DESC:The following specification particularly describes the invention and the manner in which it is to be performed:

PROCESS FOR THE PREPARATION OF ELAGOLIX AND ITS INTERMEDIATES

INTRODUCTION
The present invention provides the process for the preparation of Elagolix and its intermediates.
BACKGROUND
Elagolix sodium is a non-peptide antagonist of the gonadotropin-releasing hormone receptor and chemically known as sodium;4-[[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-4-methyl-2,6-dioxopyrimidin-1-yl]-1-phenylethyl]amino]butanoate (I) as given below.

(I)
The US patent number 7056927 B2 discloses a process for preparation of Elagolix sodium salt.
The US patent number 8765948 B2 also describes a process for preparation of Elagolix sodium.
Further, the US patent number 8765948 B2 also discloses an alternate process for the preparation of Elagolix intermediate (formula (1e)).
The present invention provides an improved and commercially viable process for the preparation of Elagolix and its intermediates thereof.

SUMMARY
First embodiment of the present application provides an improved process for the preparation of compound of formula (II), which is an intermediate in the preparation process of Elagolix sodium (I).
Second embodiment of the present application provides a purification process for the compound of formula (IV), which is an intermediate in the preparation process of Elagolix Sodium (I).

DETAILED DESCRIPTION
First embodiment of the present application provides an improved process for the preparation of compound of formula (II) comprising reducing a compound of formula (III) in presence of Raney nickel.

The reduction of compound of formula (III) with Raney nickel may be carried out in presence of aqueous ammonia to obtain the compound of formula (II).
The solvents may be used for the above reaction is selected from the group comprising water; alcohol solvent such as methanol, ethanol, isopropanol, 2-butanol and the like; ether solvent such as anhydrous diethyl ether, dioxane, tetrahydrofuran and the like; hydrocarbon solvent such as hexane, toluene and the like; halogenated hydrocarbon such as dichloromethane, trichloromethane and the like and the combination thereof. The reaction may be carried out in the temperature range of 0-60°C, preferably at 20-30°C.
Compound of formula (II) may be isolated from the reaction mixture by a conventional technique such as removal of solvent, cooling, crash cooling, concentrating the mass, evaporation, flash evaporation, simple evaporation, fast solvent evaporation, rotational drying, spray drying, thin-film drying, agitated thin film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, rotary vacuum paddle dryer, adding anti-solvent and the like. Stirring or other alternate methods such as shaking, agitation, and the like, may also be employed for the isolation.
Compound of formula (II) may be used as an intermediate in the preparation process of Elagolix sodium (I).Compound of formula (II) is further converted in to Elagolix sodium (I) by a process known in the literature.

Second embodiment of the present application provides a process for purification of the compound of formula (IV) comprising;

a) providing a solution of a compound of formula (IV) in a solvent;
b) removing the unwanted by products or impurities from the reaction mass;
c) isolating the pure compound of formula (IV).
Suitable solvent that may be used in step a) include, but are not limited to: water, aromatic hydrocarbon solvent such as benzene, toluene, xylene and the like; halogenated hydrocarbon such as dichloromethane, trichloromethane and the like; ether solvent such as anhydrous diethyl ether, dioxane, tetrahydrofuran (THF), methyl tertiay butyl ether (MTBE) and the like; ester solvent such as ethyl acetate, n-propyl acetate, n-butyl acetate, ethyl formate and the like; nitrile solvent such as acetonitrile, propionitrile, and the like; alcohol solvent such as methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol), 1-butanol, 2-butanol, benzyl alcohol and the like; ketone solvent such as acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone, and the like; polar aprotic solvent such as dimethylformamide, dimethylacetamide, dimethylsulphoxide, n-methylpyrrolidine, formamide, acetamide and the like and combination thereof.
US patent number 7056927 B2 discloses a process for preparation of compound of formula (IV) comprising the step of reacting5-bromo-1-(2-fluoro-6-(trifluoro-methyl)benzyl)-6-ethylpyrimidine2,4-(1H,3H)-dione with (R)-(-)-N-Boc-2-phenyl glycinol in presence of triphenyl phosphine, diisopropylazodicarboxylate and THF to give a crude compound of formula (IV). The compound of formula (IV) is then purified by column chromatography (silica gel) to produce a pure compound of formula (IV).
The present inventors surprisingly found a new purification process for the compound of formula (IV) comprising providing a solution of a compound of formula (IV) in a suitable solvent, preferably in a hydrocarbon solvent which may be selected from benzene, toluene, xylene and the like. Magnesium chloride is added to the solution to remove the impurities and by-products. A suitable co-solvent is added to the reaction mass. The suitable co-solvent may be selected from a group of aliphatic hydrocarbon solvent such as heptane, hexane and the like. The solution may be filtered to remove the impurities and by-products. Specifically, the solution is filtered to remove a complex of triphenyl phosphine oxide-MgCl2 complex was filtered. The obtained filtrate may be evaporated to get a gummy solid and dissolved in an alcohol solvent such as methanol, ethanol, isopropyl alcohol and the like. Specifically, the alcohol solvent may be isopropyl alcohol. Optionally, an anti-solvent may be added to the above solution, specifically water may be added to the above solution to provide a pure compound of formula (IV).
Compound of formula (IV) may be isolated from the above solution by conventional methods including removal of solvent, cooling, crash cooling, concentrating the mass, evaporation, flash evaporation, simple evaporation, fast solvent evaporation, rotational drying, spray drying, thin-film drying, agitated thin film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, rotary vacuum paddle dryer, adding anti-solvent and the like. Stirring or other alternate methods such as shaking, agitation, and the like, may also be employed for the isolation.
The advantage of the present purification process is to avoid column chromatography, as known in the art for purification of compound of formula (IV). A skilled person would know that column purification of an intermediate of an API is not preferred since the process consumes a lot of time and solvent.
Compound of formula (IV) may be used as an intermediate in the preparation process of Elagolix sodium (I). Compound of formula (IV) is further converted in to Elagolix sodium (I) by a process known in the literature.
Third embodiment of the present application provides a process for purification of the compound of formula (IV) comprising;

