DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF ELAGOLIX”

Glenmark Pharmaceuticals Limited,
Glenmark Life Sciences Limited
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

The following specification describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of elagolix and salts thereof.
BACKGROUND OF THE INVENTION
ORILISSA® (elagolix) tablets for oral administration contain elagolix sodium, the sodium salt of the active moiety elagolix. Elagolix sodium is a nonpeptide small molecule, GnRH receptor antagonist. The chemical name of elagolix is sodium 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) butanoate, depicted by compound of formula I,

I.
ORILISSA® is a tablet available in 150mg and 200mg strength, indicated for the management of moderate to severe pain associated with endometriosis.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation of elagolix sodium, a compound of formula I,

I,
comprising the steps of:
a) reacting a compound of formula XI’ with a compound of formula X in presence of a palladium catalyst, a base and optionally in presence of a ligand,

XI’ X
to obtain a compound of formula IX,

IX
b) reacting a compound of formula IX with a compound of formula VI,

IX VI
wherein x= Cl, Br, OMs or OTs in presence of a base to obtain a compound of formula V,

V
c) deprotecting a compound of formula V to obtain a compound of formula XIII,

XIII
d) reacting a compound of formula XIII with ethyl 4-bromobutanoate, a compound of formula IV, in presence of a base to obtain a compound of formula II,

II
e) hydrolyzing a compound of formula II, using sodium hydroxide or sodium C1-C4 alkoxide, to obtain elagolix, a compound of formula I,

I.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides a process wherein elagolix sodium, a compound of formula I is obtained as depicted in scheme I,

Scheme I.
In one embodiment, the present invention provides a process wherein elagolix sodium, a compound of formula I is obtained as depicted in scheme III,
Scheme III
In one embodiment, the compound of formula XI’ may be reacted with the compound formula X using palladium catalyst and organic or inorganic base. In one embodiment, the compound of formula XI’ may be reacted with the compound formula X using palladium catalyst, organic or inorganic base optionally in presence of a ligand. In one embodiment, the palladium catalyst is selected from the group consisting of palladium acetate (Pd(OAc)2), tris(dibenzylidene-acetone)palladium (Pd2(dba)3), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) and the like. In one embodiment, the organic base is selected from the group consisting of amines, organolithiums, tetraalkylammonium hydroxides, phosphonium hydroxides and the like. In one embodiment, the amine is selected from the group consisting of cyclic aliphatic amine, trialkyl amines and heterocyclic amine. In one embodiment, the cyclic aliphatic amine is selected from the group consisting of piperidine, piperazine and the like. In one embodiment, the trialkyl amine is selected from the group consisting of triethylamine, diisoporpylethylamine (DIPEA) and the like. In one embodiment, the heterocyclic amine is selected from the group consisting of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (Dabco) pyridine, pyrimidine, 4-(dimethylamino)pyridine (DMAP) and the like. In one embodiment, the organolithium is selected from the group consisting of methyllithium, n-butyllihtium, t-butyllithium and the like. In one embodiment, the tetraalkylammonium hydroxide is selected from the group consisting of tetrabutylammonium hydroxide (TBAH), tetramethylammonium hydroxide and the like. In one embodiment, the phosphonium hydroxide is selected from the group consisting of tetrabutylphosphounium hydroxide and the like. In one embodiment, the inorganic base is selected from the group consisting of metal carbonate, metal bicarbonate, metal hydroxide and metal alkoxides wherein the metal is selected from the group consisting of sodium, potassium, lithium, calcium, cesium or magnesium. In one embodiment, the metal carbonate is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, cesium carbonate, magnesium carbonate and the like. In one embodiment, the metal bicarbonate is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, calcium bicarbonate, cesium bicarbonate, magnesium bicarbonate and the like. In one embodiment, the metal hydroxide is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, cesium hydroxide, magnesium hydroxide and the like. In one embodiment, the metal alkoxide is selected from the group consisting of sodium methoxide, potassium t-butoxide, sodium ethoxide and the like. In one embodiment, the ligand is selected from the group consisting of tri-t-butylphosphonium tetrafluoroborate, tri-t-butylphosphine, triphenylphosphine and the like.
In one embodiment, a compound of formula IX may be reacted with a compound of formula VI,

