 theta.

[0020] Crystalline Form CSI of resmetirom is described in a published PCT application no. WO2021063367 (the WO’367 publication), wherein the Form CSI is characterized by X-ray powder diffraction pattern containing peaks at 5.8°±0.2°, 11.7°±0.2°, and 26.5°±0.2° 2 theta.

[0021] In the context of the present invention, the term "solvent system" means a single solvent or a mixture of two or more solvents; wherein the solvents may be selected from the first solvent, and / or the second solvent as described herein.

[0022] The base and the acid used in the above described process for the preparation of the crystalline Form CSI are as described herein below.

[0023] As used herein, the term “about” refers to any value which lies within the range defined by a number up to 10% of the value.

[0024] In the context of the present invention, the term "optionally" when used in reference to a process step means that the described process step may or may not be carried out, and that the description includes instances where the process step isRESME-2026carried out, and the instances where the said process step is not carried out. Both alternatives are intended to be within the scope of the present invention.

[0025] As used herein, the term "highly pure" means that the Form CSI of resmetirom obtained by the process of the present invention is having purity of at least 99%, typically about 99.5% and above as determined by HPLC (High performance liquid chromatography).

[0026] In another aspect, the present invention relates to a process for the preparation of crystalline Form CSI of resmetirom, wherein the process comprises the steps of:(a) providing a mixture containing ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5- isopropyl-6-oxo-l,6-dihydropyridazin-3-yl) oxy) phenyl) hydrazono) acetyl) carbamate (the compound II) in a first solvent;(b) treating the mixture obtained in the step (a) with a base to obtain a reaction mixture;(c) heating the reaction mixture of the step (b) to obtain a suspension or a solution;(d) cooling the suspension or the solution of the step (c);(e) treating the suspension or the solution of step (d) with an acid;(f) combining the resulting reaction mixture obtained in the step (e) with a second solvent to obtain a solid; and(g) optionally, isolating the solid to obtain Form CSI, and wherein the Form CSI is characterized by X-ray powder diffraction pattern containing peaks at 5.8°±0.2°, 11.7°±0.2°, and 26.5°±0.2° 2 theta.

[0027] In an embodiment, in the step (a), the first solvent is selected from a ketone, an alcohol, a dipolar aprotic solvent, water, or a mixture thereof.

[0028] In another embodiment, in the step (a), the first solvent is selected from a ketone, a dipolar aprotic solvent, water, or a mixture thereof.

[0029] In another embodiment, in the step (a), the first solvent is ketone, which is selected from methyl ethyl ketone, acetone, methyl isobutyl ketone, pentanone, cyclopentanone or cyclohexanone.RESME-2026

[0030] In another embodiment, in the step (a), the first solvent is alcohol solvent, which is selected from methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, 2-butanol, isobutanol, tertiary butanol, ethylene glycol or propylene glycol.

[0031] In another embodiment, in the step (a), the first solvent is dipolar aprotic solvent, which is selected from dimethylacetamide (DM Ac), dimethylformamide (DMF) dimethylsulfoxide (DMSO) or N-methyl-pyrrolidinone.

[0032] In an embodiment, in the step (a), the first solvent is selected from methyl ethyl ketone, dimethyl formamide, isopropyl alcohol, water or a mixture thereof.

[0033] In an embodiment, in the step (b), the base is selected from an inorganic base or an organic base.

[0034] In another embodiment, the base used in the step (b) is an organic base selected from triethylamine, pyridine, diisopropylethylamine or diisopropyl amine

[0035] In an embodiment, the base used in the step (b) is an inorganic base selected from an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate, or an alkali metal acetate.

[0036] In an embodiment, the base used in the step (b) is an inorganic base is selected from alkali metal hydroxide such as lithium hydroxide, sodium hydroxide, potassium hydroxide; the alkali metal carbonate such as lithium carbonate, sodium carbonate, potassium carbonate; alkali metal bicarbonate such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate; or alkali metal acetate such as sodium acetate, potassium acetate, lithium acetate.

[0037] In an embodiment, the base used in the step (b) is alkali metal acetate.

[0038] In an embodiment, the alkali metal acetate used in the step (b) is selected from sodium acetate, potassium acetate or lithium acetate.

[0039] In an embodiment, in the step (c), the reaction mixture of the step (b) is heated to a temperature ranging from about 60°C to about 150°C.

[0040] In another embodiment, in the step (c), the reaction mixture of the step (b) is heated to a temperature ranging from about 70°C to about 110°C.

[0041] In yet another embodiment, in the step (c), the reaction mixture of the step (b) is heated to a temperature ranging from about 80°C to about 100°C.RESME-2026

[0042] In an embodiment, in the step (c), the reaction mixture of the step (b) is stirred for suitable period. The stirring may be carried out over a period ranging from about 2 hours to about 20 hours.

[0043] In another embodiment, in the step (c), the reaction mixture of the step (b) is stirred for a period ranging from about 5 hours to about 18 hours.

[0044] In another embodiment, in the step (c), the reaction mixture of the step (b) is stirred for a period ranging from about 12 hours to about 18 hours.

[0045] In an embodiment, in the step (d), the suspension or solution of the step (c) is cooled to a temperature ranging from about 50°C to about 0°C.

[0046] In another embodiment, in the step (d), the suspension or solution of the step (c) is cooled to a temperature ranging from about 40°C to about 5 °C.

[0047] In an embodiment, the acid used in the step (e) is selected from hydrochloric acid, hydrobromic acid, acetic acid, sulphuric acid, phosphoric acid, formic acid or trifluoroacetic acid.

[0048] In an embodiment, in the step (f), the second solvent is selected from an alcohol solvent, an ester solvent, water or a mixture thereof.

[0049] In an embodiment, in the step (f), the second solvent is an alcohol, which is selected from methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, 2-butanol, isobutanol, tertiary butanol, ethylene glycol or propylene glycol.

[0050] In an embodiment, in the step (f), the second solvent is an ester solvent, which is selected from methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, or tert-butyl acetate.

[0051] In another embodiment, in the step (f), the second solvent is selected from isopropyl alcohol, n-propanol, methanol, ethanol, n-butanol, 2-butanol, isobutanol, ethylene glycol, propylene glycol, ethyl acetate, water or a mixture thereof.

