FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Elagolix intermediate.
The present invention particularly relates to an improved process for the preparation of Elagolix intermediate of Formula II which is free of impurity A
wherein the process is carried out using phase transfer catalyst which does not involve the use of base.
BACKGROUND OF THE INVENTION
Elagolix sodium is a nonpeptide small molecule, GnRH receptor antagonist. Elagolix sodium is chemically described as sodium 4-({(lR)-2-[5-(2-fluoro-3-methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-
Elagolix sodium has a molecular formula of C32H29F5N305Na and a molecular weight of

653.58. Elagolix free acid has a molecular weight of 631.60. Elagolix sodium has the following structural formula:
The empirical formula is C32H29F5N3O5 and a molecular weight of 653.58. Elagolix sodium is a white to off white to light yellow powder and is freely soluble in water.
WO 2005/007165 Al discloses pyrimidine-2,4-dione derivatives as gonadotropin-releasing hormone receptor antagonists. This application discloses the preparation of Elagolix using compound of formula II, wherein compound of formula II is prepared by coupling compound of formula III with ethyl 4-bromobutyrate using organic base. The process-is briefly described below:
Compound of formula II was chromatographed with 10:10:1 EtOAc/Hexane/Et3N to give Ig as yellow oil. The above process may not be feasible commercially as this process involves the use of chromatographic technique for the isolation and purification of compound of formula II. The major drawback with this process is the formation of unwanted pyrrolidinone impurity (herein referred as impurity A) in excess percentage which impacts the yield of final API, the said
within ICH limits. To remove the said impurity the process requires more number of

purification steps due to which the product isolated obtained in low yield.
WO 2019/115019 Al discloses a process for preparing compound of formula II, wherein compound of formula II is obtained by reacting compound of formula III with ethyl 4-bromobutyrate using an organic base such as N,N-diisopropylethylamine. The process is briefly described below:
WO '019 generally discloses the use of other bases such as inorganic base selected from carbonate (such as Na2C03, K2C03, Rb2C03, CS2CO3) or a hydroxide (such as NaOH, KOH, CsOH, Ba(OH)2, TIOH (and their hydrates)) or an alkoxide (such as NaOCH3, NaOEt, TIOEt, NaOtBu, KOtBu) or a fluoride (such as NaF, KF, CsF, Bu4NF) or an acetate (for example AcOK, AcONa) or other inorganic base (such as K.2P04) or an amine (such as Et3N, (i-Pr)2Et2N). WO '019 neither exemplifies any of the above bases nor does it describe the impurity formation of the said reaction.
The inventors of the present invention have surprisingly found that the formation of Impurity A can be reduced or eliminated by performing the reaction of
especially novel with respect to the absence of formation of impurity A when the

process carried out using inorganic base.
OBJECT OF THE INVENTION
The main object of the invention is to provide an improved process for the preparation of compound of Formula II which is free of Impurity A
wherein the reaction is carried out in the presence of inorganic base.
The further object of the invention is to provide an improved process for the preparation of compound of Formula II
Formula II wherein the reaction is carried out in the presence of phase transfer catalyst without using a base.
SUMMARY OF THE INVENTION Accordingly, the present invention provides an improved process for the preparation of compound of Formula II which is free of Impurity A

Formula II Impurity A
wherein the process comprises reacting compound of Formula III
with compound of Formula IV
Formula IV wherein R| selected from CI, Br, I, F, OMs, O-alkly and OTs, in the presence of inorganic base and a solvent to obtain compound of Formula II which is free of Impurity A.
In a preferred aspect, the present invention provides an improved process for ~^-—the.preparatiori_of_compound_of Formula IT: which isjree of Impurity A. ^
wherein the process comprises reacting compound of Formula III

