PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF FIELD OF THE INVENTION

The present invention relates to a process for the preparation of Elagolix of formula (I) and its pharmaceutically acceptable salts. The present invention also relates to an intermediate of formula (VIII) and its use in preparation of Elagolix and its pharmaceutically acceptable salts. BACKGROUND OF THE INVENTION

Elagolix, chemically known as 4-[2-[5-(2-fluoro-3-methoxyphenyl)-3-[2-fluoro-6- (trifluoromethyl)benzyl]-4-methyl-2,6-dioxo-1,2,3,6-tetrahyd ro-1-pyrimidinyl]-1(R)- phenylethylamino]butyric acid, is a gonadotropin-releasing hormone (GnRH) receptor antagonist that blocks endogenous GnRH signaling by binding competitively to GnRH receptors in the pituitary gland. Elagolix is currently being investigated in diseases that are mediated by sex hormones, such as uterine fibroids and endometriosis. Its chemical structure is represented by Formula (I).

US patent No. 7,056,927 B2 discloses Elagolix or a stereoisomer or pharmaceutically acceptable salt thereof. US patent No.8,765,948 B2 discloses process for the prepration of Elagolix or pharmaceutically acceptable salt thereof. Though, there are processes available in the literature for the preparation of Elagolix and its pharmaceutically acceptable salt, still there remains a need for an efficient and industrially applicable process for the preparation of Elagolix and its pharmaceutically acceptable salt. SUMMARY OF THE INVENTION

The present invention relates to a process for preparation of Elagolix of formula (I) and its pharmaceutically acceptable salts. The present invention also relates to an intermediate of formula (VIII) and its use in the preparation of Elagolix and its pharmaceutically acceptable salts. The use of compound of formula (VIII) in the preparation of Elagolix prevents formation of impurities and provides commercial advantages over the processes known in the art DETAILED DESCRIPTION OF THE INVENTION

The term "pharmaceutically acceptable salt" is intended to encompass acid or base addition salts. Acid addition salts of the present invention may be formed from organic and inorganic acids. Suitable organic acids include but not limited to maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandelic acid, cinnamic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, and benzenesulfonic acid. Suitable inorganic acids include but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid. The base addition salts are preferably alkali and alkaline earth metal salts (for example, lithium, sodium, potassium, magnesium, barium, calcium and the like); amine salts; or ammonium salts (for example, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, and the like). The term "halogen" means fluorine, chlorine, bromine, or iodine. The term“halo” means fluoro-, chloro-, bromo- or iodo- functional group. In one aspect, the present invention provides a process for preparing Elagolix of formula (I) or pharmaceutically acceptable salt thereof;

comprising of the following steps:

(a) contacting the compound of formula (II) with the compound of formula (III) to give the compound of formula (IV);

(b) contacting the compound of formula (IV) with a suitable reagent to give the compound of formula (V);

(c) contacting the compound of formula (V) with (2-fluoro-3- methoxyphenyl)boronic acid in the presence of palladium source to give the compound of formula (VI);

(d) contacting the compound of formula (VI) with the compound of formula (VII) to give the compound of formula (VIII);

(e) converting the compound of formula (VIII) to the compound of formula (IX);

(f) contacting the compound of formula (IX) with ethyl 4-halobutanoate in presence of a base to give the compound of formula (X);

