DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

“AN IMPROVED PROCESS FOR THE PREPARATION OF
RESMETIROM FORM I”

We, LEE PHARMA LIMITED, having address at
Sy. No: 257 & 258/1; Door No: 11-6/56-C,
Opp: IDPL Factory,
Moosapet; Balanagar (Post),
Hyderabad, Telangana; 500037- India.

The following specification particularly describes the nature of the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Resmetirom Crystalline Form I.

The present invention relates to an improved process for the preparation of Resmetirom Crystalline Form I free from other solid state forms and stable over shelf life and does not convert into any other solid state forms.

BACKGROUND OF THE INVENTION
Resmetirom (MGL-3196) is an orally administered, liver-targeted thyroid hormone receptor (THR)-ß selective agonist in development for the treatment of NASH. In patients with NASH, selectivity for THR-ß may provide metabolic benefits of thyroid hormone that are mediated by the liver, including reduction of excess hepatic fat and atherogenic lipids/lipoproteins (low-density lipoprotein cholesterol [LDL-C], triglycerides, apolipoprotein B [apoB], lipoprotein (a) [Lp(a)], apolipoprotein CIII [apoCIII]), while avoiding negative systemic effects of excess thyroid hormone in heart and bone.

Resmetirom, is a thyroid hormone receptor-beta (THR-beta) agonist indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis).

The chemical name for Resmetirom is 2-[3,5-Dichloro-4-((6-oxo-5-(propan-2-yl)-1,6-dihydropyridazin-3-yl)oxy)phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine-6-carbonitrile. The molecular formula is C17H12Cl2N6O4 and the molecular weight is 435.22. The chemical structure is:

US 9,266,861 B2 claims Resmetirom Form-I characterized by an X-ray powder diffraction pattern including peaks at about 10.5, 18.7, 22.9, 23.6, and 24.7 degrees 2?. This patent also claims a process of preparing the morphic form of claim I, the process comprising:
a) heating a mixture comprising a solvent and Compound A at a first temperature, and
b) cooling the mixture to a second temperature that is lower than the first temperature so as to obtain the morphic form of claim 1, wherein the solvent is selected from methanol, ethanol, isopropanol, methyl isobutyl ketone and a combination thereof.

US 7,452,882 B2 discloses a process for the preparation of Resmetirom wherein the resulting solid after completion of the reaction was filtered and rinsed with water followed by petroleum ether. The solid was air dried for 30 min. The solid was then diluted with hot acetonitrile. The resulting red mixture was treated with neutral decolorizing carbon, filtered through celite and rinsed with acetonitrile until no UV active material eluted. The yellow filtrate was concentrated under reduced pressure. The resulting solid was triturated with hot acetonitrile, cooled for 15 min, diluted with water and filtered. The solid was triturated again with hot acetonitrile, filtered and rinsed with acetonitrile, water, and petroleum ether to form solid which is isolated.

However, neither US ‘882 nor US ‘861 discloses an improved process for the preparation of Resmetirom Form I.

Surprisingly the inventors of the present invention found that Resmetirom Crystalline Form I prepared by the process of the present invention is free from other solid state forms, has better physicochemical characteristics, and stable over shelf life and does not convert into any other solid state forms.

OBJECT OF THE INVENTION
The main objective of the present invention is to provide to an improved process for the preparation of Resmetirom Crystalline Form I.

Another objective of the present invention is to provide an improved process for the preparation of Resmetirom Crystalline Form I free from other solid state forms and stable over shelf life and does not convert into any other solid state forms.

SUMMARY OF THE INVENTION
Accordingly, the present invention relates to an improved process for the preparation of Resmetirom Crystalline Form I.

The present invention also relates to an improved process for the preparation of Resmetirom Crystalline Form I which comprises the steps:
i) providing a solution of Resmetirom in a suitable solvent,
ii) optionally treating the solution obtained in step (i) with charcoal, and
iii) isolating the formed Resmetirom Crystalline Form I.

