Novel forms and co-crystals of resmetirom

Abstract

The present invention relates to new crystal forms of Resmetirom. The present invention also relates to novel Co-crystal of Resmetirom. Further, process to prepare these novel crystal and / or co-crystal forms is disclosed. The novel crystal forms of the present invention have improved properties. Formula (I).

Description

[0001] NOVEL FORMS AND CO-CRYSTALS OF RESMETIROM

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to novel crystalline polymorphs of Resmetirom and its process for the preparation thereof.

[0004] The present invention also relates to novel co-crystals of Resmetirom and its process for the preparation thereof.

[0005] BACKGROUND OF THE INVENTION

[0006] Resmetirom, a thyroid hormone receptor beta (THR-P) agonist, has emerged as a promising therapeutic option for NASH. It is developed for the treatment of non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD) and associated dyslipidemias.

[0007] The structural formula of Resmetirom is as follows:

[0008] Resmetirom is first disclosed in Patent No. US 7,807,674 B2. The US ‘674 patent also describes the process to prepare Resmetirom wherein Resmetirom was obtained as a yellow solid. The crystal nature of Resmetirom was not described in this patent.

[0009] United states Patent No. US 9,266,861 B2 discloses Resmetirom hydrate, anhydrous form I, methyl isobutyl ketone solvate, and dimethylacetamide solvate. There are several other polymorph forms of Resmetirom reported in literature such as the forms reported in WO 2020 / 010068, WO 2021 / 063367 and WO 2021 / 129465.

[0010] Further, few co-crystal forms of Resmetirom are reported in literature such as the ones reported in WO 2020 / 010068 (Al).

[0011] DISADVANTAGES OF THE PRIOR ART

[0012] As per the literature, the crystal form I is suitable for pharmaceutical preparations and the said form is prepared from hydrate or methyl isobutyl ketone solvate or dimethyl acetamide solvate. However, Methyl isobutyl ketone and dimethylacetamide are toxic organic solvents and are not suitable for medicinal use. Therefore, there is still a need in the art to develop novel forms of Resmetirom that are easy to prepare, have good stability, are safe, non-toxic, and have good physical and chemical properties.

[0013] Further, as per literature, Resmetirom has low tendency to form co-crystals. Only few co-crystals such as glutaric acid co crystal are known so far such as disclosed in WO 2020 / 010068 (Al). US 2023 / 0364009 Al also discloses co-crystals of Resmetirom such as caffeine and Nicotinamide Co crystals.

[0014] The inventors of the present invention have conducted numerous experiments in an attempt to obtain a better / superior form of Resmetirom and / or co-crystals.

[0015] SUMMARY OF THE INVENTION

[0016] The present invention provides novel crystalline polymorphs of Resmetirom and its process for the preparation thereof.

[0017] The present invention also provides novel co-crystals of Resmetirom and its process for the preparation thereof.

[0018] One aspect, of the present invention provides a novel crystalline form-LP of Resmetirom.

[0019] One aspect of the present invention provides a novel crystalline form-Ll of Resmetirom.

[0020] One Another aspect of the present invention provides a novel crystalline form-L2 of Resmetirom.

[0021] Further another aspect of the present invention provides a novel crystalline form-L3 of Resmetirom.

[0022] Further aspect of the present invention provides a novel Co-Crystal (1:2) of Resmetirom Benzene sulfonic acid.

[0023] Further aspects of the present invention provide process for preparation of these novel polymorphs and / or Co-Crystals.

[0024] BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 01: Shows a characteristic X-ray powder diffraction pattern (XRPD) of Resmetirom Form LP obtained as per Example- 1.

[0026] Figure 01°: Shows a characteristic X-ray powder diffraction pattern (XRPD) of Resmetirom Form LP obtained as per Example- 1°. Figure Ol1: Shows comparison of Form LP obtained according to various examples:

[0027] • Top Pattern: Form LP obtained as per Example- 11.

[0028] • Middle Pattern: Form LP obtained as per Example- 1.

[0029] • Bottom Pattern: Form LP obtained as per Example- 111.

[0030] Figure 01 : Shows a characteristic X-ray powder diffraction pattern (XRPD) of Resmetirom Form LP wet material.

[0031] Figure 02: Shows a characteristic X-ray powder diffraction pattern (XRPD) of Resmetirom Form LI.