IX VI
wherein x=Cl, Br, OMs or OTs in presence of a base to obtain a compound of formula V.
In one embodiment, the base used may be selected from organic or inorganic base.
In one embodiment, the organic or inorganic base may be selected from the group as discussed supra.
In one embodiment, the compound of formula IX may be reacted with a compound of formula VI, wherein x=Cl, Br, or OTs, in presence of a base.
In one embodiment, the compound of formula IX may be reacted with a compound of formula VI, wherein x= OTs, in presence of a base.
In one embodiment, the compound of formula V may be isolated or prepared ‘in situ’.
In one embodiment, the compound of formula V is not isolated and carried forward for the next reaction.
In one embodiment, the deprotection of a compound of formula V,

V XIII
may be carried out using the reagent selected from the group consisting of trifluoroacetic acid (TFA) in dichloromethane; hydrochloric acid (HCl) in ethyl acetate; sulfuric acid in t-butyl acetate; p-toluenesulfonic acid (PTSA); methanesulfonic acid (MsOH); phosphoric acid in THF; Lewis acids such as BF3.OEt2, TMSI, TMSOTf, TiCl4, SnCl4, AlCl3, Sn(OTf)2 and ZnBr2 and the like, to obtain a compound of formula XIII.
In one embodiment, the compound of formula XIII may be purified by
a) converting the compound of formula XII to its acid addition salt;
b) treating acid addition salt of XIII with heptane;
and c) isolating.
In one embodiment, the present invention provides an acid addition salt of a compound of formula XIII, a compound of formula XIIIA,

XIIIA
wherein HX may be selected from the group consisting of organic or inorganic acid
In one embodiment inorganic acid may be selected from the group consisting of hydrochloric acid (HCl), sulfuric acid, phosphoric acid and the like.
In one embodiment, the organic acid may be selected from the group consisting of acetic acid, mandelic acid, cinnamic acid, isonicotinic acid, nicotinic acid, oxalic acid, di-p-toluoyl-L-tartaric acid (DTTA), phthalic acid, DL-tartaric acid, 5-nitroisophtalic acid and the like.
In one embodiment, the present invention provides a hydrochloride salt of a compound of formula XIII, a compound of formula XIIIA’.

XIIIA’
In one embodiment, a compound of formula XIII may be reacted with ethyl 4-bromobutanoate, a compound of formula IV,

XIII II
to obtain a compound of formula II.
In one embodiment, the compound of formula XIII may be reacted with ethyl 4-bromobutanoate, the compound of formula IV, in presence of a base.
In one embodiment, the base may be selected from the group as discussed supra.
In one embodiment, the compound of formula II may be converted to its acid addition salt, a compound of formula IIA.

IIA
wherein HX may be selected from the group consisting of organic or inorganic acid as discussed supra.
In one embodiment, the present invention provides an acid addition salt of the compound of formula II, a compound of formula IIA.

IIA
wherein HX may be selected from the group consisting of organic or inorganic acid as discussed supra.
In one embodiment, the present invention provides a hydrochloride salt of compound of formula II, a compound of formula IIA’.

IIA’
In one embodiment, elagolix sodium, the compound formula I is obtained by hydrolysis of the compound of formula II using sodium hydroxide or sodium C1-C4 alkoxide.
In one embodiment, elagolix sodium, the compound formula I is obtained by hydrolysis of the compound of formula IIA using sodium hydroxide or sodium C1-C4 alkoxide.
In one embodiment, elagolix sodium, the compound formula I is obtained by hydrolysis of the compound of formula IIA’ using sodium hydroxide or sodium C1-C4 alkoxide.
In one embodiment, the sodium C1-C4 alkoxide is selected from the group consisting of sodium methoxide, sodium ethoxide and the like.
In one embodiment, the present invention provides a process for elagolix sodium, the compound of formula I, wherein the compound of formula IX is obtained by reacting the compound of formula XI wherein x=Br, the compound of formula XI’,

XI’,
with the compound of formula X.
In one embodiment, the present invention provides a process for the compound of formula XI,