[0052] In reference to the step (f) of the process of the present invention, the term “combining” means adding the reaction mixture of the step (e) to the second solvent, or adding the second solvent to the reaction mixture of the step (e).

[0053] In an embodiment, in the step (f), the resulting reaction mixture of the step (e) is added to the second solvent.RESME-2026

[0054] In another embodiment, in the step (f), the second solvent is added to the resulting reaction mixture of the step (e).

[0055] In an embodiment, the second solvent used in the step (f) is water.

[0056] In an embodiment, in the step (g), the crystalline Form CSI of resmetirom is isolated. Isolation of the Form CSI is carried out by any method known in the art, including filtration by gravity or by suction, centrifugation, and the like.

[0057] The crystalline Form CSI isolated in step (g) is substantially pure having purity between about 95% to 98% (w / w) as determined by HPEC (High performance liquid chromatography).

[0058] In an embodiment, the process for the preparation of crystalline Form CSI of resmetirom, further comprises the steps of:(h) the solid obtained in the step (f) is combined with the second solvent to obtain a suspension;(i) treating the suspension obtained in the step (h) with a base or a buffer to obtain a reaction mass, and optionally, filtering it to obtain a filtrate; (j) combining the reaction mass or the filtrate of the step (i) with the first solvent;(k) treating the reaction mass of the step (j) with an acid to obtain a solid; and (l) isolating the solid to obtain the highly pure Form CSI, and wherein the Form CSI is characterized by X-ray powder diffraction pattern containing peaks at 5.8°±0.2°, 11.7°±0.2°, and 26.5°±0.2° 2 theta.

[0059] In an embodiment, the process for the preparation of crystalline Form CSI of resmetirom, further comprises the steps of:(h-i) combining the solid obtained in the step (f) with the second solvent to obtain a suspension;(i-i) treating the suspension obtained in the step (h-i) with a base or a buffer to obtain a reaction mass, and optionally, separating the formed aqueous layer from the organic layer;(j-i) combining the reaction mass, or the aqueous layer of the step (i-i) with the first solvent;RESME-2026(k-i) treating the reaction mass or the aqueous layer of the step (j-i) with an acid to obtain a solid; and(1-i) isolating the solid to obtain highly pure Form CSI, and wherein the Form CSI is characterized by X-ray powder diffraction pattern containing peaks at 5.8°±0.2°, 11.7°±0.2°, and 26.5°±0.2° 2 theta.

[0060] In an embodiment, the second solvent used in the step (h) and the step (h-i) is as described in one or more embodiments of the processes for the preparation of the crystalline Form CSI of the present invention as described herein above.

[0061] In an embodiment, in the step (i), the suspension of step (h) or in the step (i-i) the suspension of the step (h-i) is treated with a base, wherein the base is selected from an organic base or an inorganic base; and wherein the organic base is selected from of triethyl amine, diisopropylethylamine, tributylamine, triphenylamine or pyridine; and the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium methoxide, or potassium tert-butoxide.

[0062] In an embodiment, in the step (i), the suspension of step (h) is treated with an organic base selected from of triethyl amine, diisopropylethylamine, tributylamine, triphenylamine or pyridine.

[0063] In an embodiment, in the step (i) the suspension of step (h) or in the step (i-i) the suspension of step (h-i) is treated with a buffer, wherein the buffer is selected from potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, or hydrates thereof.

[0064] In the process of the present invention, the reaction mass or the filtrate obtained in the step (i) or the step (i-i) may be subjected to charcoal treatment.

[0065] In an embodiment, the first solvent used in the step (j) or the step (j-i) is as described in one or more embodiments of the processes for the preparation of the crystalline Form CSI of the present invention as described herein above.RESME-2026

[0066] In reference to the step (j) of the process of the present invention, the term “combining” means adding the reaction mass or the filtrate of the step (i) to the first solvent, or adding the first solvent to the reaction mass or the filtrate of the step (i).

[0067] Accordingly, in an embodiment, in the step (j), the reaction mass, or the filtrate of the step (i) is added to the first solvent to obtain a reaction mass.

[0068] In another embodiment, in the step (j), the first solvent is added to the reaction mass, or the filtrate of the step (i) to obtain a reaction mass.

[0069] In reference to the step (j-i) of the process of the present invention, the term “combining” means adding the reaction mass or the aqueous layer of the step (i-i) to the first solvent, or adding the first solvent to the reaction mass or the aqueous layer of the step (i-i).

[0070] Accordingly, in an embodiment, in the step (j-i), the reaction mass or the aqueous layer of the step (i-i) is added to the first solvent to obtain a reaction mass.

[0071] In another embodiment, in the step (j-i), the first solvent is added to the reaction mass or the aqueous layer of the step (i-i) to obtain a reaction mass.

[0072] In an embodiment, the acid used in the step (k) or the step (k-i) is as described in one or more embodiments of the processes for the preparation of the crystalline Form CSI of the present invention as described herein above.

[0073] In another aspect, the present invention provides a further process for the preparation of crystalline Form CSI of resmetirom comprising the steps of:(a-i) providing a mixture containing resmetirom and a first solvent;(a-ii) heating the mixture of the step (a-i) to obtain a suspension or a solution; (a-iii) cooling the suspension or the solution obtained in the step (a-ii);(a-iv) adding a second solvent to the solution of the step (a-iii) to obtain a mixture; and(a-v) isolating resmetirom crystalline Form CSI from the mixture of the step (a-iv), and wherein the Form CSI is characterized by X-ray powder diffraction pattern containing peaks at 5.8°±0.2°, 11.7°±0.2°, and 26.5°±0.2° 2 theta.RESME-2026

[0074] In an embodiment, the first solvent used in the step (a-i) is as described in one or more embodiments of the processes for the preparation of the crystalline Form CSI of the present invention as described herein above.

[0075] In an embodiment, in the step (a-ii), the heating of the mixture of the step (a-i) is carried out to a temperature ranging from about 60°C to about 150°C.

[0076] In another embodiment, in the step (a-ii), the mixture of the step (a-i) is heated to a temperature ranging from about 70°C to about 110°C.

