FIELD OF THE INVENTION
The present invention relates to novel compounds of Formula I, II, III, IV, V and process of preparation thereof,

The present invention further provides use of the compounds of Formula I, II, III, IV and V for the preparation of 4-({(1R)-2-[5-(2-fluoro-3¬-methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo-3,6¬-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino)butanoic acid (Elagolix) of Formula A and pharmaceutical acceptable salts thereof.

BACKGROUND OF THE INVENTION
Elagolix has been used in trials for the treatment of Endometriosis. PCT application WO 2005/007165 discloses Elagolix as composition of matter and its process of preparation as mentioned in the scheme-1 below:
Scheme 1:

US 8,765,948 discloses another process for the preparation of compounds that are used as intermediates in the preparation of Elagolix as mentioned in the Scheme-2 and 3 below:

Scheme 2

Scheme 3:

.

Although there are certain processes known in the published references for the preparation of Elagolix, however, the present invention relates to the development of novel process for preparing Elagolix by using novel compounds as intermediates.

OBJECT OF THE INVENTION
The main object of the present invention is to provide novel compounds of Formula I, II, III, IV and V as represented below and process for the preparation thereof,
, , ,
, and .

Another object of the present invention is to provide novel compounds that can be used in the preparation of the elagolix and pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide a process for the preparation of elagolix and pharmaceutically acceptable salts thereof by employing novel intermediates.

Another object of the present invention is to provide use of compounds of Formula I, II, III, IV and V in the preparation of Elagolix and pharmaceutically acceptable salts thereof.

SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide novel compounds of Formula I,

isomers, polymorphs, and pharmaceutically acceptable salts thereof;
wherein X represents -O, -N, -NR6 and wherein R6 is represented by the formula:

R1 represents hydrogen, or nitrogen protecting group; R2 represents amide optionally substituted with alkyl, or alkoxyalkyl; diketone group substituted with C1-C6 alkoxy group; –CON(CH3)OCH3, -(CO)2OCH3, -(CO)2OC2H5; ¬and C4-C10 heterocyclic ring optionally substituted with straight or branched alkyl chain, aryl, aralkyl, alkoxy group, aliphatic cyclic ring.

In another aspect, the present invention provide novel compounds of Formula II,

isomers, polymorphs, and pharmaceutical acceptable salts thereof;
wherein R3 represents hydrogen; ketone substituted with C1-C5 alkoxy group; optionally substituted amide group; and
R4 represents hydrogen; alkenyl chain optionally substituted with alkyl, (un)substituted aromatic ring, carboxylic acid, carboxylic ester, or halogen.

In another aspect, the present invention provides novel compounds of Formula III,

isomers, polymorphs, and pharmaceutical acceptable salts thereof;
wherein R1 represents hydrogen, or nitrogen protecting group; R2 represents amide optionally substituted with alkyl, or alkoxyalkyl; diketone group substituted with C1-C6 alkoxy group; –CON(CH3)OCH3; -(CO)2OCH3, -(CO)2OC2H5; ¬C4-C10 heterocyclic ring optionally substituted with straight or branched alkyl chain, aralkyl, alkoxy group, aliphatic cyclic ring; and
R5 represents amino group, halogen selected from chloro, bromo, iodo, and fluoro group.

In another aspect, the present invention provides novel compound of Formula IV,
.

In another aspect, the present invention provides novel compound of Formula V,
.

In another aspect, the present invention provides novel compounds, as represented by following formulae:
, , , , ,
, , , ,
, , , , ,
, , , , ,
, , , , and
isomers, polymorphs and pharmaceutically acceptable salts thereof.

In one another aspect, the present invention provides process for preparing novel compounds of Formula I, II, III, IV and V, isomers, polymorphs, and pharmaceutical acceptable salts thereof.

In one another aspect, the present invention provides process for preparing elagolix and its pharmaceutical acceptable salts, by using compounds of Formula I, II, III, IV and V as intermediates.

