DESC:FIELD OF THE INVENTION
The present invention provides novel process for the preparation of Fezolinetant that involves use of novel intermediates or pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION
Fezolinetant chemically known as (4-Fluorophenyl) [(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-methanone is indicated for the treatment of moderate to severe vasomotor symptoms due to menopause and is approved and marketed as VEOZAHTM.

There is a need for the novel process for the preparation of pure Fezolinetant in high yields which is reproducible and easy to handle during large scale production. The present invention provides a process for the preparation of Fezolinetant using novel intermediates.

OBJECTIVE OF THE INVENTION
Main objective of the present invention is to provide a novel process for the preparation of Fezolinetant.

Another objective of the present invention is to provide novel intermediates that are used for the preparation of Fezolinetant.

Another objective of the present invention is to provide novel process for the preparation of Fezolinetant, wherein said Fezolinetant is isolated with high yields and purity.

SUMMARY OF THE INVENTION
Main aspect of the present invention provides novel process for the preparation of Fezolinetant of formula I.

Another aspect of the present invention provides novel intermediate compounds of formulae
, , and
isomers and salts thereof, wherein Pg is a protecting group selected from tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), benzyl (Bn), tosyl (Ts), mesyl (Ms), DMB, PMB, Allyl, diphenyl-phosphiramide (DPP), 2-trimethylsilylethanesulfonyl (SES) groups.

Another aspect of the present invention provides a process for the preparation of Fezolinetant of formula I by using novel intermediates of formula XIX, XX and XXI.

Another aspect of the present invention provides a process for the preparation of Fezolinetant of formula I
,
comprising the steps of:
a) reaction of compound of formula XIX

with 4-fluorobenzoyl chloride in a suitable solvent to give compound of formula III

g) reaction of compound of formula III with a compound of formula C in a suitable solvent to obtain compound of formula II
and;
h) conversion of compound of formula II to compound of formula I, wherein, R1, R2, R3 and R4 are independently selected from hydrogen, (un)substituted 1-4C alkyl, (un)substituted aryl, (un)substituted heteroaryl, (un)substituted cycloalkyl, (un)substituted heterocylyl, R1 and R2 together form (un)substituted cyclic or heterocyclic ring.

Another aspect of the present invention provides a process for the preparation of compound of formula XIX
,
comprising the steps of:
a) reaction of compound of formula IX with a protecting agent to form compound of formula VIII
;
b) alkylation of compound of formula VIII in presence of suitable alkylating agent and solvent to form compound of formula VII
;
c) reaction of compound of formula VII with compound of formula E to give compound of formula XXI
;
e) conversion of compound of formula XXI to compound of formula XX in presence of thionating agent and a suitable solvent;
; and
d) deprotection of compound of formula XX in presence of a suitable deprotecting agent to form compound of formula XIX; wherein Pg is a protecting group as defined above.

Another aspect of the present invention provides a process for the preparation of compound of formula XIX
,
comprising the steps of:
a) reaction of compound of formula IX with a protecting agent to form compound of formula VIII
;
b) alkylation of compound of formula VIII in presence of a suitable alkylating agent and solvent to form compound of formula VII
;
c) reaction of compound of formula VII with compound of formula F to give compound of formula XX,
, ; and
d) deprotection of compound of formula XX in presence of a suitable deprotecting agent to form compound of formula XIX; wherein Pg is a protecting group as defined above.

DETAILED DESCRIPTION OF THE INVENTION
The term “protecting group” (Pg) denotes tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), benzyl (Bn), tosyl (Ts), mesyl (Ms), DMB, PMB, Allyl, diphenyl-phosphiramide (DPP), 2-trimethylsilylethanesulfonyl (SES) groups.
Further, preferred protecting groups (Pg) are selected from tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), benzyl (Bn), tosyl (Ts), and mesyl (Ms) groups.

