DESC:The following specification particularly describes the invention and the manner in which it is to be performed:

A PROCESS FOR PREPARATION OF ELAGOLIX AND INTERMEDIATES THEREOF

INTRODUCTION
The present invention provides a process for preparation of Elagolix and intermediates thereof.
BACKGROUND OF THE INVENTION
Elagolix sodium is a non-peptide antagonist of the gonadotropin-releasing hormone receptor and chemically known as sodium;4-[[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-4-methyl-2,6-dioxopyrimidin-1-yl]-1-phenylethyl]amino]butanoate (I) as given below .

(I)
The US patent number 7056927 B2 discloses a process for preparation of Elagolix sodium salt in Example-1 as given in below scheme-I.

Scheme-I
The US patent number 8765948 B2 describes a process for preparation of Elagolix sodium in example-1 and 4 as given below scheme-II:
Scheme-II
Further, the US patent number 8765948 B2 discloses an alternate process for the preparation of compound of formula (1e) as mentioned below scheme-III.

Scheme-III
The present invention provides an improved and commercially viable process for the preparation of Elagolix and intermediates thereof.
SUMMARY
First embodiment of the present invention provides a process for preparation of the compound of formula (VII) which is an intermediate in the preparation process of Elagolix.
Second embodiment of the present invention provides a process for preparation of the compound of formula (III) which is an intermediate in the preparation process of Elagolix.
Third embodiment of the present invention provides a process for preparation of Elagolix or its pharmaceutically acceptable salt.
DETAILED DESCRIPTION
First embodiment of the present invention provides a process for preparation of compound of formula (VII)

wherein R is alkyl such as methyl, ethyl, propyl, isopropyl and the like, comprising:
a) reacting the compound of formula (II) with compound of formula (III) to obtain the compound of formula (IV)

wherein t-BOC is tertiary butoxycarbonyl group; R is as described above
b) reacting the compound of formula (IV) with the compound of formula (V) to obtain the compound formula (VI), and

c) N-deprotection of the compound of formula (VI) to obtain the compound of formula (VII)

The reaction of compound of formula (II) with compound of formula (III) to obtain the compound of formula (IV) is carried in the presence of triarylphosphine such as triphenyl phosphine and the like and azodicarboxylates such as diethyl azodicarboxylate, diisopropyl azodicarboxylate and di-tert-butyl azodicarboxylate (DIAD) and the like.
The solvents used for the reaction of compound of formula (II) with compound of formula (III) include ether solvent such as anhydrous diethyl ether, dioxane, tetrahydrofuran and the like; hydrocarbon such as hexane, toluene and the like; halogenated hydrocarbon such as dichloromethane, trichloromethane and the like or the combination thereof. The reaction carried out in the temperature range of 0-60°C, particularly 20-40°C.
The present invention also includes reaction of appropriate halo, mesylate or sulfonate ester of compound of formula (III) with compound of formula (II) to obtain the compound of formula (IV).
The reaction of compound of formula (IV) with compound of formula (V) to provide the compound of formula (VI) carried out under conditions used in Suzuki coupling reaction. Specifically, the reaction involves use of palladium catalyst such as Pd(PPh3)4, Pd(OAc)2 and the like. The reaction also uses inorganic base such as alkali metal carbonate comprising sodium carbonate, potassium carbonate and the like; alkali metal phosphates such as sodium phosphate, potassium phosphate and the like; alkali hydroxides such as sodium hydroxide, potassium hydroxide and the like. The solvent used in the reaction comprises ether such as diethylether, isopropyl ether, 1,4-dioxane, tetrahydrofuran and the like; ketone solvent such as acetone, methyl ethyl ketone and the like; hydrocarbon such as hexane, toluene and the like; alcohol solvent such as methanol, ethanol and the like; amide solvents such as dimethyl formamide, dimethyl acetamide and the like or the combination thereof. The reaction carried out in the temperature range of 0-120°C, specifically 30-100°C, more specifically 60-90°C.
The N-deprotection of compound of formula (VI) to obtain the compound of formula (VII) carried in the presence of acid. The acid comprises hydrochloric acid, trifluoroacetic acid, phosphoric acid and the like. The solvent used for deprotection selected from hydrocarbon such as hexane, toluene and the like; halogenated hydrocarbon such as dichloromethane, trichloromethane and the like; alcohol such as methanol, ethanol, propanol and the like; ether such as diethyl ether, isopropyl ether and the like; ester solvent such ethylacetate, isopropyl acetate and the like.
The N-deprotection reaction is carried in the temperature range of -20°C to 60°C, specifically 10-40°C, more specifically 0-20°C.
In each stage the compounds are isolated from the reaction mixture may involve methods including removal of solvent, cooling, crash cooling, concentrating the mass, evaporation, flash evaporation, simple evaporation, fast solvent evaporation, rotational drying, spray drying, thin-film drying, agitated thin film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, rotary vacuum paddle dryer, adding anti-solvent or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.
The present invention also covers in-situ preparation of compound of formula (VII) from the compound of formula (II) as described herein.
The present invention also covers the different order of the various N-alkylation, Suzuki coupling reaction and N-deprotection.
The first embodiment of the present invention is depicted below scheme-IV.