DETAILED DESCRIPTION
Definitions:
“Pharmaceutical acceptable 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; organic acids such as formic acids, acetic acid, diphenyl acetic 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, succinic acid, benzoic acid, p-chlorobenzoic 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, pamoic acid, 2,3-dibenzoyl-tartaric acid (in particular (+)-2,3-dibenzoyl-D-tartaric acid), acetic acid, diphenyl acetic acid, triphenylacetic acid; pharmaceutical acceptable bases such as metal salts including alkali metal or alkaline earth metal salts for example sodium, potassium, magnesium, calcium, lithium, cesium, barium, rhodium, zinc salts etc., ammonium salts; organic amines such as benethamine, benzathine, diethanolamine, ethanolamine, 4(2-hydroxy-ethyl)morpholine, 1-(2-hydroxyethyl)pyrrolidine, N-methyl glucamine, piperazine, triethanol amine and the like.

The term “isomers” as used in the context of the present invention refers to all such compounds including tautomers, cis-and trans-isomers, R- and S-enantiomers, diastereomers, D-isomers, L-isomers, and racemic mixtures of all the compounds herein described under the definitions of compound of Formula-I. Further, additional asymmetric carbon atoms may be present in a substituent such as alkyl group. The compounds herein described may have asymmetric carbon atoms and may be isolated in optically active forms by synthesis from optically active starting materials, or synthesis using optically active reagents by methods known in the prior published references.

The term “optionally substituted” or “(un) substituted” as used in the context of the present invention means that substitution is optional and therefore it is possible for the designated atom or moiety to be unsubstituted.

As used herein, unless otherwise indicated, the term “alkyl” alone or in combination refers to a monovalent saturated aliphatic hydrocarbon radical having the indicated number of carbon atoms. The alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, tert-pentyl, n-heptyl, and the like.

As used herein, the term “halo” or “halogen” means a monovalent halogen radical or atom selected from fluoro, chloro, bromo and iodo. Preferred halo groups are chloro and bromo.

As used herein, the phrase “nitrogen protecting group” means temporary substituents which protect a potentially reactive amino functional group from undesired chemical transformations.

In one embodiment, the present invention provide novel compounds of Formula I,

isomers, polymorphs, and pharmaceutical acceptable salts thereof;
wherein X represents -O, -N, -NR6 and wherein R6 is represented by the formula:

R1 represents hydrogen, or nitrogen protecting group; R2 represents amide optionally substituted with alkyl, or alkoxyalkyl; diketone group substituted with C1-C6 alkoxy group; –CON(CH3)OCH3, -(CO)2OCH3, -(CO)2OC2H5; ¬and C4-C10 heterocyclic ring optionally substituted with straight or branched alkyl chain, aralkyl, alkoxy group, aliphatic cyclic ring.

In another embodiment, the present invention provides novel compounds of Formula III,

isomers, polymorphs, and pharmaceutical acceptable salts thereof;
wherein R1 represents hydrogen, or nitrogen protecting group; R2 represents amide optionally substituted with alkyl, or alkoxyalkyl; diketone group substituted with C1-C6 alkoxy group; –CON(CH3)OCH3, -(CO)2OCH3, -(CO)2OC2H5; ¬C4-C10 heterocyclic ring optionally substituted with straight or branched alkyl chain, aralkyl, alkoxy group, aliphatic cyclic ring; and
R5 represents amino group, halogen selected from chloro, bromo, iodo, and fluoro group.

In a preferred embodiment, nitrogen protecting group is selected from any of the carbon containing moiety, sulphur containing moiety or silyl containing moiety.

Preferably, the carbon containing moiety is selected from lower alkyl, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, cyclo(lower)alkenyl, aryl, heterocyclyl, and heteroaryl, any of which can be substituted or unsubstituted; and
Preferably, silyl containing moiety includes the compounds containing one or more silyl group; and
Preferably, sulphur containing moiety includes the compounds containing sulphur group optionally substituted with oxygen group.

In another embodiment, the present invention provides compound of Formula I, wherein X represents –NR6 and R6 is represented by formula:

wherein R1 represents tert-butoxy carbonyl group and R2 represents five membered heterocyclic ring; and is represented by compound of Formula 12;
.

In another embodiment, the present invention provides compound of Formula I, wherein X represents –NR6 and R6 is represented by formula:

wherein R1 represents hydrogen and R2 represents five membered heterocyclic ring; and is represented by compound of Formula 13;
.

In another embodiment, the present invention provides compound of Formula III, wherein R1 represents tert-butoxy carbonyl group; R2 represents five membered heterocyclic ring; R5 represents chloro group; and is represented by Formula 11;
.

In another embodiment, the present invention provides compound of Formula III, wherein R1 represents hydrogen; R2 represents five membered heterocyclic ring; R5 represents chloro group; and is represented by Formula 10;
.

