Solid state forms of acoramidis and process for their preparation

Abstract

The invention of the present application relates to novel synthetic methods of Acoramidis, its intermediate compounds, its pharmaceutically acceptable salts, solid state forms and pharmaceutical compositions thereof.

Description

[0001] SOLID STATE FORMS OF ACORAMIDIS AND PROCESS FOR THEIR PREPARATION

[0002] CROSS REFERENCE

[0003] This application claims the priority of Indian provisional applications IN202441031173 filed on 18thof April 2024 and IN202441094761 filed on 2ndDecember 2024.

[0004] FIELD OF THE INVENTION

[0005] The present application relates to process for preparation of Acoramidis using new intermediates. The present application is further relating to the solid-state forms of Acoramidis and process for preparation thereof.

[0006] BACKGROUND OF THE INVENTION

[0007] The drug compound having the adopted name “Acoramidis” has chemical name: 3-(3-(3,5-Dimethyl-lH-pyrazol-4-yl)propoxy)-4-fluorobenzoic acid as below.

[0008] Acoramidis is used for treatment of Transthyretin Amyloid Cardiomyopathy (ATTR-CM) and developed by BridgeBio Pharma.

[0009] The compound Acoramidis and its use as transthyretin stabilizer is first described in PCT publication W02014100227 Al (WO ‘227). The synthetic process described in the WO ‘227 is schematically represented below:

[0010]

[0011] PCT publication WO2018151815 Al (WO ‘815) describes various salts of Acoramidis and their polymorphic forms. The WO ‘815 also describes synthetic process of Acoramidis and its salts. The synthetic process described in the WO ‘815 is schematically represented below:

[0012] Another PCT publication WO2023052652A1 describes crystalline Form 1 of Acoramidis HC1. The process of preparation of the said form is also disclosed in the application.

[0013] When evaluating the reported process to prepare Acoramidis, the inventors of the present application found the reported processes are quite challenging & are not feasible for commercial scale due to low yield, operational challenges and the like.

[0014] Therefore, there is a need for an improved process for preparation of Acoramidis in commercially viable and cost-effective manner, which is suitable for large scale cGMP production.

[0015] Discovering new solid state forms and solvates of a pharmaceutical product may yield materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, and ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New solid-state forms of a pharmaceutically useful compound can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., a different crystal habit, higher crystallinity, or polymorphic stability, which may offer better processing or handling characteristics, improved dissolution profile, or improved shelf-life (chemical / physical stability). For at least these reasons, there is a need for additional solid state forms (including solvated forms) of Acoramidis or its salts.

[0016] SUMMARY OF INVENTION

[0017] The present application generally relates to process for preparation of Acoramidis, its intermediates, pharmaceutically acceptable salts, and pharmaceutical compositions thereof.

[0018] In a first aspect, the present application provides a process for preparation of Acoramidis or a pharmaceutically acceptable salt thereof, comprising:

[0019] (a) Reacting a compound of formula V with a compound of formula IV in presence of a suitable base to form a compound of formula III

[0020] (b) Hydrolysing the compound of formula III in presence of a base or an acid to form Acoramidis,

[0021] (c) Optionally, converting Acoramidis into a pharmaceutically acceptable salt, wherein Ri is -CN or -CONH2; X is a leaving group such as a halogen, triflate, - OMs and -OTs.

[0022] In another aspect the present application provides a process for preparation of Acoramidis or a pharmaceutically acceptable salt thereof, comprising:

[0023] (a) Reacting a compound of formula V with a compound of formula VII in presence of a suitable base to form a compound of formula VI

[0024] (b) Reacting the compound of formula VI with hydrazine to form a compound of formula III

[0025] (c) Hydrolysing the compound of formula III in presence of a base or an acid to form Acoramidis, (d) Optionally, converting Acoramidis into a pharmaceutically acceptable salt. wherein Ri is -CN or -CONH2; X is a leaving group such as a halogen, triflate, -OMs and -OTs.

[0026] In another aspect the present application provides a process for preparation of Acoramidis or a pharmaceutically acceptable salt thereof, comprising: a) Hydrolysing the compound of formula III in presence of a base or an acid to form Acoramidis, b) Optionally, converting Acoramidis into a pharmaceutically acceptable salt, wherein R1 is -CN or -C0NH2; X is a leaving group.

[0027] In another aspect the present application provides intermediate compounds of formula III and formula VI

[0028] In another aspect the present application provides pharmaceutical compositions comprising Acoramidis prepared by the process of the present invention and one or more pharmaceutically acceptable excipients.

[0029] In another aspect, the present application provides novel crystalline form of Acoramidis HC1 with Urea.