XI
comprising the steps:
a) reduction of 2-fluoro-6-(trifluoromethyl)benzonitrile to obtain 1-[2-fluoro-6-(trifluoromethylphenyl]methanamine,
b) reaction of 1-[2-fluoro-6-(trifluoromethylphenyl]methanamine with urea to obtain 1-[2-fluoro-6-(trifluoromethyl)benzyl]urea,
c) reaction of 1-[2-fluoro-6-(trifluoromethyl)benzyl]urea with a reagent selected from t-butyl 3-oxobutanoate and diketene, to obtain 1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4-dione XIII,

XIII
and; d) reaction of 1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine2,4-dione (XIII) with suitable halogenating agent to obtain the compound of formula XI,

XI
wherein x=Cl, Br or I.
In one embodiment, the compound of formula XI wherein x=Br, the compound of formula XI’,

XI’
is obtained by reacting the compound of formula XIII,

XIII
with suitable brominating agent.
In one embodiment, the brominating agent is selected from the group consisting of bromine, hydrogen bromide, Phosphorus tribromide (PBr3), N-bromosuccinimide, N-bromophthalimide, carbon tetrabromide, and the like.
In one embodiment, the present invention provides a process wherein elagolix sodium, the compound of formula I,

I
is obtained in amorphous form, the process comprising,
a) dissolving elagolix sodium in first organic solvent;
b) adding a second organic solvent to the mixture obtained in step a;
c) stirring the mixture obtained in step b; and
d) isolation of amorphous elagolix sodium.
In one embodiment, the first solvent is selected from C1-C6 aliphatic ketone, C1-C6 aliphatic ester and the like
In one embodiment, C1-C6 aliphatic ketone is selected from the group consisting of as acetone, methyl isobutyl ketone, butanone and the like. In one embodiment, C1-C6 aliphatic ester is selected from the group consisting of ethyl acetate, isopropyl acetate, butyl acetate and the like. In one embodiment, the second solvent is selected from aliphatic hydrocarbons. In one embodiment, the aliphatic hydrocarbon is selected from the group consisting of heptane, hexane, cyclohexane and the like.
In one embodiment, elagolix or the sodium salt thereof, the compound of formula I, is isolated by any method known in the art. The method, may involve any of the techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like, evaporation by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying, agitated nutsche filter dryer, complete evaporation in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum, or concentrating the solution, cooling the solution if required and filtering the obtained solid by gravity or by suction, centrifugation, and the like.
In one embodiment, the present invention provides a process wherein elagolix sodium, the compound of formula I,

I
is obtained in amorphous form, the process comprising,
a) dissolving elagolix sodium in methylisobutyl ketone;
b) adding heptane to the mixture obtained in step a;
c) stirring the mixture obtained in step b; and
d) isolation of amorphous elagolix sodium by vacuum filtration.
In one embodiment, the present invention provides enantiomerically pure elagolix sodium, the compound of formula I,

I.
In one embodiment, the present invention provides enantiomerically pure elagolix sodium, the compound of formula I containing less than 1% of (1S) isomer with respect to sodium 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)butanoate, the compound of formula I, as determined by HPLC.
In one embodiment, the present invention provides a process wherein elagolix sodium, the compound of formula I is obtained as depicted in scheme II,

Scheme II.
In one embodiment, the compound of formula XI wherein x= Br, the compound of formula XI’,

XI’,
may be reacted with the compound of formula X using palladium catalyst and organic or inorganic base.
In one embodiment, the present invention provides a compound of formula VI,

VI
wherein, x= Cl, Br, I, or OTs.
In one embodiment, the present invention provides a compound of formula VII,

VII
wherein, x= Cl, Br, I, OMs or OTs.
In one embodiment, the present invention provides a process for the compound of formula VII comprising halogenation of a compound of formula XII,

XII
using a suitable halogenating agent.
In one embodiment, the suitable halogenating agent may be selected from the group consisting of iodine, bromine, hydrogen iodide, hydrogen bromide, hydrogen chloride, PI3, PBr3, PCl3, SOCl2, N-bromosuccinimide, N-bromophthalimide, carbon tetrabromide, N-iodosuccinimide, carbon tetraiodide, trimethylsilyl iodide and the like.
In one embodiment, the present invention provides a process for the compound of formula VII wherein x=Br, the compound of formula VII’,

