DESC: “PROCESS FOR PREPARING ELAGOLIX”

FIELD OF THE INVENTION
The present invention relates to a process for the preparation of Elagolix sodium comprising isolating of solid crystalline Form-P of compound (V). The present invention also relates to a solid crystalline Form-P of compound of formula (V).

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 compound of formula (VII) is reacting with formula (VIIa) in presence of PPh3, DIAD and THF to obtain the compound of formula (VIII). The compound of formula (VIII) is reacting with formula (VIIIa) in presence of Na2CO3, Pd(PPh3)4, Water and dioxane to obtain the compound of formula (IV). The compound of formula (IV) reacting with TFA and DCM to obtain solution of the compound of formula (V). The compound solution 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 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 of formula (II) is reacting with formula (III) in presence of K2CO3, DMF, Water and Isopropyl acetate to obtain the compound of formula (IV). The compound of formula (IV) reacting with methanesulphonicacid and K2CO3 in presence of water, Phosphoric acid and Isopropyl acetate to obtain solution of the compound of formula (V). The compound solution of formula (V) is reacting with Ethyl-4-bromobutyrate in presence of DMF, DIPEA, water, K2CO3, isopropyl acetate and Phosphoric acid to obtain the compound of formula (VI). The compound of formula (VI) reacting with NaOH, Ethanol and water in presence of Isopropyl acetate, MIBK and Heptane to get Elagolix sodium (I).
The above process is schematically shown as below:

Scheme-II
PCT publication no. WO2021064561 discloses a process for the preparation of Crystalline Form-N of compound of Formula-V by comprising dissolving Formula-V with isopropyl acetate and Methyl tert-butyl ether.
CN 111689907 discloses a process for the preparation of crystalline Form-A of compound of Formula-V by comprising dissolving Formula-V with isopropyl acetate and n-heptane.
The main drawback of the prior art is process for the preparation of Elagolix sodium is difficult to purity and it is therefore necessary to purify individually the process intermediates to obtain the final Elagolix sodium.

The advantage of the present invention a process for the preparation of Elagolix sodium comprising isolating of solid crystalline Form-P of compound (V) which is isolated as solid. compound of formula (V) having HPLC purity of = 98% which is high impact on the purity of final Elagolix sodium.

OBJECTIVE OF THE INVENTION
The objective of the present invention is to provide a process for the preparation of Elagolix sodium of formula (I).
In another objective of the present invention is to provide a solid crystalline Form-P of compound of formula (V).

SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of Elagolix sodium comprising isolating of solid crystalline Form-P of compound (V). The present invention also relates to a solid crystalline Form-P of compound of formula (V).

In one aspect of the present invention provides a process for the preparation of Elagolix sodium of formula (I),

comprising isolating of solid crystalline form of compound (V):

In another aspect of the present invention provides solid crystalline Form-P of compound of formula (V)

BRIEF DESCRIPTION OF THE DRAWINGS:

Figure 1: X-ray powder diffraction (PXRD) crystalline Form-P of formula (V).
Figure 2: Differential scanning calorimetry (DSC) crystalline Form-P of formula (V).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Elagolix sodium comprising isolating of solid crystalline Form-P of compound (V). The present invention also relates to a solid crystalline Form-P of compound of formula (V).

In one aspect of the present invention provides a process for the preparation of Elagolix sodium of formula (I),

comprising isolating of solid crystalline form of compound (V):

In another aspect of the present invention, further relates to a process for the preparation of Elagolix sodium, comprising
a) reacting compound of formula (II) with a compound of formula (III) in presence of potassium carbonate and suitable solvent to obtain the in-situ compound of formula (IV),

b. deprotecting the in-situ compound of formula (IV) with methane sulfonic acid in presence of potassium carbonate and suitable solvent to compound of formula (V),

c. isolating compound of formula (V) in presence of alcohol solvent,
d. reacting compound of formula (V) with Ethyl-4-bromobutyrate in presence of N, N-diisopropylethylamine and suitable solvents to produce compound of formula (VI),

d. hydrolysing of compound of formula (VI) treating with sodium hydroxide in presence suitable solvents to obtain the Elagolix sodium (I).

In an embodiment of the present invention, the formula (II) is reacting with formula (III) in presence of potassium carbonate and suitable solvent and the reaction mass was maintained for 15-19 hr at 85-110°C to obtain in-situ compound of the formula (IV), and further treating with methane sulfonic acid in presence of potassium carbonate solution and suitable solvent and the reaction mass was maintained at 50-75°C for 2 to 5hr to obtain formula (V). The obtained layer of compound of formula (V) was concentrated under reduce pressure and co-distilled with suitable solvent at 35-60°C. The obtained residue was diluted/isolating with alcohol solvent at 35-70°C and the reaction mass was cooled to 5-25°C. The precipitated solid was filtered and dried at 40-65°C to get compound of formula (V) which is isolated as solid. compound of formula (V) having HPLC purity of = 98%, which is high impact on the purity of final Elagolix sodium API.

