DESC:FIELD OF THE INVENTION:
The present invention relates an improved process for the preparation relugolix of formula I, pharmaceutically acceptable salts thereof. Over and above that, the present invention relates to providing an economical and technically facile process for the preparation of relugolix, pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION:
Relugolix (RGX; RVT-601; TAK-385) is sold under the brand names Orgovyx® and Relumina® among others, is a gonadotropin-releasing hormone antagonist (GnRH receptor antagonist) medication which is used in the treatment of prostate cancer in men and uterine fibroids in women. It is also under development for use in the treatment of endometriosis.
Relugolix is chemically known as 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d] pyrimidin-6-yl]phenyl]-3-methoxyurea and is structurally represented as below:

Relugolix and the process for its preparation was first disclosed in WO2004067535.
WO2014051164 disclosed a process for the preparation of Relugolix and the process is schematically represented as below:

SCHEME 1
The drawback associated with the above process is the formation of dimer impurity, which is very difficult to control during the process and the further purification steps result in loss of yield. Further, the above process is industrially not viable.

Journal of Medicinal Chemistry, 2011, 54, 4998–5012 discloses an alternative process for preparation of Relugolix, as depicted below:

SCHEME 2
The draw back associated with the above process is the addition of methoxyamine HCl before cyclization. The later cyclization step leads to the formation of uncyclized impurities, which are very difficult to control at plant level batches.

Thus, there is an unmet need of an improved, industrially advantageous, cost effective as well as environment-friendly process for the preparation of relugolix, pharmaceutically acceptable salts thereof with enhanced yield and purity.

The inventors of the present invention have developed an improved process but yet simple, efficient and industrially advantageous for the preparation of relugolix, pharmaceutically acceptable salts thereof with high yield and high purity.

The process of the present invention fulfills the above need and overcomes the prior-art disadvantages.

OBJECTIVE OF THE INVENTION:
The principal objective of present invention is to provide an improved process for the preparation of relugolix of formula I, pharmaceutically acceptable salts thereof.

Another objective of the present invention is to provide relugolix of formula I having purity more than 99.6%

Another objective of the present invention is to provide relugolix of formula I resulted in yield more than 70%.

Another objective of the present invention is to provide simple and economically advantageous process of relugolix of formula I.

Yet another objective of the present invention is to provide relugolix of formula I from formula II using carbonating agent.

SUMMARY OF THE INVENTION:
In an embodiment, the present invention provides a process for the preparation of relugolix of formula I, pharmaceutically acceptable salts thereof,
,
which comprises:
(a) reacting the compound of formula II with methoxyamine or its HCl salt in the presence of a carbonating agent to obtain relugolix of formula I;
,
(b) Optionally converting relugolix of formula I into its pharmaceutically acceptable salt.

In another embodiment, the carbonating agent used for the preparation of relugolix of formula I, comprises:
,
wherein,
R1 comprises –NO2, -NH2, -OCH3, -OC2H5, -Cl, -Br, -F;
X is selected from -NH-, -O-, -S-;
R2 is –OCH3, -OC2H5, nitrophenyl, methoxy phenyl, ethoxy phenyl, chloro phenyl, bromo phenyl, fluoro phenyl.

In another embodiment, the present invention provides a process for the preparation of relugolix of formula I, pharmaceutically acceptable salts thereof,
,
which comprises:
a) hydrolyzing a compound of formula VI in the presence of a metal alkoxide and suitable solvent or mixtures thereof to obtain a compound of formula V;
,
b) coupling the compound of formula V with 6-methoxypyridazin-3-amine hydrochloride in presence of a suitable organic base and propylphosphonic anhydride and suitable solvent or mixtures thereof to obtain a compound of formula IV;
,
c) cyclizing the compound of formula IV using in the presence of a metal alkoxide and a suitable solvent or mixture thereof to obtain a compound of formula III or pharmaceutically acceptable salts thereof;
,
d) reducing the compound of formula III or pharmaceutically acceptable salts thereof in the presence of a reducing agent and a solvent or mixtures thereof to obtain a compound of formula II;
,
e) reacting the compound of formula II with methoxyamine or its HCl salt in the presence of a carbonating agent to obtain relugolix of formula I;
f) optionally converting relugolix of formula I into its pharmaceutically acceptable salt.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention will now be disclosed by describing certain preferred and optional embodiments.

Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include Di-p-toluoyl-D-tartaric acid [DPTTA], p-toluene sulfonic acid [PTSA], adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and quaternary ammonium salts. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counter ions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

A process for the preparation of relugolix of formula I, pharmaceutically acceptable salts thereof, which comprises:
(a) reacting the compound of formula II with methoxyamine or its HCl salt in the presence of a carbonating agent to obtain relugolix of formula I;
(b) optionally converting relugolix of formula I into its pharmaceutically acceptable salt.

The process for preparation of relugolix of formula I, pharmaceutically acceptable salts thereof, which comprises:
(a) hydrolyzing a compound of formula VI in the presence of a metal alkoxide and suitable solvent or mixtures thereof to obtain a compound of formula V;
(b) coupling the compound of formula V with 6-methoxypyridazin-3-amine hydrochloride in presence of a suitable organic base and propylphosphonic anhydride and suitable solvent or mixtures thereof to obtain a compound of formula IV;
(c) cyclizing the compound of formula IV using in the presence of a metal alkoxide and a suitable solvent or mixture thereof to obtain a compound of formula III or pharmaceutically acceptable salts thereof;
(d) reducing the compound of formula III or pharmaceutically acceptable salts thereof in the presence of a reducing agent and a solvent or mixtures thereof to obtain a compound of formula II;
(e) reacting the compound of formula II with methoxyamine or its HCl salt in the presence of a carbonating agent to obtain relugolix of formula I;
(f) optionally converting relugolix of formula I into its pharmaceutically acceptable salt.

Solvent used in the above reaction system include but is not limited to alcohols, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers, ketones and mixtures thereof. The alcohols include, but are not limited to C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol and the like; halogenated hydrocarbons include, but are not limited to methylene chloride, ethylene chloride, chloroform and the like; hydrocarbons include, but are not limited to hexane, cyclohexane, toluene, xylene and the like; amides, include, but are not limited to dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulfoxides include, but are not limited to dimethyl sulfoxide and the like; nitriles include, but are not limited acetonitrile, propionitrile and the like; esters include, but are not limited to ethyl acetate and butyl acetate and the like; ester include, but are not limited to ethyl acetate and butyl acetate and the like; ethers include, but are not limited to diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran and the like; ketones include, but are not limited to acetone, methyl ethyl ketone, methyl isopropyl ketone and the like and mixtures there.

Hydrolyzing agent used in step (a) comprises, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, the like and mixtures thereof.

Coupling agent used in step (b) comprises metal halides but are not limited to sodium iodide, sodium bromide, sodium chloride, potassium iodide, potassium bromide, potassium chloride, lithium iodide, lithium bromide, lithium chloride, magnesium iodide, magnesium bromide, magnesium chloride, calcium iodide, calcium bromide, calcium chloride, copper iodide, copper bromide, copper chloride or mixture thereof; Dicyclohexylcarbodiimide/1-Hydroxybenzotriazole (DCC/HoBt), Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium/N,N-diisopropylethylamine (HATU/DIPEA), Propylphosphonic anhydride/triethyl amine (T3P/TEA), 3-Dimethylamino-propyl)-ethyl-carbodiimide Hydrochloride (EDC.HCl) and the like.

Cyclizing agent used in step (c) comprises, metal alkoxide such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium butoxide, sodium butoxide, sodium tert-butoxide, potassium tert-butoxide or mixtures thereof and acids such as organic acid, inorganic acid but are not limited to acetic acid, formic acid, citric acid, oxalic acid, malic acid, tartaric acid, hydrochloric acid, nitric acid, sulfuric acid, the like and mixtures there.

The suitable reducing agent used in step (d) comprises but is not limited to Palladium on carbon, Iron in HCl, Iron/NH4Cl, SnCl2, Sodium hydrosulfite, Titanium (III) chloride, Zinc/NH4Cl, Zn/hydrazine hydrate, Iron/hydrazine hydrate, raney nickel, sodium borohydride, lithium aluminium hydride and the like.

The suitable base used in the above reaction system comprises, inorganic base selected from but is not restricted to alkaline or alkaline earth metal hydride, alkaline or alkaline earth metal hydroxide, alkaline or alkaline earth metal carbonate, sodium hydride, lithium hydride, potassium hydride, aluminum hydride, zinc hydride, titanium hydride, nickel hydride, sodium aluminum hydride or mixture thereof, and organic base selected from but not restricted to lithium methoxide, sodium hydroxide, sodium methoxide, potassium methoxide, tetrabutyl ammonium methoxide, lithium isopropoxide, triethyl amine. methyl amine, diisopropyl methyl amine, diisopropyl ethyl amine, methyl amine, dimethyl amine or mixtures thereof.