a) providing a solution of a compound of formula (IV) in toluene;
b) adding magnesium chloride to the above solution;
c) removing the unwanted by-products or impurities from the above solution;
d) isolating the pure compound of formula (IV).

The present inventors surprisingly found a new purification process for the compound of formula (IV) comprising providing a solution of a compound of formula (IV) in toluene. Magnesium chloride is added to the solution to remove the impurities and by-products. A suitable co-solvent is added to the reaction mass. The suitable co-solvent may be selected from a group of aliphatic hydrocarbon solvent such as heptane, hexane and the like; The solution may be filtered to remove the impurities and by-products. Specifically, the solution is filtered to remove a complex of triphenyl phosphine oxide-MgCl2 complex was filtered. The obtained filtrate may be evaporated to get gummy solid and dissolved in an alcohol solvent such as methanol, ethanol, isopropyl alcohol and the like. Specifically, the alcohol solvent may be isopropyl alcohol. Optionally, an anti-solvent may be added to the above solution, specifically water as an anti-solvent may be added to the above solution to provide a pure compound of formula (IV).
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
EXAMPLES

Reference example: Preparation of 1-(2-fluoro-6-(trifluoromethyl)benzyl)urea.
2-Fluoro-6-(trifluoromethyl) benzonitrile (200 g), THF (2000 mL) were charged at 27°C and stirred for 10 min. The reaction mixture was heated up to 60°C. BH3 ·THF (1 M in THF; 3174 mL) was slowly added to the reaction mass at 60°C for a period for 60 min. and maintained for 12 h. The reaction mas was cooled to 0°C. The reaction mass was slowly quenched with methanol (2000 mL) at 0°C. The solvent from reaction mass was evaporated under vacuum. The obtained residue is diluted with water (2000 mL) and extracted with ethyl acetate (3X1500 mL). Both layers were separated and the organic layer was washed with brine solution (500 mL) and dried over sodium sulphate. The solvent from the organic layer was evaporated under vacuum at 45°C. Water (403.2 mL) and urea (241.3 g) were added to the obtained crude at 27°C and stirred for 10 min. Concentrated hydrochloric acid (116.06 mL) was slowly added to the reaction mixture at 27°C. The reaction mixture was heated up to 100°C and stirred for 12 h. The reaction mass was cooled to 27°C. Cold water (2000 mL) was added to the reaction mass and stirred for 2 h. Filtered the solid and washed with cold water and hexane (1000 mL). The obtained solid was diluted with ethyl acetate and stirred for 2 h. Filtered the solid and washed with ethyl acetate (1000 mL) to give the title compound.
Desfluoro impurity content: 4.57%

Example-1:Preparation of (2-fluoro-6-(trifluoromethyl)phenyl)methanamine.
2-Fluoro-6-(trifluoromethyl)benzonitrile (50 g), methanol (1000 mL), Raney-nickel (10 g) and aqueous ammonia (250 mL) were charged into hydrogenation vessel at 27°C. The reaction mixture was maintained under hydrogen pressure at 60 psi for 24 h. After completion of the reaction, the reaction mass was filtered on celite bed and washed with methanol (400 mL). The obtained filtrate was evaporated under vacuum at 30°C. Water (100 mL) was added to the reaction mass and extracted with dichloromethane (3X250 mL). The organic layer was dried with anhydrous Na2SO4 (180 g), followed by concentrated under vacuum at 30°C to give the title compound.
Yield: 88.69%
Desfluoro impurity content: 0.57%

