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 a compound of formula 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,
,
comprising the steps:
a) reacting 5-iodo-2,4-dimethoxy-6-methylpyrimidine with (2-fluoro-3-methoxy phenyl)boronic acid in presence of a base, a palladium catalyst and optionally in presence of a ligand, to obtain a compound of formula XVII,
;
b) demethylating the compound of formula XVII to obtain a compound of formula XVI,
;
c) reacting the compound of formula XVI with 2-(bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene to obtain a compound of formula IX,
;
d) reacting the compound of formula IX with a compound of formula XVA,
, ;
wherein x= Cl, Br, OTs or OMs, to obtain a compound of formula V,
;
e) deprotecting the compound of formula V to obtain a compound of formula XII,
;
f) reacting the compound of formula XII with ethyl 4-bromobutanoate, in presence of a base to obtain a compound of formula II,
; and
g) hydrolyzing a compound of formula II, using sodium hydroxide or sodium C1-C4 alkoxide, to obtain elagolix sodium, a compound of formula I.
In one embodiment, the present invention provides a process for the preparation of a compound of formula XVI,
,
comprising the steps:
a) chlorinating 6-methyluracil to obtain 2,4-dichloro-6-methylpyrimidine;
b) reacting 2,4-dichloro-6-methylpyrimidine with aq methanol in presence of a base to obtain 2,4-dimethoxy-6-methylpyrimidine;
c) iodinating 2,4-dimethoxy-6-methylpyrimidine, to obtain 5-iodo-2,4-dimethoxy-6-methylpyrimidine;
d) reacting 5-iodo-2,4-dimethoxy-6-methylpyrimidine with (2-fluoro-3-methoxy phenyl)boronic acid in presence of a base, palladium catalyst and optionally a ligand, to obtain a compound of formula XVII,
; and
e) demethylating the compound of formula XVII to obtain a compound of formula XVI.
In one embodiment, the present invention provides a process for a compound of formula IX,
,
comprising the steps:
a) reacting 5-iodo-2,4-dimethoxy-6-methylpyrimidine with (2-fluoro-3-methoxy phenyl)boronic acid in presence of a base, palladium catalyst and optionally a ligand, to obtain a compound of formula XVII,
;
b) demethylating the compound of formula XVII to obtain a compound of formula XVI,
; and
c) reacting the compound of formula XVI with 2-(bromomethyl)-1-fluoro-3-(trifluoro methyl)benzene to obtain a compound of formula IX.
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 2,
Scheme 2.
In one embodiment, the present invention provides a process for the preparation of elagolix sodium, a compound of formula I,
,
comprising the steps:
a) reacting 5-iodo-2,4-dimethoxy-6-methylpyrimidine with (2-fluoro-3-methoxy phenyl)boronic acid in presence of a base, a palladium catalyst and optionally in presence of a ligand, to obtain a compound of formula XVII,
;
b) demethylating the compound of formula XVII to obtain a compound of formula XVI,
;
c) reacting the compound of formula XVI with 2-(bromomethyl)-1-fluoro-3-(trifluoro methyl)benzene to obtain a compound of formula IX,
;
d) reacting the compound of formula IX with a compound of formula XVA,
, ;
wherein x= Cl, Br, OTs or OMs, to obtain a compound of formula V,
;
e) deprotecting the compound of formula V to obtain a compound of formula XII,
;
f) reacting the compound of formula XII with ethyl 4-bromobutanoate, in presence of a base to obtain a compound of formula II,
; and
g) hydrolyzing a compound of formula II, using sodium hydroxide or sodium C1-C4 alkoxide, to obtain elagolix sodium, a compound of formula I.
In one embodiment, the present invention provides a process wherein, reaction of 5-iodo-2,4-dimethoxy-6-methylpyrimidine with (2-fluoro-3-methoxyphenyl)boronic acid may be carried out in presence of organic or inorganic base.
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 tetrabutyl phosphonium 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, reaction of 5-iodo-2,4-dimethoxy-6-methylpyrimidine with (2-fluoro-3-methoxy phenyl)boronic acid may be carried out in presence of base, a palladium catalyst and 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 ligand is selected from the group consisting of tri-t-butyl phosphonium tetrafluoroborate, tri-t-butyl phosphine, triphenylphosphine and the like.