Formula III with compound of Formula IV
CH3

Formula IV wherein R[ selected from CI, Br, I, F, OMs, O-alkly and OTs, in the presence of Sodium bicarbonate in DMF to obtain compound of Formula II which is free of Impurity A.
In another preferred aspect, the present invention provides an improved process for the preparation of compound of Formula II which is free of Impurity A
wherein the process comprises:
a) Adding compound of Formula I]
to sodium bicarbonate in DMF; b) Adding compound of-Formula IV

Formula IV wherein R^ selected from CI, Br, I, F, OMs, O-alUy and OTs, to reaction mass of step a);
c) Raising the reaction temperature to 45-65°C and maintained for 6 hrs;
d) Extracting and isolating compound of Formula II which is free of Impurity A.
In yet another preferred aspect of the invention, the present invention provides an improved process for the preparation of compound of Formula II
which comprises reacting compound of Formula III with compound of Formula IV
wherein Ri selected from CI, Br, I, F, OMs, O-alkly and OTs, in a solvent and in the presence of phase transfer catalyst, wherein the process does not involve the use of a base.
Jn-yet-another^preferred aspect, the present invention provides an improved process for the preparation of compound of Formula II

wherein the process comprises:
a) Adding compound of Formula III
to TBAB in DMF;
b) Adding compound of Formula IV
,CH3

Formula IV wherein R| selected from CI, Br, I, F, OMs, O-alkly and OTs, to reaction mass of step a);
c) Raising the reaction temperature to 45-65°C and' maintained for 6 hrs;
d) Extracting and isolating compound of Formula II.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of compound of Formula II which is free of impurity A
The inventors of the present invention have developed an improved process for
compound or rormula li which is tree ot impurity A. 1 he process disclosed in the

prior art such as WO 2005/007165 Al involves the reaction of compound of Formula III with ethyl 4-bromobutyrate using Hunig's base and the reaction time cycle was 18-27 hours under heating conditions, which further involves the use of column chromatography technique for the isolation of compound of Formula II. The disadvantages of using organic bases, especially t-amines like Triethylamine, Diisopropylethylamine etc., are potential Nitraso amine precursors and hence it is recommended to avoid organic bases in commercial manufacturing procedures.
The current process overcomes the disadvantages of the WO '165 process by adopting efficient reagents and solvents such as using inorganic base media and it has been achieved with less reaction time cycle 4-6 hours. With lower reaction time cycles we can save the energy and it can be protected chiral molecular decomposition or inversion, the final compound was directly isolated without using column chromatography technique.
In a preferred embodiment of the invention, wherein the inorganic base is selected from alkali carbonate and bicarbonate, alkaline earth metal carbonate and bicarbonates, alkoxides and hydrides. The example of inorganic base includes but not limited to NaHC03, LiOH, NaOH, KOH, KHC03, LiHC03, Na2C03, K2C035 Li2C03, CaC03, MgC03, sodium hydride, potassium tert butoxide, sodium tert butoxide, magnesium hydroxide, MgH2, MgCl2, Mg(OMe)2, Mg(OH)2, Mg(OEl)2, MgHOMe, MgHOEt, CaH2, Ca(OMe)2 and Ca(OEt)2 and the like or mixtures thereof.
In another preferred embodiment of the invention, wherein the solvent is selected from water, methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol, dimethylsulfoxide, dimethylacetamide, dimethyl formamide, acetonitrile, propionitrile, bulyronitrile, isobutyronitrile, ether solvents, di-tert-butylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert- butylether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane, methylene chloride, ethylene dichloride,
hexane, cyclohexane, acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl

ketone, isopropyl ketone, ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec -butyl acetate, isopropyl acetate and their mixtures thereof.
In yet another preferred embodiment of the invention, phase transfer catalyst is selected from the group consisting of a quaternary ammonium salt and a quaternary phosphonium salt. Preferably the phase transfer catalyst is selected from quaternary ammonium salts selected from the group consisting of benzyltriethylammonium halide, hexadecyltrimethylammonium halide, tetrabutylammonium halide, tetramethylammonium halide, tetraethylammonium halide, tetrabutylammonium acetate and mixtures thereof.
In a preferred embodiment, the present invention provides an improved process for the preparation of compound of Formula II which is free of Impurity A.
wherein the process comprises reacting compound of Formula III
Formula III with ethyl 4-halobutanoate in the presence of Sodium bicarbonate in DMF to obtain compound of Formula II which is free of Impurity A.
process for the preparation of compound of Formula II which is free of Impurity A