[0077] In yet another embodiment, in the step (a-ii), the mixture of the step (a-i) is heated to a temperature ranging from about 80°C to about 100°C.

[0078] In an embodiment, in the step (a-ii), the reaction mixture of the step (a-i) is stirred for suitable time. The stirring may be carried out over a period ranging from about 2 hours to about 20 hours.

[0079] In an embodiment, in the step (a-iii), the suspension or the solution of step (a-ii) is cooled to a temperature ranging from about 50°C to about 0°C.

[0080] In another embodiment, in the step (a-iii), the suspension or the solution of step (a-ii) is cooled to a temperature ranging from about 40°C to about 5°C.

[0081] In an embodiment, the second solvent used in the step (a-iv) is as described in one or more embodiments of the processes for the preparation of the crystalline Form CSI of the present invention as described herein above.

[0082] In an embodiment, in the step (a-v), the crystalline form CSI of resmetirom is isolated by any method known in the art, including filtration by gravity or by suction, centrifugation, and the like.

[0083] In an aspect, the present invention provides a process for the preparation of highly pure crystalline Form CSI of resmetirom, wherein the process comprises the steps of:(b-i) providing a mixture containing ethyl (2-cyano-2-(2-(3,5-dichloro-4- ((5-isopropyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy)phenyl)hydrazono) acetyl) carbamate (the compound II) in a first solvent;(b-ii) treating the mixture obtained in the step (b-i) with a base to obtain a reaction mixture;RESME-2026(b-iii) heating the reaction mixture of the step (b-ii) to obtain a suspension or a solution;(b-iv) cooling the suspension or the solution of the step (b-iii);(b-v) treating the suspension or the solution of step (b-iv) with an acid; (b-vi) combining the resulting reaction mixture obtained in the step (b-v) with a second solvent to obtain a solid;(b-vii) the solid obtained in the step (b-vi) is combined with the second solvent to obtain a suspension or a solution;(b-viii) treating the suspension obtained in the step (b-vii) with a base or a buffer to obtain a reaction mass, and optionally, filtering it to obtain a filtrate;(b-ix) combining the reaction mass or the filtrate of step (b-viii) with the first solvent;(b-x) treating the reaction mass of the step (b-ix) with an acid to obtain a solid; and(b-xi) isolating the solid of step (b-x) to obtain the highly pure Form CSI, and wherein the Form CSI is characterized by X-ray powder diffraction pattern containing peaks at 5.8°±0.2°, 11.7°±0.2°, and 26.5°±0.2° 2 theta.

[0084] In an aspect, the present invention provides a process for the preparation of highly pure crystalline Form CSI of resmetirom, wherein the process comprises the steps of:(c-i) providing a mixture containing ethyl (2-cyano-2-(2-(3,5-dichloro-4- ((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl) oxy) phenyl) hydrazono) acetyl) carbamate (the compound II) in a first solvent; (c-ii) treating the mixture obtained in the step (c-i) with a base to obtain a reaction mixture;(c-iii) heating the reaction mixture of the step (c-ii) to obtain a suspension or a solution;(c-iv) cooling the suspension or the solution of the step (c-iii);(c-v) treating the suspension or the solution of step (c-iv) with an acid;RESME-2026(c-vi) combining the resulting reaction mixture obtained in the step (c-v) with a second solvent to obtain a solid;(c-vii) the solid obtained in the step (c-vi) is combined with the second solvent to obtain a suspension or a solution;(c-viii) treating the suspension obtained in the step (c-vii) with a base or a buffer to obtain a reaction mass, and optionally, separating the formed aqueous from the organic layer;(c-ix) combining the reaction mass or the aqueous layer of step (c-viii) with the first solvent;(c-x) treating the reaction mass or the aqueous layer of the step (c-ix) with an acid to obtain a solid; and(c-xi) isolating the solid of step (c-x) to obtain the highly pure Form CSI, and wherein the Form CSI is characterized by X-ray powder diffraction pattern containing peaks at 5.8°±0.2°, 11.7°±0.2°, and 26.5°±0.2° 2 theta.

[0085] In an embodiment, in the process for the preparation of highly pure crystalline Form CSI of resmetirom, the first solvent used in step (b-i), the step (b-ix), the step (c-i) or the step (c-ix) is as described herein above in reference to the step (a).

[0086] In an embodiment, in the process for the preparation of highly pure crystalline Form CSI of resmetirom, the base used in the step (b-ii), the step (b-viii), the step (c-ii), or the step (c-viii) is as described herein above in reference to the step (b).

[0087] In an embodiment, in the process for the preparation of highly pure crystalline Form CSI of resmetirom, the base used in the step (b-ii) the step (b-viii), the step (c-ii) or the step (c-viii) is alkali metal acetate.

[0088] In an embodiment, in the process for the preparation of highly pure crystalline Form CSI of resmetirom, the alkali metal acetate used in the step (b-ii), the step (b-viii), the step (c-ii) or the step (c-viii) is selected from sodium acetate, potassium acetate or lithium acetate.RESME-2026

[0089] In an embodiment, in the process for the preparation of highly pure crystalline Form CSI of resmetirom, in the step (b-iii), the reaction mixture of the step (b-ii), or in the step (c-iii), the reaction mixture of the step (c-ii) is heated to a temperature ranging from about 60°C to about 110°C.

[0090] In another embodiment, in the process for the preparation of highly pure crystalline Form CSI of resmetirom, in the step (b-iii), the reaction mixture of the step (b-ii), or in the step (c-iii), the reaction mixture of the step (c-ii) is heated to a temperature ranging from about 70°C to about 100°C.

[0091] In yet another embodiment, in the process for the preparation of highly pure crystalline Form CSI of resmetirom, in the step (b-iii), the reaction mixture of the step (b-ii) or in the step (c-iii), the reaction mixture of the step (c-ii) is heated to a temperature ranging from about 80°C to about 90°C.

[0092] In an embodiment, in the process for the preparation of highly pure crystalline Form CSI of resmetirom, in the step (b-iii), the reaction mixture of the step (b-ii) or in the step (c-iii), the reaction mixture of the step (c-ii) is stirred for a suitable period. The stirring may be carried out over a period ranging from about 2 hours to about 20 hours.

