DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“CRYSTALLINE SOLVATE OF RELUGOLIX AND A PROCESS FOR ITS PREPARATION”

Glenmark Life Sciences Limited;
an Indian Company, registered under the Indian Companies Act 1956 and having
its registered office at
Plot No. 170-172,
Chandramouli Industrial Estate,
Mohol Bazarpeth, Solapur 413213

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 a novel crystalline solvate of relugolix, particularly the dimethylacetamide solvate, and a process for its preparation. Also, the present invention relates to a crystalline dimethylacetamide solvate of relugolix for use in the preparation of crystalline relugolix. The present invention further relates to a process for the preparation of crystalline relugolix.

BACKGROUND OF THE INVENTION
Relugolix, also known as N-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino]-methyl]-3-(6-methoxy-3-pyridazinyl]-2,4-dioxo-1,2,3,4-tetrahydro-thieno[2,3-d]pyrimidin-6-yl]phenyl]-N'-methoxyurea, is represented by the structure of formula I.
I
Relugolix is a gonadotropin-releasing hormone (GnRH) receptor antagonist indicated for the treatment of adult patients with advanced prostate cancer.
A combination of relugolix, a GnRH receptor antagonist, estradiol, an estrogen, and norethindrone acetate, a progestin, is indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women.
Relugolix is disclosed in published PCT Application No. WO 2004/067535A1 (the WO ‘535 publication).
Certain solvates of relugolix are known in the art, particularly as reported in a few published PCT applications. WO 2014/051164A2 (the WO ‘164 publication) relates to crystalline tetrahydrofuran solvate of relugolix; WO 2021/069700A1 (the WO ‘700 publication) relates to crystalline dimethyl sulfoxide solvate of relugolix (referred to as crystalline Form XIII); WO 2021/069711A1 (the WO ‘711 publication) relates to various polymorphic forms of relugolix (crystalline Forms II, III, V, VI, VII, VIII, IX, X, XI, XII and amorphous form); and WO 2023/066941A1 (the WO ‘941 publication) relates to crystalline ethanol solvate of relugolix (referred to as crystalline Form XIV).
The object of the present invention is to provide a novel crystalline solvate of relugolix, particularly the dimethylacetamide solvate of relugolix. The crystalline dimethylacetamide solvate of relugolix of the present invention can be used to prepare other known polymorphs of relugolix. A further object of the invention is to provide a process for the preparation of crystalline relugolix.

