A process for the preparation of enantiomerically pure fezolinetant and intermediate thereof

Abstract

The present invention relates to novel, efficient and industrially advantageous process for the preparation of Enantiomerically Pure Fezolinetant of Formula-I. The present invention also relates to Fezolinetant intermediates of Formula-IV, process for the preparation of Enantiomerically pure Formula-V, and their use for the preparation of Fezolinetant of Formula-I.

Description

[0001] A PROCESS FOR THE PREPARATION OF ENANTIOMERICALLY PURE FEZOLINETANT AND INTERMEDIATE THEREOF FIELD OF THE INVENTION:

[0002] The present invention relates to novel, efficient and industrially advantageous process for the preparation of Enantiomeric ally Pure Fezolinetant of Formula-I.

[0003] The present invention also relates to Fezolinetant intermediates of Formula-IV, process for the preparation of Enantiomerically pure Formula- V, and their use for the preparation of Fezolinetant of Formula-I.

[0004] BACKGROUND OF THE INVENTION:

[0005] Fezolinetant is chemically known as (4-Fluorophenyl)[(8R)-8-methyl-3-(3-methyl-l,2,4-thiadiazol-5-yl)-5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl] methanone having the structure of Formula-I,

[0006]

[0007] [Formula I]

[0008] Fezolinetant has been developed by Astellas Pharma Inc. and approved by United States Food and Drug Administration (USFDA) on May 12th, 2023 under proprietary name Veozah®. Fezolinetant is a neurokinin 3 (NK3) receptor antagonist indicated for the treatment of moderate to severe vasomotor symptoms due to menopause.

[0009] The US patent number US9422299 (herein after US ‘299) first discloses Fezolinetant and its process by reacting (R)-tert-butyl 2-methyl-3-oxopiperazine-l-carboxylate with triethyloxonium tetrafluoroborate (EtsOBF in presence of sodium carbonate and dichloromethane to get (R)-tert-butyl 3-ethoxy-5,6-dihydro-2-methylpyrazine-l(2H)-carboxylate, which is condensed with 3-methyl-l,2,4-thiadiazole-5-carbohydrazide to obtain (8R)-tert-butyl 8-methyl-3-(3-methyl-l,2,4-thiadiazol-5-yl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate. The resulting compound is then reacted with trifluroacetic acid or 4 molar hydrochloric acid solution in 1,4-dioxane toobtain a (8R)-5,6,7,8-tetrahydro-8-methyl-3-(3-methyl-l,2,4-thiadiazol-5-yl)-[l,2,4]triazolo[4,3-a] pyrazine hydrochloride salt , which on further reaction with 4-fluorobenzoyl chloride in presence of A-methyl morpholine or sodium bicarbonate and dichloromethane results into Fezolinetant.

[0010] The major drawback of US’299 process is, when (R)-tert-butyl 2-methyl-3-oxopiperazine- 1 -carboxylate is converted to (R) -tert-butyl 3-ethoxy-5,6-dihydro-2-methylpyrazine-l(2H)-carboxylate followed by its further conversion to prepare (8R)-tert-butyl 8-methyl-3-(3-methyl-l,2,4-thiadiazol-5-yl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate, its isomer is also formed. Thus, the mixture of isomer formed when carried forward in multiple steps for the preparation of Fezolinetant, it results into the mixture of undesired isomer of Fezolinetant. Further, US’299 process requires column chromatography. Therefore, US’229 process is not an attractive option for the preparation of enantiomerically pure Fezolinetant.

[0011] The Chinese patent application CN111499640 (herein after CN‘640) discloses the process for the preparation of (8R)-5,6,7,8-tetrahydro-8-methyl-3-(3-methyl-l,2,4-thiadiazol-5-yl)-[l,2,4]triazolo[4,3-a]pyrazine by reacting 5,6,7,8-tetrahydro-8-methyl-3-(3-methyl-l,2,4-thiadiazol-5-yl)-[l,2,4]triazolo[4,3-a]pyrazine with D-(+)-dibenzoyltartaric acid, D-(+)-di-p-methylbenzoyltartaric acid, D-(+)-camphorsulfonic acid, D-(+)-camphoric acid, D-malic acid, D-(-)-citramalic acid and D-mandelic acid. Major drawback of CN’640 is that the process requires longer time, complex isolation process. Also, the process ends up with very low yield of 31%.

[0012] Most of the prior art suffers from disadvantages like complex work up, lower yield which fails to obtain enantiomerically pure Fezolinetant. Therefore, there is an urgent need to develop novel process which solves the problem of prior art.

[0013] OBJECT OF THE INVENTION:

[0014] The main object of the present invention is to provides a novel, efficient and industrially advantageous process for the preparation of Enantiomerically pure Fezolinetant of Formula-I.Another object of the present invention is to Fezolinetant intermediates of Formula- IV, process for the preparation of Enantiomerically pure Formula- V, and their use for the preparation of Fezolinetant of Formula-I.

[0015] SUMMARY OF THE INVENTION:

[0016] First aspect of the present invention is to provide a process for the preparation of enantiomerically pure Fezolinetant of Formula-I,

[0017]

[0018] [Formula I]

[0019] comprising the steps of:

[0020] a) reacting compound of Formula- II or salt or hydrate thereof,

[0021]

[0022] [Formula II]

[0023] with compound of Formula- III or hydrate thereof,

[0024]

[0025] [Formula III]

[0026] Wherein, Ri and R2 each independently selected from hydrogen, halogen, nitro, cyano, alkoxy, hydroxy, Ci to Cf, substituted or unsubstituted alkyl,to obtain compound of formula-IV,

[0027]

[0028] Wherein, Ri and R2 each independently selected from hydrogen, halogen, nitro, cyano, alkoxy, hydroxy, Ci to Cf, substituted or unsubstituted alkyl,

[0029] b) converting compound of Formula-IV to enantiomerically pure compound of Formula-V or salt or hydrate thereof; and

[0030]

[0031] [Formula V]

[0032] c) converting enantiomeric ally pure compound of Formula-V or salt or hydrate thereof to enantiomerically pure Fezolinetant of Formula-I.