In one embodiment, the present invention provides a process wherein, a compound of formula XVI may be obtained by demethylation of the compound of formula XVII.
In one embodiment, the demethylation of the compound of formula XVII may be carried out using reagents selected from the group consisting of trimethyl silyl iodide (TMSI) in dichloromethane, boron tribromide (BBr3) in dichloromethane, hydrogen bromide (HBr) in acetic acid, hydrochloric acid either in acetic acid or in a mixture of water, THF and dioxane and the like. In one embodiment, the compound of formula XVI may be reacted with 2-(bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene to obtain the compound of formula IX. In one embodiment, the compound of formula V may be obtained by reacting the compound of formula IX with the compound of formula XVA. In one embodiment, the compound of formula V may be obtained by reacting the compound of formula IX with the compound of formula XVA in presence of organic or inorganic base. In one embodiment, the compound of formula V may be obtained by reacting the compound of formula IX with the compound of formula XV. In one embodiment, the compound of formula V may be obtained by reacting the compound of formula IX with the compound of formula XV in presence of 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 XIII may be obtained by reacting the compound of formula XIV with the iodinating agent. In one embodiment, the iodinating agent may be selected from the group consisting of Iodine, hydrogen iodide, PI3, N-iodosuccinimide, carbon tetraiodide, trimethylsilyl iodide and the like. In one embodiment, the compound of formula XII may be obtained by deprotection of the compound of formula V. In one embodiment, the deprotection of the compound of formula V may be carried out by using the reagent selected from the group as discussed supra. In one embodiment, the deprotection of the compound of formula V may be carried out using the reagent selected from the group consisting of trifluoroacetic acid in dichloromethane, hydrochloric acid in ethyl acetate, sulfuric acid in t-butyl acetate, p-toluene sulfonic acid, methanesulfonic cid, phosphoric acid in THF, Lewis acids such as BF3.OEt2, TMSI, TMSOTf, TICl4, SnCl4, AlCl3, Sn(OTf)2, ZnBr2 and the like. In one embodiment, the compound of II may be obtained by reacting the compound of formula XII with ethyl 4-bromobutanoate, the compound of formula IV. In one embodiment, the compound of II may be obtained by reacting the compound of formula XII with ethyl 4-bromobutanoate, the compound of formula IV in presence of organic or inorganic base. In one embodiment, the organic base is selected from the group as discussed supra. In one embodiment, the inorganic base is selected from the group as discussed supra. 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, 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 compound of formula XVI,
.
In one embodiment, the present invention provides a compound of formula XVII,
.
In one embodiment, the present invention provides a process for the compound of formula XVI, comprising the steps:
a) chlorinating 6-methyluracil to obtain 2,4-dichloro-6-methylpyrimidine;
b) reacting 2,4-dichloro-6-methylpyrimidine with aq methanol in presence of base to obtain 2,4-dimethoxy-6-methylpyrimidine;
c) iodinating 2,4-dimethoxy-6-methylpyrimidine, to obtain 5-iodo-2,4-dimethoxy-6-methylpyrimidine; and
d) reacting 5-iodo-2,4-dimethoxy-6-methylpyrimidine with 2-fluoro-3-methoxyphenyl boronic acid to obtain the compound of formula XVII; and
e) demethylating the compound of formula XVII to obtain a compound of formula XVI.
In one embodiment, the present invention provides a process for a compound of formula IX, comprising the steps:
a) reacting 5-iodo-2,4-dimethoxy-6-methylpyrimidine with (2-fluoro-3-methoxy phenyl)boronic acid in presence of a base, palladium catalyst and optionally a ligand, to obtain a compound of formula XVII,
;
b) demethylating the compound of formula XVII to obtain a compound of formula XVI,
; and
c) reacting the compound of formula XVI with 2-(bromomethyl)-1-fluoro-3-(trifluoro methyl)benzene to obtain a compound of formula IX.
