Preparation process and intermediate of relugolix

Abstract

The present invention provides improved processes for the preparation of Rurugolil and intermediates thereof. Rerugolil is prepared by intermediates (M7) and (M8), wherein X is as described herein. The invention also provides another three methods and intermediates for preparing Rurugolil, and 2-amino-4-methyl-5-(4-nitrophenyl) thiophene-3-carboxylic acid ethyl ester (SM1) is used as an initial raw material and is protected by coupling with acyl chloride, hydroxylamine or oxime.

Description

[0001] CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 338,641, filed on May 5, 2022, which is incorporated herein in its entirety for all purposes.

[0003] STATEMENT OF RIGHTS TO INVENTS RESEARCH AND DEVELOPMENT FOUND UNDER FEDERALLY SPONSORED

[0004] not applicable

[0005] Reference to a Sequence Listing, Table or Computer Program Listing Appendix Submitted on CD-ROM

[0006] not applicable Background Art

[0007] Relugoli (brand name Orgovyx) is a gonadotropin-releasing hormone antagonist (GnRH receptor antagonist) drug used to treat prostate cancer in men and uterine fibroids in women.

[0008] The structural formula of relugolix is ​​formula (I):

[0009]

[0010] The chemical name of relugolix is ​​"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" or "N-[4-[1-[(2,6-difluorophenyl)methyl]-5-[(dimethylamino)methyl]-1,2,3,4-tetrahydro-3-(6-methoxy-3-pyridazinyl)-2,4-dioxothieno[2,3-d]pyrimidin-6-yl]phenyl]-N′-methoxyurea". The molecular formula of relugolix is ​​C 29 H 27 F 2 N 7 O 5 S, molecular weight is 623.63Da.

[0011] U.S. Patent No. 7,300,935 discloses a method for preparing relugolix, such as Figure 1 As shown: Figure 1Compound (5) in is prepared in five steps according to Reference Example 17 in WO 2000 / 056739, the steps being as follows: Step (1)—Compound (1) is prepared from nitrophenylacetone by Gewald aminothiophene synthesis; Step (2)—Compound (2) is obtained by forming carbamate using ethyl chloroformate; Step (3)—Compound (3) is generated by alkylation using 2,6-difluorobenzyl chloride; Step (4)—Compound (4) is generated by selectively brominating the 4-methyl group of Compound (3) using NBS / AIBN; and Step (5)—Compound (5) is generated by N-alkylation using (2-methoxyethyl)methylamine. Therefore, as Figure 1 As shown, relugolix is ​​prepared from compound (5) by the following steps: step (6) - compound (5) is subjected to Pd / C hydrogenation reduction to obtain compound (6); step (7) - NH generated in compound (6) 2 The group is condensed with methoxyamine using CDI as a coupling reagent to generate the urea of ​​compound (7); step (8) - compound (7) is hydrolyzed with KOH to generate compound (8); steps (9) and (10) - compound (8) is coupled with 3-amino-6-methoxypyridazine to form the bicyclic skeleton of compound (10), and then compound (9) is cyclized with NaOMe; and step (11) - finally, relugolix is ​​prepared from compound 10 using 1-chloroethyl chloroformate and dimethylamine. Refer to Reference Examples 5-7, 57 and 55 of U.S. Patent No. 7,300,935.

[0012] U.S. Patent No. 9,758,528 discloses another synthetic route for preparing relugolix and its intermediates, such as Figure 2 As shown. It includes directly introducing dimethylamine instead of (2-methoxyethyl)methylamine to generate compound (5'), which is then hydrolyzed to obtain compound (6'). Compound (6') undergoes an amide coupling reaction with 3-amino-6-methoxypyridazine to generate compound (7'), which is then cyclized with NaOMe to generate compound (8'). Compound 8' is reduced by hydrogenation on Pd / C to obtain compound (9'). The NH generated in compound (9') 2 The group is condensed with methoxyamine using CDI as a coupling reagent to obtain relugolix.

[0013] Chinese Patent Application No. 111,333,633 discloses another method for preparing relugolix and its intermediates, such as Figure 3 shown.

[0014] Chinese Patent Application No. 112,321,602 shows another route for preparing relugolix, such as Figure 4 shown. Figure 3 (i.e., the preparation method of CN 111,333,633) and Figure 4 The main difference between the two methods (i.e. the preparation method of CN 112,321,602) lies in the connection sequence of the -NHC(O)NHOMe side chains of the thiophene molecule.

[0015] Despite the above-described processes, there remains a need to develop improved processes for preparing relugolix. The present disclosure addresses this need and provides related advantages. Summary of the invention

[0016] In a first aspect of the present invention, there is provided a method for preparing relugolix or a salt thereof represented by formula (I) through intermediates (M7) and (M8).

[0017]

[0018] The preparation method comprises:

[0019] a) reacting a compound of formula (M7) or a salt thereof with a carbonylation agent in a solvent to prepare a compound of formula (M8) or a salt thereof; and

[0020]

[0021] b) preparing relugolix of formula (I) or its salt from the compound of formula (M8) or its salt;

[0022] wherein the carbonylation agent is carbonyl diimidazole (CDI) or disuccinimidyl carbonate; and

[0023] X is independently imidazolyl or O-succinimidyl; or

[0024] The carbonylating agent is a chloroformate selected from the group consisting of: CH 3 OC(O)Cl, CH 3 CH 2 OC(O)Cl, phenyl-OC(O)Cl, 4-nitrophenyl-OC(O)Cl; and

[0025] X is independently OCH 3 、OCH 2 CH 3 , O-phenyl or O-4-nitrophenyl.

[0026] The second aspect of the present invention provides a method for preparing relugolix or a salt thereof represented by formula (I) from an intermediate (M8), the method comprising:

[0027] b) combining the compound of formula (M8) or a salt thereof with methoxyamine or a salt thereof to obtain relugolix of formula (I), or a salt thereof;

[0028]

[0029] Wherein, X is imidazole, O-succinimide, OCH 3 、OCH 2 CH 3 , O-phenyl or O-4-nitrophenyl.

[0030] The third aspect of the present invention provides a method for preparing relugolix or a salt thereof represented by formula (I) through intermediates (M5) to (M8). The preparation method comprises:

[0031]

[0032] vi) combining the compound of formula (M5) or a salt thereof with 6-methoxypyridazine-3-amine to obtain a compound of formula (M6) or a salt thereof;

[0033]

[0034] vii) hydrogenating the compound of formula (M6), or a salt thereof, with a hydrogen source to obtain a compound of formula (M7), or a salt thereof;

[0035]

[0036] a) combining a compound of formula (M7) or a salt thereof with a carbonylating agent in a solvent to obtain a compound of formula (M8) or a salt thereof; and

[0037]

[0038] b) preparing relugolix or its salt of formula (I) from the compound of formula (M8) or its salt,

[0039] Wherein, the carbonylation agent is carbonyl diimidazole (CDI) or disuccinimidyl carbonate; X is imidazole or O-succinimidyl, or

[0040] The carbonylating agent is a chloroformate selected from the group consisting of: CH 3 OC(O)Cl, CH 3 CH 2 OC(O)Cl, phenyl-OC(O)Cl, 4-nitrophenyl-OC(O)Cl; and X is independently OCH 3 、OCH 2 CH 3 , O-phenyl or O-4-nitrophenyl.

