DESC:
FIELD OF THE INVENTION
The present invention provides novel processes for preparation of Amorphous Relugolix.

BACKGROUND OF THE INVENTION
Relugolix is a gonadotropin-releasing hormone (GnRH) receptor antagonist indicated for the treatment of prostate cancer and relugolix in combination with estradiol and norethindrone acetate is indicated for management of heavy menstrual bleeding associated with uterine leiomyomas. Relugolix is chemically known as N-(4-{1-[(2,6¬ difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4¬ tetrahydrothieno[2,3-d]pyrimidin-6-yl}phenyl)-N-methoxyurea.

The PCT application WO 2004/067535 A2 discloses process for preparation of relugolix. Solid forms of Relugolix are disclosed in the following applications WO 2014/051164 A2, WO 2019/178304 A2, WO 2020/230094 A2 , WO 2021/026011 A2 ,WO 2021/027937 A2 ,WO 2021/031148 A2, WO 2021/069711 A2, and WO 2021/069700 A2. Numerous crystalline forms and an amorphous form of relugolix is disclosed in these applications, the applications also disclose process for preparation of amorphous form of relugolix which involves isolation of amorphous form by solvent evaporation and freeze drying methods.

The present invention provides novel preparations of amorphous relugolix which does not utilize tedious methods of solvent evaporation and freeze drying that are unfavorable for commercial scale production. The present invention provides improved and industrial feasible process for preparation of amorphous relugolix.

SUMMARY OF THE INVENTION
The present invention provides process for preparing amorphous relugolix comprising:
a) preparing solution of relugolix in a solvent,
b) adding the solution of step (a) to water, and
c) separating the solid.

The present invention also provides process for preparing amorphous relugolix comprising:
a) treating relugolix with an acid or an acid addition salt in water,
b) treating the solution of step (a) with a base, and
c) separating the solid.

BRIEF DESCRIPTION OF THE FIGURE
Figure 1 – PXRD diffractogram of amorphous relugolix

DETAILED DESCRIPTION OF THE INVENTION
Active pharmaceutical ingredients can exist in different polymorphic form, that is crystalline or amorphous state. Crystalline and amorphous forms of active pharmaceutical ingredients can differ in physicochemical properties including hygroscopicity, flowability, tableting, dissolution rate, solubility, chemical and physical stability. Thus, selection of polymorph and its preparation method is very important aspect of product development. Preparation of polymorphic form includes many experimental variables which needs to be optimized to develop a method which consistently produce the specific form. All preparation methods for the polymorph may not be industrially feasible for large scale production, therefore further development needs to be carried out for preparation of polymorph which is consistent and industrially viable. The present invention provides improved and industrial feasible process for preparation of amorphous pharmaceutically active ingredient, relugolix

In the first embodiment, the present invention provides process for preparation of amorphous relugolix, comprising:
a) preparing solution of relugolix in the solvent,
b) adding the solution of step (a) to water, and
c) separating the solid.
In the present invention amorphous relugolix is characterized by figure. 1.

In the present process, solution of relugolix in a solvent can be prepared by heating the mixture of relugolix and the solvent from a temperature of 30°C to reflux. The solvent can be polar aprotic solvent selected from dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetone, acetonitrile, tetrahydrofuran, and the like, or mixture thereof.

The solution of relugolix in the solvent can be added to water at a temperature of 0 to 25°C, the mixture is stirred from a time period of 30 minutes to 360 minutes at 0 to 25°C. The resultant solid is separated by filtration. The wet solid is dried under vacuum at a temperature of 25 to 40°C for 120 to 360 minutes, to provide amorphous relugolix.

Typically, relugolix is dissolved in a solvent at a temperature of 30 to 100°C, solvent is polar aprotic solvent selected from dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetone, acetonitrile or tetrahydrofuran. The solution is added to pre-cooled water at a temperature of 0 to 25°C, the mixture is stirred for 30 to 360 minutes at 0 to 25°C and the solid is separated by filtration and dried under vacuum at a temperature of 25 to 40°C for 120 to 360 minutes, to yield amorphous relugolix.

In the second embodiment, the present invention also provides process for preparing amorphous relugolix comprising:

a) treating relugolix with an acid or an acid addition salt in a solvent,
b) treating the solution of step (a) with a base, and
c) separating the solid.

In the present invention amorphous relugolix is characterized by figure 1.

In the present process, the solvent is selected from water or polar aprotic solvent or mixture thereof, polar aprotic solvent is ethyl acetate or dichloromethane. Relugolix in the solvent is treated with an acid selected from organic acid like oxalic acid, benzoic acid, acetic acid, chloroacetic acid, formic acid, fluoroacetic acid, citric acid, dichloroacetic acid, methanesulfonic acid, benzenesulfonic acid and the like, or an acid addition salt of inorganic acid, such as sulphuric or phosphoric acid, for example sodium hydrogen sulfate, sodium dihydrogen phosphate or disodium hydrogen phosphate and the like.

The treatment with acid can be carried out at a temperature of 0 to 30°C, the mixture of relugolix, water and acid or an acid addition salt can be stirred for 30 to 60 minutes to get a clear solution and the solution can optionally be treated with carbon powder.