SUMMARY OF THE INVENTION
The present invention provides a crystalline dimethylacetamide solvate of relugolix characterized by one or more of the following:
A. an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 5.6, 9.3, 10.4, 16.5 and 22.5 ±0.2 degrees 2 theta;
B. a differential scanning calorimetry (DSC) thermogram having an endothermic peak at about 170 ±2°C; and
C. a thermogravimetric analysis (TGA) thermogram, showing a weight loss of about 0 weight% to 20.69 weight% determined over the temperature range of 0°C to 250°C and heating rate 10°C/min.
The present invention also provides a process for the preparation of crystalline dimethylacetamide solvate of relugolix comprising the steps of:
(a) dissolving relugolix in dimethylacetamide, optionally in the presence of an additional solvent, to form a solution;
(b) obtaining crystalline dimethylacetamide solvate of relugolix from the solution of the step (a); and
(c) isolating the crystalline dimethylacetamide solvate of relugolix.
The present invention further provides a process for the preparation of crystalline relugolix comprising the steps of:
(1) providing a mixture containing crystalline dimethylacetamide solvate of relugolix dissolved in an organic solvent;
(2) obtaining crystalline relugolix from the mixture of the step (1); and
(3) isolating the crystalline relugolix, wherein the crystalline relugolix is characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 7.3, 8.9, 9.9, 12.0, 16.6, 17.3, 22.2, 22.7, and 27.4 ±0.2 degrees 2 theta.
The present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of crystalline relugolix and a pharmaceutically acceptable excipient, wherein the crystalline relugolix is obtained from the crystalline dimethylacetamide solvate as described herein.
The present invention also provides a process for the preparation of crystalline relugolix comprising the steps of:
(i) providing a solution of relugolix in dimethyl sulfoxide;
(ii) combining the solution of the step (i) with an C1-C6 alkyl alcohol solvent to form a mixture;
(iii) obtaining crystalline relugolix from the mixture of the step (ii); and
(iv) isolating the crystalline relugolix, wherein the crystalline relugolix is characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 7.3, 8.9, 9.9, 12.0, 16.6, 17.3, 22.2, 22.7, and 27.4 ±0.2 degrees 2 theta.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic X-ray Powder Diffraction Pattern (XRPD) of crystalline dimethylacetamide solvate of relugolix as obtained in Example 1.
Figure 2 is a Differential Scanning Calorimetry (DSC) thermogram of crystalline dimethylacetamide solvate of relugolix as obtained in Example 1.
Figure 3 is a Thermogravimetric Analysis (TGA) thermogram of crystalline dimethylacetamide solvate of relugolix as obtained in Example 1.
Figure 4 is a characteristic X-ray Powder Diffraction Pattern (XRPD) of crystalline relugolix as obtained in Example 10.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel crystalline dimethylacetamide solvate of relugolix, which is characterized by various techniques as described herein including, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA).
In the context of the present invention, the term “room temperature” means a temperature of about 25°C to about 30°C.
As used herein, the term “about” refers to any value which lies within the range defined by a number up to 10% of the value.
In the context of the present invention, the term "substantially illustrated" as used in reference to Figure(s) 1, 2 and 3 may be understood to relate to any crystalline dimethylacetamide solvate of relugolix characterized with the graphical data having small variations, as are well known to the person skilled in the art, in comparison with the Figure(s) 1, 2 or 3.
In one aspect, the present invention provides a crystalline dimethylacetamide solvate of relugolix characterized by one or more of the following:
A. an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 5.6, 9.3, 10.4, 16.5 and 22.5 ±0.2 degrees 2 theta;
B. a differential scanning calorimetry (DSC) thermogram having an endothermic peak at about 170 ±2°C; and
C. a thermogravimetric analysis (TGA) thermogram, showing a weight loss of about 0 weight% to 20.69 weight% determined over the temperature range of 0°C to 250°C and heating rate 10°C/min.
In one embodiment, the crystalline dimethylacetamide solvate of relugolix is characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 5.6, 9.3, 10.4, 16.5 and 22.5 ±0.2 degrees 2 theta.
In one embodiment, the crystalline dimethylacetamide solvate of relugolix is further characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 16.4, 18.4, 18.7 ±0.2 degrees 2 theta.
In one embodiment, the crystalline dimethylacetamide solvate of relugolix is characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 5.6, 9.3, 10.4, 16.5, 18.4, 22.5 ±0.2 degrees 2 theta.
In one embodiment, the crystalline dimethylacetamide solvate of relugolix is characterized by an X-ray powder diffraction (XRPD) pattern as substantially illustrated in Figure 1.
In one embodiment, the crystalline dimethylacetamide solvate of relugolix is characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 5.6, 9.3, 10.4, 16.5 and 22.5 ±0.2 degrees 2 theta, which is substantially in accordance with Figure 1.
In one embodiment, the crystalline dimethylacetamide solvate of relugolix is characterized by a DSC thermogram having an endothermic peak at about 170 ±2°C.
In one embodiment, the crystalline dimethylacetamide solvate of relugolix is characterized by a DSC thermogram as substantially illustrated in Figure 2.
In one embodiment, the crystalline dimethylacetamide solvate of relugolix is characterized by a DSC thermogram having an endothermic peak at about 170 ±2°C, which is substantially in accordance with Figure 2.
In one embodiment, the crystalline dimethylacetamide solvate of relugolix is characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 5.6, 9.3, 10.4, 16.5 and 22.5 ±0.2 degrees 2 theta, and a DSC thermogram having an endothermic peak at about 170 ±2°C.
In one embodiment, the crystalline dimethylacetamide solvate of relugolix is characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 5.6, 9.3, 10.4, 16.5 and 22.5 ±0.2 degrees 2 theta which is substantially in accordance with Figure 1, and a DSC thermogram having an endothermic peak at about 170 ±2°C which is substantially in accordance with Figure 2.
In one embodiment, the crystalline dimethylacetamide solvate of relugolix is characterized by a thermogravimetric analysis (TGA) thermogram, showing a weight loss of about 0 weight % to 20.69 weight % determined over the temperature range of 0°C to 250°C and heating rate of 10°C/min.
In one embodiment, the crystalline dimethylacetamide solvate of relugolix is characterized by a TGA thermogram as substantially illustrated in Figure 3.
In one embodiment, the crystalline dimethylacetamide solvate of relugolix is characterized by a thermogravimetric analysis (TGA) thermogram, showing a weight loss of about 0 weight % to 20.69 weight % determined over the temperature range of 0°C to 250°C and heating rate of 10°C/min, which is substantially in accordance with Figure 3.
In one embodiment, the crystalline dimethylacetamide solvate of relugolix is characterized by gas chromatography analysis, showing presence of about 17.02 % of dimethylacetamide in residual solvent analysis.