In another aspect, the present invention also relates to an improved process for the preparation of Resmetirom Crystalline Form I which comprises the steps:
i) providing a solution of Resmetirom in a suitable solvent,
ii) raising the reaction mass temperature to 40-110 ºC while agitating the reaction mixture for 2 -5 hours,
iii) cooling the reaction mass to room temperature,
iv) filtering the material and drying the material to Resmetirom Crystalline Form I.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig.1: Represents X-ray powder diffraction pattern of Resmetirom Crystalline Form I obtained by the process of Example 1 of the present invention.
Fig.2: Represents X-ray powder diffraction pattern of Resmetirom Crystalline Form I obtained by the process of Example 2 of the present invention.
Fig.3: Represents X-ray powder diffraction pattern of Resmetirom Crystalline Form I obtained by the process of Example 3 of the present invention.
Fig.4: Represents X-ray powder diffraction pattern of Resmetirom Crystalline Form I obtained by the process of Example 4 of the present invention.
Fig.5: Represents X-ray powder diffraction pattern of Resmetirom Crystalline Form I obtained by the process of Example 5 of the present invention.
Fig.6: Represents X-ray powder diffraction pattern of Resmetirom Crystalline Form I obtained by the process of Example 6 of the present invention.
Fig.7: Represents X-ray powder diffraction pattern of Resmetirom Crystalline Form I obtained by the process of Example 7 of the present invention.
Fig.8: Represents X-ray powder diffraction pattern of Resmetirom Crystalline Form I obtained by the process of Example 8 of the present invention.
Fig.9: Represents X-ray powder diffraction pattern of Resmetirom Crystalline Form I obtained by the process of Example 9 of the present invention.

INSTRUMENTAL CONDITIONS
X-ray diffractometer
Instrument Powder X-ray diffractometer
Make & Model MalvernPANalytical & Empyrean
Source Cu, Ka
Wavelength 1.5406
Settings:
X-ray diffractometer
Sample stage mode Spinning
Spinner revolution time 1.00 (s)
Incident Beam Path optics:
PreFIX module Bragg-Brentano HD Cu
Soller slit Soller slits 0.02 rad
Mask Fixed mask 10 mm
Divergence slit Fixed slit 1/8°
Anti-scatter slit Fixed slit 1/2°
Filter None
Beam knife Beam knife for linear detectors
Diffracted Beam Path :
PreFIX module PIXcel 1D-Medipix 3 FASS
Soller slit Large Soller slits 0.02 rad.
Anti-scattering slit AS slit 7.5 mm (PIXcel)
Filter None
Detector PIXcel 1D-Medipix 3 detector[1]
Mode Scanning line detector (1D)
Active length (°2-theta) 3.3482°
Measurement or Scan Parameters :
Scan axis Gonio
Scan mode Continuous
Start angle (°) 2.0000°
End angle (°) 50.0043°
Step size (°) 0.0131303
Time per step (s) 25.500
Number of steps 3656
Scan speed (°/s) 0.131303
Generator Settings :
Tension (kV) 45
Current (mA) 40

DETAILED DESCRIPTION OF THE INVENTION
Within the context of the present invention, solvents are selected from methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tertbutyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, n-butanol, benzene, toluene, xylene, heptane, hexane and cyclohexane acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, isopropyl ketone and mixture thereof.

Within the context of the present invention, the solution obtained in step (i) is treated with charcoal.

Within the context of the present invention, the reaction mass temperature to 40-110 ºC. In some embodiments the reaction mass temperature is 54-58°C, 45-50°C, 75-85°C, 80-85°C and 90-95°C.

Within the context of the present invention, isolation methods are well known in the art. For example, in some embodiments, isolation is carried out by drying under vacuum, filtration by gravity or suction, centrifugation, filtering the reaction mixture and collecting a solid.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES
Example 1 - Process for the preparation of Resmetirom Crystalline Form I using n-butyl acetate:
The RB flask was purged with N2, charged with Dimethyl acetamide (500 ml), Ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy) phenyl) hydrazineylidene)acetyl) carbamate (100g) and potassium acetate (24.5 g) and stir the reaction mass. Raise the reaction mass temperature to 120-125°C and maintain for 3-4 hrs. The reaction mass was sampled and TLC indicated NMT 1.0% of Ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate remained. The reaction mass was cooled to 25°C and Acetic acid (25 ml), Water (1000 ml) and 2-MeTHF (1000 ml) were added. The reaction mass was stirred and separate the organic layer. The aqueous layer was again extracted with 2-MeTHF. The combined organic layers were washed 4 times with sodium chloride solution. The charcoal treatment was done at 40-45°C for organic layer and wash with 2MeTHF. Distilled out 2-MeTHF completely and add Acetone (300 ml) and heat to 55-60°C. The reaction mass cool and filtered the solid. The wet material was charged into RB flask, add Acetone (450 ml) and Ethanol (400 ml). Heat the reaction mass to 45-50°C and add charcoal. Filter the reaction mass and wash with Acetone and Ethanol mixture. The clear filtrate was charged to RB flask and heat to 45-50°C. Add the water (1000 ml) at 45-50°C and maintained stirring for 1 hour. Further reaction mass was cooled and filter the solid. Add the n-Butylacetate (400 ml) into RB flask followed by wet material and raise the temperature to 90-95°C for 3-4 hours. Reaction mass cool and filter the solid. The wet cake washed with n-butyl acetate (50 ml) and was dried at 70-75°C under vacuum to afford 65 g of form I.
HPLC Purity: 99.74%, Yield: 71.9%