In another embodiment, the present invention provides use of novel compounds of Formula I, II, III and IV; isomers, polymorphs and pharmaceutical acceptable salts thereof, in preparation of elagolix and its pharmaceutical acceptable salts.

In one another embodiment, the present invention provides process for preparing novel compounds of Formula I, II, III, IV and V; isomers, polymorphs and pharmaceutically acceptable salts thereof.

In another embodiment, the present invention provides a process of preparation of elagolix of Formula A and its pharmaceutical acceptable salts, by using novel compounds of Formula 11-13, wherein said process comprising of reaction steps as mentioned in the scheme-4 below:
Scheme-4:

In another embodiment, the suitable solvent used for preparing elagolix of Formula A and its sodium salt is selected from, but not limited to, alcohols, hydrocarbons, halogenated solvents, esters, ethers, ketones, sulfoxides, amides, nitriles, pyrrolidines, carbonates, water and so on. Specifically, the suitable solvent is selected from tetrahydrofuran, toluene, xylene, 1,4-dioxane, dichloromethane, carbon tetrachloride, chloro benzene, methanol, ethanol, isopropyl alcohol, acetonitrile, propionitrile, ethyl acetate, acetone, methyl ethyl ketone, methyl tetrahydrofuran, butyl acetate, isobutyl acetate, t-butyl acetate, propyl acetate, propylene acetate, butanol, iso-butanol, t-butanol, methyl t-butyl ketone, dimethyl sulfoxide, N-methyl pyrrolidine, dimethyl acetamide, water and mixture thereof.

In another embodiment, the cross coupling of compound of Formula 30 with (2-fluoro-3-methoxyphenyl)boronic acid is optionally carried out in presence of base selected from organic and inorganic base such as pyridine, triethyl amine, diisopropyl ethyl amine, dicyclohexyl amine, carbonates, hydroxides, bicarbonates and the like. The most preferred base is sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, calcium bicarbonates, cesium bicarbonate, cesium carbonate, lithium carbonate and bicarbonate and the like.

In another embodiment, the reaction of compound of Formula 31 with compound of Formula 11 to obtain the compound of Formula 12 is carried in the presence of triarylphosphine such as triphenyl phosphine and the like, and azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate and di-tert-butyl azodicarboxylate (DIAD) and the like.

In one another embodiment, the intermediates formed during preparation of elagolix of Formula I may optionally be not isolated and are proceeded to further steps without any purification. In a preferred embodiment, the intermediates such as compound of Formula I and III are converted to their respective salts within the reaction mixture and are proceeded to next step without isolation.

In further embodiment, the compound of Formula 11 is prepared as per the scheme mentioned in the scheme-5 below:

Scheme-5:
.
In another embodiment, the suitable solvent used for preparing compound of Formula 10 and 11 are selected from, but not limited to, alcohols, hydrocarbons, halogenated solvents, esters, ethers, ketones, sulfoxides, amides, nitriles, pyrrolidines, carbonates, water and so on. Specifically, the suitable solvent is selected from tetrahydrofuran, toluene, xylene, 1,4-dioxane, dichloromethane, carbon tetrachloride, chloro benzene, methanol, ethanol, isopropyl alcohol, acetonitrile, propionitrile, ethyl acetate, acetone, methyl ethyl ketone, methyl tetrahydrofuran, butyl acetate, isobutyl acetate, t-butyl acetate, propyl acetate, propylene acetate, butanol, t-butanol, methyl t-butyl ketone, dimethyl sulfoxide, N-methyl pyrrolidine, dimethyl acetamide, water and mixture thereof.

In another embodiment, the preparation of compounds of Formula 10 and 11 is optionally carried out in presence of the base selected from, but not limited to, organic bases selected from secondary and tertiary amines such as pyridine, triethyl amine, diisopropyl ethyl amine, dicyclohexyl amine, dimethylamino pyridine, diisopropyl amine, morpholine, aniline and the like, and inorganic bases such as carbonates, hydroxides, bicarbonates and the like. The most preferred base is sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, calcium bicarbonates, cesium bicarbonate, cesium carbonate and the like.