The term “alkyl” denotes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert. butyl. Further particular protecting alkyl groups are methyl and ethyl.

The terms “pharmaceutically acceptable salt” or “salt” are used interchangeably in the context of the present invention. “Pharmaceutically acceptable salts” or “salts” as used in the context of the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt, carbonate salts; organic acids such as succinic acid, formic acids, acetic acid, diphenyl acetic acid, palmoic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid and the like. The inorganic salts may further includes alkali metal and alkaline earth metal salts such as sodium, potassium, barium, lithium, calcium, magnesium, rhodium, zinc, cesium, selenium, and the like or, benethamine, benzathine, diethanolamine, ethanolamine, 4-(2-hydroxy-ethyl) morpholine, 1-(2-hydroxyethyl) pyrrolidine, N-methyl glucamine, piperazine, triethanol amine or tromethamine and the like.

The “suitable solvent” used is selected from the group consisting of, but not limited to, methanol, ethanol, isopropanol, 2-nitroethanol, n-butanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, toluene, acetone, ethylene glycol, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, butanenitrile, water, pyridine, dioxane, hexane, heptane, toluene, xylene, benzene, dichloromethane, diisopropylethylamine, dimethylsulfoxide, dimethylformamide, carbon disulfide, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, N-methylmorpholine (NMM), dimethylfuran, acetonitrile, dimethyl sulfone, ethyl acetate, n-propyl acetate, n-butyl acetate, isopropyl acetate, tert-butyl methyl ether (TBME), cyclopentylmethyl ether (CPME), dimethylcarbonate (DMC) and mixture thereof.

The “suitable alkylating agent” as used in the context of the present invention, is selected from the group comprising of, but not limited to, triethyloxonium tetrafluoroborate, diethyl sulfate, ethyl iodide, ethyl bromide, ethyl tosylate, triethyl aluminium and the like.
The “suitable protecting agent” as used in the context of the present invention, is selected from the group consisting of, but not limited to, di-tert-butyl dicarbonate (Boc2O), benzyl chloroformate (CbzCl), fluorenylmethyloxycarbonyl chloride (Fmoc-Cl), allyl chloroformate, benzyl chloride (BnCl), benzyl bromide (BnBr), p-toluenesulfonyl chloride (TsCl), methanesulfonyl chloride (MsCl), allyl chloride, allyl bromide, 2-(trimethylsilyl)ethanesulfonyl chloride (SES-Cl), 2,4-dimethoxybenzyl chloride, 2,4-dimethoxybenzyl bromide, p-methoxybenzyl chloride (PMBCl), diphenylphosphinic chloride (DPP-Cl).

The “suitable deprotecting agent" as used in the context of the present invention, is selected from the group comprising of, but not limited to, 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), 2-mercaptoethanol, tetrabutylammonium fluoride (TBAF), potassium fluoride, 4-methylpiperidine, piperidine, dipropylamine, diethylamine, piperazine, trifluoroacetic acid (TFA), hydrochloric acid (HCl), iodine, Pd-C/H2, sulfinic acid, palladium, polymethylhydrosiloxane, Trimethylsilyl iodide, magnesium perchlorate, zinc bromide, sodium tert-butoxide, TiCl4 in THF, sodium methoxide, sodium borohydride, Cyclohexylamine, Ethanolamine, Triethylamine, N, N-diisopropylethylamine, Methanol, ethanol, ethyl acetate, t-butanol, HBr in acetic acid and the like.

The thionating agent as used in the context of the present invention, is selected from the group comprising of, but not limited to, Lawesson’s reagent, P2S5, diphosphorus pentasulfide dipyridinium complex and the like.

In main embodiment, the present invention provides a novel compound of formula XIX’

isomers and salts thereof, wherein X=O or S; R= H or Pg;
Pg is a protecting group selected from tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), benzyl (Bn), tosyl (Ts), mesyl (Ms), DMB, PMB, Allyl, diphenyl-phosphiramide (DPP), 2-trimethylsilylethanesulfonyl (SES) groups.

