DESC:Field of The Invention
The present invention relates to a process for the preparation of Elagolix Sodium having the structural formula (I).

The present invention also relates to novel intermediates which are useful in the preparation of Elagolix Sodium.

Background of the Invention

Elagolix Sodium is a gonadotropin releasing hormone antagonist (GnRH antagonist) used in the treatment of pain associated with endometriosis in women. It is also in phase III clinical trials for the treatment of uterine fibroids in women. Endometriosis is a frequent cause of infertility, connected with a chronic pelvic and pre-menstrual pain.

Elagolix Sodium is chemically known as Sodium 4-({(1R)-2-[5-(2-fluoro-3-methoxyphenyl) -3-{[2-fluoro-6-(trifluoro methyl) phenyl]methyl}-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H) -yl]-1-phenylethyl}amino) butanoate. Food and Drug Administration granted marketing Authorisation for Elagolix Sodium in United States under the brand name “ORILISSA” for the treatment of endometriosis-associated pain.

Elagolix was first disclosed in WO 2005007165 A1. In example-1H of the said application, Elagolix fee acid is described as a white gel and it is passed through a DOWEX MSC-1 macroporous strong cation exchange column to convert the acid to its sodium salt. Finally, lyophilization gives the Elagolix Sodium as a white solid.

The reported processes for the preparation of Elagolix Sodium utilizes cation exchange column which makes it difficult for bulk manufacturing as well as it effects the overall yield making the process uneconomical.

In view of all these disadvantages, there is a significant need to develop a cost effective, stable, commercially viable process for the preparation of highly pure Elagolix Sodium with good yield.

Summary of The Invention

The present invention provides a cost effective, novel and an efficient process for the preparation of Elagolix Sodium with higher yields and purity.

In one embodiment, the present invention provides a process for the preparation of Elagolix Sodium compound of formula-I.

which comprises:
a) coupling of compound of formula-II

with compound of formula-III

in presence of a base and reagent to obtain compound of formula-IV;

b) condensation of formula-IV with compound of formula-V

in presence of base and solvent to obtain compound of formula-VI;

c) protecting of compound of formula-VI with appropriate hydroxy protecting agent in presence of a base to obtain compound of formula-VII;

d) condensation of compound of formula-VII with compound of formula-VIII

in presence of a base to obtain compound of formula-IX;

e) ring opening of compound of formula-IX in presence of concentrated hydrochloric acid to obtain compound of formula-X (Elagolix free acid);

f) salt formation of compound of formula-X with dicyclo hexyl amine in an organic solvent to obtain compound of formula-XI;

g) neutralization of compound of formula-XI with an acid followed by salt formation with sodium hydroxide in an organic solvent to obtain Elagolix Sodium of formula-I.

In another embodiment, the present invention provides a novel process for the preparation of Elagolix Sodium compound of formula-I.

which comprises:
a) coupling of compound of formula-II

with compound of formula-V

in presence of base and solvent to obtain compound of formula-XII;

b) coupling of compound of formula-XII with compound of formula-III

in presence of a base and coupling agent to obtain compound of formula-VI;

c) protecting of compound of formula-VI with appropriate hydroxy protecting agent in presence of a base to obtain compound of formula-VII;

d) condensation of compound of formula-VII with compound of formula-VIII

in presence of a base to obtain compound of formula-IX;

e) ring opening of compound of formula-IX in presence of concentrated hydrochloric acid to obtain Elagolix free acid of formula-X;

f) salt formation of Elagolix free acid of formula-X with dicyclo hexyl amine in an organic solvent to obtain compound of formula-XI;

g) neutralization of compound of formula-XI with appropriate acid followed by salt formation with sodium hydroxide in an organic solvent to obtain Elagolix Sodium of formula-I.

In yet another embodiment, the present invention provides the following novel intermediates which are useful in the preparation of Elagolix Sodium.

In yet another embodiment, the present invention provides process for the preparation of compound of formula-VII.b

which comprises:
a) reacting compound of formula-VII

with sodium azide in organic solvent to obtain compound of formula-VII.a;

b) reduction of compound of formula-VII.a with a reducing agent to obtain compound of formula-VII.b.