[0032] Figure 03: shows a characteristic X-ray powder diffraction pattern (XRPD) of Resmetirom Form L2.

[0033] Figure 04: Shows a characteristic X-ray powder diffraction pattern (XRPD) of Resmetirom Form L3.

[0034] Figure 041: Shows a characteristic X-ray powder diffraction pattern (XRPD) of Resmetirom Form L3 from example 041.

[0035] Figure 05: Shows a characteristic X-ray powder diffraction pattern (XRPD) of Resmetirom Benzenesulfonic acid co-crystal.

[0036] Figure 06: Shows Differential Scanning Calorimetry (DSC) of Resmetirom Benzenesulfonic acid co-crystal.

[0037] Figure 07: Shows C NMR spectrum of crystalline form LP of Resmetirom.

[0038] DETAILED DESCRIPTION OF THE INVENTION

[0039] Embodiment-I:

[0040] One embodiment of the present invention provides a novel crystalline form-LP of Resmetirom.

[0041] In a specific embodiment, the novel crystalline form-LP is Anhydrous crystalline Form.

[0042] Form-LP is characterized by an X-ray powder diffraction pattern having characteristic peaks at 6.05, 6.22, 9.9, 11.95 and 20.47.

[0043] In another embodiment, the Form-LP has the following X-ray diffraction peaks:

[0044] In another embodiment, the Form-LP is characterized by its X-ray powder diffraction

[0045] (XRD) pattern as illustrated in Figure-01.

[0046] 13

[0047] In another embodiment, Form-LP has a solid-state NMR spectrum comprising C chemical shifts (ppm) at 28.19+0.2, 122.71+0.2, 147.45+0.2, 147.87+0.2, 153.55+0.2, and 155.03+0.2, and 161.22+0.2.

[0048] In another embodiment, Form-LP has a solid-state NMR spectrum further comprising13C chemical shifts (ppm) at 19.54+0.2, 20.42+0.2, 21.8+0.2, 28.19+0.2, 29.32+0.2, 122.12+0.2, 122.71+0.2, 123.55+0.2, 124.31+0.2, 125.72+0.2, 126.36+0.2, 126.83+0.2, 127.25+0.2, 127.92+0.2, 128.57+0.2, 129.18+0.2, 129.8+0.2, 130.25+0.2, 136.2+0.2, 136.48+0.2,

[0049] 136.88+0.2, 143.65+0.2, 147.45+0.2, 147.87+0.2, 148.23+0.2, 153.55+0.2, 155.03+0.2,

[0050] 161.22+0.2, 161.94+0.2.

[0051] In another embodiment of the present invention provides Form LP, wherein said form has a solid-state NMR spectrum comprising 13C chemical shifts (ppm) at positions essentially the same as shown in Figure 07. Embodiment-I0:

[0052] Form-LP is characterized by an X-ray powder diffraction pattern having characteristic peaks at 5.94, 6.17, 9.8, 11.8 and 20.23.

[0053] In another embodiment, the Form-LP has the following X-ray diffraction peaks:

[0054] In another embodiment, the Form-LP is characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure-01o.

[0055] In an embodiment, the present invention provides a process for preparing crystalline Form LP of Resmetirom, comprising the following steps:

[0056] (a) dissolving Resmetirom in a solvent selected from chloro solvents such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and its mixture thereof; and

[0057] (b) isolating crystalline Form LP of Resmetirom. Embodiment-II:

[0058] Another embodiment of the present invention provides a novel crystalline form-Ll of Resmetirom.

[0059] In a specific embodiment, the novel crystalline form-Ll is Anhydrous crystalline Form.

[0060] Form-Ll is characterized by an X-ray powder diffraction pattern having characteristic peaks at 6.5, 7.7, 11.8 and 12.3+0.2 °2-theta.

[0061] In another embodiment, the Form-Ll has the following X-ray diffraction peaks:

[0062] In another embodiment, the Form-Ll is characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure-02.

[0063] In an embodiment, the present invention provides a method for preparing crystalline Form LI of Resmetirom, which comprises desolvating crystalline Form L3.

[0064] Embodiment-Ill :

[0065] Another embodiment of the present invention provides a novel crystalline form-L2 of Resmetirom.

[0066] In a specific embodiment, the novel crystalline form-L2 is Anhydrous crystalline Form.