In one embodiment, the present invention provides a process wherein elagolix sodium, a compound of formula I is obtained as depicted in scheme 1,

Scheme 1
In one embodiment, the compound of formula XIV may be obtained by reacting the compound of formula XV with 1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyluracil
In one embodiment, the compound of formula XIV may be obtained by reacting the compound of formula XV with 1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyluracil in presence of organic or inorganic base. In one embodiment, the organic base may be selected from the groups as discussed supra. In one embodiment, the inorganic base may be selected from the groups as discussed supra. In one embodiment, the ligand is selected from the group as discussed supra. In one embodiment, the compound of formula XIII may be obtained by reacting the compound of formula XIV with the iodinating agent. In one embodiment, the iodinating agent may be selected from the as discussed supra. In one embodiment, the compound of formula XIII may be reacted with 2-fluoro-3-methoxyphenylboronic acid. In one embodiment, the compound of formula XIII may be reacted with 2-fluoro-3-methoxyphenylboronic acid using palladium catalyst and organic or inorganic base. In one embodiment, the compound of formula XIII may be reacted with 2-fluoro-3-methoxyphenylboronic acid using palladium catalyst and organic or inorganic base, optionally in presence of a ligand. In one embodiment, the compound of formula XII may be obtained by deprotection of the compound of formula V. In one embodiment, the compound of II may be obtained by reacting the compound of formula XII with ethyl 4-bromobutanoate, the compound of formula IV. In one embodiment, the compound of II may be obtained by reacting the compound of formula XII with ethyl 4-bromobutanoate, the compound of formula IV in presence of organic or inorganic base. In one embodiment, the organic base is selected from the group as discussed supra. In one embodiment, the inorganic base is selected from the group as discussed supra. 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, the present invention provides a process for 1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyluracil, comprising the steps:
a) reduction of 2-fluoro-6-(trifluoromethyl)benzonitrile to obtain 1-[2-fluoro-6-(trifluoromethylphenyl]methanamine HCl;
b) reaction of 1-[2-fluoro-6-(trifluoromethylphenyl]methanamine HCl with urea to obtain 1-[2-fluoro-6-(trifluoromethyl)benzyl]urea; and
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-methyluracil.
In one embodiment, the present invention provides a process wherein elagolix sodium, the compound of formula I is obtained as depicted in scheme 3,
Scheme 3.
In one embodiment, the present invention provides a process wherein, a compound of formula III may be obtained by reacting the compound of formula IX with a compound of formula XVIII. In one embodiment, the reaction of the compound of formula IX with the compound of formula XVIII may be carried out in presence of reagent selected from the group consisting of triarylphosphine such as triphenylphosphine; azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate and the like. In one embodiment, the compound of formula II may be obtained by deprotection of the compound of formula III. In one embodiment, the deprotection of the compound of formula III may be carried out by using the reagent selected from the group as discussed supra. 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, the sodium C1-C4 alkoxide is selected from the group as discussed supra.
In one embodiment, the present invention provides a process for the compound of formula IX, comprising the steps:
a) iodination of 2-fluoro-3-methoxyphenylboronic acid to obtain 2-fluoro-1-iodo-3-methoxybenzene;
b) reaction of 2-fluoro-1-iodo-3-methoxybenzene with t-butyl 3-oxobutanoate to obtain t-butyl 2-(2-fluoro-3-methoxyphenyl)-3-oxobutanoate; OR
reaction of 2-fluoro-1-iodo-3-methoxybenzene with ethyl acetoacetate to obtain ethyl 2-(2-fluoro-3-methoxyphenyl)-3-oxobutanoate; and
c) reaction of 1-[2-fluoro-6-(trifluoromethyl)benzyl]urea with t-butyl 2-(2-fluoro-3-methoxyphenyl)-3-oxobutanoate or ethyl 2-(2-fluoro-3-methoxyphenyl)-3-oxobutanoate, to obtain the compound of formula IX.
In one embodiment, the present invention provides a process wherein elagolix sodium, the compound of formula I is obtained as depicted in scheme 4,

Scheme 4.