VII’
comprising bromination of the compound of formula XII, using suitable brominating agent. In one embodiment, the brominating agent may be selected from the group as discussed supra.
In one embodiment, the present invention provides a process for elagolix sodium, the compound of formula I, the process comprising:
a) reacting the compound of formula IX with the compound formula VII wherein x=Br, the compound of formula VII’, to obtain the compound of formula III;
b) deprotection of the compound of formula III to obtain the compound of formula II; and; c) hydrolysis of the compound of formula II to obtain elagolix sodium, the compound of formula I.
In one embodiment, the present invention provides a compound of formula VIII,

VIII
wherein, x=Cl, Br, I, OMs or OTs.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES
Example 1: Preparation of 1-[2-fluoro-6-(trifluoromethyl)phenyl]methanamine
In a 1 liter autoclave, methanol (500ml) followed by 2-fluoro-6-(trifluoromethyl)benzonitrile (50g) and Raney Nickel (40g) was added under nitrogen atmosphere. The reaction mass was stirred at about 25oC to about 30oC for about 5h to about 6h under about 4kg to about 5kg hydrogen gas pressure. After completion, the reaction mass was filtered. To the filtrate conc HCl was added and stirred for about 30min to about 40min. The solvent was distilled under vacuum, reaction mass was degased, crystallized from toluene and dried in an oven under vacuum to obtain 1-[2-fluoro-6-(trifluoromethyl)phenyl]methanamine. Yield: 53g (87%).
1H NMR (CDCl3) d 4.14 (s, 2H), 7.68-7.77 (m, 3H), 8.73 (s, 2H); Mass 194 (M+H).
Example 2: Preparation of 1-[2-fluoro-6-(trifluoromethyl)benzyl]urea
1-[2-fluoro-6-(trifluoromethyl)phenyl]methanamine (50g), urea (52g) and conc HCl was added in water. The reaction mass was heated to about 85oC to about 90oC and stirred for about 10h. Water was added to the reaction mass and stirred for about 1h. The reaction mass was filtered and washed with water. The wet crude product was purified by crystallization from toluene and dried under vacuum to obtain 1-[2-fluoro-6-(trifluoromethyl)benzyl]urea. Yield: 45g (88%).
1H NMR (DMSO) d 4.36 (s, 2H), 5.51 (s, 2H), 6.17 (d, 1H), 7.55-7.60 (m, 3H); Mass 237 (M+H).
Example 3: Preparation of 1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl pyrimidine-2,4(1H,3H)-dione
1-[2-fluoro-6-(trifluoromethyl)benzyl]urea (45g) was added in toluene (2.3 Ltr). The reaction mass was heated and stirred for about 1h to about 2h. t-butyl 3-oxobutanoate (108.08g) was slowly added to the reaction mass and stirred for about 4h to about 5h. Para toluene sulfonic acid (49.2g) was added to the reaction mass and stirred for about 1h to about 2h at about 100oC. After completion, the solvent was distilled out under vacuum, the residue was crystalized using isopropyl alcohol to obtain 1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,3H)-dione. Yield: 36g (62%).
1H NMR (DMSO) d 2.16 (s, 3H), 5.38 (s, 1H), 5.16 (s, 1H), 7.15-7.57 (m, 3H), 9.26 (br, 1H); Mass 303 (M+H).
Example 4: Preparation of 1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl pyrimidine-2,4(1H,3H)-dione
1-[2-fluoro-6-(trifluoromethyl)benzyl]urea (100g) and sodium iodide (95.2g) was added in acetonitrile (800ml). The reaction mass was cooled and diketene (53.4g) was slowly added followed by trimethyl chlorosilane (69g) and stirred for about 20h to about 24h at about 25oC to about 30oC. After completion, water was slowly added to the reaction mass, cooled to about 0oC to about 5oC and stirred for about 3h to about 4h. The slurry was filtered, washed with water and dried under vacuum to obtain 1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,3H)-dione.
Example 5: Preparation of compound XI’