[0030] In another aspect, the present application provides crystalline form DC1 of Acoramidis HC1 with urea.

[0031] In another aspect of the present invention provides a process for the preparation of solid-state form of Acoramidis HC1, comprising a mixture comprising Acoramidis HC1 and Urea in suitable solvent(s).

[0032] In another aspect, the present application provides a pharmaceutical composition comprising Solid state form of Acoramidis or its salts thereof and at least one pharmaceutically acceptable excipient.

[0033] BRIEF DESCRIPTION OF THE DRAWING

[0034] Figure 1 is an illustrative X-ray powder diffraction pattern of Acoramidis HC1 with Urea, prepared by the method of Example 17.

[0035] Figure 2 is an illustrative X-ray powder diffraction pattern of Acoramidis HC1 with Urea, prepared by the method of Example 18.

[0036] DETAILED DESCRIPTION OF INVENTION

[0037] As used herein, the following definitions shall apply unless otherwise indicated.

[0038] The term "leaving group" refers to a functional group or atom which can be replaced by another functional group or atom through a substitution reaction (such as affinity substitution reaction). For example, representative leaving groups include triflate; Halogen such as chlorine, bromine and iodide; sulfonate group, such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonates and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.

[0039] “Base” used in the present invention refers to inorganic and organic base. The organic base used in the present invention includes but not limited to triethylamine, pyridine, DBU, DABCO, DIPEA, DMAP, NaOMe, NaOEt, t-BuOK, BuLi, t-BuLi, LHMDS, imidazole and like. The inorganic base used in the present invention includes but not limited to NaH, Cs2CO3, K2CO3, NaHCO3, NaOH, KOH, LiOH, Na2CO3and like or mixture thereof.

[0040] Suitable solvent as used herein include, but are not limited to, alcohols, aliphatic hydrocarbons, alicyclic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, esters, ethers, nitriles, polar aprotic solvents, ketones, water or mixtures thereof. An "alcohol solvent" is an organic solvent containing a carbon bound to a hydroxyl group. "Alcoholic solvents" include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1 -propanol, 2-propanol (isopropyl alcohol), 2- methoxyethanol, 1 -butanol, 2-butanol, z -butyl alcohol, / -butyl alcohol, 2- ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, / -pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, Cl-6 alcohols, or mixtures thereof.

[0041] An "aliphatic or alicyclic hydrocarbon solvent" refers to a liquid, non-aromatic, hydrocarbon, which may be linear, branched, or cyclic. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of a hydrocarbon solvent include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3 -methylpentane, 2,3-dimethylbutane, neohexane, / / -heptane, isoheptane, 3- methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3- dimethylpentane, 3 -ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3- methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, C5-C8 aliphatic hydrocarbons, petroleum ethers, or mixtures thereof.

[0042] "Aromatic hydrocarbon solvent" refers to a liquid, unsaturated, cyclic, hydrocarbon containing one or more rings which has at least one 6-carbon ring containing three double bonds. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of aromatic hydrocarbon solvents include, but are not limited to, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C10 aromatic hydrocarbons, or mixtures thereof.

[0043] An "ester solvent" is an organic solvent containing a carboxyl group -(C=O)- O- bonded to two other carbon atoms. "Ester solvents" include, but are not limited to, ethyl acetate, / / -propyl acetate, n-butyl acetate, isobutyl acetate, / -butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, C3-6 esters, or mixtures thereof.

[0044] A "halogenated hydrocarbon solvent" is an organic solvent containing a carbon bound to a halogen. "Halogenated hydrocarbon solvents" include, but are not limited to, dichloromethane, 1 ,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1- trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or mixtures thereof.

[0045] A "ketone solvent" is an organic solvent containing a carbonyl group -(C=O)- bonded to two other carbon atoms. "Ketone solvents" include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, C3-6 ketones, 4- methyl- pentane-2-one or mixtures thereof.

[0046] A "nitrile solvent" is an organic solvent containing a cyano -(ON) bonded to another carbon atom. "Nitrile solvents" include, but are not limited to, acetonitrile, propionitrile, C2-6 nitriles, or mixtures thereof.

[0047] A "polar aprotic solvent" has a dielectric constant greater than 15 and is at least one selected from the group consisting of amide-based organic solvents, such as N,N- dimethylformamide (DMF), N, A-dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), formamide, acetamide, propanamide, hexamethyl phosphoramide (HMPA), and hexamethyl phosphorus triamide (HMPT); nitro-based organic solvents, such as nitromethane, nitroethane, nitropropane, and nitrobenzene; pyridine -based organic solvents, such as pyridine and picoline; sulfone -based solvents, such as dimethylsulfone, diethylsulfone, diisopropylsulfone, 2-methylsulfolane, 3- methylsulfolane, 2,4-dimethylsulfolane, 3,4-dimethy sulfolane, 3-sulfolene, and sulfolane; and sulfoxide-based solvents such as dimethylsulfoxide (DMSO).

