DESC:FIELD OF THE INVENTION
Present invention provides novel intermediates or pharmaceutically acceptable salts thereof which are used for the preparation of Fezolinetant.

BACKGROUND OF THE INVENTION
Fezolinetant chemically known as (4-fluorophenyl)-[(8R)-8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-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 still a need for the preparation of pure Fezolinetant in high yields which is reproducible and easy to handle during large scale production.

In view of the above, the present invention provides a process for the preparation of Fezolinetant using novel intermediates.

OBJECT OF THE INVENTION
Main object of the present invention is to provide novel intermediates that are used for the preparation of Fezolinetant.

Another object of the present invention provides a novel process for the preparation of Fezolinetant.

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

Another object of the present invention provides a process for the preparation of novel intermediates by involving commercially viable process which results in improved yield and purity.

SUMMARY OF THE INVENTION
Main aspect of the present invention provides novel compounds of formulae

isomers and salts thereof;
wherein Pg is a protecting group, R1 and R2 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 Fezolinetant of formula I by using novel intermediates of formula II, III, IV, V and VI or pharmaceutically acceptable salts thereof.

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

comprising the steps of:
a) reacting compound of formula V with a compound of formula B,
,
to give compound of formula IV
;
b) conversion of compound of formula IV to compound of formula III
;
c) reacting compound of formula III with a compound of formula C to form compound of formula II
; and
d) conversion of compound of formula II to compound of formula I;
wherein pg is a protecting group selected from tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), benzyl (Bn), DMB, PMB, Allyl, diphenyl-phosphiramide (DPP), 2-trimethylsilylethanesulfonyl (SES); R1 and R2 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; R3 and R4 selected from 1-4C alkyl.

Another aspect of the present invention provides a novel process for the preparation of Fezolinetant of formula I through the formation of novel intermediate of formula

wherein R is (un)substituted 1-4C alkyl.

Another aspect of the present invention provides a process for the preparation of compound of formula I, comprising the steps of:
a) alkylation of compound of formula XIII to form compound of formula XII

wherein R is (un)substituted 1-4C alkyl group;
b) reacting compound of formula XII with a compound of formula D to form compound of formula XI
;
c) reducing compound of formula XI to form compound of formula X
; and
d) conversion of compound of formula X to Fezolinetant of formula I.

Another aspect of the present invention provides a process for the preparation of compound of formula XIII.

Another aspect of the present invention provides novel intermediate compound of formula,

wherein R is (un)substituted 1-4C alkyl.

DETAILED DESCRIPTION OF THE INVENTION

The term “Suitable protecting agent” (Pg) denotes tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn) DMB ,PMB, Allyl, diphenyl-phosphiramide (DPP),2-trimethylsilylethanesulfonyl (SES) groups. Further particular protecting groups are the tert-butoxycarbonyl (Boc) and the fluorenylmethoxycarbonyl (Fmoc) groups. More particular protecting group is the fluorenylmethoxycarbonyl (Fmoc) group.

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” as used in the context of the present invention, is selected from the group comprising of, but 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, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-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, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, butanenitrile, water and mixture thereof.

In main embodiment, the present invention provides novel compounds of formulae VI, V, IV, III and II,

wherein, Pg is a protection group and R1 and R2 are independently hydrogen, alkyl, aryl, cycloalkyl, substituted alkyl, R1 and R2 together form cyclic ring.

In another embodiment, the present invention provides a process for the preparation of Fezolinetant of formula I, using the compounds of formulae VI, V, IV, III and II.

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

comprising the steps of:
a) reacting compound of formula V with a compound of formula B,
,
to give compound of formula IV
;
b) conversion of compound of formula IV to compound of formula III
;
c) reacting compound of formula III with a compound of formula C to form compound of formula II
; and
d) conversion of compound of formula II to compound of formula I;
wherein pg is a protecting group selected from tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), benzyl (Bn), DMB, PMB, Allyl, diphenyl-phosphiramide (DPP), 2-trimethylsilylethanesulfonyl (SES); R1 and R2 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; R3 and R4 selected from 1-4C alkyl.

In another embodiment, the present invention provides a process for the preparation of Fezolinetant of formula I, 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 to form compound of formula VII;
c) reacting compound of formula VII with a compound of formula A to give compound of formula VI;
d) deprotecting the compound of formula VI to form compound of formula V;
e) reacting the compound of formula V with a compound of formula B to give compound of formula IV;
f) conversion of compound of formula IV to compound of formula III;
g) reacting compound of formula III with a compound of formula C to form compound of formula II; and
h) conversion of compound of formula II to compound of formula I.