In preferred embodiment, the present invention provides novel compounds of formulae
, , and
isomers and salts thereof, wherein, Pg is a protecting group as defined above.

In another embodiment, the present invention provides a process for the preparation of Fezolinetant of formula I, using the compounds of formulae XXI, XX, and XIX.

Another embodiment of the present invention provides a process for the preparation of Fezolinetant of formula I,

comprising the steps of:
a) reaction of compound of formula XIX with a 4-fluorobenzoyl chloride in a suitable solvent;
, ,
to give compound of formula III;
b) reaction of compound of formula III with a compound of formula C in a suitable solvent to form compound of formula II,
, ; and;
h) conversion of compound of formula II to compound of formula I, wherein, R1, R2, R3 and R4 are independently selected from hydrogen, (un)substituted 1-4C alkyl, (un)substituted aryl, (un)substituted heteroaryl, (un)substituted cycloalkyl, (un)substituted heterocylyl, R1 and R2 together form (un)substituted cyclic or heterocyclic ring.

In another embodiment, the solvent used for the conversion of compound of formula XIX to compound of formula III is selected from, but not limited to, dichloromethane, N-methyl morpholine (NMM), ethyl acetate, n-propyl acetate, n-butyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, methanol, ethanol, isopropanol and the like.

In another embodiment, the solvent used for the conversion of compound of formula III to compound of formula II is selected from, but not limited to, dichloromethane, isopropanol, methanol, ethanol, isopropanol, ethyl acetate, n-propyl acetate, n-butyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, tert-butyl methyl ether (TBME), cyclopentylmethyl ether (CPME), dimethylcarbonate (DMC) and the like.

Another embodiment of the present invention provides a process for the preparation of compound of formula XIX
,
comprising the steps of:
a) reaction of compound of formula IX with a suitable protecting agent to form compound of formula VIII
;
b) alkylation of compound of formula VIII in presence of a suitable alkylating agent and solvent to form compound of formula VII
;
c) reaction of compound of formula VII with compound of formula E to give compound of formula XXI
; ;
e) conversion of compound of formula XXI to compound of formula XX in presence of thionating agent and a suitable solvent,
; and
f) deprotection of compound of formula XX in presence of a suitable deprotecting agent to form compound of formula XIX; wherein Pg is a protecting group as defined above.

Another embodiment of the present invention provides a process for the preparation of compound of formula XIX
,
comprising the steps of:
a) reaction of compound of formula IX with a suitable protecting agent to form compound of formula VIII

b) alkylation of compound of formula VIII in presence of a suitable alkylating agent and solvent to form compound of formula VII
;
c) reaction of compound of formula VII with compound of formula F to give compound of formula XX
, and
d) deprotection of compound of formula XX in presence of a suitable deprotecting agent to form compound of formula XIX
;
wherein Pg is a protecting group as defined above.

In another embodiment, process for the preparation of compound of formula I, comprising conversion of compound of formula II to compound of formula I.

In another embodiment, the solvent used for the conversion of compound of formula VIII to compound of formula VII is selected from, but not limited to, dichloromethane, isopropanol, methanol, ethanol, ethyl acetate, n-propyl acetate, n-butyl acetate, isopropyl acetate, 2-methyltetrahydrofuran, tetrahydrofuran, tert-butyl methyl ether (TBME), cyclopentylmethyl ether (CPME), hexane, heptane, 3-Methoxybutan-2-one, dimethylcarbonate (DMC) and the like.

In another embodiment, the solvent used for the conversion of compound of formula XXI to compound of formula XX is selected from, but not limited to, dichloromethane (DCM), toluene, xylene, benzene, acetonitrile, Tetrahydrofuran (THF), pyridine, dioxane, carbon disulfide and the like.