[0033] Second aspect of the present invention is to provide a process for preparation of compound of formula-IV,

[0034]

[0035] [Formula IV]

[0036] Wherein, Ri and R2 each independently selected from hydrogen, halogen, nitro, cyano, alkoxy, hydroxy, Ci to Cf, substituted or unsubstituted alkyl,

[0037] comprising reacting compound of Formula-II or salt or hydrate thereof,

[0038]

[0039] [Formula II]

[0040] with compound of Formula- III or hydrate thereof,

[0041]

[0042] [Formula III]

[0043] Wherein, Ri and R2 each independently selected from hydrogen, halogen, nitro, cyano, alkoxy, hydroxy, Ci to Cf, substituted or unsubstituted alkyl.

[0044] Third aspect of the present invention is to provide a process for the preparation of enantiomerically pure compound of Formula-V or salt or hydrate thereof;

[0045]

[0046] [Formula V]

[0047] comprising reacting compound of formula- IV,

[0048]

[0049] [Formula IV]

[0050] Wherein, Ri and R2 each independently selected from hydrogen, halogen, nitro, cyano, alkoxy, hydroxy, Ci to Cf, substituted or unsubstituted alkyl,

[0051] with base.

[0052] Fourth aspect of the present invention is to provide a compound of formula- IV,

[0053]

[0054] [Formula IV]

[0055] Wherein, Ri and R2 each independently selected from hydrogen, halogen, nitro, cyano, alkoxy, hydroxy, Ci to Cf, substituted or unsubstituted alkyl.

[0056] Fifth aspect of the present invention is to provide a process for the preparation of crystalline Form-5 of Fezolinetant comprising reacting compound of Formula-V or salt or hydrate thereof,

[0057]

[0058] [Formula V]with compound of Formula- VI,

[0059]

[0060] [Formula VI]

[0061] in presence of base and solvent selected from the group consisting of water, acetonitrile, acetone, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl isobutyl ketone, methyl ethyl ketone or mixture thereof.

[0062] Sixth aspect of the present invention is to provide a process for the preparation of crystalline Form-5 of Fezolinetant comprising treating Fezolinetant with solvent selected from the group consisting of isopropanol, n-propanol, methyl isobutyl ketone, methyl ethyl ketone or mixture thereof.

[0063] DETAILED DESCRIPTION:

[0064] The invention will now be described in detail in connection with certain preferred embodiments, so that various aspects thereof may be fully understood and appreciated.

[0065] The best methods and materials of performing the present invention are described here. The present invention provides a novel, efficient and industrially advantageous process for the preparation of enantiomerically pure Fezolinetant of Formula-I.

[0066] According to first embodiment, the present invention provides a process for the preparation of enantiomerically pure Fezolinetant of Formula-I,

[0067]

[0068] [Formula I]

[0069] comprising the steps of:

[0070] a) reacting compound of Formula- II or salt or hydrate thereof,

[0071]

[0072] [Formula II]

[0073] with compound of Formula- III or hydrate thereof,

[0074]

[0075] [Formula III]

[0076] Wherein, Ri and R2 each independently selected from hydrogen, halogen, nitro, cyano, alkoxy, hydroxy, Ci to Cf, substituted or unsubstituted alkyl,

[0077] to obtain compound of formula-IV,

[0078]

[0079] Wherein, Ri and R2 each independently selected from hydrogen, halogen, nitro, cyano, alkoxy, hydroxy, Ci to Cf, substituted or unsubstituted alkyl.

[0080] b) converting compound of Formula-IV to enantiomerically pure compound of Formula- V or salt or hydrate thereof; and

[0081]

[0082] [Formula V]

[0083] c) converting enantiomerically pure compound of Formula-V or salt thereof to enantiomerically pure Fezolinetant of Formula-I.

[0084] In the first embodiment of the step a), compound of Formula-II or salt or hydrate thereof can be prepared by the process known in the prior-art.

[0085] In the first embodiment of step a), the enantiomeric excess (ee) of compound of Formula-II can be 50% to 95%, preferably 80% to 95%.

[0086] In the first embodiment of step a), reaction of compound of Formula-II or salt or hydrate thereof with compound of Formula-Ill or hydrate thereof can be carried out in presence of solvent.

[0087] In the first embodiment of step a), reaction of compound of Formula-II or salt or hydrate thereof with compound of Formula-Ill or hydrate thereof can be carried out at 5°C to reflux temperature of solvent used.

[0088] In the first embodiment of step a), compound of Formula-Ill can be selected from dibenzoyl-L-tartaricacid, di-p-toluyl-L-tartaric acid, di-p-nitro-benzoyl-L-tartaric acid, di-p-chloro-benzoyl-L-tartaric acid, di-p-fluoro-benzoyl-L-tartaric acid, di-p-bromo-benzoyl-L-tartaric acid, di-p-iodo-benzoyl-L-tartaric acid, di-p-methoxy-benzoyl-L-tartaric acid, di-p-ethoxy-benzoyl-L-tartaric acid, di-p-hydroxy-benzoyl-L-tartaric acid, di-p-cyano-benzoyl-L-tartaric acid, di-ethylbenzoyl-L-tartaric acid, di-isopropylbenzoyl-L-tartaric acid, di-propylbenzoyl-L-tartaric acid or mixture(s) thereof.