The carbonating agent used for the preparation of relugolix of formula I, comprises:
,
wherein,
R1 comprises –NO2, -NH2, -OCH3, -OC2H5, -Cl, -Br, -F;
X is selected from -NH-, -O-, -S-;
R2 is –OCH3, -OC2H5, nitrophenyl, methoxy phenyl, ethoxy phenyl, chloro phenyl, bromo phenyl, fluoro phenyl.

The invention described herein comprises in various objects and their description as mentioned above, with respect to characteristics and processes adopted. While these aspects are emphasized in the invention, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as described.

EXAMPLES
Example 1: Preparation of Relugolix of formula (I)
Dichloromethane (1200 ml) and bis(4-Nitrophenyl) carbonate (276.2 g) were charged in RBF at 25-35 °C. To this, N,N-diisopropylethyl amine (130.16 g) was added followed by methoxy amine hydrochloride (83.42 g) lot wise and maintained for 45-60min. 6-(4-Aminophenyl)-1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-1H,2H,3H,4H-thieno[2,3-d]pyrimidine-2,4-dione (100 g) was added into the reaction mass and maintained for 8-10 hours. Purified water (800 ml) was added and stirred reaction mass, separate the layers followed by washing the organic layer with purified water (800 ml X 2). The residue was dissolved in acetone (704 ml) at 50-55 °C. methanesulphonic acid (14.24 g) was added to the above solution followed by the addition of acetone (176 ml) within 10-20 minutes at an ambient temperature, maintained for 45-60 minutes at 50-55 °C. The reaction mass was cooled to 20-30 °C followed by filtration, suck dry under nitrogen atmosphere. The obtained wet cake was dissolved in methanol (440 ml) followed by the addition of solution of sodium carbonate (14.24 gm) in purified water (440 ml) at 25-35 °C for 1 hour and then filtered. The above obtained solid was added into mixture in methanol (150 ml) and Dichloromethane (150 ml), followed by filtration and distillation under vacuum below 50 °C and the residue was charged with acetonitrile (300 ml) and heated to 60-65°C, cooled to room temperature, stirred for one hour followed by filtration to get Relugolix of formula (I) with purity 99.7%, Yield: 72%

Example 2: Preparation of Relugolix of formula (I)
Dichloromethane (1200 ml) and bis(4-Nitrophenyl) carbonate (276.2 g) were charged in RBF at 25-35 °C. N,N-diisopropylethyl amine (130.16 g) was added followed by methoxyamine hydrochloride (83.42 g) lot wise and maintained for 45-60min. 6-(4-Aminophenyl)-1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino) methyl]-3-(6-methoxypyridazin-3-yl)-1H,2H,3H,4H-thieno[2,3-d] pyrimidine-2,4-dione (100 g) was added into the reaction mass and maintained for 8-10 hour. After completion of reaction, purified water (800ml) was added in to the reaction mass and the layers were separated. Again the organic layer was washed with purified water (800ml X 2) followed by distilling the solvent from organic layer. The residue was dissolved in acetone (680 ml) at 50-55 °C followed by addition of methanesulphonic acid (13.8 g) solution in acetone (170 ml) within 10-20 minutes, at ambient temperature. The reaction mass was maintained for 45-60 min at 50-55°C, followed by cooling to 20-30°C and then filtered under nitrogen atmosphere. The wet cake was dissolved in methanol (425ml) followed by the addition of solution of sodium carbonate (13.8g) in purified water (425ml) at 25-35 °C, maintained for 1 hour. The reaction mass was filtered and dried. The above obtained solid was dissolved into mixture in methanol (152ml) and dichloromethane (152ml), followed by distillation under vacuum below 50 °C and to the residue was charged ethyl acetate (228ml) and heated to 60-65°C, cooled to room temperature, stirred for one hour followed by filtration to get Relugolix of formula (I) with purity 99.6%, yield: 71%