Detailed Description of the Invention
Accordingly, the present invention provides various processes for the preparation of Elagolix Sodium of compound of formula-I.

The main embodiment of the present invention provides an improved process for the preparation of Elagolix Sodium of formula (I) as shown in the Scheme-I given below.

Scheme-I

In step-1, the compound of formula-II is coupled with compound of formula-III in presence of a reagent and a base to obtain compound of formula-IV
The base used in the reaction is selected from inorganic base such as alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates or organic base such as tri ethyl amine, diisopropylethylamine and pyridine, preferably using potassium hydroxide.

The reaction temperature may range from 60-80 °C and preferably at a temperature in the range from 65-75 °C. The duration of the reaction may range from 8-12 hours, preferably for a period of 9-11 hours.

The coupling reagent used in the reaction is selected from Tetrakis (triphenyl phosphine) palladium, palladium acetate, Tris (dibenzylidene acetone) di palladium, preferably using Tetrakis (triphenyl phosphine) palladium.

The amount of coupling agent used in the reaction may be in the range of 1.0 to 3.0 molar equivalents and preferably 1.5 to 2.5 molar equivalents.

Solvent used in the reaction is selected from alcoholic solvents such as methanol, ethanol, propanol; chlorinated solvents such as dichloromethane, carbon tetrachloride; ester solvents such as ethyl acetate, isopropyl acetate; aromatic organic solvents such as toluene, xylene; ketone solvents such as acetone, methyl isobutyl ketone; and water or its mixture thereof. Preferably using acetone: water mixture.

In step-2, the compound of formula-IV is condensed with compound of formula-V in the presence of a base and organic solvent to obtain compound of formula-VI.

The reaction temperature may range from 20-40 °C and preferably at a temperature in the range from 25-35 °C. The duration of the reaction may range from 2-6 hours, preferably for a period of 3-4 hours.

The base used in the reaction is selected from inorganic base such as alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates or organic base such as tri ethyl amine, diisopropylethylamine and pyridine, preferably using potassium carbonate.

Solvent used in the reaction is selected from alcoholic solvents such as methanol, ethanol, propanol; chlorinated solvents such as dichloromethane, carbon tetrachloride; ester solvents such as ethyl acetate, isopropyl acetate; aromatic organic solvents such as toluene, xylene; ketone solvents such as acetone, methyl isobutyl ketone; and water or its mixture thereof. Preferably using isopropyl alcohol.

In step-3, the compound of formula-VI is protected with an appropriate hydroxy protecting group in presence of a base and solvent to obtain compound of formula-VIII.
The hydroxy protecting group used in the reaction may be selected from benzyloxycarbonyl, C1-C6 straight chain or branched chain alkoxy carbonyl such as methoxycarbonyl, ethoxy carbonyl, tert-butyloxycarbonyl, acetyl, trichloroacetyl, trifluoroacetyl, 1-ethoxyethyl, benzoyl, benzyl, p-methoxybenzyl, methylthiomethyl, pivaloyl, trityl (triphenylmethyl), methoxy-iso-propanyl, tri(C1-C6 straight chain or branched chain alkyl)silyl groups such as trimethyl silyl, tri-ethyl silyl, triisopropylsilyl, tri-iso-propylsilyloxy methyl, tert-butyl-dimethylsilyl, tert-butyl- biphenylsilyl, furanidinyl, dihydropyran, tetrahydropyran, trichloroethoxy carbonyl or methane sulfonyl; preferably using methane sulfonyl group.

The base used in the reaction is selected from inorganic base such as alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates or organic base such as tri ethyl amine, diisopropylethylamine or pyridine, preferably using triethylamine.

Solvent used in the reaction is selected from alcoholic solvents such as methanol, ethanol, propanol; chlorinated solvents such as dichloromethane, carbon tetrachloride; nitrile solvent such as acetonitrile, propionitrile; ester solvents such as ethyl acetate, isopropyl acetate; aromatic organic solvents such as toluene, xylene; ketone solvents such as acetone, methyl isobutyl ketone; preferably using acetonitrile.
The protecting group may be deprotected by treating with sodium azide followed by reduction to obtain required amine compound.

