DESC:“IMPROVED PROCESS FOR THE PREPARATION OF ELAGOLIX”

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Elagolix sodium with simple, high purity and good yield.

BACKGROUND OF THE INVENTION
Elagolix sodium as active moiety chemically known as sodium 4-({(1R)-2-[5-(2-fluoro-3­methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl) phenyl] methyl}-4-methyl-2,6-dioxo-3,6­Dihydropy rimidin-1(2H)-yl]-1-phenylethyl} amino) butanoate, and structurally represented as below.

Elagolix Sodium 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 is the first and currently the only marketed member of a new class of GnRH modulators, which is described as "second-generation" due to their non-peptide and small-molecule nature and oral activity. 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.
PCT publication no. WO 2005007165 A1 discloses a process for the preparation Elagolix sodium, which comprises the compound of formula (V) is reacting with Ethyl-4-bromobutyrate in presence of ACN/DIEA to obtain the compound of formula (V). The compound of formula (V) is reacting with NaOH to produce Elagolix sodium (I).
The above process is schematically shown as below:

Scheme-I
US 8765948 discloses a process for the preparation Elagolix sodium, which comprises compound the of formula (V) is reacting with Ethyl-4-bromobutyrate in presence of IPA/DMF/ DIPEA to obtain the compound of formula (VI). The compound of formula (VI) reacting with NaOH and Ethanol to get Elagolix sodium (I).
The above process is schematically shown as below:

Scheme-II
PCT publication no. WO2021130776 discloses a process for the preparation of Elagilix sodium which comprises the compound of formula (V) is reacting with ethyl-4-bromobutanoate in presence of tert-butyl ammonium bromide, sodium carbonate and Toluene to obtain the compound of the formula (VI). The compound of formula (VI) reacting with NaOH and isopropanol to get Elagolix sodium (I).
The above process is schematically shown as below:

PCT publication no. WO2021083554 discloses a process for the preparation of Elagilix sodium which comprises the compound of formula (V) is reacting with ethyl-4-bromobutanoate in presence of tert-butyl ammonium iodide, isopropyl acetate, diisopropylethylamine (DIPEA) and water to obtain the compound of the formula (VI). The compound of formula (VI) reacting with NaOH and isopropyl acetate to get Elagolix sodium (I).
The above process is schematically shown as below:

Prior art process involved in the reaction comprising by the compound of formula (V) is reacting with ethyl-4-bromobutanoate in presence organic solvents to obtain the compound of the formula (VI), which is not an eco-friendly process, resulting lower yield and making the process not suitable for commercial manufacturing and expensive.

The advantage of the present invention comprising by the compound of formula (V) is reacting with ethyl-4-bromobutanoate in presence water or absence of organic solvents to obtain the compound of the formula (VI) was not disclosed in the literature well known to those skilled in the art. Therefore, there is always a need in the preparation of pharmaceutical compounds to develop a process which is advantageous than the existing process in order to increase the yields, to be eco-friendly, most suitable for commercial manufacturing and cost effective. The present invention is providing industrial applicable process with high purity and good yield.

SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of Elagolix sodium with simple, high purity and good yield.

The present invention provides a process for the preparation of Elagolix sodium of formula (I), comprising the steps of;
a) reacting the compound of the formula (V) with ethyl-4-bromobutanoate in presence of organic base, phase transfer catalyst and water or absence of an organic solvent to obtain in-situ compound of formula (VI), and

b) reacting in-situ compound of the formula (VI) with inorganic base in presence of solvent to obtained the formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of Elagolix sodium with simple, high purity and good yield.

The present invention provides a process for the preparation of Elagolix sodium of formula (I), comprising the steps of;
reacting the compound of the formula (V) with ethyl-4-bromobutanoate in presence of organic base, phase transfer catalyst and water or absence of an organic solvent to obtain in-situ compound of formula (VI), and

reacting in-situ compound of the formula (VI) with inorganic base in presence of solvent to obtained the formula (I).