(g) treating the compound of formula (X) with a base; to give Elagolix of formula (I) or pharmaceutically acceptable salt thereof. The process according to this invention is described in detail. The reaction conditions such as solvents and temperature given are meant to provide preferred ranges and examples for the respective transformation that can be principally applied but are not supposed to restrict them to the selection given. Starting materials that may be used as the input for the process of the present invention may be obtained by any process including the process described in the art. The compound of formula (IV) can be prepared in step (a) by reacting compound of formula (II) with the compound of formula (III) followed by treatment with an acid at a temperature of about 0°C to refluxing temperature. The acid used in step (a) may be selected from a carboxylic acid or a sulphonic acid; such as trifluoroacetic acid, trifluoromethane sulphonic acid, methane sulphonic acid, formic acid, tartaric acid or p-toluenesulphonic acid and the like; hydrochloric acid; hydrobromic acid; sulphuric acid; phosphoric acid and sodium hydrogen phosphate. Preferably p-toluenesulphonic acid may be used as acid catalyst. The reaction of step (a) can be carried out in suitable solvent selected from the group consisting of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof in any suitable proportion. Examples of suitable solvent includes but not limited to methanol, ethanol, isopropanol, butanol, iso- butanol, ethyl acetate, methyl acetate, tertiarybutyl acetate, iso-propyl acetate, acetone, methylisobutyl ketone, methylethyl ketone, diethyl ketone, dimethyl ketone, toluene, ethyl ether, methyl ether, diisopropylether, methyltertbutyl ether, dioxane, xylene, tetrahydrofuran, N,N-dimethylformamide, N-methyl acetamide, N,N-dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone, dichloromethane, acetonitrile, or mixture of these solvents in any suitable proportion. The compound of formula (V) can be prepared in step (b) by contacting the compound of formula (IV) with a suitable brominating agent. Brominating agent used in step (b) may be selected from the group consisting of bromine, N-bromosuccinimide(NBS), dibromoisocyanuric acid, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, benzyltrimethylammonium tribromide, pyridinium bromide perbromide, 4-dimethylaminopyridinium bromide perbromide, 1-butyl-3-methylimidazolium tribromide, 1,8-diazabicyclo[5.4.0]- 7- undecene hydrogen tribromide, N-bromophthalimide, N-bromosaccharin, and N- bromoacetamide in any suitable proportion. The organic solvents that can be used for carrying out the bromination reaction of step (b) include chlorinated hydrocarbons such as dichloromethane and dichloroethane; esters such as methyl acetate, ethyl acetate and iso-propyl acetate; ether solvents such as diethyl ether and diisopropyl ether; acetic acid; alcohols such as methanol, ethanol, n- propanol, iso-propanol, n-butanol and iso-butanol or mixture of these solvents in any suitable proportion. The compound of formula (VI) can be prepared in step (c) by contacting compound of formula (V) with (2-fluoro-3-methoxyphenyl)boronic acid in the presence of palladium source, optionally in the presence of a phosphine ligand and base. The reaction temperatures are in the range of 20°C to reflux conditions, preferably 50°C to 90°C. Palladium source can be selected from the group consisting of Tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), [1,1′- Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2), Tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), Palladium(II) acetate (Pd(OAc)2), Pd(dbpf)Cl2, palladium dichloride, and bistriphenylphosphinepalladium dichloride or mixtures thereof in any suitable proportion. Phosphine ligand can be selected from the group consisting of triphenylphosphine (Ph3P), tri-p-tolylphosphine (p-Tol3P), tricyclohexylphosphine (PCy3), tri-t- butylphosphine (t-Bu3P), (Cy2P(Ph-Ph)), bi-dentate 1,1'-bis(diphenylphosphino)ferrocene (dppf), l,4-bis(diphenylphosphino)ferrocene (dppb), tricyclohexylphosphine, tri-t- butylphosphonium tetrafluoroborate and tris(4-methoxy-3,5-dimethylphenyl)phosphine or mixtures thereof in any suitable proportion. The base used in step (c) can be any inorganic or organic base. The inorganic base may be selected from the group consisting of hydroxides of alkali and alkaline metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, rubidium hydroxide, cesium hydroxide, potassium t-butoxide and the like; carbonates of alkali and alkaline metals such as sodium carbonate, potassium carbonate, sodium methylate and the like; and bicarbonates of alkali and alkaline metals such as sodium bicarbonate, potassium bicarbonate and the like. The organic base may be selected from the group consisting of