Example-2: Preparation of Preparation of 1-(2-fluoro-6-trifluoromethyl)benzyl) urea.
(2-Fluoro-6-(trifluoromethyl)phenyl)methanamine (45.2 g) obtained from example-1, water (94.9 mL) and urea (56.26 g) were charged at 30°C and stirred for 10 min. Con hydrochloric acid (27.32 mL) was added to the reaction mixture at 30°C. The reaction mass was heated up to 100°C and stirred for 12 h. The reaction mass was cooled to 30°C. Cold water was added to the reaction mass at 30°C and stirred for 60 min. Filtered the solid and washed with water (200 mL) and hexane (100 mL) and ethyl acetate 100 mL) to give the title compound
Desfluoro impurity content: 1.77%

Example-3: Preparation of tert-butyl (R)-(2-(5-bromo-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)carbamate.
5-bromo-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (114 g), THF (900 mL) were charged into RBF at 26°C. (R)-(-)-N-Boc-2-phenyl glycinol (88.72 g) and triphenylphosphine (117.68 g) were added to the reaction mass at 27°C and stirred for 10 minutes. Diisopropylazodicarboxylate (88.89 mL) was slowly added drop wise to reaction mass at 27°C over a period of 30 min under nitrogen atmosphere and the reaction mixture was stirred at the same temperature for 3 h. After completion of the reaction, the organic solvent was evaporated under reduced pressure at 45°C. The obtained residue was diluted with MTBE (1051 mL) and cooled to 0°C and stirred for 15 min. The obtained solid was filtered and washed with MTBE (100 mL). The filtrate and washings were combined and evaporated under reduced pressure at 45°C to give the title compound.
Purity by HPLC: 81.65%

Example-4: Purification of tert-butyl (R)-(2-(5-bromo-3-(2-fluoro-6-(trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)carbamate.
The crude obtained from example2 (280 g) was charged in to the RBF at 27°C.
Toluene (1400 mL) and magnesium chloride (88.71 g) were added to the reaction mixture and stirred at 27°C for 10 min. The reaction mixture was heated to 65°C and maintained for 60 min. Heptane (1400 mL) was added to the reaction mixture at same temperature and stirred for 30 min. The reaction mass was cooled to 27°C and the obtained solid was filtered on celite bed and washed with 1000 mL of toluene: heptane (1:1) mixture. The obtained filtrate was evaporated under reduced pressure at 45°C to get a gummy solid. The obtained gummy solid was dissolved in IPA (250 mL), cooled to 0°C and stirred for 30 minutes. Water (125 mL) was added to the reaction mixture and stirred at 0°C for 30 min. The obtained solid was filtered under vacuum and dried for 1h. The obtained solid was diluted with toluene (130 mL), followed by hexane (1300 mL), and the reaction mixture was stirred at RT for 16h. The solid product obtained was filtered and dried under vacuum for 2h to give the title compound.
Yield: 60.41%
Purity by HPLC: 96.89%
,CLAIMS:WE CLAIM:

1) A process for the preparation of compound of formula (II) comprising reducing a compound of formula (III) in presence of Raney nickel.

2) The process according to claim 1, wherein the step is carried out in presence of aqueous ammonia.
3) A process for purification of the compound of formula (IV) comprising;

a) providing a solution of a compound of formula (IV) in a solvent;
b) removing the unwanted by products or impurities from the reaction mass;
c) isolating the pure compound of formula (IV).
4) The process according to claim 3, wherein the solvent used in step a) comprises water, benzene, toluene, xylene, dichloromethane, trichloromethane, anhydrous diethyl ether, dioxane, tetrahydrofuran (THF), methyl tertiay butyl ether (MTBE), ethyl acetate, n-propyl acetate, n-butyl acetate, ethyl formate, acetonitrile, propionitrile, methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol), 1-butanol, 2-butanol, benzyl alcohol, acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone, dimethylformamide, dimethylacetamide, dimethylsulphoxide, n-methylpyrrolidine, formamide, acetamide.
5) A process for purification of the compound of formula (IV) comprising;

a) providing a solution of a compound of formula (IV) in toluene;
b) adding magnesium chloride to the above solution;
c) removing the unwanted by-products or impurities from the above solution;
d) isolating the pure compound of formula (IV).