Process for preparing relugolix

Abstract

The present invention relates to a process for preparing relugolix or a pharmaceutical salt thereof. It also relates to novel intermediates and their use for the preparation of relugolix.

Description

[Technical Field]

[0001] The present invention relates to a process for preparing relugolix or a pharmaceutical salt thereof. It also relates to novel intermediates and their use for the preparation of relugolix. [Background technology]

[0002] Relugolix, represented by the compound of formula (I), is the International Generally Recognized Name (INN) for 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, C 29 H 27 It has an empirical formula of F2N7O5S and a molecular weight of 623.6 g / mol. [ka]

[0003] Relugolix is ​​a non-peptide gonadotropin-releasing hormone (GnRH)-receptor antagonist that is used in the treatment of prostate cancer in men and uterine fibroids in women.

[0004] International Publication No. WO2004067535A1 describes the preparation of relugolix, as shown in Scheme 1. In this case, a compound of formula (II) is coupled with 3-amino-6-chloropyridazine of formula (III) to give a compound of formula (IV), which is cyclized in situ in the presence of sodium methoxide (NaOMe) in methanol (MeOH) to give a compound of formula (V) without isolation. After a debenzylation step using H in the presence of Pd / C and a subsequent methylation step using methyl iodide (CHI), relugolix was obtained. The use of a protecting group, such as a benzyl protecting group on the amine moiety, is undesirable on an industrial scale because it adds unnecessary reaction steps to the overall synthetic process. Furthermore, the final methylation step involves the use of methyl iodide, which is highly volatile and mutagenic. [ka]

[0005] J. Med. Chem. 2011, 54, 4998-5012 describes the preparation of relugolix, as shown in Scheme 2. In this case, a compound of formula (VII) was reacted with ethyl chloroformate of formula (VIII-a) to give a compound of formula (IX-a). This compound was coupled with 2,6-difluorobenzyl chloride of formula (X) to give a compound of formula (XI-a), which, after a bromination step using N-bromosuccinimide (NBS) in the presence of 2,2'-azobis(isobutyronitrile) (AIBN), gave compound (XII-a). The bromo group of compound (XII-a) was replaced by reacting this compound with (2-methoxyethyl)methylamine of formula (XIII). The resulting nitro compound of formula (XIV) was then reduced with H2 in the presence of Pd / C to give compound (XV). This compound was subjected to a coupling step with methoxyamine in the presence of 1,1'-carbonyldiimidazole (CDI) to give a compound of formula (XVI), which was then subjected to a hydrolysis reaction in the presence of NaOH to give a compound of formula (XVII). The compound of formula (XVII) was reacted with 3-amino-6-methoxypyridazine of formula (XVIII), and the resulting corresponding amide was not isolated but was cyclized in situ in the presence of sodium methoxide (NaOMe) in methanol (MeOH) to give a compound of formula (XIX). Relugolix was obtained by reacting this compound with 1-chloroethyl chloroformate and then adding dimethylamine. [ka]

[0006] International Publication No. WO2014051164A1 discloses another synthetic approach to obtaining relugolix. In this case, as shown in Scheme 3, the bromo group of the compound of formula (XII-a) obtained as disclosed in Scheme 2 above was replaced by reacting with dimethylamine. The compound of formula (XX-a) thus obtained was hydrolyzed in the presence of KOH to obtain a compound of formula (XXI). This compound was reacted with 3-amino-6-methoxypyridazine of formula (XVIII) to obtain the corresponding amide of formula (XXII-a), which was cyclized in the presence of sodium methoxide (NaOMe) in methanol (MeOH) to obtain a compound of formula (XXIII), which was reduced with H2 in the presence of Pd / C to obtain a compound of formula (XXIV). After a subsequent coupling step with methoxyamine in the presence of 1,1'-carbonyldiimidazole (CDI), relugolix was obtained. [ka]

[0007] Chinese Patent Applications CN112745304A and CN112321602A disclose another synthetic approach to obtain relugolix, as shown in Scheme 4. In this case, a compound of formula (XXII) was converted to a compound of formula (XXV) using a reducing agent. This compound was reacted with methoxyamine in the presence of a coupling agent to obtain a compound of formula (XXVI), which gave relugolix after a cyclization reaction. In Scheme 4, R represents a substituted or unsubstituted C1-C6 saturated or unsaturated alkyl or C1-C6 alkylaryl, preferably methyl, ethyl, propyl, allyl, chloroethyl, benzyl (as described in CN112745304A), and C 3-7 - an alkyl group or an aryl group (as described in CN112321602A). [ka]

[0008] Chinese Patent Application No. CN111333633A discloses another approach to obtaining relugolix. In this case, as shown in Scheme 5, a nitro compound of formula (XX), obtained by replacing the halogen group of compound (XII) with dimethylamine, is reduced with H2 in the presence of Pd / C to obtain an amine compound of formula (XXVII), which, after reaction with methoxyamine in the presence of a coupling agent, gives a compound of formula (XXVIII). This compound is converted to a compound of formula (XXIX) after hydrolysis in the presence of a base, which is reacted with 3-amino-6-methoxypyridazine of formula (XVIII) to give the corresponding amide of formula (XXVI), which, after cyclization, gives relugolix. According to CN111333633A, the R and R groups in Scheme 5 are independently C1-C6 linear or branched alkyl, preferably R is ethyl or isobutyl, R is ethyl, and X represents Cl, Br, or I. [ka]

[0009] Indian Patent Application No. IN202021052222A discloses the preparation of relugolix from the compound of formula (XX) by the same synthetic strategy as shown in Scheme 5, wherein R and R1 are independently C1-5 alkyl selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and t-butyl.

[0010] Chinese Patent Application No. CN113501830A discloses the preparation of relugolix from the compound of formula (XX) by the same synthetic strategy as shown in Scheme 5, wherein R and R1 are independently ethyl.

[0011] Chinese Patent Application No. CN113444105A discloses the preparation of relugolix from the compound of formula (XXVII) by the same synthetic strategy as shown in Scheme 5, wherein R and R1 are independently ethyl.

[0012] Chinese patent application CN114685468A discloses the preparation of relugolix from compounds of formula (XX) by the same synthetic strategy as shown in Scheme 5, wherein R is benzyl or substituted benzyl, C 7-10 It is a straight or branched chain alkyl, preferably benzyl or octyl, and R1 is ethyl.

[0013] Other synthetic approaches for preparing relugolix are disclosed in Chinese Patent Applications CN114621249A, CN114790189A, CN114230576A, CN114031626A, CN113135934A, CN113429423A, CN111423452A, CN110194776A, CN115073490A and International Publication Nos. WO2019020102A1 and WO2022214645A1.

[0014] Some of the above prior art documents disclose the preparation of relugolix with low yields, which means increased costs for the relugolix process and pharmaceutical compositions containing this active ingredient, which already results in an expensive drug. Moreover, some of the above prior art documents disclose the use of explosive and difficult-to-handle reagents, and require purification by column chromatography.

[0015] Therefore, there is a need to develop a viable and scalable process for the synthesis of relugolix, or a pharmaceutically acceptable salt thereof, in high purity and in commercially acceptable yield from what is known in the prior art. The present invention fulfills this and related needs. Summary of the Invention

[0016] The present inventors have discovered a new process for preparing relugolix or a pharmaceutically acceptable salt thereof that overcomes and / or minimizes some of the drawbacks of processes disclosed in the prior art. The new process makes it possible to obtain these compounds in unexpectedly high overall yields and at the same time with high purity. The process is easy to scale up to an industrial scale and allows for the production of relugolix in high overall yields and with the purity required for pharmaceutical use without the need for extensive purification steps, resulting in a more cost-effective process and producing less residue than previously known processes.

[0017] In a first aspect of the invention, there is provided a process for preparing relugolix of formula (I), or a pharmaceutically acceptable salt thereof, comprising: a) cyclizing the compound of formula (XXVI-b) in the presence of a base selected from the group consisting of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), and 1,1,3,3-tetramethylguanidine (TMG) in the presence of a suitable solvent to obtain relugolix; [ka] and b) optionally converting relugolix of formula (I) into a pharmaceutically acceptable salt thereof.

[0018] A second aspect of the present invention relates to a compound of formula (XXVII-b.HCl) [ka]

[0019] Finally, another aspect of the invention relates to compounds of formula (XX-b. oxalate). [ka] DETAILED DESCRIPTION OF THE INVENTION

[0020] All terms used herein in this application are to be understood in their ordinary sense as known in the art, unless otherwise specified. Other, more specific definitions for certain terms used in this application are set forth below and are intended to be applied uniformly throughout the specification and claims.