[0067] Form-L2 is characterized by an X-ray powder diffraction pattern having characteristic peaks at 6.6, 7.9, 11.9 and 12.4 +0.2 °2-theta. In another embodiment, the Form-L2 has the following X-ray diffraction peaks:

[0068] In another embodiment, the Form-L2 is characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure-03.

[0069] Embodiment- V :

[0070] One another embodiment of the present invention provides a novel crystalline form-L3 of Resmetirom.

[0071] In a specific embodiment, the novel crystalline form-L3 is Acetone- acetonitrile solvate Form.

[0072] Form-L3 is characterized by an X-ray powder diffraction pattern having characteristic peaks at 6.5, 7.8, 8.4 and 10.1 ±0.2 °29. In another embodiment, the Form-L3 has the following X-ray diffraction peaks:

[0073] In another embodiment, the Form-L3 is characterized by its X-ray powder diffraction (XRD) pattern as illustrated in Figure-04. In an embodiment, the present invention provides a process for preparing crystalline

[0074] Form L3 of Resmetirom, comprising the following steps:

[0075] (a) dissolving Resmetirom in a solvent selected from nitrile solvents such as acetonitrile or ketone solvents such as acetone, methyl isobutyl ketone, methyl ethyl ketone, or a mixture thereof; (b) heating the obtained solution to about 40-60°C;

[0076] (c) cooling the solution obtained in step (b);

[0077] (d) isolating crystalline Form L3 of Resmetirom. Embodiment- V:

[0078] One embodiment of the present invention provides Resmetirom Benzenesulfonic acid Co-crystal.

[0079] In one embodiment, the present invention provides Anhydrous Co-Crystal (1:2) of Resmetirom Benzene sulfonic acid.

[0080] The Resmetirom Benzenesulfonic acid co-crystal is characterized by an X-ray powder diffraction pattern having characteristic peaks at 12.5, 19.5, 22.1, 24.0, 25.8 and 28.5 ±0.2 °2- theta.

[0081] In another embodiment, the Resmetirom Benzenesulfonic acid co-crystal has the following X-ray diffraction peaks: In another embodiment, the benzenesulfonic acid co-crystal is characterized by its X- ray powder diffraction (XRD) pattern as illustrated in Figure-05.

[0082] In an embodiment, the present invention provides a process for preparing a co-crystal of Resmetirom, comprising the following steps:

[0083] (a) dissolving Resmetirom in a ketone solvent selected from acetone, methyl isobutyl ketone, methyl ethyl ketone and its mixture thereof;

[0084] (b) adding benzene sulfonic acid to the solution obtained in step (a);

[0085] (c) adding a hydrocarbon solvent (e.g., toluene, xylene, cyclohexane, hexane, heptane, n- pentane, petroleum ether) to the solution from step (b);

[0086] (d) isolating the co-crystal of Resmetirom.

[0087] Crystalline polymorphs of Resmetirom of the present invention may have advantageous properties selected from at least one of the following: chemical purity, flowability, solubility, dissolution rate, morphology or crystal habit, stability, such as chemical stability as well as thermal and mechanical stability with respect to polymorphic conversion, stability towards dehydration and / or storage stability, low content of residual solvent, a lower degree of hygroscopicity, flowability, and advantageous processing and handling characteristics such as compressibility and bulk density.

[0088] All PXRD patterns were generated using MalvernPANAlytical PXRD using below mentioned instrument settings and method parameters.

[0089] Scan Axis : Gonio

[0090] Start Position [°29] : 2.0023

[0091] End Position [°29] : 49.9853

[0092] Step Size [°29] : 0.0130

[0093] Scan Step Time [s] : 23.9700

[0094] Scan Type : Continuous

[0095] PSD Mode : Scanning

[0096] PSD Length [°29] : 3.35

[0097] Offset [°29] : 0.0000

[0098] Divergence and Antiscattering Slit Type : Fixed

[0099] Divergence Slit Size [°] : 0.1799

[0100] Specimen Length [mm] : 10.00

[0101] Anode Material : Cu

[0102] Intended Wavelength : K-al K-al [A] : 1.54060

[0103] Generator Settings : 40 mA, 45 kV

[0104] Goniometer Radius [mm] : 240.00

[0105] Spinning : Yes

[0106] In another embodiment, the process for the preparation of Resmetirom according to the present invention is schematically represented as follows;