The solution can be further treated with base selected from inorganic base which includes hydroxide, alkoxides, carbonates and bicarbonates of alkali or alkaline earth metal like sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate. The base is added to the solution to attain a pH of 7 to 8.5, the treatment with base can be carried out at a temperature of 0 to 30°C.

The mixture is stirred from a time period of 30 minutes to 360 minutes at 0 to 30°C. The resultant solid is separated by filtration. The wet solid is dried under vacuum at a temperature of 25 to 40°C for 120 to 360 minutes, to provide amorphous relugolix.

Typically, relugolix is treated with organic acid or an acid addition salt of inorganic acid in a solvent selected from water or polar aprotic solvent at a temperature of 0 to 30°C, if the solvent is water immiscible the aqueous layer is separated for further treatment. The solution is optionally treated with carbon. The solution is further treated with inorganic base at a temperature of 0-30°C to attain pH of 7 to 8.5. The mixture is stirred for 30 to 360 minutes at 0 to 25°C and the solid is separated by filtration and dried under vacuum at a temperature of 25 to 40°C for 120 to 360 minutes, to yield amorphous relugolix.

Relugolix utilized for preparation of amorphous form can be prepared by methods known in WO 2004/067535 or WO 2014/051164.

The X-ray powder diffraction spectrum (XRPD) was recorded at room temperature using PANalytical X’Pert PRO diffractogram with Cu Ka radiation (? = 1.54060 Å), running at 45 kV and 40 mA.

The present invention is further illustrated by the following representative examples and does not limit the scope of the invention

Example 1
To a mixture of relugolix ( 10 g) and water (150 ml) at 25°C, was added oxalic acid (2.4 g) and stirred for 10 minutes, the solution was filtered to get clear solution. To the solution was added 20% aqueous potassium carbonate solution to adjust the pH 7 to 7.3, the mixture was stirred for 150 minutes. The solid was filtered and dried under vacuum for 120 minutes to get amorphous relugolix.

Example 2
To a mixture of relugolix ( 4 g) and ethyl acetate (100 ml) at 25°C, was added 10% sodium hydrogen sulfate solution (80 ml) and stirred for 10 minutes. The aqueous layer was separated and treated with carbon. To the solution was added 20% aqueous potassium carbonate solution to adjust the pH 8 to 8.5, the mixture was stirred for 360 minutes. The solid was filtered and dried under vacuum for 120 minutes to get amorphous relugolix.

Example 3
A mixture of relugolix (0.5 g) and dimethyl acetamide (1.25 ml) was heated at 70°C and stirred for 10 minutes to get clear solution, the solution was cooled to about 25°C. The solution was added to water (15 ml) at 0-5°C and stirred for 150 minutes. The solid was filtered and dried under vacuum for 180 minutes to get amorphous relugolix.

Example 4
A mixture of relugolix (0.5 g) and dimethyl formamide (1 ml) was heated at 70°C and stirred for 10 minutes to get clear solution, the solution was cooled to about 25°C. The solution was added to water (15 ml) at 0-5°C and stirred for 150 minutes. The solid was filtered and dried under vacuum for 180 minutes to get amorphous relugolix.

Example 5
A mixture of relugolix (0.4 g) and dimethyl sulfoxide (0.8 ml) was heated at 65°C and stirred for 10 minutes to get clear solution, the solution was cooled to about 25°C. The solution was added to water (12 ml) at 0-5°C and stirred for 150 minutes. The solid was filtered and dried under vacuum for 180 minutes to get amorphous relugolix.
,CLAIMS:
1. A process for preparation of amorphous relugolix, comprising:
d) preparing solution of relugolix in the solvent,
e) adding the solution of step (a) to water, and
f) separating the solid.

2. The process as claimed in claim 1 wherein, the solvent is polar aprotic solvent.

3. The process as claimed in claim 2 wherein, polar aprotic solvent is dimethylformamide, dimethylacetamide, dimethyl sulfoxide, acetone, acetonitrile or tetrahydrofuran.

4. A process for preparation of amorphous relugolix comprising:
d) treating relugolix with an acid or an acid addition salt in a solvent,
e) treating the solution of step (a) with a base, and
f) separating the solid.

5. The process as claimed in claim 4 wherein, the solvent is water or polar aprotic solvent.

6. The process as claimed in claim 5 wherein, polar aprotic solvent is ethyl acetate or dichloromethane.

7. The process as claimed in claim 4 wherein, the acid is organic acid or an acid addition salt of inorganic acid.

8. The process as claimed in claim 7 wherein, the organic acid is oxalic acid, benzoic acid, acetic acid, chloroacetic acid, formic acid, fluoroacetic acid, citric acid, dichloroacetic acid, methanesulfonic acid or benzenesulfonic acid.

9. The process as claimed in claim 7 wherein, the acid addition salt of inorganic acid is sodium hydrogen sulfate, sodium dihydrogen phosphate or disodium hydrogen phosphate.

10. The process as claimed in claim 4 wherein, the base is sodium carbonate, potassium carbonate, cesium carbonate or sodium bicarbonate.