In another embodiment, the present invention provides a process for the preparation of Fezolinetant of formula I, comprising conversion of compound of formula III to yield compound of formula I.

In another embodiment, the present invention provides a process for the preparation of Fezolinetant of formula I, comprising the steps of:
a) reaction of compound of formula IX with a suitable protecting agent to form compound of formula VIII-a
;
b) alkylation of compound of formula VIII to form compound of formula VII
;
c) reacting compound of formula VII with a compound of formula A to give compound of formula VI
;
d) deprotecting the compound of formula VI to form compound of formula V
;
e) reacting the compound of formula V with a compound of formula B to give compound of formula IV
;
f) conversion of compound of formula IV to compound of formula III
;
g) reacting compound of formula III with a compound of formula C to form compound of formula II
; and
h) conversion of compound of formula II to compound of formula I.

In another embodiment, the present invention provides a process for the preparation of compound of formula I, comprising the steps of:
a) alkylation of compound of formula XIII to form compound of formula XII;
b) reacting compound of formula XII with a compound of formula D to form compound of formula XI;
c) reducing compound of formula XI to form compound of formula X; and
d) conversion of compound of formula X to Fezolinetant of formula I.

In another embodiment, the present invention provides a process for the preparation of compound of formula I, comprising conversion of compound of formula X

to get Fezolinetant of formula I.

In another embodiment, the present invention provides a process for the preparation of compound of formula I, comprising the steps of:
a) alkylation of compound of formula XIII to form compound of formula XII-a
;
b) reacting compound of formula XII-a with a compound of formula D to form compound of formula XI
;
c) reducing compound of formula XI to form compound of formula X
; and
d) conversion of compound of formula X to Fezolinetant of formula I.

In another embodiment, the present invention provides a process for the preparation of compound of formula XIII
,
comprising the steps of:
a) reaction compound of formula XVIII with a chlorinating agent to form compound of formula XVII
; and
b) reacting compound of formula XVII with a compound of formula IX

to form a compound of formula XIII.

In another embodiment, the present invention provides a process for the preparation of compound of formula XIII
,
comprising the steps of:
a) alkylation of compound of formula XVI to form compound of formula XV

wherein R is (un)substituted 1-4C alkyl; and
b) reaction of compound of formula XV with a compound of formula IX

to form a compound of formula XIII.

In another embodiment, the present invention provides a process for the preparation of pharmaceutically acceptable salt of Fezolinetant of formula I, comprising addition of suitable pharmaceutically acceptable acid or base to the Fezolinetant.

In another embodiment, the present invention provides a process for the purification of Fezolinetant of formula I, comprising desalinization of salt of Fezolinetant.
In another embodiment, the present invention provides a process for the preparation of pure Fezolinetant, comprising the steps of;
a) providing a solution of salt of Fezolinetant in one or more suitable solvent;
b) adding suitable acid or base to the solution; and
c) isolating the pure Fezolinetant.

In another embodiment, the present invention provides a process for the preparation of pure Fezolinetant, comprising the steps of;
a) providing a solution of Fezolinetant in one or more suitable solvent; and
b) isolating the pure Fezolinetant.

In another embodiment, the present invention provides a process for the preparation of pure Fezolinetant, comprising the steps of;
a) providing a solution of Fezolinetant in one or more suitable solvent; and
b) adding suitable amount of anti-solvent to the solution of Fezolinetant at suitable temperature to obtain pure Fezolinetant.

In another embodiment, the present invention provides solid form 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 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, the present invention provides the Fezolinetant of Formula I that is characterized by particle size distribution wherein, d90 is 0.1µm to 200µm, preferably d90 is 2.0 µm to 150µm. Preferably, the particle size distribution d90 is not more than 1.0mm.

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 XV:
Charge 4-nitrobezonitrile (1.0 g) and ethanol (5.0 ml) into 100.0ml RBF at RT. Charge hydrochloric acid (6.0 ml) to the reaction mass at RT. Heat the reaction mass to reflux for 10-12 h. Distil out reaction mass under vacuum at NMT 50 °C. charge ethyl acetate (10.0 ml) and adjust the pH (7.0-8.5) with 2N Sodium hydroxide. Separate the layers at RT. Distil out ethyl acetate layer under Vacuum to obtain title compound. Crude wt. 1.1 g.

Example 2: Preparation of compound of formula XIII:
Charge compound of formula XV (1.0 g) and toluene (5.0 ml) into 100.0ml RBF at RT. Charge (3R)-3-methyl-2-piperazinone (6.0 g) to the reaction mass at RT. Added slowly Trimethylaluminium (2.0 g) to the reaction mass. Heat the reaction mass to reflux for 10-12 h. Distil out reaction mass under vacuum at NMT 50 °C and charge ethyl acetate (10.0 ml) and DM water (10.0 ml). Separate the layers at RT. Distil out ethyl acetate layer under Vacuum to get title compound. Crude wt. 1.2 g.

