DESC:FIELD OF THE INVENTION
The present invention relates to improved process for the preparation of Relugolix, compound of Formula (I), substantially free from impurities. In particular, the invention relates to improved process for the preparation of high purity Relugolix free from impurities, and pharmaceutical composition comprising Relugolix, having a purity of about 99.0% or more, when measured by area percentage of HPLC.
BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
The secretion of anterior pituitary hormones is feedback-controlled by peripheral hormones secreted from target organs of various hormones and by secretion-regulating hormones from the hypothalamus. At present, nine hormones belonging to the above have been found, for example, thyrotropin-releasing hormone (TRH) and gonadotropin-releasing hormone [GnRH, sometimes referred to as LH-RH (luteinizing hormone-releasing hormone)]. Secretion of these hormones is associated with their corresponding receptors, and thus, the secretion of a particular anterior pituitary hormone can be achieved by finding antagonists or agonists that act specifically and selectively on the receptor.
International (PCT) Publication No. WO 2004/067535 discloses a class of small molecule GnRH receptor antagonists useful in treating endometriosis, uterine fibroids and prostate cancer and its chemical name is 1-(4-(7-(2,6-difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazin-3-yl)-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)phenyl)-3-methoxyurea. Relugolix has good activity and can effectively treat the endocrine and reproductive system diseases, and its structure is shown in Formula (I),
.
(I)
Relugolix, when taken orally once a day, rapidly lowers estrogen and progestin levels in women. Wutian conducted study to compare the safety and effectiveness of Relugolix and leuprorelin in treating menorrhagia uterine fibrosis and the safety and effectiveness of the two drugs in treating pain symptoms associated with uterine fibrosis through a series of phase III clinical studies conducted in Japan, and finally confirms the safety and effectiveness of Relugolix for uterine fibroids. In addition, Wutian medicine was subjected to a phase II clinical study of Relugolix endometriosis and prostate cancer, demonstrating that Relugolix significantly reduces pain caused by endometriosis, as well as reduces serum testosterone to castration levels and significantly reduces Prostate Specific Antigen (PSA).
International (PCT) Publication No. WO 2014/051164 and WO 2015/062391 disclose the process for the preparation of Relugolix.
Chinese Patent No. CN 110194776 discloses the process for the preparation of Relugolix.
Identification of impurities is a critical analytical activity in the drug development process whose goal is to fully elucidate the chemical structures of unknown impurities present in either drug substances or drug products above a particular threshold. In a pharmaceutical product, an impurity is first and foremost a quality issue, since it could potentially compromise the efficacy of the drug product. Secondly, impurities also cause safety concerns. It is impractical to have a drug substance or drug product with a purity of 100%. Therefore, the objective is to know the plausible of impurities for allowing assessment of their toxicological implications and for understanding their formation mechanisms, which is an important knowledge for improving the synthetic chemical pathway and optimizing the formulation.
In view of the above, it is therefore desirable to provide a composition comprising Relugolix having higher purity and substantially free from one or more impurities, which could plausibly affect the safety and efficacy of the drug product as stated above and method of its preparation thereof. Therefore, the present invention provides a process for the preparation of Relugolix and compositions thereof suitable for the preparation of drug substance/drug product having higher purity.
The literature references mentioned herein above suffer from major drawback that the reaction needs to be carried out under the conditions of heating and pressurizing, and the requirement on equipment is high. Also, the method has problems such as small batch size, thin layer chromatography purification in post-treatment, low yield, etc.
Therefore, there is need to provide an alternative commercially feasible and scalable process for the preparation of Relugolix involving simple steps with low cost, high yield, mild reaction conditions, low equipment requirement and high product purity. The present invention provides an improved process for the preparation of Relugolix with high purity. Further, the present invention thereby extends to the process for the preparation of Relugolix substantially free from impurities.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation of Relugolix having a purity of about 99.0% or more. In another embodiment, the present invention provides a pharmaceutical compositions comprising Relugolix having a purity of about 99.0% or more, and an impurity, a compound of Formula (VII), a compound of Formula (VIII), a compound of Formula (IX), a compound of Formula (X) and a compound of Formula (XI), present relative to Relugolix, in an amount of 0.15%, or less, respectively, by weight, when measured by area percentage of HPLC.
In one general aspect, there is provided a process for the preparation of high purity Relugolix, the process comprising:
(a) reacting a compound of Formula (II) with o-methoxyamine hydrochloride in the presence of a coupling agent to obtain a compound of Formula (I); and