Scheme-IV
The second embodiment of the present invention provides a process for preparation of compound of formula (III)

(III)
wherein R is alkyl such as methyl, ethyl, propyl and the like, comprising:
a) reacting R-(-)-2-phenylglycinol with 4-halao butyric acid alkyl ester to obtain the compound of formula (IIIa)

(IIIa)
b) N-protection of compound of formula (IIIa) to obtain the compound of formula (III)
The second embodiment of the present invention is depicted below scheme-IV.
Scheme-IV
The term “halo” refers fluroro, chloro, bromo and iodo. The term alkyl refers methyl, ethyl, propyl, butyl, isopropyl and the like.
The reaction of R-(-)-2-phenylglycinol with 4-halao butyric acid alkyl ester carried in organic solvent. The organic solvent is selected from ether such as diethyl ether, 1,4-dioxane, tetrahydrofuran and he like; ketone such as acetone, methyl ethyl ketone and the like.
Base used in this reaction includes organic and inorganic base. Organic base is selected from amine such as methyl amine, ethyl amine, diethyl amine, triethyl amine, piperazine and the like. Inorganic base selected from alkali metal carbonates and hydoxides such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like. The reaction is carried out in the temperature range of 0-100°C, preferably 20-90°C, more preferably 30-80°C.
N-protection of compound of formula (IIIa) is carried out using di-tert-butyl dicarbonate in organic solvent. The organic solvent is selected from ether such as diethyl ether, 1,4-dioxane, tetrahydrofuran and he like; ketone such as acetone, methyl ethyl ketone and the like.
Base used in this reaction includes organic and inorganic base. Organic base is selected from amine such as methyl amine, ethyl amine, diethyl amine, triethyl amine, piperazine and the like. Inorganic base selected from alkali metal carbonates and hydoxides such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like. N-protection is carried out in the temperature range of -10 to 50°C, preferably 10 to 40°C, more preferably 20-35°C.
In each stage the compounds are isolated from the reaction mixture may involve methods including removal of solvent, cooling, crash cooling, concentrating the mass, evaporation, flash evaporation, simple evaporation, fast solvent evaporation, rotational drying, spray drying, thin-film drying, agitated thin film drying, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying, rotary vacuum paddle dryer, adding anti-solvent or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.
Third embodiment of the present invention provides a process for preparation of Elagolix or its pharmaceutically acceptable salt comprising:
a) converting the compound of formula (II) to compound of formula (VII) as described herein and
b) ester hydrolysis of compound of formula (VII) to Elagolix or its pharmaceutically acceptable salt.
The ester hydrolysis of compound of formula (VII) to Elagolix or its pharmaceutically acceptable salt is carried out by the process known in the literature.
Examples
Example-1: Preparation of ethyl (R)-4-((2-hydroxy-1-phenylethyl)amino) butanoate (IIIa; R is ethyl)
R-(-)-2-phenylglycinol (10 g), DMAP (0.17 g) were added in THF (80 ml) at room temperature under nitrogen atmosphere. Triethylamine (30.48 ml) was added to the reaction mixture and stirred for five minutes. Ethyl-4-bromo butyrate (15.64 ml) was added and the reaction mixture heated to 80°C then stirred for 16 hours. Water (20 volumes) followed by ethyl acetate (200 ml) were added to separate the aqueous and organic layer. The organic layer was washed with 1N HCl (100 ml) followed by neutralize the resulting aqueous layer with saturated sodium carbonate solution then extract with ethyl acetate (100 ml) and the organic layer was dried over anhydrous sodium sulfate then evaporated below 50°C under reduced pressure to obtain the title compound. Yield: 14.50 g. Purity: 94.75% (by HPLC). 1H NMR (400 MHz, DMSO-d6): d 7.17-7.30 (m, 5H), 4.83 (m, 1H), 3.99 (q, 2H), 3.58 (dd, 1H, J = 8.8, 4.4 Hz), 3.88 (m, 1H ), 3.27 (m, 1H), 2.38 (m, 1H), 2.26 (m, 3H), 2.10 (s, 1H), 1.61 (m, 2H), 1.12 (t, 3H); m/z: 252 (MH+)
Example-2: Preparation of ethyl (R)-4-((tert-butoxycarbonyl)(2-hydroxy-1-phenylethyl) amino)butanoate (III; R is ethyl)