In one embodiment, the crystalline dimethylacetamide solvate of relugolix is characterized by an X-ray powder diffraction (XRPD) pattern as depicted in Figure 1, a DSC thermogram as depicted in Figure 2; a thermogravimetric analysis (TGA) as depicted in Figure 3, and any combination of the Figure(s) 1, 2 and 3.
In another aspect, the present invention provides a process for the preparation of crystalline dimethylacetamide solvate of relugolix comprising the steps of:
(a) dissolving relugolix in dimethylacetamide, optionally in the presence of an additional solvent, to form a solution;
(b) obtaining crystalline dimethylacetamide solvate of relugolix from the solution of the step (a); and
(c) isolating the crystalline dimethylacetamide solvate of relugolix.
In the context of the present invention relating to the process for the preparation of crystalline dimethylacetamide solvate of relugolix, the term “optionally” means dissolving relugolix in dimethylacetamide, either in the presence of an additional solvent or in the absence of an additional solvent.
In one embodiment, the additional solvent used in the step (a) is selected from the group consisting of an C1-C6 alkyl alcohol, an C2-C4 alkyl sulfoxide, a C1-C6 haloalkane, water, and a mixture thereof.
As used herein, the term “alkyl” includes linear and branched alkyl.
In one embodiment, the C1-C6 alkyl alcohol is selected from the group consisting of methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, and n-pentyl alcohol.
In one embodiment, the C2-C4 alkyl sulfoxide is selected from dimethyl sulfoxide or diethyl sulfoxide.
In one embodiment, the C1-C6 haloalkane is selected from the group consisting of dichloromethane, chloroform, and dichloroethane.
In one embodiment, the step (a) is carried out at a temperature of about 30°C to about 50°C.
In one embodiment, the step (a) is carried out at a temperature of about 35°C to about 45°C.
In one embodiment, the molar ratio of relugolix to dimethylacetamide used in the step (a) is in the range of about 1 to 1 to about 1 to 2.5.
In one embodiment, the step (b) of obtaining the crystalline dimethylacetamide solvate of relugolix comprises:
(bi) cooling and stirring the solution obtained in the step (a); or
(bii) removing the solvent from the solution obtained in the step (a); or
(biii) treating the solution of the step (a) with an anti-solvent to form a mixture and optionally, cooling and stirring the obtained mixture.
In one embodiment, in the step (bi), the cooling is carried out to a temperature of below about 30°C.
In the context of the present invention, the term “below about 30°C” as used herein means the temperature ranging from about 30°C to about 15°C, preferably about 30°C to about 20°C, more preferably about 30°C to about 25°C.
In one embodiment, in the step (bi), the solution of the step (a) is cooled to a temperature ranging from about 30°C to about 20°C.
In one embodiment, in the step (bi), the solution of the step (a) is cooled to a temperature ranging from about 30°C to about 25°C.
In one embodiment, in the step (bi), the solution of the step (a) may be stirred for a suitable time. The stirring time may range from about 30 minutes to about 10 hours, or longer.
In one embodiment, stirring in the step (bi) may be continued for any desired time period to obtain the crystalline dimethylacetamide solvate of relugolix.
In one embodiment, in the step (bi), the solution of the step (a) is stirred for a period ranging from about 1 hour to about 2 hours.
In one embodiment, in the step (bi), the solution of the step (a) is stirred for a period ranging from about 1 hour to about 2 hours at a temperature ranging from about 40°C to about 45°C.
In one embodiment, in the step (bii), the crystalline dimethylacetamide solvate of relugolix is obtained by removing the solvent from the solution obtained in the step (a). Removal of solvent may be accomplished by substantially complete evaporation of the solvent; or concentrating the solution, cooling the solution, if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg.
In one embodiment, in the step (biii), the crystalline dimethylacetamide solvate of relugolix is obtained by adding an anti-solvent to the solution obtained in the step (a) to form a mixture and optionally, cooling and stirring the obtained mixture.
In one embodiment, in the step (biii), the anti-solvent is selected such that the dimethylacetamide solvate of relugolix is precipitated out from the solution.
In one embodiment, the anti-solvent used in the step (biii) is selected from the group consisting of methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, n-pentyl alcohol, water, and a mixture thereof.
In one embodiment, in the step (c) of the above process, the crystalline dimethylacetamide solvate of relugolix is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.
In one embodiment, the isolated crystalline dimethylacetamide solvate of relugolix may be further dried. Drying may be suitably carried out in an equipment conventionally used in the art for the purpose, such as a tray drier, a vacuum oven, an air oven, a fluidized bed drier, a spin flash drier, a flash drier and the like. The drying may be carried out at a temperature ranging from about room temperature to about 100°C with or without vacuum. The drying may be carried out for any desired time until the product having the desired quality is obtained. The drying time may vary from about 1 hour to about 25 hours, or longer.
In one embodiment, the present invention provides a process for the preparation of crystalline dimethylacetamide solvate of relugolix comprising the steps of:
(a) dissolving relugolix in dimethylacetamide to form a solution;
(b) obtaining crystalline dimethylacetamide solvate of relugolix from the solution of the step (a); and
(c) isolating the crystalline dimethylacetamide solvate of relugolix.
In one embodiment, the steps (a), (b) and (c) are carried out as discussed herein above.
In one embodiment, the present invention provides a process for the preparation of crystalline dimethylacetamide solvate of relugolix comprising the steps of:
(a) dissolving relugolix in dimethylacetamide to form a solution;
(b) obtaining crystalline dimethylacetamide solvate of relugolix from the solution of the step (a) by cooling and stirring the solution obtained in the step (a); and
(c) isolating the crystalline dimethylacetamide solvate of relugolix.
In one embodiment, the step (a) is carried out at a temperature of about 30°C to about 50°C.
In one embodiment, the molar ratio of relugolix to dimethylacetamide used in the step (a) is in the range of about 1 to 1 to about 1 to 2.5.
In one embodiment, in the step (b), the cooling is carried out to a temperature of below about 30°C.
In one embodiment, in the step (b), the solution of the step (a) is cooled to a temperature ranging from about 30°C to about 20°C.
In one embodiment, in the step (c) of the above process, the crystalline dimethylacetamide solvate of relugolix is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.
In another aspect, the present invention provides a crystalline dimethylacetamide solvate of relugolix for use in the preparation of crystalline relugolix, wherein the crystalline relugolix is characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 7.3, 8.9, 9.9, 12.0, 16.6, 17.3, 22.2, 22.7, and 27.4 ±0.2 degrees 2 theta.
