DESC:
Field of invention

The present invention relates to a novel process for the preparation of the Gonadotropin-Releasing Hormone Receptor (GnRH) antagonist of Formula (I) and to novel intermediates which are produced during the course of carrying out the said novel process.

BACKGROUND OF THE INVENTION

Relugolix, is a once a daily selective antagonist of Gonadotropin-Releasing Hormone Receptor, under development for the treatment of certain pathologies, production of testicular testosterone-which stimulates prostate cancer growth and ovarian estradiol- which stimulates endometriosis and uterine leiomyoma.

Relugolix is chemically termed as l-(4-(l-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-l,2,3,4-tetrahydrothieno(2,3- d)pyrimidin-6-yl)phenyl)-3-methoxyurea, having the following chemical structure:

The earliest known synthesis of Relugolix and pharmaceutically acceptable salts thereof, is described in the US Patent No. 7,300,935 B2
U.S. Patent No. 9,758,528 B2 discloses an alternate process to prepare Relugolix.

In addition, J . Med. Chem., 201 1, 54 (14), pp. 4998 - 5012, refers to pharmacological and chemical aspects of Relugolix.

Although the above-mentioned patent applications already describe a process to manufacture the Relugolix and its salts thereof, an object of the present invention is a new improved and commercially viable process for the manufacture of this compound.

OBJECT OF THE INVENTION

The object of the present invention is to provide a novel process for preparing Relugolix or pharmaceutically acceptable salts thereof.

Yet another object of the present invention is to provide a novel process via novel intermediate for preparing Relugolix or pharmaceutically acceptable salts thereof.

Yet another object of the present invention is to provide a process for the synthesis of Relugolix or pharmaceutically acceptable salts thereof which is simple, economical and suitable for industrial scale-up.

SUMMARY OF THE INVENTION

This invention is directed to novel process of preparing Relugolix of Formula I or pharmaceutically acceptable salts of Relugolix and intermediates thereof.

In a first embodiment, the invention provides a process for preparing Relugolix
of Formula I, or salts thereof which comprises:
converting compound of Formula II

wherein R2 is C1-C5 alkyl, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and t- butyl;
to Relugolix of Formula I or salts thereof.

In an embodiment conversion comprises, cyclizing compound of Formula II in the presence of a suitable base and suitable solvent.

In a second embodiment, the invention provides a compound of Formula (II)

wherein R2 is C1-C5 alkyl, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and t- butyl.

In a third embodiment, the invention provides a process for preparing compound of Formula (II), which comprises:
coupling compound of Formula (III)

wherein R2 is C1-C5 alkyl, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and t- butyl,
with a compound of Formula (VII) or salt thereof,

in the presence of a suitable amide coupling reagent.

In a fourth embodiment, the invention provides a compound of Formula (III)

wherein R2 is C1-C5 alkyl, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and t- butyl.

In a fifth embodiment, the invention provides a process for preparing compound of Formula (III), which comprises:
hydrolysis of compound of Formula (IV)

wherein R1 is C1-C5 alkyl and R2 is C1-C5 alkyl, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and t- butyl.

In a sixth embodiment, the invention provides a compound of Formula (IV)

wherein R1 is C1-C5 alkyl and R2 is C1-C5 alkyl, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and t- butyl.

In a seventh embodiment, the invention provides a process for preparing compound of Formula (IV), which comprises:
reacting compound of Formula (V),

wherein R1 is C1-C5 alkyl and R2 is C1-C5 alkyl, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and t- butyl,
with methoxyamine of Formula (VIII),or a salt thereof.

In an eighth embodiment, the invention provides a process for preparing compound of Formula (V), which comprises:
reducing compound of Formula (VI),

in the presence of a suitable reducing agent.

In a ninth embodiment, the present invention provides Relugolix (I) or pharmaceutically acceptable salts thereof; prepared according to the process described above, having a purity of more than about 95%, preferably at least 99%, more preferably at least 99.5% by HPLC.

In a tenth embodiment, the invention provides a pharmaceutical composition comprising Relugolix or its pharmaceutically acceptable salts thereof, prepared by a process as described above, together with one or more pharmaceutically acceptable excipients. Such excipients are well known to those skilled in the art.
Dosage forms include solid dosage forms like tablets, powders, granulates, capsules, sachets, aggregates, suppositories, troches, and lozenges, as well as liquid syrups, suspensions, and elixirs.