In step-4, compound of formula-VII coupled with compound of formula-VIII in presence of a base to obtain compound of formula-IX.

Base used in the reaction is selected from alkali metal carbonates such as sodium carbonate, potassium carbonate and alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide and potassium methoxide Preferably, sodium methoxide.

The reaction temperature may range from 20-40 °C and preferably at a temperature in the range from 25-35 °C. The duration of the reaction may range from 05-20 hours, preferably for a period of 10-12 hours.

In step-5, ring opening reaction of compound of formula-IX with concentrated hydrochloric acid to obtain compound of formula-X.

The reaction temperature may range from 20-40 °C and preferably at a temperature in the range from 25-35 °C. The duration of the reaction may range from 1-4 hours, preferably for a period of 2-3 hours.
In step-6, salt formation of Elagolix free acid of formula-X with an appropriate base such as Dicyclohexyl amine, triethyl amine, tri ethanol amine in an organic solvent to obtain Elagolix salt of formula-XI; preferably using base is dicyclo hexyl amine.

Elagolix free acid of formula-X may react with an appropriate acid such as hydrochloric acid, hydrobromic acid, acetic acid, sulfuric acid, tri fluoro acetic acid, phosphoric acid, formic acid, methane sulfonic acid, para-toluene sulfonic acid, salicylic acid, benzoic acid, succinic acid, oxalic acid, maleic acid, fumaric acid, malic acid to obtain Elagolix salt; preferably using salicylic acid

Solvent used in the reaction is selected from alcoholic solvents such as methanol, ethanol, propanol; chlorinated solvents such as dichloromethane, carbon tetrachloride; nitrile solvent such as acetonitrile, propionitrile; ester solvents such as ethyl acetate, isopropyl acetate; aromatic organic solvents such as toluene, xylene; preferably using toluene.

In step-7, neutralization of Elagolix salt of formula-XI with appropriate acid such as acetic acid followed by salt formation with aqueous sodium hydroxide or sodium hydroxide flakes to obtain Elagolix Sodium of compound of formula-I.

In another embodiment, the present invention provides a process for the preparation of Elagolix Sodium of formula (I) as shown in the scheme-II given below.

Scheme-II

In step-1, condensation of compound of formula-II with compound of formula-V in presence of a base and solvent to obtain compound of formula-XII.
The base used in the reaction is selected from inorganic base such as alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates or organic base such as tri ethyl amine, diisopropylethylamine or pyridine, preferably using potassium carbonate.

Solvent used in the reaction is selected from alcoholic solvents such as methanol, ethanol, propanol, isopropanol; chlorinated solvents such as dichloromethane, carbon tetrachloride; nitrile solvent such as acetonitrile, propionitrile; ester solvents such as ethyl acetate, isopropyl acetate; aromatic organic solvents such as toluene, xylene; ketone solvents such as acetone, methyl isobutyl ketone; preferably using isopropanol.
In step-2, compound of formula-XII is coupled with compound of formula-III in presence of a base and coupling agent to obtain compound of formula-VI.
The base used in the reaction is selected from inorganic base such as alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates or organic base such as tri ethyl amine, diisopropylethylamine or pyridine, preferably using sodium carbonate.
The coupling reagent used in the reaction is selected from Tetrakis (triphenyl phosphine) palladium, palladium acetate, Tris (dibenzylidene acetone) di palladium, preferably using Tetrakis (triphenyl phosphine) palladium.

In step-3, the compound of formula-VI is protected with a hydroxy protecting group in presence of a base and solvent to obtain compound of formula-VIII.

