DESC:“PROCESS FOR 5-(2-FLUORO-3-METHOXYPHENYL)-1-(2-FLUORO-6-(TRIFLUOROMETHYL) BENZYL)-6-METHYLPYRIMIDINE-2,4(1H,3H)-DIONE”

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1h,3h) dione (IV), which is used as a key intermediate for the preparation of Elagolix sodium.

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. WO2018198086 A1 discloses a process for the preparation Elagolix sodium, which comprises coupling of compound of formula-II with compound of formula-III in presence of potassium hydroxide, palladium acetate acetone, water and tri tert-butyl phosphoniumtetra fluoroborate to obtain the compound of formula (IV). The compound of formula IV converting into Elagolix sodium (I).

The above process is schematically shown as below:

Prior art process involved coupling of compound of formula-II with compound of formula-III in absence of catalyst to obtain the compound of the formula (IV). In absence of catalyst increase the time and decrease the rate of reaction.

PCT publication no. WO 2021064561 A1 discloses a process for the preparation Elagolix sodium, which comprises coupling of compound of formula-II with compound of formula-III in presence of potassium hydroxide, potassium iodide, palladium acetate acetone, water and tri tert-butyl phosphoniumtetra fluoroborate to obtain the compound of formula (IV). The compound of formula IV converting into Elagolix sodium (I).
The above process is schematically shown as below:

Prior art process involved coupling of compound of formula-II with compound of formula-III in presence of potassium iodide to obtain the compound of the formula (IV) with low yield and purity. Using potassium iodide in the reaction mild irritant, overexposure can have adverse effects, which is not an eco-friendly, commercially not suitable and not industrially applicable process.

The advantage of the present invention by using ammonium halo catalyst or alkyl silyl halide during the reaction between compound of formula-II with compound of formula-III, which is reduce the time of reaction and increase the rate of reaction, which 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 commercially suitable, industrially applicable and cost effective process. The present invention is providing the compound of formula (IV) with high yield and purity.

SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1h,3h) dione (IV), which is used as a key intermediate for the preparation of Elagolix sodium.

The present invention provides a process for the preparation of 5-(2-fluoro-3-methoxyphenyl) -1-(2-fluoro-6-(trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1h,3h)-dione(IV), comprising the steps of;

a) reacting the compound of the formula (IIA) with N-bromosucinimide obtain compound of formula (II);

b) coupling of compound of formula-II with compound of formula-III in presence of a base, coupling agent, ligand and ammonium halo catalyst or alkyl silyl halide to obtain compound of formula-IV; and

c) converting the compound of formula IV into Elagolix sodium (I).

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1h,3h) dione (IV). which is used as a key intermediate for the preparation of Elagolix sodium.

The present invention provides a process for the preparation of 5-(2-fluoro-3-methoxyphenyl) -1-(2-fluoro-6-(trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1h,3h)-dione (IV), comprising the steps of;

a) reacting the compound of the formula (IIA) with N-bromosucinimide to obtain compound of formula (II);

b) coupling of compound of formula-II with compound of formula-III in presence of a base, coupling agent, ligand and ammonium halo catalyst or alkyl silyl halide to obtain compound of formula-IV; and

c) converting the compound of formula IV into Elagolix sodium (I).

In an embodiment of the present invention, the formula (IIA) is reacting with N-bromosucinimide in presence sodium thiosulfate, methanol, water and the reaction maintain for 3-5 hours at 50 - 750C. After completion of reaction cool the reaction mass to room temperature and stir for one hour then filtered and wash with methanol. Wet material is slurry with 5% sodium thiosulfate solution at room temperature, filtered and wash with water, this material again slurry with water and wash with water followed by purified in methanol to get wet compound (II).
The compound of the formula (II) is reacting with compound of formula (III) in presence of base, Ammonium halo catalyst or Alkyl silyl halide and solvent at 15-40°C at the same temperature ligand was added to the resulting reaction mixture, heat the reaction mixture to 35 - 60°C at the same temperature coupling agent was added to the resulting reaction mixture. After completion of the reaction, reaction was mass cool to RT, filtered and wash with mixture of base and solvents followed by cool the reaction mixture to 15-40°C, filtered the reaction mixture and washed with methanol solvent and dried to get the title wet compound (IV).