In an eleventh embodiment, the invention provides the use of Relugolix or its pharmaceutically acceptable salts thereof, prepared by a process as described above in medicine.

In a twelfth embodiment, the invention provides Relugolix or its pharmaceutically acceptable salts thereof, prepared by a process as described above for use in the treatment of diseases caused by gonadotropin releasing hormone (e.g., endometriosis, uterine fibroid and prostate cancer), and can be used for the prophylaxis or treatment of the above-mentioned diseases.

In a thirteenth embodiment, the invention provides the use of Relugolix or its pharmaceutically acceptable salts thereof, prepared by a process as described above, in the manufacture of a medicament for treating diseases caused by gonadotropin releasing hormone (e.g., endometriosis, uterine fibroid and prostate cancer).

In a fourteenth embodiment, the invention provides the use of Relugolix or its pharmaceutically acceptable salts thereof, prepared by a process as described above in the treatment of diseases caused by gonadotropin releasing hormone (e.g., endometriosis, uterine fibroid and prostate cancer).

In a fifteenth embodiment, the invention provides a method of treating diseases caused by gonadotropin releasing hormone (e.g., endometriosis, uterine fibroid and prostate cancer) in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of Relugolix or its pharmaceutically acceptable salts thereof, prepared by a process as described above.

DETAILED DESCRIPTION OF THE EMBODIMENTS

The present invention provides a process for the preparation of Relugolix of Formula I or its pharmaceutically acceptable salts thereof which process is economical, fast and results in a high purity Relugolix product.

In an embodiment, the process for the preparation of of Relugolix of Formula I or its pharmaceutically acceptable salts thereof is as depicted below in scheme 1.

Scheme 1

wherein R1 is C1-C5 alkyl and R2 is C1-C5 alkyl, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and t- butyl.

The compounds of Formula II, III and IV are hitherto unreported intermediates useful in the process for the preparation of Relugolix as described herein.

The intermediate compounds of formula (VI), (VII) and (VIII) may be prepared by a process known in the art.

In one embodiment, the nitro group is reduced to the amine group by catalytic hydrogenation in the presence of a noble metal catalyst. Suitably, the hydrogenation catalyst includes noble metal catalysts such as palladium, platinum, ruthenium or rhodium supported on carbon, Raney-Ni, clay, silica or alumina. In this embodiment, the reduction is suitably carried out at a temperature ranging from about 25° C to about reflux temperature of the solvent used.

The solvent for catalytic reduction is selected from methanol, ethanol, tetrahydrofuran and the like.

In another embodiment, the nitro reduction is carried out using a hydrogen donating compound in the presence of a hydrogen transfer catalyst.

Suitably, the hydrogen donating compound is hydrazine hydrate.

Suitably, the hydrogen transfer catalyst is selected from the group consisting of FeCl3.6H2O-activated carbon, Fe (III) oxide hydroxide, Fe (III) oxide, Zn-C, Fe-C, Pd-C, Pt-C, Raney Ni, graphite and clays. Alternatively, the reduction may be carried out using Zn/HCl, Fe/HCI, SnCl2 and the like.

In yet another embodiment, the nitro compound is reduced with hydrazine hydrate, supported on a solid material such as alumina, silica gel and clay.

In yet another embodiment reduction may be carried out using sodium dithionate, sodium hydrosulphide, ammonium sulphide and the like.

In yet another embodiment reduction may be carried out using catalytic transfer hydrogenation using C–Fe3O4–Pd catalyst or by dissolving metal method reduction
In one embodiment compound of Formula V is isolated.

In another embodiment compound of Formula V is not isolated and can be used in the next step without isolation.

Hereinafter, “without isolation” means the obtained compound in each step can be used directly for the next reaction as the reaction mixture or as a crude product, or can also be isolated according to a conventional method from the reaction mixture, and can also be easily
purified according to a separation means (e.g., recrystallization, distillation, chromatography etc.).

In an embodiment, compound V is coupled with methoxyamine VIII or a salt thereof, to obtain substituted urea of Formula IV.

The reaction is conducted in the presence of 1, 1’-carbonyldiimidazole ( CDI ) or Bis(1-benzotriazolyl)methanethione or a salt thereof.

Preferably, reaction is conducted using 1, 1’-carbonyldiimidazole ( CDI ) in the presence of a suitable base and suitable solvent.