(II) (I)
(b) purifying the compound obtained at step (a) in a solvent or a mixture of solvents to obtain a compound of Formula (I), wherein the obtained compound of Formula (I) is having a purity of 99.0% or more by weight, and a compound of Formula (VII), a compound of Formula (VIII), a compound of Formula (XI), a compound of Formula (X), or a compound of Formula (XI) is present in an amount 0.1% or less, relative to the compound of Formula (I) by weight, by area percentage of HPLC.
In another general aspect, there is provided an impurity, a compound of Formula (VII),
.
(VII)
In another general aspect, there is provided an impurity, a compound of Formula (VIII),
.
(VIII)
In another general aspect, there is provided an impurity, a compound of Formula (IX),
.
(IX)
In another general aspect, there is provided an impurity, a compound of Formula (X),
.
(X)
In another general aspect, there is provided an impurity, a compound of Formula (XI),
.
(XI)
In another general aspect, there is provided a pharmaceutical compositions comprising Relugolix having a purity of 99.0% or more and a compound of Formula (VII) and a compound of Formula (VIII) present relative to Relugolix, in an amount of 0.15%, or less, by weight, by area percentage of HPLC, together with one or more pharmaceutically acceptable excipient, diluents and carriers.
DETAILED DESCRIPTION OF THE INVENTION
The aforementioned general and further specific aspects of the invention are fulfilled by the description of the invention provided herein after.
The above and other objects of the present invention are achieved by the process of the present invention, which leads to Relugolix and compositions thereof suitable for pharmaceutical use. The invention provides substantially pure Relugolix suitable for development of finished formulations, which exhibit better control of impurities and stability under various stress conditions.
Optionally, the solution, prior to any solid formation, can be filtered to remove any undissolved solids, solid impurities prior to removal of the solvent. Any filtration system and filtration techniques known in the art can be used.
All ranges recited herein include the endpoints, including those that recite a range “between” two values. Terms such as “about”, “generally”, “substantially,” and the like are to be construed as modifying a term or value such that it is not an absolute. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
The term “high purity” refers to “substantially pure” herein means Relugolix having a purity of about 99.0% or more, preferably 99.5% or more, by weight, and a compound of Formula (VII) present in an amount relative to Relugolix of about 0.1% or less, or compound of Formula (VIII) present in an amount relative to Relugolix of about 0.1% or less, by weight, by are percentage of HPLC. In particular, the Relugolix comprises of one or more compounds of Formula (VII), Formula (VIII) within the permissible ICH limits suitable for pharmaceutical preparations. For example, but not limited to about 0.15% or less, to about 0.1% or less, or more particularly to about 0.05% or less, or most particularly not in detectable amount, by weight, by area percentage of HPLC, relative to Relugolix.
As used herein, the phrase “not in detectable amount” abbreviated as ND, refers to the level of impurity in the product, which is below the level of detection limit of the HPLC method.
As used herein, the term “solution” or “reaction mixture” does not limit to a clear solution only and includes any hazy or opaque mass obtained.
As used herein the term “obtaining” may include filtration, filtration under vacuum, centrifugation, and decantation for isolation of the product. The product may be preceded for further steps with or without isolation and with or without drying in case of the product was isolated. The product obtained may be further or additionally dried to achieve the desired moisture values. For example, the product may be dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
As used herein, the term “composition” used herein means a physical mixture of two or more components.
As used herein, the term "pharmaceutical composition" is intended to encompass a drug product including the active ingredient(s), pharmaceutically acceptable excipients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients. Accordingly, the pharmaceutical compositions encompass any composition made by admixing the active ingredient, active ingredient dispersion or composite, additional active ingredient(s), and pharmaceutically acceptable excipients.
The term “treating” means mixing, stirring, slurring, keeping that at any temperature or conditions.
The term “cooling” herein means the reaction mixture is cooled at temperature from about 0 °C to about 35 °C, In particular, from about 5 °C to about 30 °C, More particularly, from about 5 °C to about 25 °C, after the reaction mixture is being heted.
The terms herein below are interchangeable and used in the description.
“CDI” refers to carbonyldiimidazole
“DCM” refers to dichloromethane
“MDC” refers to methylene dichloride
“ACN” refers to acetonitrile
“DMSO” refers to dimethyl sulfoxide
“MeOH” refers to methanol
“DIPEA” refers to N,N-Diisopropylethylamine
“HPLC” refers to high Performance Liquid Chromatography
“API” refers to active Pharmaceutical Ingredient
“Hrs” refers to hours
“ND” refers to not (non) detectable amount
In general, the solvents may be removed from the reaction mixture in order to obtain solid or precipitate. The solvents may be removed by one or more of filtration, filtration under vacuum, centrifugation, decantation, distillation and distillation under vacuum.
The product(s) obtained may further be converted to any other physical forms thereof which includes but not specifically limited to salt(s), solvate(s), hydrate(s), co-crystal(s) and solid dispersion(s) in either crystalline or amorphous forms.
In one general aspect, there is provided a process for the preparation of high purity Relugolix, the process comprising:
(a) reacting a compound of Formula (II) with an o-methoxyamine hydrochloride in the presence of a coupling agent to obtain a compound of Formula (I) ; and