In another embodiment, the present invention provides a process for the preparation of compound of formula I, comprising conversion of compound of formulae XXI, XX, XIX and III to compound of formula I.

In another embodiment, the present invention provides a process for the preparation of compound of formula I according to the following scheme:

In another embodiment, the present invention provides solid forms of Fezolinetant.

In another embodiment, the present invention provides solid form of Fezolinetant selected from crystalline, amorphous, solid dispersion or premix.

In another embodiment, the present invention provides substantially pure Fezolinetant of Formula I characterized by the chemical purity of 90.0% and above, preferably 95% and above, more preferably 98% and above and most preferably 99% and above by HPLC.

In another embodiment, the present invention provides substantially pure Fezolinetant of Formula I characterized by the purity of 99.0% and above, preferably 99.5% and above, and most preferably 99.9% and above by HPLC.

In another embodiment, the present invention further provides Fezolinetant, having an optical purity of =96%, preferably =98%, more preferably >99%, even more preferably =99.9%. For the purposes of the present invention, the term "optical purity" is defined as the percentage of a given enantiomer in an enantiomeric mixture when measured by chiral HPLC.

In another embodiment, the process for purification to obtain optically pure material i.e. Fezolinetant may involve purification by solvent crystallization, wherein the solvent can be selected from, but not limited to, methyl tert.-butyl ether (MTBE), isopropyl acetate, ethyl acetate and mixture thereof.

In another embodiment, the process of preparing Fezolinetant may involve isolation and/or purification of intermediate, or may be carried out in one pot without isolation of intermediates.

In another embodiment, Fezolinetant of Formula I having a median value (D50) of the particle size distribution less than 100 µm, and/or a D10 of the particle size distribution less than 10 µm, and /or a D90 of the particle size distribution less than 200 µm.

In a preferred embodiment of the present invention, Fezolinetant of Formula I having a D10 of the particle size distribution less than 10 µm. In a particularly preferred embodiment, D10 of the particle size distribution is not more than 1 µm.

In a preferred embodiment of the present invention, Fezolinetant of Formula I having a D50 of the particle size distribution less than 100 µm. In a particularly preferred embodiment, D50 of the particle size distribution is not more than 5 µm.

In a preferred embodiment of the present invention, Fezolinetant of Formula I having a D90 of the particle size distribution less than 200 µm. In a particularly preferred embodiment, D90 of the particle size distribution is not more than 10 µm.

In another embodiment, particle size distribution was determined with a Malvern Mastersizer 3000.

In another embodiment, the present invention provides anhydrous Fezolinetant of formula I, that has a water content of less than 5% by weight, more preferably less than 2% and most preferably less than 1%.

Certain specific aspects and embodiments of the present application will be explained in details with reference of the following examples, which are provided only for purposes of illustration and should not able constructed as limited the scope of the application in any manner.

EXAMPLES

Example 1: Preparation of compound of formula VIII (wherein Pg is Fmoc):
Charged (3R)-3-methylpiperazin-2-one (50.0 g) and acetone [250 ml] into round bottom flask. Added sodium bicarbonate [110.0 g] to it and cooled to 0-5ºC. Slowly added Fluorenylmethyloxycarbonyl chloride (Fmoc-Cl) [135.0 g] to the above reaction mass. Stirred for 1 hour. Distilled out solvent completely and charged water (300 ml). Extracted material with Ethyl acetate and washed organic layer with water. Concentrated organic layer to get title compound as crude material [140.0 g]. Yield: 95 % and Purity: 97.0 %.

Example 2: Preparation of compound of formula VIII (wherein Pg is Cbz):
Charged (3R)-3-methylpiperazin-2-one (50.0 g), acetone [250 ml] and water [750 ml] into round bottom flask. Added sodium bicarbonate [74.0 g] to it and cooled to 0-5ºC. Slowly added Benzyl chloroformate (CbzCl) [82.16 g] to the above reaction mass. Stirred for 1 hour. After completion, filter the solid formed,suck dried and washed with water [100.0 ml]. Dried the wet cake in air oven at 50-55ºC to get title compound as crude material [107.0 g]. Yield: 98.0% and Purity: 98.0%.