The base can be selected from the group comprising of triethylamine, trimethylamine, diethylamine, diethanolamine, diisopropylethylamine, pyridine, DMAP, dicyclohexylamine, triethanolamine, meglumine, ethylenediamine, picoline. quinoline, BuLi, 1,8-diazabicyclo [ 5.4.0] undec-7-ene and the like. Most preferably, the base is selected from the group comprising of amine bases.

The solvent is selected from acetone, acetonitrile, dioxane, dichloromethane, DMF, DMA, NMP, THF and the like or a mixture of solvents thereof.

The reaction is carried out at a temperature of about -10°C to about 80°C, preferably about 0°C to about 70°C, more preferably about 10°C to about 60°C; preferably, for about 30 minutes to about 20 hours, more preferably about 1 hour to about 15 hours, most preferably about 2 hours to about 12 hours.

Preferably, the reaction mixture is quenched with water, and the product is isolated, for example by extraction and distillation.

In one embodiment compound IV is isolated.

In another embodiment compound of Formula IV is not isolated and can be used in the next step without isolation.

In one embodiment ester compound IV is hydrolyzed under acidic or basic conditions in the presence of a suitable solvent.

The base can be selected from the group comprising of organic bases and inorganic base.

The inorganic base may be selected from the group comprising of alkali or alkaline earth metal carbonates, such as cesium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, barium carbonate, sodium bicarbonate or potassium bicarbonate; alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide or barium hydroxide; alkali or alkaline earth metal alkoxide such as sodium methoxide or sodium ethoxide.

Preferably, the reaction is carried out in the presence of aprotic polar solvents, protic polar solvents, ethers, mixtures of one or more organic solvent, wherein the organic solvent is preferably selected from the group comprising polar aprotic solvent such as N,N- dimethylacetamide (DME), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), sulfolane, diglyme, 1,4-dioxane and the like; C1-C5 alcoholic solvent such as methanol, ethanol, isopropanol, n-butanol, t-butanol and the like, ether solvent such as tetrahydrofuran (THF) and the like; nitrile solvent such as acetonitrile, propionitrile and the like, ketone solvent such as acetone, methyl isobutyl ketone and the like; water and mixtures thereof. Preferably, hydrolysis is carried out in the presence of an alcohol, THF , water acetone, acetonitrile, and the like or mixture thereof.

The reaction is carried out at a temperature of about 0°C to about 80°C, preferably about 5°C to about 70°C, more preferably about 10°C to about 60°C; preferably, for about an hour to about 30 hours, more preferably about 2 hours to about 25 hours, most preferably about 3 hours to about 20 hours.

Preferably, the reaction mixture is quenched with water, acidified with a suitable acid, preferably hydrochloric acid and the product is isolated, for example by extraction and distillation.

Alternatively, the ester may be hydrolyzed by heating under reflux with a dilute acid like dilute hydrochloric acid or dilute sulfuric acid.

In an alternative embodiment compound IV, is hydrolyzed with an enzyme that hydrolyzes an ester to an acid to obtain a reaction mixture and maintaining the reaction mixture to obtain the intermediate. The enzyme can be isolated from a natural source or synthesized with recombinant technology. Preferably, the enzyme is a hydrolase.

As used herein, "hydrolase" refers to an enzyme that catalyzes the hydrolysis of a chemical bond in a stereo selective manner, optionally with the aid of co-factor. Hydrolases are commercially available, for example, from Codexis, Inc. under the catalog numbers NZL-102-LYO, NZL-103-LYO, NZL-107-LYO.

In one embodiment acid compound III is isolated.

In another embodiment acid compound of Formula III is not isolated and can be used in the next step without isolation.

In an embodiment, acid compound of Formula III is coupled with 3-amino-6-methoxypyridazine of Formula VII or a salt thereof, in the presence of a suitable coupling agent.

In an embodiment, a suitable coupling agent for use in a process according to the present invention can be selected from but are not limited to propylphosphonic anhydride,
phenylsilane, carbodiimides such as N, N’-carbonyldiimidazole (CDI), N-N'- dicyclohexylcarbodiimide (DCC), and 1-ethyl-3-(3 '- dimethylaminopropyl)carbodiimide (EDCI). The carbodiimides may be used in conjunction with additives such as dimethylaminopyridine (DMAP) or 1-hydroxybenzotriazole (HOBt). Amide coupling reagents also include amininum and phosphonium based reagents, such as N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b] pyridine-1-ylmethylene ]-N- methyl methanaminium hexafluorophosphate N -oxide (HATU), N-[(1H-benzotriazol-1-yl)(dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate N-oxide (HBTU), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), and benzotriazol-1-yl-N-oxy-tris(pyrrolidino ) phosphonium hexafluorophosphate (PyBOP).