Ethyl (R)-4-((2-hydroxy-1-phenylethyl)amino)butanoate (14 g) was added to THF (140 ml) at room temperature. The reaction mixture was cooled to 0-5°C. Triethylamine (16.9 mL) was added to the reaction mixture followed by Di-tert-butyl dicarbonate (13.37 g) was added to reaction mixture at 0-5°C. The reaction mixture was heated to room temperature and stirred for 16 hours. Water (300 mL) and ethyl acetate (300 mL) were added and the layers were separated. The organic layer was washed with sodium chloride then died over sodium sulfate followed by evaporation at 45°C to obtain the crude compound. The crude compound was purified by silica gel (60/120 mesh) with15-20% EtOAc/Hexane to obtain the title compound as a pale yellow syrup. Yield: 9.5 g. Purity: 95.42% (by HPLC). 1H NMR (400 MHz, CDCl3): d 7.24-7.34 (m, 5H), 5.08 (m, 1H), 4.09 (m, 4H), 3.10 (m, 2H), 3.00 (s, 1H), 2.21(m, 2H), 1.82 (m, 2H), 1.46 (s, 9H), 1.23 (t, 3H). m/z: 352.20 (MH+)
Example-3: Preparation of ethyl (R)-4-((2-(5-bromo)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)(tert-butoxycarbonyl)amino)butanoate (IV; R is ethyl)
Ethyl(R)-4-((tert-butoxycarbonyl)(2-hydroxy-1-phenylethyl)amino) butanoate(III; R is ethyl) (1.0 g), 5-bromo-1-(2-fluoro-6-trifluoromethyl)benzyl-6-methylpyrimidine-2,4 (1H, 3H)-dione (II) (1.08 g), Triphenyl phosphine (1.49 g) were added to THF (30 mL) at room temperature under nitrogen atmosphere. DIAD (1.11 mL) was added to the reaction mixture and stirred for 16 hours at room temperature. Water (60 volume) was added to the reaction mixture followed by ethylacetate (60 mL) was added then the layers were separated. The organic layer was dried over sodium sulfate and evaporated below 50°C under reduced pressure to obtain the crude compound. The crude compound was purified by silica gel (60/120 mesh) with15-20% EtOAc/Hexane to obtain the title compound. Yield (1.3 g). Purity: 68.87% (by HPLC); 1H NMR (DMSO-d6) d 1.15-2.0 (11H), 2.43-2.48 (4H), 3.9 (2H), 4.71-4.8 (5H), 5.3 -5.4 (3H), 7.28-7.3 (8H), 8.4 (2H); m/z: 616 (M-BOC)+
Example-4: Preparation of ethyl (R)-4-((tert-butoxycarbonyl)-2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)amino)-butanoate (VI; R is ethyl)
Ethyl(R)-4-((2-(5-bromo)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)(tert-butoxycarbonyl) amino)butanoate (IV; R is ethyl) (0.9 g), 2-fluoro-3-methoxy phenyl boronic acid (V) (0.214 g) and sodium carbonate (0.797 g) were added to the mixture of 1,4-dioxane (9 mL) and water (3.06 mL) at room temperature under nitrogen atmosphere. Argon gas was bubbled through for 30 minutes. Tetrakis (triphenylphosphine)palladium (0.145 g) was added to the reaction mixture at room temperature then heated to 90-95 °C and stirred for 5 hours. The reaction mixture cooled to room temperature and filtered through celite bed then the filtrate washed with ethyl acetate (9 mL) and water (36 mL) was added and stirred for 30 minutes at room temperature. Ethyl acetate (36 mL) was added and the separated organic layer washed with brine and dried over sodium sulfate followed by evaporation at 45°C to obtain the crude compound. The crude compound was purified by silica gel (60/120 mesh) with 20-25% EtOAc/Hexane to obtain the title compound as yellow solid. Yield: 0.5 g; Purity: 75.1% (by HPLC); m/z: 660 (M-BOC)+.
Example-5: Preparation of ethyl (R)-4-((2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)amino)-butanoate (VII; R is ethyl)
Ethyl(R)-4-((tert-butoxycarbonyl)-2-(5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-trifluoromethyl)benzyl)-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)-1-phenylethyl)amino)-butanoate (VI; R is ethyl) (0.4 g) was added to dichloromethane (4 mL) at room temperature. The reaction mixture was cooled to 0-5°C then trifluoroacetic acid (2 mL) was added and stirred for five hours at 0-5°C. Saturated sodium bicarbonate solution (40 mL) was added to the reaction mixture followed by dichloromethane (40 mL) was added. The organic layer was washed with brine then dried over sodium sulfate and evaporated at 35°C to obtain the crude compound. The crude compound purified by silica gel (60/120 mesh) with 30-35% EtOAc/Hexane to obtain the title compound as yellow solid. Yield: 160 mg; Purity: 88.6% (by HPLC). 1H NMR (400 MHz, DMSO-d6): d 7.64 (m, 1H), 7.54 (m, 2H), 7.15-7.27 (m, 6H), 6.85 (m, 2H), 5.31 (s, 2H), 3.99 (m, 3H), 3.87 (m, 2H), 3.83 (s, 3H), 2.30-2.16 (m, 4H), 2.10 (s, 3H), 1.50 (m, 2H), 1.10 (t, 3H). m/z: 660 (MH+)
,CLAIMS:We Claim:
1. A process for preparation of compound of formula (VII)