Example 3: Preparation of compound of formula VII (wherein Pg is Fmoc):
Charged freshly dried sodium carbonate (120.0 g) and anhydrous dichloromethane [500 ml] in a round-bottom flask. Added compound of formula VIII material [100 g] to above reaction mass and cooled to 0-5 ºC. Charged triethyloxonium tetrafluoroborate (120.0g) at same temperature. Stirred the reaction mass at room temperature for 12-15 hours. Quenched reaction mass with water (300 ml) and extracted the desired product with dichloromethane. Washed organic layer with saturated sodium chloride solution. Concentrated organic layer to get title compound as crude material [121.0 g]. Yield: 94.0 % and Purity: 92.0%.

Example 4: Preparation of compound of formula VII (wherein Pg is Cbz):
Charged freshly dried sodium carbonate (90.0 g) and anhydrous dichloromethane [500 ml] in a round-bottom flask. Added compound of formula VIII material [100 g] to above reaction mass and cooled to 0-5 ºC. Charged triethyloxonium tetrafluoroborate (90.0g) at same temperature. Stirred the reaction mass at room temperature for 12-15 hours. Quenched reaction mass with water (300 ml) and extracted the desired product with dichloromethane. Washed organic layer with saturated sodium chloride solution. Concentrated organic layer to get title compound as crude material [110.0 g]. Yield: 99.0 % and Purity: 90.0%.

Example 5: Preparation of compound of formula XXI (wherein Pg is Fmoc):
Charged compound of formula VII material [110.0 g] and n-butanol [500 ml] in a round-bottom flask. Added 2-hydrazinyl-2-oxoacetamide [76.0 g] to it and heated to reflux for 12-15 hours. After completion of the reaction cooled and distilled out solvent. Extracted desired organic compound with dichloromethane,washed organic layer with water and saturated sodium chloride solution. Concentrated organic layer to get title compound as crude material [120.0 g]. Desired product is obtained in pure form by column chromatography in [Pure material= 103 g].
Yield: 84.0% and Purity: 98.0%.

Example 6: Preparation of compound of formula XXI (wherein Pg is Cbz):
Charged compound of formula VII material [110.0 g] and ethylene glycol [1100 ml] in a round-bottom flask. Added 2-hydrazinyl-2-oxoacetamide [58.2 g] to it and heated to 100-105º for 12-15 hours. After completion of the reaction cooled the reaction mass. Extracted desired organic compound with dichloromethane, washed organic layer with water and saturated sodium chloride solution. Concentrated organic layer to get title compound as crude material [110.0 g].
Yield: 80.0%.

Example 7: Preparation of compound of formula XX (wherein Pg is Fmoc):
Charged compound of formula XXI (100.0 g) and dry tetrahydrofuran (500.0 ml) into a round bottom flask. Charged Lawesson's Reagent (172.0 g) to the reaction mass at room temperature and heat to reflux and stir at same temperature for 10-12 hours. After reaction completion, distilled out solvent completely and extracted desired organic compound with ethyl acetate. Washed organic layer with saturated sodium bicarbonate. Concentrate organic layer to get title compound as crude material [100.0 g]. Yield: 96.0 % and Purity: 96.0 %.

Example 8: Preparation of compound of formula XX (wherein Pg is Fmoc):
Charged compound of formula VII material [100.0 g] and n-butanol [500 ml] in a round-bottom flask. Added 2-hydrazinyl-2-oxoethanethioamide [40.0 g] to it and heated to reflux for 12-15 hours. After completion of the reaction, cooled and distilled out solvent. Extracted desired organic compound with dichloromethane and washed organic layer with water and saturated sodium chloride solution. Concentrated organic layer to get title compound as crude material [114.0 g]. Desired product is obtained in pure form by column chromatography in [Pure material= 101 g]. Yield 87.0% and Purity 98.0%.