(II) (I)
(b) purifying the compound obtained at step (a) in a solvent or a mixture of solvents to obtain compound of Formula (I), wherein the obtained compound of Formula (I) is having a purity of 99.0% or more by weight, by area percentage of HPLC.
In general, the coupling agent in step (a) comprises of 1,1'-carbonyldiimidazole (CDI) or triphosgene.
In general, the reaction of the compound of Formula II with o-methoxyamine hydrochloride and the coupling agent may be carried out in the presence of a base and solvent or a mixture of solvents.
In general, the base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydride, sodium methoxide, potassium tert-butoxide, sodium pentoxide, pyridine, 2,6-lutidine, n-butyl lithium, or tetrabutylammonium bromide, tetrabutylammonium hydroxide, tetramethyl ammonium hydroxide, N,N- diisopropylethylamine(DIPEA) or Hünig's, 4-dimethylaminopyridine (DMAP), triethylamine (ET3N), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 2,6-di-tert-butylpyridine and 1,8-diazabicyclo[5.4. 0]undec-7-ene(DBU). In particular, N, N-diisopropylethylamine may be used.
In general, the solvent comprises one or more of toluene, xylene, ethyl benzene, heptane, n-hexane, cyclohexane, acetone, ethyl acetate, ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate, dimethylformamide (DMF), dimethylacetamide (DMAc), methanol, ethanol, isopropyl alcohol tetrahydrofuran, acetonitrile, dimethylsulfoxide (DMSO), dichloromethane, ethylene dichloride, chlorobenzene, chloroform, carbon tetrachloride, or mixture thereof. In particular, dichloromethane may be used.
In general, the process at step (a) further comprises:
(a) preparing solution-A by dissolving the coupling agent solvent at 20-30°C;
(b) preparing solution-B by dissolving the base and the compound of Formula II in solvent at 25-35 °C;
(c) adding the solution-B in to solution-A at 6 to 12°C, to obtain reaction mixture;
(d) maintaining the reaction for 75 to 90 mins at 6-12°C;
(e) preparing a solution-C by dissolving o-methoxyamine hydrochloride and a base in solvent with 10-15 min stirring;
(f) adding the solution-C to above reaction mixture at 6-12°C; and
(g) maintaining the reaction mixture for 25-30 hrs to obtain a compound of Formula (I) as crude.
In general, the coupling agent at step (a) comprises of 1,1'-carbonyldiimidazole (CDI) or triphosgene.
In general, the solvent at step (a), step (b) or (e) comprises one or more of toluene, xylene, ethyl benzene, heptane, n-hexane, cyclohexane, acetone, ethyl acetate, ethyl acetate, isopropyl acetate, t-butyl acetate, and isobutyl acetate, dimethylformamide (DMF), dimethylacetamide (DMAc), methanol, ethanol, isopropyl alcohol tetrahydrofuran, acetonitrile, dimethylsulfoxide (DMSO), dichloromethane, ethylene dichloride, chlorobenzene, chloroform or carbon tetrachloride. In particular, dichloromethane may be used.
In general, the base at step (b) or step (e) comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydride, sodium methoxide, potassium tert-butoxide, sodium pentoxide, pyridine, 2,6-lutidine, n-butyl lithium, tetrabutylammonium bromide, tetrabutylammonium hydroxide, tetramethyl ammonium hydroxide, N,N- diisopropylethylamine(DIPEA) Hünig's, 4-dimethylaminopyridine (DMAP), triethylamine (ET3N), 1,5-diazabicyclo(4.3.0)non-5-ene (DBN), 2,6-di-tert-butylpyridine or 1,8-diazabicyclo[5.4. 0]undec-7-ene(DBU). In particular, N, N-diisopropylethylamine may be used.
In general, the impurity, a compound is represented by a structure of Formula (VII),
.
(VII)
In another general aspect, there is provided Relugolix having an impurity, a compound of Formula (VII) of 0.50% or less, preferably less than 0.10% or less, more preferably less than 0.05% or less, most preferably not in detectable amount as determined by weight, by high performance liquid chromatography (HPLC).
The compound of formula (VII) is formed by degradation of Relugolix under basic condition.