1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,3H)-dione (25g) was added to acetic acid; bromine (26.47g) was slowly added and stirred for about 5h at about 25oC to about 30oC. After completion, the reaction mass was filtered, washed with ethyl acetate and dried in an oven under vacuum to obtain 5-bromo-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,3H)-dione (XI’).
Yield: 22g (70%). 1H NMR (DMSO) d 2.44 (s, 3H), 5.49 (s, 1H), 7.27-7.59 (m, 3H), 8.79 (br, 1H); Mass 381 (M+H).
Example 6: Preparation of compound IX
The compound XI (2g) and 2-fluoro-3-methoxyphenylboronic acid (X, 1g) was added in acetone. The reaction mass cooled to about 10oC to about 15°C and aq solution of potassium hydroxide (1.1g) was added under stirring. The reaction mass was heated to about 25oC to about 30°C under nitrogen atmosphere. Tri t-butyl phosphonium tetrafluoroborate (60mg) was added to the reaction mass and heated to about 40oC to about 45oC. Palladium acetate (60mg) was added to the reaction mass and stirred for about 20h to about 22h at about 50oC to about 55°C. After completion, the reaction mass was cooled, acetic acid (0.6ml) was slowly added and stirred for about 1h to about 2h at about 25oC to about 30°C. The reaction mass was filtered, washed with methanol. The crude product was purified from methanol and dried to obtain 5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4 (1H,3H)-dione (IX). Yield: 1.6 g (72%).
1H NMR (DMSO) d 2.05-2.09 (s, 3H), d 3.84 (s, 3H), d 5.34 (s, 1H), d 6.73-6.75 (s, 1H), d 7.15-7.17 (d, 1H), d 7.56-7.67 (m, 1H), d 11.58 (s, 1H), MS m/z (H+1) 327.
Example 7: Preparation of (2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl 4-methylbenzene sulfonate
Tert-butyl [(1R)-2-hydroxy-1-phenyl ethyl]carbamate (10g) and triethyl amine (6.4g) was added to dichloromethane (60ml), cooled to about 0oC to about 5oC and stirred for about 10 min to about 15 min. A mixture of p-toluene sulphonyl chloride (10.43g) in dichloromethane (20ml) was added to the reaction mass and stirred for about 2h to about 3h at about 15oC. After completion, the organic layer was separated, washed with saturated sodium chloride solution and concentrated under vacuum. The residue obtained was dissolved in toluene and crystals were isolated. The obtained crystals were dried in vacuum tray drier under vacuum to obtain (2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl 4-methylbenzene sulfonate.
Yield: 13.3g (80.0%). 1H NMR (CDCl3) d 1.36-1.4 (s, 9H), d 3.10-3.13 (s, 3H), d 4.17-4.28 (m, 1H), d 4.93 (m, 1H), d 5.18 (br, 1H), d 7.20-7.68 (m, 9H), MS m/z (H+1) 375.
Example 8: Preparation of compound V
The compound IX (5g) and potassium carbonate (6.5g) was added to DMF (50ml) under nitrogen atmosphere at about 25oC to about 30oC. (2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl 4-methylbenzenesulfonate (11g) was added to the reaction mass under stirring and heated to about 55oC to about 60oC for about 18h to about 20h. After completion, the reaction mass was cooled, poured in water with vigorous stirring and extracted with dichloromethane. The dichloromethane layers are washed with 10% brine solution and distilled under vacuum. The residue was purified by flash column chromatography to obtain tert-butyl{(1R)-2-[5-(2-fluoro-3-methoxy phenyl)-3-[2-fluoro-6-(trifluoromethyl)benzyl]-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}carbamate (V). Yield 10 g (83%).
Example 9: Preparation of compound VII’’
A solution of Iodine (4.97g) in dry dichloromethane was added drop wise to a solution of triphenylphosphine (4.66g) and imidazole (1.21g) in dry dichloromethane at about 0oC to about 5°C. A solution of ethyl 4-{(tert-butoxycarbonyl)[(1R)-2-hydroxy-1-phenylethyl]amino}butanoate (4.21g) in dry dichloromethane was added to the reaction mass at about 0°C to about 5oC. The reaction mass was heated to about 25oC to about 30oC and stirred for about 8h. The reaction mass was eluted by flash chromatography using ether and 10% ethyl acetate/hexane as solvent system to obtain ethyl 4-{(tert-butoxycarbonyl)[(1R)-2-iodo-1-phenylethyl]amino}butanoate (VII’’) as off-white solid. Yield: 3.54g (64%).