[0107] Scheme- 1

[0108] Step a) of the foregoing process involves, reacting 3,6-Dichloro-4-isopropyl pyridazine of formula (8) with 4-Amino-2,6-dichloro phenol (7) and sodium iodide in the presence of a base in a suitable solvent under appropriate reaction conditions to provide 3,5-dichloro-4-((6-chloro- 5-isopropylpyridazin-3-yl)oxy)aniline of formula (6). The base is selected from “alkali metal carbonates” such sodium carbonate, potassium carbonate, lithium carbonate and the like, preferably potassium carbonate. The solvent is selected from “polar aprotic solvents” such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like, preferably dimethyl sulfoxide. The step a) reaction is carried out at a suitable temperature and maintains for a sufficient period of time till completion of the reaction; preferably carried out at 80-100°C for 10-16 hrs.

[0109] Step b) of the foregoing process involves, reacting 3,5-dichloro-4-((6-chloro-5- isopropylpyridazin-3-yl)oxy)aniline of formula (6) with sodium acetate and acetic acid under appropriate reaction conditions to provide 6-(4-amino-2,6-dichlorophenoxy)-4- isopropylpyridazin-3-yl acetate of formula (5). The step b) reaction is carried out at a suitable temperature and maintains for a sufficient period of time till completion of the reaction; preferably carried out at 90-110°C for 20-24 hrs.

[0110] Step c) of the foregoing process involves, reacting 6-(4-amino-2,6-dichlorophenoxy)-4- isopropylpyridazin-3-yl acetate of formula of formula (5) with Sodium hydroxide solution in a suitable solvent under appropriate reaction conditions to provide 6-(4-amino-2,6- dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one of formula (4). The solvent is selected from “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, n-pentane, petroleum ether and the like, preferably toluene. The step c) reaction is carried out at a suitable temperature and maintains for a sufficient period of time till completion of the reaction; preferably carried out at 110-130°C for 3-4 hrs.

[0111] Step d) of the foregoing process involves, reacting 6-(4-amino-2,6-dichlorophenoxy)-4- isopropylpyridazin-3(2H)-one of formula (4) with sodium nitrite in acetic acid and cone. Hydrochloric acid, then condensing with Cyanoacetyl urethane (3) in the presence of Sodium acetate and water followed by purification in IPE under appropriate reaction conditions to provide ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dehydropyridazin-3- yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate of formula (2). The step d) reaction is carried out at a suitable temperature and maintains for a sufficient period of time till completion of the reaction; preferably carried out at 0-5°C for 1-4 hrs.

[0112] Step e) of the foregoing process involves, cyclizing ethyl (E)-(2-cyano-2-(2-(3,5-dichloro-4- ((5-isopropyl-6-oxo-l,6-dehydropyridazin-3-yl)oxy)phenyl)hydrazineylidene)acetyl)carbamate of formula (2) in presence of Potassium acetate and Dimethyl acetamide under appropriate reaction conditions to provide 2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6-dihydropyridazin-3- yl)oxy) phenyl) -3,5-dioxo-2,3,4,5-tetrahydro-l,2,4-triazine-6-carbonitrileof formula (1). The step e) reaction is carried out at a suitable temperature and maintains for a sufficient period of time till completion of the reaction; preferably carried out at 120-125°C for 3-4 hrs. The obtained solid was dissolved or suspended in a mixture of acetone and acetonitrile to obtain the solid as form L3, named as acetone-acetonitrile solvate. The solvate was further dissolved or suspended in methylene dichloride to obtain crystalline form LP of Resmetirom.

[0113] In another embodiment, the present invention provides, Resmetirom obtained according to the present invention could be crystalline form or co-crystal form. In another embodiment, the present invention provides, the crystalline Resmetirom obtained according to the present invention could be in form LP, form LI, Form L2, Form L3 or cocrystal with benzene sulfonic acid.

[0114] In another embodiment, the present invention provides preparation of crystalline form LP of Resmetirom obtained according to the present invention without isolation of crystalline form of Resmetirom, having the PXRD is characterized by an X-ray powder diffraction pattern having characteristic peaks at about 10.5, 18.7, 22.9, 23.6 and 24.7 degree 29.