(I) (VII)
Degradation of the drug substance is one of the main sources of impurities in a drug substance and drug product. One of the mechanisms for the degradation is through a hydrolysis degradation, which may occur during the manufacturing process, under acidic or basic condition. The present invention provides preparartion of carboxamide impurity by hydrolysis of Relugolix under basic condition. The present invention provides a Relugolix having a purity of about 99% or more by weight, and the compound of Formula (VII) present in an amount relative to Relugolix of about 0.15% or less, by weight, by area percentage of HPLC, and which is well within the standard permissible limits of impurities as per the ICH.
In general, the impurity, a compound is represented by structure of Formula (VIII),
.
(VIII)
In another general aspect, there is provided Relugolix having an impurity, a compound of Formula (VIII) of 0.30% or less, preferably less than 0.10% or less, more preferably less than 0.05% or less, most preferably not in detectable amount as determined by weight, by high performance liquid chromatography (HPLC).
The compound of Formula (VIII) which is process related impurity, is formed in preparing Relugolix from amine compound of Formula (II) in the presence of an o-ethoxylamine hydrochloride, CDI and DIPEA base in DCM solvent.

(II) (VIII)
This impurity of Formula (VIII) as evident from above is one of the potential impurities, which can be formed during the manufacturing process of Relugolix. Thus, there is need to provide a process which provides Relugolix which is substantially free from impurity (VIII). The present invention provides a Relugolix having a purity of about 99.0 % or more, by weight, and a compound of Formula (VIII) present in an amount relative to Relugolix of about 0.15% or less by weight, by area percentage of HPLC, and which is well within the standard permissible limits of impurities as per the ICH.
In another general aspect, there is provided substantially pure Relugolix having a chiral purity of 99% or more, by weight, when measured by area percentage of HPLC. In particular, Relugolix having a chiral purity 99.0% or more, more particularly, a purity of 99.5% or more by weight, when measured by area percentage of HPLC.
In general, oxo impurity, a compound is represented by structure of Formula (IX),
.
(IX)
In another general aspect, there is provided Relugolix having an impurity, a compound of Formula (IX) of 0.30% or less, preferably less than 0.10% or less, more preferably less than 0.05% or less, most preferably not in detectable amount as determined by weight, by high performance liquid chromatography (HPLC).
In general, dimer impurity, a compound is represented by structure of Formula (X),
.
(X)
In another general aspect, there is provided Relugolix having a dimer impurity, a compound of Formula (X) of 0.30% or less, preferably less than 0.10% or less, more preferably less than 0.05% or less, most preferably not in detectable amount as determined by weight, by high performance liquid chromatography (HPLC).
In general, amide impurity, a compound is represented by structure of Formula (XI),