[0048] An "ether solvent" is an organic solvent containing an oxygen atom -O- bonded to two other carbon atoms. "Ether solvents" include, but are not limited to, diethyl ether, diisopropyl ether, methyl Z-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2- methoxyethanol, 2-ethoxyethanol, anisole, C2-6 ethers, or the like.

[0049] As used herein "crystalline" refers to compounds or compositions where the structural units are arranged in fixed geometric patterns or lattices, so that crystalline solids have rigid long range order. The structural units that constitute the crystal structure can be atoms, molecules, or ions. Crystalline solids show definite melting points.

[0050] As used herein, the term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example "about 10" should be construed as meaning within the range of 9 to 11 , preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.

[0051] The present application generally relates to process for preparation of Acoramidis, its intermediates, pharmaceutically acceptable salts, and pharmaceutical compositions thereof.

[0052] In a first aspect the present application provides a process for preparation of Acoramidis or a pharmaceutically acceptable salt thereof, comprising:

[0053] (a) Reacting a compound of formula V with a compound of formula IV in presence of a suitable base to form a compound of formula III

[0054] (b) Hydrolysing the compound of formula III in presence of a base or an acid to form Acoramidis,

[0055] (c) Optionally, converting Acoramidis into a pharmaceutically acceptable salt. wherein Ri is -CN or -CONH2; X is a leaving group such as a halogen, triflate, - OMs and -OTs.

[0056] The step (a) of the process involves reaction of compound of formula V with a compound of formula IV in presence of a suitable base and a solvent to form compound of formula III. The compound of formula V can be a compound of formula Va or a compound of formula Vb.

[0057] The base can be selected from the group comprising sodium carbonate, potassium carbonate, triethyl amine and diisopropyl ethyl amine. The solvent can be selected from the group comprising DMF, DMSO, THF, diisopropyl ether and diethyl ether.

[0058] The compound of formula V, the compound of formula IV, the base and the solvent are mixed and stirred for about 5 to 10 hours. The reaction mixture may be quenched with water and the compound of Formula III may be isolated by extracting with a suitable solvent such as ethyl acetate.

[0059] The step (b) of the process involves hydrolysis of compound of formula III using a suitable base or a suitable acid. The compound of formula III can be a compound of formula Illa or a compound of formula Illb.

[0060] The compound of formula III and the base are mixed and stirred for about 5 hours and the reaction mixture may be acidified and extracted with a suitable solvent like ethyl acetate and the ethyl acetate may be concentrated to obtain Acoramidis. The crude obtained may be purified and converted to a pharmaceutically acceptable salt.

[0061] In another aspect, the present application provide preparation of Acoramidis hydrochloride salt. Acoramidis is mixed with hydrochloric acid in a suitable solvent such as methanol or isopropanol and stirred for about 3 hours. The solid may isolated by filtration to obtain Acoramidis hydrochloride salt.

[0062] In another aspect the present application provides a process for preparation of Acoramidis or a pharmaceutically acceptable salt thereof, comprising: (a) Reacting a compound of formula V with a compound of formula VII in presence of a suitable base to form a compound of formula VI

[0063] (b) Reacting the compound of formula VI with hydrazine to form a compound of formula III

[0064] (c) Hydrolysing the compound of formula III in presence of a base or an acid to form Acoramidis,

[0065] (d) Optionally, converting Acoramidis into a pharmaceutically acceptable salt. wherein Ri is -CN or -CONH2; X is a leaving group such as a halogen, triflate, -OMs and -OTs.

[0066] The step (a) of the process involves reaction of compound of formula V with a compound of formula VII in presence of a suitable base and a solvent to form compound of formula VI. The compound of formula V can be a compound of formula Va or a compound of formula Vb.

[0067] The base can be selected from the group comprising sodium carbonate, potassium carbonate, triethyl amine and diisopropyl ethyl amine. The solvent can be selected from the group comprising DMF, DMSO, THF, diisopropyl ether and diethyl ether.

[0068] The compound of formula V, the compound of formula VII, the base and the solvent are mixed and stirred for about 5 to 10 hours. The reaction mixture may be quenched with water and the compound of Formula VI may be isolated by extracting with a suitable solvent such as ethyl acetate. The compound of formula VI can be a compound of formula Via or a compound of formula VIb.