A particularly suitable coupling reagent for use in the above process according to the present invention is selected from propylphosphonic anhydride. Propylphosphonic anhydride (T3P) is a highly reactive n-propyl phosphonic acid cyclic anhydride, generally used as a coupling agent and water scavenger with low toxicity. It offers several advantages over traditional reagents, such as easy work up due to water-soluble by-products, and above all it gives high yields and purity.

Generally, coupling using T3P is conducted in the presence of a suitable base.

In an embodiment, base is selected from but are not limited to the group comprising of one or more of amine bases, such triethylamine, trimethylamine, diethylamine, diethanolamine, diisopropylethylamine, DMAP, dicyclohexylamine, triethanolamine, meglumine, ethylenediamine, pyridine picoline. quinoline, 1,8-diazabicyclo [ 5.4.0] undec-7-ene (DBU) and the like. Most preferably, the base is selected from the group comprising of TEA, DBU, DIEA and pyridine.

Preferably, the reaction is carried out in the presence of an aromatic hydrocarbons, aprotic polar solvents, aliphatic ethers, mixtures of one or more organic solvent, wherein the organic solvent is preferably selected from the group consisting of C6-C10 substituted aromatic hydrocarbons, and C1-C5 halogenated hydrocarbons. Preferably, organic solvent is selected from but not limited to an aromatic hydrocarbons such as toluene, xylene and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; polar aprotic solvent such as N,N- dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), sulfolane, diglyme, 1,4-dioxane and the like; ether solvent such as methyl /-butyl ether, diisoproyl ether, tetrahydrofuran (THF) and the like; ester solvent such as methyl acetate, ethyl acetate, isopropyl acetate and the like; nitrile solvent such as acetonitrile, propionitrile and the like, halogenated solvent such as dichloromethane, dichloroethane, chloroform and the like; ketone solvent such as acetone, methyl isobutyl ketone and the like and mixtures thereof.

Optionally, halogenated solvent is used in combination with polar solvent to increase overall solvent power.

Preferably, the reaction is carried out under inert atmosphere, such as under nitrogen or argon, preferably nitrogen.

The reaction may be carried out at a temperature ranging from -10°C to about boiling point of the solvent used. Preferably, the reaction is carried out at a temperature of about 0°C to about 100°C, preferably about 20°C to about 80°C, more preferably about 25°C to about 60°C; preferably, for about an hour to about 25 hours, more preferably about 2 hours to about 20 hours, most preferably about 3 hours to about 10 hours.

The amide of formula (II) is easily isolated from the reaction mixture by quenching reaction mass in ice cooled water and extracting the base in organic solvent like dichloromethane, toluene or ethyl acetate.

In an embodiment, amide of formula (II) is subjected to cyclization in the presence of a suitable base.

In an embodiment, base is selected from but are not limited to the group comprising of one or more of an inorganic or organic base. The inorganic base may be selected from the group consisting of alkali or alkaline earth metal carbonates, such as cesium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, lithium carbonate or barium carbonate; alkali or alkaline earth metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide or barium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide; alkyllithiums such as BuLi; alkali metal amides such as sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide. Organic bases may be aliphatic or aromatic and may be selected from, but not limited to triethyl amine, di-isopropyl amine, pyridine, picoline, diethyl amine, piperidine, N,N-diisopropylethylamine. Most preferably, the base is N,N-diisopropylethylamine and the like.

Preferably, the reaction is carried out in the presence of an aprotic polar solvents, protic polar solvents, aliphatic ethers, esters, nitriles, ketone, aromatic hydrocarbons, aliphatic hydrocarbon, water and mixtures of one or more organic solvent.