Example 2 - Process for the preparation of Resmetirom Crystalline Form I using isobutyl acetate :
The RB flask was purged with N2, charged with Dimethyl acetamide (500 ml), Ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy) phenyl) hydrazineylidene)acetyl)carbamate (100 g) and potassium acetate (24.5 g) and stir the reaction mass. Raise the reaction mass temperature to 120-125°C and maintain for 3-4 hrs. The reaction mass was sampled and TLC indicated NMT 1.0% of Ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene) acetyl) carbamate remained. The reaction mass was cooled to 25°C and add Acetic acid (25 ml), Water (1000 ml) and 2-MeTHF (1000 ml). The reaction mass was stirred and separate the organic layer. The aqueous layer was again extracted with 2-MeTHF. The combined organic layers were washed 4 times with sodium chloride solution. The charcoal treatment was done at 40-45°C for organic layer and wash with 2MeTHF. Distilled out 2-MeTHF completely and add Acetone (300 ml) and heat to 55-60°C. The reaction mass cool and filtered the solid. The wet material was charged into RB flask, add Acetone (450 ml) and Ethanol (400 ml). Heat the reaction mass to 45-50°C and add charcoal. Filter the reaction mass and wash with Acetone and Ethanol mixture. The clear filtrate charge to RB flask and heat to 45-50°C. Add the water (1000 ml) at 45-50°C and maintained stirring for 1 hour. Further reaction mass was cooled and filter the solid. Add the isobutyl acetate (400 ml) into RB flask followed by wet material and raise the temperature to 90-95°C for 3-4 hours. Reaction mass cool and filter the solid. The wet cake washed with isobutyl acetate (50 ml) and was dried at 70-75°C under vacuum to afford 60 g of form I.
HPLC Purity: 99.47%, Yield: 71.9%

Example 3 - Process for the preparation of Resmetirom Crystalline Form I using MIBK:
The RB flask was purged with N2, charged with Dimethyl acetamide (500 ml), Ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl) hydrazineylidene)acetyl)carbamate (100 g) and potassium acetate (24.5 g) and stir the reaction mass. Raise the reaction mass temperature to 120-125°C and maintain for 3-4 hrs. The reaction mass was sampled and TLC indicated NMT 1.0% of Ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl) carbamate remained. The reaction mass was cooled to 25°C and add Acetic acid (25 ml), Water (1000 ml) and 2-MeTHF (1000 ml). The reaction mass was stirred and separate the organic layer. The aqueous layer was again extracted with 2-MeTHF. The combined organic layers were washed 4 times with sodium chloride solution. The charcoal treatment was done at 40-45°C for organic layer and wash with 2MeTHF. Distilled out 2-MeTHF completely and add Acetone (300 ml) and heat to 55-60°C. The reaction mass cool and filtered the solid. The wet material was charged into RB flask, add Acetone (450 ml) and Ethanol (400 ml). Heat the reaction mass to 45-50°C and add charcoal. Filter the reaction mass and wash with Acetone and Ethanol mixture. The clear filtrate charge to RB flask and heat to 45-50°C. Add the water (1000 ml) at 45-50°C and maintained stirring for 1 hour. Further reaction mass was cooled and filter the solid. Add the MIBK (400 ml) into RB flask followed by wet material and raise the temperature to 90-95°C for 3-4 hours. Cool the Reaction mass and filter the solid. Reaction mass cool and filter the solid. The wet cake washed with MIBK (50 ml) and was dried at 70-75°C under vacuum to afford 65 g of form I.
Purity: 99.71%, Yield: 71.9%