[0093] In another embodiment, in the step (b-iii), the reaction mixture of the step (b-ii), or in the step (c-iii), the reaction mixture of the step (c-ii) is stirred for a period ranging from about 5 hours to about 18 hours.

[0094] In an embodiment, in the step (b-iii), the reaction mixture of the step (b-ii), or in the step (c-iii), the reaction mixture of the step (c-ii) is stirred for a period ranging from about 12 hours to about 18 hours.

[0095] In an embodiment, in the process for the preparation of highly pure crystalline Form CSI of resmetirom, in the step (b-iv), the suspension or solution of the step (b-iii), or in the step (c-iv), the suspension or solution of the step (c-iii), is cooled to a temperature ranging from about 50°C to about 0°C.

[0096] In another embodiment, in the process for the preparation of highly pure crystalline Form CSI of resmetirom, in the step (b-iv), the suspension or solution of the step (b-iii), or in the step (c-iv), the suspension or solution of the step (c-iii), is cooled to a temperature ranging from about 40°C to about 5 °C.RESME-2026

[0097] In an embodiment, in the process for the preparation of highly pure crystalline Form CSI of resmetirom, the second solvent used in the step (b-vi), the step (b-vii), the step (c-vi) or the step (c-vii), is as described herein above.

[0098] In an embodiment, in the process for the preparation of highly pure crystalline Form CSI of resmetirom, the buffer used in step (b-viii), or the step (c-viii) is as described herein above in reference to the step (i).

[0099] In an embodiment, in the process for the preparation of highly pure crystalline Form CSI of resmetirom, the acid used in the step (b-v), the step (b-x), the step (c-v) or the step (c-x) is as described herein above in reference to the step (e).

[0100] Unless otherwise specifically indicated, the crystalline Form CSI of resmetirom obtained by the processes of the present invention has a purity ranging from about 95% (w / w) to about 99.9% (w / w) as determined by HPLC.

[0101] The crystalline Form CSI of resmetirom obtained by the processes of the present invention is characterized by an PXRD pattern having peaks at 5.8°, 11.7°, and 26.5°±0.2° 2 theta.

[0102] The crystalline Form CSI of resmetirom obtained by the processes of the present invention is characterized by an PXRD pattern which is substantially as illustrated in the Figure 1 or Figure 2.

[0103] In an aspect, the process for the preparation of crystalline Form CSI as described above in one or more aspects of the present invention provides the crystalline Form CSI containing an impurity selected from a compound of the Formula A (the “Impurity A”) or a compound of the Formula C (the “Impurity C”),in less than about 0.2 % w / w as determined by High Performance Liquid Chromatography (HPLC).RESME-2026

[0104] In an embodiment, the present invention provides a process for the preparation of crystalline Form CSI of resmetirom wherein the content of each of the Impurity A and the Impurity C (as described above) present in the resulting crystalline Form CSI of resmetirom is from about 0.02 % to about 0.2 % w / w as determined by HPLC.

[0105] Further, a stability study was carried out on the crystalline Form CSI of resmetirom, which is obtained by the process of the present invention. The stability study was carried out as per the method described in the experimental section. The results of stability study as presented in the experimental section confirms that the crystalline Form CSI of resmetirom obtained by the process of the present invention as described herein, is stable over a period of 3 months under the storage conditions specified herein.