[0115] EXAMPLES

[0116] Example- 1:

[0117] Preparation of Form-LP of Resmetirom:

[0118] Resmetirom Form- L3 (from example-4) (10 gm) was taken in to a 500 ml Round bottomed flask. Slurred the compound at 25-30°C in Dichloromethane (200 mL) for 6 hours. Filtered the slurry mass at 25-30°C. The wet solid was recorded the XRD.

[0119] PXRD: Fig 012

[0120] The wet solid material was dried at 25-30°C for 2 hours in vacuum tray dryer (VTD) followed by drying at 45-50° C for 2 hours further followed by drying at 70-75° C for another 2 hours to get crystalline anhydrous Form LP.

[0121] PXRD: Fig 01.

[0122] Example-10:

[0123] Preparation of Form-LP of Resmetirom:

[0124] Resmetirom Form- L3 (from example-4) (20 gm) was taken in to a 500 ml Round bottomed flask. Slurred the compound at 25-30°C in Dichloromethane (400 mL) for 6 hours. Filtered the slurry mass at 25-30°C. The wet solid material was dried at 25-30°C for 2 hours in vacuum tray dryer (VTD) followed by drying at 45-50° C for 2 hours further followed by drying at 70-75° C for another 2 hours to get crystalline anhydrous Form LP.

[0125] PXRD: Fig 01°

[0126] Example-11:

[0127] Preparation of Form-LP of Resmetirom:

[0128] The filtered mother liquors of Form L3 (prepared as per the conditions of Example-4) were dry distilled at 55-60 °C and the resultant isolated solid was slurred in dichloromethane (150 ml) for 6 hours. Filtered the solid and dried under vaccum tray dryer for about 45-50° C for 2 hours further followed by drying at 70-75° C for another 2 hours to get crystalline anhydrous Form LP.

[0129] PXRD: Fig 011top pattern.

[0130] Example-111:

[0131] In another experiment, the filtered mother liquors of Form L3 were dry distilled at 55- 60 °C and the resultant isolated solid was slurred in dichloromethane (50 ml) for 6 hours. Filtered the solid and dried under vaccum tray dryer at 45-50° C for 2 hours and further dried at 70-75° C for another 2 hours to get crystalline anhydrous Form LP.

[0132] PXRD: Fig 011bottom shown pattern.

[0133] Example-2:

[0134] Preparation of Form-Ll of Resmetirom:

[0135] Resmetirom Form L-3 (from example-3) was subjected to desolvation under Nitrogen atmosphere at 10°C / min ramp using Thermogravimetric analysis apparatus up to a temperature of 175° C and cooled it back to 25-30 °C which had resulted Form-Ll.

[0136] PXRD: Fig 02

[0137] Example-3:

[0138] Preparation of Form-L2 of Resmetirom:

[0139] Resmetirom Form L-3 (from example-3) was subjected to desolvation under Nitrogen atmosphere at 10°C / min ramp using Thermogravimetric analysis apparatus up to a temperature of 180° C and cooled it back to 25-30 °C which had resulted Form-L2.

[0140] PXRD: Fig. 03

[0141] Example-4:

[0142] Preparation of Form-L3 of Resmetirom:

[0143] Resmetirom (1.0 gm) was dissolved in acetonitrile (35 ml) and acetone (35 ml) mixture at 50°C. Filtered the solution at the same temperature. The above solution was cooled to 25-30°C. Stirred the solution at same temperature for 14 hours. Filtered the product. Dried the solid under vacuum at Room temperature for 6 hours and then under vacuum for 6 hours to obtain the Acetone- acetonitrile solvate form L3 of Resmetirom.

[0144] PXRD: Fig. 04 Example-41:

[0145] Preparation of Form-L3 of Resmetirom:

[0146] Resmetirom (25.0 gm) was dissolved in acetonitrile (875 ml) and acetone (875 ml) mixture at 50°C. Filtered the solution at the same temperature. The above solution was cooled to 25-30°C and stirred at same temperature for 14 hours. The obtained solid was filtered followed by drying under Vacuum at 25-30° C for 4 hours to get the title compound.