In another aspect, the present invention provides a process for the preparation of crystalline relugolix comprising the steps of:
(1) providing a mixture containing crystalline dimethylacetamide solvate of relugolix dissolved in an organic solvent;
(2) obtaining crystalline relugolix from the mixture of the step (1); and
(3) isolating the crystalline relugolix, wherein the crystalline relugolix is characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 7.3, 8.9, 9.9, 12.0, 16.6, 17.3, 22.2, 22.7, and 27.4 ±0.2 degrees 2 theta.
In one embodiment, in the step (1), the organic solvent is selected from the group consisting of an C1-C6 alkyl alcohol such as methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, and n-pentyl alcohol and the like; an C2-C4 alkyl sulfoxide such as dimethyl sulfoxide, diethyl sulfoxide; and the like; a C1-C6 haloalkane such as dichloromethane, dichloroethane, chloroform and the like; and a mixture thereof.
In one embodiment, the step (1) is carried out at a temperature of about 30°C to about 60°C.
In one embodiment, the step (1) is carried out at a temperature of about 35°C to about 45°C.
In one embodiment, the step (2) of obtaining crystalline relugolix comprises cooling the mixture of the step (1).
In one embodiment, in the step (2), the cooling is carried out to a temperature of below about 30°C.
In one embodiment, in the step (2), the mixture of the step (1) is cooled to a temperature ranging from about 30°C to about 20°C.
In one embodiment, in the step (2), the mixture of the step (1) is cooled to a temperature ranging from about 30°C to about 25°C.
In one embodiment, in the step (3), the crystalline relugolix is isolated by any method known in the art. The method, may involve any of techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.
In an embodiment of the present invention, crystalline relugolix prepared from dimethylacetamide solvate of relugolix, is obtained in substantially pure form.
As used herein, the term “substantially pure,” when used in reference to the crystalline form of relugolix, indicates purity of the crystalline form greater than 90 %, including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98 and 99 % as determined using high performance liquid chromatography (HPLC).
In another aspect, the present invention also provides a process for the preparation of crystalline relugolix comprising the steps of:
(i) providing a solution of relugolix in dimethyl sulfoxide;
(ii) combining the solution of the step (i) with an C1-C6 alkyl alcohol to form a mixture;
(iii) obtaining crystalline relugolix from the mixture of the step (ii); and
(iv) isolating the crystalline relugolix, wherein the crystalline relugolix is characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 7.3, 8.9, 9.9, 12.0, 16.6, 17.3, 22.2, 22.7, and 27.4 ±0.2 degrees 2 theta.
In one embodiment, the step (i) is carried out at a temperature of about 25°C to about 60°C.
In one embodiment, the step (i) is carried out at a temperature of about 25°C to about 45°C.
In one embodiment, in step (i), the solution may be stirred for a suitable time. Stirring may be continued for any desired time period to achieve a complete dissolution of relugolix.
In one embodiment, the C1-C6 alkyl alcohol is selected from methyl alcohol, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, n-pentyl alcohol, or a mixture thereof.
In the context of the present invention, the term “combining” means adding the solution of the step (i) to an C1-C6 alkyl alcohol, or adding an C1-C6 alkyl alcohol to the solution of the step (i).
In one embodiment, the step (ii) comprises adding the solution of the step (i) to C1-C6 alkyl alcohol or adding C1-C6 alkyl alcohol to the solution of the step (i).
In one embodiment, the step (ii) is carried out at a temperature of about 35°C to about 70°C.
In one embodiment, the step (ii) is carried out at a temperature of about 45°C to about 50°C.
In one embodiment, the step (iii) of obtaining crystalline relugolix comprises cooling the mixture of the step (ii).
In one embodiment, in the step (iii), the cooling of the mixture of the step (ii) is carried out to a temperature of below about 30°C.
In one embodiment, in the step (iii), the mixture of step (ii) is cooled to a temperature of about 30°C to about 20°C.
In one embodiment, in the step (iii), the mixture of the step (ii) is cooled to a temperature of about 30°C to about 25°C.
In the step (iv) of the above process, relugolix, the compound I, is isolated from the solution by any method known in the art. The method, may involve any of the techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like.
In one embodiment, the crystalline form of relugolix obtained as per the process of the present invention is substantially free of crystalline Form XIII of relugolix and crystalline Form XIV of relugolix.
In one embodiment, the term "substantially free" means the amount referred to is in no detectable quantity.
In the context of the present invention relating to the process for the preparation of crystalline form of relugolix, the term "no detectable quantity" refers to crystalline Form XIII of relugolix and crystalline Form XIV of relugolix in an amount of less than about 0.5% w/w. Preferably, less than about 0.1%w/w, still more preferably, absent.
In an embodiment, the crystalline dimethylacetamide solvate of relugolix of the present invention may have a D90 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns, and most preferably less than about 10 microns.
In an embodiment, the crystalline dimethylacetamide solvate of relugolix of the present invention may have a D50 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns, and most preferably less than about 10 microns.
In an embodiment, the present invention relates to a pharmaceutical composition comprising crystalline relugolix and at least one pharmaceutically acceptable excipient, wherein the crystalline relugolix is prepared from the dimethylacetamide solvate of relugolix as described herein.
In an embodiment, the crystalline relugolix contained in the pharmaceutical composition of the present invention may have a D90 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns, and most preferably less than about 10 microns.
In an embodiment, the crystalline relugolix contained in the pharmaceutical composition of the present invention may have a D50 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns, and most preferably less than about 10 microns.
The particle size disclosed herein can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state relugolix or solvate thereof into any of the foregoing desired particle size range.
The examples that follow are provided to enable one skilled in the art to practice the invention, and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES
GENERAL METHODS:
The present invention provides the crystalline dimethylacetamide solvate of relugolix, obtained by the above processes, as characterized and analyzed by the following techniques:
A. X-ray powder diffraction profile was obtained using an X-ray Diffractometer: Empyrean X-Ray Diffractometer
B. DSC: TA DSC.250
Temperature range is 30°C to 300°C and heating rate is 10°C/minute.
C. Thermo Gravimetric Analyzer: TGA Q500 V20. 13 Build 39. Thermogram was recorded at 30-250°C at the rate of 10°C/min.