In an embodiment of the present invention, the compound of formula (V) is reacting with Ethyl 4-bromobutyrate in presence of N, N-Diisopropylethylamine and suitable solvents, and the reaction mass was maintained for 15-19 hr at 45-70°C to get residue in-situ of compound formula (VI). The obtained residue was treated with sodium hydroxide in presence suitable solvent and the reaction mass was maintained for 2 to 5 hr at 15-40°C and then extracted from suitable solvents. The obtained precipitated solid was filtered and dried at 35-60°C to obtain Elagolix sodium (I) having HPLC purity of = 99.5%.

According to an embodiment of the present invention, wherein the suitable solvent is selected from acetone, acetonitrile, ethyl acetate, water, isopropyl alcohol, methanol, ethanol, toluene, dimethyl sulfoxide, dimethylformamide, dichloromethane, isopropyl acetate, n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, ethyl acetate, xylene, hexane, heptane and water or mixtures thereof.

According to an embodiment of the present invention, wherein the alcohol solvent is selected from methanol, ethanol, n-propanol, pentanol, hexanol, heptanol butanol, isobutanol and isopropanol and/or mixtures thereof.

In yet another aspect of the present invention provides process for the preparation of Elagolix sodium having = 99.5% HPLC purity.

In yet another aspect of the present invention provides solid crystalline Form-P of compound of formula (V)

According to embodiment of the present invention provides crystalline Form-P of compound of Formula-V, having 2? values 4.49°, 9.01°, 09.71°, 10.47°, 11.43°, 11.62°, 12.09°, 13.11°, 14.70°, 15.94°, 16.20°, 16.56°, 17.27°, 18.12°, 18.47°, 19.14°, 22,14°, 23,15°, 24,64° and 24.95° (2?±0.2°).

According to embodiment of the present invention provides crystalline Form-P of compound of Formula-V, in addition to powder x-ray diffractogram having peaks about 4.49, 9.01, 9.71, 10.47, 11.43, 11.62, 12.09, 13.11, 14.70, 14.87, 15.38, 15.94, 16.20, 16.56, 17.27, 18. 12, 18.47, 19.14, 20.05, 21.02, 22.14, 22.56, 23.15, 23.96, 24.64, 24.95, 25.28, 26.39, 27.33, 28, 12, 29.07, 29.68, 30.93, 32.25,33.22, 33.73, 34.85, 35. 36, 37.42, 39.76, 40.34,41. 48, 42.57, 43.33, 45.24 and 47.04 (2?±0.2°).

According to the embodiment of the present invention, the PXRD spectrum of crystalline Form-P of compound of Formula-V as shown in Figure 1.

According to the embodiment of the present invention, the graph of differential scanning calorimetry (DSC) of the crystalline Form-P of compound of Formula-V have an endothermic peak at approximately 162-174°C at heating rate 50°C to 300°C at 5°C/min.

According to the embodiment of the present invention, the DSC thermogram of crystalline Form-P of compound of Formula-V as shown in Figure 2.

In yet another aspect of the present invention provides pure formula (V) having = 98% HPLC purity.

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

EXAMPLES
Example-1: Preparation of (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1- (2-fluoro-6-(trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (Formula V)
100g (0.23 moles) of 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione and 115 g (0.36 mole) of (R)-2-((tert-butoxycarbonyl) amino)-2-phenylethyl methanesulfonate added into round bottom flask (RBF), and further added 194g (1.40 mole) of potassium carbonate and N, N-Dimethylformamide (600 ml) at 25-30°C. The reaction mass was raised to 95-100°C and the reaction mass was maintained for 16-18 hr at 95-100°C. After completion of the reaction, the reaction mass was diluted with water (1200 ml) and extracted with isopropyl acetate (600 ml). The organic layer was washed with 10% NaCl solution and the organic layer was taken for next reaction.
55g (0.57 mole) of methane sulfonic acid was added to above organic layer at 10-15°C, then reaction mass temperature was raised to 60-65°C and the reaction mass was maintained for 3-4hr at 60-65°C. After completion of the reaction, reaction mass pH was adjusted to 9 to 10 with 30% potassium carbonate solution and extracted with isopropyl acetate (600 ml). The isopropyl acetate layer was washed with 8% H3PO4 solution and the organic layer was removed, the resulting aqueous layer was washed with isopropyl acetate (750 ml) to remove impurities. Finally, the aqueous layer was basified pH ~9 to 10 with 30% potassium carbonate solution and extracted with isopropyl acetate (600 ml). The isopropyl acetate layer was concentrated under reduced pressure and co-distilled with acetone (100 ml) at 45-50°C. The obtained residue was diluted with methanol (300 ml) at 45-50°C and the mass was cooled to 10-15°C. The precipitated solid was filtered and dried at 50-55°C to get (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (Formula V).
Yield: 65%
Purity by HPLC: = 98%