Example 4 - Process for the preparation of Resmetirom Crystalline Form I using Toluene:
The RB flask was purged with N2, charged with Dimethyl acetamide (500 ml), Ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl) carbamate (100 g) and potassium acetate (24.5 g) and stir the reaction mass. Raise the reaction mass temperature to 120-125°C and maintain for 3-4 hrs. The reaction mass was sampled and TLC indicated NMT 1.0% of Ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl) hydrazineyl idene)acetyl) carbamate remained. The reaction mass was cooled to 25°C and add Acetic acid (25 ml), Water (1000 ml) and 2-MeTHF (1000 ml). The reaction mass was stirred and separate the organic layer. The aqueous layer was again extracted with 2-MeTHF. The combined organic layers were washed 4 times with sodium chloride solution. The charcoal treatment was done at 40-45°C for organic layer and wash with 2MeTHF(200 ml). Distilled out 2-MeTHF completely and add Acetone (300 ml) and heat to 55-60°C. The reaction mass cool and filtered the solid. The wet material was charged into RB flask, add Acetone (450 ml) and Ethanol (400 ml). Heat the reaction mass to 45-50°C and add charcoal. Filter the reaction mass and wash with Acetone and Ethanol mixture. The clear filtrate charge to RB flask and heat to 45-50°C. Add the water (1000 ml) at 45-50°C and maintained stirring for 1 hour. Further reaction mass was cooled and filter the solid. Add the Toluene (400 ml) into RB flask followed by wet material and raise the temperature to 90-95°C for 3-4 hours. Reaction mass cooland filter the solid. The wet cake was washed with Toluene (50 ml) and was dried under vacuum to afford 70-75 g of form I.
Purity: 99.47%, Yield: 82.9%

Example 5 - Process for the preparation of Resmetirom Crystalline Form I using n-Butanol and maintenance at 80-85°C
The RB flask was purged with N2, charged with Dimethyl acetamide (500 ml), Ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl) hydrazineylidene)acetyl) carbamate (100 g) and potassium acetate (24.5 g) and stir the reaction mass. Raise the reaction mass temperature to 120-125°C and maintain for 3-4 hrs. The reaction mass was sampled and TLC indicated NMT 1.0% of Ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl) carbamate remained. The reaction mass was cooled to 25°C and add Acetic acid (25 ml), Water (1000 ml) and 2-MeTHF (1000 ml). The reaction mass was stirred and separate the organic layer. The aqueous layer was again extracted with 2-MeTHF. The combined organic layers were washed 4 times with sodium chloride solution. The charcoal treatment was done at 40-45°C for organic layer and wash with 2MeTHF. Distilled out 2-MeTHF completely and add Acetone (300 ml) and heat to 55-60°C. The reaction mass cool and filtered the solid. The wet material was charged into RB flask, add Acetone (450 ml) and Ethanol (400 ml). Heat the reaction mass to 45-50°C and add charcoal. Filter the reaction mass and wash with Acetone and Ethanol mixture. The clear filtrate charge to RB flask and heat to 45-50°C. Add the water (1000 ml) at 45-50°C and maintained stirring for 1 hour. Further reaction mass was cooled and filter the solid. Add the n-Butanol (400 ml) into RB flask followed by wet material and raise the temperature to 80-85°C for 3-4 hours. Reaction mass cool and filter the solid. The wet cake washed with n-Butanol (50 ml) and was dried under vacuum to afford 60-65 g of form I.
HPLC Purity: 99.95%, Yield: 71.9%