1H NMR (CDCl3) d 1.15 (t, 3H), 1.44 (s, 9H), 1.90-2.06 (m, 2H), 2.30-2.38 (t, 2H), 3.22-3.26 (d, 2H), 3.29-3.37 (t, 2H), 4.08-4.12 (q, 2H), 5.29 (t, 1H), 6.85 (m, 2H), 7.23-7.34 (m, 3H); Mass 462 (M+H).
Example 10: Preparation of compound III
The compound IX (0.8g) and potassium carbonate (0.75g) was added in dimethyl formamide under nitrogen atmosphere at about 25oC to about 30oC. The compound VII’’ (1.12g) was added to the reaction mass and heated to about 55oC to about 60oC for about 18h to about 20h under stirring. After completion, the reaction mass was cooled and poured in to water under vigorous stirring. The product was extracted with dichloromethane. The dichloromethane layer was washed with 10% brine solution and distilled under vacuum. The residue was purified by flash column chromatography to obtain ethyl 4-[(tert-butoxycarbonyl){(1R)-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]butanoate (III). Yield: 1.2g (85%).
1H NMR (DMSO) d 1.18-1.29 (m, 3H), 1.4 (s, 9H), 2.02-2.11 (t, 2H), 2.33-2.44 (t, 3H), 2.44-2.51 (m, 2H), 3.96 (s, 3H), 4.09-4.19 (m, 4H), 4.19-4.37 (m, 1H), 5.5 (t, 2H), 6.77-7.39 (m, 11H); Mass 760 (M+H).
Example 11: Preparation of compound III
The compound IX (0.8g) and potassium carbonate (0.75g) was added in dimethyl formamide under nitrogen atmosphere at about 25oC to about 30oC. Ethyl 4-{(tert-butoxycarbonyl)[(1R)-2-bromo-1-phenylethyl]amino}butanoate (VII’, 1.01g) was added to the reaction mass and heated to about 55oC to 60oC for about 18h to about 20h under stirring. After completion, the reaction mass was cooled and poured in to water under vigorous stirring. The product was extracted with dichloromethane. The dichloromethane layer was washed with 10% brine solution and distilled under vacuum. The residue was purified by flash column chromatography to obtain ethyl 4-[(tert-butoxycarbonyl){(1R)-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]butanoate (III). Yield: 1.2g (85%).
1H NMR (DMSO) d 1.18-1.29 (m, 3H), 1.4 (s, 9H), 2.02-2.11 (t, 2H), 2.33-2.44 (t, 3H), 2.44-2.51 (m, 2H), 3.96 (s, 3H), 4.09-4.19 (m, 4H), 4.19-4.37 (m, 1H), 5.5 (t, 2H), 6.77-7.39 (m, 11H); Mass 760 (M+H).
Example 12: Preparation of compound II
Trifluoroacetic acid (10ml) was slowly added into a solution of the compound III (3.35g) in dichloromethane under nitrogen atmosphere and stirred. After completion, the reaction mass was cooled to about 25oC to about 30oC, aq solution of sodium bicarbonate was added and extracted with ethyl acetate. The ethyl acetate layer was washed with 10% brine solution and distilled under vacuum to obtain ethyl 4-({(1R)-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)butanoate (II) as oily mass. Yield: 2.8g.
1H NMR (CDCl3) d 1.18-1.29 (m, 3H), 2.02-2.11 (t, 3H), 2.33-2.44 (t, 3H), 2.44-2.51 (m, 2H), 3.96 (s, 3H), 4.09-4.19 (m, 4H), 4.19-4.37 (m, 1H), 5.5 (t, 2H), 6.77-7.39 (m, 11H); Mass 660.80 (M+H).
Example 13: Preparation of elagolix sodium (I)
An aqueous solution of sodium hydroxide (1.5g) was added to the compound II (10g) in ethanol and stirred for about 2h at about 40oC to about 45oC. After completion, the reaction mass was cooled to about 25oC to about 30oC, water was added and washed with ethyl acetate and n-Heptane mixture (6:4). The aqueous layer was concentrated, the residue was treated with aq sodium hydroxide (0.3g) under stirring at about 25oC to about 30oC for about 30min and extracted with methyl isobutyl ketone. The methyl isobutyl ketone layer was washed with 20% w/w aq sodium chloride solution, filtered through hyflo bed and concentrated to minimum volume; n-heptane was added to it and stirred for about 2h to about 3h at about 25oC to about 30oC. The reaction mass was filtered, suck dried and further dried in vacuum oven for about 12h at about 55oC to about 60oC to obtain elagolix sodium (I). Yield: 7.0 g (70%).