In an embodiment of the present invention, the formula (V) is reacting with ethyl 4-bromobutanoate in presence organic base, phase transfer catalyst and water or absence of organic solvent and the reaction is carried out at temperature at 80-110°C for 18-22hrs. After competition of the reaction mass was cooled to 30-35°C and diluted water, then extracted with isopropyl acetate. The organic layer was treated with a solution of 10% ortho phosphoric acid, followed by slow addition of a solution of 30% potassium carbonate to adjust pH 9-10, while mixing to get in-situ compound of the formula (VI).
The in-situ of compound of the formula (VI) reacting with inorganic base in presence of solvent, and the reaction is carried out at temperature 20-35°C for 2 to 5 hr. After completion of the reaction, the reaction mass was concentrated under reduced pressure at below 50°C. The obtained crude material was dissolved in water and washed with isopropyl acetate to remove impurities. The organic layer was added dropwise to n-Heptane at 10-15°C for 30-45min and maintained for 45-60 min at 10-15°C. The precipitated solid was filtered under nitrogen atmosphere and the wet material was dried under vacuum at 45-50°C for 20-24°C to get pure Elagolix sodium with 99.7% purity by HPLC and 60% of yield.

According to an embodiment of the present invention, wherein the Phase transfer catalyst (PTC) is selected from tetrabutylammonium iodide, tetraoctylammonium bromide, tetrabutylammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyltrimethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium acetate, benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, methyltrioctylammonium chloride tetrabutylammonium thiocyanate, tetrabutylphosphonium bromide, tetrapropylammonium bromide, tributylbenzylammonium bromide, benzyltriethylammonium chloride, and ethyltriphenylphosphonium bromide.

According to an embodiment of the present invention, wherein the organic base is selected from diisopropylethylamine (DIPEA), dimethylaminopyridine (DMAP), triethylamine (TEA), trimethylamine, methyl amine, ethyl amine, diethylamine, tertiary butyl amine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 5-diazabicyclo[4.3.0]non-5-ene (DBN) and pyridine.
According to an embodiment of the present invention, wherein the solvent is selected from alcohols such as methanol, ethanol, propanol, butanol, n-propyl alcohol, isopropyl alcohol, and t-butyl alcohol; nitriles such as acetonitrile and propionitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; and aromatic hydrocarbons such as toluene, heptane and xylene; esters such as ethyl acetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methyl isobutyl ketone,pentanone, ethylmethylketone, diethyl ketone; halogenated hydrocarbons such as chloroform, dichloromethane; ethers such as diethyl ether, tetrahydrofuran, dioxane or water and or mixtures thereof.

According to an embodiment of the present invention, wherein the inorganic base is selected from alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide; alkali metal carbonates such as caesium carbonate, sodium carbonate potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate.

In yet another aspect of the present invention provides process for the preparation of Elagolix sodium having = 99.7% HPLC purity.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