triethyl amine, diisopropylethyl amine, diethyl amine, isopropyl amine, morpholine, N-methyl morpholine, pyridine, ammonia, 1,8- diazabicyclo[5.4.0] undec-7-ene, 1,4-diazabicyclo[2.2.2] octane, and the like or mixtures thereof. The reaction of step (c) can be carried out in suitable solvent selected from the group consisting of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles water or mixtures thereof in any suitable proportion Examples of suitable solvent includes but not limited to methanol, ethanol, isopropanol, butanol, iso- butanol, ethyl acetate, methyl acetate, tertiarybutyl acetate, iso-propyl acetate, acetone, methylisobutyl ketone, methylethyl ketone, diethyl ketone, dimethyl ketone, toluene, ethyl ether, methyl ether, diisopropylether, methyltertbutyl ether, cyclopentylmethyl ether, dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, N,N-dimethylformamide, N- methyl acetamide, N,N-dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone dichloromethane, dimethoxyethane, acetonitrile, xylene, water or mixture of these solvents in any suitable proportion. The compound of formula (VIII) can be prepared in step (d) by reacting compound of formula (VI) with the compound of formula (VII). This reaction may optionally be carried out in presence of base at a temperature of about 5°C to about 70°C, preferably at ambient temperature. The inventors of the present invention surprisingly noticed that use of corresponding carboxybenzyl (cbz) protected compound of formula (VIII) in the reaction step (d) provides commercial advantages over the processes known in the art. For example, the process of the present invention provides higher overall yield rendering a low-cost manufacturing of Elagolix . The processes known from the art also involve tedious chromatographic separation methods. Furthermore, the processes known from the art involves the use of t-Butyloxycarbonyl (boc) protected intermediate compounds for the preparation of Elagolix or pharmaceutically acceptable salts thereof form impurities, which in turn affect yield and quality of the product. The present invention also provides a control over the formation of such impurities, which substantially improves overall yield of the process and quality of the product. The base used in step (d) can be any inorganic or organic base. The inorganic base may be selected from the group consisting of hydroxides of alkali and alkaline metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, rubidium hydroxide, cesium hydroxide and the like; carbonates of alkali and alkaline metals such as sodium carbonate, potassium carbonate and the like; and bicarbonates of alkali and alkaline metals such as sodium bicarbonate, potassium bicarbonate and the like. The organic base may be selected from the group consisting of triethyl amine, diisopropylethyl amine, diethyl amine, isopropyl amine, morpholine, N-methyl morpholine, pyridine, ammonia, 1,8-diazabicyclo[5.4.0] undec-7-ene, 1,4- diazabicyclo[2.2.2] octane, and the like or mixtures thereof. The reaction of step (d) can be carried out in suitable solvent selected from the group consisting of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof in any suitable proportion. Examples of suitable solvent includes but not limited to methanol, ethanol, isopropanol, butanol, iso- butanol, ethyl acetate, methyl acetate, tertiarybutyl acetate, iso-propyl acetate, acetone, methylisobutyl ketone, methylethyl ketone, diethyl ketone, dimethyl ketone, toluene, ethyl ether, methyl ether, diisopropylether, methyltertbutyl ether, dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methyl acetamide, N,N-dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone, dichloromethane, acetonitrile, xylene or mixture of these solvents in any suitable proportion. The compound of formula (IX) can be prepared from compound of formula (VIII) in step (e) by conventional amino deprotection processes such as reduction, acid treatment and the like. Acid treatment can be carried out by treating the compound of formula (VIII) with organic or inorganic acids. The organic acid may be selected form carboxylic acid or sulphonic acid such as trifluoroacetic acid, trifluoromethane sulphonic acid, methane sulphonic acid, formic acid, tartaric acid and p-touenesulphonic acid. The inorganic acid may be selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and sodium hydrogen phosphate. The said reaction may be carried out at a temperature from about 05°C to 70°C, preferably about 25°C to 50°C. Alternatively, the reaction of step (e) may be carried out by catalytic hydrogenation in the presence of hydrogen. The hydrogenation catalysts that can be used for example platinum, palladium on charcoal carbon, platinum oxide, palladium dioxide, Raney nickel and the like, preferably palladium-carbon. The reaction may be