[0147] PXRD: Fig. 041

[0148] Example-5:

[0149] Preparation of Resmetirom Benzenesulfonic acid Co-Crystal:

[0150] Benzene sulfonic acid (1.8 gm) was dissolved in Methyl Ethyl Ketone (110 ml) at 25-30 °C. Resmetirom (5 gm) was added to the above solution and dissolved at 50 °C. Filtered the solution. The filtered solution was added to a solution of Cyclohexene (250 ml) taken in a separate flask at 25-30 °C. The reaction mass was maintained at 25-30 °C for 6 hours. Filtered the reaction mass. The wet solid obtained was added to 100 ml water under stirring in a round bottom flask. The reaction mass was maintained under stirring at 200 rpm for 30 minutes. Filtered the reaction mass. Dried the product under vacuum at 40-45 °C for 12 hours.

[0151] Yield: -80%.

[0152] PXRD: Fig 05

[0153] Melting Point: 288.46° C (by DSC).

[0154] DSC: Fig 06

[0155] Example-6:

[0156] Preparation of 3,5-dichloro-4-((6-chloro-5-isopropylpyridazin-3-yl aniline (6)

[0157] Dimethyl sulfoxide (DMSO) (140 g), 3,6-Dichloro-4-isopropylpyridazine (35 g), 4- Amino-2,6-dichlorophenol (33 g), and Potassium carbonate (102 g) were charged under a nitrogen atmosphere at room temperature. After stirring, Potassium iodide (3.5 g) was added and stirred for 10-15 minutes. The temperature was raised to 90-95 °C for 12-15 hours, then cooled to room temperature. Ethyl acetate (500 mL) was added and stirred for 10-15 minutes, followed by filtration. The reaction was quenched with deionized water at 10-15°C, and the temperature was raised to 25-30°C. Sodium bisulfate (3.5 g) was added, and the mixture was settled. The aqueous and organic layers were separated. Ethyl acetate was added to the aqueous layer, stirred, and separated again. The organic layer was washed with Sodium chloride solution (21.0 g) and Basic carbon, then filtered. After a final wash with Ethyl acetate. The solvent was distilled off, and MTBE was added. The solvent was removed below 45°C, then the mixture was stirred at 40-45°C for 30-60 minutes. It was cooled to 0-5°C for 1-2 hours. The material was dried at room temperature for 2-3 hours and at 40-45°C for 6-8 hours to obtain the title compound.

[0158] Example 7:

[0159] Preparation of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3-yl acetate (5)

[0160] Acetic acid (235 ml), Sodium acetate (29 g), and 3,5-Dichloro-4-((6-chloro-5- isopropylpyridazin-3-yl) oxy)aniline (29.0) were charged at room temperature under a nitrogen atmosphere. The reaction mass was stirred for 10-15 minutes, then the temperature was raised to 95-100°C and maintained for 20-24 hours. After completion of the reaction, the reaction mass was cooled to 70-75°C, and Acetic acid was distilled off under vacuum. The reaction mass was further cooled, and deionized water was added at room temperature to adjust the pH to approximately 3.5. The mixture was stirred for 10-15 minutes, and the pH was adjusted to 5.0-5.5 using Sodium hydroxide solution at 25-30°C. The reaction mass was maintained at 25- 30°C for 2-3 hours. Afterward, the material was washed to get the wet solid.

[0161] Example 8:

[0162] Preparation of 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3 -one (4)

[0163] Sodium hydroxide solution (50 mL), Toluene (150 mL), and the wet solid obtained from example 7 were charged and stirred for 10-15 minutes at room temperature. The reaction mass was maintained at 120-125°C under 3-4.0 kg / cm2pressure for 3-4 hours. The mass was cooled to 80-85°C. The aqueous and organic layers were separated. The aqueous layer was treated with Ethyl acetate (275 mL) and adjusted to pH 5.0-5.5 using HC1 (30mL). The aqueous layer was washed with Ethyl acetate and the organic layer with Sodium chloride solution. The organic layer was heated, and Sodium sulfate and Pencarb(N) -carbon were added at 40-45°C, stirred for 15-30 minutes, filtered, and the Ethyl acetate was distilled off under vacuum at below 45°C. The mass was cooled, Ethyl acetate added, stirred for 20-30 minutes, and n- Heptane was charged at 25-30°C under nitrogen. The reaction was cooled to 10-15°C for 1-2 hours and washed with n-Heptane. The material was dried for 2-3 hours at room temperature and 6-8 hours at 40-45°C to get the title compound.