Example 3: Preparation of Relugolix of formula (I)
Acetonitrile (500 ml) and bis(4-Nitrophenyl) carbonate (276.2 g) were charged in glass assembly at 25-35 °C. N,N-diisopropylethyl amine (130.16 g) was added followed by methoxy amine hydrochloride (83.42 g) lot wise and maintained for 45-60 minutes. 6-(4-Aminophenyl)-1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino) methyl]-3-(6-methoxypyridazin-3-yl)-1H,2H,3H,4H-thieno[2,3-d] pyrimidine-2,4-dione (100 g) was added into the reaction mass and maintained for 8-10 hours. After completion of reaction, the solvent was distilled out completely below 50 °C. Purified water (800 ml) and dichloromethane (1000 ml) were added in to the reaction mass and then the layers were separated out. The separated organic layer was washed with purified water (800 ml x 2) followed by distillation of solvent from organic layer completely and degassed it. Thus obtained residue was dissolved in acetone (688 ml) at 50-55 °C. To this solution, a solution of methanesulphonic acid (13.9 g) in acetone (172 ml) was added within 10-20 minutes at an ambient temperature. After maintaining for 45-60 min at 50-55 °C, the reaction mass was cooled to 20-30 °C, followed by filtration, suck dried under nitrogen atmosphere. The obtained wet cake was dissolved in methanol (430 ml), followed by the addition of a solution of sodium carbonate (13.9 g) in purified water (430 ml) at 25-35 °C, maintained for 1 hour followed by filtration and dried. The above obtained solid was dissolved in methanol (156 ml) and dichloromethane (156 ml) mixture, followed by distillation completely under vacuum below 50 °C and residue was charged with acetonitrile (292 ml) and heated to 60-65°C, cooled to room temperature, stirred for one hour followed by filtration to get Relugolix of formula (I) with purity 99.75%.

Example 4: Preparation of Relugolix of formula (I)
Dichloromethane (500 ml) and bis(4-Nitrophenyl) carbonate (72.0 g) were charged in glass assembly at 25-35 °C. N,N-diisopropylethyl amine (47.0 g) was added followed by methoxyamine hydrochloride (20.0 g) lot wise at 0-5°C, and maintained it for 45-60 minutes. 6-(4-Aminophenyl)-1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-1H,2H,3H,4H-thieno[2,3-d]pyrimidine-2,4-dione (100 g) was added into the reaction mass at 0-5°C and maintained it for 2 hours at 25-30°C. After completion of reaction, Dichloromethane (500 ml) and Purified water (300 ml) was added in to the reaction mass then separate the layers followed by washing the organic layer with purified water (300 ml) and distilled out solvent completely under reduced pressure. Dichloromethane (400 ml) was added in to the reaction mass, cooled to 0-5°C and maintained it for two hours at an ambient temperature followed by filtration and drying to get Relugolix crude. The crude product was dissolved in acetone (910 ml) at 50-55 °C followed by addition of a solution of methanesulphonic acid (14.72 g) in acetone (364 ml) within 30-45 minutes and maintained it for 60 minutes at an ambient temperature. Then reaction mass was cooled to 20-30 °C and then to 15-20 °C, maintained it for 2 hours at an ambient temperature. Filter reaction mass under nitrogen atmosphere to get methanesulphonic acid salt of Relugolix. The obtained wet cake was dissolved in methanol (455 ml) and added to a solution of sodium carbonate (14.72 g) in purified water (455 ml) at 25-35 °C and maintained it for 2 hours and then filtered and dried. Thus obtained solid was dissolved into the mixture of methanol (150 ml) and Dichloromethane (150 ml) and filtered. Distilled out completely under vacuum below 50 °C and the residue was charged with a mixture of acetonitrile (75 ml) and ethyl acetate (75 ml) and distilled out solvent completely below 50°C then charged a mixture of acetonitrile (150 ml) and ethyl acetate (150 ml) and heated to 60-65°C and maintained it. Cooled reaction mixture to 25-30 °C and maintained it for 1 hour followed by filtration and drying to get Relugolix of formula (I) with purity >99.7%, yield: 70.3%.