EXAMPLE 1: Preparation of dimethylacetamide solvate of relugolix
Relugolix (10g) taken in dimethylacetamide (22mL) was stirred at a temperature ranging from about 35°C to about 45°C for about 50-60 min. The reaction mixture was cooled to a temperature of about 20-30°C and stirred for about 50-60 min. The resulting solid was filtered, washed with dimethylacetamide and dried under reduced pressure for about 4 hours to about 5 hours to yield titled product as off-white solid.
Yield: 8.2g (82%).
Purity: 99.72% by HPLC
TGA analysis of dimethylacetamide solvate of relugolix:
Solvent Loss up to 250°C
Dimethylacetamide 20.69%

XRPD peaks of dimethylacetamide solvate of relugolix:
Pos. [°2?] d- spacing [Å] Rel. Int. [%] Pos. [°2?] d-spacing [A] Rel. Int. [%] Pos. [°2?] d-spacing [A] Rel. Int. [%]
5.64 15.65 5.02 20.16 4.40 14.24 30.69 2.91 2.42
8.42 10.50 0.37 20.84 4.26 6.88 31.23 2.86 1.82
8.91 9.92 0.95 21.07 4.21 13.59 31.74 2.82 1.80
9.35 9.45 100 21.51 4.13 8.07 32.22 2.78 4.48
9.81 9.01 1.62 21.64 4.10 6.58 32.58 2.75 1.27
10.05 8.80 1.53 22.15 4.01 2.08 33.21 2.70 4.54
10.36 8.53 8.29 22.48 3.95 17.98 33.46 2.68 1.98
11.04 8.01 5.92 22.79 3.90 9.35 33.92 2.64 1.05
11.29 7.83 1.38 22.95 3.87 5.04 34.66 2.59 2.13
12.33 7.17 5.63 23.39 3.80 13.39 34.90 2.57 1.55
12.76 6.93 3.39 23.48 3.79 13.04 35.55 2.52 1.20
13.49 6.56 4.61 23.86 3.73 13.63 36.39 2.47 2.06
13.65 6.48 4.16 24.58 3.62 7.16 37.18 2.42 0.99
15.10 5.86 0.91 25.26 3.52 6.45 38.19 2.35 1.62
15.69 5.64 0.48 25.66 3.47 6.39 38.88 2.31 0.71
15.96 5.55 1.26 26.08 3.41 4.53 39.53 2.28 0.66
16.38 5.41 11.4 26.89 3.31 7.5 40.17 2.24 1.38
16.54 5.36 16.54 26.97 3.30 7.22 40.84 2.21 0.54
16.93 5.23 4.90 27.22 3.27 1.89 41.81 2.16 0.84
17.94 4.94 9.36 27.87 3.20 4.9 42.44 2.13 0.61
18.19 4.87 10.98 28.23 3.16 3.17 42.98 2.10 0.22
18.36 4.83 14.51 28.44 3.14 2.62 43.88 2.06 0.52
18.74 4.73 2.14 28.86 3.09 0.90 44.35 2.04 0.45
19.32 4.59 8.64 29.40 3.04 6.11 45.36 2.00 1.47
19.69 4.51 8.88 29.74 3.00 1.94 45.92 1.97 2.19
19.91 4.46 10.66 30.41 2.94 7.23 47.51 1.91 1.19