Preferably, organic solvent is selected from but not limited to an aromatic hydrocarbons such as toluene, xylene and the like; aliphatic hydrocarbon solvent such as hexane, heptane and the like; polar aprotic solvent such as N,N- dimethylacetamide (DME), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), tetrahydrofuran (THF), sulfolane, diglyme, 1,4-dioxane and the like; C1-C5 alcoholic solvent such as methanol, ethanol, isopropanol, n-butanol, t-butanol and the like, ether solvent such as methyl /-butyl ether, diisoproyl ether, tetrahydrofuran (THF) and the like; ester solvent such as methyl acetate, ethyl acetate, isopropyl acetate and the like; nitrile solvent such as acetonitrile, propionitrile and the like, halogenated solvent such as dichloromethane, dichloroethane, chloroform and the like; ketone solvent such as acetone, methyl isobutyl ketone and the like; water and mixtures thereof. Preferably, cyclization is carried out in the presence of an alcohol, ethers , nitriles, water or a mixture thereof.

The reaction may be carried out at a temperature ranging from -10°C to about boiling point of the solvent used. Preferably, the reaction is carried out at a temperature of about 0°C to about 100°C, preferably about 10°C to about 80°C, more preferably about 20°C to about 60°C; preferably, for about an hour to about 30 hours, more preferably about 2 hours to about 25 hours, most preferably about 3 hours to about 20 hours.

The Relugolix of Formula (I) is easily isolated from the reaction mixture by quenching reaction mass in ice cooled water, treating with an acid and extracting the base in organic solvent like dichloromethane, toluene or ethyl acetate.

The Relugolix of Formula (I) may be further purified by known techniques such as recrystallization, distillation and chromatography, and the like

The process of the present invention may further comprise: converting Relugolix base of Formula (I) to a pharmaceutically acceptable salt thereof. The acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, pivalic acid and organic salts such as formic acid, fumaric acid, trifluoroacetic acid, tartaric acid, acetic acid, oxalic acid, malonic acid, mandelic acid, succinic acid, maleic acid, malic acid, lactic acid, citric acid, methane sulfonic acid, benzenesulfonic acid, p-hydroxy benzoic acid, glutamic acid, p-toluene sulfonic acid and the like.

Relugolix base of Formula (I) may be formed into a physiologically acceptable salt with an inorganic base (e.g., alkali metals and alkaline earth metals such as sodium, potassium, calcium, magnesium, etc.; ammonia, and the like) or an organic base (e.g., trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, and the like).

In a preferred embodiment, when R1 is ethyl and R2 is ethyl, the compound obtained by the process of the invention includes compound of formula (IIA), compound of formula (IIIA) and compound of formula (VA).

and

Accordingly, a process for preparing Relugolix of Formula (I) according to the present invention is exemplified in Scheme 2.

Scheme 2

The present invention will be described in more details in the following by way of examples, which are illustrative of further embodiments and shall not construe a limitation of the invention.
Examples:

Example 1:
Ethyl 5-(4-aminophenyl)-2-((2,6-difluorobenzyl) (ethoxycarbonyl)amino)-4-((dimethylamino)methyl) thiophene-3-carboxylate (VA)

Ethyl 2-((2,6-difluorobenzyl) (ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl) thiophene-3-carboxylate (VIA) (50.0 g, 91.40 mmol) was added to methanol (400 ml) and conc. Hydrochloric acid (6.75 g, 65.62 mmol, 0.8 eq). 10% Pd on carbon (5.0 g, containing 50% water) was added there to under nitrogen atmosphere, and the mixture was stirred at ambient temperature for 4 hr under hydrogen pressure of 2 kg/cm2. The pH pf the mixture was adjusted to 6 to 7 with triethylamine at room temperature. Activated carbon (4.0 g) was added there to, and the mixture was stirred for 20-60 min. The activated carbon and catalyst were filtered off and washed with methanol (100 ml). The filtrate was warmed to 40 ± 50C for about 30min, cooled to 5 ± 50C, and aged with stirring for about 2 hr. The crystals were collected by filtration, washed with methanol (100 ml), and dried at 45 - 500C, under reduced pressure until the weight became constant to give an almost white crystal of Ethyl 5-(4-aminophenyl)-2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl) thiophene-3-carboxylate.