[0089] In the first embodiment of step a), solvent can be selected from the group consisting of alcohol such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such asacetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, A,A-dimethylformamide or A-methylpyrrolidone; water; or mixture(s) thereof.

[0090] In the first embodiment of step a), reaction of compound of Formula-II or salt or hydrate thereof with compound of Formula-Ill or hydrate thereof can be carried out for 15 minutes to 6 hours.

[0091] In the first embodiment of step a), compound of Formula-IV can be isolated by various methods such as cooling, crystallization, evaporation, distillation or by solvent antisolvent method.

[0092] In the first embodiment of step a), salt can be selected from hydrochloride, hydrobromide, sulphate, phosphate or acid phosphate, acetate, maleate, fumarate, oxalate, succinate, lactate, tartrate, citrate, gluconate, p-toluenesulphonate or benzenesulphonate salt of compound of Formula-II.

[0093] In the first embodiment of step a), salt of compound of Formula-II can also be treated with base to obtain a free acid of Formula II or its hydrate, which can be then reacted with compound of Formula- III or hydrate thereof.

[0094] Base can be selected from the group consisting of organic base or inorganic base; inorganic bases can be selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; ammonia such as aqueous ammonia, ammonia gas, methanolic ammonia and "organic bases" can be selected from the group consisting of methylamine, ethyl amine, diisopropyl amine, diisopropylethyl amine (DIPEA), diisobutylamine, triethylamine, tert-butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), A-methyl morpholine (NMM), methyl pyridine (NMP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), imidazole or mixture(s) thereof.

[0095] In the first embodiment of step a), compound of formula- IV is having enantiomeric excess (ee) purity of more than 99.0%, preferably more than 99.7% by chiral High-performance liquid chromatography.

[0096] In the first embodiment of step b), conversion of compound of Formula-IV to enantiomerically pure compound of Formula-V can be carried out using base and solvent.

[0097] In the first embodiment of step b), base can be selected from the group consisting of organic base or inorganic base; inorganic bases selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; ammonia such as aqueous ammonia, ammonia gas, methanolic ammonia and "organic bases" selected from the group consisting of methyl amine, ethyl amine, diisopropyl amine, diisopropylethyl amine (DIPEA), diisobutylamine, triethylamine, tert-butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), methyl pyridine (NMP), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole or mixture(s) thereof.

[0098] In the first embodiment of step b), solvent can be selected from the group consisting of alcohol such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol ;ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, A,A-dimethylformamide or A-methylpyrrolidone; water; or mixture(s) thereof.

[0099] In the first embodiment of step b), conversion of compound of Formula-IV to enantiomerically pure compound of Formula-V can be carried at a temperature 20°C to 60°C.

[0100] In the first embodiment of step b), reaction of compound of formula IV with base and solvent can be carried out for 15 minutes to 6 hours.

[0101] In the first embodiment of step b), after the completion of the reaction, halogenated solvents selected from group consisting of dichloromethane, dichloroethane, chloroform, trichloroethylene or mixture(s) thereof and alcohol selected from methanol, ethanol, n-propanol, isopropanol, n-butanol or mixture thereof can be added to reaction mixture. Resulting mixture can be allowed to settle aqueous and organic layer. The obtained organic layer can be filtered, and filtrate can be distilled below 60°C followed by treatment with acid in presence of alcohol to obtain a compound of Formula-V.

[0102] Acid can be selected form the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, oxalic acid, lactic acid, tartaric acid, gluconic acid, benzenesulphonic acid, toluenesulphonic acid or mixture thereof.

[0103] Acid can also be used as alcoholic acid such as methanolic hydrochloric acid, ethanolic hydrochloric acid, 2-propanolic hydrochloric acid, n-propanolic hydrochloric acid, n-butanolic hydrochloric acid, isobutanolic hydrochloric acid, 2-butanolic hydrochloric acid, n-pentenolic hydrochloric acid or mixture(s) thereof.

[0104] Alcohol can be selected form methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, 2-butanol, n-pentanol or mixture(s) thereof.In the first embodiment of step b), an enantiomerically pure compound of Formula- V can be isolated by various methods such as cooling, crystallization, evaporation, distillation or solvent-anti solvent method.

[0105] Resulting enantiomerically pure compound of Formula-V can have purity greater than 99.9% by High-performance liquid chromatography (HPLC) and more than 99.9% of an enantiomerically excess (ee) of compound of Formula-V.

[0106] In the first embodiment of step c), an enantiomerically pure compound of Formula-V can be converted into an enantiomerically pure Fezolinentnt of Formula- 1.

[0107] In the first embodiment of step c), enantiomerically pure compound of Formula-V or salt or hydrate can be converted to enantiomerically pure Fezolinetant of Formula-I by reacting 4-fluorobenzoyl chloride of Formula- VI with enantiomerically pure compound of formula-V in presence of base and solvent selected from the group consisting of water, acetonitrile, acetone, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl isobutyl ketone, methyl ethyl ketone or mixture thereof.

[0108] In the first embodiment of step c), base can be selected from the group consisting of organic base or inorganic base; inorganic bases selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; ammonia such as aqueous ammonia, ammonia gas, methanolic ammonia and organic bases selected from the group consisting of methyl amine, ethyl amine, diisopropyl amine, diisopropylethyl amine (DIPEA), diisobutylamine, triethylamine, tert-butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), A- methyl morpholine (NMM), methyl pyridine (NMP), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole or mixture(s) thereof.

[0109] In the first embodiment of step c), reaction of 4-fluorobenzoyl chloride of Formula- VI with enantiomerically pure compound of formula-V in presence of base and solvent can be carried out at a temperature about 0°C to 50°C for 30 minutes to 6 hours.In the first embodiment of step c), enantiomeric ally pure Fezolinetant of Formula-I can be isolated by various method such as cooling, crystallization, evaporation, distillation or by solvent- anti solvent method.