1H NMR (CDCl3) d 1.71-1.82 (d, 2H), 2.07 (s, 3H), 2.37-2.42 (d, 2H), 2.66-2.72 (m, 2H), 3.88-3.89 (s, 3H), 4.39-4.51 (m, 2H), 4.60-4.66 (t, 1H), 5.21-5.59 (m, 2H), 6.79-7.55 (m, 11H); Mass 632.32 (M+H).
Example 14: Preparation of compound XIII
The compound IX (50 g, compound IX) and potassium carbonate (48.66 g) were added to DMF (250ml) under nitrogen atmosphere at about 25oC to about 30°C. (2R)-2-[(tert-butoxycarbonyl)amino]- 2-phenylethyl methanesulfonate (73.94 g, compound VI) was added to the reaction mass and stirred for about 16h to about 18h at about 50°C to about 60°C. After completion, the reaction mass was cooled and poured into water under vigorous stirring. The product was extracted with ethyl acetate. Methane sulfonic acid (35g) was added to the organic layer and stirred for about 4h at about 55oC to about 60°C. After completion, the reaction mass was cooled to about 25oC to about 30°C and neutralized with aqueous solution of potassium carbonate. The organic layer was separated and treated with aqueous phosphoric acid solution. The aqueous layer was separated and treated with aqueous solution of potassium carbonate. The product was extracted with ethyl acetate. EtOAc-HCl was slowly added to the organic layer followed by n-Heptane. The organic layer was distilled out under reduced pressure; hydrochloride salt of 3-[(2R)-2-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-6-methylpyrimidine-2,4(1H,3H)-dione (XIII) was isolated with n-heptane at ambient temperature and dried under vacuum at about 45oC to about 55°C for about 10h. Yield: 58g. The hydrochloride salt of XIII (56g) was dissolved in ethyl acetate and basified with aqueous solution of potassium carbonate. The organic layer was separated and distilled under reduced pressure to obtain compound XIII as white solid. Yield: 43g (67.2%).
Examples 15: Preparation of ethyl 4-({(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo-3,6-dihydro pyrimidin-1(2H)-yl]-1-phenylethyl}amino)butanoate hydrochloride (IIA’)
N,N-diisopropylethylamine (12.2g) and ethyl-4-bromobutyrate (16.4g) were added to a solution of compound XIII (39.5g) in dimethyl formamide, at room temperature and the reaction mixture was stirred for about 22h to about 24h at about 55°C to about 60°C. After completion, the reaction mass was cooled to about 25°C to about 30°C, water and isopropyl acetate were added to it. The organic layer was separated and washed with water, treated with aqueous solution of ortho-phosphoric acid. The organic layer was separated and again treated with aqueous solution of ortho-phosphoric acid. The combined aqueous layers were washed with isopropyl acetate. Methylene dichloride was added to aqueous layer and neutralized with aqueous solution of potassium carbonate. The organic layer was separated, washed with water and concentrated to obtain ethyl 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)butanoate as viscous oil (II), Yield: 40g. The compound II (40g) was dissolved in isopropyl acetate and conc. hydrochloric acid (7.25 mL) was slowly added to it under stirring. The organic layer was concentrated to minimum volume and added slowly to n-heptane (395 mL) at about 0oC to about 5°C and stirred for about 30 min. The reaction mass was filtered, suck dried and further dried in vacuum oven for about 12h at about 55°C to about 60°C to obtain hydrochloride salt of compound II. Yield: 33.8 g (67.1%).