In another embodiment, the present invention provides a process for preparing Elagolix of Formula A and pharmaceutically acceptable salts thereof,
comprising the steps of:
a) reacting 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione of Formula 31 with tert-butyl-(3-(1,3-dioxolan-2-yl)propyl)(2-chloro-1-phenylethyl)carbamate of Formula 11 in presence of solvent to get tert-butyl-(3-(1,3-dioxolan-2-yl)propyl)(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)carbamate of Formula 12;
; and
b) converting compound of Formula 12 to Elagolix of Formula A and pharmaceutically acceptable salts thereof.

In another embodiment, the present invention provides process of preparing Elagolix of Formula A and pharmaceutically acceptable salts thereof,
comprising the steps of:
a) deprotecting tert-butyl-(3-(1,3-dioxolan-2-yl)propyl)(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)carbamate of Formula 12 to get 3-(2-((3-(1,3-dioxolan-2-yl)propyl)amino)-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione of Formula 13 in presence of suitable solvent;
; and
b) converting compound of Formula 12 to Elagolix of Formula A and pharmaceutically acceptable salts thereof.

In a preferred embodiment, the present invention provides a substantially pure amorphous form of elagolix and its pharmaceutical acceptable salts and process of preparation thereof, wherein said amorphous form is substantially free of any crystalline form.

In another embodiment, the present invention provides a substantially pure and stable crystalline form of elagolix and its pharmaceutical acceptable salts.

In another embodiment, the present invention provides a substantially pure elagolix and pharmaceutically acceptable salts thereof, wherein said elagolix is substantially free from compounds of Formula 12 and 13.

In further embodiment, the present invention provides elagolix and its pharmaceutically acceptable salts characterized by particle size distribution with d90 between 0.1µm to 200µm.

In a preferred embodiment, the elagolix and its pharmaceutically acceptable salts is characterized by particle size distribution with d90 between 2.0 µm to 150µm.

In one another embodiment, the elagolix and its pharmaceutically acceptable salts prepared as per the process of the present invention is characterized with purity above 99%, preferably above 99.5%, and more preferably above 99.9%.

In one another embodiment, the elagolix and its pharmaceutically acceptable salts prepared as per the process of the present invention is characterized with enantiomeric purity of 99.0% and above, preferably 99.9% and above, wherein said elagolix and its pharmaceutically acceptable salts are substantially free from S-enantiomer.

In a preferred embodiment, the present invention provides a substantially pure crystalline form of elagolix and its pharmaceutically acceptable salts, processes for preparation thereof, and pharmaceutical compositions prepared therefrom.

In another preferred embodiment, the present invention provides a solid dispersion of elagolix and pharmaceutically acceptable salts thereof, together with a pharmaceutically acceptable carrier, processes for preparation thereof, and pharmaceutical compositions prepared therefrom.

In one another embodiment, the present invention further provides a composition comprising elagolix or its pharmaceutically acceptable salts along with one or more pharmaceutically acceptable excipients.

In one another embodiment, the present invention provides a method of treating pain associated with endometriosis which comprises administering to a patient in need of such treatment a therapeutically effective amount of Elagolix or a pharmaceutically acceptable prodrug, polymorph, salt, or solvate thereof.

In one another embodiment, the present invention provides a method of treating pain associated with endometriosis which comprises administering to a patient in need of such treatment a therapeutically effective amount of Elagolix or a pharmaceutically acceptable prodrug, polymorph, salt, or solvate thereof, wherein said Elagolix is prepared as per the process of the present invention.

In further embodiment, the present invention provides a pharmaceutical composition comprising elagolix and/ or its pharmaceutical acceptable salts along with atleast one another active ingredient selected from Estradiol, Norethindrone acetate or mixture thereof, for the management of heavy menstrual bleeding associated with uterine fibroids.

The embodiments of the present invention are exemplified herein below:

Example 1: Preparation of tert-butyl (R)-(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydro pyrimidin-1(2H)-yl)-1-phenylethyl)(4-(methoxy(methyl)amino)-4-oxobutyl)carbamate of Formula 8:
A mixture of methyl-2-(2-fluoro-3-methoxyphenyl)-3-((2-fluoro-6-(trifluoromethyl)benzyl)(methoxycarbonyl)amino)but-2-enoate of Formula 4 (95.0 g), Et3N (60.92g) and tert-butyl (R)-(2-amino-1-phenylethyl)(4-(methoxy(methyl)amino)-4-oxobutyl)carbamate of Formula 7 (95.3g) in dichloromethane (950.0 mL) was refluxed for 24 hours. The cooled reaction mixture was diluted with dichloromethane (950.0 mL) and washed with saturated aqueous NaHCO3 (158.3 mL) and brine (1200.0 mL). The organic phase was dried (MgSO4) and evaporated to dryness. Purification by flash chromatography (3:1 cyclohexane-EtOAc) afforded the pure compound was dissolved in MeOH (475.0 mL) at r.t. was added an aqueous solution of 1M KOH (6.74g). The reaction mixture was refluxed until complete consumption of the starting materials as monitored by TLC. The aqueous layer was washed with dichloromethane (2850.0 mL), and then acidified with concentrated HCl to pH 6 to obtain a solid precipitate, which was collected by filtration. The precipitate was thoroughly washed with H2O to afford compound of Formula 8 (140.0 g, yield: 90.0 %).

Example 2: Preparation of (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)amino)-N-methoxy-N-methylbutanamide of Formula 9:
tert-butyl (R)-(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl) benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl) (4-(methoxy(methyl) amino)-4-oxobutyl)carbamate of Formula 8 (135.0g) was dissolved in 390.0 mL/390.0 mL dichloromethane/TFA. The resulting yellow solution was stirred at room temperature for 2 hours. The volatiles were evaporated and the residue was partitioned between EtOAc/ sat. NaHCO3. The organic phase was dried over NaSO4. Evaporation gave compound of Formula 9 (86.96 g, 74% yield).

Example 3: Preparation of Elagolix:
A suspension of (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenyl ethyl)amino)-N-methoxy-N-methylbutanamide of Formula 9 (85.0g) and potassium tert-butoxide (4.25g) in Et2O (1147.0 mL) was treated with water (4.01ml) and stirred at 25°C for 18 hours. Crushed ice was added and the mixture was allowed to warm to room temperature and then washed with Et2O. The aqueous phase was acidified with 1 N HCl at 0°C. The resulting precipitate was collected by filtration, washed with water, and dried in vacuum to afford the acid Elagolix (63.10 g, 91.0 % yield).

Example 4: Preparation of Elagolix sodium salt:
A solution of Elagolix (60.0g) in ethanol (1147.0 mL) was added 2.33 % NaOH solution aq. (180 ml) and stirred at 25°C for 1 hours. The solution was filtered and washed with MIBK (120 mL). The filtrate was extracted with MIBK (120 mL) and organic layer was washed with 50% NaOH solution aq. (120 mL). Organic layer was washed with brine solution (120 mL) and dried over Na2SO4. Distilled out solvent from organic layer to get crude material. Add water (240 mL) and lyophilized to get desired material 61 g.

Example 5: Preparation of tert-butyl (R)-(3-(1,3-dioxolan-2-yl)propyl)(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)carbamate of Formula 12:
To compound 5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,3H)-dione (Formula 31) (40.0 g) in 900 mL of acetonitrile were added tert-butyl (R)-(3-(1,3-dioxolan-2-yl)propyl)(2-chloro-1-phenylethyl)carbamate of Formula 11 (44.0 g) and Hunig's base (27.28g). After reflux at 95°C for overnight, the reaction mixture was cooled to ambient temperature and the volatiles were removed. The residue was chromatographed with 10:10:1 EtOAc/Hexane/ Et3N to give tert-butyl (R)-(3-(1,3-dioxolan-2-yl)propyl)(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)carbamate (55.6 g yield 78.0 %).

Example 6: Preparation of (R)-3-(2-((3-(1,3-dioxolan-2-yl)propyl)amino)-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione of Formula 13:
tert-butyl (R)-(3-(1,3-dioxolan-2-yl)propyl)(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenyl ethyl)carbamate (53.0 g) was dissolved in 200.0 mL/200.0 mL dichloromethane/trifluoroacetic acid (TFA). The resulting yellow solution was stirred at room temperature for 2 hours. The volatiles were evaporated and the residue was partitioned between EtOAc/saturated sodium bicarbonate. The organic phase was dried over Na2SO4. Evaporation gave compound of Formula 13 as yellow oil (34.0 yield 74.01 %).