carried out at a hydrogen pressure in the range of about 0.1 kg to 20 kg.. The reaction may be carried out for a period of about 2 hours to about 24 hours. The deprotection reaction can be carried out in the presence of a solvent. The solvents that can be used, include but are not limited to alcohols such as ethanol, methanol, propanol, butanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like or mixtures thereof; esters such as ethylacetate, isopropylacetate, tertiary butyl acetate and the like; ethers such as tetrahydrofuran, 1,4- dioxane, and the like; hydrocarbon solvents such as n-hexane, n-heptane, cyclohexane, toluene, xylene and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), acetonitrile and the like; or mixture of these solvents. Preferably the organic solvent selected is methanol. The compound of formula (X) can be prepared in step (f) by contacting the compound of formula (IX) with ethyl 4-halobutanoate under standard coupling conditions using suitable base at a temperature preferably at about 30oC to about 70oC. The base used in step (f) can be any organic base. The suitable base may be selected from the group consisting of triethyl amine, diisopropylethyl amine, diethyl amine, isopropyl amine, morpholine, N-methyl morpholine, pyridine, ammonia, 1,8- diazabicyclo[5.4.0] undec-7-ene, 1,4-diazabicyclo[2.2.2] octane, and the like or mixtures thereof. The reaction of step (f) can be carried out in suitable solvent selected from the group consisting of alcohols, amides, sulphoxides, pyrrolidones, ethers, hydrocarbons, ketones, esters, nitriles or mixtures thereof in any suitable proportion. Examples of suitable solvent includes but not limited to methanol, ethanol, isopropanol, butanol, iso- butanol, ethyl acetate, methyl acetate, tertiarybutyl acetate, iso-propyl acetate, acetone, methylisobutyl ketone, methylethyl ketone, diethyl ketone, dimethyl ketone, toluene, ethyl ether, methyl ether, diisopropylether, methyltertbutyl ether, dioxane, tetrahydrofuran, N,N-dimethylformamide, N-methyl acetamide, N,N-dimethylacetamide, dimethylsulphoxide, N-methylpyrrolidone, dichloromethane, acetonitrile, xylene or mixture of these solvents in any suitable proportion. The compound of formula (I) or it’s pharmaceutically acceptable salt can be prepared in step (g) by treating the compound of formula (X) with aqueous base in a suitable solvent. Base used in step (g) can be selected from the group consisting of hydroxides of alkali and alkaline metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide calcium hydroxide, ammonium hydroxide, rubidium hydroxide, cesium hydroxide and the like; carbonates of alkali and alkaline metals such as sodium carbonate, potassium carbonate and the like; and bicarbonates of alkali and alkaline metals such as sodium bicarbonate, potassium bicarbonate and the like. Suitable solvents that can be used in the step (g) include but are not limited to water, alcoholic solvents such as methanol, ethanol, isopropanol and the like; or mixture of these solvents. The obtained precipitate may be isolated using conventional techniques known in the art. One skilled in the art may appreciate that there are many ways to separate a solid from the mixture, for example it may be separated by using any techniques such as filtration, centrifugation, decantation and the like. After separation, the solid may optionally be washed with a suitable solvent. The obtained compound may optionally be further dried. Drying may be suitably carried out in equipment such as tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer and the like. The drying may be carried out at temperature about 40°C to about 60°C, optionally under reduced pressure. The drying may be carried out for any time periods necessary for obtaining a product with desired purity such as from about 1 hour to about 25 hours or longer. In yet another aspect of the present invention, Elagolix or it’s pharmaceutically acceptable salt prepared according to the processes of the present invention can be substantially pure having a chemical purity greater than about 99% by weight as determined using high performance liquid chromatography and provide overall good yield. In yet another aspect, the present invention provides pharmaceutical composition comprising Elagolix or it’s pharmaceutically acceptable salt prepared according to process of present invention with one or more pharmaceutically acceptable excipients and their use in the treatment of endometriosis & uterine fibroids. The term“pharmaceutically acceptable excipients” used in the pharmaceutical composition of invention comprise but are not limited to diluents, binders, pH stabilizing agents, disintegrants, surfactants, glidants and lubricants known in the art. In yet another aspect, present invention provides a compound of formula (VIII).