The hydroxy protecting group used in the reaction may be selected from benzyloxycarbonyl, C1-C6 straight chain or branched chain alkoxy carbonyl such as methoxycarbonyl, ethoxy carbonyl, tert-butyloxycarbonyl, acetyl, trichloroacetyl, trifluoroacetyl, 1-ethoxyethyl, benzoyl , benzyl, p-methoxybenzyl, methylthiomethyl, pivaloyl, trityl (triphenylmethyl), methoxy-iso-propanyl, tri(C1-C6 straight chain or branched chain alkyl)silyl groups such as trimethyl silyl, tri-ethyl silyl, triisopropylsilyl, tri-iso-propylsilyloxy methyl, tert-butyl-dimethylsilyl, tert-butyl- biphenylsilyl, furanidinyl, dihydropyran, tetrahydropyran, trichloroethoxy carbonyl and methane sulfonyl; preferably using methane sulfonyl group.
The base used in the reaction is selected from inorganic base such as alkali metal hydroxides, alkali metal carbonates and alkali metal bicarbonates or organic base such as tri ethyl amine, diisopropylethylamine or pyridine, preferably using triethylamine

Solvent used in the reaction is selected from alcoholic solvents such as methanol, ethanol, propanol; chlorinated solvents such as dichloromethane, carbon tetrachloride; nitrile solvent such as acetonitrile, propionitrile; ester solvents such as ethyl acetate, isopropyl acetate; aromatic organic solvents such as toluene, xylene; ketone solvents such as acetone, methyl isobutyl ketone; preferably using acetonitrile. Optionally the protecting group may be deprotected by treating with sodium azide followed by reduction to obtain required amine compound.

In step-4, compound of formula-VII coupled with compound of formula-VIII in presence of a base to obtain compound of formula-IX.
Base used in the reaction is selected from alkali metal carbonates such as sodium carbonate, potassium carbonate and alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide or potassium methoxide Preferably, sodium methoxide.
The reaction temperature may range from 20-40 °C and preferably at a temperature in the range from 25-35 °C. The duration of the reaction may range from 05-20 hours, preferably for a period of 10-12 hours.

In step-5, ring opening reaction of compound of formula-IX with concentrated hydrochloric acid to obtain compound of formula-X.

The reaction temperature may range from 20-40 °C and preferably at a temperature in the range from 25-35 °C. The duration of the reaction may range from 1-4 hours, preferably for a period of 2-3 hours.
In step-6, salt formation of Elagolix free acid of formula-X with an appropriate base such as Dicyclohexyl amine, triethyl amine, tri ethanol amine in an organic solvent to obtain Elagolix salt of formula-XI; preferably using base is dicyclo hexyl amine.

Solvent used in the reaction is selected from alcoholic solvents such as methanol, ethanol, propanol; chlorinated solvents such as dichloromethane, carbon tetrachloride; nitrile solvent such as acetonitrile, propionitrile; ester solvents such as ethyl acetate, isopropyl acetate; aromatic organic solvents such as toluene, xylene; preferably using toluene.

In step-7, neutralization of Elagolix salt of formula-XI with appropriate acid such as acetic acid followed by salt formation with aqueous sodium hydroxide or sodium hydroxide flakes to obtain Elagolix Sodium of compound of formula-I.

In yet another embodiment the present invention provides an another improved process for the preparation of Elagolix Sodium of formula (I) as shown in the scheme-III given below:

Scheme-III
In step-1, compound of formula-VII is reacted with sodium azide in presence of organic solvent to obtain compound of formula-VII.a. Then it is reduced by using appropriate reducing agent to obtain compound of formula-VII.b.
Solvent used in the reaction is selected from alcoholic solvents such as methanol, ethanol, propanol; chlorinated solvents such as dichloromethane, carbon tetrachloride; nitrile solvent such as acetonitrile, propionitrile; ester solvents such as ethyl acetate, isopropyl acetate; aromatic organic solvents such as toluene, xylene; ketone solvents such as acetone, methyl isobutyl ketone; preferably using acetonitrile or dimethyl sulfoxide.
The reducing agent used in the reaction may be selected from lithium aluminium hydride or palladium on carbon or raney nickel or boron trifluoride diethyl etherate or zinc-ammonium formate; preferably using palladium on carbon.

Compound of formula-VII.b may react with an appropriate acid such as hydrochloric acid, hydrobromic acid, acetic acid, sulfuric acid, tri fluoro acetic acid, phosphoric acid, formic acid, methane sulfonic acid, para-toluene sulfonic acid, salicylic acid, benzoic acid, succinic acid, oxalic acid, maleic acid, fumaric acid, malic acid to obtain corresponding salt.