[0164] Example 9:

[0165] Preparation of ethyl E)- 2-cvano-2- 2- 3,5-dichloro-4- 5-isopropyl-6-oxo-l,6- dihvdropyridazin-3-yl)oxy)phenyl)hvdrazineylidene)acetyl)carbamate.

[0166] Acetic acid (91.0 g) and 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one (14 g) were charged and stirred for 10-15 minutes at room temperature. Concentrated HC1 (34.0-36.0% w / v) (15.40 mL) was added, and the mixture was stirred for another 10-15 minutes. The reaction mass was then cooled to 0-5°C and stirred for 10-15 minutes. Sodium nitrite solution (3.71 g) was added slowly over 30-60 minutes at 0-5°C, and maintained for 1-2 hours. N-Cyanoacetyl urethane (8.33 g) was added, and the reaction mass was stirred for 10-15 minutes at 0-5°C. Sodium acetate solution (11.06 g) was added, and the reaction was maintained for 2-3 hours at 0-5°C. Deionized water was added slowly, and the mixture was stirred for 30-45 minutes at 0-5°C. The material was centrifuged, spin-dried, and washed with deionized water to obtain wet solid. The wet solid was charged into the reactor with deionized water and stirred for 10-15 minutes at room temperature. The reaction mass was cooled to 0- 5°C and maintained for 30-45 minutes. The material was centrifuged, spin-dried, and washed with chilled deionized water to obtain wet solid. Isopropyl ether and wet material were added to the reactor and maintained for 30-45 minutes at 45-50°C. The reaction mass was cooled and stirred for 1-2 hours at room temperature. The material was centrifuged, spin-dried, and washed with chilled deionized water. The material was dried in the tray dryer for 2-3 hours at room temperature, followed by 4-6 hours at 40-45 °C to obtain the title compound.

[0167] Example 10:

[0168] Preparation of Form LP of Resmetirom

[0169] Dimethyl acetamide (DMA) (500 mL) was charged into a clean and dry round-bottom flask at 25-30°C. To this Ethyl l-(2-cyano-2-(2-(3,5-dichloro-4-((5-isopropyl-6-oxo-l,6- dihydropyridazin-3-yl)oxy) phenyl) hydrazineylidene) acetyl) carbamate (100 g) was added, followed by potassium acetate (24.5 g). The reaction mixture was stirred for 15 minutes at 25- 30°C under nitrogen atmosphere. The temperature was then raised to 120-125°C and maintained for 3-4 hours. After completion of the reaction, the mass was cooled to 25-35 °C and treated sequentially with acetic acid (25.0 mL) and chilled water, followed by extraction with 2-methyl tetrahydrofuran (2-MeTHF) (10.0 vol). The organic phase was separated, and the aqueous layer was re-extracted with fresh 2-MeTHF (2.0 vol). Combined organic layers were subjected to successive washes with freshly prepared sodium chloride solutions.The purified organic phase was treated with activated carbon (Pencarb-N) at 40-45 °C for 20 minutes, filtered through a Hyflow bed, and washed with hot 2-MeTHF (50 mL). The filtrate was subjected to partial solvent recovery (-80%) under reduced pressure (-700+50 mmHg) below 55°C. The resulting concentrate was treated with acetone (100 mL) and acetonitrile (100 mL), distilled under vacuum, and degassed for 30-45 minutes. The mass was cooled to 25- 30°C. A fresh mixture of acetone (900 mL) and acetonitrile (900 mL) was charged and the mixture heated to 45-50°C. After maintaining for 30 minutes, it was filtered through a Hyflow bed and the clear filtrate stirred at 25-30°C for 15-20 hours with seeding. The resulting crystalline product was isolated by filtration, washed with acetone (50 mL) and acetonitrile (50 mL), and partially dried under vacuum. The wet cake (ca. 60 g) was dried under hot air at 25- 30°C for 4-5 hours to obtain an intermediate solid (~52 g). This solid was further suspended in methylene dichloride (20.0 vol), stirred for 6 hours at 25-30°C, filtered, washed with fresh MDC (50.0 mL), and dried for 4-5 hours at 40-45°C to afford the final purified compound (dry weight: ~46 g).