[0041] The fourth aspect of the present invention provides a compound selected from the group consisting of, or a salt thereof,

[0042]

[0043]

[0044] Wherein, in formula (M8), X is imidazole, O-succinimide, OCH 3 、OCH 2 CH 3 , O-phenyl or O-4-nitrophenyl.

[0045] The fifth aspect of the present invention provides a compound selected from the following group, or a salt thereof:

[0046]

[0047] in,

[0048] R is C 1-4 Alkyl, O-NR 1 R 2 or ON=CR 3 R 4 ;

[0049] R 1 and R 2 are independently hydrogen, tert-butyloxycarbonyl (Boc), C 1-4 Alkyl or phenyl; and

[0050] R 3 and R 4 are independently hydrogen, C 1-4 Alkyl or phenyl. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1 The method for preparing relugolix disclosed in US Pat. No 7,300,935 is shown.

[0052] Figure 2 The method for preparing relugolix disclosed in US Pat. No. 9,758,528 is shown.

[0053] Figure 3 The preparation method of relugolix disclosed in Chinese Patent No. 111,333,633 is shown.

[0054] Figure 4 The preparation method of relugolix disclosed in Chinese Patent No. 112,321,602 is shown.

[0055] Figure 5 The preparation of relugolix via synthetic route-1 is shown.

[0056] Figure 6The preparation of relugolix via synthetic route-2 is shown.

[0057] Figure 7 The preparation of relugolix via synthetic route-3 is shown.

[0058] Figure 8 The preparation of relugolix via synthetic route-4 is shown. DETAILED DESCRIPTION

[0059] I.General

[0060] The present invention provides an improved process for preparing relugolix and its intermediates. Figure 5-8 Prepared by the synthetic routes 1-4 in, through intermediates (M5) to (M8), especially intermediates (M7) and (M8). Therefore, intermediate (M7) reacts with a carbonylating agent (such as CDI) to generate intermediate (M8), such as intermediate (M8-1). After intermediate (M8) (such as intermediate (M8-1)) reacts with methoxyamine hydrochloride or methoxyamine free base, relugolix is ​​obtained. The present invention also provides three other routes (synthetic routes 2, 3 and 4) for preparing relugolix and their intermediates, wherein 2-amino-4-methyl-5-(4-nitrophenyl)thiophene-3-carboxylic acid ethyl ester (SM1) is used as a starting material and is protected by coupling with an acyl chloride (such as acetyl chloride), a hydroxylamine (such as N-tert-butoxycarbonyl-N-methylhydroxylamine) or an oxime (such as benzophenone oxime). Therefore, as Figure 6-8 As shown, relugolix is ​​prepared starting from intermediates (ie, M1'-1 to M'4-1, M1'-2 to M4'-2 or M1'-3 to M4'-3) via intermediates (M5) to (M8).

[0061] II. Definitions

[0062] Unless otherwise indicated, in all chemical formulae of the present invention (e.g., claims, examples and Figure 1-8 In the chemical formula of The substituent represented by refers to methyl.

[0063] "Salt" refers to an acid salt or base salt of a compound used in the method of the present invention. Salts useful in the present invention include, but are not limited to, phosphates, sulfates, chlorides, bromides, carbonates, nitrates, acetates, mesylates, sodium salts, potassium salts, and calcium salts. Examples of pharmaceutically acceptable salts include mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, quaternary ammonium salts (methyl iodide, ethyl iodide, etc.) salts, and alkali metal or alkaline earth metal salts (sodium, potassium, calcium, etc.). It should be understood that pharmaceutically acceptable salts are non-toxic. For more information on suitable pharmaceutically acceptable salts, reference may be made to Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pennsylvania, 1985, which is incorporated herein by reference.

[0064] "Base" refers to a functional group that can deprotonate water to produce hydroxide ions. Useful bases in the present invention include organic bases and inorganic bases. Exemplary organic bases include tertiary amines and basic alkoxides, as defined herein. Exemplary inorganic bases include basic bicarbonates, basic carbonates, and basic hydroxides, as defined herein.

[0065] "Tertiary amine" refers to an amine having the formula N(R) 3 Compounds wherein the R groups may be alkyl, aryl, heteroalkyl, heteroaryl, etc., or two R groups together form an N-linked heterocycloalkyl. The R groups may be the same or different. Non-limiting examples of tertiary amines include triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, dimethylaniline, diethylaniline, 1,8-bis(dimethylamino)naphthalene, quinuclidine, and 1,4-diazabicyclo[2.2.2]octane (DABCO).

[0066] The "amidino compound" of the present invention refers to a class of compounds including, but not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

[0067] "Alkaline bicarbonate" refers to a class of compounds consisting of an alkali metal cation and a bicarbonate anion (HCO 3 - ) compounds. Alkali carbonates useful in the present invention include lithium bicarbonate (LiHCO 3 ), sodium bicarbonate (NaHCO 3 ), potassium bicarbonate (KHCO 3 ) and cesium bicarbonate (CsHCO 3 ).

[0068] "Alkaline carbonate" refers to a class of carbonates composed of alkali metal cations and carbonate anions (CO 3 2-) compounds. The alkaline carbonates suitable for the present invention include lithium carbonate (Li 2 CO 3 ), sodium carbonate (Na 2 CO 3 ), potassium carbonate (K 2 CO 3 ) and cesium carbonate (Cs 2 CO 3 ).

[0069] "Strong base" includes basic alkoxides as defined herein.

[0070] "Alkaline hydroxide" refers to an alkali metal cation and a hydroxide anion (OH - The alkaline hydroxides useful in the present invention include lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium hydroxide (CsOH) and calcium hydroxide (Ca(OH) 2 ).

[0071] "Alkaline alkoxide" refers to a class of compounds consisting of an alkali metal cation and an alkoxide anion (RO - )(where R is C 1-4 The basic alkoxides useful in the present invention include, but are not limited to, sodium isopropoxide, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, and potassium isopropoxide.

[0072] "Combining" refers to the process of combining at least two different substances to react with each other. However, it should be understood that the reaction product produced thereby can be produced directly from the reaction between the added reagents, or from one or more intermediate products of the added reagents produced in the reaction mixture.

[0073] "Solvent" refers to a substance, such as a liquid, that can dissolve a solute. Solvents can be polar or nonpolar, and can be protic or aprotic. Polar solvents generally have a dielectric constant greater than about 5 or a dipole moment greater than about 1.0, while nonpolar solvents have a dielectric constant less than about 5 or a dipole moment less than about 1.0. Protic solvents are characterized by having removable protons, such as hydroxyl or carboxyl groups. Aprotic solvents do not have such groups. Representative polar protic solvents include alcohols (methanol, ethanol, propanol, isopropanol, etc.), acids (formic acid, acetic acid, etc.), and water. Representative polar protic solvents include dichloromethane, chloroform, tetrahydrofuran, diethyl ether, acetone, ethyl acetate, dimethylformamide, dimethylacetamide, acetonitrile, and dimethyl sulfoxide. Representative polar aprotic solvents include alkanes (pentane, hexane, etc.), cycloalkanes (cyclopentane, cyclohexane, etc.), benzene, toluene, diethyl ether, and 1,4-dioxane. Other solvents are also suitable for use in the context of the present invention.