[0069] The step (b) involves reaction of compound of formula VI with hydrazine in a suitable solvent. The hydrazine is hydrazine hydrate and the solvent is a C1-4 alcohol. The compound of formula VI, hydrazine hydrate and the solvent are mixed and stirred for about 5 hours. The reaction mass may be quenched with water and may be extracted with a suitable solvent such as ethyl acetate to obtain the compound of formula III.

[0070] The step (c) of the process involves hydrolysis of compound of formula III using a suitable base or a suitable acid. The compound of formula III can be a compound of formula Illa or a compound of formula Illb. The compound of formula III and the base are mixed and stirred for about 5 hours and the reaction mixture may be acidified and extracted with a suitable solvent like ethyl acetate and the ethyl acetate may be concentrated to obtain Acoramidis. The crude obtained may be purified and converted to a pharmaceutically acceptable salt.

[0071] In another aspect the present application provides a process for preparation of Acoramidis or a pharmaceutically acceptable salt thereof, comprising: a) Hydrolysing the compound of formula III in presence of a base or an acid to form Acoramidis, b) Optionally, converting Acoramidis into a pharmaceutically acceptable salt, wherein R1 is -CN or -C0NH2; X is a leaving group.

[0072] In another aspect, the present application provides novel intermediate compounds of formula Illa, formula Illb, formula Via and formula VIb.

[0073] In another aspect the present application provides pharmaceutical compositions comprising Acoramidis prepared by the process of the present invention and one or more pharmaceutically acceptable excipients. In another aspect, the present application provides crystalline form DC1 of Acoramidis HC1 with urea, characterized by a powder X-ray diffraction pattern, as illustrated by Figure 1.

[0074] In another aspect, the present invention provides a process of preparing crystalline form DC1 of Acoramidis HC1 with urea comprising contacting Acoramidis HC1 with urea in an organic solvent, isolating clear solution and drying.

[0075] In another aspect, the present application provides crystalline form DC1 of Acoramidis HC1 with urea, characterized by a PXRD pattern comprising the peaks at about 6.2, 10.5, 12.3, 13,0, 14.3, 15.0, 15.6, 16.2, 16.8, 17.318.5, 18.9, 21.1, 21.8, 22.6, 23.0, 23.5, 24.1, 24.5, 25.6, 26.2, 27.4, 28.6, 29.7, 30.6, 31.4, 32.5, 33.2, 34.4, 37.0 and 37.8 ± 0.2° 20.

[0076] In another aspect, the present application provides crystalline Form DC-1 of Acoramidis HC1 with urea, characterized by a powder X-ray diffraction pattern, as illustrated by Figure 1.

[0077] In embodiments, Acoramidis or its salts used in this invention may be obtained by any methods known in the art.

[0078] In embodiments, the crystalline Form may be isolated by separating the solids from the solvent through suitable techniques known in the art such as evaporation, filtration, decantation and the like.

[0079] In embodiments, the isolated solid may be dried under suitable drying conditions such as aerial drying, drying under vacuum or inert gas at a suitable temperature of about 25 °C or above.

[0080] In embodiments, the crystalline form of the present application are stable under thermal, humid and stress conditions.

[0081] In another aspect, the present application provides a crystalline Form DC-1 of Acoramidis HC1 with urea, and its the pharmaceutical compositions thereof, comprising Acoramidis HC1 with a chemical purity of atleast 99% by HPLC or at least 99.5% by HPLC or at least 99.9% by HPLC.

[0082] The Acoramidis or a pharmaceutically acceptable salt prepared by the process of the present invention and their pharmaceutical compositions or formulations may be used as medicaments, particularly for the treatment of cardiomyopathy.

[0083] Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

[0084] EXAMPLES

[0085] Example-1: Preparation of 3-(3-(3,5-dimethyl-lH-pyrazol-4-yl)propoxy)-4- fluorobenzonitrile (compound of formula Illa)

[0086] 4-Fluoro-3 -hydroxy Benzo nitrile (3 g), 4-(3 -bromopropyl) -3,5-dimethyl-lH- Pyrazole (6.18 g) potassium carbonate (7.56 g) and Dimethylformaide (30 mL) were charged into a 100 mL round bottom flask and the mixture was stirred for 8 hours at 25-35°C. The progress of reaction was monitored by TLC and after completion of reaction, the reaction mixture was quenched with water (30 mL). The reaction mixture was extracted with ethyl acetate (2 x 15 mL). The combined organic layer was washed with water (15 mL) and aqueous sodium chloride solution (15 mL). The organic layer was concentrated under vacuum at below 50°C to afford the title compound (5.5 g, 92% yield).