(XI)
In another general aspect, there is provided Relugolix having an impurity, a compound of Formula (XI) of 0.30% or less, preferably less than 0.10% or less, more preferably less than 0.05% or less, most preferably not in detectable amount as determined by weight, by high performance liquid chromatography (HPLC).
In another general aspect, the compound of Formula (1) obtained by the process of present inventon, wherein the compound of Formula (I) is having a purity of 99.0% or more by weight, and at least one of;
(a) compound of Formula (VII) present in an amount 0.1% or less by weight relative to compound of Formula (I);

(VII)
(b) compound of Formula (VIII) present in an amount 0.1% or less by weight relative to compound of Formula (I);

(VIII)
(c) compound of Formula (IX) present in an amount 0.1% or less by weight relative to compound of Formula (I);

(IX)
(d) compound of Formula (X) present in an amount 0.1% or less by weight relative to compound of Formula (I); or

(X)
(e) compound of Formula (XI) present in an amount 0.1% or less by weight relative to compound of Formula (I);

(XI),
by area percentage of HPLC.
In general, the purity of Relugolix obtained by the process of the present invention is provided herein Table-1 for three batches.

Table-1: Summary of HPLC analysis of Relugolix
Batch Impurity (VII) Impurity (VIII) Oxo
(IX) Dimer (X)
Unreacted compound of formula II Amide (XI) Other unspecified impurity Purity
1 ND ND 0.02 0.03 0.02 0.04 0.05 99.66%
2 ND ND 0.01 0.02 0.01 0.05 0.07 99.72%
3 ND ND 0.02 0.03 0.01 0.05 0.06 99.7%

In another general aspect, there is provided a pharmaceutical compositions comprising Relugolix having a purity of about 99.0% or more and a compound of Formula (VII), compound of Formula (VIII), compound of Formula (IX), compound of Formula (X) or compound of Formula (XI) present relative to Relugolix, in an amount of about 0.15%, or less, by weight, by area percentage of HPLC, together with one or more pharmaceutically acceptable excipient, diluents and carriers.
In another general aspect, thereis provided a pharmaceutical compositions comprising Relugolix of the invention. As used herein, the term "pharmaceutical compositions" includes pharmaceutical Formulations like tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
In another general aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of Relugolix together with one or more pharmaceutically acceptable excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants.
In another general aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of Relugolix having a purity of about 99.0% or more and, a compound of Formula (VII), compound of Formula (VIII), compound of Formula (IX), compound of Formula (X) or compound of Formula (XI) present relative to Relugolix, in an amount of about 0.15%, or less, by weight, by area percentage of HPLC, together with one or more pharmaceutically acceptable excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants.
In general, the process for preparation Relugolix of the present invention can be summarized as depicted in Scheme-1.