[0074] "Carbonylating agent" refers to a reagent that can add a carbonyl group -C(O)- to a compound. Representative carbonylating agents include, but are not limited to, phosgene or phosgene equivalents (such as diphosgene, triphosgene, carbonyldiimidazole (CDI) and disuccinimidyl carbonate) or chloroformate (such as CH 3 OC(O)Cl, CH 3 CH 2 OC(O)Cl, phenyl-OC(O)Cl, 4-nitrophenyl-OC(O)Cl or succinimidyl chloroformate).

[0075] A "trifluoroacetylating agent" is a reagent that can convert a trifluoroacetyl group -C(O)CF 3 Reagents added to the compound. Representative trifluoroacetylating agents include, but are not limited to, trifluoroacetic anhydride (TFAA) and trifluoroacetyl chloride.

[0076] "Brominating agent" refers to an agent capable of adding a bromo-Br group to a compound. Representative brominating agents include, but are not limited to, bromine, N-bromosuccinimide, triphenylphosphonium dibromide, tetrabutylammonium tribromide, trimethylphenylammonium tribromide, N-bromoacetamide, pyridinium tribromide, dibromodimethylhydantoin, tribromoisocyanuric acid, N-bromosaccharin, and 1,2-dibromo-1,1,2,2-tetrachloroethane.

[0077] "About" refers to a range of values ​​including the specified value that one of ordinary skill in the art would consider to be reasonably similar to the specified value. In certain embodiments, the term "about" refers to within a standard deviation using measurements generally accepted in the art. In certain embodiments, "about" refers to a range extending to + / -10% of the specified value. In certain embodiments, "about" refers to the specified value.

[0078] Preparation method

[0079] In a first aspect of the present invention, there is provided a method for preparing relugolix or a salt thereof represented by formula (I) through intermediates (M7) and (M8).

[0080]

[0081] The preparation method comprises:

[0082] a) combining the compound of formula (M7) or its salt with a carbonylation agent in a solvent to prepare a compound of formula (M8) or its salt; and

[0083]

[0084]

[0085] b) preparing relugolix of formula (I) or its salt from the compound of formula (M8) or its salt;

[0086] wherein the carbonylation agent is carbonyl diimidazole (CDI) or disuccinimidyl carbonate; and

[0087] X is independently imidazolyl or O-succinimidyl; or

[0088] The carbonylating agent is a chloroformate selected from the group consisting of: CH 3 OC(O)Cl, CH 3 CH 2 OC(O)Cl, phenyl-OC(O)Cl, 4-nitrophenyl-OC(O)Cl; and X is independently OCH 3 、OCH 2 CH 3 , O-phenyl or O-4-nitrophenyl.

[0089] The second aspect of the present invention provides a method for preparing relugolix or a salt thereof represented by formula (I) from an intermediate (M8). The preparation method comprises:

[0090] b) combining the compound of formula (M8) or a salt thereof with methoxyamine or a salt thereof to obtain relugolix of formula (I) or a salt thereof;

[0091]

[0092] Wherein, X is imidazole, O-succinimide, OCH 3 、OCH 2 CH 3 , O-phenyl or O-4-nitrophenyl.

[0093] In some embodiments, step a) further comprises a base which is a tertiary amine and / or an amino compound. In some embodiments, the tertiary amine is triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, dimethylaniline, diethylaniline, 1,8-bis(dimethylamino)naphthalene, quinuclidine, 1,4-diazabicyclo[2.2.2]octane (DABCO) or a mixture thereof. In some embodiments, the amidine compound is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) or a mixture thereof. In some embodiments, step a) further comprises 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

[0094] Regarding step a), in some embodiments, the carbonylating agent is carbonyl diimidazole (CDI) or disuccinimidyl carbonate. In some embodiments, the carbonylating agent is carbonyl diimidazole (CDI). In some embodiments, the carbonylating agent is disuccinimidyl carbonate. In some embodiments, the carbonylating agent is a chloroformate selected from the group consisting of: CH 3 OC(O)Cl, CH 3 CH 2 OC(O)Cl, phenyl-OC(O)Cl or 4-nitrophenyl-OC(O)Cl.

[0095] In some embodiments, the carbonylating agent is carbonyldiimidazole (CDI) or disuccinimidyl carbonate; X in formula (M8) is imidazole or O-succinimidyl. In some embodiments, the carbonylating agent is carbonyldiimidazole (CDI); X in formula (M8) is imidazole. In some embodiments, the carbonylating agent is disuccinimidyl carbonate; X in formula (M8) is O-succinimidyl. In some embodiments, the carbonylating agent is a chloroformate selected from the group consisting of: CH 3 OC(O)Cl, CH 3 CH 2 OC(O)Cl, phenyl-OC(O)Cl or 4-nitrophenyl-OC(O)Cl; X in formula (M8) is OCH 3 、OCH 2 CH 3 , O-phenyl or O-4-nitrophenyl.

[0096] In some embodiments, X in formula (M8) is an imidazole group; the compound of formula (M8) is a compound represented by formula (M8-1), or a salt thereof:

[0097]

[0098] In some embodiments, the carbonylating agent is carbonyldiimidazole (CDI); X in formula (M8) is imidazole; the compound of formula (M8) is a compound of formula (M8-1), or a salt thereof.

[0099] About step a), in some embodiments, the solvent is an aprotic solvent. Suitable aprotic solvents include tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (2-MeTHF), ethyl acetate (EtOAc), dimethylformamide (DMF), dichloromethane (DCM), toluene, dimethylacetamide (DMAc), isopropyl acetate (IPAc), acetonitrile or a mixture thereof. In some embodiments, the solvent is an aprotic solvent selected from the group consisting of tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (2-MeTHF), ethyl acetate (EtOAc), dimethylformamide (DMF), dichloromethane (DCM), toluene, dimethylacetamide (DMAc), isopropyl acetate (IPAc), acetonitrile or a mixture thereof. In some embodiments, the solvent is tetrahydrofuran.

[0100] Regarding step b), in some embodiments, step b) is performed without separating the compound of formula (M8) or its salt. In some embodiments, the compound of formula (M8) or its salt is prepared in situ. In some embodiments, step b) is performed without separating the compound of formula (M8-1) or its salt. In some embodiments, the compound of formula (M8-1) or its salt is prepared in situ.

[0101] Generally, step b) can be performed by combining a compound of formula (M8) or a salt thereof (e.g., formed in step a)) and methoxyamine or a salt thereof in any order. In some embodiments, relugolix or a salt thereof of formula (I) is formed by: 1) adding a compound of formula (M8) or a salt thereof (e.g., formed in step a)) to methoxyamine or a salt thereof; or 2) adding methoxyamine or a salt thereof to a compound of formula (M8) or a salt thereof (e.g., formed in step a)).

[0102] In some embodiments, the mixture of step a) comprising a compound of formula (M8) or a salt thereof is added to methoxyamine or a salt thereof to form relugolix or a salt thereof of formula (I). In some embodiments, the mixture of step a) comprising a compound of formula (M8) or a salt thereof is added to a solution of methoxyamine or a salt thereof to form relugolix or a salt thereof of formula (I). In some embodiments, the solution of methoxyamine or a salt thereof is formed in the same solvent as step a). In some embodiments, the mixture of step a) comprises a compound of formula (M8-1) or a salt thereof and THF; the solution of methoxyamine or a salt thereof comprises methoxyamine and THF.