[0110] Resulting Fezolinetant of Formula-I can have purity greater than 99.9% by High-performance liquid chromatography (HPLC) and 100% an enantiomerically excess (ee) of Fezolinetant of Formula-I.

[0111] According to the second embodiment, the present invention provides the preparation of compound of Formula-IV,

[0112]

[0113] Wherein, Ri and R2 each independently selected from hydrogen, halogen, nitro, cyano, alkoxy, hydroxy, Ci to Cf, substituted or unsubstituted alkyl,

[0114] comprising reacting compound of Formula-II or salt or hydrate thereof,

[0115]

[0116] [Formula II]

[0117] with compound of Formula- III or hydrate thereof,

[0118]

[0119] [Formula III]

[0120] Wherein, Ri and R2 each independently selected from hydrogen, halogen, nitro, cyano, alkoxy, hydroxy, Ci to Cf, substituted or unsubstituted alkyl.

[0121] In the second embodiment, compound of Formula-II or salt or hydrate thereof can be prepared by the process known in the prior-art.

[0122] In the second embodiment, the enantiomeric excess (ee) of compound of Formula-II can be 50% to 95%, preferably 80% to 95%.

[0123] In the second embodiment, reaction of compound of Formula-II or salt or hydrate thereof with compound of Formula- III or hydrate thereof can be carried out in presence of solvent.

[0124] In the second embodiment, reaction of compound of Formula-II or salt or hydrate thereof with compound of Formula-Ill or hydrate thereof can be carried out at 5 °C to reflux temperature of solvent used.

[0125] In the second embodiment, compound of Formula-Ill can be selected from dibenzoyl-L-tartaricacid, di-p-toluyl-L-tartaric acid, di-p-nitro-benzoyl-L-tartaric acid, di- -chloro-benzoyl-L-tartaric acid, di-p-fluoro-benzoyl-L-tartaric acid, di-p-bromo-benzoyl-L-tartaric acid, di-p-iodo-benzoyl-L-tartaric acid, di-p-methoxy-benzoyl-L-tartaric acid, di-p-ethoxy-benzoyl-L-tartaric acid, di-p-hydroxy-benzoyl-L-tartaric acid, di-p-cyano-benzoyl-L-tartaric acid, di-ethylbenzoyl-L-tartaric acid, di-isopropylbenzoyl-L-tartaric acid, di-propylbenzoyl-L-tartaric acid or mixture(s) thereof.In the second embodiment, solvent can be selected from the group consisting of alcohol such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, A,A-dimethylformamide or A-methylpyrrolidone; water; or mixture(s) thereof.

[0126] In the second embodiment, reaction of compound of Formula-II or salt or hydrate thereof with compound of Formula- III or hydrate thereof can be carried out for 15 minutes to 6 hours.

[0127] In the second embodiment, compound of Formula-IV can be isolated by various methods such as cooling, crystallization, evaporation, distillation or by solvent antisolvent method.

[0128] In the second embodiment, salt can be selected from hydrochloride, hydrobromide, sulphate, phosphate or acid phosphate, acetate, maleate, fumarate, oxalate, succinate, lactate, tartrate, citrate, gluconate, toluenesulphonate or benzenesulphonate salt of compound of Formula-II.

[0129] In the second embodiment, salt of compound of Formula-II can also be treated with base to obtain a free acid of Formula II or its hydrate, which can be then reacted with compound of Formula-Ill or hydrate thereof.

[0130] Base can be selected from the group consisting of organic base or inorganic base; inorganic bases can be selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesiumbicarbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; ammonia such as aqueous ammonia, ammonia gas, methanolic ammonia and organic bases can be selected from the group consisting of methyl amine, ethyl amine, diisopropyl amine, diisopropylethyl amine (DIPEA), diisobutylamine, triethylamine, tert-butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), methyl pyridine (NMP), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0] non5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole or mixture(s) thereof.

[0131] In the second embodiment, compound of formula-IV is having enantiomeric excess (ee) purity of more than 99.0%, preferably more than 99.7% by chiral High-performance liquid chromatography.

[0132] According to the third embodiment, the present invention provides a process for the preparation of enantiomerically pure compound of Formula-V or salt or hydrate thereof;

[0133]

[0134] [Formula V]

[0135] comprising reacting compound of formula-IV,

[0136]

[0137] Wherein, Ri and R2 each independently selected from hydrogen, halogen, nitro, cyano, alkoxy, hydroxy, Ci to Cf, substituted or unsubstituted alkyl,with base.

[0138] In the third embodiment, conversion of compound of Formula-IV to enantiomerically pure compound of Formula-V can be carried out using base and solvent.

[0139] In the third embodiment, base can be selected from the group consisting of organic base or inorganic base; inorganic bases selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; ammonia such as aqueous ammonia, ammonia gas, methanolic ammonia and "organic bases" selected from the group consisting of methyl amine, ethyl amine, diisopropyl amine, diisopropylethyl amine (DIPEA), diisobutylamine, triethylamine, tert-butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), methyl pyridine (NMP), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole or mixture(s) thereof.

[0140] In the third embodiment, solvent can be selected from the group consisting of alcohol such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol ;ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, A,A-dimethylformamide or A-methylpyrrolidone; water; or mixture(s) thereof.

[0141] In the third embodiment, conversion of compound of Formula-IV to enantiomerically pure compound of Formula-V can be carried at a temperature 20°C to 60°C.In the third embodiment, reaction of compound of formula IV with base and solvent can be carried out for 15 minutes to 6 hours.