[0021] For purposes of the present invention, all ranges given include both the lower and upper limits of the range. Ranges and values ​​given, e.g., temperature, time, etc., should be considered approximate unless otherwise specified.

[0022] As used herein, the term "about" refers to a range of values ​​of ±10% of the specified value. For example, the expression "about 10" includes ±10% of 10, i.e., 9 to 11.

[0023] The term "room temperature" refers to the temperature of the environment without heating or cooling, generally between 20°C and 25°C.

[0024] As used in this specification and the appended claims, the singular forms "a," "an," and "the" are intended to include plural referents unless the context clearly dictates otherwise.

[0025] As mentioned above, a first aspect of the present invention provides a process for preparing relugolix of formula (I), or a pharmaceutically acceptable salt thereof, comprising: a) cyclizing the compound of formula (XXVI-b) in the presence of a base selected from the group consisting of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), and 1,1,3,3-tetramethylguanidine (TMG) in the presence of a suitable solvent to obtain relugolix; [ka] and b) optionally converting relugolix of formula (I) into a pharmaceutically acceptable salt thereof.

[0026] Step a) comprises cyclization of the compound of formula (XXVI-b) in the presence of a base selected from the group consisting of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), and 1,1,3,3-tetramethylguanidine (TMG).

[0027] In one embodiment of the present invention, the base used in step (a) is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0028] The amount of base used in step (a), preferably 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), is 0.05 to 6 equivalents, preferably 0.1 to 5 equivalents, more preferably 0.1 to 2.5 equivalents, based on the compound of formula (XXVI-b).

[0029] Non-limiting examples of suitable solvents that can be used in step a), which can be used alone or as a mixture of solvents, include: water; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, sec-butanol, or tert-butanol; ketones, such as acetone, methyl ethyl ketone, or methyl isobutyl ketone; ethers, such as tetrahydrofuran, dioxane, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, or methyl tert-butyl ether; esters, such as ethyl acetate, methyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, or tert-butyl acetate; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene, or dichlorobenzene; polar aprotic solvents such as N,N-dimethylformamide, acetonitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or dimethyl sulfoxide; hydrocarbon aliphatic solvents such as methylcyclohexane, cyclohexane, heptane, or hexane; aromatic hydrocarbon solvents such as toluene, benzene, o-xylene, m-xylene, or p-xylene.

[0030] Preferably, the reaction occurs in the presence of dimethyl sulfoxide.

[0031] Preferably, the reaction is carried out at a temperature in the range of -10°C to 70°C, preferably 0°C to 60°C, more preferably 20°C to 50°C.

[0032] The relugolix of formula (I) obtained in step a) can be isolated from the reaction mixture by any method known in the art. Preferably, the relugolix is ​​isolated by filtration.

[0033] The relugolix of formula (I) obtained in step a) can be purified by any method known in the art, such as crystallization or slurrying. Preferably, relugolix can be purified by crystallization.

[0034] Optionally, the relugolix of formula (I) obtained in step a) may be converted into its pharmaceutical salt, which may be purified by any method known in the art, such as crystallization or slurrying.

[0035] The term "pharmaceutically acceptable salt" refers to any salt that possesses the desired pharmacological activity of the parent compound and is formed from a non-toxic pharmaceutically acceptable acid, including, but not limited to, organic and / or inorganic acids. Such acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, acetic acid, fumaric acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, oxalic acid, malonic acid, malic acid, maleic acid, tartaric acid, succinic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, and salicylic acid.

[0036] In certain embodiments, optionally in combination with one or more features of the various embodiments described above or below, the process further comprises, before step a), the step of: i) coupling a compound of formula (XXVII-b.HCl) with methoxyamine or a salt thereof in the presence of a coupling agent and a suitable solvent to give a compound of formula (XXVIII-b); [ka] ii) hydrolyzing the compound of formula (XXVIII-b) obtained in step (i) to give a compound of formula (XXIX-b). [ka] , and iii) coupling the compound of formula (XXIX-b) obtained in step (ii) with 3-amino-6-methoxypyridazine of formula (XVIII) in the presence of a coupling agent in a suitable solvent to give a compound of formula (XXVI-b). [ka]

[0037] The coupling step i) is carried out in the presence of methoxyamine or a salt thereof. Preferably, the coupling step i) is carried out in the presence of the hydrochloride salt of methoxyamine (methoxyamine . HCl).

[0038] The amount of methoxyamine, preferably methoxyamine hydrochloride, is 0.5 equivalents to 8 equivalents, preferably 1 equivalent to 5 equivalents, based on the compound of formula (XXVII-b.HCl).

[0039] Non-limiting examples of suitable coupling agents that can be used in coupling step i) are propylphosphonic anhydride (T3P), 1,1'-carbonyldiimidazole (CDI), 1,1'-carbonylditetrazole (CDT), N,N'-disuccinimidyl carbonate (DSC), bis(trichloromethyl) carbonate (BTC), N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. , 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), triphosgene, acid chlorides such as oxalyl chloride, pivaloyl chloride, etc., alkyl chloroformates such as methyl chloroformate, and bis(1-benzotriazolyl)methanethione.

[0040] Preferably, the coupling agent used in step i) is 1,1'-carbonyldiimidazole (CDI).

[0041] The amount of coupling agent, preferably 1,1'-carbonyldiimidazole (CDI), is 0.5 equivalents to 8 equivalents, preferably 1 equivalent to 5 equivalents, based on the compound of formula (XXVII-b.HCl).

[0042] The coupling step i) is carried out in the presence of a base, preferably selected from the group consisting of triethylamine, trimethylamine, diethylamine, diethanolamine, diisopropylethylamine, pyridine, dimethylaminopyridine (DMAP), dicyclohexylamine, triethanolamine, meglumine, ethylenediamine, picoline, quinoline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

[0043] Preferably, the base used in step i) is a mixture of triethylamine and sodium carbonate.

[0044] Non-limiting examples of suitable solvents that can be used in step i) (which can be used alone or as a mixture of solvents) include: ketones such as acetone, methyl ethyl ketone, or methyl isobutyl ketone; ethers such as tetrahydrofuran, dioxane, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, or methyl tert-butyl ether; esters such as ethyl acetate, methyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, or tert-butyl acetate; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene, or dichlorobenzene; polar aprotic solvents such as N,N-dimethylformamide, acetonitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or dimethyl sulfoxide; hydrocarbon aliphatic solvents such as methylcyclohexane, cyclohexane, heptane, or hexane; aromatic hydrocarbon solvents such as toluene, benzene, o-xylene, m-xylene, or p-xylene.

[0045] Preferably, the coupling step i) is carried out using acetonitrile as solvent.

[0046] The coupling step i) may be carried out at a temperature ranging from 20°C to 80°C, preferably from 40°C to 60°C.

[0047] The compound of formula (XXVIII-b) can be isolated before the hydrolysis step ii) or it can be used in the next step ii) without isolation.

[0048] The compound of formula (XXVIII-b) may be purified by any method known in the art before being used in the next processing step.

[0049] The hydrolysis step ii) can be carried out in the presence of a base or an acid, but is not limited thereto. Non-limiting examples of suitable bases include sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, and sodium ethoxide. Non-limiting examples of suitable acids include hydrochloric acid, sulfuric acid, and phosphoric acid.

[0050] Preferably, the hydrolyzing agent used in step ii) is sodium hydroxide.

[0051] The hydrolysis step ii) may be carried out at a temperature ranging from 20°C to 60°C, preferably from 30°C to 50°C.

[0052] The compound of formula (XXIX-b) can be isolated before the coupling step iii) or alternatively, it can be used in step iii) without isolation.

[0053] The compound of formula (XXIX-b) may be purified by any method known in the art before being used in the next processing step.

[0054] Non-limiting examples of suitable solvents that can be used in step ii) (which can be used alone or as a mixture of solvents) include water; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, sec-butanol or tert-butanol; ketones such as acetone, methyl ethyl ketone or methyl isobutyl ketone; ethers such as tetrahydrofuran, dioxane, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether or methyl tert-butyl ether; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene or dichlorobenzene; polar aprotic solvents such as N,N-dimethylformamide, acetonitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or dimethyl sulfoxide; hydrocarbon aliphatic solvents such as methylcyclohexane, cyclohexane, heptane or hexane; aromatic hydrocarbon solvents such as toluene, benzene, o-xylene, m-xylene or p-xylene.

[0055] Preferably, the hydrolysis step ii) is carried out in the presence of acetone and water.