Example 9: Preparation of compound of formula XX (wherein Pg is Cbz):
Charged compound of formula XXI (100.0 g) and dry tetrahydrofuran (500.0 ml) into a round bottom flask. Charged Lawesson's Reagent (135.0 g) to the reaction mass at room temperature and heat to reflux and stir at same temperature for 10-12 hours. After reaction completion, distilled out solvent completely and extracted desired organic compound with ethyl acetate. Washed organic layer with saturated sodium bicarbonate. Concentrated organic layer to get title compound as crude material [101.0 g]. Yield: 96.0 % and Purity: 97.0%.

Example 10: Preparation of compound of formula XX (wherein Pg is Cbz):
Charged compound of formula VII material [100.0 g] and ethylene glycol [500 ml] in a round-bottom flask. Added 2-hydrazinyl-2-oxoethanethioamide [52.0 g] to it and heated to 100-105ºC for 12-15 hours. After completion of the reaction, cooled the reaction mass. Extracted desired organic compound with dichloromethane and washed organic layer with water and saturated sodium chloride solution. Concentrated organic layer to get title compound as crude material [118.0 g]. Desired product is obtained in pure form by column chromatography in [Pure material= 100 g]. Yield 83.0% and Purity 97.0%.

Example 11: Preparation of compound of formula XIX:
Charge compound of formula XX (Fmoc protected) (100.0 g) and dichloromethane [600 ml] and into RBF at room temperature. Added 20.0 % piperidine in dichloromethane and stirred for 5-6 hours at reflux temperature. After reaction completion, extracted desired organic compound with dichloromethane. Washed organic layer with saturated sodium chloride solution. Concentrated organic layer to get title compound as crude material [45.0 g]. Yield: 95.0 % and Purity: 95.0%.

Example 12: Preparation of compound of formula XIX:
Charged compound of formula XX (Cbz protected) (100.0 g) and methanol [600 ml] into autoclave. Added 10.0g Palladium on carbon [50% wet] to it. Hydrogenated the reaction mass under Hydrogen gas pressure for 5-6 hours at temperature 50-55ºC. After completion of reaction, filtered the reaction mass and concentrate the FML to get title compound as crude material [55.0 g]. Yield: 93% and Purity: 96.0%.

Example 13: Procedure for purification/resolution of compound of formula XIX using L (+) Tartaric Acid:
Charged ethanol (1000 ml) and Compound of formula XIX (50.0 g) and heated to reflux. Added 50 ml DM water in RBF and stirred it at 75-85ºC for 30 minutes. After clarity of the reaction mass, charged L-(+)- tartaric acid [29.0g] in the above mass. Stirred it for 60-90 minute at 75-85ºC. Gradually cooled the reaction mass to 20-25ºC. Stirred it for 2-3 hour at 40-45ºC. Gradually cooled the reaction mass to 20-25ºC in NLT 2.0 hours. Stirred it for 4-5 hours at 20-25ºC. Filtered the solid material and washed with 50 ml ethanol at same temperature. Suck dried properly and unloaded the material to obtain wet cake-I (55.0 g).
Leaching method:
Charged ethanol (500 ml), water 25 ml and wet cake-I (55.0 g) in RBF. Heated the above mass at 75-85ºC. Gradually cooled the reaction mass to 20-25ºC. Stirred it for 4-5 hours at 20-25ºC. Filtered it and washed with 50 ml ethanol. Suck dried properly and unloaded the material to obtain the wet cake –II (50.0 g).
Obtaining the Free base of formula XIX:
Charged D.M. Water (150 ml), Wet cake-II (50.0 g) in four-neck round bottom flask. Stirred it for 20-30 minutes at 20-30ºC. Meanwhile prepared the solution of sodium carbonate (saturated solution, 150 ml) and added to above reaction mass. Distilled out water under vacuum and degassed it. Charged tertiary butanol (500 ml) in residue obtained and stirred at 60-65ºC for 1 hour and filtered it. Collected solid obtained and again charged it into RBF followed by addition of tertiary butanol (500 ml). Stirred at 60-65ºC for 1 hour and filtered it. Washed with tertiary butanol (100 ml). Combined both FMLs and distilled out to get free base of formula XIX [25.0 g]. Chiral Purity=99.5%.