wherein R is alkyl such as methyl, ethyl, propyl, isopropyl and the like, comprising:
a) reacting the compound of formula (II) with compound of formula (III) to obtain the compound of formula (IV)

wherein t-BOC is tertiary butoxycarbonyl group; R is as described above;
b) reacting the compound of formula (IV) with the compound of formula (V) to obtain the compound formula (VI), and

c) N-deprotection of the compound of formula (VI) to obtain the compound of formula (VII)

2. The process of claim 11, wherein the reaction of compound of formula (II) with compound of formula (III) to obtain the compound of formula (IV) is carried in the presence of triarylphosphine and azodicarboxylates.
3. A process for the preparation of compound of formula (III)

(III)
wherein R is alkyl such as methyl, ethyl, propyl and the like, comprising:
a) reacting R-(-)-2-phenylglycinol with 4-halao butyric acid alkyl ester to obtain the compound of formula (IIIa) and

(IIIa)
b) N-protection of compound of formula (IIIa) to obtain the compound of formula (III).
4. A process for preparation of Elagolix or its pharmaceutically acceptable salt comprising the steps of:
a) converting the compound of formula (II) to compound of formula (VII) as described herein and
b) ester hydrolysis of compound of formula (VII) to Elagolix or its pharmaceutically acceptable salt.