Example 3: Preparation of compound of formula XVII:
Charge 4-nitrobenzoic acid (5.0 g) and dichloromethane (25.0 ml) into 250.0ml RBF at RT. Charge slowly Thionyl chloride (6.0 g) to the reaction mass at RT. Heat the reaction mass to reflux for 3-4 h. Distil out reaction mass under vacuum at NMT 50 °C to get title compound. Crude wt. 5.2 g.

Example 4: Preparation of compound of formula XIII:
Charge compound of formula XVII (5.0 g) and dichloromethane (15.0 ml) into 250.0ml RBF at RT. Charge (3R)-3-methyl-2-piperazinone (6.0 g) to the reaction mass at RT. Added slowly diisopropylethylamine (6.0 g) to the reaction mass. Heat the reaction mass to reflux for 10-12 h. Distil out reaction mass under vacuum at NMT 50 °C. Charge ethyl acetate (10.0 ml) and DM water (10.0 ml). Separate the layer at RT. Distil out ethyl acetate layer under Vacuum to get title compound. Crude wt. 6.3 g.

Example 5: Preparation of compound of formula XII-a:
Charge compound of formula XIII (1.0 g) and dichloromethane (10.0 ml) into 100.0ml RBF at RT. Charge Sodium carbonate (2.0 g) to the reaction mass at RT. Add slowly Triethyloxonium fluoroborate (1.8 g) at RT to the reaction mass and stir reaction mass at reflux for 12.0 h. Charge DM water (8.0 ml) at RT. Separate the layers at RT. Distil out dichloromethane layer under Vacuum to get title compound. Crude wt. 1.1 g.

Example 6: Preparation of compound of formula XI:
Charge compound of formula XII-a (1.0 g) and methanol (10.0 ml) into 100.0ml RBF at RT. Charge 3-Methyl-1,2,4-thiadiazole-5-carbohydrazide (compound A) (2.0 g) to the reaction mass at RT. Reflux reaction mass overnight. Distil out reaction mass under Vacuum to get crude. Crystalized material by using MTBE. wt. 0.80 g. Purity: 99.83% by HPLC.

Example 7: Preparation of compound of formula X:
Charge compound of formula XI (0.50 g) and methanol (2.0 ml) in 100.0ml RBF at RT. Charge 10.0 % ammonium chloride (10.0 ml) and zinc dust (1.5 g) at RT to the reaction mass. Stir the reaction mass at RT. Filter the reaction mass through Buckner funnel. Charge dichloromethane to the filtrate at RT. Separate the layers. Distil out dichloromethane layer to get the title product. wt. 0.55 g. Purity: 99.84% by HPLC.

Example 8: Preparation of compound of formula I:
Charge acetic acid (10.0ml) and compound of formula X (0.50 g) into 100.0ml RBF at RT. Cool the reaction mass to 0-10 °C. Add sodium nitrite (1.42 g) at 0-10 °C to the reaction mass and stir at 0-10 °C for 2.0 h. charge slowly tetra fluoroboric acid (1.5 g) at RT and heat the reaction mass to 80 °C. Charge dichloromethane (10.0 ml) to the reaction mass and separate the layers. Distil out dichloromethane layer under vacuum. Charge isopropyl ether (10.0 ml) stir and filter to get the desired Fezolinetant. wt. 0.3 g. Purity: 98.88% by HPLC.

Example 9: Preparation of compound of formula D:
Charge Acetamide (10.0 g) and (chlorocarbonyl)sulfenyl chloride (13.5 g) at RT in 250.0ml RBF. Charge dry toluene (52.0 ml) to the reaction mass. Reflux the reaction mass for 2.0 h. Evaporate the solvent under reduced pressure and dissolve the residue in toluene (50.0 ml). Charge Methyl cyanoformate (20.0 g) at RT and reflux the reaction mass for 8.0 h. evaporate the solvent. To the Crude material charge ethanol (25.0 ml) and hydrazine hydrate (25.0 ml) at RT. Stir the reaction mass at RT. Crystalize the material by using dichloromethane and Methanol.

Example 10: Preparation of compound of formula VIII-a:
Charge (3R)-3-methyl-2-piperazinone (5.0 g) and acetonitrile (25.0 ml) into 250.0ml RBF at RT. Charge slowly 10.0 % aqueous sodium carbonate (10.0 ml) at RT to the reaction mass. Add slowly 9-fluorenylmethyl chloroformate (10.2 g) and heat the reaction mass to reflux for 3-4 h. Distil out reaction mass under vacuum at NMT 50 °C. Charge ethyl acetate (30.0 ml). separate the layer at RT to get title compound. Crude wt. 5.2 g.