[0087] 1H NMR (500 MHz, DMSO-d6) 5: 12.22 (bs, 1H), 7.70-7.68- (m, 2H), 7.48-7.43 (m, 2H), 4.04-4.01 (t, 2H), 2.46.2.43 (t, 2H), 2.05 (s, 6H), 1.86-1.83 (quin, 2H) ppm.

[0088] Mass (m / z): 274.13 (M + H)+ .

[0089] Example 2: Preparation of Acoramidis by base hydrolysis

[0090] Compound of formula Illa (1 g) and sodium hydroxide (1.2 g) in water (10 mL) were charged into a round bottom flask and the mixture was heated to reflux temperature and stirred for 5 hours at same temperature. The progress of reaction was monitored by TLC and after completion of the reaction, the mass was cooled to 25°C and pH was adjusted to 2.0 using con. Hydrochloric acid. The mixture was extracted with ethyl acetate (3 x 10 mL) and the combined organic layer was concentrated under pressure at below 50°C to afford Acoramidis (0.7 g, 65% yield).

[0091] ’ H NMR (500 MHz, DMSO-d6) 5: 12.53 (bs, 1H), 7.60-7.53 (m, 2H), 7.35-7.31 (m, 2H), 4.02-4.00 (t, 2H), 2.49.2.44 (t, 2H), 2.05 (s, 6H), 1.86-1.84 (quin, 2H) ppm.

[0092] Mass (m / z): 293.12 (M + H)+ .

[0093] Example 3: Preparation of Acoramidis by acid hydrolysis

[0094] A mixture of compound of formula Illa (0.3 g) and con. Hydrochloric acid (3 mL) in water (3.0 mL) was heated to reflux temperature and stirred for 4-5 hr at same temperature. The progress of reaction was monitored by TLC and after completion of reaction, the reaction mass was cooled to 25°C and pH was adjusted to 8.0 using aq. Lithium hydroxide and the resulted mass was washed with ethyl acetate (3 mL). The aq. Layer pH was adjusted to 2.0 using con. Hydrochloric acid. The mixture was extracted with ethyl acetate (2 x 3 ml) and the combined organic layer was concentrated under reduced pressure at below 50°C to afford Acoramidis (0.25 g, 78% yield). Example 4: Preparation of 3-(3-(3,5-dimethyl-lH-pyrazol-4-yl)propoxy)-4- fluorobenzamide (compound of formula Illb)

[0095] 4-Fluoro-3 -hydroxy Benzamide (7.0 g), 4-(3-bromopropyl) -3,5-dimethyl-lH- Pyrazole (12.74 g) potassium carbonate (15.57 g) and Dimethylformaide (70 mL) were charged into a 250 mL round bottom flask and the mixture was stirred for 8 hours at 25-35°C. The progress of reaction was monitored by TLC and after completion of reaction, the reaction mixture was quenched with water (70 mL). The mixture was extracted with ethyl acetate (2 x 35 ml). The combined organic layer was washed with water (35 mL) and aqueous sodium chloride solution (35 mL). The organic layer was concentrated under reduced pressure at below 50°C to afford the title compound (8 g, 60% yield).

[0096] ’ H NMR (500 MHz, CDC13) 8: 7.97 (bs, 1H), 7.61-7.59 (m, 1H), 7.46-7.49 (m, 1H), 7.37 (bs, 1H), 7.26-7.30 (m, 1H), 4.01-3.99 (t, 2H), 2.49.2.45 (t, 2H), 2.06 (s, 6H), 1.87-1.85 (quin, 2H) ppm.

[0097] Mass (m / z): 292.14 (M + H)+ .

[0098] Example 5: Preparation of Acoramidis by acid hydrolysis

[0099] A mixture of compound of formula Illa (1 g) and con. Hydrochloric acid (10.0 mL) in water (10 mL) was heated to reflux temperature and stirred for 4-5 hr at same temperature. The progress of reaction was monitored by TLC and after completion of reaction, the reaction mass was cooled to 25°C and pH was adjusted to 8.0 using aq. Lithium hydroxide and the resulted mass was washed with ethyl acetate (10 mL). The aq. Layer pH was adjusted to 2.0 using con. Hydrochloric acid. The mixture was extracted with ethyl acetate (2 x 10 ml) and the combined organic layer was concentrated under reduced pressure at below 50°C to afford Acoramidis (0.7 g, 70% yield).