In yet another aspect, the compound of formula (VIII) can be further converted to Elagolix. In yet another aspect, compound of formula (VIII) can be further converted to pharmaceutically acceptable salts of Elagolix. In yet another specific aspect, compound of fomula (VIII) can be further converted to sodium or calcium salt of Elagolix. One skilled in the art will recognize that additional starting compounds and/or reagents are commercially available or may be easily prepared according to conventional methods well known to these skilled in the art. EXAMPLES

Following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be interpreted as a limitation thereon. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention. Example 1

Step -1: Preparation of 2,2,6-trimethyl-4H-1,3-dioxin-4-one

To a solution of tert-butyl-3-oxobutanoate (8.0 g, 50.6 mmol) in acetone (50.0 mL) and acetic anhydride (50.0 mL) was added dropwise conc. sulphuric acid (2.5 mL) at 0°C. After being stirred at ambient temperature for 5 h, the reaction mixture was poured into 1 M HCl and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous NaHCO3 and brine, dried over MgSO4 and filtered. After removal of the solvent, the residue was purified by column chromatography on silica gel (0 to 30 % ethyl acetate in hexane) to afford 2,2,6-trimethyl- 4H-1,3-dioxin-4-one (7.0 g, 98%) as a colorless oil.1H NMR (400 MHz, CDCl3) δ 5.26 (s, 1H), 2.00 (s, 3H), 1.70 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 168.7, 161.1, 106.2, 93.7, 24.9, 19.8; FT-IR (neat) cm-13000, 1739, 1640, 1393, 1358, 1273, 1206, 1032, 902, 806 cm-1; MS: 143.3 [M+H]+. Step-2: Preparation of 1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine- 2,4(1H,3H)-dione 2-Fluoro-6-trifluoromethyl-benzyl)-urea (6.0 g) and 2,2,6-trimethyl-4H-1,3- dioxin-4-one (4.0 g) in toluene (100 mL) was refluxed for 2 h. To this mixture was added p-toluene sulfonic acid (7.0 g) and again refluxed for 1 h. Toluene was removed under reduced pressure and crude residue obtained was stirred for 2h in IPA (50 mL). Solid material obtained was filtered, washed with IPA and then dried to give 1-(2-fluoro-6- (trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione ( 6.60 g, 86%) as colorless solid.1H NMR (400 MHz, DMSO-d6) δ 11.25 (s, 1H), 7.55 (m, 3H), 5.56 (s, 1H), 5.21 (s, 2H), 4.36 (brs, 1H), 2.19 (s, 3H); MS: 303.2 [M+H]+. Step-3: Preparation of 5-bromo-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6- methylpyrimidine-2,4(1H,3H)-dione

Bromine (3.2 g) was added to a solution of 1-(2-fluoro-6-(trifluoromethyl)benzyl)- 6-methylpyrimidine-2,4(1H,3H)-dione (6.0 g, 0.019 mmol) in acetic acid and stirred for 3 h at ambient temperature. Residue obtained was filtered and filtrate was diluted with ethyl acetate. The ethyl acetate layer was washed with sat. NaHCO3 solution. Organic layer was separated, washed with Na2S2O3 solution and then concentrated to give titled solid material (6.6 g, 87 %). Step-4: 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl) benzyl)-6-methyl pyrimidine-2,4(1H,3H)-dione

KOH solution (10 mL) (6.03 g, 0.107 mol) was added to a solution of (2-fluoro-3- methoxyphenyl)boronic acid (10.0 g, 0.026 mol) and 5-bromo-1-(2-fluoro-6- (trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (5.35 g, 0.031 mol) in acetone (30 mL) and water (20 mL). Reaction mixture was degassed for 30 min, then tri- t-butylphosphonium tetrafluoroborate (80 mg) and Pd(OAc)2 (30 mg) was added. Reaction mixture was stirred at 70⁰C for 10 h and further cooled to ambient temperature. Acetic acid (4.5 mL) was added to give colorless material, which was filtered, washed with methanol and dried to give 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6- (trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (8.49 g, 76 %).1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 7.58 (m, 3H), 7.15 (m, 2H), 6.72 (m, 1H), 5.33 (s, 2H) 3.84 (s, 3H), 2.08 (s, 3H); MS: 427.3 [M+H]+. Step-5: Preparation of benzyl (R)-(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6- (trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrim idin-1(2H)-yl)-1- phenylethyl) carbamate