[0056] The coupling step iii) of a compound of formula (XXIX-b) with a compound of formula (XVIII) is carried out in the presence of a coupling agent in a suitable solvent.

[0057] Non-limiting examples of suitable coupling agents that can be used in coupling step iii) are propylphosphonic anhydride (T3P), 1,1'-carbonyldiimidazole (CDI), 1,1'-carbonylditetrazole (CDT), N,N'-disuccinimidyl carbonate (DSC), bis(trichloromethyl) carbonate (BTC), N,N'-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. , 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU), triphosgene, acid chlorides such as oxalyl chloride, pivaloyl chloride, etc., alkyl chloroformates such as methyl chloroformate, etc., and bis(1-benzotriazolyl)methanethione.

[0058] Preferably, the coupling agent used in step iii) is propylphosphonic anhydride (T3P).

[0059] The amount of the coupling agent, preferably propylphosphonic anhydride (T3P), is 0.5 to 8 equivalents, preferably 1 to 5 equivalents, based on the compound of formula (XXIX-b).

[0060] Non-limiting examples of suitable solvents that can be used in coupling step iii) (which can be used alone or as a mixture of solvents) include: ketones, such as acetone, methyl ethyl ketone, or methyl isobutyl ketone; ethers, such as tetrahydrofuran, dioxane, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, or methyl tert-butyl ether; esters, such as ethyl acetate, methyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, acetic acid, halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene, or dichlorobenzene; polar aprotic solvents such as N,N-dimethylformamide, acetonitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or dimethyl sulfoxide; hydrocarbon aliphatic solvents such as methylcyclohexane, cyclohexane, heptane, or hexane; aromatic hydrocarbon solvents such as toluene, benzene, o-xylene, m-xylene, or p-xylene.

[0061] Preferably, the solvent used in the coupling step iii) is ethyl acetate.

[0062] The coupling step iii) is carried out in the presence of a base, preferably selected from the group consisting of triethylamine, trimethylamine, diethylamine, diethanolamine, diisopropylethylamine, pyridine, dimethylaminopyridine (DMAP), dicyclohexylamine, triethanolamine, meglumine, ethylenediamine, picoline, quinoline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

[0063] Preferably, the base used in coupling step iii) is diisopropylethylamine.

[0064] The coupling step iii) can be carried out at a temperature ranging from 20°C to 80°C, preferably from 30°C to 50°C.

[0065] The compound of formula (XXVI-b) can be isolated before step a) or it can be used in step a) without isolation.

[0066] The compound of formula (XXVI-b) may be purified by any method known in the art before being used in the next processing step.

[0067] In another particular embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process further comprises, before step i), the step of: iv) neutralizing the compound of formula (XX-b. oxalate) to obtain the compound of formula (XX-b), [ka] and v) reducing the compound of formula (XX-b) obtained in step (iv) to obtain a compound of formula (XXVII-b), which is further converted to a compound of formula (XXVII-b.HCl). [ka] .

[0068] Neutralization step (iv) may be carried out by treating the compound of formula (XX-b. oxalate) with a suitable base such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate and lithium bicarbonate.

[0069] Preferably, the neutralizing agent used in step iv) is potassium carbonate.

[0070] The compound of formula (XX-b) can be isolated before step v) or it can be used in step v) without isolation.

[0071] The compound of formula (XX-b) may be purified by any method known in the art before being used in the next processing step.

[0072] Preferably, the reduction step (v) comprises catalytic hydrogenation of the compound of formula (XX-b) with hydrogen in the presence of a catalyst.

[0073] The term "catalytic hydrogenation" refers to treatment with hydrogen in the presence of a catalyst. The catalyst can be homogeneous or heterogeneous. The catalyst typically comprises a transition metal catalyst. The transition metal catalyst is preferably selected from the group comprising palladium, platinum, nickel and rhodium catalysts or mixtures thereof. Preferably, the catalyst is palladium on charcoal (Pd / C).

[0074] The catalytic hydrogenation of the compound of formula (XX-b) is carried out at a temperature in the range of 0°C to 50°C, preferably 15°C to 45°C, more preferably 20°C to 40°C.

[0075] Preferably, the amount of catalyst used is 0.5% w / w to 10% w / w or less, preferably 1% to 5%, based on the amount of compound of formula (XX-b) used in the preparation of compound of formula (XXVII-b).

[0076] Preferably, the catalytic hydrogenation is carried out under a hydrogen pressure ranging from about atmospheric pressure to 6 bar, preferably from 2 to 4 bar.

[0077] Preferably, the catalytic hydrogenation occurs at a temperature in the range of 10°C to 60°C, more preferably 20°C to 50°C, even more preferably at about 30°C.

[0078] Non-limiting examples of suitable solvents that can be used in the reduction step (v), which can be used alone or as a mixture of solvents, include water; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, sec-butanol, or tert-butanol; ethers, such as tetrahydrofuran, dioxane, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, or methyl tert-butyl ether; esters, such as ethyl acetate, methyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, or tert-butyl acetate; polar aprotic solvents, such as N,N-dimethylformamide, acetonitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or dimethyl sulfoxide; hydrocarbon aliphatic solvents, such as methylcyclohexane, cyclohexane, heptane, or hexane; aromatic hydrocarbon solvents, such as toluene, benzene, o-xylene, m-xylene, or p-xylene.

[0079] The compound of formula (XXVII-b) formed after the hydrogenation step can be isolated before being converted to the hydrochloride salt, or it can be converted in situ without being isolated.

[0080] The compound of formula (XXVII-b) may be purified by any method known in the art before being used in the next processing step.

[0081] Conversion of the compound of formula (XXVII-b) to the compound of formula (XXVII-b.HCl) is carried out by reacting the resulting compound of formula (XXVII-b) with hydrogen chloride (HCl) by any method known in the art.

[0082] Non-limiting examples of suitable solvents (which may be used alone or as a mixture of solvents) that may be used in the conversion of a compound of formula (XXVII-b) to a compound of formula (XXVII-b.HCl) include: water; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, sec-butanol, or tert-butanol; aromatic hydrocarbon solvents, such as benzene or nitrobenzene; ketones, such as acetone, methyl ethyl ketone, or methyl isobutyl ketone; ethers, such as tetrahydrofuran, dioxane, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, Examples of suitable solvents include methyl ether, cyclopentyl methyl ether, or methyl tert-butyl ether; esters such as ethyl acetate, methyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, or tert-butyl acetate; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene, or dichlorobenzene; polar aprotic solvents such as N,N-dimethylformamide, acetonitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or dimethyl sulfoxide; and hydrocarbon aliphatic solvents such as methylcyclohexane, cyclohexane, heptane, or hexane. Preferably, the solvent is ethyl acetate or isopropanol.

[0083] The compound of formula (XXVII-b.HCl) thus obtained may be purified by any method known in the art before being used in the next process step.

[0084] In another particular embodiment, optionally in combination with one or more features of the various embodiments described above or below, the process further comprises, before step iv), the following step: vi) reacting the compound of formula (VII) with methyl chloroformate of formula (VIII-b) to give a compound of formula (IX-b), vii) reacting the compound of formula (IX-b) obtained in step (vi) with 2,6-difluorobenzyl bromide of formula (Xa) to give a compound of formula (XI-b), viii) brominating the compound of formula (XI-b) obtained in step (vii) with N-bromosuccinimide (NBS) to obtain a compound of formula (XII-b); ix) reacting the compound of formula (XII-b) obtained in step (viii) with dimethylamine to give a compound of formula (XX-b), and x) reacting the compound of formula (XX-b) obtained in step ix) with oxalic acid to obtain a compound of formula (XX-b. oxalate). [ka]

[0085] Step vi) is carried out in the presence of methyl chloroformate (VIII-b) using a suitable solvent.

[0086] Non-limiting examples of suitable solvents that can be used in step vi) (which can be used alone or as a mixture of solvents) include: aromatic hydrocarbon solvents, such as toluene, benzene, o-xylene, m-xylene, p-xylene, or nitrobenzene; ketones, such as acetone, methyl ethyl ketone, or methyl isobutyl ketone; ethers, such as tetrahydrofuran, dioxane, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, or methyl tert-butyl ether; esters, such as methyl ether, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, or methyl tert-butyl ether; For example, ethyl acetate, methyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, or tert-butyl acetate; halogenated solvents, for example, dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene, or dichlorobenzene; polar aprotic solvents, for example, N,N-dimethylformamide, acetonitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or dimethyl sulfoxide; hydrocarbon aliphatic solvents, for example, methylcyclohexane, cyclohexane, heptane, or hexane.