Example 11: Preparation of compound of formula VIII-b:
Charge (3R)-3-methyl-2-piperazinone (5.0 g) and dichloromethane (25.0 ml) into 250.0ml RBF at RT. Charge slowly triethylamine (9.0 ml) at RT. Add slowly Di-tert-butyl dicarbonate (12.2 g) to the reaction mass and heat to reflux for 3-4 h. Distil out reaction mass under vacuum at NMT 50 °C. Charge ethyl acetate (30.0 ml). separate the layer at RT. Crude wt. 5.2 g.

Example 12: Preparation of compound of formula VII-a:
Charge compound of formula VIII-a (5.0 g) and dichloromethane (30.0 ml) into100.0ml RBF at RT. Charge Sodium carbonate (8.0 g) at RT. Add slowly Triethyloxonium fluoroborate (6.2 g) to the reaction mass at RT. Stir reaction mass at reflux for 12.0 h. Charge DM water (18.0 ml) at RT. Separate the layer at RT. Distil out dichloromethane layer under Vacuum to get title compound. Crude wt 6.3 g.

Example 13: Preparation of compound of formula VI-a:
Charge compound of formula VII-a (5.0 g) and methanol (30.0 ml) into 250.0ml RBF at RT. Charge Cyanoformohydrazide (9.0 g) to the reaction mass at RT. Stir reaction mass at reflux for 12.0 h. Distil out reaction mass under vacuum. Charge DM water (30.0 ml) at RT and dichloromethane (30.0 ml) at RT. Separate the layers at RT. Distil out dichloromethane layer under Vacuum to get title compound. Crude wt 5.5 g.

Example 14: Preparation of compound of formula V:
Charge compound of formula VI-a (5.0 g) and 20.0 % Piperidine in dimethylformamide (11.0 ml) in 250.0ml RBF at RT. Charge Hydrochloric Acid (10.0 g) to the reaction mass at RT and stir at RT for 6.0 h. Charge DM water (18.0 ml) and ethyl acetate (25.0 ml) at RT. Separate the layers at RT. Distil out ethyl acetate layer under Vacuum to get title compound. Crude wt 1.9 g.

Example 15: Preparation of compound of formula IV:
Charge compound of formula V (1.0 g) and dichloromethane (15.0 ml) into 100.0ml RBF at RT. Add slowly compound of formula B (2.2 g) to the reaction mass at RT. Add slowly trimethylamine 2.6 g at RT to the reaction mass and stir at reflux for 5.0 h. Charge DM water (10.0 ml) at RT. Separate the layers at RT. Distil out dichloromethane layer under Vacuum. Crude wt 1.9 g.

Example 16: Preparation of compound of formula III:
Charge compound of formula IV (1.0 g), methanol (10.0 ml) and tetrahydrofuran (10.0 ml) at RT into 100.0ml RBF. Add slowly ammonium sulfide (2.0 g) at 15 °C. Stir reaction mass at 15 °C for 5.0 h under N2. Charge DM water (10.0 ml) and ethyl acetate (20.0 ml) at RT. Separate the layers at RT. Wash the organic layer with brine solution. Distil out ethyl acetate layer under Vacuum to get title compound. Crude wt 1.1 g. Purity: 98% by HPLC.

Example 17: Preparation of compound of formula II:
Charge compound of formula III (1.0 g) and dichloromethane (18.0 ml) into 100.0ml RBF at RT. Charge 1,1-dimethoxy-N,N-dimethyl-ethanamine (0.95 g) at 15 °C. Stir the reaction mass at 15 °C for 12.0 h. Distil out reaction mass under Vacuum to get title compound. Crude wt 1.3 g. Purity: 98.3% by HPLC.

Example 18: Preparation of compound of formula I:
Charge compound of formula II (1.0 g) and ethanol (10.0 ml) into 100.0ml RBF at RT. Charge pyridine (1.0 g) to the reaction mass at RT. Add slowly amino hydrogen sulfate (2.1 g) in methanol (10.0ml) to the reaction mass at 15 °C. Stir reaction mass at 15 °C for 5.0 h under N2. Charge DM water (15.0 ml) at RT. Charge ethylacetate (15.0 ml) at RT. Separate the layers at RT. wash the Organic layer with brine solution. Distil out ethyl acetate layer under Vacuum. Charge isopropyl ether (10.0 ml). Stir and filter to get the desired Fezolinetant. wt. 0.4 g. Purity: 99.1% by HPLC.