According to an embodiment of the present invention, wherein the 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.

According to an embodiment of the present invention, ammonium halo catalyst is selected from ammonium iodide, ammonium chloride, ammonium bromide and ammonium fluoride. And alkyl silyl halide is selected from trimethyl silyl iodide, trimethyl silyl chloride, trimethyl silyl bromide, triethyliodosilane, triethylchlorosilane and triethylbromosilane.

According to an embodiment of the present invention, wherein the coupling agent is selected from the group consisting of palladium acetate, palladium chloride, bis(acetonitrile) palladium dichloride, bis (triphenyl phosphene) palladium chloride, palladium bis (acetyl acetonate) or Tetrakis (triphenyl phosphine) palladium; wherein said ligand is Tri-tert- butylphosphonium tetrafluoroborate (TTB-HBF4); wherein said catalyst is selected from the group consisting of potassium iodide, dimethyl amino pyridine or quaternary ammonium salt; wherein said acid is selected from the group consisting of acetic acid, trifluoroacetic acid or methane sulfonic acid.

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, tetrahydrofuran and N,N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; and aromatic hydrocarbons such as toluene, heptane and xylene; esters such as ethylacetate, methylacetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methylisobutyl ketone,pentanone, ethylmethylketone, diethylketone; halogenated hydrocarbons such as chloroform, dichloromethane; ethers such as diethyl ether, tetrahydrofuran, dioxane or water and or mixtures thereof.

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

EXAMPLES
Example 1: 5-Bromo-1-(2-fluoro-6-(trifluoromethyl) benzyl)-6-methyl pyrimidine-2,4(1H,3H)-dione.

14.13 g of N-Bromo Succinimide was added to a solution of 1-(2-fluoro-6-(trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1H,3H)-dione (20 g) (Formula-I) in methanol (60 ml) and maintained the reaction for 4 hours at 60-65°C. After completion of reaction, the reaction mass was cooled to room temperature and stirred for one hour, filtered and washed with methanol (10 ml). Wet material was slurry with 5% thiosulfate solution (100 ml) at room temperature, filtered and washed with water (20ml) and this material again slurry with water (100 ml) at RT. The obtained wet material was dissolved in methanol (60 ml), temperature was allowed to rise to 60 -65°C for 60 min, the reaction mass was cooled to RT, filtered and washed with methanol (10ml) to get title of compound.
Dry compound wt: 20 g,
Yield: 79 %
Purity by HPLC (%): 99.46,

Example 2: 5-(2-Fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl) benzyl)-6-methyl pyrimidine-2,4(1H,3H)-dione.

Aqueous potassium hydroxide (8.8 g KOH in 30 ml water) solution was added to a mixture of (2-fluoro-3-methoxyphenyI) boronic acid [compound of formula-III] (8.91 grams), Ammonium iodide (4.56 g,), Acetone (60 mL) and water 30 mL at 25-30°C and stirred for 10 minutes at the same temperature.1-(2-Fluoro-6-(trifluoromethyl)benzyl)-5-bromo-6-methyI-1Hpyrimidine-2,4-dione [Compound of formula-II] (10 grams) and tri tert-butyl phosphonium tetra fluoroborate (0.16 grams) were added to the resulting reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature, heated the reaction mixture to 45 - 50°C and stirred for 20 minutes at the same temperature, palladium acetate (0.06grams) was added to the resulting reaction mixture at 45- 50°C and the temperature was allowed to rise to 60-65°C and stirred for 2 hours. After completion of the reaction, reaction mass cooled to RT, filtered and washed with (mixture of KOH (0.75g) + water (15ml) +Acetone (7.5ml)), the obtained reaction mass added to the mixture of THF (20ml) & Acetic acid (15ml) and water (10ml) at 60°C and stirred for 30- 45 minutes at the same temperature. The reaction mass was cooled to 25-30°C and stirred for 2 hours at the same temperature, filtered and washed with methanol (20 ml) and dried to get the title compound.
9 gms, yield: 81%,
Purity by HPLC (%): 99.68

Example 3: 5-(2-Fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl) benzyl)-6-methyl pyrimidine-2,4(1H,3H)-dione.

