DESC:
FIELD OF THE INVENTION
The present invention provides novel intermediates for elagolix, process for preparation of these intermediates and process for preparation of elagolix and its pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION
Elagolix is a gonadotropin-releasing hormone receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis and marketed as Orilissa® with active ingredient as Elagolix sodium. The chemical name for elagolix sodium is 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 and represented by formula (I)

The application WO 2005007165 (A1) discloses Pyrimidine-2, 4-dione derivatives including elagolix as gonadotropin-releasing hormone receptor antagonists, the application also discloses process for preparation of these derivatives. Another application WO 2009062087 (A1) disclose process for preparation of uracil derivative including elagolix.

The reported methods for preparation of elagolix involves use of sensitive reagents and tedious isolation and purification methods. The present invention provides a novel, economical and industrially feasible process for preparation of elagolix.

SUMMARY OF THE INVENTION
The present invention provides process for preparation of elagolix (I) or its sodium salt comprising:
i) reacting compound (III) with compound (IV) to give compound (V),

wherein X is halogen and R is alkyl,
ii) reacting compound (V) and compound (VI) to give compound (VII), and


iii) converting compound (VII) to elagolix (I) or its sodium salt.

The present invention provides novel compounds (III) and (V) for preparation of elagolix.

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides process for preparation of elagolix (I) or its sodium salt comprising:
i) reacting compound (III) with compound (IV) to give compound (V),

wherein X is halogen and R is alkyl,
ii) reacting compound (V) and compound (VI) to give compound (VII), and


iii) converting compound (VII) to elagolix (I) or its sodium salt.

In second embodiment, the present invention further provides process for preparation of compound (III),

i) reacting compound (I) with halogenating agent to give compound (II),

ii) reacting compound (II) with compound (II’) wherein P is hydroxy protecting group, P’ is amino protecting group, and

iii) deprotecting the resultant compound to give compound (III).

Hydroxy and amino protecting group may be selected from groups known to those skilled in the art, including protecting groups disclosed in Greene, Theodora W.; Wuts, Peter G. M., Protective Groups in Organic Synthesis. 3rd Ed. (1999). Examples of a hydroxy protecting group (P) may include lower alkyl; aralkyl like benzyl; acyl like acetyl, pivaloyl, benzoyl; alkoxyalkyl like methoxymethyl, methoxyethyl; lower alkylsulfonyl like methanesulfonyl; arylsulfonyl like benzenesulfonyl, toluenesulfonyl; alkoxycarbonyl like methoxycarbonyl and tetrahydropyranyl (THP) and other protecting groups may include p-methoxybenzyl, silyl, trityl and the like. Suitable examples of the nitrogen protecting group (P’) include tert-butyloxycarbonyl , benzyloxy carbonyl, acetyl, triflouoroacetyl, benzyl, phthalimido, tosyl, p-methoxybenzylcarbonyl, 9-fluorenylmethyloxycarbonyl, carbamate, p-methoxybenzyl, p-methoxyphenyl , tosyl, phenyl sulfonyl, trimethylsilylethoxymethyl and benzoyl.

In the third embodiment, the present invention provides novel compounds (III) and (V) for preparation of elagolix.

wherein X is halogen, selected from Chloro, Bromo or Iodo.

wherein X is halogen, selected from Chloro, Bromo or Iodo and R is alkyl selected from linear or branched like methyl, ethyl, isopropyl, n-butyl and the like.

The present invention provides novel compounds (III), wherein X is bromo, referred herein as compound (III’)

The compound (III’) is characterized by 1H NMR (CDCl3): d 7.57 (m, 1H), 7.46 – 7.34 (m, 3H), 7.28 (m, 2H), 7.25 (m, 2H), 5.56 (s, 2H), 4.42 – 4.34 (m, 2H), 4.14 – 4.10(m, 1H), 2.57 (s, 3H) and 1.79 (m, 2H); Mass: m/z 502.3 [M+1].

The present invention provides novel compounds (V), wherein X is bromo and R is ethyl, referred herein as compound (V’)

The compound (V’) is characterized by 1H NMR (CDCl3): d 7.58 (m, 1H), 7.42 – 7.27 (m, 7H), 5.52 – 5.50 (m, 2H), 4.18 – 4.08 (m, 5H), 3.50 (m, 1H), 2.53 – 2.30 (m, 5H), 2.29 – 2.18 (m, 4H), 1.30 (t, 3H); MS: 616.2 [M+1]+.
In the present invention, the reaction of compound (I) with halogenating agent can be carried out in presence of solvent and a catalyst at a temperature of 0 to 40°C for 6 to 8 hours. Compound (I) can be prepared by methods known in art.