Scheme-1
Examples:
Example-1: Preparation of ethyl (2,6-difluorobenzyl)-[4-dimethylaminomethyl-3- (6-methoxypyridazin-3-ylcarbamoyl)-5-(4-nitrophenyl)thiophen-2-yl]carbamate (IV)
In 5L 4-necked round bottom flask, 2-[(2,6-Difluorobenzyl)ethoxycarbonylamino]-4-dimethylaminomethyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid (100.0 g) and 3-amino-6-methoxypyridazine hydrochloride (46.6 g) were added in dimethylacetamide (300 mL) followed by addition of N,N-diisopropylethylamine (62.1 g) into the reaction mass at 25 to 35 °C. Reaction mass was stirred for 30-40 minutes at 55 to 60 °C followed by addition of propylphosphonic anhydride 50% ethyl acetate solution, reaction was maintained for 120 to 150 minutes at 55 to 60 °C. After in-process reaction results complies, cool the reaction mass up to 20 to 30 °C and water (800 mL) was added in the reaction mass, followed by addition of sodium hydroxide solution to adjust the pH between NLT 7 to NMT 9.5. Reaction mass was stirred for 90-120 minutes at 20 to 30 °C and filtered followed by washing with methanol to obtain ethyl (2,6-difluorobenzyl)-[4-dimethylaminomethyl-3-(6-methoxypyridazin-3-ylcarbamoyl)-5- (4-nitrophenyl) thiophen-2-yl]carbamate. Yield: 98.0%, HPLC area percent: 99.0%
Example-2: Preparation of 1-(2,6-Difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)-6-(4-nitrophenyl)thieno[2,3-d]pyrimidine-2,(1H,3H)-dione hydrochloride (III)
In a 4-necked 5L round bottom flask, ethyl (2,6-Difluorobenzyl)-[4- dimethylaminomethyl-3-(6-methoxypyridazin-3-ylcarbamoyl)-5-(4-nitrophenyl) thiophen-2-yl]carbamate (100.0 g), sodium methoxide (1.72 g) were added in methanol (2300 mL) and THF (170 mL) solvents mixture at 25 to 35 °C. Reaction temperature was raise upto 50 to 60 °C and maintained for 90 to 120 mins. Reaction mass was cooled upto 20 to 30 °C followed by addition of hydrochloric acid (47.0 g) and stir for 30 minutes, add the isopropanol (1000 ml) and stirred for 30 min. Reaction mass was further cooled upto 0 to 10 °C and filtered to obtain 1-(2,6-Difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)-6-(4-nitrophenyl)thieno-[2,3-d]pyrimidine-2,(1H,3H- dione hydrochloride. Yield: 98.0%, HPLC area percent: 99.0%
Example-3: Preparation of 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)thieno[2,3-d]pyrimidine-2,4 (IH, 3H)-dione (II)
In 5 L 4-necked round bottom flask, 1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl)-6-(4-nitrophenyl)thieno[2,3-d]pyrimidine-2, (1H,3H)–dione hydrochloride (100.0 g) was added in methanol (1400 mL) and conc. hydrochloride acid (15.75 g). 10% Pd-C (5.0 g) were also added at thereto under inert atmosphere under hydrogen pressure of 2.5 to 3.0 kg/cm2 at 20 to 25 °C and stirred for 5-7 hrs. After in-process complies, filter the reaction mass to remove the Pd/C catalyst from reaction mass. Methanol was distilled under vacuum and water was charge in the reaction mass, pH of reaction mass was adjusted with sodium bicarbonate upto 8 to obtain the solid product which was filtered to get the 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl) thieno[2,3-d]pyrimidine-2,4-(IH,3H)–dione. Yield: 90.0%, HPLC area percent: 98.0%
Example-4: Preparation of 1-[4-[1-[(2,6-Difluorophenyl)methyl]-5-[(dimethyl amino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea (I)
In 2 L 4-necked round bottom flask, 1,1’-carbonyldiimidazole (59.0 g) was added in DCM (400 mL) at 25 to 35°C. Reaction mixture was cooled to 6 to 12 °C to prepare the solution-A. In another 2L RB flask, a compound of Formula II (100.0 g) and N,N -diisopropylethylamine (24.0 g) were added in DCM (900 mL) at 25 to 35 °C followed by stirring for 30 to 60 minutes to prepare the solution-B. The solution B was added to solution A at 6 to 12 °C in 60 to 180 mints followed by maintaining reaction mass for 60 to 90 minutes. In another 1L RB flask, o-methoxyamine hydrochloride (76.0 g) and N,N-diisopropylethylamine (118.0 g) were added in DCM (300 mL) at 25 to 35 °C to prepare the solution C. The solution-C was added to above reaction mixture at 6 to 12 °C followed by maintaining reaction mass for 120 to 180 minutes. The reaction was monitored by HPLC and after in-process complies, water (500 mL) was added into the reaction mass followed by stirring for 30 minutes at 25 to 35 °C. The organic layer was separated & washed with water followed by distillation to obtain residue which was further crystallized with DCM to obtain Relugolix crude. Yield: 80%, HPLC Purity: 98%.