[0087] Preferably, step vi) is carried out using toluene as the solvent.

[0088] Step vi) can be carried out at a temperature ranging from 20°C to 130°C, preferably from 40°C to 115°C, more preferably at about 105°C.

[0089] The amount of methyl chloroformate (VIII-b) is 0.8 to 10 equivalents, preferably 1 to 5 equivalents, more preferably 2 to 2.5 equivalents, based on the compound of formula (VII).

[0090] The compound of formula (IX-b) can be isolated before the alkylation step vii) or it can be used in step vii) without isolation.

[0091] The compound of formula (IX-b) may be purified by any method known in the art before being used in the next processing step.

[0092] The alkylation step vii) by reacting a compound of formula (IX-b) with 2,6-difluorobenzyl bromide of formula (Xa) is carried out in the presence of a base in a suitable solvent.

[0093] Non-limiting examples of suitable solvents that can be used in the alkylation step vii) (which can be used alone or as a mixture of solvents) include: water; aromatic hydrocarbon solvents such as toluene, benzene, o-xylene, m-xylene, p-xylene, or nitrobenzene; ketones such as acetone, methyl ethyl ketone, or methyl isobutyl ketone; ethers such as tetrahydrofuran, dioxane, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, or methyl tert-butyl ether; esters such as ethyl acetate, methyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, or tert-butyl acetate; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene, or dichlorobenzene; polar aprotic solvents such as N,N-dimethylformamide, acetonitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or dimethyl sulfoxide; hydrocarbon aliphatic solvents such as methylcyclohexane, cyclohexane, heptane, or hexane.

[0094] Preferably, step vii) is carried out using acetonitrile as solvent.

[0095] The alkylation step vii) is carried out in the presence of a base, preferably selected from the group consisting of triethylamine, trimethylamine, diethylamine, diethanolamine, diisopropylethylamine, pyridine, dimethylaminopyridine (DMAP), dicyclohexylamine, triethanolamine, meglumine, ethylenediamine, picoline, quinoline, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

[0096] Preferably, the alkylation step vii) is carried out in the presence of potassium carbonate.

[0097] Step vii) may be carried out at a temperature ranging from 20°C to 110°C, preferably from 40°C to 95°C, more preferably at about 85°C.

[0098] The amount of compound (Xa) is 0.8 to 5 equivalents, more preferably 1 to 2.5 equivalents, more preferably 1.05 to 1.5 equivalents, based on the compound of formula (IX-b).

[0099] The compound of formula (XI-b) can be isolated before the bromination step viii) or it can be used in step viii) without isolation.

[0100] The compound of formula (XI-b) may be purified by any method known in the art before being used in the next processing step.

[0101] The bromination step viii) is carried out in the presence of N-bromosuccinimide (NBS) and a radical initiator in a suitable solvent.

[0102] Non-limiting examples of radical initiators that can be used alone or as a mixture of radical initiators include 2,2′-azobis(isobutyronitrile) (AIBN), 2,2′-azobis(2,4-dimethylvalolinitrile) (AMVN), 4,4-azobis(4-cyanovaleric acid), 1,1′-azobis(cyclohexanecarbonitrile), benzoyl peroxide, and tert-butyl peroxide.

[0103] Preferably, the bromination step viii) is carried out in the presence of 2,2'-azobis(isobutyronitrile) (AIBN) as a radical initiator.

[0104] Non-limiting examples of suitable solvents that may be used in the bromination step viii) (which may be used alone or as a mixture of solvents) include water; aromatic hydrocarbon solvents such as benzene or nitrobenzene; ketones such as acetone, methyl ethyl ketone, or methyl isobutyl ketone; ethers such as tetrahydrofuran, dioxane, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, cyclopentyl methyl ether, or methyl tert-butyl ether; esters such as ethyl acetate, methyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, or tert-butyl acetate; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene, or dichlorobenzene; polar aprotic solvents such as N,N-dimethylformamide, acetonitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or dimethyl sulfoxide; hydrocarbon aliphatic solvents such as methylcyclohexane, cyclohexane, heptane, or hexane.

[0105] Preferably, step viii) is carried out using ethyl acetate as the solvent.

[0106] The bromination step viii) may be carried out at a temperature ranging from 20°C to 110°C, preferably from 40°C to about 95°C, more preferably at about 85°C.

[0107] The bromination step viii) is carried out in the presence of N-bromosuccinimide (NBS), the amount of which is 0.8 to 3 equivalents, more preferably 1 to 2.0 equivalents, more preferably 1.05 to 1.5 equivalents, based on the compound of formula (XI-b).

[0108] The compound of formula (XII-b) can be isolated before the amination step ix) or it can be used in step ix) without isolation.

[0109] The compound of formula (XII-b) may be purified by any method known in the art before being used in the next processing step.

[0110] The amination step ix) is carried out in the presence of dimethylamine in a suitable solvent.

[0111] Non-limiting examples of suitable solvents that can be used in the amination step ix) (which can be used alone or as a mixture of solvents) include: water; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, sec-butanol, or tert-butanol; aromatic hydrocarbon solvents, such as benzene or nitrobenzene; ketones, such as acetone, methyl ethyl ketone, or methyl isobutyl ketone; ethers, such as tetrahydrofuran, dioxane, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, cyclopentylmethyl ether, esters such as ethyl acetate, methyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, or tert-butyl acetate; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene, or dichlorobenzene; polar aprotic solvents such as N,N-dimethylformamide, acetonitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or dimethyl sulfoxide; hydrocarbon aliphatic solvents such as methylcyclohexane, cyclohexane, heptane, or hexane.

[0112] Preferably, step ix) is carried out using a mixture of acetone and water as solvent.

[0113] The amination step ix) may be carried out at a temperature ranging from -5°C to 50°C, preferably from 0°C to 25°C, more preferably at about 5°C.

[0114] The amination step ix) is carried out in the presence of dimethylamine, the amount of which is 0.8 to 10 equivalents, more preferably 1 to 7.5 equivalents, more preferably 3 to 5 equivalents, based on the compound of formula (XII-b).

[0115] The compound of formula (XX-b) can be isolated before step x) or it can be used in step x) without isolation.

[0116] Preferably, the compound of formula (XX-b) formed by reacting the compound of formula (XII-b) with dimethylamine is converted in situ to the compound of formula (XX-b. oxalate).

[0117] The conversion of the compound of formula (XX-b) to the compound of formula (XX-b. oxalate) is carried out by reacting the resulting compound of formula (XX-b) with oxalic acid by any method known in the art.

[0118] In certain embodiments, the process comprises reacting a compound of Formula (XX-b) with a solution of oxalic acid in an organic solvent, without isolation. In another particular embodiment, the process comprises reacting a compound of Formula (XX-b) with oxalic acid in solid form, without isolation.

[0119] Non-limiting examples of suitable solvents (which may be used alone or as a mixture of solvents) that may be used in the conversion of a compound of formula (XX-b) to a compound of formula (XX-b. oxalate) include: water; alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol, sec-butanol, or tert-butanol; aromatic hydrocarbon solvents, such as benzene or nitrobenzene; ketones, such as acetone, methyl ethyl ketone, or methyl isobutyl ketone; ethers, such as tetrahydrofuran, dioxane, diisopropyl ether, diethyl ether, 2-methyltetrahydrofuran, Cyclopentyl methyl ether or methyl tert-butyl ether; esters such as ethyl acetate, methyl acetate, isopropyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, or tert-butyl acetate; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichloroethane, chlorobenzene, or dichlorobenzene; polar aprotic solvents such as N,N-dimethylformamide, acetonitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidone, or dimethyl sulfoxide; hydrocarbon aliphatic solvents such as methylcyclohexane, cyclohexane, heptane, or hexane. Preferably, the solvent is ethanol.

[0120] The compound of formula (XX-b. oxalate) can be isolated before being used in the next process step or can be used without isolation. Preferably, the compound of formula (XX-b. oxalate) is isolated before being used in the next process step.

[0121] The compound of formula (XX-b. oxalate) may be purified by any method known in the art before being used in the next processing step.

[0122] As noted above, the invention also relates to intermediates used in the processes disclosed herein.

[0123] As mentioned above, the second aspect of the present invention relates to compounds of formula (XXVII-b.HCl). [ka]

[0124] As mentioned above, the third aspect of the present invention relates to compounds of formula (XX-b. oxalate). [ka]

[0125] Example Hereinafter, the present invention will be described in more detail and specifically with reference to examples, which, however, are not intended to limit the present invention.