The halogenating reagent can be selected from bromine, N-Bromosuccinimide, Bromodimethylsulfonium bromide, N-Bromoacetamide, Bromotrimethylsilane, N-Bromophthalimide, Tetrabutylammonium Bromide, 1,3-Dibromo5,5-dimethylhydantoin, Benzyltrimethylammonium Dichloroiodate Chlorine, N-Chlorosuccinimide, N-Chlorophthalimide, 1,3-Dichloro5,5-dimethylhydantoin, Iodine, N-Iodosuccinimide, 1,3-Diiodo-5,5-dimethylhydantoin, Trimethylsilyl Iodide and the like in presence of suitable catalyst.

The solvent can be selected from organic polar or non-polar solvent. Polar solvent can be selected from alcohols like methanol, ethanol, butanol, propanol; nitriles like acetonitrile, propionitrile, butyronitrile; ethers like tetrahydrofuran, dioxane, dimethoxyethane, dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; other polar solvents like dimethylacetamide, dimethylformamide, dimethyl sulfoxide, acetic acid. Non-polar solvent can be selected from hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof.

The reaction of compound (II) with compound (II’) can be carried out in presence of base in an appropriate solvent at a temperature of 0 to 60 °C for 10-12 hours.

The base is an inorganic base selected form hydroxide, alkoxides, carbonates and bicarbonates of alkali or alkaline earth metal like sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate. The solvent can be selected from organic polar or non-polar solvent. Polar solvent can be selected from alcohols like methanol, ethanol, butanol, propanol; nitriles like acetonitrile, propionitrile, butyronitrile; ethers like tetrahydrofuran, dioxane, dimethoxyethane, dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; other polar solvents like dimethylacetamide, dimethylformamide, dimethyl sulfoxide. Non-polar solvent can be selected from hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof.

The resultant compound after the reaction of compound (II) and compound (II’) is deprotected using acid catalyst, base catalyst or appropriate reagent known to person skilled in art. The deprotection reaction can be carried out in-situ without isolation of the resultant compound to give compound (III).

The reaction of compound (III) and compound (IV) can be carried out in presence of base and solvent at a temperature of 30°C to reflux temperature of solvent for a period of 12-24 hours.

The base can be selected from organic or inorganic base; organic base can be selected form alkyl amines like triethyl amine, tributyl amine or diisopropylethylamine; inorganic bases include hydroxide, alkoxides, carbonates and bicarbonates of alkali or alkaline earth metal like sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate. The solvent can be selected from organic polar or non-polar solvent. Polar solvent can be selected from alcohols like methanol, ethanol, butanol, propanol; nitriles like acetonitrile, propionitrile, butyronitrile; ethers like tetrahydrofuran, dioxane, dimethoxyethane, dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; esters like ethyl acetate, ethyl acetoacetate, butyl acetate, propyl acetate; ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone; other polar solvents like dimethylacetamide, dimethylformamide, dimethyl sulfoxide. Non-polar solvent can be selected from hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof.

The reaction of compound (V) and compound (VI) can be carried out in presence of palladium catalyst, base and solvent at temperature of 25°C to reflux temperature of the solvent for a period of 8-10 hours.

The palladium catalyst can be selected from Tris(dibenzylideneacetone)dipalladium and tri tertbutyl phosphonium tetrafluoroborate, 1,1-(bis-di-t-butylphosphino)ferrocene palladium dichloride, Palladium (II) acetate, Tetrakis(triphenylphosphine)palladium and the like. The base can be selected from organic or inorganic base; organic base can be selected form alkyl amines or aromatic amines like triethyl amine, tributyl amine, diisopropylethylamine, pyridine, pyrimidine, 2,4,6-Tri-tert-butylpyrimidine, aniline, 4-methoxyaniline, N,N-Dimethylaniline, 3-Nitroaniline; inorganic bases include hydroxide, alkoxides, carbonates and bicarbonates of alkali or alkaline earth metal like sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate or mixture of base. The solvent can be selected from organic polar or non-polar solvent. Polar solvent can be selected from alcohols like methanol, ethanol, tert-butanol, propanol; nitriles like acetonitrile, propionitrile, butyronitrile; ethers like tetrahydrofuran, dioxane, dimethoxyethane, dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1 ,2-dimethbxy ethane, tetrahydrofuran, 1,4-dioxane and the like; other polar solvents like dimethylacetamide, dimethylformamide, dimethyl sulfoxide. Non-polar solvent can be selected from hydrocarbon solvent such as hexane, heptane, cyclohexane, petroleum ether, benzene, toluene, xylene, anisole and the like; chlorinated hydrocarbons like chloroform, dichloro methane, ethylene dichloride; or mixtures thereof.

The compound (VII) can be converted to elagolix by carrying out deprotection reaction of compound (VII) by using acid catalyst, base catalyst or appropriate reagent corresponding to the protecting group.

Elagolix can be converted to its pharmaceutically acceptable salt by methods known in art. Pharmaceutically acceptable salt may be selected from base addition salts of alkali or alkaline earth metal salts like lithium, sodium, potassium, magnesium, barium, calcium; amine salts; or ammonium salts like dibenzylammonium, benzylammonium, 2-hydroxyethylammonium.

