DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)
&
THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

NOVEL POLYMORPHS OF ELAGOLIX SODIUM

We, SMS Pharmaceuticals Limited,
a company incorporated under the companies act, 1956 having address at
Plot No.72, H. No.8-2-334/3 & 4 Road No.5, Opp. SBI Executive Enclave, Banjara Hills, Hyderabad-500034, Telangana, India.

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

FIELD OF THE INVENTION
The present invention relates to novel polymorphs of Elagolix.

The present invention particularly relates to novel polymorph Form-S of Elagolix.

The present invention further relates to a process for the preparation of novel polymorph Form-S of Elagolix.

BACKGROUND OF THE INVENTION
Elagolix sodium is a nonpeptide small molecule, GnRH receptor antagonist. Elagolix sodium is chemically described as sodium 4-({(1R)-2-[5-(2-fluoro-3­methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxo-3,6­dihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino)butanoate Elagolix sodium has a molecular formula of C32H29F5N3O5Na 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 A1 discloses pyrimidine-2,4-dione derivatives as gonadotropin-releasing hormone receptor antagonists. The compound Elagolix is disclosed as one example of such pyrimidine-2,4-dione derivatives. In Example 1H of said application Elagolix free acid was formed as an intermediate during production of the Elagolix sodium salt and was described as a white gel after extraction with ethyl acetate and evaporation of the solvent. The gel was passed through a DOWEX MSC-1 macroporous strong cation-exchange column to convert the acid to the sodium salt. Finally, lyophilization gave the sodium salt of Elagolix as a white solid.

According to Chen C. et al. "Discovery of Sodium R-(+)-4-{2-[5-(2-Fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylamino}butyrate (Elagolix), a Potent and Orally Available Nonpeptide Antagonist of the Human Gonadotropin-Releasing Hormone Receptor" J. Med. Chem., 2008, 51 (23), 7478-7485 Elagolix free acid was either obtained as white foam or as gel after extraction with ethyl acetate and subsequent evaporation of the solvent. As already previously described in WO 2005/007165 A1 the gel was passed through a DOWEX MSC-1 macroporous strong cation-exchange column to convert it to the sodium salt, which was obtained as white solid after lyophilization.

The inventors of the present invention have tried isolation of Elagolix sodium salt with different set of solvents and surprisingly found novel polymorph of Elagolix sodium which contains mixture of crystalline and amorphous Elagolix sodium. The said polymorph here referred as polymorphic Form-S of Elagolix sodium.

OBJECT OF THE INVENTION
The main object of the invention is to provide novel polymorphic Form-S of Elagolix sodium.

The further object of the invention is to provide process for the preparation of novel polymorphic Form-S of Elagolix sodium.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides novel polymorphic Form-S of Elagolix Sodium of Formula-I

Formula I
wherein Form-S is characterized by an X-ray powder diffraction pattern having peaks expressed as 2? angle positions at about 27.44, 31.76, and 45.49 ±2?.

In a preferred aspect, the present invention provides novel polymorphic Form-S of Elagolix Sodium of Formula-I

Formula I
wherein Form-S is a mixture of amorphous and crystalline which is characterized by X-ray powder diffraction pattern having a broader peak and sharp peaks expressed as 2? angle positions at about 27.44, 31.76, and 45.49 ±2?.

In another preferred aspect, the present invention provides a process for the preparation of novel polymorphic Form-S of Elagolix Sodium

Formula I
which comprises
dissolving crude Elagolix sodium in a solvent or mixture of solvents,
stir the reaction mass,
optionally cooling the reaction mass,
isolating polymorphic Form-S of Elagolix Sodium.

In yet another preferred aspect, the present invention provides a process for the preparation of novel polymorphic Form-S of Elagolix Sodium

Formula I
which comprises
treating Elagolix with NaOH solution,
adding ketone solvent to the reaction mass,
optionally distil the solvent,
adding solvent to the above mass,
isolated polymorphic Form-S of Elagolix Sodium.

In yet another preferred aspect, the present invention provides a process for the preparation of compound of Formula II, an intermediate of Elagolix or its salts

Formula II
which is free of the following impurities

which involves the reaction of compound of Formula III

Formula III
with compound of Formula IV

Formula IV
in the presence of base and in a solvent, wherein the compound of Formula IV was added lot wise manner at RT.

BRIEF DESCRIPTION OF THE DRAWING
FIG. 1: Illustrates the characteristic powder X-ray diffraction (XRD) pattern of crystalline Form-S of Elagolix sodium.

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides novel polymorphic Form-S of Elagolix Sodium of Formula-I

Formula I
The inventors of the present invention have developed a novel polymorphic Form-S of Elagolix Sodium, which is highly pure and stable and can be used for formulation.