[0142] In the third embodiment, after the completion of the reaction, halogenated solvents selected from group consisting of dichloromethane, dichloroethane, chloroform, trichloroethylene or mixture(s) thereof and alcohol selected from methanol, ethanol, n-propanol, isopropanol, n-butanol or mixture thereof can be added to reaction mixture. Resulting mixture can be allowed to settle aqueous and organic layer. The obtained organic layer can be filtered, and filtrate can be distilled below 60°C followed by treatment with acid in presence of alcohol to obtain a compound of Formula-V.

[0143] Acid can be selected form the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, oxalic acid, lactic acid, tartaric acid, gluconic acid, benzenesulphonic acid, toluenesulphonic acid or mixture thereof.

[0144] Acid can also be used as alcoholic acid such as methanolic hydrochloric acid, ethanolic hydrochloric acid, 2-propanolic hydrochloric acid, n-propanolic hydrochloric acid, n-butanolic hydrochloric acid, isobutanolic hydrochloric acid, 2-butanolic hydrochloric acid, n-pentenolic hydrochloric acid or mixture(s) thereof.

[0145] Alcohol can be selected form methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, 2-butanol, n-pentanol or mixture(s) thereof.

[0146] In the third embodiment, an enantiomeric ally pure compound of Formula-V can be isolated by various methods such as cooling, crystallization, evaporation, distillation or solvent-anti solvent method.

[0147] Resulting enantiomerically pure compound of Formula-V can have purity greater than 99.9% by High-performance liquid chromatography (HPLC) and more than 99.9% of an enantiomerically excess (ee) of compound of Formula-V.

[0148] According to the fourth embodiment, the present invention provides compound of formula IV,

[0149]

[0150] [Formula IV]

[0151] Wherein, Ri and R2 each independently selected from hydrogen, halogen, nitro, cyano, alkoxy, hydroxy, Ci to Cf, substituted or unsubstituted alkyl.

[0152] In the fourth embodiment, halogens can be selected form chlorine, bromine, iodine and fluorine.

[0153] In the fourth embodiment, compound of the Formula IV can be selected from the group consisting of

[0154] In the first embodiment of step a), Ri and R2 can be para substituted and can be selected from the group consisting of hydrogen, methyl, nitro, chloro, fluoro, bromo, iodo, methoxy, ethoxy, hydroxy, cyano, ethyl, isopropyl, n-propyl.

[0155] According to the fifth embodiment, the present invention provides process for the preparation of Crystalline Form-5 of Fezolinetant comprising reacting compound of formula V or salt or hydrate thereof,

[0156]

[0157] [Formula V]

[0158] with compound of Formula- VI,

[0159]

[0160] [Formula VI]in presence of base and solvent selected from the group consisting of water, acetonitrile, acetone, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl isobutyl ketone, methyl ethyl ketone or mixture thereof.

[0161] Form-5 of Fezolinetant is referred as Crystalline Form-5 of Fezolinetant as disclosed in US20230271967.

[0162] In the fifth embodiment, base can be selected from the group consisting of organic base or inorganic base; inorganic bases selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; ammonia such as aqueous ammonia, ammonia gas, methanolic ammonia and organic bases selected from the group consisting of methyl amine, ethyl amine, diisopropyl amine, diisopropylethyl amine (DIPEA), diisobutylamine, triethylamine, tert-butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), methyl pyridine (NMP), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0] non5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole or mixture(s) thereof.

[0163] In the fifth embodiment, reaction of 4-fluorobenzoyl chloride of Formula- VI enantiomerically pure compound of formula-V in presence of base and solvent can be carried out at a temperature about 0°C to 50°C for 30 minutes to 6 hours.

[0164] In the fifth embodiment, enantiomerically pure Fezolinetant of Formula-I can be isolated by various method such as cooling, crystallization, evaporation, distillation or by solvent- anti solvent method.

[0165] Resulting Fezolinetant of Formula-I can have purity greater than 99.9% by High-performance liquid chromatography (HPLC) and 100% an enantiomerically excess (ee) of Fezolinetant of Formula-I.

[0166] According to sixth embodiment, the present invention provides a process for the preparation of crystalline Form-5 of Fezolinetant comprising treating Fezolinetant withsolvent selected from the group consisting of isopropanol, n-propanol, methyl isobutyl ketone, methyl ethyl ketone or mixture thereof.

[0167] Form-5 of Fezolinetant is referred as Crystalline Form-5 of Fezolinetant as disclosed in US20230271967.

[0168] In the sixth embodiment, treatment of Fezolinetant with solvent can be carried out by methods such as recrystallisation, slurry wash or distillation.

[0169] In the sixth embodiment, crystalline Form-5 of Fezolinetant can be obtained by heating Fezolinetant in presence of solvent at 40°C to reflux temperature followed by further cooling from 0°C to 25 °C.

[0170] In the sixth embodiment, crystalline Form-5 of Fezolinetant can be isolated by various method such as cooling, crystallization, evaporation, distillation or addition of antisolvent.

[0171] EXAMPLES:

[0172] The following examples are illustrative of some of the embodiments of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.

[0173] Example 01: Preparation of (R)-tert-butyl-2-methyl-3-oxopiperazine-l-carboxylate

[0174] To a stirred mixture of dichloromethane (4.0 L) and (3R)-3-methylpiperazin-2-one (1.0 Kg), di-tert-butyl dicarbonate (2.0 Kg) was added at 20°C to 30°C and the resulting mixture was stirred for 1 hour. Solution of purified water (1.0 L) and hydrochloric acid (0.05 Kg) were added into the resulting mixture at 20°C to 35°C. Resulting mixture was stirred and allowed to separate organic and aqueous layers. The resulting organic layer was extracted with purified water. Both the resulted aqueous layers combined and extracted with dichloromethane. All the organic layers were combined and distilled out completely to obtain a residue. To the resulting residue, n-heptane (1.0 L) was added, and the resulted mixture was distilled under vacuum at 50°C to 60°C. n-heptane (4 L) was added to distilled mass and stirred the mixture for 1 hour at 20°C to 35 °C. Resulting solid was filtered and washed with n-heptanefollowed by drying under vacuum at 50°C to 60°C to obtain a title compound (1.74 Kg) having HPLC purity of 99.5%.