[0106] The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention.RESME-2026EXAMPLESGeneral Methods:1. HPLC method:High performance liquid chromatography (HPLC) was performed with the conditions described below for detecting chemical purity:Column: Waters X Bridge C8, 150 X 4.6mm, 3.5m; Column Temperature: 50°C, Mobile phase:Buffer: 0.02M Ammonium formate in water. Adjust pH 6.5 with dilute ammonia solution;Mobile Phase A: Buffer: Acetonitrile (95:05, v / v); Mobile Phase B = Acetonitrile (100%);Diluent: Methanol: Methanol: Water (950:50 v / v); Flow Rate: 1.0 mL / Minutes, Detection: 240nm; Injection Volume: 5 pL.2) Powder X-Ray Diffraction (PXRD) (Instrumental settings):The crystalline Form CSI of resmetirom obtained by the processes of the present invention is characterized and analyzed by powder X-ray diffraction (PXRD) technique and the measurements were performed on Philips X-Ray Diffractometer model Empyrean (PANalytical) Detector: PIXcel-lD using Cu lamp and wavelength of the X-ray radiation: K-al 1.54060[A], K-a2 1.54443 [A] under the following conditions:The measurements were carried out with a PreFIX module programmable Seller slit and anti-scatter Slit (Offset 0.00°); Generator settings: 40 mA / 45 kV, tube current 40 mAmp Time per step: 50s, Step size: 0.013, Peak width 2.00 and start angle (o) 2.0 and End angle: 50.0; Scan type: continuous; measurement performedRESME-2026at 25°C. The PXRD instrument is calibrated using NIST SRM 640e silicon standard and NIST SRM 1976c Alumina.Sample preparation: Take an adequate amount of the sample to fill the sample holder using back-loading technique. Then load the sample holder between the X-ray optics-path and scan using the above described parameters. Integrate the obtained powder X-ray diffraction profiles using HighScore Software.Example 1: Preparation of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1, 6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl) carbamate (the compound II)A mixture of 3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenylamine (50 g), water (100 mL) and concentrated hydrochloric acid (47.5 mL) was added to acetic acid (400 mL). The reaction mixture was cooled to a temperature of about 5°C to about 10°C. An aqueous solution of sodium nitrate (11.1 g in 25 mL) was added to the reaction mixture. The reaction mixture was stirred at a temperature of about 5°C to aboutlO°C for 15 minutes, and then aqueous sodium acetate (36.2 g in 150 mL water) was added to it. To this mixture, N-cyanoacetylurethane (25.3 g) was added. The orange precipitate formed in the suspension was stirred at a temperature ranging from about 5°C to about 10°C for 60 minutes. The temperature of the reaction mixture was increased to a temperature of about 20°C to about 30°C and stirred for 60 minutes. The product was filtered and washed with water. The product was dried in vacuum tray dryer at a temperature of about 35°C to about 45°C to obtain ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy) phenyl) hydrazono) acetyl) carbamate (compound II) as an orange solid.Yield: 74 g; Purity: 97.67 % (as determined by HPLC).Example 2: Purification of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1, 6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl) carbamate (compound II).RESME-2026A mixture of crude ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl) carbamate (compound II, 10 g) in tetrahydrofuran (50 mL) was heated to a temperature of about 60°C to about 70°C and stirred for 60 minutes. The reaction mixture was cooled to room temperature and stirred. The product obtained was filtered and washed with tetrahydrofuran. The wet product was dried in air oven at a temperature of about 50°C to about 60°C to obtain ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl) carbamate (compound II).Yield: 8.7 g; Purity: 99.56% (as determined by HPLC).Example 3: Preparation of Crystalline Form CSI of ResmetiromA mixture of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl) carbamate (Compound II, 100 g) in methyl ethyl ketone (800 mL) was treated with sodium acetate (20.45 g) at room temperature. The reaction mixture was heated to a temperature of about 70°C to about 80°C and maintained for about 17 to about 20 hours. After completion of the reaction, the reaction mixture was cooled to a temperature of about 20°C to about 30°C and then acetic acid (50.0 mL) was added to it and the reaction mixture was stirred. To this water (2000 mL) was added slowly at a temperature of about 20°C to about 30°C. The reaction mixture was stirred at a temperature of about 20°C to about 30°C. The product was filtered and washed with water. Yield (Wet product): ~175g.An aqueous solution of trisodium orthophosphate dodecahydrate (54 g in 270 mL water) was added to the mixture of wet product and water (1800 mL) and stirred to obtain a clear solution. Norit charcoal (9.0 g) was added to this solution and stirred for a period of about 60 minutes to about 70 minutes. The reaction mixture was filtered and washed with water. To the filtrate, methyl ethyl ketone (540 mL) was added and the pH was adjusted to less than 6.0 with acetic and stirred. The obtained product was filtered and washed with water. Yield: 110 g (approx.).Methyl ethyl ketone (600 mL) and ethyl acetate (225 mL) were added to a mixture of the wet product and water (750 mL) and stirred. An aqueous solution of trisodiumRESME-2026orthophosphate dodecahydrate (40 g in 200 mL water) were added to obtain a clear solution and the pH was adjusted to less than 6.0 with acetic and stirred. The product was filtered and washed with water. The wet product was dried in tray dryer at a temperature in the range of about 50°C to about 60°C for 10-18 hours to obtain the Form CSI.Yield: 63.20 g; Purity: 99.84% (as determined by HPLC).Example 4: Preparation of Crystalline Form CSI of ResmetiromTo a mixture of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl) carbamate (compound II, 10 g) in methyl ethyl ketone (100 mL), sodium acetate (2.04 g) was added at room temperature. The reaction mixture was heated to a temperature of about 70°C to about 80°C and maintained for 17 hours. After completion of the reaction, the reaction mixture was cooled to a temperature of about 20°C to about 30°C, and then acetic acid (5.0 mL) was added. The insoluble material was filtered. The above filtrate (~50 mL) was added slowly to water (150 mL) at a temperature of about 20°C to about 30°C and stirred. The product was filtered and washed with water. The wet product was dried in tray dryer at a temperature of about 50°C to about 60°C for a period of about 10 hours to about 18 hours to obtain the Form CSI. Yield: 3.5 g; Purity: 97.38% (as determined by HPLC).Example 5: Preparation of Crystalline Form CSI of ResmetiromA mixture of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl) carbamate (compound II, 10 g) in methyl ethyl ketone (100 mL) was treated with sodium acetate (2.04 g) at room temperature. The reaction mixture was heated to a temperature of about 70°C to about 80°C and maintained for about 17 hours. After completion of the reaction, the reaction mixture was cooled to a temperature of about 20°C to about 30°C, and then acetic acid (5.0 mL) was added. The insoluble material was filtered. Water (300 mL) was added slowly at a temperature of about 20°C to about 30°C to the filtrate. The reaction mixture was stirred to a temperature of about 20°C to about 30°C. The product was filtered and washed with water. The wet product