Example 5: Preparation of 2-((2,6-difluorophenyl)methyl](ethoxycarbonyl) amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl)thiophene-3-carboxylic acid
To a solution of 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino) methyl)-5-(4-nitrophenyl)thiophene-3-carboxylic acid ethyl ester (100 g) in Industrial solvent (900 ml), purified water (260 ml) and aqueous solution of Potassium hydroxide (15.4 g in 60 ml) were added successively at room temperature. Raised the temperature of reaction mixture to 60-65°C and maintained it for 8 hrs. After completion of reaction, cooled reaction mass to room temperature and adjusted pH to 6.0 – 7.0 using dilute hydrochloric acid solution followed by distillation of solvent completely under vacuum. Industrial solvent (50 ml), ethyl acetate (50 ml) and purified water (600 ml) was then added to the residue at below 50 °C and cooled the reaction mass to room temperature. The resultant solid was filtered and dried to give 2-((2,6-difluorophenyl)methyl](ethoxycarbonyl) amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl )thiophene-3-carboxylic acid (84.4 g, Yield: 88.9%).

Example 6: Preparation of Ethyl-N-[(2,6-difluorophenyl)methyl]-N-[4-(dimethylamino)methyl]-3-[(6-methoxypyridazine-3-yl)carbamoyl]-5-(4-nitrophenyl)thiophene-2-yl]carbamate
N,N-diisopropylethylamine was added to the solution of 2-((2,6-difluorophenyl)methyl](ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl )thiophene-3-carboxylic acid (100 g) and 6-Methoxypyridazin-3-amine hydrochloride (37 g) in N,N-dimethyl acetamide (460 ml) at room temperature followed by addition of Propylphosphonic anhydride (50% solution in ethyl acetate, 147 g) at 60-65°C. After completion of reaction, reaction mixture was cooled to room temperature. Purified water was then added to the reaction mixture and pH of reaction mixture was adjusted to 8.0 – 9.0 using dilute sodium hydroxide solution. The resultant solid was then filtered and dried to obtain Ethyl-N-[(2,6-difluorophenyl)methyl]-N-[4-(dimethylamino)methyl]-3-[(6-methoxypyridazine-3-yl)carbamoyl]-5-(4-nitrophenyl)thiophene-2-yl]carbamate (114 g, Yield: 95%).

Example 7: Preparation of 1-[(2,6-Difluorophenyl)methyl]-5-[(dimethylamino) methyl]-3-(6-methoxypyridazine-3-yl)-6-(4-nitrophenyl)-1H,2H,3H,4H-thieno[2,3-d]pyrimidine-2,4-dione Hydrochloride
To a slurry of Ethyl-N-[(2,6-difluorophenyl)methyl]-N-[4-(dimethylamino)methyl]-3-[(6-methoxypyridazine-3-yl)carbamoyl]-5-(4-nitrophenyl)thiophene-2-yl]carbamate (100 g) in tetrahydrofuran (170 ml) and methanol (2500 ml), sodium methoxide (6 g) was added at room temperature. Reaction mixture was then heated to 60-65°C and maintained it for 60 min. at an ambient temperature. After completion of reaction, cooled reaction mass to room temperature and concentrated hydrochloric acid (25 ml) and Isopropyl alcohol (1000 ml) was added successively added to the reaction mass. Further cooled reaction mass to 0-10 °C and filtered the product and dried to give 1-[(2,6-Difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazine-3-yl)-6-(4-nitrophenyl)-1H,2H,3H,4H-thieno[2,3-d]pyrimidine-2,4-dione Hydrochloride (94 g, Yield: 95.5%).

Example 8: Preparation of 6-(4-Aminophenyl)-1-[(2,6-difluorophenyl) methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-1H,2H,3H,4H-thieno[2,3-d]pyrimidine-2,4-dione
1-[(2,6-Difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazine-3-yl)-6-(4-nitrophenyl)-1H,2H,3H,4H-thieno[2,3-d]pyrimidine-2,4-dione. Hydrochloride (100g), was hydrogenated over 10% Pd/C (50% wet, 5 g) in presence of concentrated hydrochloric acid (13.7 ml) and methanol (800 ml) in an autoclave reactor under 4-6 bar hydrogen gas pressure at room temperature. After completion of reaction, filtered reaction mixture through hyflow bed and triethylamine (85 ml) was added to the filtrate ML at 40-45 °C to adjust pH 8.0-9.0 followed by cooling reaction mass 0-10 °C. After maintaining the reaction mass for 2 hrs. at an ambient temperature, filtered product and dried to give 6-(4-Aminophenyl)-1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-1H,2H,3H,4H-thieno[2,3-d]pyrimidine-2,4-dione (80g, Yield: 89.6%).