wherein the process comprises:
a) Adding compound of Formula III
to sodium bicarbonate in DMF;
b) Adding ethyl 4-halobutanoate to reaction mass of step a);
c) Raising the reaction temperature to 45-65°C and maintained for 6 hrs;
d) Extracting compound of Formula II using orthophbsphoric acid;
e) Isbiatirif cornpou"n3"of Formula" II whicrTis"free~of Inipufity"AT ~
In yet another preferred embodiment, the present invention provides an improved process for the preparation of compound of Formula II
a) Adding compound of Formula III

to TBAB in DMF;
b) Adding ethyl 4-halobutanoate to reaction mass of step a);
c) Raising the reaction temperature to 45-65°C and maintained for 6 hrs;
d) Extracting compound of Formula II using orthophosphoric acid;
e) Isolating compound of Formula II.
In yet another preferred embodiment of the present invention the compound of Formula II as prepared according to any of the process of the present invention further converted to Elagolix or its salts, wherein the process involves the hydrolysis of compound of Formula II using sodium hydroxide as a base and MIBK as a solvent. The final sodium salt of Elagolix is isolated using n-heptane.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.

In a 500 mL round bottom flask 30.0 gms of 3-[(2R)-2-Amino-2-phenylethyl]-5-(2-fluoro-3- methylphenyl)-l-[[2-fluoro -6- (Trifluoromethyl)phenyl]methyl]-6-methyl-2, 4(lH,3H)-pyrimidinedione, 18.3 gms of Sodium bicarbonate were taken in 60.0mL of N,N-dimethyl formamide under gentle stirring at Room temperature. 18.07 gms of 4-Bromo ethyl butyrate were added dropwise to the above reaction mixture over a period of 15-20 minutes. Once addition completed, maintained the reaction mass for 30 minutes at room temperature and then slowly raised temperature to 50-60 °C and maintained for 6 hours. Once starting materials complies over HPLC monitoring, the reaction mass was cooled to room temperature, diluted with 250 mL of Water and the resulting mixture was extracted with isopropyl acetate (3X lOOmL). The combined organic layers were washed with Water (2x 50 mL) and the organic layer was extracted with 20% Orthophosphoric acid (2X 150 mL). The resulting aqueous layer further washed with isopropyl acetate (2X lOOmL) and the resulting aqueous layer pH was adjusted with 45% aqueous Potassium carbonate (72 Gms) and the entire basic solution was extracted with isopropyl acetate (3x lOOmL). The resulting organic layer was concentrated under reduced pressure and the resulting crude mass was co-distilled with Absolute ethanol (30mL) to give compound of Formula II which is free of impurity A.
Yield: 30 gm; HPLC purity 99.0%.

Spectral characterization data of Elaaolix pvrrolidinone impurity (Impurity-A)
In a 500 mL round bottom flask 30.0 gms of 3-[(2R)-2-Amino-2-phenylethyl]-5-(2-fluoro-3- methylphenyl)-l-[[2-fluoro -6- (Trifluoromethyl)phenyl]methyl]-6-methyl-2, 4(lH,3H)-pyrimidinedione, 35.4 gms of Tetra butyl ammonium bromide (TBAB) were taken in 150.OmL of N,N-dimethyl formamide un3er"g5itlFstirringlit~^~"" Room temperature. 21.4 gms of 4-Bromo ethyl butyrate were added dropwise to the above reaction mixture over a period of 15-20 minutes. Once addition completed, maintained the reaction mass for 30 minutes at room temperature and then slowly raised temperature to 45-50 °C and maintained for 12 hours. Once starting materials complies over HPLC monitoring, the reaction mass was cooled to room temperature,