Purification of Relugolix:
In 5 L 4-necked round bottom flask, Relugolix (100.0 g) was charged in acetonitrile (115 mL) and methanol (286 mL) followed by heating upto 45 to 65 °C and maintain for 45 to 60 minutes. Reaction mass was cooled upto 25 to 35 °C and maintained for 120 to 180 minutes followed by further cool to 0 to 8 °C for 180 to 240 minutes. Reaction mass was filtered to obtain Relugolix. Yield: 85%, Purity: 99%
In another 5 L 4-necked round bottom flask, charge obtained Relugolix (100.0 g) and dimethyl sulfoxide (200 mL) at 25 to 35 °C and stirred to get clear solution followed by fine filtered the reaction mass to remove the undissolved solid. Methanol (400 mL) was added to reaction mass at 25 to 35 °C and stirred the reaction mass for 8 to 10 hrs. Reaction mass was further cooled to 0 to 10 °C and maintained reaction mass for 5 to 6 hrs, solid obtained was filter and dry at 55 to 65 °C under vacuum to get the pure Relugolix API. Yield: 80% Purity: 99.60%
HPLC method detail:
Mobile Phase : KH2P04 anhydrous/CH3CN/H3PO4/H2O(HPLC grade)
Column : Inertsil ODS-3V (250 x 4.6) mm
Detector : UV detector (measurement wavelength 230 nm)
Flow rate : 1.0 mL/ min
Injection Volume : 10 µL
Column oven temperature : 25 °C
Sample cooler temperature : 25 °C
Run time : 75 min
Example-5: 2-{[(2,6-difluorophenyl)methyl]amino}-4-[(dimethylamino)methyl]-5-{4-[(methoxycarbamoyl)amino]phenyl}-N-(6-methoxypyridazin-3-yl)thiophene-3-carboxamide (VII)
In 500 ml 4-necked round bottom flask, Relugolix API (7.0g) and sodium hydroxide solution were added at 80 to 90 °C for 6 to 8 hrs. After completion of reaction, reaction mass was cooled followed by adjusting the pH up to 7.0 to 7.5 by conc. hydrochloride to obtain compound of Formula (VII).
Example-6: 1-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-ethoxyurea (VIII)
In 1 L 4-necked round bottom flask, 1,1’-carbonyldiimidazole (59.0 g) was added in DCM (400 ml) at 25 to 35 ?. Reaction mixture was cooled to 6 to 12 °C to prepare the solution-A. In another 5L RB flask, compound of Formula II (100.0 g) and N,N–diisopropylethylamine (24.0 g) were added in DCM (900 mL) at 25 to 35 °C followed by stirring for 30 to 60 minutes to prepare the solution-B. The solution B was added to solution A at 6 to 12 °C in 60 to 180 minutes followed by maintaining reaction mass for 60 - 90 minutes. In another 5L round bottom flask, o-ethoxyamine hydrochloride (76.0 g) and N,N–diisopropylethylamine (118.0 g) were added in DCM (300 ml) at 25 to 35 °C to prepare the solution C. The solution-C was added to above reaction mixture at 6 to 12 °C followed by maintaining reaction mass for 120 to180 minutes. Water (500 ml) was added into the reaction mass followed by stirring for 30 minutes at 25 to 35 °C. The organic layer was separated & washed with water followed by distillation to obtain residue which was further crystallized with DCM to obtain a compound of Formula (VIII).
While the present invention has been described in terms of a few specific embodiments, modification and equivalents thereof, in light of the teaching and disclosure of the present invention, that are apparent to the skilled artisan, are to be construed as included within the scope of the invention.
,CLAIMS:We claim,
1. A process for the preparation of a compound of Formula (I), the process comprising:
(a) reacting a compound of Formula (II) with an o-methoxyamine hydrochloride in the presence of a coupling agent to obtain a compound of Formula (I); and