Example14: Preparation of compound of formula III:
Charged compound of formula XIX (50.0 g) and dichloromethane (400.0 ml) into a round bottom flask. Added N-methyl morpholine [64.0g] to above reaction mass and cooled to 0-5º C. Slowly added 4-fluorobenzoyl chloride [44.0g] {freshly prepared from 4-fluorobenzoic acid using thionyl chloride and dicholoromethane solvent} dropwise to above reaction mass at 0-5º C. Stirred at room temperature for 3-4 hours. After completion of the reaction, extracted desired organic material with dichloromethane and wash organic layer with water. Concentrated the organic layer to get title crude material [80.0 g]. Yield: 98.0 and Purity: 94.0%.

Example 15: Preparation of compound II-a:
Charged compound of formula III [80.0] and dicholoromethane (500 ml) into a round-bottom flask. Added 1,1-dimethoxy-N, N-dimethyl-ethanamine [67.0 g] at 15-20ºC. Stirred at room temperature for 12-15 hours. After completion of the reaction, distilled out solvent and degassed to get crude material [90.0 g].
Yield: 92.0 and Purity: 92.0%.

Example 16: Preparation of compound of formula I:
Charged compound of formula II-a [90.0] and ethanol [720 ml] into a round-bottom flask. Added pyridine [110 ml] and Hydroxylamine-O-sulphonic acid [110.0 g] to it. The reaction mixture was stirred at 15-25ºC for 5-6 hours. After completion of the reaction, extracted desired organic material with ethyl acetate and washed organic layer with water and saturated solution of sodium chloride. Concentrated organic layer to get title compound as crude material [80.0 g]. Crude material was further purified by crystallisation in ethyl acetate to get pure material [Fezolinetant] [50.0g]. Yield: 60.0 % and Purity: 99.0 %.
,CLAIMS:WE CLAIM:
1. A process for the preparation of Fezolinetant of formula I

comprising the steps of:
a) reacting compound of formula XIX

with 4-fluorobenzoyl chloride in a solvent;

to give compound of formula III
;
g) reacting compound of formula III with a compound of formula C in a solvent

to form compound of formula II
and;
h) converting compound of formula II to compound of formula I, wherein, R1, R2, R3 and R4 are independently selected from hydrogen, (un)substituted 1-4C alkyl, (un)substituted aryl, (un)substituted heteroaryl, (un)substituted cycloalkyl, (un)substituted heterocylyl, R1 and R2 together form (un)substituted cyclic or heterocyclic ring.

2. A process for the preparation of compound of formula XIX
,
comprising the steps of:
a) reacting compound of formula IX

with a suitable protecting agent to form compound of formula VIII
;
b) alkylating compound of formula VIII in presence of a suitable alkylating agent and solvent to form compound of formula VII
;
c) reacting compound of formula VII with compound of formula E

to give compound of formula XXI
;
e) converting compound of formula XXI to compound of formula XX in presence of thionating agent and a solvent
and;
f) deprotecting compound of formula XX in presence of a suitable deprotecting agent to form compound of formula XIX

wherein Pg is a protecting group selected from tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), allyloxycarbonyl (Alloc), benzyl (Bn), tosyl (Ts), mesyl (Ms), DMB, PMB, Allyl, diphenyl-phosphiramide (DPP), 2-trimethylsilylethanesulfonyl (SES) groups.