[0126] Example 1: Preparation of Relugolix of Formula (I) Methyl (2,6-difluorobenzyl)(4-((dimethylamino)methyl)-3-((6-methoxypyridazin-3-yl)carbamoyl)-5-(4-(3-methoxyureido)phenyl)thiophen-2-yl)carbamate (XXVI-b) (0.5 g, 0.76 mmol) was dissolved in DMSO (1.25 mL), and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) (0.03 g, 0.19 mmol, 0.25 eq) was added to the solution. The mixture was stirred at 20-25° C. for 24 hours, ethanol (8.75 mL) was added, and the resulting mixture was stirred at 20-25° C. for 16 hours. HPLC analysis of the reaction mixture showed the presence of relugolix (97.8%), compound (XXVI-b) (0.04%), impurity A (0.07%) and impurity B (0.32%). After filtering and drying the suspension under vacuum at 40-50° C., crude relugolix was obtained (0.37 g, 77% yield, HPLC 98.6%).

[0127] Crude relugolix samples obtained according to the same procedure and with similar purity were combined (2.94 g) and dissolved in DMSO (7.4 mL). The solution was heated to 35°C and filtered. Ethanol (51.5 mL) was added to the filtered solution, and the solution was stirred at this temperature for 1 hour, then cooled to 20-25°C and stirred for 18 hours. The resulting suspension was filtered, and the cake was washed with ethanol. The resulting solid was dried under vacuum at 40°C to give relugolix (2.54 g, 86.4% yield, HPLC 99.5%). [ka]

[0128] Example 2: Preparation of Relugolix of Formula (I) Methyl (2,6-difluorobenzyl)(4-((dimethylamino)methyl)-3-((6-methoxypyridazin-3-yl)carbamoyl)-5-(4-(3-methoxyureido)phenyl)thiophen-2-yl)carbamate (XXVI-b) (25.98 g, 0.040 mol) was dissolved in DMSO (65 mL), and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) (1.81 g, 0.012 mmol, 0.3 eq) was added to the solution. The mixture was stirred at 20-25° C. for 24 hours and heated to 35-40° C. Then, ethanol (455 mL) was added, and seeding with relugolix Form I was performed during the addition. The resulting mixture was stirred at 35-40° C. for 1 hour, cooled to 20-25° C., and stirred at this temperature for 15 hours. The suspension was filtered to obtain crude relugolix, which was dissolved in DMSO (56 mL) at 35-40°C. Ethanol (22.2 mL) was added, the solution was filtered, and the filter was washed with ethanol (56 mL). Maintaining this temperature, additional ethanol (311 mL) was loaded onto the filtered solution, and seeding with relugolix Form I was performed during the addition. The mixture was stirred for 1 hour, then cooled to 20-25°C and stirred for 15 hours. The resulting suspension was filtered, and the cake was washed with ethanol. The resulting solid was dried under vacuum at 45-50°C to obtain relugolix (18.79 g, 76% yield, HPLC 99.8%).

[0129] Example 3: Preparation of ethyl 2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylate of formula (XXVIII-b) A mixture of 1,1'-carbonyldiimidazole (CDI) (20.42 g, 0.126 mol, 1.7 eq), acetonitrile (120 mL), and triethylamine (6.37 g, 0.063 mol, 0.85 eq) was cooled to 5-10 °C. Methoxyamine hydrochloride (11.75 g, 0.141 mol, 1.9 eq) was added portionwise while maintaining this temperature. The suspension was warmed to 20-25 °C, and sodium carbonate (8.64 g, 0.081 mol, 1.1 eq) was added. Ethyl 5-(4-aminophenyl)-2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-((dimethylamino)methyl)thiophene-3-carboxylate hydrochloride (XXVII-b.HCl) (40 g, 0.074 mol) was then added. The mixture was heated to 48-52°C and stirred at this temperature for 2 hours. The reaction was cooled to 40°C, deionized water (160 mL) was added, and the mixture was cooled to 20-25°C. Deionized water (160 mL) was added to the resulting suspension, and the mixture was then cooled to 0-5°C. The resulting suspension was stirred for 1 hour, filtered, and the cake was washed with deionized water. The resulting solid was dried under vacuum at 40-45°C to a constant weight to give the compound of formula (XXVIII-b) (34 g, 80% yield, HPLC 98.8%).

[0130] Example 4: Preparation of ethyl 2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylate of formula (XXVIII-b) A mixture of 1,1'-carbonyldiimidazole (CDI) (76.57 g, 0.472 mol, 1.7 eq), acetonitrile (450 mL), and triethylamine (23.89 g, 0.236 mol, 0.85 eq) was cooled to 5-10 °C. Methoxyamine hydrochloride (44.08 g, 0.528 mol, 1.9 eq) was added portionwise. The mixture was warmed to 20-25 °C and stirred until completely dissolved. It was then loaded into a flask containing ethyl 5-(4-aminophenyl)-2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-((dimethylamino)methyl)thiophene-3-carboxylate hydrochloride (XXVII-b.HCl) (150 g, 0.278 mol). Finally, sodium carbonate (32.38 g, 0.306 mol, 1.1 eq) was added. The mixture was heated to 45-50°C and stirred at this temperature for 2 hours. The reaction was cooled to 40°C, deionized water (600 mL) was added, the mixture was cooled to 20-25°C, seeded with the solid compound of formula (XXVIII-b), and stirred for about 30 minutes. Deionized water (600 mL) was added, and the mixture was then cooled to 0-5°C and stirred for 1 hour. The suspension was filtered, and the cake was washed with deionized water. The resulting wet solid corresponded to the compound of formula (XXVIII-b) (123.1 g dry equivalent, 77% yield, HPLC 98.7%).

[0131] Example 5: Preparation of 2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylic acid of formula (XXIX-b) Ethyl 2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylate (XXVIII-b) (30 g, 0.052 mol) was dissolved in acetone (90 mL) at 20-25° C., and then deionized water (120 mL) was added along with 50% w / w aqueous NaOH solution (5.41 g, 0.067 mol, 1.3 eq). The resulting solution was heated to 45-50° C. and stirred at this temperature for 26 hours. The reaction mixture was cooled to 20-25° C., and the pH was adjusted to 6.0-7.0 with concentrated HCl. The mixture was concentrated to dryness under reduced pressure. Isopropanol (86 mL) was added to the residue, and the resulting suspension was concentrated to dryness under reduced pressure. Isopropanol (71 mL) was added to the residue, and the mixture was heated to 60°C and stirred for 10 minutes. The suspension was cooled to 20-25°C and filtered. The cake was washed with isopropanol. The resulting solid was suspended in acetonitrile (274 mL), and the suspension was heated to 60-70°C. Deionized water (23 mL) was added, and the thin suspension was filtered, washing the filter with acetonitrile. The filtered solution was distilled under vacuum to a final residue of approximately 170 mL. The suspension was cooled to 0-(-5)°C, stirred for 1 hour, filtered, and the resulting cake was washed with cold acetonitrile. The resulting solid was dried under vacuum at 45-50°C to give the compound of formula (XXIX-b) (16.65 g, 58% yield, HPLC 99.4%).

[0132] Example 6: Preparation of 2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylic acid of formula (XXIX-b) Ethyl 2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylate (XXVIII-b) (100 g dry equivalent, 0.173 mol) was dissolved in acetone (300 mL) at 20-25° C., then deionized water (400 mL) was added along with 50% w / w aqueous NaOH (18.04 g, 0.225 mol, 1.3 eq). The resulting solution was heated to 45-50° C. and stirred at this temperature for 26 hours. The reaction mixture was cooled to 20-25° C., and the pH was adjusted to 6.0-7.0 with concentrated HCl. The mixture was concentrated to dryness under reduced pressure. Isopropanol (285 mL) was added to the residue, and the resulting suspension was concentrated to dryness under reduced pressure. Isopropanol (238 mL) was added to the residue, and the mixture was heated to 60°C and stirred for 10 minutes. The suspension was cooled to 20-25°C and filtered. The cake was washed with isopropanol. The resulting solid was suspended in acetonitrile (913 mL), and the suspension was heated to 65-70°C. Deionized water (76 mL) was added, and the thin suspension was filtered, rinsing the filter with acetonitrile. The filtered solution was distilled under vacuum to a final residue of approximately 913 mL. Acetonitrile (304 mL) was added, and the mixture was distilled under vacuum to a final residue of approximately 913 mL. Acetonitrile (304 mL) was added, and the mixture was distilled under vacuum to a final residue of approximately 571 mL. The suspension was cooled to 0-(-5)°C, stirred for 1 hour, filtered, and the resulting cake was washed with cold acetonitrile. The resulting solid was dried under vacuum at 45-50° C. to give the compound of formula (XXIX-b) (88.0 g, 93% yield, HPLC 99.1%).