Example 7: Preparation of Elagolix:
(R)-3-(2-((3-(1,3-dioxolan-2-yl)propyl)amino)-2-phenylethyl)-5-(2-fluoro-3-methoxy phenyl)-1-(2-fluoro-6-(trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (30.0 g), THF solution (440.0 mL), oxone (287.92 g) water (440.0 mL) added with stirring at 0°C. Mixed liquor was stirred in the room temperature for 12 hours, and EtOAc(500ml) was added. Layer separation was done. The organic layer was washed with brine, dried (Na2SO4).To evaporation the residue was subjected to silica gel column chromatography (70:30 hexane/EtOAc) to get Elagolix (25.18 g, 87.67 %).

Example 8: Preparation of tert-butyl (R)-(4-amino-4-oxobutyl)(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)carbamate of Formula 16:
To a stirred solution of 5-(2-fluoro-3-methoxyphenyl)-3-[2-fluoro-6-(trifluoromethyl)benzyl]-4-methyl-2H-1,3-oxazine-2,6(3H)-dione of Formula 15 (100.0 g) in DMF (306.0 mL) heated at 80°C was added dropwise a solution of tert-butyl (4-amino-4-oxobutyl)[(1R)-2-amino-1-phenylethyl]carbamate of Formula 20 (75.22 g, 234.03 mmol) in dimethylformamide (DMF) (153.0 mL) over a period of 30 minutes. After 4 hours of additional stirring at the same temperature, the mixture was cooled and cold water (1840.0 mL) was added with stirring. The resulting precipitate was collected, washed with cold water (2 x 153.0 mL) and dried at 60°C. Recrystallization (diethyl ether). To a solution of the crystalized material in 766.0 mL of THF was added Et3N (1.01 g). At ice-bath temperature and with stirring, a solution of trichloroacetyl chloride (22.978 g) in THF (766.0 mL) was added dropwise over a period of 1.5 hours. The reaction mixture was stirred for a further 3 hours and allowed to stand overnight. The precipitate was collected and suspended in water (1227.0 mL). The suspended solid was collected and the filtrate was evaporated to dryness and water (920.0 mL) was added to the residue with stirring. The suspension was filtered again to give an additional amount. The two crops were combined and recrystallized from ethanol to give the pure compound of Formula 16.

Example 9: Preparation of Elagolix:
Compound of Formula 16 (100.0 g) was dissolved in 290.0 mL/290.0 mL dichloromethane/TFA. The resulting yellow solution was stirred at room temperature for 2 hours. The volatiles were evaporated and the residue was partitioned between EtOAc/ sat. NaHCO3. The organic phase was dried over NaSO4 and then filtered. Evaporation of the organic layer gave unprotected compound of Formula 17 (63.86 g, 74% yield). A mixture of compound of Formula 17 (60.0 g) and 1 N hydrochloric acid (600.0 ml) was refluxed for 4 hours was refluxed. Reaction mixture was cool to RT and extracted with dichloromethane (600.0 mL). Layers were separated and the organic layer was concentrated under vacuum up to 40-45°C. The residue was recrystallized in ethyl acetate and hexane to afford Elagolix (42.34 g, 70.46 %).

Example 10: Preparation of methyl (R)-5-((tert-butoxycarbonyl)(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)amino)-2-oxopentanoate compound of Formula 22:
To compound methyl (S)-5-((tert-butoxycarbonyl)(2-chloro-1-phenylethyl)amino)-2-oxopentanoate of Formula 21 (124.0 g) in 2000.0 mL of acetonitrile were added 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (115.0 g) and Hunig's base (35.0 g). After reflux at 95°C, overnight, the reaction mixture was cooled to ambient temperature and the volatiles were removed. The residue was chromatographed with 10:10:1 EtOAc/Hexane/ Et3N to give methyl (R)-5-((tert-butoxycarbonyl)(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl) benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)amino)-2-oxopentanoate (162.7g and yield 78.0 %).

Example 11: Preparation of methyl (R)-5-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)amino)-2-oxopentanoate of Formula 23:
Compound of Formula 22 (160.0g) was dissolved in 460.0 mL/460.0 mL dichloromethane/trifluoroacetic acid (TFA). The resulting solution was stirred at room temperature for 2 hours. The volatiles were evaporated and the residue was partitioned between EtOAc/ sat. NaHCO3. The organic phase was dried over Na2SO4. Evaporation gave methyl (R)-5-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)amino)-2-oxopentanoate (103.0g, 74% yield).