Example 2:
Ethyl 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylate (IVA)

Acetonitrile (30ml) and 1,1-carbonyldiimidazole (CDI, 5.01 g, 30.90 mmol, 1.7 eq) were charged into a reactor, and the mixture was stirred. Triethylamine (1.5 g, 15.42 mmol, 0.85 eq) was added there to with stirring, and cooled to internal temperature to 10 ± 50C. Methoxy amine hydrochloride (VIII) (2.90 g, 34,72 mmol, 1.91 eq) was added there to with stirring in small portions at internal temperature of 300C. The mixture was stirred at internal temperature of 25 ± 50C, and after confirming the dissolution of the mixture, the solution was stirred for additional 10 min or more. Then Ethyl 5-(4-aminophenyl)-2-((2,6-difluorobenzyl) (ethoxycarbonyl)amino)-4-((dimethylamino)methyl) thiophene-3-carboxylate (VA) (10.00 g 19.34 mmol) was added there to with stirring. The reaction mixture was warmed to internal temperature of 50 ± 50C and stirred at the same temperature for 2 hr. Triethylamine (2.35 g, 23.22 mmol, 1.28 eq) was added there to with stirring at internal temperature of 50 ± 50C. Water (40 ml) was added dropwise there to at internal temperature of 40-500C. The mixture was aged with stirring at internal temperature 25 ± 50C for 1 hr. The crystals were collected by filtration and washed with a mixed solvent of water (16 ml) and acetonitrile (4 ml) to give crystals of Ethyl 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylate.

Example 3:
2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylic acid (IIIA)

Ethyl 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylate (IVA) (8.0 g, 13.56 mmol) was suspended in a mixed solvent of methanol (70 ml) and water (20 ml), 48% aqueous potassium hydroxide solution (2.56 g, 21.92 mmol, 1.5 eq) was added there to, and the mixture was stirred at 60 ± 50C for 5 hr. The reaction mixture was cooled to 25 ± 50C and the pH o the mixture was adjusted to 6.0-7.0 with 6N hydrochloric acid. The mixture was concentrated to about 30 ml below 500C under reduced pressure, and methanol (4 ml) and ethyl acetate (4 ml) were added there to internal temperature 40 ± 50C. Then water (50 ml) was added there to at the same temperature for 1 hr. The mixture was cooled to internal temperature of 25 ± 50C and stirred at the same temperature for 3 hr. The crystals were collected by filtration, washed successively with methanol/ water (1:9, 25 ml) and cooled ethyl acetate (25 ml), and dried at 45 ± 50C to obtain 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylic acid.

Example 4:
Ethyl (2,6-difluorobenzyl)(4-((dimethylamino)methyl)-3-((6-methoxypyridazin-3-yl)carbamoyl)-5-(4-(3-methoxyureido)phenyl)thiophen-2-yl)carbamate (IIA)

Under a nitrogen atmosphere, 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylic acid (IIIA)
(7.0 g,12.45 mmol) and 3-amino-6-methoxypyridazine hydrochloride (VII) (2.43 g, 15.01 mmol, 1.2 eq) were added to N,N-dimethylacetamide (DMAc, 30 ml). The mixture was warmed to internal temperature of 55 ± 50C and stirred for 30 min. 50% Propyl phosphonic anhydride (T3P) in ethyl acetate solution (9.55 g, 15.01 mmol, 1.2 eq) was added dropwise there to at internal temperature of 600C. The mixture was stirred at internal temperature of 55 ± 50C, and water (50 ml) was added dropwise there to at the same temperature. Then, 8N aqueous sodium hydroxide solution was added there to at 25 ± 50C. While vigorously stirring, and the pH of the mixture was adjusted to 7.5-8.5, and the mixture was stirred at 25 ± 50C for 30 min. The crystals were collected by filtration, washed with methanol (25 ml), and dried at 40 ± 50C, under reduced pressure until the weight became constant to obtain Ethyl (2,6-difluorobenzyl)(4-((dimethylamino)methyl)-3-((6-methoxypyridazin-3-yl)carbamoyl)-5-(4-(3-methoxyureido)phenyl)thiophen-2-yl)carbamate.

Example 5:
1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea (I)

Ethyl(2,6-difluorobenzyl)(4-((dimethylamino)methyl)-3-((6-methoxypyridazin-3-yl) carbamoyl)-5-(4-(3-methoxyureido)phenyl)thiophen-2-yl)carbamate (IIA) (8.0 g, 11.96 mmol), methanol (190 ml), tetrahydrofuran (13 ml) and 28% sodium methoxide methanol solution (0.5 g, 2.40 mmol, 0.2 eq) were stirred at 50 ± 50C for 1 hr. The mixture was cooled to 25 ± 50C, conc. hydrochloric acid (3 g, 30 mmol, 2.4 eq) was added dropwise there to and the mixture was stirred for 20 min. Isopropyl alcohol (75 ml) was added there to and the mixture was stirred at 25 ± 50C for 30 min, and then at 5 ± 50C for 60 min. The crystals were collected by filtration, washed with cooled methanol/isopropyl alcohol (1:1, 20 ml), and dried at internal temperature of 600C to obtain 1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea i.e. Relugolix which was further purified by crystallization.