(R)-2-(((benzyloxy)carbonyl)amino)-2-phenylethyl methanesulfonate (7.45 g, 0.021 g) was added to a solution of 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6- (trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (7.0 g, 0.0164 mol), K2CO3 (5.66 g, 0.041 mmol) in DMF (40 mL). The reaction mixture was stirred for 14 h at ambient temperature. Reaction mixture was poured into water and then extracted with ethyl acetate (2 X 50 mL). Organic layer was washed with water, brine and concentrated to give residue which was triturated with EtOAc: hexane mixture to provide benzyl (R)- (2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromet hyl)benzyl)-4-methyl-2,6- dioxo-3,6-dihydro pyrimidin-1(2H)-yl)-1-phenylethyl)carbamate as colorless solid (9.7 g, 87%).1H NMR (400 MHz, DMSO-d6) δ 7.75 (m, 4H), 7.25 (m, 11 H), 6.65 (m, 1H), 5.31 (s, 2H), 5.04 (m, 3H), 4.05 (m, 3H), 3.86 (s, 3H), 2.10 (s, 3H); MS: 678.4 [M-H]+. Step 6: Preparation of (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1 - (2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4( 1H,3H)-dione

To a solution of benzyl (R)-(2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6- (trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrim idin-1(2H)-yl)-1- phenylethyl)carbamate (9.0 g, 0.0132 mol) in MeOH (60 mL) was added 10% Pd/C (1.8 g, 50% aq) and stirred under hydrogen atmosphere for 5 h. Reaction mixture was filtered through celite and filtrate was concentrated to give (R)-3-(2-amino-2-phenylethyl)-5-(2- fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzy l)-6-methylpyrimidine-2,4 (1H,3H)-dione (6.9 g, 97 %).1H NMR (400 MHz, DMSO-d6) δ 7.31 (m, 3H), 7.17 (m, 7 H), 6.7 (m, 1H), 5.33 (s, 2H), 4.04 (m, 2H), 3.86 (s, 3H), 2.10 (m, 2H), 1.99 (s, 3H); MS: 546.23 [M+H]+. Step-7: Preparation of ethyl (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6- (trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrim idin-1(2H)-yl)-1- phenylethyl) amino)butanoate

To a solution of (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1 - (2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4( 1H,3H)-dione (20.0 g, 0.0366 mol) in DMF (120 mL), DIPEA (8.30 mL g, 0.047 mol) and ethyl 4- bromobutanoate (5.77 mL, 0.0403 mol) were added and reaction mixture was stirred at 60⁰C for 5 h. Reaction mixture was cooled, poured into water and extracted with ethyl acetate ( 2 X 200 mL). Organic layer was washed with water, brine and then concentrated to give residue which was further purified with column chromatography (MeOH:DCM) to provide ethyl (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6- (trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrim idin-1(2H)-yl)-1- phenylethyl)amino)butanoate (20.1 g, 83 %).1H NMR (400 MHz, DMSO-d6) δ 7.64 (m, 3H), 7.20 (m, 7 H), 6.72 (m, 1H), 5.33 (s, 2H), 4.00 (m, 3H), 3.86 (s, 3H), 2.23 (m, 4H), 2.09 (s, 3H); MS: 660.3 [M+H]+. Step-8: Preparation of Sodium (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6- (trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrim idin-1(2H)-yl)-1- phenylethyl)amino)butanoate

To a solution of ethyl (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6- (trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrim idin-1(2H)-yl)-1- phenylethyl) amino)butanoate (15.0 g, 0.022 mol) in ethanol (60 mL) was added NaOH (1.81 g, 0.045 mol) solution (60 mL). Reaction mixture was stirred at ambient temperature for 2 h. Ethanol was removed under reduced pressure and was extracted with 2-butanone (3 X 80 mL) by making aqueous layer saturated with NaCl. Combined organic layer was washed with brine and concentrated to ~50 mL. It was passed through micron and then added into heptane (100 mL). Precipitate material was filtered and washed with heptane to provide sodium (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2- fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dih ydropyrimidin-1(2H)-yl)-1- phenylethyl)amino)butanoate (11.8 g, 80 %).1H NMR (400 MHz, DMSO-d6) δ 7.63 (m, 3H), 7.18 (m, 7 H), 6.65 (m, 1H), 5.32 (s, 2H), 3.95 (m, 3H), 3.84 (s, 3H), 2.26 (m, 2H), 2.07 (s, 3H), 1.78 (m, 2H), 1.45 (m, 2H); MS: 632.2 [M+H free acid]+.