Example 12: Preparation of Elagolix:
A mixture of methyl (R)-5-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)amino)-2-oxopentanoate of Formula 23 (100.0 g) in sodium 10% (w/v) aqueous sodium hydroxide solution (pH: 9-10) was stirred at RT until disappearance of the step-04 by thin layer chromatography (TLC). 30 % H2O2 was added to the reaction mixture and stirred for 1 hour at RT. 1N HCl solution was added slowly at 0-5°C to adjust pH: 1-2 and the resulting mixture was extracted with ethyl acetate (2x500.0 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and concentrated. The resulting residue was subjected to silica gel column chromatography to afford Elagolix (79.6 g, 85.0 %).
,CLAIMS:WE CLAIM
1. Compound of Formula I,

isomers, polymorphs, and pharmaceutical acceptable salts thereof;
wherein X represents -O, -N, -NR6 and wherein R6 is represented by the formula:

R1 represents hydrogen, or nitrogen protecting group; R2 represents amide optionally substituted with alkyl, or alkoxyalkyl; diketone group substituted with C1-C6 alkoxy group; –CON(CH3)OCH3; -(CO)2OCH3, -(CO)2OC2H5; ¬and C4-C10 heterocyclic ring optionally substituted with straight or branched alkyl chain, aryl, aralkyl, alkoxy group, aliphatic cyclic ring.

2. Compound of Formula II,

isomers, polymorphs, and pharmaceutical acceptable salts thereof;
wherein R3 represents hydrogen; ketone substituted with C1-C5 alkoxy group; optionally substituted amide group; and
R4 represents hydrogen; alkenyl chain optionally substituted with alkyl, (un)substituted aromatic ring, carboxylic acid, carboxylic ester, or halogen.

3. Compound of Formula III,

isomers, polymorphs, and pharmaceutical acceptable salts thereof;
wherein R1 represents hydrogen, or nitrogen protecting group; R2 represents amide optionally substituted with alkyl, or alkoxyalkyl; diketone group substituted with C1-C6 alkoxy group; –CON(CH3)OCH3; -(CO)2OCH3, -(CO)2OC2H5; ¬C4-C10 heterocyclic ring optionally substituted with straight or branched alkyl chain, aralkyl, alkoxy group, aliphatic cyclic ring; and
R5 represents amino group, halogen selected from chloro, bromo, iodo, and fluoro group.

4. The compound as claimed in any of the preceding claims, wherein said compound is represented by formula selected from,
, , , , , , , , ,
, , , , ,
, , , , ,
, , , , and
isomers, polymorphs and pharmaceutically acceptable salts thereof.

5. A process for preparing elagolix of Formula A and pharmaceutically acceptable salts thereof,
,
comprising the steps of:
a) reacting 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione of Formula 31 with tert-butyl-(3-(1,3-dioxolan-2-yl)propyl)(2-chloro-1-phenylethyl)carbamate of Formula 11 in presence of solvent to get tert-butyl-(3-(1,3-dioxolan-2-yl)propyl)(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)carbamate of Formula 12;
; and
b) converting compound of Formula 12 to elagolix of Formula A and pharmaceutically acceptable salts thereof.

6. A process of preparing elagolix of Formula A and pharmaceutically acceptable salts thereof,
,
comprising the steps of:
a) deprotecting tert-butyl-(3-(1,3-dioxolan-2-yl)propyl)(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)carbamate of Formula 12 to get 3-(2-((3-(1,3-dioxolan-2-yl)propyl)amino)-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H, 3H)-dione of Formula 13 in presence of suitable solvent;
; and
b) converting compound of Formula 12 to elagolix of Formula A and pharmaceutically acceptable salts thereof.

7. The process as claimed in claims 5 and 6, wherein said solvent is selected from the group comprising of tetrahydrofuran, toluene, xylene, 1,4-dioxane, dichloromethane, carbon tetrachloride, chloro benzene, methanol, ethanol, isopropyl alcohol, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, methyl tetrahydrofuran, butyl acetate, isobutyl acetate, t-butyl acetate, propyl acetate, propylene acetate, butanol, t-butanol, methyl t-butyl ketone, dimethyl sulfoxide, N-methyl pyrrolidine, dimethyl acetamide, water and mixture thereof.

8. Substantially pure elagolix of Formula A and pharmaceutically acceptable salts thereof, wherein said elagolix is substantially free from compounds of Formula 12 and 13.

9. A composition comprising elagolix sodium of Formula A or pharmaceutically acceptable salts thereof, with atleast one another active ingredient selected from estradiol, norethindrone acetate or mixture thereof.