In one embodiment, the present invention provides a process wherein, the compound of formula XVI may be obtained by reacting 5-iodo-6-methyluracil with 2-fluoro-3-methoxyphenylboronic acid. In one embodiment, 5-iodo-6-methyluracil may be reacted with 2-fluoro-3-methoxyphenylboronic acid using palladium catalyst and organic or inorganic base. In one embodiment, 5-iodo-6-methyluracil may be reacted with 2-fluoro-3-methoxyphenylboronic acid using palladium catalyst and organic or inorganic base, optionally in presence of a ligand.In one embodiment, the palladium catalyst is selected from the group as discussed supra. In one embodiment, the organic or inorganic base is selected from the group as discussed supra. In one embodiment, the ligand is selected from the group as discussed supra. In one embodiment, the compound of formula XVI may be reacted with 2-(bromomethyl)-1-fluoro-3-(trifluoromethyl)benzene to obtain the compound of formula IX. In one embodiment, the present invention provides a process wherein, a compound of formula III may be obtained by reacting the compound of formula IX with a compound of formula XVIII. In one embodiment, the reaction of the compound of formula IX with the compound of formula XVIII may be carried out in presence of reagent selected from the group consisting of triarylphosphine such as triphenylphosphine; azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate and the like. In one embodiment, the compound of formula II may be obtained by deprotection of the compound of formula III. In one embodiment, the deprotection of the compound of formula III may be carried out by using the reagent selected from the group as discussed supra. In one embodiment, the present invention provides a process wherein, 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, the sodium C1-C4 alkoxide is selected from the group as discussed supra. In one embodiment, the present invention provides a process for 5-iodo-6-methyluracil, comprising the steps:
a) reacting ethyl acetoacetate with urea to obtain ethyl 3-(carbamoylamino)but-2-enoate;
b) cyclization of ethyl 3-(carbamoylamino)but-2-enoate to obtain 6-methyluracil; and
c) iodination of 6-methyluracil.
In one embodiment, the present invention provides a compound of formula XIV,

XIV.
In one embodiment, the present invention provides a process for the compound of formula XIV, comprising the steps:
a) reacting 1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyluracil with the compound of formula XV.
In one embodiment, the present invention provides a compound of formula XIII,

In one embodiment, the present invention provides a process for the compound of formula XIII, comprising the steps:
a) reacting 1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyluracil with the compound of formula XV to obtain the compound of formula XIV;
b) iodination of the compound of formula XIV.
In one embodiment, the present invention provides a process wherein elagolix sodium, the compound of formula I, is obtained in amorphous form, comprising the steps:
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.
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, 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, 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.
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.
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 hydrochloride
In an autoclave, 2-fluoro-6-(trifluoromethyl)benzonitrile (50g) and Raney Nickel (40g) was added in methanol (500ml) under nitrogen atmosphere. The reaction mass stirred at about 25oC to about 30oC for about 5h to about 6h under about 4 to about 5 hydrogen gas pressure. After completion, the reaction mass filtered, conc-HCl was added and stirred for about 30min to about 45min. The solvent was distilled out under vacuum and degased. The residue was crystallized in toluene and dried in oven under vacuum to obtain 1-[2-fluoro-6-(trifluoromethyl)phenyl]methanamine hydrochloride. Yield: 53g (87%).
Example 2: Preparation of 1-[2-fluoro-6-(trifluoromethyl)benzyl]urea
In a four neck RBF, 1-[2-fluoro-6-(trifluoromethyl)phenyl]methanamine (50g) and urea (52g) was added in water. The reaction mass heated to about 90oC and stirred for about 10h. After completion, water was added to the reaction mass, stirred for about 1h. The reaction mass was filtered and washed with water. The wet crude was purified by crystallization in toluene, dried in oven under vacuum to obtain 1-[2-fluoro-6-(trifluoromethyl)benzyl]urea. Yield: 45g (88%).