Examples:
Preparation of Elagolix sodium
(R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoro ethyl) benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (100g, 0.1833 mole), diisopropylethyl amine (47.4g, 0.3519 mole), TBAI (Tetrabutylammonium iodide) (13g) and ethyl 4-bromobutanoate (46.5, 0.2437mole) were taken in water (500 ml) at 20-25°C. The reaction mass was heated to 95-100°C and then maintained the reaction mass temperature at 95-100°C for 20hrs. After completion of the reaction, reaction mass was cooled to 20-25°C and diluted water (600 ml), then extracted with isopropyl acetate (300*2). The organic layer was treated with a solution of 10% ortho phosphoric acid (1200 ml). The mixture was stirred, allowed to settle, and the layers were separated. Again the organic layer was treated with a solution of 10% phosphoric acid (300 ml). The mixture was stirred, allowed to settle, and the layers were separated. The aqueous phosphate layers were combined and washed with isopropyl acetate (45ml). After layer separation, isopropyl acetate (300 ml) was added to the aqueous layer, followed by slow addition of a solution of 30% potassium carbonate (1200 ml) to adjust pH 9-10, while mixing. The layers were separated and the organic layer was concentrated under reduced pressure to get in-situ of (R)-ethyl 4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-(trifluoromethyl) benzyl)-4-ethyl-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl) amino) butanoate.
The above residue diluted with ethanol (400 ml) at 25-30°C and sodium hydroxide solution (14.6g, 0.365 mole) (NaOH dissolved in 100 ml of water) was added. The obtained reaction mass maintained at 25-30°C for 3 to 4 hr. After completion of the reaction, the reaction mass was concentrated under reduced pressure at below 50°C. The obtained crude material was dissolved in water (500 ml) and washed with isopropyl acetate (450ml) to remove impurities. The aqueous layer was saturated with NaCl (120g) and extracted with Methyl isobutyl ketone (600 ml). The organic layer was concentrated under reduced pressure at below 50°C and the obtained residue was diluted with Methyl isobutyl ketone (200 ml), then the organic layer was filtered through 0.4-micron filter paper. After that, the organic layer was added dropwise to n-Heptane (800 ml) at 10-15°C for 30-45min and maintained for 45-60 min at 10-15°C. The precipitated solid was filtered under nitrogen atmosphere and the wet material was dried under vacuum at 45-50°C for 20-24°C to get pure Elagolix sodium.
Yield: 60%
Purity by HPLC: = 99.7%
,CLAIMS:WE CLAIMS:
1. A process for the preparation of Elagolix sodium, comprising the steps of;
a) reacting the compound of the formula (V) with ethyl-4-bromobutanoate in presence of organic base, phase transfer catalyst and water or absence of an organic solvent to obtain in-situ compound of formula (VI), and

b) reacting in-situ compound of the formula (VI) with inorganic base in presence of solvent to obtained the formula (I).

2. The process as claimed in claim 1, wherein the Phase transfer catalyst (PTC) is selected from tetrabutylammonium iodide, tetraoctylammonium bromide, tetrabutylammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyltrimethylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium acetate, benzyltriethylammonium chloride, methyltricaprylammonium chloride, methyltributylammonium chloride, methyltrioctylammonium chloride tetrabutylammonium thiocyanate, tetrabutylphosphonium bromide, tetrapropylammonium bromide, tributylbenzylammonium bromide, benzyltriethylammonium chloride, and ethyltriphenylphosphonium bromide.

3. The process as claimed in claim 1, wherein an organic base is selected from diisopropylethylamine (DIPEA), dimethylaminopyridine (DMAP), triethylamine (TEA), trimethylamine, methyl amine, ethyl amine, diethylamine, tertiary butyl amine, N, N-dimethylaniline, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 5-diazabicyclo [4.3.0] non-5-ene (DBN) and pyridine.

4. The process as claimed in claim 1, wherein the solvent is selected from alcohols such as methanol, ethanol, propanol, butanol, n-propyl alcohol, isopropyl alcohol, and t-butyl alcohol; nitriles such as acetonitrile and propionitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; and aromatic hydrocarbons such as toluene, heptane and xylene; esters such as ethyl acetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methyl isobutyl ketone,pentanone, ethylmethylketone, diethyl ketone; halogenated hydrocarbons such as chloroform, dichloromethane; ethers such as diethyl ether, tetrahydrofuran, dioxane or water and or mixtures thereof.

5. The process as claimed in claim 1, wherein the inorganic base is selected from alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide; alkali metal carbonates such as caesium carbonate, sodium carbonate potassium carbonate or lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate.

6. The process as claimed in claim 1, wherein step (a) is carried out at a temperature in the range of 95-100°C for 20 hrs.

7. The process as claimed in claim 1, wherein step (b) is carried out at a temperature in the range of 25-30°C for 3 to 4 hrs.