[0175] Example 02: Preparation of 3-methyl-l,2,4-thiadiazole-5-carbohydrazide

[0176] To a stirred mixture of hydrazine hydrate (0.48 Kg) and isopropyl alcohol (8.0 L), ethyl-3-methyl-l,2,4-thiadiazole-5-carboxylate solution (1.0 Kg 3-methyl- 1,2,4-thiadiazole-5-carboxylate and 2.0 L isopropyl alcohol) was added at 20°C to 35°C and stirred for 1 hour. Resulting mixture was filtered and washed with isopropyl alcohol (2.0 L) followed by drying under vacuum at 60°C to 65°C to obtain a title compound (0.83 Kg) having HPLC purity of 99.2%.

[0177] Example 03: Preparation of (8R) -tert-butyl 8-methyl-3-(3-methyl-l,2,4-thiadiazol-5-yl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate

[0178] To a stirred mixture of (R)-tert-butyl-2-methyl-3-oxopiperazine-l-carboxylate (1.0 Kg) and dichloromethane (5.0 L), sodium carbonate (1.11 Kg) was added at 25°C to 35°C. Triethyloxonium tetrafluoroborate solution (1.11 Kg triethyloxonium tetrafluoroborate and 2.0 L dichloromethane) was added into the resulting mixture at 25°C to 35°C and stirred for 1 hour at the same temperature. After completion of the reaction, purified water was added into the reaction mixture at 25°C to 30°C. The resulting mixture was stirred and allowed to separate aqueous and organic layers. Dichloromethane was added into aqueous layer and resulting mixture was stirred and allow to separate layers. Combined both organic layers and washed twice with purified water. Resulting organic layer was distilled under vacuum below 50°C to obtain oily mass. To the resulting oily mass, methanol (4.0 L), 3-methyl- 1, 2, 4-thiadiazole-5-carbohydrazide (0.7 Kg) was added at 25 °C to 35 °C. The resulting mixture was heated to 60°C to 70°C and maintain for 24 hours at the same temperature. The resulting mixture was distilled out under vacuum below 70°C. Purified water was added to distilled mass. Resulting mixture was cooled to 25 °C to 35 °C and stirred for 1 hour at the same temperature. The resulting solid was filtered and washed by purified water followed by drying under vacuum at 60°C to 70°C to obtain a title compound (1.13 Kg) having purity: 99.0% and enantiomeric excess purity 94.97%.Example 04: Preparation of (8R)-5,6,7,8-tetrahydro-8-methyl-3-(3-methyl-l,2,4-thiadiazol-5-yl)-[l,2,4]triazolo[4,3-a] pyrazine hydrochloride salt of formula V

[0179] To a stirred mixture of (8R)-tert-butyl 8-methyl-3-(3-methyl-l,2,4-thiadiazol-5-yl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxyla (1.0 Kg) and isopropyl alcohol (2.0 L), isopropyl alcohol- hydrochloric acid (2.7 Kg) was added at 25°C to 35°C. The resulting mixture was heated to 55 °C to 60°C and maintained for 2 hours at the same temperature. After the completion of the reaction, distilled out solvent under vacuum below 60°C followed by cooling at 25°C to 35°C. Water (2.0 L) was added to resulting mass followed by addition of caustic lye (0.5 kg), dichloromethane (4.0 L) and methanol (1.0 L) at 25°C to 35°C. The resulting mixture was allowed to separate organic and aqueous layers. Resulted organic layer distilled out under vacuum below 60°C followed by cooling to 25°C to 35°C. To the obtained mixture, acetone (6.65 L) and water (0.35 L) were added and stirred at 25°C to 35°C. Dibenzoyl-L-tartaric acid (1.12 Kg) was added to the mixture at 25°C to 35°C. Resulting mixture was heated at 55°C to 60°C and maintained for 1 hour at the same temperature. After the completion of the reaction, resulted mixture was cooled to 0°C to 5 °C and stirred for 1 hour. Resulting mixture was filtered and wash with acetone (1.0 L) to obtain a solid . Water (2.0 L), sodium carbonate solution (0.4 Kg sodium carbonate and 2.0 L water) was added to resulting solid followed by addition of dichloromethane and methanol. Resulting mixture was stirred and allowed to separate organic and aqueous layers. Resulted organic layer was distilled out under vacuum below 60°C and isopropyl alcohol (2.0 L) and isopropyl alcohol- hydrochloric acid (0.55 Kg) were added to the distilled mass and heated at 55°C to 60°C for 30 minutes followed by cooling to 25°C to 35°C and maintained for 30 minutes. Resulting mixture was filtered and washed with isopropyl alcohol followed by drying under vacuum 60°C to 70°C to obtain title compound (0.60 Kg) having purity 99.9%, enantiomeric excess purity 99.96%.

[0180] Example 05: Preparation of Fezolinetant

[0181] To a stirred mixture of dichloromethane (5 L) and (8R)-5,6,7,8-tetrahydro-8-methyl-3-(3-methyl-l,2,4-thiadiazol-5-yl)-[l,2,4]triazolo[4,3-a] pyrazine hydrochloride (1.0 Kg), sodium bicarbonate (0.77 Kg) and 4-Fluorobenzoyl chloride (0.61 Kg) were added and maintained for 1 hour at 25°C to 30°C. After completion of the reaction, water wasadded to the mixture and allowed to separate organic and aqueous layers. Resulted organic layer was distilled below 60°C and isopropyl alcohol (3.0 L) was added to distilled mass. Resulting mixture was stirred at 70°C to 80°C for 30 minutes followed by cooling at 10°C to 20°C and stirred for 30 minutes at the same temperature. The resulting mixture was filtered and washed with isopropyl alcohol (1.0 L) followed by drying under vacuum at 60°C to 70°C to obtain a title compound (1.25 Kg) having HPLC purity of 99.9% and enantiomeric access 100% by chiral HPLC.