Example 3: Preparation of 1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-mehyluracil
1-[2-fluoro-6-(trifluoromethyl)benzyl]urea (45g) was added in toluene (2.3lit) and stirred under heating for about 1h to about 2h. Tertiary butyl acetoacetate (108.1g) was slowly added to the reaction 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 reduced pressure and the obtained residue was crystalized in isopropyl alcohol to obtain 1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyluracil. Yield: 36g (62%).
Example 4: Preparation of XIV
In a four neck RBF, 1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methylpyrimidine-2,4(1H,3H)-dione (15g) was added to dimethyl formamide (80ml), at about 30oC. (2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl methanesulfonate (compound XV) (25g) and potassium carbonate (15g) was added to the reaction mass and stirred at about 55oC for about 12h. After completion, the reaction mass was cooled below 20oC, water was added and extracted with ethyl acetate. The organic layer was washed with 10% brine solution and distilled out below 45oC under vacuum. The residue was purified by using column chromatography (silica gel: 60-120 mesh, 20% ethyl acetate in hexane as a mobile phase) to obtain compound XIV as white solid. Yield: 19.6g (75.2%).
Example 5: Preparation of XIII
N-iodosuccinimide (13.2g) was added to the reaction mixture containing compound XIV (15g) in dimethyl formamide (80ml) at about 30oC. The reaction mass heated to about 60oC and stirred for about 10h. After completion, the reaction mass was cooled to about 30oC, water was added and stirred for about 1h. The heterogeneous mass was filtered and washed with hexane. The residue was purified using column chromatography (silica gel: 60-120 mesh, 40% ethyl acetate in hexane as a mobile phase) to obtain compound XIII as off white solid. Yield: 15g (80.2%).
Example 6: Preparation of V
In a four neck RBF, compound XIII (1g) was added to 1,4-dioxane (6ml). 2-Fluoro-3-methoxyphenylboronic acid (0.36g) was added to the reaction mass under nitrogen atmosphere and stirred. Sodium carbonate (1g), water (2ml) and Pd(PPh3)4 (0.18g) was added to the reaction mass and stirred at about 85oC for about 14h. After completion, the reaction mass was cooled to about 25oC to about 30oC, brine solution was added and extracted with ethyl acetate. The organic layer was concentrated. The residue was purified using flash chromatography (silica gel: 60-120 mesh, 20% ethyl acetate in hexane as a mobile phase) to obtain compound V as pale yellow solid. Yield: 0.63 g (63.2%).
Example 7: Preparation of XII
In a four neck RBF, compound V (15g) was added in methylene dichloride (30ml). Trifluoroacetic acid (30ml) was added to the reaction mass over a period of about 30min at about 30oC and stirred the reaction mass for about 3h. After completion, the solvent was distilled out. To the residue methanol and water (1:1) mixture was added and washed mixture of 30% of ethyl acetate in heptane. The aqueous layer was concentrated under vacuum below 50oC, saturated with sodium bicarbonate and extracted with ethyl acetate at pH of about 8. The separated organic layer was washed with 10% brine solution and concentrated to obtain compound XII as pale yellow foamy solid. Yield: 12g (95.2 %).
Example 8: Preparation of II
In a four neck RBF, compound XII (11.7g) was added in dimethyl formamide (40ml) under stirring. Ethyl-4-bromobutanoate (5.5g) and N,N-diisopropylethylamine (3.55g) was added to the reaction mass at about 30oC and stirred for about 12h to about 15h at about 55oC. After completion, ethyl acetate and water was added to the reaction mass. The organic layer was separated, washed with 10% brine solution and concentrated under vacuum below 45oC. The oily residue was purified using column chromatography (silica gel: 60-120, 40% ethyl acetate in hexane as a mobile phase) to obtain compound II. Yield: 10.5g (yield 74.4%).
Example 9: Preparation of Elagolix sodium (I).