In a preferred embodiment, the present invention provides a novel polymorphic Form-S of Elagolix Sodium of Formula-I

Formula I
wherein Form-S is characterized by an X-ray powder diffraction pattern having peaks expressed as 2? angle positions at about 27.44, 31.76, and 45.49 ±2?.

In another preferred embodiment, the present invention provides novel polymorphic Form-S of Elagolix Sodium of Formula-I

Formula I
wherein Form-S is a mixture of amorphous and crystalline which is characterized by X-ray powder diffraction pattern having a broader peak and sharp peaks expressed as 2? angle positions at about 27.44, 31.76, and 45.49 ±2?.

In yet another preferred embodiment, the present invention provides a process for the preparation of novel polymorphic Form-S of Elagolix Sodium

Formula I
which comprises
dissolving crude Elagolix sodium in MIBK solvent,
stir the reaction mass,
distil the solvent,
heptane was added,
stir the reaction mass,
isolating polymorphic Form-S of Elagolix Sodium.

In yet another preferred embodiment, the present invention provides a process for the preparation of novel polymorphic Form-S of Elagolix Sodium

Formula I
which comprises
treating Elagolix with NaOH solution,
adding MIBK solvent to the reaction mass,
distil the solvent,
heptane was added,
stir the reaction mass,
isolating polymorphic Form-S of Elagolix Sodium.

In yet another preferred embodiment, the present invention provides a process for the preparation of compound of Formula II, an intermediate of Elagolix or its salts

Formula II
which is free of the following impurities

which involves the reaction of compound of Formula III

Formula III
with compound of Formula IV

Formula IV
in the presence of DIPEA and in NMP, wherein the compound of Formula IV was added lot wise manner at RT.

According to the process of the present invention, the inventors have successfully prepared highly pure Elagolix Sodium and its intermediates which are free of the following impurities.

The formation of impurities b & c observed when compound of Formula II was prepared according to the process disclosed in the prior art such as WO 2018/198086 A1.

The prior art process involves the N-Alkylation reaction of primary amine of Formula III at high temperatures, that is above room temperature and observed the difficulty of controlling di-alkylation (impurity-b) by product Elagolix diethyl ester and mono alkylated cyclized (impurity-c) pyrrolidn-2-one impurity which were then carry forwarded impurities as corresponding di carboxylic acid (impurity-a) and as such (impurity-c) respectively in final API. The di-carboxylic impurity removal is very critical from Elagolix sodium API once it is there along, as because API also being a mono carboxylic acid.

In commercial or scale up point of view the formation of this impurities in API levels is uncertain. The inventors of the present inventors have tried different ways to reduce the formation of the said impurities and observed the absence of the above impurities when reaction is performed at RT. The reaction of compound of Formula III with Formula IV was carried out at Room temperature (25-35ºC) with excess moles of Formula IV (2.7eq) to avoid the formation of above said two impurities in API and to land up with a good commercial / scalable process without any hesitation.

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.

Examples:
Example-1: Preparation of 1-(2-fluoro-6-(trifluoromethyl) benzyl)-5-iodo-6-methylpyrimidine-2,4(1H, 3H)-dione:

In a 500mL dry round bottom flask 70gms of 1-(2-fluoro-6-(Trifluoromethyl) benzyl)-6-methylpyrimidine-2, 4(1H, 3H)-dione was taken in 350mL anhydrous Methanol under gentle stirring at room temperature and then added 95.0gm of Iodine mono chloride at room temperature and slowly heated the reaction mass to 45-550C and maintained for 3-4 hours. After reaction was completed over TLC it was cooled to room temperature under gentle stirring the obtained precipitated Off-white crystalline solid was filtered and washed with 70 mL Methanol. The resulting solid was purified by Methanol slurry at room temperature to get 95 gm (Yield: 95.86%).

Example-2: Preparation of 1-(2-fluoro-6-(trifluoro methyl) benzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2, 4(1H, 3H)-dione:

In a 500 ml clean & Dry round bottom flask 85gm of 1-(2-fluoro-6-(trifluoro methyl) benzyl)-5-iodo-6-methylpyrimidine-2, 4(1H, 3H)-dione was taken in a 225mL Acetone at room temperature under gentle stirring and then added 34.17 gm of 2-fluoro-3-methoxyphenylboronic acid was added portion wise. 14.4% aqueous potassium hydroxide was added drop wise to a pre-cooled reaction mixture to 10-200C followed by addition of Tri-t-butyl phosphine tetra fluoro borate (603 mg, 0.01moles). Slowly raised the reaction temperature upto 40-500C and maintained for 20-30 minutes then added 220mg of palladium acetate (0.005moles) subsequently raised the temperature to further 100C and then maintained for 1-2 hours at 50-600C until the reaction complies. Once reaction complies reaction mass was quenched with Acetic acid and stirred for 30 minutes at room temperature the resulting solid was filtered and washed with 50ML of Water, the obtained cake was dried and reported the yield 70 gm ( 82.71%).