acetate. (3X lOOmL). The combined organic layers were washed with Water (2x 50 mL) and the organic layer was extracted with 20% Orthophosphoric acid (2X 150 mL). The resulting aqueous layer further washed with isopropyl acetate (2X lOOmL) and the resulting aqueous layer pH was adjusted with 45% aqueous Potassium carbonate (72 Gms) and the entire basic solution was extracted with isopropyl acetate (3x lOOmL). The resulting organic layer was concentrated under reduced pressure and the resulting crude mass was co-distilled with Absolute ethanol (30mL). Yield: 30 gm; HPLC purity NLT 98.0%.
In a 500mL round bottom flask an Ethanolic solution of 4-({(lR)-2- [5-(2-fluoro-3-methoxyphenyl)-3-{[2-fluoro-6-(Trifluoromethyl) phenyl] methyl}-4-methyl-2,6-dioxo-3,6-dihydropyrimidin-l(2H)-yl]-l-phenylethyl} amino) butanoate was taken into 150mL of 5% Sodium hydroxide solution at room temperature under controlled stirring operation and it maintained for 60 minutes to complete the starting material over TLC. Once reaction completed the reaction mixture was diluted with Water (50mL), the aqueous reaction mixture was washed with MIBK (2x lOOmL) to remove unwanted impurities and followed by pH (-14) adjustment with 48% NaOH solution to make sodium salt. The resulting salt solution-was extracted with isopropyl acetate (3x lOOmL), the combined organic layers were concentrated to get crude Elagolix sodium, which is isolated as solid material in n-Heptane to affoard 20gm with purity NLT 99.0%, Any other impurity NMT 0.1%.

We Claim:
1. An improved process for the preparation of compound of Formula II which is. free of Impurity A
wherein the process comprises reacting compound of Formula III
wherein R, selected from CI, Br, 1, F, OMs, O-alkly and OTs, in the presence of inorganic base and a solvent to obtain compound of Formula II which is free of Impurity A.
2. The process as claimed in claim 1, wherein inorganic base is preferably selected from inorganic base is selected from alkali carbonate and bicarbonate, alkaline earth metal carbonate and bicarbonates, alkoxides and hydrides. The example of inorganic base includes but not limited to NaHC03, LiOH, NaOH, KOH, KHC03; LiHC03, Na2C03, K2C03, Li2C03, CaC03; MgC03, sodium hydride, potassium

Mg(OMe)2, Mg(OH)2, Mg(OEt)2, MgHOMe, MgHOEt, CaH2, Ca(OMe)2 and Ca(OEt)2 and the like or mixtures thereof.
3. An improved process for the preparation of compound of Formula II which is free of Impurity A.
wherein the process comprises reacting compound of Formula III
with compound of Formula IV

to sodium bicarbonate in DMF; b) Adding compound of Formula IV
to reaction mass of step a);
c) Raised the reaction temperature to 45-65°C and maintained for 6 hrs;
d) Extracting and isolating compound of Formula II which is free of Impurity A.
5. An improved process for the preparation of compound of Formula II
which comprises reacting compound of Formula III with compound of Formula IV
wherein R] selected from CI, Br, I, F, OMs, O-alkly and OTs, in a solvent and in the presence of phase transfer catalyst, wherein the process does not involve the

6. An improved process as claimed in claim 5, wherein phase transfer catalyst is
selected from benzyltriethylammonium halide, hexadecyltrimethylammonium
halide, tetrabutylammonium halide, tetramethylammonium halide,
tetraethylammonium halide, tetrabutylammonium acetate and mixtures thereof
7. An improved process as claimed in claim 5, wherein the process comprises:
a) Adding compound of Formula III
to TBAB in DMF; b) Adding compound of Formula IV
to reaction mass of step a); c) Raised the reaction temperature to 45-65°C and maintained for 6 hrs; Extracting and isolating compound of Formula II.