[0103] In some embodiments, methoxylamine or a salt thereof is added to the mixture of step a) comprising a compound of formula (M8) or a salt thereof to form relugolix or a salt thereof of formula (I). In some embodiments, methoxylamine hydrochloride is added to the mixture of step a) comprising a compound of formula (M8-1) or a salt thereof to form relugolix or a salt thereof of formula (I).

[0104] Generally, step a) can be performed at any suitable temperature. In some embodiments, step a) is performed at a temperature of 20° C. to 50° C. In some embodiments, step a) is performed at room temperature.

[0105] In general, step b) can be performed at any suitable temperature. In some embodiments, step b) is performed at a temperature of 20°C to 50°C. In some embodiments, step b) is performed at room temperature. In some embodiments, step b) is performed in THF at room temperature.

[0106] In some embodiments, the yield of relugolix isolated by two steps (i.e., steps a) and b) is at least about 85% or 90%. In some embodiments, the yield of relugolix isolated by steps a) and b) is at least about 90% (e.g., 92.9%). In some embodiments, the yield of relugolix isolated by steps a) and b) is about 92.9%.

[0107] In some embodiments, before step a), the preparation method further comprises steps vi) to vii):

[0108]

[0109] vi) combining the compound of formula (M5) or a salt thereof with 6-methoxypyridazine-3-amine to obtain a compound of formula (M6) or a salt thereof;

[0110]

[0111] vii) hydrogenating the compound of formula (M6) or a salt thereof with a hydrogen source to prepare a compound of formula (M7) or a salt thereof.

[0112]

[0113] The third aspect of the present invention provides a method for preparing relugolix or a salt thereof represented by formula (I) through intermediates (M5) to (M8). The preparation method comprises:

[0114]

[0115] vi) combining the compound of formula (M5) or a salt thereof with 6-methoxypyridazine-3-amine to obtain a compound of formula (M6) or a salt thereof;

[0116]

[0117] vii) hydrogenating the compound of formula (M6) or a salt thereof with a hydrogen source to prepare a compound of formula (M7) or a salt thereof;

[0118]

[0119] a) combining a compound of formula (M7) or a salt thereof with a carbonylating agent in a solvent to obtain a compound of formula (M8) or a salt thereof; and

[0120]

[0121] b) converting the compound of formula (M8) or its salt to obtain relugolix or its salt represented by formula (I);

[0122] Wherein, the carbonylation agent is carbonyldiimidazole (CDI) or disuccinimidyl carbonate; X is imidazole or O-succinimidyl, or

[0123] The carbonylating agent is a chloroformate selected from the group consisting of: CH 3 OC(O)Cl, CH 3 CH 2 OC(O)Cl, phenyl-OC(O)Cl, 4-nitrophenyl-OC(O)Cl; and X is independently OCH 3 、OCH 2 CH 3 , O-phenyl or O-4-nitrophenyl.

[0124] Regarding step vi), in some embodiments, step vi) is carried out in an aprotic solvent using 6-methoxypyridazine-3-amine and an amide coupling reagent. In some embodiments, step vi) is carried out in DCM using 6-methoxypyridazine-3-amine and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI). In some embodiments, step vi) is carried out in DCM at room temperature. In some embodiments, the yield of the isolated compound of formula (M6) is greater than 90% (e.g., 91%).

[0125] About step vii), in some embodiments, the hydrogen source is hydrogen. In some embodiments, step vii) is carried out with hydrogen exceeding 10% Pd / C in alcohols (such as MeOH). In some embodiments, step vii) is carried out with hydrogen exceeding 10% Pd / C in methanol (MeOH). In some embodiments, step vii) is carried out with hydrogen exceeding 10% Pd / C in methanol (MeOH) in the presence of acid (such as 32% HCl). In some embodiments, step vii) is carried out with hydrogen exceeding 10% Pd / C in the presence of hydrochloric acid (such as 32% HCl) in methanol (MeOH). In some embodiments, step vii) is carried out at room temperature. In some embodiments, the compound of formula (M7) is isolated with a yield greater than 95% (e.g., 96%).

[0126] Steps a) and b) are as described herein.

[0127] IIIA. Synthetic Route-1

[0128] Relugoli or its salt represented by formula (I) can be prepared by the following nine steps:

[0129] Steps i) to v) obtaining intermediate (M5) via intermediates (M1) to (M4);

[0130] Steps vi) and vii) provide intermediate (M7) via intermediates (M5) and (M6); and

[0131] Finally, steps a) and b) provide relugolix or its salt represented by formula (I) via intermediates (M7) and (M8).

[0132] Figure 5 A representative synthetic scheme for this route is shown.

[0133] In some embodiments, before step a), the preparation method further comprises steps i) to vii):

[0134]

[0135] i) combining the compound of formula (SM1) or a salt thereof with 2,6-difluorobenzyl bromide or 2,6-difluorobenzyl chloride to obtain a compound of formula (M1) or a salt thereof;

[0136]

[0137] ii) combining the compound of formula (M1) or a salt thereof with a trifluoroacetylating agent to obtain a compound of formula (M2) or a salt thereof;

[0138]

[0139] iii) combining the compound of formula (M2), or a salt thereof, with a brominating agent to obtain a compound of formula (M3), or a salt thereof;

[0140]

[0141] iv) combining the compound of formula (M3) or its salt with dimethylamine or its salt to obtain the compound of formula (M4) or its salt;

[0142]

[0143] v) hydrolyzing the compound of formula (M4) or its salt with a base to obtain the compound of formula (M5) or its salt;

[0144]

[0145] vi) combining the compound of formula (M5), or a salt thereof, with 6-methoxypyridazine-3-amine to obtain a compound of formula (M6), or a salt thereof; and

[0146]

[0147] vii) hydrogenating the compound of formula (M6), or a salt thereof, with a hydrogen source to obtain a compound of formula (M7), or a salt thereof;

[0148]

[0149] Regarding step i), in some embodiments, step i) is carried out in an aprotic solvent using 2,6-difluorobenzyl bromide. In some embodiments, step i) is carried out in dimethylacetamide (DMAc) using 2,6-difluorobenzyl bromide. In some embodiments, step i) is carried out at a temperature of about 80° C. In some embodiments, the yield of the isolated compound of formula (M1) is greater than 90% (e.g., about 94%).

[0150] About step ii), in some embodiments, step ii) is carried out in a non-protonic solvent with a trifluoroacetylating agent and a tertiary amine. In some embodiments, the trifluoroacetylating agent is trifluoroacetic anhydride (TFAA). In some embodiments, step ii) is carried out in dichloromethane (DCM) with trifluoroacetic anhydride (TFAA) and triethylamine (TEA). In some embodiments, step ii) is carried out at a temperature of about 25°C. In some embodiments, the yield of the isolated compound of formula (M2) is greater than 90% (e.g., about 95%).

[0151] About step iii), in some embodiments, step iii) is carried out in a non-protonic solvent with a brominating agent and a free radical initiator (such as azobisisobutyronitrile). In some embodiments, the brominating agent is N-bromosuccinimide. In some embodiments, step iii) is carried out with N-bromosuccinimide and azobisisobutyronitrile (AIBN) in a mixture of ethyl acetate (EtOAc) and trifluorotoluene. In some embodiments, step iii) is carried out at a temperature of about 70°C. In some embodiments, the compound of formula (M3) is isolated with a yield of about 90%.