[0133] Example 7: Preparation of methyl (2,6-difluorobenzyl) (4-((dimethylamino)methyl)-3-((6-methoxypyridazin-3-yl)carbamoyl)-5-(4-(3-methoxyureido)phenyl)thiophen-2-yl)carbamate of formula (XXVI-b) 2-((2,6-Difluorobenzyl)(methoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylic acid (XXIX-b) (15.0 g, 0.027 mol) was mixed with ethyl acetate (150 mL) and diisopropylethylamine (9.54 g, 0.074 mol, 2.7 eq) at 20-25°C. The mixture was stirred until dissolved. Then, 6-methoxypyridazin-3-amine (XVIII) (5.82 g, 0.046 mol, 1.7 eq) and propylphosphonic anhydride (T3P) 50% w / w in ethyl acetate solution (43.5 g, 0.068 mol, 2.5 eq) were added. The mixture was heated to 35-40°C and stirred at this temperature for 4 hours. The reaction was cooled to 10-15°C, and deionized water (75 mL) and ethyl acetate (150 mL) were added, followed by Na2CO3 until the pH of the aqueous phase was 8-9. The biphasic mixture was stirred for 15 minutes, and the organic phase was separated. The organic phase was distilled under atmospheric pressure to a final residue of approximately 50 mL. The suspension was cooled to 0-(-5)°C, stirred for 1 hour, and filtered. The cake was washed with cold ethyl acetate. The resulting solid was dried under vacuum at 40-45°C to give the compound of formula (XXVI-b) (14.9 g, 83% yield, HPLC 97.7%).

[0134] Example 8: Preparation of methyl (2,6-difluorobenzyl) (4-((dimethylamino)methyl)-3-((6-methoxypyridazin-3-yl)carbamoyl)-5-(4-(3-methoxyureido)phenyl)thiophen-2-yl)carbamate of formula (XXVI-b) 2-((2,6-Difluorobenzyl)(methoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-(3-methoxyureido)phenyl)thiophene-3-carboxylic acid (XXIX-b) (30.0 g, 0.055 mol) was mixed with 6-methoxypyridazin-3-amine (XVIII) (8.21 g, 0.066 mol, 1.2 eq), diisopropylethylamine (12.72 g, 0.098 mol, 1.8 eq), and ethyl acetate (240 mL) at 20-25°C. The mixture was stirred for 10 minutes. Then, a 50% w / w solution of propylphosphonic anhydride (T3P) in ethyl acetate (55.7 g, 0.088 mol, 1.6 eq) was added over 10-15 minutes, maintaining the temperature below 35°C. The mixture was heated to 45-50°C and stirred at this temperature for 1 hour. The reaction was cooled to 20-25°C and subjected to distillation under vacuum to a final residue of approximately 135 mL. The distillation residue was cooled to 5-10°C and deionized water (175 mL) was added slowly while maintaining the temperature below 15°C. The mixture was warmed to 15-20°C and the pH was adjusted to 8-8.5 with a solution of Na2CO3 (5 g) in deionized water (820 mL). The resulting suspension was cooled to 5-10°C, stirred for 1 hour, and filtered. The cake was washed with cold deionized water and then with cold ethyl acetate.

[0135] The wet solid was treated with DMSO (81 mL) and the mixture was heated to 35-40° C. Ethanol (485 mL) was added while maintaining this temperature. The suspension was stirred at this temperature for 1 hour, cooled to 20-25° C., stirred for an additional 15 hours, cooled again to 10° C. and stirred for 1 hour. The suspension was filtered, and the filter was washed with cold ethanol.

[0136] The obtained wet solid corresponded to the compound of formula (XXVI-b) (26.96 g dry equivalent, 75% yield, HPLC 99.5%).

[0137] Example 9: Preparation of ethyl 2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl)thiophene-3-carboxylate of formula (XX-b) Ethyl 2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl)thiophene-3-carboxylate oxalate (XX-b oxalate) (14.81 g) and potassium carbonate (5.25 g) were suspended in ethyl acetate (74 mL), the temperature was lowered to 0-10° C., and deionized water (74 mL) was loaded while maintaining this temperature. The mixture was stirred at 0-10° C. for about 1 hour, then it was warmed to 20-25° C. and the phases were allowed to settle. The aqueous phase was separated, and the organic phase was washed twice with deionized water (2×30 mL) and distilled at atmospheric pressure to a final residual volume of approximately 25 mL. Ethyl acetate (30 mL) was loaded, and the distillation was repeated to the same residual volume. Again, ethyl acetate (30 mL) was loaded, and the distillation was repeated to the same residual volume. The volume of the final solution was adjusted to approximately 185 mL and used as such. The solution contains approximately 12.6 g of the compound of formula (XX-b).

[0138] Example 10: Preparation of ethyl 2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl)thiophene-3-carboxylate of formula (XX-b) Potassium carbonate (11.97 g) was dissolved in deionized water (150 mL) and the solution was cooled to 5-10°C. Ethyl 2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl)thiophene-3-carboxylate oxalate (XX-b oxalate) (30 g dry equivalent, 0.048 mol) was added, followed by ethyl acetate (150 mL). The mixture was stirred at 5-10°C for 1 hour, warmed to 20-25°C, and stirred for an additional 2 hours. The phases were allowed to settle, and the pH of the aqueous phase was confirmed to be 8-8.5. The aqueous phase was separated, and the organic phase was washed twice with deionized water (2 x 60 mL) and distilled at atmospheric pressure to a final residual volume of approximately 45 mL. Ethyl acetate (60 mL) was loaded, and the distillation was repeated to the same residual volume. Ethyl acetate (60 mL) was loaded again, and the distillation was repeated to the same residual volume. Ethyl acetate (103 mL) and activated carbon (1.3 g) were added onto the distillation residue, and the mixture was stirred at 20-25° C. for 1 hour, filtered, and the filter was washed with ethyl acetate (13 mL). Activated carbon (1.3 g) was added onto the filtered solution, and the mixture was stirred at 20-25° C. for 1 hour, filtered, and the filter was washed with ethyl acetate (13 mL).

[0139] The volume of the final solution was adjusted to approximately 370 mL with ethyl acetate and used as such The solution contains approximately 25.67 g of the compound of formula (XX-b).

[0140] Example 11: Preparation of ethyl 5-(4-aminophenyl)-2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-((dimethylamino)methyl)thiophene-3-carboxylate hydrochloride of formula (XXVII-b.HCl) To a solution of ethyl 2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl)thiophene-3-carboxylate (XX-b) (1.5 g, 3.0 mmol) in ethyl acetate (21 mL) was loaded wet 10% Pd / C (0.03 g dry equivalent, 2% w / w) and the mixture was stirred at 25-30° C. under 2 bar hydrogen pressure for 4 h. The catalyst was removed by filtration and the filtered solution was concentrated under atmospheric pressure to a final residue of about 15 mL. A 20% w / w solution of hydrogen chloride in isopropanol (0.56 g, 3.1 mmol, 1.1 eq) was added at 20-25° C. The resulting suspension was stirred at 20-25° C. for 1 h and filtered. The cake was washed with ethyl acetate. The solid was dried under vacuum at 40-45° C. to a constant weight to give the compound of formula (XXVII-b.HCl) (1.23 g, 81% yield, HPLC 99.5%).

[0141] Example 12: Preparation of ethyl 5-(4-aminophenyl)-2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-((dimethylamino)methyl)thiophene-3-carboxylate hydrochloride of formula (XXVII-b.HCl) To a solution of ethyl 2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl)thiophene-3-carboxylate (XX-b) (25.67 g, 0.048 mol) in ethyl acetate (approximately 355 mL) was loaded wet 10% Pd / C (0.51 g dry equivalent, 2% w / w) and the mixture was stirred at 2 bar hydrogen pressure for 4 hours at 25-30° C. The catalyst was removed by filtration and the filtered solution was concentrated under atmospheric pressure to a final residue of approximately 208 mL. An 18.56% w / w solution of hydrogen chloride in isopropanol (8.52 g) was added at 20-25° C. The resulting suspension was stirred at 20-25° C. for 1 hour and filtered. The cake was washed with ethyl acetate. The solid was dried under vacuum at 40-45° C. to constant weight to give the compound of formula (XXVII-b.HCl) (19.97 g, 77% yield, HPLC 99.5%).