Example-3: Preparation of tert-butyl (S)-2-(3-(2-fluoro-6-(trifluoro methyl) benzyl)-5-(2-fluoro-3-methoxyphenyl)-2, 3-dihydro-4-methyl-2, 6-dioxopyrimidin-1(6H)-yl)-1-phenylethylcarbamate:

In a 1000 ML round bottom flask 60 gm of 1-(2-fluoro-6-(trifluoro methyl) benzyl)-5-(2-fluoro-3-methoxyphenyl)-6-methylpyrimidine-2, 4(1H, 3H)-dione, 41.76gm of tert-butyl (R)-2-hydroxy-1-phenylethylcarbamate and 55.38 gm of Triphenyl phosphine was taken in 360mL of Tetrahydrofuran at room temperature under gentle stirring with inert atmosphere. 48. 37gm of DIAD (Diisopropyl azodicarboxilate) was added drop wise to a cooled reaction mixture at 20-250C and maintained for 3-4 hours at same temperature until the reaction complies. Once reaction was completed then the whole reaction mixture was subjected for de-BOC operation with 66gm of Concentrated Hydrochloric acid and further maintained for 3 hours at 50-600C. Once de-BOC process completed remove the solvent under reduced pressure and the obtained syrupy compound was co-distilled with (120mL) Isopropyl acetate. The resulting light yellow color syrup was subjected for acid base workup with 10% aq. ortho phosphoric acid (63.5gm) and 20% aq. potassium carbonate (148g) and then the obtained crude mass was isolated in Mixture of Isopropyl acetate (2V) and Heptane (3V), dried and reported yield 50gm ( 65.13%)

Example-4: Preparation of ethyl 4-((S)-2-(3-(2-fluoro-6-(trifluoro methyl) benzyl)-5-(2-fluoro-3-methoxyphenyl)-2,3-dihydro-4-methyl-2, 6-dioxopyrimidin-1(6H)-yl)-1-phenylethylamino) butanoate (Formula-II):

In a 500mL round bottom flask added 20.6gm of Ethyl-4-bromobutyrate to mixture of 34 gm of tert-butyl (S)-2-(3-(2-fluoro-6-(trifluoro methyl) benzyl)-5-(2-fluoro-3-methoxyphenyl)-2,3-dihydro-4-methyl-2,6-dioxopyrimidin-1(6H)-yl)-1-phenylethylcarbamate, 12.08gm of Diisopropyl ethylamine and 34 ml of N-methyl-2-pyrrollidone at room temperature and stirred for 3 hours; then added second lot of Ethyl-4-bromobutyrate (12.16gm) and maintained for 18 hours. Once reaction completed then reaction mass was diluted with Isopropyl acetate followed by Water. The obtained organic layer was subjected for acid and base treatment to remove un-wanted impurities and by products. The final organic solvent was removed under reduced pressure and the resulting syrupy compound ethyl 4-((S)-2-(3-(2-fluoro-6-(trifluoro methyl) benzyl)-5-(2-fluoro-3-methoxyphenyl)-2, 3-dihydro-4-methyl-2, 6-dioxopyrimidin-1(6H)-yl)-1-phenylethylamino) butanoate was directly taken for next step after release test ( Yield 30gm; 73.52% ).

Example-5: Preparation of ethyl 4-((S)-2-(3-(2-fluoro-6-(trifluoro methyl) benzyl)-5-(2-fluoro-3-methoxyphenyl)-2,3-dihydro-4-methyl-2, 6-dioxopyrimidin-1(6H)-yl)-1-phenylethylamino) butanoate:

In a 250mL round bottom flask added 32.76gm of Ethyl-4-bromobutyrate to mixture of 34 gm of tert-butyl (S)-2-(3-(2-fluoro-6-(trifluoro methyl) benzyl)-5-(2-fluoro-3-methoxyphenyl)-2,3-dihydro-4-methyl-2,6-dioxopyrimidin-1(6H)-yl)-1-phenylethylcarbamate, 12.08gm of Diisopropyl ethylamine and 34 ml of N-methyl-2-pyrrollidone at room temperature and maintained for 18 hours. Once reaction completed then reaction mass was diluted with Isopropyl acetate followed by Water. The obtained organic layer was subjected for acid and base treatment to remove un-wanted impurities and by products. The final organic solvent was removed under reduced pressure and the resulting syrupy compound ethyl 4-((S)-2-(3-(2-fluoro-6-(trifluoro methyl) benzyl)-5-(2-fluoro-3-methoxyphenyl)-2, 3-dihydro-4-methyl-2, 6-dioxopyrimidin-1(6H)-yl)-1-phenylethylamino) butanoate was directly taken for next step after release test ( Yield 26gm; 61.26% ).