[0152] Regarding step iv), in some embodiments, step iv) is carried out in an aprotic solvent using dimethylamine hydrochloride or dimethylamine and a tertiary amine. In some embodiments, step iv) is carried out in dimethylacetamide (DMAc) using dimethylamine hydrochloride and trimethylamine. In some embodiments, step iv) is carried out at about 0°C to room temperature. In some embodiments, the compound of formula (M4) is converted into its hydrochloride (HCl). In some embodiments, the hydrochloride of the compound of formula (M4) is isolated with a yield greater than 95% (e.g., 98%).

[0153] About step v), in some embodiments, step v) is carried out with an alkaline hydroxide in alcohol. In some embodiments, the alkaline hydroxide is sodium hydroxide. In some embodiments, sodium hydroxide is an aqueous solution. In some embodiments, step v) adopts an aqueous solution of sodium hydroxide in ethanol (EtOH). In some embodiments, step v) is carried out at a temperature of about 70°C to about 80°C. In some embodiments, the yield of the isolated compound of formula (M5) is greater than 90% (e.g., 92%).

[0154] Regarding step vi), in some embodiments, step vi) is carried out in an aprotic solvent using 6-methoxypyridazine-3-amine and an amide coupling reagent. In some embodiments, step vi) is carried out in DCM using 6-methoxypyridazine-3-amine and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI). In some embodiments, step vi) is carried out in DCM at room temperature. In some embodiments, the yield of the isolated compound of formula (M6) is greater than 90% (e.g., 91%).

[0155] About step vii), in some embodiments, the hydrogen source is hydrogen. In some embodiments, step vii) is carried out with hydrogen exceeding 10% Pd / C in alcohols (such as MeOH). In some embodiments, step vii) is carried out with hydrogen exceeding 10% Pd / C in methanol (MeOH). In some embodiments, step vii) is carried out with hydrogen exceeding 10% Pd / C in methanol (MeOH) in the presence of acid (such as 32% HCl). In some embodiments, step vii) is carried out with hydrogen exceeding 10% Pd / C in the presence of hydrochloric acid (such as 32% HCl) in methanol (MeOH). In some embodiments, step vii) is carried out at room temperature. In some embodiments, compound of formula (M7) is isolated with a yield greater than 95% (such as 96%).

[0156] In one aspect, the present invention provides a preparation method, preparing a compound of formula (M1) according to step i), preparing a compound of formula (M2) according to step ii) or steps i)-ii), preparing a compound of formula (M3) according to step iii) or steps i)-iii), preparing a compound of formula (M4) according to step iv) or steps i)-iv), preparing a compound of formula (M5) according to step v) or steps i)-v), preparing a compound of formula (M6) according to step vi) or steps i)-vi), or preparing a compound of formula (M7) according to step vii) or steps i)-vii), each of which is defined and described herein.

[0157] In another aspect, the present invention provides a process for preparing relugolix or a salt thereof of formula (I) according to steps i) to vii) and steps a) and b), wherein each step is defined and described herein.

[0158] IIIB. Synthetic Route-2, Route-3 and Route-4

[0159] Relugoli or its salt represented by formula (I) can be prepared by the following nine steps:

[0160] ● Steps i-1) to v-1) via intermediate (M1') to (M4') to obtain intermediate (M5)

[0161] - Steps vi) and vii) provide intermediate (M7) via intermediates (M5) and (M6); and

[0162] ●Finally, steps a) and b) provide relugolix or its salt represented by formula (I) through intermediates (M7) and (M8).

[0163] Figure 6-8 Representative synthetic schemes for these routes are shown.

[0164] In some embodiments, before step vi), the preparation method further comprises steps i-1) to vii-1):

[0165]

[0166] i-1) Compound (SM1) or its salt and C 1-4 Compound SM2 of alkyl-C(O)Cl, or a combination of a carbonylating agent and a hydroxylamine or oxime of compound SM2, to obtain a compound of formula (M1′), or a salt thereof;

[0167]

[0168] ii-1) combining the compound of formula (M') or a salt thereof with 2,6-difluorobenzyl bromide or 2,6-difluorobenzyl chloride to obtain a compound of formula (M2') or a salt thereof;

[0169]

[0170] iii-1) brominating the compound of formula (M2') or its salt with a brominating agent to obtain the compound of formula (M3') or its salt;

[0171]

[0172] iv-1) combining the compound of formula (M3'), or a salt thereof, with dimethylamine or a salt thereof to obtain a compound of formula (M4'), or a salt thereof;

[0173]

[0174] v-1) hydrolyzing the compound of formula (M4') or its salt with a base to obtain the compound of formula (M5) or its salt;

[0175]

[0176] in,

[0177] The hydroxylamine is HO-NR 1 R 2 As shown; and the oxime is HO-N=CR 3 R 4 As shown;

[0178] In formulas M1' to M4', R is C 1-4 Alkyl, O-NR 1 R 2 or ON=CR 3 R 4 ;

[0179] R 1 and R 2 are independently hydrogen, tert-butyloxycarbonyl (Boc), C 1-4 Alkyl or phenyl; and

[0180] R 3 and R 4 are independently hydrogen, C 1-4 Alkyl or phenyl.

[0181] Regarding step i-1), in some embodiments, compound SM2 is C 1-4 Alkyl-C(O)Cl. In some embodiments, compound SM2 is acetyl chloride.

[0182] Regarding step i-1), in some embodiments, compound SM2 is hydroxylamine or oxime; the carbonylating agent is carbonyldiimidazole (CDI), disuccinimidyl carbonate, CH 3 OC(O)Cl, CH 3 CH 2 In some embodiments, the carbonylating agent is carbonyldiimidazole (CDI) or disuccinimidyl carbonate. In some embodiments, the carbonylating agent is carbonyldiimidazole (CDI). In some embodiments, the hydroxylamine is N-tert-butyloxycarbonyl-N-methylhydroxylamine. In some embodiments, the oxime is benzophenone oxime.

[0183] Regarding step ii-1), in some embodiments, step ii-1) is performed with 2,6-difluorobenzyl bromide in dimethylacetamide (DMAc).

[0184] Regarding step iii-1), in some embodiments, the brominating agent is N-bromosuccinimide. In some embodiments, step iii-1) is carried out with N-bromosuccinimide and azobisisobutyronitrile in a solvent including ethyl acetate (EtOAc).

[0185] Regarding step iv-1), in some embodiments, step iv-1) is performed in dimethylacetamide (DMAc) using dimethylamine or dimethylamine hydrochloride and triethylamine.

[0186] Regarding step v-1), in some embodiments, step v-1) is performed in ethanol (EtOH) using sodium hydroxide.