[0182] Example 06: Preparation of Fezolinetant crystalline Form-5.

[0183] To a stirred mixture of dichloromethane (5.0 mL) and (8R)-5,6,7,8-tetrahydro-8-methyl-3-(3-methyl-l,2,4-thiadiazol-5-yl)-[l,2,4]triazolo[4,3-a]pyrazine hydrochloride (0.75 g), sodium bicarbonate (0.88 g), 4 -Fluorobenzoyl chloride (0.44 g) were added and maintained for 2 hours at 25°C to 30°C. After completion of the reaction, water (5.0 mL) was added to the mixture at 25°C to 30°C and allowed the mixture to separate organic and aqueous layers. Resulting aqueous layer was extracted twice by dichloromethane. Finally organic layers were combined and distilled out under vacuum below 50°C. Isopropyl alcohol (4.0 mL) was added to distilled mass and heated at 70°C to 75°C followed by stirring for 30 minutes at same temperature. Resulting mixture was cooled at 10°C to 20°C and stirred for 1.0 hour at the same temperature. Resulting solid was filtered followed by drying under vacuum at 60°C to 65 °C to obtain a titled compound (0.85 g) having HPLC purity of 99.9% by HPLC.

[0184] Example 07: Preparation of Fezolinetant crystalline Form-5.

[0185] To a stirred mixture of 2-methyltetrahydrofuran (5.0 mL) and (8R)-5,6,7,8-tetrahydro-8-methyl-3-(3-methyl-l,2,4-thiadiazol-5-yl)-[l,2,4]triazolo[4,3-a] pyrazine hydrochloride (0.75 g), sodium bicarbonate (0.88 g) and 4-Fluorobenzoyl chloride (0.44 g) were added and maintained for 2 hours at 25°C to 30°C. After completion of the reaction, resulting mixture was filtered and washed with 2-methyltetrahydrofuran (5.0 mL) to obtain wet material. Water (8.0 mL) were added to resulted wet material and stirred at 25°C to 30°C for 1 hour. Resulting solid was filtered and washed with water followed by drying under vacuum at 60°C to 65 °C to obtain a title compound (0.8 g) having HPLC purity of 99.82%.Example 08: Preparation of Fezolinetant crystalline Form-5.

[0186] To a stirred mixture of acetonitrile (5.0 mL) and (8R)-5,6,7,8-tetrahydro-8-methyl-3-(3-methyl-l,2,4-thiadiazol-5-yl)-[l,2,4]triazolo[4,3-a] pyrazine hydrochloride (0.75 g), sodium bicarbonate (0.88 g) and 4 -Fluorobenzoyl chloride (0.44 g) were added and maintained for 2 hours at 25°C to 30°C. After the completion of the reaction, purified water (5.0 mL) was added and stirred for 2 hours at 25°C to 30°C. Resulting mixture was filtered and washed with acetonitrile and purified water followed by drying to obtain titled compound (0.84 g) having HPLC purity of 99.95%.

[0187] Example 09: Preparation of Fezolinetant crystalline Form-5.

[0188] To a stirred mixture of acetone (5.0 mL) and (8R)-5,6,7,8-tetrahydro-8-methyl-3-(3-methyl-l,2,4-thiadiazol-5-yl)-[l,2,4]triazolo[4,3-a] pyrazine hydrochloride (0.75 g), sodium bicarbonate (0.88 g) and 4 -Fluorobenzoyl chloride (0.44 g) were added and maintained for 2 hours at 25°C to 30°C. After the completion of the reaction, purified water (5.0 mL) was added and stirred for 3 hours at 25°C to 30°C. Resulting mixture was filtered and washed with acetone and water followed by drying under vacuum at 60°C to 65°C to obtain a title compound (0.95 g) having HPLC purity 99.95%.

[0189] Example 10: Preparation of Fezolinetant crystalline Form-5.

[0190] To a stirred mixture of water (5.0 mL) and (8R)-5,6,7,8-tetrahydro-8-methyl-3-(3-methyl-l,2,4-thiadiazol-5-yl)-[l,2,4]triazolo[4,3-a] pyrazine hydrochloride (0.75 g), sodium bicarbonate (0.88 g) and 4 -Fluorobenzoyl chloride (0.44 g) were added and maintained for 2 hours at 25°C to 30°C. 4-Fluorobenzoyl chloride (0.10 g) and water (1.0 mL) were added to resulting mixture and stirred for 15 minutes at 25°C to 30°C.

[0191] 20% sodium bicarbonate solution was added to Resulting mixture and stirred for 1 hour at 25°C to 30°C. Resulting mixture was filtered and washed with water (5.0 mL) followed by drying under vacuum at 60°C to 65°C to obtain a title compound (0.82 g).

[0192] Example 11: Preparation of crystalline Form-5 of Fezolinetant

[0193] Stirred mixture of Fezolinetant (1.0 Kg) and isopropyl alcohol (9.50 L) at 75°C to 80°C for 15 minutes. Resulted solution was cooled to 0°C to 5°C and maintained for 30 minutes at the same temperature. Resulting solid was filtered and washed with isopropyl alcohol followed by drying under vacuum at 60°C to 65 °C to obtain a title compound (0.95 Kg) having HPLC purity of 99.9%, enantiomeric excess 100%.