Example-2: Preparation of (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1- (2-fluoro-6-(trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (Formula V)
100g (0.23 moles) of 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione and 115 g (0.36 mole) of (R)-2-((tert-butoxycarbonyl) amino)-2-phenylethyl methanesulfonate added into round bottom flask (RBF), and further added 194g (1.40 mole) of potassium carbonate and N, N-Dimethylformamide (600 ml) at 25-30°C. The reaction mass was raised to 95-100°C and the reaction mass was maintained for 16-18 hr at 95-100°C. After completion of the reaction, the reaction mass was diluted with water (1200 ml) and extracted with isopropyl acetate (600 ml). The organic layer was washed with 10% NaCl solution and the organic layer was taken for next reaction.
55g (0.57 mole) of methane sulfonic acid was added to above organic layer at 10-15°C, then reaction mass temperature was raised to 60-65°C and the reaction mass was maintained for 3-4hr at 60-65°C. After completion of the reaction, reaction mass pH was adjusted to 9 to 10 with 30% potassium carbonate solution and extracted with isopropyl acetate (600 ml). The isopropyl acetate layer was washed with 8% H3PO4 solution and the organic layer was removed, the resulting aqueous layer was washed with isopropyl acetate (750 ml) to remove impurities. Finally, the aqueous layer was basified pH ~9 to 10 with 30% potassium carbonate solution and extracted with isopropyl acetate (600 ml). The isopropyl acetate layer was concentrated under reduced pressure and co-distilled with acetone (100 ml) at 45-50°C. The obtained residue was diluted with ethanol (300 ml) at 45-50°C and the mass was cooled to 10-15°C. The precipitated solid was filtered and dried at 50-55°C to get (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (Formula V).
Yield: 70%
Purity by HPLC: = 98%

Example-3: Preparation of Preparation of Elagolix Sodium
100g (0.18moles) of (R)-3-(2-amino-2-phenylethyl)-5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione into RBF, added 47.5g (0.24 moles) of Ethyl 4-bromobutyrate, 45.5g (0.35 moles) of N, N-Diisopropylethylamine and N, N-Dimethylformamide (200 ml) at 25-30°C. The reaction mass temperature was raised to 55-60°C and the reaction mass was maintained for 16-18 hr at 55-60°C. After completion of the reaction, the reaction mass was diluted with water (1200 ml) and extracted with isopropyl acetate (600 ml). The organic layer was washed with 8% H3PO4 solution and the organic layer was removed. The aqueous layer was washed with isopropyl acetate (750 ml) to remove impurities. Finally, the aqueous layer was basified pH ~9 to 10 with 30% potassium carbonate solution and extracted with isopropyl acetate (600 ml). The isopropyl acetate layer was concentrated under reduced pressure to get residue of (R)-ethyl 4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro- 6-(trifluoromethyl) benzyl)-4-methyl- 2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)-1-phenylethyl) amino) butanoate.
The above residue was diluted with ethanol (400 ml) and sodium hydroxide solution (14.6g (0.36 moles) in water (80 ml)) was added at 25-30°C. The reaction mass was maintained for 3-4 hr at 25-30°C. After completion of the reaction solvent was removed under reduced pressure at 45-50°C, then diluted with water (500 ml) and the aqueous layer was washed with isopropyl acetate (650 ml), after that sodium chloride (150g) was added, then extracted with MIBK (600 ml). Finally, the MIBK layer was added to n-Heptane (1200 ml) to get precipitation. The precipitated solid was filtered and dried at 45-50°C to get Elagolix sodium.
Yield: 65%
Purity by HPLC: = 99.5%
,CLAIMS:WE CLAIM:

1. A process for the preparation of Elagolix sodium, comprising
a) reacting compound of formula (II) with a compound of formula (III) in presence of potassium carbonate and suitable solvent to obtain the compound of formula (IV),

b) deprotecting the compound of formula (IV) with methane sulfonic acid, in presence of potassium carbonate and suitable solvent to compound of formula (V),

c) isolating compound of formula (V) in presence of alcohol solvent,
d) reacting compound of formula (V) with Ethyl-4-bromobutyrate in presence of N, N-diisopropylethylamine and suitable solvents to produce compound of formula (VI),

e) hydrolysing of compound of formula (VI) with sodium hydroxide in presence suitable solvents to obtain the Elagolix sodium (I).

2. The process as claimed in claim 1, wherein the suitable solvent is selected from acetone, acetonitrile, ethyl acetate, water, isopropyl alcohol, methanol, ethanol, toluene, dimethyl sulfoxide, dimethylformamide, dichloromethane, isopropyl acetate, n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, ethyl acetate, xylene, hexane, heptane and water or mixtures thereof.

3. The process as claimed in claim 1, wherein the alcohol solvent is selected from methanol, ethanol, n-propanol, pentanol, hexanol, heptanol butanol, isobutanol and isopropanol and/or mixtures thereof.

4. A crystalline form P of compound of Formula-V.

5. The crystalline form P of compound of Formula-V as claimed in claim 4, wherein the crystalline form has the XRPD diffraction peaks at values 4.49°, 9.01°, 09.71°, 10.47°, 11.43°, 11.62°, 12.09°, 13.11°, 14.70°, 15.94°, 16.20°, 16.56°, 17.27°, 18.12°, 18.47°, 19.14°, 22,14°, 23,15°, 24,64° and 24.95° (2?±0.2°).