Example-6: Preparation of sodium 4-((S)-2-(3-(2-fluoro-6-(trifluoromethyl) benzyl)-5-(2-fluoro-3-methoxyphenyl)-2,3-dihydro-4-methyl-2,6 -dioxopyrimidin-1(6H)-yl)-1-phenylethylamino) butanoate:

The above resulting syrupy compound 30gm of ethyl 4-((S)-2-(3-(2-fluoro-6-(trifluoro methyl) benzyl)-5-(2-fluoro-3-methoxyphenyl)-2, 3-dihydro-4-methyl-2, 6-dioxopyrimidin-1(6H)-yl)-1-phenylethylamino) butanoate was taken in 170mL of Absolute ethanol and then added 3% Aqueous Sodium hydroxide solution (5.1gm) at room temperature with controlled stirring operation and maintained for 1hour to complies the reaction. Once reaction completed removed the ethanol under reduced pressure. The resulting syrupy compound was diluted with water ( 238 mL), filtered thru the celite cake to remove unwanted particles in the reaction mass and the resulting aqueous filtrate mother liquor was washed with MIBK ( 3x 136mL). The compound aqueous layer was taken in 340mL of MIBK and adjusted pH basic with 48% sodium hydroxide solution (68 gm). The resulting MIBK layer was treated with saturated brine solution (135mL) and dried over anhydrous sodium sulfate (5gm) and then removed the solvent completely under reduced pressure and the obtained crude mass was isolated in Heptanes and dried under vacuum to get 25gm of pure Form-S of Elagolix. (84.17%):

We claim:
A novel polymorphic Form-S of Elagolix Sodium of Formula-I

Formula I
wherein Form-S is characterized by an X-ray powder diffraction pattern having peaks expressed as 2? angle positions at about 27.44, 31.76, and 45.49 ±2?.

A novel polymorphic Form-S as claimed in claim 1, wherein Form-S is a mixture of amorphous and crystalline which is further characterized by X-ray powder diffraction pattern having a broader peak and sharp peaks expressed as 2? angle positions at about 27.44, 31.76 and 45.49 ±2?.
A process for the preparation of novel polymorphic Form-S of Elagolix Sodium

Formula I
which comprises
dissolving crude Elagolix sodium in a solvent or mixture of solvents,
stir the reaction mass,
optionally cooling the reaction mass,
isolating polymorphic Form-S of Elagolix Sodium.

A process for the preparation of novel polymorphic Form-S as claimed in claim 3,
which comprises
dissolving crude Elagolix sodium in MIBK solvent,
stir the reaction mass,
distil the solvent,
heptane was added,
stir the reaction mass,
isolating polymorphic Form-S of Elagolix Sodium.

A process for the preparation of compound of Formula II, an intermediate of Elagolix or its salts

Formula II
which is free of the following impurities

which involves the reaction of compound of Formula III

Formula III
with compound of Formula IV

Formula IV
in the presence of DIPEA and in NMP, wherein the compound of Formula IV was added lot wise manner at RT.

Dated this Twenty first (21st) day of May, 2020.

Authorized Signatory
___________________________
(Dr. Venkat Rao Sirugu Battula)
SMS Pharmaceuticals Ltd

Formula I
,CLAIMS:We claim:
A novel polymorphic Form-S of Elagolix Sodium of Formula-I

Formula I
wherein Form-S is characterized by an X-ray powder diffraction pattern having peaks expressed as 2? angle positions at about 27.44, 31.76, and 45.49 ±2?.

A novel polymorphic Form-S as claimed in claim 1, wherein Form-S is a mixture of amorphous and crystalline which is further characterized by X-ray powder diffraction pattern having a broader peak and sharp peaks expressed as 2? angle positions at about 27.44, 31.76 and 45.49 ±2?.
A process for the preparation of novel polymorphic Form-S of Elagolix Sodium

Formula I
which comprises
dissolving crude Elagolix sodium in a solvent or mixture of solvents,
stir the reaction mass,
optionally cooling the reaction mass,
isolating polymorphic Form-S of Elagolix Sodium.

A process for the preparation of novel polymorphic Form-S as claimed in claim 3,
which comprises
dissolving crude Elagolix sodium in MIBK solvent,
stir the reaction mass,
distil the solvent,
heptane was added,
stir the reaction mass,
isolating polymorphic Form-S of Elagolix Sodium.

A process for the preparation of compound of Formula II, an intermediate of Elagolix or its salts

Formula II
which is free of the following impurities

which involves the reaction of compound of Formula III

Formula III
with compound of Formula IV

Formula IV
in the presence of DIPEA and in NMP, wherein the compound of Formula IV was added lot wise manner at RT.