Claims

We Claim:

1. A process for the preparation of enantiomeric ally pure Fezolinetant of Formula-I,[Formula I]comprising the steps of:a) reacting compound of Formula- II or salt or hydrate thereof,[Formula II]with compound of Formula- III or hydrate thereof in presence of solvent,[Formula III]Wherein, Ri and R2 each independently selected from hydrogen, halogen, nitro, cyano, alkoxy, hydroxy, Ci to Cf, substituted or unsubstituted alkyl,to obtain compound of formula-IV,Wherein, Ri and R2 each independently selected from hydrogen, halogen, nitro, cyano, alkoxy, hydroxy, Ci to Cf, substituted or unsubstituted alkyl.b) converting compound of Formula-IV, in the presence of a base and a solvent to obtain an enantiomerically pure compound of Formula-V or salt or hydrate thereof; and[Formula V]c) converting enantiomerically pure compound of Formula-V or salt or hydrate thereof in presence of a base and a solvent to obtain an enantiomerically pure Fezolinetant of Formula-I.

2. The process as claimed in claim 1, wherein compound of Formula- III is selected from dibenzoyl-L-tartaricacid, di-p-toluyl-L-tartaric acid, di-p-nitro-benzoyl-L-tartaric acid, di-p-chloro-benzoyl-L-tartaric acid, di-p-fluoro-benzoyl-L-tartaric acid, di- -bromo-benzoyl-L-tartaric acid, di-p-iodo-bcnzoyl-L-tartaric acid, di-p-mcthoxy-benzoyl-L-tartaric acid, di-p-cthoxy-bcnzoyl-L-tartaric acid, di-p-hydroxy-bcnzoyl-L-tartaric acid, di-p-cyano-bcnzoyl-L-tartaric acid, di-ethylbenzoyl-L-tartaric acid, di-isopropylbenzoyl-L-tartaric acid, di-propylbenzoyl-L-tartaric acid or mixture(s) thereof.

3. The process as claimed in claim 1, wherein in step a) solvent is selected from the group consisting of alcohol such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, A,A-dimethylformamide or A-methylpyrrolidone; water; or mixture(s) thereof.

4. The process as claimed in claim 1, wherein in step b) base is selected from the group consisting of organic base or inorganic base; inorganic bases selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; ammonia such as aqueous ammonia, ammonia gas, methanolic ammonia and "organic bases" selected from the group consisting of methyl amine, ethyl amine, diisopropyl amine, diisopropylethyl amine (DIPEA), diisobutylamine, triethylamine, tert-butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), methyl pyridine (NMP), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole or mixture(s) thereof; and solvent is selected from the group consisting of alcohol such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol ;ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethylacetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, A,A-dimethylformamide or A-methylpyrrolidone; water; or mixture(s) thereof.

5. The process as claimed in claim 1, wherein in step c), base is selected from the group consisting of organic base or inorganic base; inorganic bases selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; ammonia such as aqueous ammonia, ammonia gas, methanolic ammonia and organic bases selected from the group consisting of methyl amine, ethyl amine, diisopropyl amine, diisopropylethyl amine (DIPEA), diisobutylamine, triethylamine, tert-butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), A- methyl morpholine (NMM), methyl pyridine (NMP), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole or mixture(s) thereof; and solvent is selected from the group consisting of water, acetonitrile, acetone, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl isobutyl ketone, methyl ethyl ketone or mixture thereof.

6. A process for preparation of compound of formula-IV,[Formula IV]Wherein, Ri and R2 each independently selected from hydrogen, halogen, nitro, cyano, alkoxy, hydroxy, Ci to Cf, substituted or unsubstituted alkyl,comprising reacting compound of Formula-II or salt or hydrate thereof,[Formula II]with compound of Formula- III or hydrate thereof in presence of solvent,[Formula III]Wherein, Ri and R2 each independently selected from hydrogen, halogen, nitro, cyano, alkoxy, hydroxy, Ci to Cf, substituted or unsubstituted alkyl.

7. A process for the preparation of enantiomerically pure compound of Formula-V or salt or hydrate thereof;[Formula V]comprising reacting compound of formula- IV,Wherein, Ri and R2 each independently selected from hydrogen, halogen, nitro, cyano, alkoxy, hydroxy, Ci to Cf, substituted or unsubstituted alkyl,in presence of a base and a solvent.

8. A compound of formula- IV,Wherein, Ri and R2 each independently selected from hydrogen, halogen, nitro, cyano, alkoxy, hydroxy, Ci to Cf, substituted or unsubstituted alkyl.

9. A process for the preparation of crystalline Form-5 of Fezolinetant comprising reacting compound of Formula-V or salt or hydrate thereof,[Formula V]with compound of Formula- VI,[Formula VI]in presence of base and solvent.

10. The process as claimed in claim 9, wherein base is selected from the group consisting of organic base or inorganic base; inorganic bases selected from alkali metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; ammonia such as aqueous ammonia, ammonia gas, methanolic ammonia and organic bases selected from the group consisting of methyl amine, ethyl amine, diisopropyl amine, diisopropylethyl amine (DIPEA), diisobutylamine, triethylamine, tert-butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), methyl pyridine (NMP), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0] non5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole or mixture(s) thereof; and solvent is selected from the group consisting of water, acetonitrile, acetone, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl isobutyl ketone, methyl ethyl ketone or mixture thereof.

11. A process for the preparation of crystalline Form-5 of Fezolinetant comprising treating Fezolinetant with solvent.

12. The process as claimed in claim 11, wherein solvent is selected from the group consisting of isopropanol, n-propanol, methyl isobutyl ketone, methyl ethyl ketone or mixture thereof.

13. The process claimed in claim 11, wherein the treating step comprises recrystallisation, slurry wash or distillation thereof.

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