[0100] Example 6: Preparation of 3-(3-bromopropoxy)-4-fluorobenzonitrile

[0101] 4-fluoro-3 -hydroxy benzo nitrile (5 g) ,1,3-dibromopropane (36.8 g) potassium carbonate (6.05g) and DMF (66.5 mL) were charged into a round bottom flask and the mixture was stirred for 3 hours at 30 °C. Ethyl acetate (2500 mL) and Brine solution (835 mL) were added to the reaction mixture at stirred for 10 minutes. Organic layer was separated and washed twice with Brine solution (2 x 835 mL). The organic layer was concentrated under reduced pressure at below 50°C. The crude product was purified by Column chromatography to afford title compound (8.0 g, 85% yield).

[0102] ’ H NMR (500 MHz, CDC13) 8: 7.27-7.24- (m, 2H), 7.18-7.14 (m, 1H), 4.21-4.18 (t, 2H), 3.63- 3.60 (t, 2H), 2.39-2.34 (q, 2H) ppm.

[0103] Example 7: Preparation of 3-((4-acetyl-5-oxohexyl)oxy)-4-fluorobenzonitrile

[0104] (compound of formula Via)

[0105] 3-(3-Bromopropoxy)-4-Fluorobenzonitrile (7.0g) and Toluene (62.8 mL) were charged into a round bottom flask and added a mixture Acetyl acetone (5.43g) and DBU (8.26g) in Toluene (26.9 mL) at 30 °C and stirred the mixture at same temperature for 3 hours. The reaction mass was washed with water (70 mL). Separated the aqueous and organic layers and the organic layer was concentrated under reduced pressure at below 50°C to afford the compound of formula Via (7.0 g, 93% yield). Example 8: Preparation of 3-(3-(3,5-dimethyl-lH-pyrazol-4-yl)propoxy)-4- fluorobenzonitrile (compound of formula Illa)

[0106] 3-((4-acetyl-5-oxohexyl) oxy)-4-fluorobenzonitrile ((compound of formula Via, 2.0 g), hydrazine hydrate monohydrate (2.0 g) and IPA (lOmL) were charged into a round bottom flask and the mixture was stirred at 28 °C for 3 hours. After completion of reaction, the reaction mass was concentrated under reduced pressure at 50°C. The crude product was purified by column chromatography to afford the title compound (1.4 g, 71% yield).

[0107] Example 9: Preparation of 3-(3-bromopropoxy)-4-fluorobenzamide

[0108] 4-fluoro-3 -hydroxybenzamide (1.0 eq), 1,3 -dibromopropane (5.0 eq), potassium carbonate (1.2 eq) and DMF (13.3 vol) were charged into a round bottom flask and the mixture was stirred for 3 hours at 28 °C. After completion of reaction, the reaction mass was diluted with Ethyl acetate (20 vol) and the resulted mass was washed with saturated brine solution (10 vol). Organic layer was separated and concentrated under reduced pressure at 50°C to afford title compound.

[0109] Example 10: Preparation of 3-((4-acetyl-5-oxohexyl)oxy)-4-fluorobenzamide

[0110] (compound of formula VIb) 3-(3-bromopropoxy)-4-fluorobenzamide (1.0 eq) was added to a mixture of Acetyl acetone (2.0 eq) and DBU (2.0eq) in Toluene (13 vol) and the mixture was stirred at 28 °C. After completion of reaction, the reaction mass was washed with water (10.0 vol). Layers were separated and the organic layer was concentrated under reduced pressure at 50°C to afford the compound of formula VIb.

[0111] Example 11: Preparation of 3-(3-(3,5-dimethyl-lH-pyrazol-4-yl)propoxy)-4- fluorobenzamide (compound of formula Illb)

[0112] A mixture of 3-((4-acetyl-5-oxohexyl) oxy)-4-fluorobenzamide (l.Oeq) and hydrazine hydrate monohydrate (2.5 eq) in IPA (5.0 vol) was stirred at 25-35°C for 3 hours. After completion of the reaction, the reaction mass was concentrated under reduced pressure at 50°C. The crude was purified by column chromatography to afford the compound of formula Illb.