Example 19: Preparation of compound of formula B:
Charge 4-fluorobenzoic acid (20.0 g) and dichloromethane (60.0 ml) in 100.0ml RBF at RT. Charge trimethylamine (25.0 g) to the reaction mass at RT. Add slowly methane sulfonyl chloride (30.0 g) to the reaction mass at RT. Stir reaction mass at reflux for 12.0 h. Charge DM water (100.0 ml) at RT. Separate the layer at RT. Distil out dichloromethane layer under Vacuum to get title compound. Crude wt 22.0 g.

Example 20: Purification of Fezolinetant:
To the crude Fezolinetant (0.5 g) charge acetonitrile (2.5 ml) and heat the reaction mass to reflux. Slowly cool to RT and filter to get 0.256 g Fezolinetant.
Purity: 99.94% by HPLC.

Example 21: Purification of Fezolinetant:
To the crude Fezolinetant (0.5 g) charge methyl ethyl ketone (3.2 ml) and heat the reaction mass to reflux. Slowly cool to RT and filter to get 0.32 g Fezolinetant.
Purity: 99.93% by HPLC.

Example 22: Purification of Fezolinetant:
To the crude Fezolinetant (0.5 g) charge ethanol (5.0 ml) and heat the reaction mass to reflux. Slowly cool to RT and filter to get 0.12 g Fezolinetant.
Purity: 99.92% by HPLC.

Example 23: Purification of Fezolinetant:
To the crude Fezolinetant (0.5 g) charge tetrahydrofuran and toluene (2.0 ml) and heat the reaction mass to 55 °C. Slowly cool to RT and filter to get 0.32 g Fezolinetant. Purity: 99.91% by HPLC.
,CLAIMS:We claim:
1. A process for the preparation of Fezolinetant of formula I, comprising:
a) reacting compound of formula V with a compound of formula B,
,
to give compound of formula IV
;
b) conversion of compound of formula IV to compound of formula III
;
c) reacting compound of formula III with a compound of formula C to form compound of formula II
; and
d) conversion of compound of formula II to compound of formula I;
wherein pg is a protecting group selected from tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc), benzyl (Bn), DMB, PMB, Allyl, diphenyl-phosphiramide (DPP), 2-trimethylsilylethanesulfonyl (SES); R1 and R2 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; R3 and R4 selected from 1-4C alkyl.

2. The process as claimed in claim 1, wherein process for the preparation of Fezolinetant of formula I, comprising:
a) reacting the compound of formula V with a compound of formula B,
,
to give compound of formula IV
;
b) conversion of compound of formula IV to compound of formula III
;
c) reacting compound of formula III with a compound of formula C-1 to form compound of formula II-a
; and
d) conversion of compound of formula II to compound of formula I.

3. The process as claimed in claim 1 or 2, wherein compound of formula V is synthesized using a process comprising:
a) reaction of compound of formula IX with a protecting agent to form compound of formula VIII
;
b) alkylation of compound of formula VIII to form compound of formula VII
,
wherein pg is as defined in claim 1;
c) reacting compound of formula VII with a compound of formula A
, ,
to give compound of formula VI
;
d) deprotecting the compound of formula VI to form compound of formula V
.

4. A process for the preparation of compound of formula I, comprising the steps of:
a) alkylation of compound of formula XIII to form compound of formula XII
, ,
wherein R is (un)substituted 1-4C alkyl group;
b) reacting compound of formula XII with a compound of formula D to form compound of formula XI
;
c) reducing compound of formula XI to form compound of formula X
; and
d) conversion of compound of formula X to Fezolinetant of formula I.

5. The process as claimed in claim 4, wherein preparation of compound of formula XIII,
,
comprising the steps of:
a) reaction of compound of formula XVIII with a chlorinating agent to form compound of formula XVII
, ; and
b) reacting compound of formula XVII with a compound of formula IX

to form a compound of formula XIII;
or
a) alkylation of compound of formula XVI to form compound of formula XV

wherein R is (un)substituted 1-4C alkyl; and
b) reaction of compound of formula XV with a compound of formula IX

to form a compound of formula XIII.

6. Compound of formula II, formula III, formula IV, formula V, formula VI, and formula XII

isomers and salts thereof; wherein pg, R, R1 and R2 are as defined above.

7. The process as claimed in preceding claims, wherein Fezolinetant compound of formula I having a purity of greater than 99.9% by HPLC.

Dated 03rd Day of Oct, 2024
For Mankind Pharma Ltd.

Dr. Anil Kumar

Chief Scientific Officer