3. A process for the preparation of compound of formula XIX
,
comprising the steps of:
a) reacting compound of formula IX

with a suitable protecting agent to form compound of formula VIII
;
b) alkylating compound of formula VIII in presence of a suitable alkylating agent and solvent to form compound of formula VII
;
c) reacting compound of formula VII with compound of formula F

to give compound of formula XX
and;
d) deprotecting compound of formula XX in presence of a suitable deprotecting agent to form compound of formula XIX

wherein Pg is a protecting group as defined above.

4. The process as claimed in claim 2 and 3, wherein the suitable alkylating agent is selected from group comprising triethyloxonium tetrafluoroborate, diethyl sulfate, ethyl iodide, triethyl aluminium, ethyl bromide and ethyl tosylate.

5. The process as claimed in claim 2 and 3, wherein the suitable deprotecting agent is selected from group comprising 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), 2-mercaptoethanol, tetrabutylammonium fluoride (TBAF), potassium fluoride, 4-methylpiperidine, piperidine, dipropylamine, diethylamine, piperazine, trifluoroacetic acid (TFA), hydrochloric acid (HCl), iodine, Pd-C/H2, sulfinic acid, palladium, polymethylhydrosiloxane, trimethylsilyl iodide, magnesium perchlorate, zinc bromide, sodium tert-butoxide, TiCl4 in THF, sodium methoxide, sodium borohydride, cyclohexylamine, ethanolamine, triethylamine, N, N-diisopropylethylamine, methanol, ethanol, ethyl acetate, t-butanol, HBr in acetic acid.

6. The process as claimed in claim 2, wherein the thionating agent in step e) is selected from Lawesson’s reagent, P2S5, diphosphorus pentasulfide dipyridinium complex.

7. The process as claimed in claim 2 and 3, wherein suitable protecting agent is selected from group consisting of di-tert-butyl dicarbonate (Boc2O), benzyl chloroformate (CbzCl), fluorenylmethyloxycarbonyl chloride (Fmoc-Cl), allyl chloroformate, benzyl chloride (BnCl), benzyl bromide (BnBr), p-toluenesulfonyl chloride (TsCl), methanesulfonyl chloride (MsCl), allyl chloride, allyl bromide, allyl alcohol, allyl chloroformate, 2-(trimethylsilyl)ethanesulfonyl chloride (SES-Cl), 2,4-dimethoxybenzyl chloride, 2,4-dimethoxybenzyl alcohol, 2,4-dimethoxybenzyl bromide, p-methoxybenzyl chloride (PMBCl), diphenylphosphinic chloride (DPP-Cl).

8. The process as claimed in claim 1, 2 and 3, wherein the suitable solvent is selected from group consisting of methanol, ethanol, isopropanol, 2-nitroethanol, n-butanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, toluene, acetone, ethylene glycol, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, butanenitrile, water, pyridine, dioxane, hexane, heptane, toluene, xylene, benzene, dichloromethane, diisopropylethylamine, dimethylsulfoxide, dimethylformamide, carbon disulfide, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, N-methylmorpholine (NMM), dimethylfuran, acetonitrile, dimethyl sulfone, ethyl acetate, n-propyl acetate, n-butyl acetate, isopropyl acetate, tert-butyl methyl ether (TBME), cyclopentylmethyl ether (CPME), dimethylcarbonate (DMC) and mixtures thereof..

9. A compound of formula XIX’

isomers and pharmaceutically acceptable salts thereof, wherein X=O or S; R= H or Pg; Pg is a protecting group as defined above.

10. Fezolinetant of formula I as claimed in claim 1, having percentage purity of 99.0% and above, preferably 99.5% and above, and most preferably 99.9% and above by HPLC.

Dated this 10th Day of March, 2025
For Mankind Pharma Ltd.

Dr. Anil Kumar

Chief Scientific Officer