In the present invention, compound (VII) can be treated with alkaline solution of sodium carbonate or sodium hydroxide to directly give elagolix sodium (I). The present invention provides elagolix sodium (I) with HPLC purity of greater than 99%.

The present invention is further illustrated by the following representative examples and does not limit the scope of the invention.

Examples

1. Process for preparation of compound (II)
A mixture of compound (I) (18 g) and methanol (90ml) was cooled to 5-10°C, and a solution of bromine (4.5 ml) in methanol (18 ml) was added to it. The mixture was stirred for 6 hours at 25-30°C. The solid was filtered and dried, to yield the title compound.

2. Process for preparation of compound (III’)
A mixture of compound (II) (40.0 g), dimethylformamide (200 ml), potassium carbonate (52 g) and (R)-2-((tert-butoxycarbonyl)amino)-2-phenylethyl methanesulfonate (66.28 g) was stirred at 55-60°C for about 8 hours. Water (1000 ml) and ethylacetate (500 ml) was added to the reaction mixture, the organic layer was separated and concentrated under vacuum. The residue was diluted with methylene dichloride (960 ml) and trifluoro acetic acid (100 ml) was added to it and stirred for 30 minutes. A solution of potassium carbonate (150g) in water (500 ml) was added to the mixture. The organic layer was separated and treated with phosphoric acid. The aqueous layer was separated, and pH of the layer was adjusted to 9-11 by potassium carbonate solution and methylene dichloride (500 ml) was added to the solution. The organic layer separated and concentrated under vacuum to yield the title compound.

3. Process for preparation of compound (V’).
A mixture of Compound (III’) (50 g), N,N-dimethyl formamide (100 ml), N,N-diisopropylethylamine (26 g) and ethyl 4-bromobutanoate (33.15 g) was stirred at 55-60°C about 10 hours. Water (750 ml) was added to the mixture at 25-30°C, followed by addition of methylene dichloride (500 ml). The organic layer separated and concentrated under vacuum to yield the title compound.

4. Process for preparation of compound (VII, R is ethyl).
A mixture of compound (V’) (66 g), 1,4-dioxane (660 ml), 2-fluoro-3-methoxyphenylboronic acid (27.5 g), cesium carbonate (69.9 g), tri tertbutyl phosphonium tetrafluoroborate and tris (dibenzylideneacetone) dipalladium (0.99 g) was stirred at 40-45°C for about 6 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum to yield the title compound.

5. Process for preparation of Elagolix sodium (I).
To the compound of example 4, ethanol (450 ml) and sodium hydroxide solution was added. The mixture was stirred for 30 minutes and then concentrated. Water was added to it followed by extraction with methyl isobutyl ketone. The organic layer was separated, partially concentrated and was added into cyclohexane. The solid obtained was filtered and dried to yield the title product.
,CLAIMS:
1. A process for preparation of elagolix (I) or its sodium salt comprising
i) reacting compound (III) with compound (IV) to give compound (V),

wherein X is halogen and R is alkyl,
ii) reacting compound (V) and compound (VI) to give compound (VII), and

iii) converting compound (VII) to elagolix (I) or its sodium salt.

2. A process for preparation of compound (III) of claim 1, comprising
i) reacting compound (I) with halogenating agent to give compound (II),

ii) reacting compound (II) with compound (II’) wherein P is hydroxy protecting group, P’ is amino protecting group, and

iii) deprotecting the resultant compound to give compound (III).

3. Compounds (III) and (V)

wherein X is halogen, selected from Chloro, Bromo or Iodo and R is alkyl.

4. Compounds (III’) and (V’)

5. The process as claimed in claim 1 wherein, the reaction of step (i) is carried out in presence of base and solvent.

6. The process as claimed in claim 1 wherein, the reaction of step (ii) is carried out in presence of palladium catalyst, base and solvent.

7. The process as claimed in claim 1 wherein, compound (VII) is converted to elagolix (I) sodium by treatment with sodium carbonate or sodium hydroxide.

8. The process as claimed in claim 2 wherein, halogenating agent is selected from bromine, N-bromosuccinimide, bromodimethylsulfonium bromide, N-bromoacetamide, bromotrimethylsilane, N-bromophthalimide, tetrabutylammonium Bromide, 1,3-dibromo5,5-dimethylhydantoin, benzyltrimethylammonium dichloroiodate chlorine, N-chlorosuccinimide, N-chlorophthalimide, 1,3-dichloro5,5-dimethylhydantoin, iodine, N-iodosuccinimide, 1,3-diiodo-5,5-dimethylhydantoin or trimethylsilyliodide.

9. The process as claimed in claim 2 wherein, the reactions of steps (i) and (ii) is carried out in presence of base and solvent.

10. The processes as claimed in claims 5, 6 and 9 wherein, base is selected from potassium carbonate, cesium carbonate, triethyl amine, tributyl amine or diisopropylethylamine and solvent is selected from dimethylformamide or 1,4-dioxane.