EXAMPLE 2: Preparation of crystalline relugolix
Dimethylacetamide solvate of relugolix (10g) was dissolved in dimethyl sulfoxide (20 mL) at about 40°C to about 45°C. The reaction mass was filtered, washed with mixture of dimethyl sulfoxide (2mL) and ethyl alcohol (10mL) to obtain clear filtrate. The filtrate was added in ethyl alcohol (150mL) at about 40°C to about 45°C. The reaction mixture was stirred at about room temperature for about 10-12hr. The solid was filtered, washed with ethyl alcohol and dried under reduced pressure for about 4-5 hr to yield titled product as off-white solid (7g, 70%).
Purity: 99.64% by HPLC.

EXAMPLE 3: Preparation of crystalline relugolix
Dimethylacetamide solvate of relugolix (10g) was dissolved in a mixture of methyl alcohol (12mL) and methylene dichloride (48mL) at about 20°C to about 30°C. The reaction mass was filtered to obtain a clear filtrate. The filtrate was distilled under reduced pressure completely, then methyl alcohol (40mL) was added, and the reaction mixture was stirred at about room temperature for about 10-12 hr. The solid was filtered, washed with methyl alcohol and dried under reduced pressure for about 4-5 hr to yield titled product as off-white solid (8g, 80%). Purity: 99.72% by HPLC.

EXAMPLE 4: Preparation of crystalline relugolix
Relugolix (5 g) was dissolved in dimethylformamide (17.5 mL) at a temperature ranging from about 25°C to about 35°C. The reaction mass was filtered, washed with dimethylformamide (2.5mL) to obtain a filtrate. The filtrate was added in ethyl alcohol (95 mL) at about 45°C to about 55°C and stirred for about 2-3 hr. The reaction mixture was stirred at about room temperature for about 10-12 hr. The solid was filtered, washed with ethyl alcohol and dried under reduced pressure for about 4-5 hr to yield titled product as off-white solid (4.1 g, 82%). Purity: 99.79% by HPLC.

EXAMPLE 5: Preparation of crystalline relugolix
Relugolix (5 g) was dissolved in dimethyl sulfoxide (9 mL) at about 25°C to about 35°C and ethyl alcohol (5 mL) was added to it. The reaction mass was filtered, washed with mixture of dimethyl sulfoxide and ethyl alcohol to obtain a clear filtrate. The filtrate was added in ethyl alcohol (87 mL) at about 40°C to about 50°C and stirred for about 3-4 hr. The reaction mixture was stirred at about room temperature for about 1-2 hr. The solid was filtered, washed with ethyl alcohol and dried under reduced pressure for about 4-5 hr to yield titled product as off-white solid (4.2 g, 84%).

EXAMPLE 6: Preparation of crystalline relugolix
Relugolix (10g) was dissolved in dimethyl sulfoxide (18 mL) at about 25°C to about 35°C. The reaction mass was filtered, washed with dimethyl sulfoxide to obtain a filtrate. The filtrate was added to ethyl alcohol (290 mL) at about 40°C to about 50°C and stirred for about 3-4 hr. The reaction mixture was stirred at room temperature for about 1-2 hr. The solid was filtered, washed with ethyl alcohol and dried under reduced pressure for about 4-5 hr to yield titled product as off-white solid (8.1 g, 81%).