[0187] Regarding step i-1), in some embodiments, the compound SM is C 1-4 Alkyl-C(O)Cl; the compound of any one of formulas (M1') to (M4') is a compound represented by any one of formulas (M1'-1) to (M4'-1), or a salt thereof:

[0188]

[0189] Regarding step i-1), in some embodiments, compound SM is acetyl chloride, and the compound represented by any one of formulas (M1'-1) to (M4'-1) is a compound represented by any one of formulas (M1'-1a) to (M4'-1a), or a salt thereof:

[0190]

[0191] Regarding step i-1), in some embodiments, compound SM2 is hydroxylamine or oxime; the compound of any one of formulas (M1') to (M4') is a compound represented by any one of formulas (M1'-2) to (M4'-2) and (M1'-3) to (M4'-3), or a salt thereof:

[0192]

[0193]

[0194] Among them, R 1 and R 2 are independently hydrogen, tert-butyloxycarbonyl (Boc), C 1-4 alkyl or phenyl; and R 3 and R 4 are independently hydrogen, C 1-4 Alkyl or phenyl.

[0195] Regarding step i-1), in some embodiments, the hydroxylamine is N-tert-butyloxycarbonyl-N-methylhydroxylamine; the compound of any one of formulas (M1'-2) to (M4'-2) is a compound represented by any one of formulas (M1'-2a) to (M4'-2a), or a salt thereof:

[0196]

[0197] Regarding step i-1), in some embodiments, the oxime is benzophenone oxime; the compound of any one of formulas (M1'-3) to (M4'-3) is a compound represented by any one of formulas (M1'-3a) to (M4'-3a), or a salt thereof:

[0198]

[0199] IV. Compounds

[0200] The fourth aspect of the present invention provides a compound selected from the following group, or a salt thereof:

[0201]

[0202]

[0203] Wherein, in formula (M8), X is imidazole, O-succinimide, OCH 3 、OCH 2 CH 3 , O-phenyl or O-4-nitrophenyl.

[0204] The fifth aspect of the present invention provides a compound selected from the following group, or a salt thereof:

[0205]

[0206] Where R is C 1-4 Alkyl, O-NR 1 R 2 or ON=CR 3 R 4 ;

[0207] R 1 and R 2 are independently hydrogen, tert-butyloxycarbonyl (Boc), C 1-4 Alkyl or phenyl; and

[0208] R 3 and R 4 are independently hydrogen, C 1-4 Alkyl or phenyl.

[0209] In some embodiments, the compound, or a salt thereof, is selected from the group consisting of:

[0210]

[0211]

[0212] V. Examples

[0213] Example 1: Preparation of relugolix via Synthesis Route-1

[0214] Figure 5 A synthetic route-1 for the preparation of relugolix is ​​described.

[0215] In synthetic route-1, SM1 is alkylated with 2,6-difluorobenzyl chloride to give M1, which is then amidated with TFAA to give M2. In the presence of AIBN as a free radical initiator, M2 reacts with NBS to selectively brominate the methyl group to give M3. Then, using triethylamine as a base, dimethylamine hydrochloride is used to replace the bromine group in M3 to give M4. M4 can be hydrolyzed with NaOH to give M5, which is then coupled with 3-amino-6-methoxypyridazine to give M6. The nitro group in M6 can be hydrogenated with Pd / C to give M7. The NH in M7 is activated by CDI / DBU. 2 The group is then cyclized to give M8-1. Finally, relugolix can be synthesized by reacting M8-1 with methoxyamine hydrochloride.

[0216] Preparation of M1

[0217]

[0218] In a suitable reactor, SM1 (10.0 g), 2,6-difluorobenzyl bromide (8.12 g) and DMAc (100 ml) were added. The resulting mixture was heated to 80 °C and then stirred overnight. After the reaction was completed, it was cooled to room temperature and then NaHCO was added. 3 The resulting slurry was stirred at room temperature for 1 hour. After filtration, the wet cake was washed with H 2 O, and then dried under vacuum at 60 °C to obtain M1 (13.3 g, yield 94%).

[0219] Preparation of M2

[0220]

[0221] In a suitable reactor, M1 (5.0 g), DCM (50 ml) and triethylamine (4.5 ml) were added. The mixture was cooled to 0-10°C. TFAA (6.80 g) was added slowly. The resulting mixture was warmed to room temperature and then stirred for 12 hours. After completion, NaHCO3 The solution was stirred at room temperature for 1 hour. After phase separation, the organic layer was washed with H 2 O (50 mL) three times, then the solvent was exchanged with n-heptane to 3 volumes. The resulting slurry was filtered through a Buchner funnel. The wet cake was washed with n-heptane (15 mL) and then dried under vacuum at 50° C. to give M2 (5.83 g, 95% yield).

[0222] Preparation of M3

[0223]

[0224] M2 (10.0 g), EtOAc (40 ml) and trifluorotoluene (40 ml) were added to a suitable reactor. N-bromosuccinimide (4.21 g) and AIBN (0.31 g) were then added. The reaction mixture was heated to 70 °C and then stirred for 4 hours. After the reaction was completed, it was cooled to room temperature and quenched with H 2 The mixture was stirred for 1 h at 4 ℃ for 2 h. The mixture was stirred for 1 h. The mixture was stirred for 2 h. The mixture was stirred for 3 h. The mixture was stirred for 2 h. The mixture was stirred for 3 h. The mixture was stirred for 2 h. The mixture was stirred for 3 h. The mixture was stirred for 4 ...3 h. The mixture was stirred for 2 h. The mixture was stirred for 3 h. The mixture was stirred for 4 h.

[0225] Preparation of M4

[0226]

[0227] M3 (12.0 g), dimethylamine hydrochloride (2.45 g) and DMAc (72 ml) were added to a suitable reactor. The mixture was cooled to 0-10°C. Triethylamine (5.28 g) was added dropwise. The resulting mixture was heated to room temperature and then stirred for 12 hours. After stirring, IPAc (96 mL) and H 2 O (48 mL). After phase separation, the organic layer was washed with H 2 O (48 mL), NaHCO 3 Aqueous solution (48 mL) and H 2 The mixture was concentrated to 3 volumes by solvent exchange with toluene. n-heptane (36 mL) was added. The slurry was cooled to 0-10° C. and then stirred for 1 hour. After filtration, the wet cake was washed with toluene / n-heptane (30 mL, v / v=1 / 1) and then dried under vacuum at 45° C. to obtain M4 hydrochloride (11.85 g, 98% yield).

[0228] Preparation of M5

[0229]

[0230] In a suitable reactor, add M4 hydrochloride (2.0 g) and EtOH (20 ml). Heat the mixture to 55-60°C and then add 10% NaOH (5.9 mL). Heat the mixture to 70-80°C and then stir overnight. After completion, cool the solution to room temperature and then add H 2 O (36 mL). The solution was neutralized to pH 5-6 with 1N HCl. The resulting suspension was cooled to 0-10°C and then stirred for 1 hour. After filtration, the wet cake was washed with H 2 O (10 mL), and then dried in vacuo at 60 °C to afford M5 (1.36 g, yield 92%).

[0231] Preparation of M6

[0232]

[0233] M5 (5.00 g), 3-amino-6-methoxypyridazine (1.70 g), EDCI hydrochloride (4.29 g) and dichloromethane (50 ml) were added to a suitable reactor. The mixture was stirred at room temperature overnight. After completion, H 2 O (100 mL). The mixture was stirred at room temperature for 1 hour. After phase separation, the organic layer was washed with H 2 O (15 mL) twice and then concentrated to 3 volumes by solvent exchange with IPA. To the resulting suspension was added H 2 O (30 mL). The mixture was stirred at room temperature for 1 hour. After filtration, the wet cake was washed with IPA / H 2 O (15 mL, v / v = 1 / 2), and then dried in vacuo at 50 °C to afford M6 (5.64 g, yield 91%).