Example 6 - Process for the preparation of Resmetirom Crystalline Form I using n-Butanol and maintenance at 54-58°C
The RB flask was purged with N2, charged with Dimethyl acetamide (500 ml), Ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl) hydrazineylidene)acetyl) carbamate (100 g) and potassium acetate (24.5 g) and stir the reaction mass. Raise the reaction mass temperature to 120-125°C and maintain for 3-4 hrs. The reaction mass was sampled and TLC indicated NMT 1.0% of Ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl) carbamate remained. The reaction mass was cooled to 25°C and add Acetic acid (25 ml), Water (1000 ml) and 2-MeTHF (1000 ml). The reaction mass was stirred and separate the organic layer. The aqueous layer was again extracted with 2-MeTHF. The combined organic layers were washed 4 times with sodium chloride solution. The charcoal treatment was done at 40-45°C for organic layer and wash with 2MeTHF. Distilled out 2-MeTHF completely and add Acetone (300 ml) and heat to 55-60°C. The reaction mass cool and filtered the solid. The wet material was charged into RB flask, add Acetone (450 ml) and Ethanol (400 ml). Heat the reaction mass to 45-50°C and add charcoal. Filter the reaction mass and wash with Acetone and Ethanol mixture. The clear filtrate charge to RB flask and heat to 45-50°C. Add the water (1000 ml) at 45-50°C and maintained stirring for 1 hour. Further reaction mass was cooled and filter the solid. Add the n-Butanol (400 ml) into RB flask followed by wet material and raise the temperature to 54-58°C for 3-4 hours. Reaction mass cool and filter the solid. The wet cake washed with n-Butanol (50 ml) and was dried under vacuum to afford 60-65 g of form I.
HPLC Purity: 99.47%, Yield: 71.9%

Example 7 - Process for the preparation of Resmetirom Crystalline Form I using n-Butanol and maintenance at 45-50°C
The RB flask was purged with N2, charged with Dimethyl acetamide (500 ml), Ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy) phenyl) hydrazineylidene)acetyl) carbamate (100 g) and potassium acetate (24.5 g) and stir the reaction mass. Raise the reaction mass temperature to 120-125°C and maintain for 3-4 hrs. The reaction mass was sampled and TLC indicated NMT 1.0% of Ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl) carbamate remained. The reaction mass was cooled to 25°C and add Acetic acid (25 ml), Water (1000 ml) and 2-MeTHF (1000 ml). The reaction mass was stirred and separate the organic layer. The aqueous layer was again extracted with 2-MeTHF. The combined organic layers were washed 4 times with sodium chloride solution. The charcoal treatment was done at 40-45°C for organic layer and wash with 2MeTHF. Distilled out 2-MeTHF completely and add Acetone (300 ml) and heat to 55-60°C. The reaction mass cool and filtered the solid. The wet material was charged into RB flask, add Acetone (450 ml) and Ethanol (400 ml). Heat the reaction mass to 45-50°C and add charcoal. Filter the reaction mass and wash with Acetone and Ethanol mixture. The clear filtrate charge to RB flask and heat to 45-50°C. Add the water (1000 ml) at 45-50°C and maintained stirring for 1 hour. Further reaction mass was cooled and filter the solid. Add the n-Butanol (400 ml) into RB flask followed by wet material and raise the temperature to 45-50°C for 3-4 hours. Reaction mass cool and filter the solid. The wet cake washed with n-Butanol (50 ml) and was dried under vacuum to afford 60-65 g of form I.
HPLC Purity: 99.37%, Yield: 71.9%

Example 8 - Process for the preparation of Resmetirom Crystalline Form I using n-Butanol and THF at 80-85°C
The RB flask was purged with N2, charged with Dimethyl acetamide (500 ml), Ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy) phenyl)hydrazineylidene)acetyl) carbamate (100 g) and potassium acetate (24.5 g) and stir the reaction mass. Raise the reaction mass temperature to 120-125°C and maintain for 3-4 hrs. The reaction mass was sampled and TLC indicated NMT 1.0% of Ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl) hydrazineylidene) acetyl) carbamate remained. The reaction mass was cooled to 25°C and add Acetic acid (25 ml), Water (1000 ml) and 2-MeTHF (1000 ml). The reaction mass was stirred and separate the organic layer. The aqueous layer was again extracted with 2-MeTHF(200 ml). The combined organic layers were washed 4 times with sodium chloride solution. The charcoal treatment was done at 40-45°C for organic layer and wash with 2MeTHF. Distilled out 2-MeTHF completely and add Acetone (300 ml) and heat to 55-60°C. The reaction mass cool and filtered the solid. The wet material was charged into RB flask, add Acetone (450 ml) and Ethanol (400 ml). Heat the reaction mass to 45-50°C and add charcoal. Filter the reaction mass and wash with Acetone and Ethanol mixture. The clear filtrate charge to RB flask and heat to 45-50°C. Add the water (1000 ml) at 45-50°C and maintained stirring for 1 hour. Further reaction mass was cooled and filter the solid. Add the n-Butanol(400 ml) and THF (50 ml) mixture into RB flask followed by wet material and raise the temperature to 80-85°C for 3-4 hours. Reaction mass cool to 25-30°C and Maintain for 1-2 hrs at 25-30°C, filter the solid. The wet cake wash with n-butanol (50 ml) and was dried at 70-75°C under vacuum to afford 70-75 g of form I.
HPLC Purity: 99.96%, Yield: 82.9%