Aqueous potassium hydroxide (8.8 g KOH in 30 ml water) solution was added to a mixture of (2-fluoro-3-methoxyphenyI) boronic acid [compound of formula-III] (8.92 grams), Ammonium iodide (7.6 g,), acetone (60 mL) and water 30 mL) at 25-30 °C under nitrogen atmosphere and stirred for 10 minutes at the same temperature, 10 g of 1-(2-fluoro-6-(trifluoromethyl) benzyl)-5-bromo-6-methyI-1Hpyrimidine-2,4-dione [Compound of formula-II ] and tri tert-butyl phosphonium tetra fluoroborate (0.16 grams) were added to the resulting reaction mixture at 25-30 °C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 45 -50°C and stirred for 20 minutes at the same temperature followed by palladium acetate (0.06 grams) was added to the resulting reaction mixture at 45- 50°C. Heated the reaction mixture to 60-65°C and stirred for 2 hours at the same temperature. After completion of the reaction, mass cooled to RT, filtered and washed with (mixture of KOH (0.75g) + water (15ml) +Acetone (7.5ml)), the reaction mass added to the mixture of THF (20ml) & Acetic acid (15ml) and water (10ml) at 60°C and stirred for 30- 60 minutes at the same temperature. Cooled the reaction mixture to 25-30 °C and stirred for 2 hours at the same temperature. Filtered the reaction mixture and washed with methanol (20 ml) and dried to get the title compound.
Dry compound wt: 9.5 g,
yield: 85 %,
Purity by HPLC (%): 99.79
,CLAIMS:We Claims:

1. A process for the preparation of 5-(2-fluoro-3-methoxyphenyl)-1-(2-fluoro-6-(trifluoromethyl) benzyl)-6-methylpyrimidine-2,4(1h,3h)-dione (IV), comprising the steps of:
a) reacting the compound of the formula (IIA) with N-bromosucinimide to obtain compound of formula (II);

b) coupling of compound of formula-II with compound of formula-III in presence of a base, coupling agent, ligand and ammonium halo catalyst or alkyl silyl halide to obtain compound of formula-IV; and

c) converting the compound of formula IV into Elagolix sodium (I).

2. The process as claimed in claim 1, wherein the 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.

3. The process as claimed in claim 1, wherein the ammonium halo catalyst is selected from ammonium iodide, ammonium chloride, ammonium bromide and ammonium fluoride.

4. The process as claimed in claim 1, wherein the alkyl silyl halide is selected from trimethyl silyl iodide, trimethyl silyl chloride, trimethyl silyl bromide, triethyliodosilane, triethylchlorosilane and triethyl bromosilane.

5. The process as claimed in claim 1, wherein the coupling agent is selected from palladium acetate, palladium chloride, bis (acetonitrile) palladium dichloride, bis (triphenyl phosphene) palladium chloride, palladium bis (acetyl acetonate) or Tetrakis (triphenyl phosphine) palladium.

6. The process as claimed in claim 1, wherein the coupling reaction in step b) is carried about 20°C to 50°C for about 10 to 25 minutes.

7. The process as claimed in claim 1, wherein said ligand is selected from Tri-tert- butylphosphonium tetra fluoroborate (TTB-HBF4).

8. 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, tetrahydrofuran and N,N-dimethyl acetamide; sulfoxides such as dimethyl sulfoxide and diethyl sulfoxide; and aromatic hydrocarbons such as toluene, heptane and xylene; esters such as ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, methoxy ethyl acetate; ketones such as acetone, methyl isobutyl ketone, pentanone, ethyl methyl ketone, diethyl ketone; halogenated hydrocarbons such as chloroform, dichloromethane; ethers such as diethyl ether, tetrahydrofuran, dioxane and water or mixtures thereof.