[0113] Example 12: Preparation of 3-((4-acetyl-5-oxohexyl)oxy)-4-fluorobenzonitrile

[0114] (compound of formula Via)

[0115] A mixture 4-fluoro-3-hydroxy benzo nitrile (1.0 eq), 3-(3-bromopropyl)pentane-2,4- dione (1.1 eq) and potassium carbonate (1.2eq ) in DMF (10.0 vol) was stirred for 3 hours, at 28 °C. After completion of reaction, the reaction mass diluted with Ethyl acetate (10 vol). The resulted mass was washed with brine solution (10.0 vol) and concentrated under reduced pressure at 50°C. to afford the compound of formula Via. Example 13: Preparation of 3-((4-acetyl-5-oxohexyl)oxy)-4-fluorobenzamide

[0116] (compound of formula VIb)

[0117] A mixture 4-fluoro-3-hydroxy benzamide (1.0 eq), 3-(3-bromopropyl)pentane-2,4- dione (1.1 eq) and potassium carbonate (1.2eq ) in DMF (10.0 vol) was stirred for 3 hours, at 28 °C. After completion of reaction, the reaction mass was diluted with Ethyl acetate (10 vol). The resulted mass was washed with brine solution (10.0 vol) and concentrated under reduced pressure at 50°C. to afford compound of formula VIb.

[0118] Example 14: Preparation of 3-(3-(3,5-dimethyl-lH-pyrazol-4-yl)propoxy)-4- fluorobenzonitrile (compound of formula Illa)

[0119] A mixture of 4-Fluoro-3-hydroxy Benzo nitrile (56.5 g, 1.05 eq), 4-(3-bromopropyl)- 3,5-dimethyl-lH-pyrazole hydrochloride (100.0 g, 1.0 eq) and potassium carbonate (191.0 g, 3.5 eq) in Dimethylformaide (1000 mL, 10.0 vol) was stirred for 16-18 hr at 25-35°C. The progress of reaction was monitored by TLC and after completion of reaction, the reaction was quenched with water (1500 mL, 15.0 vol). The compound was extracted with ethyl acetate ( 1800.0 ml, 18.0 vol), the combined organic layer was washed with water (500.0 mL, 5.0 vol) and aqueous solution of sodium chloride (500.0 mL, 5.0 vol). The organic layer was concentrated under vacuum at below 50°C and finally co distilled with toluene( 1000.0 ml) to afford stage- 1 (98 g, 90.7 % yield).

[0120] Melting range / Melting Point: 88.2-92.2 deg C

[0121] XH NMR (500 MHz, DMSO) 5: 11.81 (s, 1H), 7.70-7.65- (m, 1H), 7.45-7.40 (m, 2H), 4.03-4.00 (t, 2H), 2.50-2.40. (t, 2H), 2.04 (s, 6H), 1.87-1.830 (m, 2H) ppm. Mass (m / z): 274.1145 (M + H)+ .

[0122] PXRD (20) characteristic peaks: 4.049, 12.15, 12.4, 13.66, 14.69, 15.88, 16.22, 18.75, 19.40, 19.67, 20.29, 20.92, 22.00, 22.97, 23.76, 24.03, 24.33, 25.08, 25.99, 26.72, 27.016, 27.49, 28.18, 29.58, 30.78, 31.52, 32.08, 32.74, 33.10, 33.71, 35.59, 36.62, 36.94, 38.62, 40.17 +0.2

[0123] Example 15: Preparation of Acoramidis by base hydrolysis

[0124] A mixture of Stage-1 (80.0 g) and sodium hydroxide (93.6 g, 8.0 eq) in water (800.0 mL, 10.0 vol) was heated to reflux temperature and maintained for and stirred for 4-5 hr at same temperature. The progress of reaction was monitored by TLC and after completion of reaction, the mass was cooled to 25-35°C and washed with Ethyl acetate(800.0 ml ,10.0 vol). Finally aqueous layer pH was adjusted to 1.0 to 2.0 by using IN Hydrochloric acid solution( 1200.0 ml, 15.0 vol) at 0-5 deg C. The filtered compound was dried to afford ACORAMIDIS HYDROCHLORIDE. (63.0 g, 65% yield).

[0125] Example 16: Preparation of 3-(3-(3,5-dimethyl-lH-pyrazol-4-yl)propoxy)-4- fluorobenzamide (compound of formula IHb)

[0126] The 3-(3-(3,5-dimethyl-lH-pyrazol-4-yl)propoxy)-4-fluorobenzonitrile was taken into mixture of acetic acid (3.2 vol ), sulphuric acid ( 1.6 vol) and stirred at 90-95 deg C for 30-60 mins. The reaction progress was monitored by TLC, and after completion of the reaction, the reaction mass was quenched with water (10.0 vol ) and followed by added saturated sodium bicarbonate solution at 0-5 deg C to get neutral ph. The compound was isolated by filtration and drying to afford 3-(3-(3,5-dimethyl-lH- pyrazol-4-yl) propoxy) -4-fluorobenzamide (3.2 gm, 60%).