was driedRESME-2026in tray dryer at a temperature of about 50°C to about 60°C for a period of about 10 hours to about 18 hours to obtain the Form CSI.Yield: 9.2 g; Purity: 96% (as determined by HPLC).Example 6: Preparation of Crystalline Form CSI of ResmetiromA mixture of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl) carbamate (compound n, 10 g) in methyl ethyl ketone (100 mL) was treated with sodium acetate (2.04 g) at room temperature. The reaction mixture was heated to a temperature of about 70°C to about 80°C and maintained for 17 hours. After completion of the reaction, the reaction mixture was cooled to a temperature of about 20°C to about 30°C and then acetic acid (5.0 mL) was added. The insoluble material was filtered. The filtrate was slowly added to water (300 mL) at a temperature of about 20°C to about 30°C. The reaction mixture was stirred at a temperature of 20°C to 30°C. The product was filtered and washed with water. The wet product was dried in tray dryer at a temperature of about 50°C to about 60°C for a period of about 10 to about 18 hours to obtain the Form CSI.Yield: 9.4 g; Purity: 96% (as determined by HPLC).Example 7: Preparation of Crystalline Form CSI of ResmetiromA mixture of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl) carbamate (compound n, 10 g), methyl ethyl ketone (110 mL) and water (7 mL) was treated with sodium acetate (2.0 g) at room temperature. The reaction mixture was heated to a temperature of about 70°C to about 80°C and maintained for period of about 17 hours. After completion of the reaction, the reaction mixture was cooled to a temperature of about 20°C to about 30°C and then acetic acid (5.0 ml) was added.The reaction mixture (half volume) was added slowly to water (150 mL) at a temperature 20°C to about 30°C and was stirred. The product was filtered and washed with water. The wet product was dried in tray dryer at a temperature of about 50°C to about 60°C for period of about 10 to about 18 hours to obtain the Form CSI.Yield: 3.2 g; Purity: 96.51 % (as determined by HPLC).RESME-2026Example 8: Preparation of Crystalline Form CSI of ResmetiromA mixture of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl) carbamate (compound II, 10 g), methyl ethyl ketone (110 mL) and water (7 mL) was treated with sodium acetate (2.0 g) at room temperature. The reaction mixture was heated to a temperature of about 70°C to about 80° C and maintained for 17 hours. After completion of the reaction, the reaction mixture was cooled to a temperature of about 20°C to about 30°C and then acetic acid (5.0 mL) was added. The reaction mixture (half volume) was added slowly to a mixture of water (150 mL) and resmetirom CSI Form (250 mg) at a temperature in of about 20°C to about 30°C, followed by stirring. The product was filtered and washed with water. The wet product was dried in tray dryer at a temperature in the range of 50°C to about 60°C for a period of about 10 hours to about 18 hours to obtain the Form CSI.Yield: 3.5 g; Purity: 96.77% (as determined by HPLC).Example 9: Preparation of Crystalline Form CSI of ResmetiromA mixture of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl) carbamate (compound II, 40 g) and dimethyl formamide (200 mL) was treated with sodium acetate (13.63 g) at room temperature. The reaction mixture was heated to a temperature of about 90°C to about 100°C and maintained for a period of about 6 hours. After completion of the reaction, the reaction mixture was cooled to a temperature of about 20°C to about 30°C and then acetic acid (20.0 mL) was added.The reaction mixture (62.5 mL, one fourth volume of the above reaction mixture) was added slowly at a temperature of about 20°C to about 30°C to a mixture of water (150 mL) and resmetirom form CSI (150 mg). The reaction mixture was stirred at a temperature of about 20°C to about 30°C. The product was filtered and washed with water. The wet product was dried in tray dryer at a temperature of about 50°C to about 60°C for a period of about 10 hours to about 18 hours to obtain the Form CSI.RESME-2026Yield: 8.7 g; Purity: 98.19% (as determined by HPLC).Example 10: Preparation of Crystalline Form CSI of ResmetiromA mixture of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl) carbamate (compound II, 40 g) and dimethyl formamide (200 mL) was treated with sodium acetate (13.63 g) at room temperature. The reaction mixture was heated to a temperature of about 90°C to about 100°C and maintained for a period of about 6 hours. After completion of the reaction, the reaction mixture was cooled to a temperature of about 20°C to about 30°C and then acetic acid (20.0 mL) was added.To the above reaction mixture (~15 mL), isopropyl alcohol (45mL) was added and stirred for a period of about 12 hours to about 18 hours. To this water (100 mL) was added at a temperature of about 20°C to about 30°C and stirred. The product was filtered and washed with water. The wet product was dried in tray dryer at a temperature of about 50°C to about 60°C for a period of about 10 hours to about 18 hours to obtain the Form CSI.Yield: 1.75 g; Purity: 98.57 % (as determined by HPLC).Example 11: Preparation of Crystalline Form CSI of ResmetiromA mixture of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl) carbamate (compound II, 40 g) and dimethyl formamide (200 mL) was treated with sodium acetate (13.63 g) at room temperature. The reaction mixture was heated to a temperature of about 90°C to about 100°C and maintained for a period of about 6 hours. After completion of the reaction, the reaction mixture was cooled to a temperature of about 20°C to about 30°C and then acetic acid (20.0 mL) was added.From the above reaction, the reaction mixture (~15 mL) was added to a mixture of isopropyl alcohol (45 mL) and resmetirom Form CSI (150 mg), followed by the addition of water (100 mL) at a temperature of about 20°C to about 30°C. The reaction mixture was stirred at a temperature of about 20°C to about 30°C. The product was filtered and washed with water. The wet product was dried in tray dryerRESME-2026at a temperature of about 50°C to about 60°C for a period of about 10 hours to about 18 hours to obtain the Form CSI.Yield: 1.92 g; Purity: 98.56% (as determined by HPLC).Example 12: Preparation of Crystalline Form CSI of ResmetiromTo a mixture of ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazono)acetyl) carbamate (compound II, 40 g) and dimethyl formamide (200 mL), sodium acetate (13.63 g) was added at room temperature. The reaction mixture was heated to a temperature of about 90°C to about 100°C and maintained for a period of about 6 hours at a temperature of about 90°C to about 100°C. After completion of the reaction, the reaction mixture was cooled to a temperature of about 20°C to about 30°C and then acetic acid (20.0 mL) was added. From the above reaction mixture (~15 mL) was added to a mixture of methyl ethyl ketone (45 mL) and resmetirom Form CSI (150 mg). To this water (100 mL) was added at a temperature of about 20°C to 30°C and stirred. The product was filtered and washed with water. The wet product was dried in tray dryer at a temperature of about 50°C to 60°C for 10-18 hours to obtain the Form CSI.Yield: 1.92 g; Purity: 99.18% (as determined by HPLC).Example 13: Purification of ResmetiromA mixture of crude resmetirom (3.0 g) and methyl ethyl ketone (45 mL) was heated to a temperature of about 70°C to about 80° C to obtain a clear solution. The solution was filtered and cooled to a temperature of about 