Aqueous sodium hydroxide solution (1.5 g in 20 ml of water) was added to compound II (10g) in ethanol (40ml). The initial turbid solution becomes clear solution which was stirred for about 2h at about 40oC to about 45oC. After completion, the reaction mass cooled to about 25oC to about 30oC, water was added, and washed with ethyl acetate and n-Heptane mixture (60:40). The aqueous layer was concentrated and treated with sodium hydroxide (0.3g) under stirring at about 25oC to about 30oC for about 30min and extracted with methyl isobutyl ketone. The combined organic layer was washed with 20% brine solution, filtered through hyflo bed and concentrated to a minimum volume. n-heptane (400ml) was added under vigorous stirring for about 2h to about 3 h at about 25oC to about 30oC. The reaction mass was filtered, suck dried, further dried in vacuum oven for 12h at about 55oC to about 60oC to obtain elagolix sodium (I). Yield: 7g (70%).
Example 10: Preparation of 2,4-dichloro-6-methyl pyrimidine.
6-methyluracil (10g) and phosphorous oxychloride (164g/100ml) was added to 4-neck RBF at about 25oC and stirred for about 5h at reflux temperature. After the completion, reaction mass was cooled to about 25oC, quenched in crushed ice and extracted with ethyl acetate. The organic layer was washed with water, concentrated under vacuum below 45oC and degased to obtain light yellow colored 2,4-dichloro-6-methyl pyrimidine. Yield: 9.1g (70.4%).
Example 11: Preparation of 2,4-dimethoxy-6-methylpyrimidine.
2,4-dichloro-6-methyl pyrimidine (9g) was added in to a mixture of methanol (100ml) and water (100ml) at about 30oC and stirred for about 10h. After the completion, solvent was distilled out under vacuum at about 45oC. Water was added to the residue and extracted with ethyl acetate. The organic layer was washed with water, concentrated under vacuum and degased to obtain 2,4-dimethoxy-6-methylpyrimidine. Yield: 6.2g (73%).
Example 12: Preparation of 5-iodo-2,4-dimethoxy-6-methylpyrimidine
To the reaction mixture of 2,4-dimethoxy-6-methyl pyrimidine (6g) in acetic acid (85ml) N-iodosuccinimide (10.5g) was added at about 25oC and stirred for about 8h at about 85oC. After the completion, the excess acetic acid was distilled out, water was added and extracted with methylene dichloride. The organic layer was washed with water, distilled under vacuum and degased well to obtain 5-iodo-2,4-dimethoxy-6-methylpyrimidine as pale yellow color solid. Yield: 10g (92%).
Example 13: Preparation of XVII
In a four neck RBF, 2,4-dimethoxy-5-iodo-6-methylpyrimidine (1g), 2-fluoro-3-methoxyphenylboronic acid (1.21g) and acetonitrile (60ml) was added under nitrogen gas atmosphere. The sodium carbonate solution (2M, 30ml) was added to the reaction mass at about 30oC and flushed thoroughly with nitrogen gas to deoxygenize at about 30oC. Pd(PPh3)4 (0.41g) was added to the reaction mass and stirred for about 45min at about 80oC. After the completion, the reaction mass was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulphate, distilled out under vacuum and degased well. The crude was purified using column chromatography (silica gel: 60-120 mesh as stationary phase; and 8% ethyl acetate in hexane as a mobile phase) to obtain compound XVII as brown solid. Yield: 0.7g (70.0%).
Example 14: Preparation of 5-(2-fluoro-3-methoxyphenyl)-6-methyluracil (XVI)
In a four neck RBF, compound XVII (0.5g), acetic acid (4ml) and concentrated hydrochloric acid (4ml) was added at about 30oC. The reaction mass was stirred for about 2h at reflux temperature. After the completion, reaction mass was cooled to about 25oC to about 30oC, water was added and stirred. The reaction mass was refluxed for about 15min. The reaction mass was then cooled to below 5oC and filtered. The solid was washed with water, dried under vacuum at about 55oC for about 4h to obtain compound XVI. Yield: 0.27g (60%).
Example 15: Preparation of 5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyluracil (IX)
In a four neck RBF, compound XVI (1g) and Bis(trimethylsilyl)acetamide (1.7g) was added at about 30oC. The reaction mass was stirred for about 2h at reflux temperature. The reaction mass was cooled to about 25oC to about 30oC, 2-fluoro-3-trifluoromethylbenzyl bromide (1.13g) was added and stirred for about 16h at reflux temperature. After the completion, the reaction mass cooled to about 25oC to about 30oC, methanol was added and stirred for about 2h. The solvent was distilled out below 45oC. The residue was purified using column chromatography (silica gel: 60-120 mesh as stationary phase; and 50% ethyl acetate in hexane as a mobile phase) to obtain compound IX. Yield: 1.2g (70%).