EXAMPLE 7: Preparation of 2-((2,6-difluorobenzyl) (ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylic acid
Step 1: Preparation of ethyl 5-(4-aminophenyl)-2-((2,6-difluorobenzyl) (ethoxycarbonyl)amino)-4-((dimethylamino)methyl)thiophene-3-carboxylate
To the stirred solution of ethyl 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl)thiophene-3-carboxylate (10g) and water (50mL) was added acetic acid (10mL) and hydrogenated over 10% palladium on carbon (50% wet, 0.3g) under 2-3 kg/cm2 hydrogen pressure at about 65-70°C for about 5-6hr. After completion of reaction, reaction mixture was filtered through celite and washed with water. To the clear filtrate were added ethyl acetate and pH was adjusted by adding sodium bicarbonate under stirring. The two layers were separated, and the organic layer containing ethyl 5-(4-aminophenyl)-2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)thiophene-3-carboxylate was used as such in the next step. HPLC Purity: 94.99%.
Step 2: Preparation of ethyl 2-((2,6-difluorobenzyl)(ethoxycarbonyl) amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylate
To the stirred solution of 1,1'-carbonyldiimidazole (4.5g), ethyl acetate (20mL) and triethylamine (1.57g) was added methoxyamine hydrochloride (2.3g) at about 10°C to about 20°C. The reaction mixture was warmed to about 20°C to about 30°C and stirred for about 1hr. The organic layer containing ethyl 5-(4-aminophenyl)-2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)thiophene-3-carboxylate in ethyl acetate (30mL) of step 1 was added thereto under stirring. The reaction mixture was warmed to about 50°C to about 60°C and stirred for about 2-3hr. After completion of reaction, triethylamine was added (2.21g) at about same temperature under stirring. After cooling the reaction mixture, water was added under stirring. The two layers were separated and the organic layer was concentrated under reduced pressure ethyl 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylate as an oil. HPLC Purity: 96.19%.
Step 3: Preparation of 2-((2,6-difluorobenzyl)(ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylic acid
To the stirred solution of compound ethyl 2-((2,6-difluorobenzyl) (ethoxycarbonyl) amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido) phenyl) thiophene-3-carboxylate in methyl alcohol (80mL) was added aqueous sodium hydroxide solution (3.6g sodium hydroxide in 30mL of water). The reaction mixture was warmed to temperature of about 55°C to about 60°C and stirred for about 6-7hr. After completion of reaction, the reaction mixture was cooled to about below 25°C and the pH of the reaction mixture was adjusted to about 6 to about 6.5 by using dilute hydrochloric acid. The reaction mass was concentrated under reduced pressure to obtain an oily residue. To the residue, was added water, dichloromethane and methyl alcohol, and the mixture was stirred for about 4-5hr at about 5°C to about 15°C and filtered to obtain wet cake. The obtained wet cake was dissolved in solution of sodium hydroxide in water and to this solution was added dichloromethane and methyl alcohol. The reaction mixture was cooled, and pH of the reaction mixture was adjusted to about 6 to about 6.5 by using dil. hydrochloric acid. The reaction mixture was stirred for about 4-5hr at about 5°C to about 15°C and filtered to obtain wet cake. The obtained wet cake was again dissolved in solution of sodium hydroxide in water and to this solution was added dichloromethane and methyl alcohol. The reaction mixture was cooled, and pH of the reaction mixture was adjusted to about 6 to about 6.5 by using dil. hydrochloric acid. The reaction mixture was stirred for about 4-5hr at about 5°C to about 15°C, filtered, washed with ethyl acetate and dried under reduced pressure to obtain 2-((2,6-difluorobenzyl) (ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido) phenyl) thiophene-3-carboxylic acid as of white to cream yellow solid (1.2g, 69%), HPLC Purity: 99.68%.

EXAMPLE 8: Preparation of ethyl (2,6-difluorobenzyl)(4-((dimethylamino) methyl)-3-((6-methoxypyridazin-3-yl)carbamoyl)-5-(4-(3-methoxyureido)phenyl) thiophen-2-yl) carbamate
Under a nitrogen atmosphere, to the stirred solution of 2-((2,6-difluorobenzyl) (ethoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido)phenyl) thiophene-3-carboxylic acid (2.5g) and 3-amino-6-methoxypyridazine (0.66g) in ethyl acetate (7.5mL) and diisopropylethylamine (0.23g) was slowly added 50% propylphosphonic anhydride (T3P) ethyl acetate solution (4.9g) at about 20°C to about 30°C. The reaction mixture was stirred at about same temperature for about 3-4 hr. After completion of the reaction, aqueous sodium bicarbonate solution was added and stirred for about 8hr. The reaction mass was filtered, washed with water followed by ethyl acetate to obtain wet cake. Methyl alcohol was added to the wet cake followed by addition of aqueous sodium bicarbonate solution and the reaction mixture was stirred for about 1-2hr. The reaction mass was filtered and washed with water followed by methyl alcohol. The solid was dried under reduced pressure for about 3-4 hr at about 50°C to about 60°C to yield ethyl (2,6-difluorobenzyl)(4-((dimethylamino)methyl)-3-((6-methoxypyridazin-3-yl)carbamoyl)-5-(4-(3-methoxyureido) phenyl) thiophen-2-yl) carbamate as off-white solid (2.5g, 84%). HPLC Purity: 98.16%.

EXAMPLE 9: Preparation of Relugolix
To the stirred solution of ethyl (2,6-difluorobenzyl)(4-((dimethylamino)methyl)-3-((6-methoxypyridazin-3-yl)carbamoyl)-5-(4-(3-methoxyureido)phenyl)thiophen-2-yl) carbamate (2g) in methyl alcohol (8mL) was added 25% sodium methoxide solution (0.3g). The mixture was stirred at about 45°C to about 50°C for about 2.5hr. After completion of reaction, the reaction mixture was cooled and stirred at temperature of about 20°C to about 30°C for about 5hr. The solid was filtered, washed with methyl alcohol. Water was added to the wet cake and the mixture was stirred for about 1hr. The reaction mass was filtered, washed with water followed by methyl alcohol. The solid was dried under reduced pressure for about 3-4hr at about 50°C to about 60°C to yield (1-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-3-methoxyurea (1.54g, 83%). HPLC Purity: 99.33%.