25°C to about 30°C. To this, water (50 mL) was added slowly to obtain a reaction mixture. The reaction mixture was stirred for two hours and then filtered and washed with water. The wet product was dried in a tray dryer at a temperature of about 50°C to about 60°C for a period of about 12 hours to obtain the Form CSI.Yield: 1.1 g; Purity: 98.90% (as determined by HPLC).RESME-2026Example 14: Purification of ResmetiromA mixture of crude resmetirom (4.0 g) and water (40 mL) was heated to a temperature of about 70°C to about 80°C. Methyl ethyl ketone (50 mL) was slowly added to obtain a clear solution. The solution was gradually cooled to a temperature of about 20°C to about 30°C. The product was filtered and washed with a mixture of methyl ethyl ketone and water. The wet product was dried in tray dryer at a temperature of about 50 to about 60°C for a period of aboutl2 hours to obtain the Form CSI.Yield: 1.6 g; Purity: 99.41% (as determined by HPLC).Example 15: Purification of ResmetiromTo a mixture of crude resmetirom (5.0 g) and water (100 mL), aqueous solution of trisodium orthophosphate dodecahydrate was added to obtain a clear solution. To this solution, norit charcoal (1.0 g) was added followed by stirring and filtering. To the filtrate, methyl ethyl ketone (10 mL) was added and the pH was adjusted to less than 6.0 with acetic acid. Methyl ethyl ketone (10 mL) was added to the reaction mixture and stirred. The product was filtered and washed with water. The wet product was dried in tray dryer to a temperature of about 50°C to about 60°C for a period of about 12 hours to obtain the Form CSI.Yield: 4.3 g; Purity: 98.40% (as determined by HPLC).Example 16: Purification of ResmetiromTo a mixture of crude resmetirom (2.0 g) and water (20 mL), aqueous solution of trisodium orthophosphate dodecahydrate (2.4 g in 12 mL water) was added to obtain a clear solution. This was followed by the addition of methyl ethyl ketone (16 mL) and ethyl acetate (5 mL). The pH of the reaction mixture was adjusted to less than 6.0 with acetic acid and stirred. The product was filtered and washed with water. The wet product was dried in tray dryer at a temperature of about 50°C to about 60°C for a period of about 10 hours to about 18 hours to obtain the Form CSI. Yield: 1.4 g; Purity: 99.75% (as determined by HPLC).RESME-2026Example 17: Purification of ResmetiromA mixture of crude resmetirom (5.0 g) and methyl ethyl ketone (75 mL) was heated to a temperature of about 70°C to about 80°C to get a clear solution. To this solution, norit charcoal (1.0 g) was added followed by stirring and filtering. The filtrate was cooled to a temperature of about 25°C to about 30°C. To this, was water (150 mL) was added slowly. The reaction mixture was stirred for a period of about 60 minutes to about 90 minutes. The product was filtered and washed with water. The wet product was dried in tray dryer at a temperature of about 50°C to about 60°C for a period of about 10 hours to about 18 hours to obtain the Form CSI.Yield: 2.4 g; Purity: 99.40% (as determined by HPLC).Example 18: Preparation of crystalline Form CSI of resmetirom.A mixture of ethyl (Z)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate (415 gm) in methyl ethyl ketone (3320 mL) was treated with sodium acetate (141.47 gm) at a temperature of about 25°C to about 30°C to obtain a reaction mixture. The reaction mixture was heated to a temperature of about 70°C about 80°C and maintained for a period of about 17-20 hours. After completion of the reaction, the reaction mixture was cooled to a temperature of about 25 °C about 35 °C followed by addition of acetic acid (726.25 gm). The reaction mixture was stirred at a temperature of about 25 °C to about 35 °C followed by slow addition of water (6640 mL) at a temperature of about 20°C about 30°C. The reaction mixture was stirred at a temperature of about 25-35°C and filtered to obtain the wet solid (405 gm).Trisodium orthophosphate dodecahydrate (278.63 gm) was added to a mixture of the wet solid, water (4980 mL) and ethyl acetate (1245 mL) and stirred. The aqueous layer was separated from the organic layer, and the aqueous layer was treated with norit charcoal (20.75 gm). To this, methyl ethyl ketone (415 mL) was added and stirred for a period of about 60-70 minutes at a temperature of about 30-35°C. The reaction mixture was filtered through hyflo bed. To the filtrate, methyl ethyl ketone (415 mL), ethyl acetate (830 mL) were added and the pH was adjustedRESME-2026to less than 6.0 with acetic acid and again stirred followed by filtration to obtain the solid (378 gm).The wet solid was dried in vacuum tray dryer at a temperature of 50-60°C for 12 hours to obtain crystalline Form CSI of resmetirom (305 gm).HPLC Purity: 99.98%Example 19: Preparation of crystalline Form CSI of resmetiromTo the wet solid of resmetirom (65 gm) was added water (780 ml mL) and ethyl acetate (195 mL) and stirred to obtain a reaction mixture. Trisodium orthophosphate dodecahydrate (47.69 gm) was added to the reaction mixture. The layers were separated and to the aqueous layer, methyl ethyl ketone (65 mL) was added and stirred for a period of 60-70 minutes at a temperature of about 30-35°C. The reaction mixture was filtered and to the filtrate, methyl ethyl ketone (65 mL), ethyl acetate (130 mL) were added and pH was adjusted to less than 6.0 with acetic acid and again stirred, this was followed by filtration to obtain the solid (85.3 gm). The obtained wet solid was suspended in water (325 ml) and the reaction mixture was heated to a temperature of 50-60°C and stirred it for a period of about 60-90 minute. The reaction mixture was cooled to a temperature of about 25-30°C and stirred. The solid was filtered and dried in vacuum tray dryer at a temperature of about 50-60°C for 12 hours to obtain crystalline Form CSI of resmetirom (55 gm).Example 20: Stability study for the crystalline Form CSI obtained by the process of the present inventionMethod followed for the stability study:The stability study for the crystalline Form CSI was carried out by storing the Form CSI obtained by the process of the present invention over a period of 3 months at temperature and relative humidity (RH) storage conditions of 25 °C / 60% RH and 40°C / 75% RH.The stability of the crystalline Form CSI was determined by evaluating the change in the physical state of the Form CSI at the end of the stability study period of 3 months. The change in physical state of the stored Form CSI was measured byRESME-2026powder X-ray diffraction (PXRD) method, and the PXRD data, particularly the characteristic PXRD 2-theta peaks, of the crystalline Form CSI at the end of the stability study period of 3 months was compared with the PXRD data (the characteristic PXRD 2-theta peaks) of the crystalline Form CSI as determined initially i.e. prior to the crystalline form CSI was subjected to stability study.Results of the stability study:The results of the stability study carried out for crystalline Form CSI, which is prepared by the process of the present invention, are presented in the following Table I. As mentioned herein above, the stability of the crystalline Form CSI is determined by change in its physical state as measured by the PXRD method.Table 1The results of the stability study presented in the above Table I indicates that the Form CSI prepared by the process of the present invention is found to be stable over a period of 3 months at the specified temperature and relative humidity storage conditions.