,CLAIMS:
1. A process for preparing Relugolix of Formula I,

Formula I
or salts thereof which comprises:
converting compound of Formula II

wherein R2 is C1-C5 alkyl, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and t- butyl; to Relugolix of Formula I or salts thereof.

2. The process according to claim 1, wherein conversion comprises, cyclizing compound of Formula II in the presence of a suitable base and suitable solvent.

3. The process according to claim 2, wherein a base is selected from the group comprising of one or more of an inorganic or organic base.

4. The process according to claim 2, wherein solvent is selected from aprotic polar solvents, protic polar solvents, aliphatic ethers, esters, nitriles, ketone, aromatic hydrocarbons, aliphatic hydrocarbon, water and mixtures of one or more organic solvent.

5. The process of claim 1, wherein the compound of Formula (II) is a compound of Formula (IIA).

6. The process according to any preceding claims wherein, compound of Formula (II), is prepared by the process which comprises:
coupling compound of Formula (III)

wherein R2 is C1-C5 alkyl, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and t- butyl,
with a compound of Formula (VII) or salt thereof,

in the presence of a suitable amide coupling reagent.

7. The process according to claim 6, wherein a suitable coupling agent is selected from propylphosphonic anhydride, phenylsilane, carbodiimides such as N, N’-carbonyldiimidazole (CDI), N-N'- dicyclohexylcarbodiimide (DCC), and 1-ethyl-3-(3'- dimethylaminopropyl)carbodiimide (EDCI), dimethylaminopyridine (DMAP), 1-hydroxybenzotriazole (HOBt) and amide coupling reagents such as amininum and phosphonium based reagents.
8. The process of claim 6, wherein the compound of Formula (III) is a compound of Formula (IIIA).

9. The process according to claims 6 to 8, wherein compound of Formula (III), is prepared by the process which comprises:
hydrolysis of compound of Formula (IV)

wherein R1 is C1-C5 alkyl and R2 is C1-C5 alkyl, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and t- butyl.

10. The process according to claim 9, wherein hydrolysis is carried out under acidic or basic conditions in the presence of a suitable solvent, wherein base is selected from organic bases or inorganic base and acid is selected from dilute hydrochloric acid or dilute sulfuric acid.

11. The process of claim 9, wherein the compound of Formula (IV) is a compound of Formula (IVA).

12. The process according to claims 9 to 11, wherein compound of Formula (IV), is prepared by the process which comprises:
reacting compound of Formula (V),

wherein R1 is C1-C5 alkyl and R2 is C1-C5 alkyl, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl and t- butyl, with methoxyamine of Formula (VIII),or a salt thereof.

13. The process according to claim 12, wherein the reaction is conducted in the presence of 1, 1’-carbonyldiimidazole ( CDI ) or Bis(1-benzotriazolyl)methanethione or a salt thereof.

14. The process of claim 12, wherein the compound of Formula (V) is a compound of Formula (VA).

15. The process according to claims 12 to 14, wherein compound of Formula (V), is prepared by the process which comprises:
reducing compound of Formula (VI),

in the presence of a suitable reducing agent.

16. The process according to claim 15, wherein the reduction is carried by catalytic hydrogenation in the presence of a noble metal catalyst.
17. A process according to any one of claims 1 to 16, wherein the Relugolix (I) is converted to a pharmaceutically acceptable salt thereof.

18. Relugolix (I) or pharmaceutically acceptable salts thereof having a purity of more than about 99.5% by HPLC.

19. Novel intermediate compound of Formula (II).

20. Novel intermediate compound of Formula (IIA).

21. Novel intermediate compound of Formula (III).

22. Novel intermediate compound of Formula (IIIA).

23. Novel intermediate compound of Formula (IV).

24. Novel intermediate compound of Formula (IVA).

25. A pharmaceutical composition comprising Relugolix or its pharmaceutically acceptable salts thereof according to claim 17, together with one or more pharmaceutically acceptable excipients.

26.Use of Relugolix or its pharmaceutically acceptable salts thereof according to claim 17, in the treatment of diseases caused by gonadotropin releasing hormone (e.g., endometriosis, uterine fibroid and prostate cancer).