Example 16: Preparation of II
Trifluoroacetic acid (10ml) was slowly added to III (3.35g) in methylene dichloride (20ml) and stirred. After the completion, reaction mass was cooled to about 25oC to about 30oC, ethyl acetate, saturated sodium bicarbonate solution was added to it and stirred for about 1h. The organic layer was separated, washed with brine solution and concentrated under vacuum to obtain compound II as oily residue. Yield: 2.80g. ,CLAIMS:WE CLAIM
1. A process for the preparation of elagolix sodium, a compound of formula I,

comprising the steps:
a) reacting 5-iodo-2,4-dimethoxy-6-methylpyrimidine with (2-fluoro-3-methoxy phenyl)boronic acid in presence of a base, a palladium catalyst and optionally in presence of a ligand, to obtain a compound of formula XVII,
;
b) demethylating the compound of formula XVII to obtain a compound of formula XVI,
;
c) reacting the compound of formula XVI with 2-(bromomethyl)-1-fluoro-3-(trifluoro methyl)benzene to obtain a compound of formula IX,
;
d) reacting the compound of formula IX with a compound of formula XVA,
, ;
wherein x= Cl, Br, OTs or OMs, to obtain a compound of formula V,
;
e) deprotecting the compound of formula V to obtain a compound of formula XII,
;
f) reacting the compound of formula XII with ethyl 4-bromobutanoate, in presence of a base to obtain a compound of formula II,
; and
g) hydrolyzing a compound of formula II, using sodium hydroxide or sodium C1-C4 alkoxide, to obtain elagolix sodium, a compound of formula 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 (dibennylidene 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 a compound of formula XVII in step ‘c’ is carried out using reagent selected from the group consisting of trimethyl silyl iodide, boron tribromide, hydrogen bromide, hydrochloric acid, sulfuric acid, acetic acid or a mixture.
6. The process as claimed in claim ‘1’, wherein deprotection of a compound of formula V in step ‘e’ 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.
7. The process as claimed in claim ‘1’, wherein the base used in step ‘f’ is selected from the group consisting of triethyl amine, DIPEA, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate.
8. 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
9. A process for the preparation of a compound of formula XVI,
,
comprising the steps:
a) chlorinating 6-methyluracil to obtain 2,4-dichloro-6-methylpyrimidine;
b) reacting 2,4-dichloro-6-methylpyrimidine with aq methanol in presence of a base to obtain 2,4-dimethoxy-6-methylpyrimidine;
c) iodinating 2,4-dimethoxy-6-methylpyrimidine, to obtain 5-iodo-2,4-dimethoxy-6-methylpyrimidine;
d) reacting 5-iodo-2,4-dimethoxy-6-methylpyrimidine with (2-fluoro-3-methoxy phenyl)boronic acid in presence of a base, palladium catalyst and optionally a ligand, to obtain a compound of formula XVII,
; and
e) demethylating the compound of formula XVII to obtain a compound of formula XVI.
10. A process for a compound of formula IX,
,
comprising the steps:
a) reacting 5-iodo-2,4-dimethoxy-6-methylpyrimidine with (2-fluoro-3-methoxy phenyl)boronic acid in presence of a base, palladium catalyst and optionally a ligand, to obtain a compound of formula XVII,
;
b) demethylating the compound of formula XVII to obtain a compound of formula XVI,
; and
c) reacting the compound of formula XVI with 2-(bromomethyl)-1-fluoro-3-(trifluoro methyl)benzene to obtain a compound of formula IX.

Dated this 24th day of October, 2019
(Signed)____________________
DR. MADHAVI KARNIK
SENIOR GENERAL MANAGER-IPM
GLENMARK LIFE SCIENCES LIMITED