[0234] Preparation of M7

[0235]

[0236] M6 (1.29 g) and MeOH (15 ml) were added to a suitable reactor. 32% HCl (0.64 mL) was added followed by Pd / C (10 wt%). The mixture was stirred at room temperature overnight under a hydrogen pressure of 0.1-0.2 MPa. After completion, the mixture was filtered through a Buchner funnel filled with diatomaceous earth. The diatomaceous earth was washed with MeOH (4 mL). The combined filtrate was concentrated to 5 volumes and then NaHCO was added. 3 To the resulting suspension was added H 2O (6 mL). The mixture was stirred at room temperature for 1 hour. After filtration, the wet cake was washed with MeOH / H 2 O (4 mL, v / v = 1 / 3), and then dried in vacuo at 55 °C to afford M7 (1.17 g, yield 96%).

[0237] Preparation of Relugoli

[0238]

[0239] M7 (27.0 g), CDI (27.5 g) and THF (216 ml) were added to a suitable reactor, followed by DBU (9.47 g). The mixture was stirred at room temperature for 3 hours. After completion, methoxyamine hydrochloride (21.6 g) and THF (162 ml) were added to another reactor, followed by triethylamine (20.9 g). The above M8-1 solution was slowly added to the reactor containing methoxyamine. THF (54 mL) was added for rinsing. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, solvent replacement was performed with EtOAc, and the reaction solution was concentrated to 5 volumes. EtOAc (270 mL) was added, followed by 5% NaHCO 3 (405 mL). The resulting mixture was stirred at room temperature for 30 minutes. The resulting suspension was filtered through a Buchner funnel to retain the solid. The organic layer was washed with H 2 The organic layer was combined with the above solid, and then solvent replacement was performed with MeOH and concentrated to 5 volumes. The suspension was heated to reflux and then stirred for 1 hour. The suspension was cooled to room temperature and then stirred for 2 hours. After filtration, the wet cake was washed with MeOH / H 2 The mixture was washed with 4% paraformaldehyde (2% HCl, 0.1% NaOH) and then dried in vacuo at 45°C to give relugolix (29.8 g, yield 92.9%).

[0240] Example 2: Preparation of relugolix via Synthesis Route-2

[0241] Figure 6 A synthetic route-2 for the preparation of relugolix is ​​described.

[0242] In Scheme-2, SM1 is acetylated with acetyl chloride to give M1'-1, which is then N-alkylated with 2,6-difluorobenzyl bromide to give M2'-1. In the presence of AIBN as a free radical initiator, M2'-1 reacts with NBS to selectively brominate on the methyl group to give M3'-1. The bromo group in M3'-1 can then be replaced by dimethylamine to give M4'-1. M5 can also be obtained by hydrolysis of M4'-1. Relugoli can be prepared from M5 as described in Scheme-1.

[0243] Example 3: Preparation of relugolix via synthetic route-3 or route-4

[0244] In synthetic route-3 or route-4, SM1 is coupled with hydroxylamine (such as N-tert-butyloxycarbonyl-N-methylhydroxylamine) or oxime (such as benzophenone oxime) using CDI to generate M1'-2 or M1'-3, which is then N-alkylated with 2,6-difluorobenzyl chloride to obtain M2'-2 or M2'-3. In the presence of AIBN as a free radical initiator, M2'-2 or M2'-3 reacts with NBS, and the methyl group can be selectively brominated to generate M3'-2 or M3'-3. Then, the bromine group in M3'-2 or M3'-3 can be replaced by dimethylamine to obtain M4'-2 or M4'-3. M5 can also be obtained by hydrolysis of M4'-2 or M4'-3. As described in synthetic route-1, relugolix can be prepared from M5.

[0245] Although the above invention has been described in some detail by way of illustration and example for ease of understanding, it will be appreciated by those skilled in the art that certain changes and modifications may be implemented within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were incorporated individually. In the event of a conflict between the present application and the references provided herein, the present application shall prevail.

Claims

1. A method for preparing relugolix or a salt thereof represented by formula (I), comprising: a) reacting a compound of formula (M7) or a salt thereof with a carbonylating agent in a solvent to obtain a compound of formula (M8) or a salt thereof; as well as b) converting the compound of formula (M8) or a salt thereof into relugolix of formula (I) or a salt thereof; wherein the carbonylation agent is carbonyl diimidazole (CDI) or disuccinimidyl carbonate; and X is independently imidazolyl or O-succinimidyl; or The carbonylation reagent is a chloroformate selected from the group consisting of CH3OC(O)Cl, CH3CH2OC(O)Cl, phenyl-OC(O)Cl, 4-nitrophenyl-OC(O)Cl; and X is independently OCH3, OCH2CH3, O-phenyl or O-4-nitrophenyl.

2. A method for preparing relugolix or a salt thereof represented by formula (I), comprising: b) reacting the compound of formula (M8) or a salt thereof with methoxyamine or a salt thereof to obtain relugolix of formula (I) or a salt thereof; Wherein, X is imidazole, O-succinimide, OCH3, OCH2CH3, O-phenyl or O-4-nitrophenyl.

3. The preparation method according to claim 1, characterized in that: The carbonylating agent is carbonyldiimidazole (CDI), and X is an imidazole group; or The carbonylating agent is disuccinimidyl carbonate, and X is O-succinimidyl.

4. The preparation method according to claim 3, characterized in that: The carbonylating agent is carbonyldiimidazole (CDI), and X is an imidazole group.

5. The preparation method according to any one of claims 1 to 4, characterized in that X is an imidazole group; and the compound of formula (M8) is a compound represented by formula (M8-1), or a salt thereof:

6. The preparation method according to claim 1, characterized in that: The solvent is an aprotic solvent selected from the group consisting of tetrahydrofuran (THF), 2-methyl-tetrahydrofuran (2-MeTHF), ethyl acetate (EtOAc), dimethylformamide (DMF), dichloromethane (DCM), toluene, dimethylacetamide (DMAc), isopropyl acetate (IPAc), acetonitrile, or a combination thereof.

7. The preparation method according to claim 6, characterized in that: The solvent is THF.

8. The preparation method according to claim 1, characterized in that: The step a) further comprises a base selected from the group consisting of triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, dimethylaniline, diethylaniline, 1,8-bis(dimethylamino)naphthalene, quinuclidine, 1,4-diazabicyclo[2.2.2]-octane (DABCO), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), or a combination thereof.