Example 16: Preparation of Elagolix sodium (I)
An aqueous solution of sodium hydroxide was added to hydrochloride salt of compound II (15 g) in methanol and stirred for about 3h at about 35°C to about 40°C. After completion, the reaction mass was cooled to about 25°C to about 30°C, water was added and washed with ethyl acetate and n-heptane mixture (6:4). The aqueous layer was concentrated, the residue was treated with aqueous sodium hydroxide under stirring at about 25°C to about 30°C for about 30 min and extracted with methyl isobutyl ketone. The methyl isobutyl ketone layer was washed with 20% w/w aqueous sodium chloride solution, filtered through hyflo-bed and concentrated to minimum volume; n-heptane was added to it and stirred for about 2h to about 3h at about 25°C to about 30°C. The reaction mass was filtered, suck dried and further dried in vacuum oven for about 12h at about 55°C to about 60°C to obtain Elagolix sodium (I). Yield: 10.6 g (75.2%). ,CLAIMS:WE CLAIM:
1. A process for the preparation of elagolix sodium, a compound of formula I,

I,
comprising the steps of:
a) reacting a compound of formula XI’ with a compound of formula X in presence of a palladium catalyst, a base and optionally in presence of a ligand,

XI’ X
to obtain a compound of formula IX,

IX.
b) reacting a compound of formula IX with a compound of formula VI,

IX VI
wherein x= Cl, Br, OTs or OMs, in presence of a base to obtain a compound of formula V,

V
c) deprotecting a compound of formula V to obtain a compound of formula XIII,

XIII
d) reacting a compound of formula XIII with ethyl 4-bromobutanoate, compound of formula IV, in presence of a base to obtain a compound of formula II,

II
e) hydrolyzing a compound of formula II, using sodium hydroxide or sodium C1-C4 alkoxide, to obtain elagolix, a compound of formula I,

I.
2. The process as claimed in claim 1, wherein the base used in step ‘a’ is selected from group consisting of sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.
3. The process as claimed in claim 1, wherein palladium catalyst used in step ‘a’ is selected from the group consisting of palladium acetate (Pd(OAc)2), tris(dibeznylidene-acetone)palladium (Pd(bda)3), and tetrakis(triphenylphosphine)palladium (Pd(PPh3)4).
4. The process as claimed in claim 1, wherein the ligand used in step ‘a’ is selected from the group consisting of tri-t-butylphosphonium tetrafluoroborate, tri-t-buylphosphine and triphenylphosphine.
5. The process as claimed in claim 1, wherein deprotection of compound of formula V in step ‘c’ is carried out using reagent selected from the group consisting of trifluoroacetic acid, hydrochloric acid, sulfuric acid, p-toluene sulfonic acid (PTSA), methanesulfonic acid (MsOH), phosphoric acid and Lewis acid.
6. The process as claimed in claim 1, wherein the base used in step ‘d’ is selected from the group consisting of triethyl amine, DIPEA, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.
7. The process as claimed in claim 1, wherein sodium C1-C4 alkoxide is selected from the group consisting of sodium methoxide, sodium ethoxide and sodium butoxide.
8. The process as claimed in claim 1, wherein elagolix sodium, a compound of formula I,

I
is obtained in amorphous form, the process comprising:
i) dissolving elagolix sodium in first organic solvent;
ii) adding a second solvent to the mixture obtained in step ‘a’;
iii) stirring the mixture obtained in step ‘b’;
and
iv) isolation of amorphous elagolix sodium.
9. The process as claimed in claim 8, wherein the first solvent is selected from the group consisting of acetone, butanone and MIBK, ethyl acetate, isopropyl acetate.
10. The process as claimed in claim 8, wherein second solvent is selected from the group consisting of heptane, hexane and cyclohexane.