,CLAIMS:We claim:
1. A process for the preparation of relugolix of formula I, pharmaceutically acceptable salts thereof,
,
comprising:
(a) reacting the compound of formula II with methoxyamine or its HCl salt in the presence of a carbonating agent to obtain relugolix of formula I;
,
(b) Optionally converting relugolix of formula I into its pharmaceutically acceptable salt.

2. The process according to claim 1, wherein the carbonating agent comprises

R1 is selected from –NO2, -NH2, -OCH3, -OC2H5, -Cl, -Br, -F;
X is selected from -NH-, -O-, -S-;
R2 is –OCH3, -OC2H5, nitrophenyl, methoxy phenyl, ethoxy phenyl, chloro phenyl, bromo phenyl, fluoro phenyl.

3. The process according to claim 1, wherein the preparation of formula II, pharmaceutically acceptable salts thereof,

comprising:
a) hydrolyzing a compound of formula VI in the presence of a metal alkoxide and suitable solvent or mixtures thereof to obtain a compound of formula V;
,
b) coupling the compound of formula V with 6-methoxypyridazin-3-amine hydrochloride in presence of a suitable organic base and propylphosphonic anhydride and suitable solvent or mixtures thereof to obtain a compound of formula IV;
,
c) cyclizing the compound of formula IV using in the presence of a metal alkoxide and a suitable solvent or mixture thereof to obtain a compound of formula III or pharmaceutically acceptable salts thereof;
,
d) reducing the compound of formula III or pharmaceutically acceptable salts thereof in the presence of a reducing agent and a solvent or mixtures thereof to obtain a compound of formula II;

4. The process according to claim 3, wherein suitable solvent are selected from alcohols, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, nitriles, esters, ethers, ketones and mixtures thereof.

5. The process according to claim 4, wherein the alcohols include C1-6 alcohols selected from methanol, ethanol, butanol, isopropanol and the like; halogenated hydrocarbons include methylene chloride, ethylene chloride, chloroform and the like; hydrocarbons include hexane, cyclohexane, toluene, xylene and the like; amides include dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and the like; sulfoxides include dimethyl sulfoxide and the like; nitriles include acetonitrile, propionitrile and the like; esters include ethyl acetate and butyl acetate and the like; ester include ethyl acetate and butyl acetate and the like; ethers include diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,4-dioxane, tetrahydrofuran and the like; ketones include acetone, methyl ethyl ketone, methyl isopropyl ketone and the like and mixtures thereof.

6. The process according to claim 3, wherein the metal alkoxide is selected from sodium methoxide, sodium ethoxide, potassium ethoxide, potassium butoxide, sodium butoxide, sodium tert-butoxide, potassium tert-butoxide and acids such as organic acid, inorganic acid but are not limited to acetic acid, formic acid, citric acid, oxalic acid, malic acid, tartaric acid, hydrochloric acid, nitric acid, sulfuric acid, the like and mixtures there.

7. The process according to claim 3, wherein the hydrolyzing agent is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and mixtures thereof.

8. The process according to claim 3, wherein the coupling agent is selected from metal halides include sodium iodide, sodium bromide, sodium chloride, potassium iodide, potassium bromide, potassium chloride, lithium iodide, lithium bromide, lithium chloride, magnesium iodide, magnesium bromide, magnesium chloride, calcium iodide, calcium bromide, calcium chloride, copper iodide, copper bromide, copper chloride or mixtures thereof; Dicyclohexylcarbodiimide/1-Hydroxybenzotriazole (DCC/HoBt), Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium/N,N-diisopropylethylamine (HATU/DIPEA), Propylphosphonic anhydride/triethyl amine (T3P/TEA), 3-Dimethylamino-propyl)-ethyl-carbodiimide Hydrochloride (EDC.HCl) or mixtures thereof.

9. The process according to claim 3, wherein the suitable base is selected from inorganic base such as alkaline or alkaline earth metal hydride, alkaline or alkaline earth metal hydroxide, alkaline or alkaline earth metal carbonate, sodium hydride, lithium hydride, potassium hydride, aluminum hydride, zinc hydride, titanium hydride, nickel hydride, sodium aluminum hydride, or organic base selected from lithium methoxide, sodium hydroxide, sodium methoxide, potassium methoxide, tetrabutyl ammonium methoxide, lithium isopropoxide, triethyl amine. methyl amine, diisopropyl methyl amine, diisopropyl ethyl amine, methyl amine, dimethyl amine or mixtures thereof.