Neutralization of corresponding salt by using appropriate base like sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bi carbonate, triethyl amine, aqueous ammonia to get pure compound of formula-VII.b

EXPERIMENTAL PORTION

The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention
Example-1: Process for the preparation of Elagolix Sodium

Stage-1: Synthesis of 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione
Aqueous potassium hydroxide solution is added to a mixture of 2-fluoro-3-methoxyphenyl boronic acid (10 grams), acetone, water and 5-bromo-1-(2-fluoro-6-trifluoromethyl) benzyl)-6-methyl pyrimidine-2,4(1H,3H)-dione (5.35 grams) at 25-30°C and stirred for 30 minutes at the same temperature. Tetrakis (triphenyl phosphine) palladium (2.9 grams) and tri-t-butylphosphonium tetrafluoroborate (0.08 grams) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 70-75°C and stirred for 8-10 hours at the same temperature. Cooled the resulting reaction mixture to 25-30°C. Acetic acid is added to the reaction mixture and stirred for 15 minutes. Filtered the precipitated solid and washed with methanol to get the title compound.

Stage-2: Synthesis of compound of formula-VI
Aqueous potassium carbonate solution (48.6 grams) is added to a mixture of (5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl)benzyl)-6-methylpyrimidine-2,4- (1H,3H)-dione (50 grams) and isopropyl alcohol (150 mL) at 25-30°C and stirred for 30 minutes at the same temperature. Chiral styrene oxide (15.5 grams) is added to the reaction mixture at 25-30 °C and stirred for 3-4 hours at same temperature. Filtered the unwanted solids and wash with isopropanol. The obtained filtrate pH adjusted to 4.0-4.5 with acetic acid. Volatiles were removed from the reaction mixture under reduced pressure and the obtained residue is dissolved in ethyl acetate and stirred for 10 minutes. Filtered the precipitated solid and dried to get the title compound.
Yield: 80 %.

Stage-3: Synthesis of compound of formula-VII
Compound obtained in stage-2 was added to a mixture of triethylamine (19.5 grams) and acetonitrile at 25-30 °C and stirred for 10 minutes at the same temperature. Methane sulfonyl chloride (11 grams) was added to the resulting reaction mixture at 0-10 °C and stirred for 6-8 hours at the same temperature. Filtered the reaction mixture and volatiles were removed from the obtained filtrate under reduced pressure. The obtained crude was dissolved in methanol and water at 25-30 °C and stirred for 10 minutes at the same temperature. Filtered the precipitated solid and dried to get the title compound.
Yield: 80 %

Stage-4: Synthesis of compound of formula-IX
Sodium methoxide solution (62 mL) was added to 2-Pyrrolidinone (6.13grams) at 25-30°C and stirred for 1-2hours at the same temperature. The resulting solution was added to a mixture of acetonitrile and compound obtained in stage-3 at 25-30 °C. Stirring the reaction mixture for 10-12 hours. Volatiles were removed from the reaction mixture under reduced pressure and the obtained crude was dissolved in dichloromethane and filtered the precipitated solid to get the title compound. Yield: 79 %.

Stage-5: Synthesis of compound of formula-X (Elagolix free acid)
Compound obtained in stage-4 was dissolved in methanol (20 mL) and diluted hydrochloric acid (50 mL) was added to the reaction mixture at 25-30 °C. Heated the reaction mixture to reflux temperature and stirred for 2-4 hours at the same temperature. Cooled the reaction mixture to 25-30 °C and stirred for 2-3 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound.
Yield: 84 %