[0127] Melting range / Melting Point : 143.2-144.7 deg C

[0128] ’H NMR (500 MHz, DMSO) 5: 11.97 (s, 1H), 8.04 (s,lH)7.63-7.61 (d, 1H), 7.49 (S,1H),7.4(S.1H), 7.29-7.25 (t, 1H), 4.01-3.99 (t, 2H), 2.50-2.44.2.44 (t, 2H), 2.04 (s, 6H), 1.86-1.84 (m, 2H) ppm.

[0129] Example 17: Preparation of crystalline form DC-1 of Acoramidis HC1 with Urea.

[0130] Charged 160 mg of Acoramidis Hydrochloride, 60 mg of Urea and 2 ml of Isopropyl alcohol into the conical flask. Stirred the mixture for 10 - 15 min and temperature raised to 45 °C. Maintained the reaction mass for 18-20 hrs at 45 °C. Reaction mass cooled to room temperature and maintained for 6-8 hrs at 30+5 °C. Filtered the solid material under vacuum and washed with 2 ml of Isopropyl alcohol. Obtained solid material dried for 45 hrs at 50 °C. and unloaded the compound. The resultant solid PXRD is given in Fig.l.

[0131] PXRD (29) characteristic peaks for Form DC1: 6.2, 10.5, 12.3, 13,0, 14.3, 15.0, 15.6, 16.2, 16.8, 17.318.5, 18.9, 21.1, 21.8, 22.6, 23.0, 23.5, 24.1, 24.5, 25.6, 26.2, 27.4, 28.6, 29.7, 30.6, 31.4, 32.5, 33.2, 34.4, 37.0 and 37.8+0.2

[0132] Example 18: Preparation of crystalline form DC-1 of Acoramidis HC1 with Urea.

[0133] Charged 4.0 g of Acoramidis Hydrochloride, 1.46 g of Urea and 48 ml of Isopropyl alcohol into the conical flask. Stirred the mixture for 10 - 15 min and temperature raised to 45 °C. Maintained the reaction mass for 20 hrs at 45 °C. Filtered the solid material under vacuum and washed with 20 ml of Isopropyl alcohol. Obtained solid material dried for 20 hrs at 50 °C. and unloaded the compound. The resultant solid PXRD is given in Fig.2.

Claims

CLAIMSClaim 1: A process for preparation of Acoramidis or a pharmaceutically acceptable salt thereof, comprising:(a) Hydrolysing the compound of formula III in presence of a base or an acid to form Acoramidis,(b) Optionally, converting Acoramidis into a pharmaceutically acceptable salt, wherein Ri is -CN or -CONH2; X is a leaving group.Claim 2: A process for preparation of Acoramidis or a pharmaceutically acceptable salt thereof, comprising:(a) reacting a compound of formula V with a compound of formula IV in presence of a suitable base to form a compound of formula III,(b) Hydrolysing the compound of formula III in presence of a base or an acid to form Acoramidis,(c) Optionally, converting Acoramidis into a pharmaceutically acceptable salt, wherein Ri is -CN or -CONH2; X is a leaving group.Claim 3: A process for preparation of Acoramidis or a pharmaceutically acceptable salt thereof, comprising:(a) Reacting a compound of formula V with a compound of formula VII in presence of a suitable base to form a compound of formula VI,(b) Reacting the compound of formula VI with hydrazine to form a compound of formula III,(c) Hydrolysing the compound of formula III in presence of a base or an acid to form Acoramidis,(d) Optionally, converting Acoramidis into a pharmaceutically acceptable salt, wherein Ri is -CN or -CONH2; X is a leaving group.Claim 4: The process as claimed in claims 1 to 3, the leaving group is selected from triflate, chloride, bromide, iodide, mesylate, tosylate, p-bromobenzenesulfonate, p- toluenesulfonates, acetoxy and trifluoroacetoxy.Claim 5: A crystalline form of Acoramidis HC1 comprising Acoramidis HC1 and urea.Claim 6: Crystalline form as claimed in claim 5, provides crystalline form DC1 of Acoramidis HC1 with urea.Claim 7: Crystalline form as claimed in claim 6, provides crystalline form DC1 of Acoramidis HC1 with urea characterized by a PXRD pattern comprising the peaks at about 6.2, 10.5, 13.0, 14.3, 15.0, 15.6, 16.2, 16.8, 17.3, 18.9, 21.1 ± 0.2° 20.Claim 8: A process for the preparation of crystalline form of Acoramidis HC1 comprising: a) Dissolving Acoramidis HC1 and urea in an organic solvent, and b) Isolating the solid.Claim 9: Compound of formula IllaClaim 10: Compound of formula ViaViaClaim 11: Compound of formula VIb C / H2NOC .0.F VIb

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