Example 9 - Process for the preparation of Resmetirom Crystalline Form I using n-Butanol +THF at 56-58°C
The RB flask was purged with N2, charged with Dimethyl acetamide (500 ml), Ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy) phenyl) hydrazineylidene)acetyl) carbamate (100 g) and potassium acetate (24.5 g) and stir the reaction mass. Raise the reaction mass temperature to 120-125°C and maintain for 3-4 hrs. The reaction mass was sampled and TLC indicated NMT 1.0% of Ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl) carbamate remained. The reaction mass was cooled to 25°C and add Acetic acid (25 ml), Water (1000 ml) and 2-MeTHF (1000 ml). The reaction mass was stirred and separate the organic layer. The aqueous layer was again extracted with 2-MeTHF. The combined organic layers were washed 4 times with sodium chloride solution. The charcoal treatment was done at 40-45°C for organic layer and wash with 2-MeTHF. Distilled out 2-MeTHF completely and add Acetone(300 ml) and heat to 55-60°C. The reaction mass cool and filtered the solid. The wet material was charged into RB flask, add Acetone (450 ml) and Ethanol (400 ml). Heat the reaction mass to 45-50°C and add charcoal. Filter the reaction mass and wash with Acetone and Ethanol mixture. The clear filtrate charge to RB flask and heat to 45-50°C. Add the water (1000 ml) at 45-50°C and maintained stirring for 1 hour. Further reaction mass was cooled and filter the solid. Add the n-Butanol (400 ml) +THF (50 ml) into RB flask followed by wet material and raise the temperature to 56-58°C for 3-4 hours. Reaction mass cool and filter the solid. The wet cake washed with n-Butanol (50 ml) and was dried under vacuum to afford 60-65 g of form I.
HPLC Purity: 99.45%, Yield: 71.9%

Example 10 - Process for the preparation of Resmetirom Crystalline Form I using n-Butanol at 75-85°C
Charge n-Butanol and Resmetirom wet material into reactor and stir for 5-10 min at room temperature. Raise the temperature and maintain for 3-4 hrs at 75-85°C. Cool the reaction mas maintain for 1-2 hrs at room temperature. Centrifuge and spin dry the material followed by n-Butanol washing then unload the material. Dry the material for 2-3 hrs at 25-30°C and for 6-8 hrs at 70-75°C under vacuum.
,CLAIMS:We claim:
1. An improved process for the preparation of Resmetirom Crystalline Form I which comprises the steps:
i) providing a solution of Resmetirom in a suitable solvent,
ii) optionally treating the solution obtained in step (i) with charcoal, and
iii) isolating the formed Resmetirom Crystalline Form I.
2. An improved process for the preparation of Resmetirom Crystalline Form I which comprises the steps:
i) providing a solution of Resmetirom in a suitable solvent,
ii) raising the reaction mass temperature to 40-110 ºC while agitating the reaction mixture for 2 -5 hours,
iii) cooling the reaction mass to room temperature,
iv) filtering the material and drying the material to Resmetirom Crystalline Form I.
3. The process as claimed in claims 1&2, wherein the solvent is methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, -butyl acetate, isobutyl acetate, sec-butyl acetate, di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tertbutyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 2-methoxyethanol and dimethoxyethane, n-butanol, benzene, toluene, xylene, heptane, hexane and cyclohexane acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, isopropyl ketone and mixture thereof.
4. The process as claimed in claim 3, wherein the solvent is specifically n-butyl acetate, isobutyl acetate, methyl isobutyl ketone, toluene, n-butanol, tetrahydrofuran and mixtures thereof.
Dated this Thirtieth (30th) day of April, 2025

______________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883