Claims

WE CLAIM:

1. A crystalline Form LP of Resmetirom, characterized by a solid-state NMR spectrum comprising13C chemical shifts (ppm) at 28.19+0.2, 122.71+0.2, 147.45+0.2, 147.87+0.2, 153.55+0.2, and 155.03+0.2, and 161.22+0.2.

2. A crystalline Form LP of Resmetirom, characterized by at least one of the following parameters:(a) a powder X-ray diffraction (PXRD) spectrum comprising at least one peak at the following °29 angles (±0.2°): 6.05, 6.22, 9.9, 11.95, and 20.47;(b) optionally, further characterized by at least one peak at °29 angles (±0.2°): 16.11, 19.32, 20.58, 25.03, 25.26, 26.05, or 30.62;(c) a powder X-ray diffraction spectrum substantially as shown in Figure 01;(d) a powder X-ray diffraction spectrum substantially as shown in Figure 01°;(e) a solid-state NMR spectrum comprising C chemical shifts (ppm) at 28.19+0.2, 122.71+0.2, 147.45+0.2, 147.87+0.2, 153.55+0.2, and 155.03+0.2, and 161.22+0.2(f) a C NMR spectrum substantially as shown in Figure 07.

3. A process for preparing crystalline Form LP of Resmetirom, comprising the following steps:(a) dissolving Resmetirom in a solvent selected from chloro solvents such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and its mixture thereof; and(b) isolating crystalline Form LP of Resmetirom.

4. A crystalline Form LI of Resmetirom, characterized by at least one of the following parameters:(a) a powder X-ray diffraction spectrum comprising at least one peak at the following °29 angles (+0.2°); 6.5, 7.7, 11.8, and 12.3;(b) optionally, further characterized by at least one peak at °29 angles (±9.2°): 23.43;(c) a powder X-ray diffraction spectrum substantially as shown in Figure 02.

5. A process for preparing crystalline Form LI of Resmetirom, which comprises desolvating crystalline Form L3.

6. A crystalline Form L3 of Resmetirom, characterized by at least one of the following parameters:(a) a powder X-ray diffraction spectrum comprising at least one peak at the following °29 angles (+0.2°): 6.5, 7.8, 8.4, and 10.1;(b) optionally, further characterized by at least one peak at °29 angles (±0.2°): 19.77, 22.66, or 23.69;(c) a powder X-ray diffraction spectrum substantially as shown in Figure 04;(d) a powder X-ray diffraction spectrum substantially as shown in Figure 041.

7. A process for preparing crystalline Form L3 of Resmetirom, comprising the following steps:(a) dissolving Resmetirom crude in a solvent selected from nitrile solvents such as acetonitrile or ketone solvents such as acetone, methyl isobutyl ketone, methyl ethyl ketone, or a mixture thereof;(b) heating the obtained solution to about 40-60°C;(c) cooling the solution obtained in step (b);(d) isolating crystalline Form L3 of Resmetirom.

8. A co-crystal of Resmetirom, characterized by at least one of the following parameters:(a) a PXRD spectrum comprising at least one peak at the following °29 angles (±0.2°): 11.88, 12.5, 19.5, 22.1, 24.0, 25.8, and 28.5;(b) optionally, further characterized by at least one peak at °29 angles (±0.2°): 13.81, 17.26, 19.92, 21.17, 22.95, or 24.88;(c) a PXRD spectrum substantially as shown in Figure 05;(d) a differential scanning calorimetry (DSC) spectrum substantially as shown in Figure 06.

9. A process for preparing a co-crystal of Resmetirom, comprising the following steps:(a)dissolving Resmetirom in a ketone solvent selected from acetone, methyl isobutyl ketone, methyl ethyl ketone and its mixture thereof;(b) adding benzene sulfonic acid to the solution obtained in step (a);(c) adding a hydrocarbon solvent (e.g., toluene, xylene, cyclohexane, hexane, heptane, n- pentane, petroleum ether) to the solution from step (b);(d) isolating the co-crystal of Resmetirom.

10. The process as claimed in any of the preceding claims, wherein the Resmetirom used is selected from Resmetirom crude or crystalline Form L3.

11. The process as claimed in any of the preceding claims, wherein isolation is carried out using techniques selected from, but not limited to, decantation, filtration (gravity or suction), centrifugation, adding solvent to make a slurry followed by filtration, or other techniques specific to the equipment used, and optionally washing with a solvent.

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