Claims

RESME-2026CLAIMS1. A process for the preparation of crystalline Form CSI of resmetirom, wherein the process comprises reacting ethyl (2-cyano-2-(2-(3,5-dichloro-4-((5- isopropyl-6-oxo-l,6-dihydropyridazin-3-yl) oxy) phenyl) hydrazono) acetyl) carbamate (the compound II) with a base, followed by treatment with an acid, and isolating the Form CSI from the reaction mass; wherein the conversion of the compound II to the Form CSI is carried out in the presence of a solvent system, and wherein the Form CSI is characterized by X-ray powder diffraction pattern containing peaks at 5.8°±0.2°, 11.7°±0.2°, and 26.5°±0.2° 2 theta.

2. A process for the preparation of crystalline Form CSI of resmetirom, wherein the process comprises the steps of:(a) providing a mixture containing ethyl (2-cyano-2-(2-(3,5-dichloro-4- ((5-isopropyl-6-oxo-l,6-dihydropyridazin-3-yl) oxy) phenyl) hydrazono) acetyl) carbamate (the compound II) in a first solvent; (b) treating the mixture obtained in the step (a) with a base to obtain a reaction mixture;(c) heating the reaction mixture of the step (b) to obtain a suspension or a solution;(d) cooling the suspension or the solution of the step (c);(e) treating the suspension or the solution of step (d) with an acid;(f) combining the resulting reaction mixture obtained in the step (e) with a second solvent to obtain a solid; and(g) optionally, isolating the solid to obtain Form CSI, and wherein the Form CSI is characterized by X-ray powder diffraction pattern containing peaks at 5.8°±0.2°, 11.7°±0.2°, and 26.5°±0.2° 2 theta.

3. The process as claimed in claim 2, wherein the process further comprises the steps of:RESME-2026(h) combining the solid obtained in the step (f) with a second solvent to obtain a suspension;(i) treating the suspension obtained in the step (h) with a base or a buffer to obtain a reaction mass, and optionally, filtering it to obtain a filtrate; (j) combining the reaction mass or the filtrate of the step (i) with the first solvent;(k) treating the reaction mass of the step (j) with an acid to obtain a solid;and(l) isolating the solid to obtain highly pure Form CSI, and wherein the Form CSI is characterized by X-ray powder diffraction pattern containing peaks at 5.8°±0.2°, 11.7°±0.2°, and 26.5°±0.2° 2 theta.

4. The process as claimed in claim 2, wherein the process further comprises the steps of:(h-i) combining the solid obtained in the step (f) with a second solvent to obtain a suspension;(i-i) treating the suspension obtained in the step (h-i) with a base or a buffer to obtain a reaction mass, and optionally, separating the formed aqueous layer from the organic layer;(j-i) combining the reaction mass, or the aqueous layer of the step (i-i) with the first solvent;(k-i) treating the reaction mass, or the aqueous layer of the step (j-i) with an acid to obtain a solid; and(1-i) isolating the solid to obtain highly pure Form CSI, and wherein the Form CSI is characterized by X-ray powder diffraction pattern containing peaks at 5.8°±0.2°, 11.7°±0.2°, and 26.5°±0.2° 2 theta.

5. The process as claimed in any one of the claims 2, 3 and 4, wherein the first solvent used in the step (a), the step (j) or the step (j-i) is selected from a ketone, an alcohol, a dipolar aprotic solvent, water or a mixture thereof.RESME-20266. The process as claimed in any one of the claims 1, 2, 3, and 4, wherein the base is selected from an organic base or an inorganic base; and wherein the organic base is selected from triethylamine, pyridine, diisopropylethylamine or diisopropyl amine, and the inorganic base is selected from the alkali metal hydroxide, the alkali metal carbonate, the alkali metal bicarbonate or the alkali metal acetate; wherein the alkali metal hydroxide is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide; the alkali metal carbonate is selected from lithium carbonate, sodium carbonate, potassium carbonate; alkali metal bicarbonate is selected from lithium bicarbonate, sodium bicarbonate, potassium bicarbonate; or alkali metal acetate is selected from sodium acetate, potassium acetate, lithium acetate.

7. The process as claimed in claim 3 or claim 4, wherein the buffer used in the step (i) or the step (i-i) is selected from potassium dihydrogen phosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium phosphate, or hydrates thereof.

8. The process as claimed in claim 2, wherein in the step (c), the reaction mixture of the step (b) is heated to a temperature ranging from about 60°C to about 150°C.

9. The process as claimed in claim 2, wherein in the step (d), the suspension or solution of the step (c) is cooled to a temperature ranging from about 50°C to about 0°C.

10. The process as claimed in any one of the claims 2, 3 and 4, wherein the second solvent used in the step (f), the step (h) or the step (h-i) is selected from an alcohol solvent, an ester solvent, water or a mixture thereof.RESME-202611. The process as claimed in any one of the claims 1, 2, 3, and 4, wherein the acid is selected from hydrochloric acid, hydrobromic acid, acetic acid, sulphuric acid, phosphoric acid, formic acid and trifluoroacetic acid.

12. The process for the preparation of crystalline Form CSI of resmetirom comprising the steps of:(a-i) providing a mixture containing resmetirom and a first solvent;(a-ii) heating the mixture of the step (a-i) to obtain a suspension or a solution; (a-iii) cooling the suspension or the solution obtained in the step (a-ii);(a-iv) adding a second solvent to the solution of the step (a-iii) to obtain a mixture; and(a-v) isolating resmetirom crystalline Form CSI from the mixture of the step (a-iv), and wherein the Form CSI is characterized by X-ray powder diffraction pattern containing peaks at 5.8°±0.2°, 11.7°±0.2°, and 26.5°±0.2° 2 theta.

13. The process as claimed in claim 12, wherein the first solvent used in the step (a-i), is selected from a ketone, an alcohol, a dipolar aprotic solvent, water or a mixture thereof.

14. The process as claimed in claim 12, wherein in the step (a-ii), the reaction mixture of the step (a-i) is heated to a temperature ranging from about 60°C to about 150°C.

15. The process as claimed in claim 12, wherein in the step (a-iii), the solution is cooled to a temperature ranging from about 50°C to about 0°C.

16. The process as claimed in claim 12, wherein the second solvent used in the step (a-iv) is selected from an alcohol solvent, an ester solvent, water or a mixture thereof.

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