[0142] Example 13: Preparation of ethyl 2-((methoxycarbonyl)amino)-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate of formula (IX-b) Ethyl 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate (VII) (100 g, 0.326 mol) was suspended in toluene (250 mL). The suspension was heated to 98-105°C. Methyl chloroformate (VIII-b) (67.9 g, 0.718 mol, 2.2 eq) was added dropwise over 2 hours. The addition funnel was washed with toluene (50 mL). The mixture was stirred at this temperature for 3 hours. The mixture was cooled to 60-70°C, and methanol (900 mL) was added dropwise. The mixture was heated to reflux and stirred for 3 hours. The resulting suspension was cooled to 20-25°C, stirred at this temperature for 1 hour, and filtered. The resulting solid was washed with methanol and then heptane. The collected solid, corresponding to the compound of formula (IX-b), was dried at 45-50° C. under vacuum to constant weight (116.5 g, 98% yield, HPLC 99.9%, yellow solid).

[0143] Example 14: Preparation of ethyl 2-((methoxycarbonyl)amino)-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate of formula (IX-b) Ethyl 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate (VII) (103 g, 0.336 mol) was suspended in toluene (282 mL). The suspension was heated to 95-105°C. Methyl chloroformate (VIII-b) (70 g, 0.741 mol, 2.2 eq) was added dropwise over 2 hours. The addition funnel was washed with toluene (11.5 mL). The mixture was stirred at this temperature for 5 hours. The mixture was cooled to 60-70°C, and methanol (866 mL) was added dropwise. The mixture was stirred at this temperature for 3 hours. The resulting suspension was cooled to 20-25°C, stirred at this temperature for 1 hour, and filtered. The resulting solid was washed with methanol and then heptane. The solid, corresponding to the compound of formula (IX-b), was dried under vacuum at 45-55° C. to constant weight (112.7 g, 92% yield, HPLC 100.0%, yellow solid).

[0144] Example 15: Preparation of ethyl 2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate of formula (XI-b) Ethyl 2-((methoxycarbonyl)amino)-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate (IX-b) (75.17 g, 0.206 mol), 2,6-difluorobenzyl bromide (Xa) (47.2 g, 0.227 mol, 1.1 eq), and potassium carbonate (31.34 g, 0.227 mol, 1.1 eq) were mixed with acetonitrile (376 mL), and the suspension was heated to reflux and stirred at this temperature for 10 hours. The reaction mixture was cooled to 45-55°C, and it was distilled under vacuum to a residue of approximately 90 mL. Deionized water (376 mL) was added at 45-55°C, followed by the slow addition of heptane (451 mL). The resulting suspension was cooled to 0-5°C, stirred at this temperature for 1 hour, and filtered. The solid was washed successively with cold deionized water (368 mL), cold heptane (180 mL), and three times with a 3:1 w / w mixture of heptane / ethyl acetate (75.2 mL). The collected solid, corresponding to the compound of formula (XI-b), was dried under vacuum at 50° C. (81.79 g, 81% yield, HPLC 99.9%).

[0145] Example 16: Preparation of ethyl 2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate of formula (XI-b) Ethyl 2-((methoxycarbonyl)amino)-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate (IX-b) (90.0 g, 0.247 mol), 2,6-difluorobenzyl bromide (Xa) (56.5 g, 0.273 mol, 1.1 eq), and potassium carbonate (37.5 g, 0.273 mol, 1.1 eq) were mixed with acetonitrile (453 mL), and the suspension was heated to reflux and stirred at this temperature for 10 hours. The reaction mixture was cooled to 50-55° C., and it was distilled under vacuum to a residue of approximately 200 mL. Deionized water (454 mL) was added at 50-55° C., followed by the slow addition of heptane (539 mL). The resulting suspension was cooled to 0-5° C., stirred at this temperature for 1 hour, and filtered. The solid was washed successively with cold deionized water (100 mL), cold heptane (146 mL), and three times with a 3:1 w / w mixture of heptane / ethyl acetate (3 x 47 mL). The collected solid, corresponding to the compound of formula (XI-b), was dried under vacuum at 50°C (118.2 g, 97.5% yield, HPLC 100.0%).

[0146] Example 17: Preparation of ethyl 4-(bromomethyl)-2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-5-(4-nitrophenyl)thiophene-3-carboxylate of formula (XII-b) Ethyl 2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate (XI-b) (99.98 g, 0.204 mol), 2,2'-azobis(isobutyronitrile) (AIBN, 10.03 g, 0.061 mol, 0.3 eq), and N-bromosuccinimide (NBS, 54.51 g, 0.306 mol, 1.5 eq) were mixed with ethyl acetate (500 mL) and deionized water (3.93 mL). The suspension was heated to reflux and stirred at this temperature for 1 h. The reaction mixture was cooled to 20-25 °C, and deionized water (400 mL) was charged along with additional ethyl acetate (100 mL) and brine (55 mL). The aqueous phase was separated. The organic phase was washed with deionized water (200 mL) and brine (55 mL) and concentrated under reduced pressure to an oily mass. Ethyl acetate (100 ml) was added at 50-55° C., the mixture was cooled to 20-25° C., and heptane (400 mL) was added slowly over at least 1 hour. The suspension was stirred at this temperature for 2 hours, then cooled to 0-5° C., stirred at this temperature for 2 hours, and filtered. The cake was washed three times with a 2:1 v / v mixture of heptane / ethanol (3×150 mL). The collected solid corresponds to the compound of formula (XII-b) (98.2 g dry equivalent, 85% yield, HPLC 94.3%).

[0147] Example 18: Preparation of ethyl 4-(bromomethyl)-2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-5-(4-nitrophenyl)thiophene-3-carboxylate of formula (XII-b) Ethyl 2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylate (XI-b) (118 g, 0.241 mol), 2,2'-azobis(isobutyronitrile) (AIBN, 11.8 g, 0.072 mol, 0.3 eq), and N-bromosuccinimide (NBS, 64.3 g, 0.361 mol, 1.5 eq) were mixed with ethyl acetate (589 mL) and deionized water (4.72 mL). The suspension was heated to reflux and stirred at this temperature for 1 hour. The reaction mixture was cooled to 20-30°C, and deionized water (472 mL) was charged along with additional ethyl acetate (118 mL) and brine (83 mL). After stirring for 15 minutes and allowing the phases to settle, the aqueous phase was separated. The organic phase was washed with deionized water (236 mL) and brine (83 mL) and concentrated under reduced pressure to an oily mass. The mixture was flushed twice with ethyl acetate (2 x 118 mL) under reduced pressure. Ethyl acetate (118 mL) was added at 50-55°C, the mixture was cooled to 20-30°C, and heptane (471 mL) was added slowly over at least 1 hour. The suspension was stirred at this temperature for 2 hours, then it was cooled to 0-5°C, stirred at this temperature for 2 hours, and filtered. The cake was washed three times with a 2:1 v / v mixture of heptane / ethanol (3 x 70 mL). The collected solid corresponds to the compound of formula (XII-b) (118.3 g dry equivalent, 86% yield, HPLC 96.5%).

[0148] Example 19: Preparation of ethyl 2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl)thiophene-3-carboxylate oxalate (XX-b. oxalate) Dimethylamine 40% in water (78 mL, 0.615 mol, 5 eq) was dissolved in acetone (280 mL) at 20-30° C. The solution was cooled to 0-10° C., and a suspension of ethyl 4-(bromomethyl)-2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-5-(4-nitrophenyl)thiophene-3-carboxylate (XII-b) (69.98 g dry equivalent, 0.123 mol) in acetone (350 mL) was added slowly at this temperature. The dropping funnel was washed with acetone (70 mL). The mixture was stirred at 0-10° C. for 1 h. The resulting suspension was heated to 30-40° C. and distilled under vacuum at a temperature below 40° C. to a final residue of approximately 110 mL. The residue was cooled to 20-25°C, and ethyl acetate (350 mL) and an aqueous solution of Na2CO3 (13 g in 350 mL) were added. The biphasic mixture was stirred, and the aqueous phase was separated. The organic phase was washed with an aqueous solution of Na2CO3 (13 g in 350 mL), followed by a mixture of deionized water (175 mL) and brine (39 mL). The organic phase was distilled under reduced pressure to a final residue of approximately 110 mL. Ethyl acetate (175 mL) was added, and the resulting mixture was distilled under vacuum to a final residue of 110 mL. Ethyl acetate (175 mL) was added, and the resulting mixture was distilled under vacuum to a final residue of 110 mL. Ethyl acetate (280 mL) was added, followed by activated carbon (3.5 g); the dark mixture was stirred at 20-25°C for 1 hour, filtered, and the filter was washed with ethyl acetate (2 x 140 mL). A mixture of oxalic acid dihydrate (23.24 g) in ethanol (35 mL) was dissolved by heating, and the solution was slowly added to the previously filtered organic solution, rinsing the material with ethyl acetate (70 mL). The suspension was stirred for 4 hours at 20-25°C, cooled to 0-5°C, and stirred for 2 hours. The resulting suspension was filtered, and the cake was washed with ethyl acetate to give the compound of formula (XX-b. oxalate) (48 g dry equivalent, 63%, HPLC 99.6%).