EXAMPLE 10: Preparation of crystalline relugolix
Relugolix (6 g) was dissolved in dimethyl sulfoxide (10.8 mL) at about 25°C to about 45°C. The reaction mass was filtered, washed with dimethyl sulfoxide (1.2 mL) to obtain a filtrate. The filtrate was slowly added in ethyl alcohol (78 mL) at about 45°C to about 50°C and the resulting mixture was stirred at about 45°C to about 50°C for about 4-5hr. The reaction mixture was gradually cooled to about 35°C to about 25°C for about 2-3hr. The solid was filtered, washed with ethyl alcohol and dried under reduced pressure at about 50°C to about 60°C for about 6-7 hr to obtain product (4.8g, 81%).
HPLC Purity: 99.73%.
XRD: 7.3, 8.9, 9.9, 12.0, 16.6, 17.3, 22.2, 22.7, and 27.4 ±0.2 degrees 2 theta
The crystalline form of relugolix has no detectable quantity of Form XIII of relugolix and Form XIV of relugolix as determined by absence of characteristic peak reflections at about 5.6±0.2 degrees 2 theta and 8.38±0.2 degrees 2 theta respectively.

Stability data of crystalline relugolix prepared by the process of the present invention at periodic intervals:
Storage Conditions Polymorphic forms Time
1 month 2 months 3 months 6 months
25°C at 60%RH Form XIII and
Form XIV ND ND ND ND
40°C at 75%RH ND ND ND ND
ND- not detected

CLAIMS:WE CLAIM:

1. A crystalline dimethylacetamide solvate of relugolix characterized by one or more of the following:
A. an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 5.6, 9.3, 10.4, 16.5 and 22.5 ±0.2 degrees 2 theta;
B. a differential scanning calorimetry (DSC) thermogram having an endothermic peak at about 170 ±2°C; and
C. a thermogravimetric analysis (TGA) thermogram, showing a weight loss of about 0 weight% to 20.69 weight% determined over the temperature range of 0°C to 250°C and heating rate 10°C/min.

2. A process for the preparation of crystalline dimethylacetamide solvate of relugolix as claimed in claim 1, comprising the steps of:
(a) dissolving relugolix in dimethylacetamide, optionally in the presence of an additional solvent, to form a solution;
(b) obtaining crystalline dimethylacetamide solvate of relugolix from the solution of the step (a); and
(c) isolating the crystalline dimethylacetamide solvate of relugolix.

3. The process as claimed in claim 2, wherein the step (a) is carried out at a temperature ranging from about 30°C to about 50°C.

4. The process as claimed in claim 2, wherein the step (b) of obtaining the crystalline dimethylacetamide solvate of relugolix comprises:
(bi) cooling and stirring the solution obtained in the step (a); or
(bii) removing the solvent from the solution obtained in the step (a); or
(biii) treating the solution of the step (a) with an anti-solvent to form a mixture and optionally, cooling and stirring the obtained mixture.

5. The process as claimed in claim 4, wherein in the step (bi), the cooling is carried out to a temperature of below about 30°C.

6. The process as claimed in claim 4, wherein in the step (biii), the anti-solvent is selected from the group consisting of C1-C6 alkyl alcohol, water; and a mixture thereof.

7. A process for the preparation of crystalline relugolix comprising the steps of:
(1) providing a mixture containing crystalline dimethylacetamide solvate of relugolix dissolved in an organic solvent;
(2) obtaining crystalline relugolix from the mixture of the step (1); and
(3) isolating the crystalline relugolix, wherein the crystalline relugolix is characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 7.3, 8.9, 9.9, 12.0, 16.6, 17.3, 22.2, 22.7, and 27.4 ±0.2 degrees 2 theta.

8. The process as claimed in claim 7, wherein in the step (1), the organic solvent is selected from the group consisting of C1-C6 alkyl alcohol, C2-C4 alkyl sulfoxide, C1-C6 haloalkane, and a mixture thereof.

9. The process as claimed in claim 7 or claim 8, wherein the step (1) is carried out at a temperature ranging from about 30°C to about 60°C.

10. The process as claimed in claim 7, wherein the step (2) of obtaining crystalline relugolix comprises cooling the mixture of the step (1), wherein the cooling is carried out to a temperature of below about 30°C.

11. A process for the preparation of crystalline relugolix comprising the steps of:
(i) providing a solution of relugolix in dimethyl sulfoxide;
(ii) combining the solution of the step (i) with an C1-C6 alkyl alcohol solvent to form a mixture;
(iii) obtaining crystalline relugolix from the mixture of the step (ii); and
(iv) isolating the crystalline relugolix, wherein the crystalline relugolix is characterized by an X-ray powder diffraction (XRPD) spectrum having peak reflections at about 7.3, 8.9, 9.9, 12.0, 16.6, 17.3, 22.2, 22.7, and 27.4 ±0.2 degrees 2 theta.

12. The process as claimed in claim 11, wherein the step (i) is carried out at a temperature of about 25°C to about 60°C, and the step (ii) is carried out at a temperature of about 35°C to about 70°C.

13. The process as claimed in claim 11, wherein the step (iii) of obtaining crystalline relugolix comprises cooling the mixture of the step (ii), wherein the cooling is carried out to a temperature of below about 30°C.

Dated this 12th day of August, 2024

___________________
Swati Veera
General Manager-IPM
Glenmark Life Sciences Limited