Stage-6: Synthesis of compound of formula-XI (Elagolix DCHA salt)
Compound obtained in stage-5 (15 grams) was dissolved in methylene chloride (150 mL) at 25-30°C and stirred for 10 minutes at the same temperature. Sodium carbonate solution (45 mL) was added to the resulting reaction mixture at 25-30 °C. Both the aqueous and organic layers were separated and volatiles were removed from the organic layer under reduced pressure. The obtained crude was dissolved in toluene (150 mL) and cyclohexyl amine (6.2grams) g was added to the resulting reaction mixture. Heated the reaction mixture to reflux temperature and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 25-30 °C. Filtered the precipitated solid, washed with toluene and dried to get the title compound.
Yield: 85 %
Stage-7: Synthesis of Elagolix Sodium
Elagolix free acid obtained in stage-6 was dissolved in methylene chloride (100 mL) and acetic acid was slowly added to the reaction mixture for adjustment of pH to a range of 4 to 4.5. Water was added to the reaction mixture and both the organic and aqueous layers were separated. Volatiles were removed from the organic layer under reduced pressure. The obtained crude was dissolved in methanol and stirred for 10 minutes. Aqueous sodium hydroxide solution was added to the reaction mixture and stirred for 60 minutes at the same temperature. Filtered the reaction mixture and volatiles were removed from the obtained filtrate under reduced pressure. Methyl isobutyl ketone and heptane were added to the obtained crude at 25-30 °C and stirred for 9-10 hours at the same temperature. Filtered the precipitated solid and dried to get the title compound.
Yield: 90 %

Example-2: Process for the preparation of Elagolix Sodium

Stage-1: Synthesis of compound of formula-XII
Aqueous potassium carbonate solution was added to a mixture of isopropanol and 5-bromo-1-(2-fluoro-6-(Trifluoromethyl)benzyl)-6-methyl pyrimidine-2,4(1H,3H)-dione at 25-30 °C and stirred for 30 minutes at the same temperature. Chiral styrene oxide was added to the reaction mixture at 25-30 °C and stirred for 4 hours at the same temperature. Filtered the unwanted solids and washed with isopropanol. Obtained filtrate pH was adjusted to 4.0-4.5 with acetic acid. Volatiles were removed from the reaction mixture under reduced pressure. The obtained crude was dissolved in ethyl acetate. Heptane was added to the reaction mixture and filtered the precipitated solid to get the title compound.
Yield: 80 %

Stage-2: Synthesis of compound of formula-VI
Aqueous potassium hydroxide solution was added to a mixture of 2-fluoro-3-methoxyphenyl boronic acid (10 grams), compound obtained in stage-1, acetone (30 mL) and water (20 mL) at 25-30 °C. Tetrakis(triphenylphosphine)palladium and tri-t-butyl phosphonium tetrafluoroborate were added to the reaction mixture at 25-30 °C. Heated the reaction mixture to 70-75 °C and stirred for 10 hours at the same temperature. Cooled the reaction mixture to 25-30 °C. Acetic acid was added to the reaction mixture. Filtered the precipitated solid and dried to get the title compound.
Yield: 75 %

Stage-3: Synthesis of compound of formula-VII
Compound obtained in stage-2 was added to a mixture of triethylamine (19.5 grams) and acetonitrile at 25-30 °C and stirred for 10 minutes at the same temperature. Methane sulfonyl chloride (11 grams) was added to the resulting reaction mixture at 0-10 °C and stirred for 6-8 hours at the same temperature. Filtered the reaction mixture and volatiles were removed from the obtained filtrate under reduced pressure. The obtained crude was dissolved in methanol and water at 25-30 °C and stirred for 10 minutes at the same temperature. Filtered the precipitated solid and dried to get the title compound.
Yield: 80 %

Stage-4: Synthesis of compound of formula-IX
Sodium methoxide solution (62 mL) was added to 2-Pyrrolidinone (6.13 grams) at 25-30 °C and stirred for 1-2hours at the same temperature. The resulting solution was added to a mixture of acetonitrile and compound obtained in stage-3 at 25-30 °C. Stirring the reaction mixture for 10-12 hours. Volatiles were removed from the reaction mixture under reduced pressure and the obtained crude was dissolved in dichloromethane and filtered the precipitated solid to get the title compound. Yield: 79 %.