[0149] Example 20: Preparation of ethyl 2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-4-((dimethylamino)methyl)-5-(4-nitrophenyl)thiophene-3-carboxylate oxalate (XX-b. oxalate) Dimethylamine 40% in water (117 g, 1.036 mol, 5 eq) was dissolved in acetone (470 mL) at 20-30° C. The solution was cooled to 0-10° C., and a suspension of ethyl 4-(bromomethyl)-2-((2,6-difluorobenzyl)(methoxycarbonyl)amino)-5-(4-nitrophenyl)thiophene-3-carboxylate (XII-b) (118 g dry equivalent, 0.207 mol) in acetone (588 mL) was added slowly at this temperature. The mixture was stirred at 0-10° C. for 1 hour. The resulting suspension was heated to 30-40° C. and distilled under vacuum at a temperature below 40° C. until near dryness. The residue was cooled to 20-30° C., and ethyl acetate (589 mL) and an aqueous solution of Na2CO3 (11 g in 295 mL) were added. The biphasic mixture was stirred, and the aqueous phase was separated. The organic phase was washed with an aqueous solution of Na2CO3 (11 g in 295 mL) and then with a mixture of deionized water (380 mL) and sodium chloride (33 g). The organic phase was distilled under reduced pressure until nearly dry. The mixture was flushed under reduced pressure twice with ethyl acetate (2 x 295 mL). Ethyl acetate (472 mL) was added, followed by activated carbon (6 g); the dark mixture was stirred at 20-30 °C for 1 hour, filtered, and the filter was washed with ethyl acetate (2 x 235 mL). Oxalic acid dihydrate (39 g) was added onto the previously filtered organic solution. The suspension was stirred at 20-30 °C for 4 hours, cooled to 0-5 °C, and stirred for 2 hours. The resulting suspension was filtered, and the cake was washed with ethyl acetate to give the compound of formula (XX-b. oxalate) (124 g dry equivalent, 93%, HPLC 98.9%).

[0150] Comparative Example 1: Preparation of Relugolix Methyl (2,6-difluorobenzyl)(4-((dimethylamino)methyl)-3-((6-methoxypyridazin-3-yl)carbamoyl)-5-(4-(3-methoxyureido)phenyl)thiophen-2-yl)carbamate (XXVI-b) (0.5 g, 0.76 mmol) was mixed with methanol (4.8 mL) and a 30% methanolic solution of sodium methoxide (0.28 mL, 1.53 mmol, 2 eq), and the mixture was stirred at 20-25° C. for 6 hours. Additional sodium methoxide (0.07 mL, 0.38 mmol, 0.5 eq) was then added, and the mixture was stirred for 18 hours. The solvent was distilled off, and HPLC analysis of the reaction mixture residue showed the presence of relugolix (6.6%), compound XXVI-b (3.4%), impurity A (9.9%), and impurity B (61.8%).

[0151] Comparative Example 2: Preparation of Relugolix Methyl (2,6-difluorobenzyl)(4-((dimethylamino)methyl)-3-((6-methoxypyridazin-3-yl)carbamoyl)-5-(4-(3-methoxyureido)phenyl)thiophen-2-yl)carbamate (XXVI-b) (0.6 g, 0.92 mmol) was mixed with methanol (6 mL) and sodium ethoxide (0.12 g, 1.83 mmol, 2.0 eq), and the mixture was stirred at 20-25° C. for 2 hours. HPLC analysis of the reaction mixture showed the presence of relugolix (48.0%), compound XXVI-b (0.2%), impurity A (10.2%), and impurity B (39.6%).

[0152] Comparative Example 3: Preparation of Relugolix Methyl (2,6-difluorobenzyl)(4-((dimethylamino)methyl)-3-((6-methoxypyridazin-3-yl)carbamoyl)-5-(4-(3-methoxyureido)phenyl)thiophen-2-yl)carbamate (XXVI-b) (0.5 g, 0.76 mmol) was mixed with methanol (6 mL) and sodium t-butoxide (0.15 g, 1.53 mmol, 2.0 eq), and the mixture was stirred at 20-25° C. for 2 hours. HPLC analysis of the reaction mixture showed the presence of relugolix (78.0%), compound XXVI-b (2.4%), impurity A (3.7%), and impurity B (14.6%).

[0153] Table 1 below summarizes the HPLC results measured on samples from the reaction mixture obtained after the cyclization step of the compound of formula (XXVI-b) using different bases. [Table 1]

Claims

1. 1. A process for preparing relugolix of formula (I), or a pharmaceutically acceptable salt thereof, comprising: a) cyclizing the compound of formula (XXVI-b) in the presence of a base selected from the group consisting of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), and 1,1,3,3-tetramethylguanidine (TMG) in the presence of a suitable solvent to obtain relugolix; and 【Chemistry 1】 b) optionally converting said relugolix of formula (I) into a pharmaceutically acceptable salt thereof. The process includes:

2. 2. The process of claim 1, wherein the base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

3. Before step a), i) coupling the compound of formula (XXVII-b.HCl) with methoxyamine or a salt thereof in the presence of a coupling agent and a suitable solvent to give the compound of formula (XXVIII-b); 【Chemistry 2】 ii) hydrolyzing the compound of formula (XXVIII-b) obtained in step (i) to give a compound of formula (XXIX-b), and 【Transformation 3】 iii) coupling said compound of formula (XXIX-b) obtained in step (ii) with 3-amino-6-methoxypyridazine of formula (XVIII) in the presence of a coupling agent and in a suitable solvent to give a compound of formula (XXVI-b). 【Chemistry 4】 The process of any of claims 1-2, further comprising:

4. 4. The process of claim 3, wherein the methoxyamine is in the form of its hydrochloride salt.

5. The process according to any of claims 3-4, wherein the coupling agent in step i) is 1,1'-carbonyldiimidazole (CDI).

6. The process of any of claims 3-5, wherein the hydrolyzing agent in step ii) is sodium hydroxide.

7. The process according to any one of claims 3 to 6, wherein the coupling agent in step iii) is propylphosphonic anhydride (T3P).

8. Before step i), iv) neutralizing the compound of formula (XX-b. oxalate) to obtain a compound of formula (XX-b), and 【Transformation 5】 v) reducing the compound of formula (XX-b) obtained in step (iv) to obtain a compound of formula (XXVII-b), which is further converted to a compound of formula (XXVII-b.HCl), 【Transformation 6】 The process of any one of claims 3-7, further comprising:

9. 9. The process of claim 8, wherein the neutralizing agent in step iv) is potassium carbonate.

10. The process according to any of claims 8-9, wherein said reduction step v) comprises catalytic hydrogenation of the compound of formula (XX-b) with hydrogen in the presence of a catalyst, preferably palladium on charcoal (Pd / C).

11. 11. The process according to any of claims 8-10, wherein converting the compound of formula (XXVII-b) to a compound of formula (XXVII-b.HCl) comprises reacting the compound of formula (XXVII-b) with hydrogen chloride (HCl).

12. Before step iv), vi) reacting the compound of formula (VII) with methyl chloroformate of formula (VIII-b) to give a compound of formula (IX-b); vii) reacting the compound of formula (IX-b) obtained in step (vi) with 2,6-difluorobenzyl bromide of formula (X-a) to give a compound of formula (XI-b); viii) brominating the compound of formula (XI-b) obtained in step (vii) with N-bromosuccinimide (NBS) to obtain a compound of formula (XII-b); ix) reacting the compound of formula (XII-b) obtained in step (viii) with dimethylamine to give a compound of formula (XX-b); and x) reacting the compound of formula (XX-b) obtained in step ix) with oxalic acid to obtain a compound of formula (XX-b. oxalate) 【Transformation 7】 The process of any of claims 8-11, further comprising:

13. Compound of formula (XXVII-b.HCl). 【Transformation 8】

14. Compound of formula (XX-b. oxalate). 【Chemistry 9】

Images