9. The preparation method according to claim 8, characterized in that: The step a) further comprises 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

10. The preparation method according to claim 1, characterized in that: Before step a), the method further comprises steps i) to vii): i) combining the compound of formula (SM1) or a salt thereof with 2,6-difluorobenzyl bromide or 2,6-difluorobenzyl chloride to obtain a compound of formula (M1) or a salt thereof; ii) combining the compound of formula (M1) or a salt thereof with a trifluoroacetylating agent to obtain a compound of formula (M2) or a salt thereof; iii) brominating the compound of formula (M2) or its salt with a brominating agent to obtain the compound of formula (M3) or its salt; iv) combining the compound of formula (M3), or a salt thereof, with dimethylamine or a salt thereof to obtain a compound of formula (M4), or a salt thereof; v) hydrolyzing the compound of formula (M4) or its salt with a base to obtain the compound of formula (M5) or its salt; vi) combining the compound of formula (M5) or a salt thereof with 6-methoxypyridazine-3-amine to obtain a compound of formula (M6) or a salt thereof; vii) hydrogenating the compound of formula (M6), or a salt thereof, with a hydrogen source to obtain a compound of formula (M7), or a salt thereof; 11. The preparation method according to claim 10, characterized in that: In step ii), the trifluoroacetylating agent is trifluoroacetic anhydride (TFAA); In step iii), the brominating agent is N-bromosuccinimide; In step v), the base is sodium hydroxide; as well as In step vii), the hydrogen source is hydrogen gas.

12. The preparation method according to claim 10, characterized in that: Step i) is carried out using 2,6-difluorobenzyl bromide or 2,6-difluorobenzyl chloride in dimethylacetamide (DMAc); Step ii) is carried out using trifluoroacetic anhydride (TFAA) and triethylamine (TEA) in dichloromethane (DCM); Step iii) is carried out using N-bromosuccinimide and azobisisobutyronitrile in a mixture of ethyl acetate (EtOAc) and trifluorotoluene; Step iv) is carried out with dimethylamine hydrochloride and trimethylamine in dimethylacetamide (DMAc); alternatively, conversion to the hydrochloride salt of the compound of formula (M4) is carried out by adding hydrochloric acid in isopropanol; Step v) is carried out with sodium hydroxide in ethanol (EtOH); Step vi) is carried out using 6-methoxypyridazin-3-amine and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) hydrochloride in dichloromethane (DCM); and Step vii) was carried out with 10% hydrogen on Pd / C in methanol (MeOH).

13. A compound, or a salt thereof, selected from the group consisting of: in, In formula (M8), X is an imidazole group, an O-succinimide group, OCH3, OCH2CH3, an O-phenyl group or an O-4-nitrophenyl group.

14. A method for preparing relugolix or a salt thereof represented by formula (I), comprising: vi) combining the compound of formula (M5) or a salt thereof with 6-methoxypyridazine-3-amine to obtain a compound of formula (M6) or a salt thereof; vii) hydrogenating the compound of formula (M6), or a salt thereof, with a hydrogen source to obtain a compound of formula (M7), or a salt thereof; a) combining a compound of formula (M7) or a salt thereof with a carbonylating agent in a solvent to obtain a compound of formula (M8) or a salt thereof; as well as b) preparing relugolix or its salt of formula (I) from the compound of formula (M8) or its salt, Wherein, the carbonylation reagent in step a) is carbonyl diimidazole (CDI) or disuccinimidyl carbonate; X is imidazole or O-succinimidyl, or The carbonylating agent in step a) is a chloroformate selected from the group consisting of: CH3OC(O)Cl, CH3CH2OC(O)Cl, phenyl-OC(O)Cl, 4-nitrophenyl-OC(O)Cl; and X is independently OCH3, OCH2CH3, O-phenyl or O-4-nitrophenyl.

15. The preparation method according to claim 14, characterized in that: Before step vi), the method further comprises steps i-1) to vii-1): i-1) Compound (SM1) or its salt and C 1-4 Compound SM2 of alkyl-C(O)Cl, or a combination of a carbonylating agent and a hydroxylamine or oxime of compound SM2, to obtain a compound of formula (M1′), or a salt thereof; ii-1) combining the compound of formula (M') or a salt thereof with 2,6-difluorobenzyl bromide or 2,6-difluorobenzyl chloride to obtain a compound of formula (M2') or a salt thereof; iii-1) brominating the compound of formula (M2') or its salt with a brominating agent to obtain the compound of formula (M3') or its salt; iv-1) combining the compound of formula (M3') or a salt thereof with dimethylamine or a salt thereof to obtain a compound of formula (M4') or a salt thereof; v-1) hydrolyzing the compound of formula (M4') or its salt with a base to obtain the compound of formula (M5) or its salt; in, The hydroxylamine is HO-NR 1 R 2 As shown; The oxime is HO-N=CR 3 R 4 As shown; In formulas M1' to M4', R is C 1-4 Alkyl, O-NR 1 R 2 or ON=CR 3 R 4 ; R 1 and R 2 are independently hydrogen, tert-butyloxycarbonyl (Boc), C 1-4 Alkyl or phenyl; and R 3 and R 4 are independently hydrogen, C 1-4 Alkyl or phenyl.

16. The preparation method according to claim 15, characterized in that: In step i-1), the compound SM2 is hydroxylamine or oxime; the carbonylating agent is carbonyldiimidazole (CDI), disuccinimidyl carbonate, CH3OC(O)Cl, CH3CH2OC(O)Cl, phenyl-OC(O)Cl or 4-nitrophenyl-OC(O)Cl.

17. The preparation method according to claim 15, characterized in that: In step i-1), the compound SM2 is acetyl chloride, the hydroxylamine is N-Boc-N-methylhydroxylamine, or the oxime is benzophenone oxime.

18. The preparation method according to claim 15, characterized in that: In step iii-1), the brominating agent is N-bromosuccinimide; and in step v-1), the base is sodium hydroxide.

19. The preparation method according to claim 15, characterized in that: In step i-1), the compound SM is C 1-4 Alkyl-C(O)Cl; and the compound of any one of formulas (M1') to (M4') is respectively a compound represented by any one of formulas (M1'-1) to (M4'-1), or a salt thereof:

20. The preparation method according to claim 19, characterized in that: The compound SM is acetyl chloride, and the compound of any one of formulas (M1'-1) to (M4'-1) is a compound represented by any one of formulas (M1'-1a) to (M4'-1a), or a salt thereof:

21. The preparation method according to claim 15, characterized in that: In step i-1), the compound SM2 is hydroxylamine or oxime; and the compound of any one of formulas (M1') to (M4') is a compound represented by any one of formulas (M1'-2) to (M4'-2) and (M1'-3) to (M4'-4), or a salt thereof: Among them, R 1 and R 2 are independently hydrogen, tert-butyloxycarbonyl (Boc), C 1-4 alkyl or phenyl; and R 3 and R 4 are independently hydrogen, C 1-4 Alkyl or phenyl.

22. The preparation method according to claim 21, characterized in that: In step i-1), the hydroxylamine is N-Boc-N-methylhydroxylamine; and the compound represented by any one of formulas (M1'-2) to (M4'-2) is a compound represented by any one of formulas (M1'-2a) to (M4'-2a), or a salt thereof:

23. The preparation method according to claim 21, characterized in that: In step i-1), the oxime is benzophenone oxime; the compound of any one of formulas (M1'-3) to (M4'-3) is respectively a compound represented by any one of formulas (M1'-3a) to (M4'-3a), or a salt thereof:

24. A compound, or a salt thereof, selected from the group consisting of: in, R is C 1-4 Alkyl, O-NR 1 R 2 or ON=CR 3 R 4 ; R 1 and R 2 are independently hydrogen, tert-butyloxycarbonyl (Boc), C 1-4 Alkyl or phenyl; and R 3 and R 4 are independently hydrogen, C 1-4 Alkyl or phenyl.

25. The compound according to claim 24, or a salt thereof, wherein The compound is selected from the group consisting of:

Images