(II) (I)
(b) purifying the compound obtained at step (a) in a solvent or a mixture of solvents to obtain the compound of Formula (I), wherein the obtained compound of Formula (I) is having a purity of 99.0% or more by weight, by area percentage of HPLC.

2. The compound of Formula (I) prepared by the process as claimed in claim 1, wherein the compound of Formula (I) is having a purity of 99.0% or more by weight, and at least one of:
(a) a compound of Formula (VII) present in an amount 0.1% or less by weight, relative to the compound of Formula (I);

(VII)
(b) a compound of Formula (VIII) present in an amount 0.1% or less by weight, relative to the compound of Formula (I);

(VIII)
(c) a compound of Formula (IX) present in an amount 0.1% or less, by weight, relative to the compound of Formula (I);

(IX)
(d) a compound of Formula (X) present in an amount 0.1% or less by weight, relative to the compound of Formula (I); or

(X)
(e) a compound of Formula (XI) present in an amount 0.1% or less by weight, relative to the compound of Formula (I),

(XI),
by area percentage of HPLC.

3. The process as claimed in claim 1, wherein the process at step (a) further comprises:
(a) preparing a solution-A by dissolving a coupling agent in a solvent or a mixture of solvents;
(b) preparing a solution-B by dissolving a compound of Formula (II) and a base in a solvent or a mixture of solvents;
(c) adding the solution-B into the solution-A to obtain a reaction mixture;
(d) preparing a solution-C by dissolving o-methoxyamine hydrochloride and a base in a solvent or a mixture of solvents; and
(e) adding the solution-C obtained at step (d) into the reaction mixture at step (c) to obtain the compound of Formula (I),
wherein the base is selected from N,N-diisopropylethylamine (DIPEA), triethylamine, or 4-dimethylaminopyridine, and the solvent is selected from ethyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, dimethylformamide, dimethylacetamide, dimethylsulfoxide, dichloromethane, ethylene dichloride, or a mixture thereof.

4. The process as claimed in claim 1 or claim 3, wherein the coupling agent is selected from 1,1'-carbonyldiimidazole (CDI) or triphosgene.

5. The process as claimed in claim 1, wherein the reaction of Formula (II) with o-methoxyamine hydrochloride is performed in the presence of a base and solvent, wherein the base is selected from N,N-diisopropylethylamine (DIPEA), triethylamine or 4-dimethylaminopyridine, and the solvent is selected from ethyl acetate, isopropyl acetate, t-butyl acetate, isobutyl acetate, dimethylformamide, dimethylacetamide, dimethylsulfoxide, dichloromethane, ethylene dichloride, or a mixture thereof.

6. A compound of Formula (VII).

(VII)
7. A compound of Formula (VIII).

(VIII)
8. A compound of Formula (IX).

(IX)
9. A compound of Formula (X).

(X)
10. A compound of Formula (XI).

(XI)

Dated this 4th day of October 2022.

(HARIHARAN SUBRAMANIAM)
IN/PA-93
Of SUBRAMANIAM & ASSOCIATES
ATTORNEYS FOR THE APPLICANTS