Stage-5: Synthesis of compound of formula-X (Elagolix free acid)
Compound obtained in stage-4 was dissolved in methanol (20 mL) and diluted hydrochloric acid (50 mL) was added to the reaction mixture at 25-30 °C. Heated the reaction mixture to reflux temperature and stirred for 2-4 hours at the same temperature. Cooled the reaction mixture to 25-30 °C and stirred for 2-3 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound.
Yield: 84 %

Stage-6: Synthesis of compound of formula-XI (Elagolix DCHA salt)
Compound obtained in stage-5 (15 grams) was dissolved in methylene chloride (150 mL) at 25-30 °C and stirred for 10 minutes at the same temperature. Sodium carbonate solution (45 mL) was added to the resulting reaction mixture at 25-30 °C. Both the aqueous and organic layers were separated and volatiles were removed from the organic layer under reduced pressure. The obtained crude was dissolved in toluene (150 mL) and cyclohexyl amine (6.2grams) was added to the resulting reaction mixture. Heated the reaction mixture to reflux temperature and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 25-30 °C. Filtered the precipitated solid, washed with toluene and dried to get the title compound.
Yield: 85 %

Stage-7: Synthesis of Elagolix Sodium
Elagolix free acid obtained in stage-6 was dissolved in methylene chloride (100 mL) and acetic acid was slowly added to the reaction mixture for adjustment of pH to a range of 4 to 4.5. Water was added to the reaction mixture and both the organic and aqueous layers were separated. Volatiles were removed from the organic layer under reduced pressure. The obtained crude was dissolved in methanol and stirred for 10 minutes. Aqueous sodium hydroxide solution was added to the reaction mixture and stirred for 60 minutes at the same temperature. Filtered the reaction mixture and volatiles were removed from the obtained filtrate under reduced pressure. Methyl isobutyl ketone and heptane were added to the obtained crude at 25-30°C and stirred for 9-10 hours at the same temperature. Filtered the precipitated solid and dried to get the title compound.
Yield: 90 %.
,CLAIMS:
1. A process for the preparation of Elagolix Sodium of formula-1

which comprises:
a) coupling of compound of formula-II

with compound of formula-III

in presence of a base and a coupling reagent to obtain compound of formula-IV;

b) condensation of formula-IV with compound of formula-V

in presence of a base and a solvent to obtain compound of formula-VI;

c) protecting of compound of formula-VI with appropriate hydroxy protecting agent in presence of a base to obtain compound of formula-VII;

d) condensation of compound of formula-VII with compound of formula-VIII in presence of a base to obtain compound of formula-IX;

e) ring opening of compound of formula-IX in presence of concentrated hydrochloric acid to obtain compound of formula-X (Elagolix free acid);

f) salt formation of compound of formula-X with dicyclo hexyl amine in an organic solvent to obtain compound of formula-XI;

g) neutralization of compound of formula-XI with appropriate acid followed by salt formation with sodium hydroxide in an organic solvent to obtain Elagolix Sodium of formula-I.

2. A process for the preparation of Elagolix Sodium of formula-1

which comprises:
a) coupling of compound of formula-II

with compound of formula-V

in presence of base and solvent to obtain compound of formula-XII;

b) coupling of compound of formula-XII with compound of formula-III

in presence of a base and coupling agent to obtain compound of formula-VI;

c) protecting of compound of formula-VI with appropriate hydroxy protecting agent in presence of a base to obtain compound of formula-VII;

d) condensation of compound of formula-VII with compound of formula-VIII

in presence of a base to obtain compound of formula-IX;

e) ring opening of compound of formula-IX in presence of concentrated hydrochloric acid to obtain Elagolix free acid of formula-X;

f) salt formation of Elagolix free acid of formula-X with dicyclo hexyl amine in an organic solvent to obtain compound of formula-XI;

g) neutralization of compound of formula-XI with appropriate acid followed by salt formation with sodium hydroxide in an organic solvent to obtain Elagolix Sodium of formula-I.

3. A process for the preparation of compound of formula-VII.b

which comprises:
a) reacting compound of formula-VII

with sodium azide in organic solvent to obtain compound of formula-VII.a;

b) reduction of compound of formula-VII.a with a reducing agent to obtain compound of formula-VII.b.