Process for preparing elagolix sodium and intermediates thereof

Abstract

The present invention provides an improved process for the preparation of Elagolix and its intermediates. The intermediate of formula VII is derived from the compound of formula V and the N-benzylidene-protected compound of formula IV. The present invention is suitable for large-scale production, avoids the use of potentially genotoxic substances, and can be carried out under mild conditions. TIFF2022548655000044.tif53165

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 62 / 902,086, filed September 18, 2019, which is incorporated in its entirety for all purposes.

[0002] STATEMENT REGARDING RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT Not applicable

[0003] (See sequence list, etc.) Not applicable [Background technology]

[0004] Elagolix sodium (trade name Orilissa®) is a gonadotropin-releasing hormone (GnRH) receptor agonist indicated for the relief of severe pain associated with endometriosis. Elagolix sodium has the formula shown below: [ka] The chemical name of elagolix sodium is 4-({(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-{[2-fluoro-6-(trifluoromethyl)phenyl]methyl}-4-methyl-2,6-dioxy-3,6-dihydropyrimidin-1(2H)-yl]-1-phenylethyl}amino)butanoic acid. 32 H 29 It has a molecular formula of F5N3O5Na and a molecular weight of 653.58 Da.

[0005] Orilissa is the first FDA-approved oral tablet developed over 10 years specifically to relieve severe endometriosis pain in women.

[0006] U.S. Patent No. 7,056,927 B2 discloses the preparation of elagolix sodium, as shown in Scheme 1 in Figure 1. The preparation involves the construction of compound C from 2-fluoro-6-(trifluoromethyl)benzonitrile via intramolecular cyclization, followed by the introduction of Br at the C5 position to give compound D. Compound D was alkylated at the N3 position with N-Boc-D-phenylglycinol via a Mitsunobu reaction to provide compound E. Compound E was then reacted with 2-fluoro-3-methoxyphenylboronic acid in the presence of a Pd catalyst, followed by Suzuki coupling and subsequent de-Bocation to give compound F. The NH2 group of compound F was alkylated with ethyl 4-bromobutyl ether to give compound G. Finally, elagolix sodium was obtained by hydrolysis of compound G with NaOH.

[0007] U.S. Patent No. 8,765,948 B2 discloses two general methods for the preparation of elagolix sodium and its intermediates, as shown in Scheme 2 in Figure 2 and Scheme 3 in Figure 3, respectively. As shown in Figure 2, the first method involved introducing iodine (I) instead of bromine (Br) at the C5 position, followed by Suzuki reaction with 2-fluoro-3-methoxyphenylboronic acid to obtain compound 1d. Compound 1f was obtained by treating compound 1d with compound 1e under basic conditions, followed by Boc removal reaction. Subsequently, the NH2 group of compound 1f was alkylated with ethyl 4-bromobutyrate to obtain compound 1g. Elagolix sodium was obtained after hydrolysis under basic conditions. As shown in Figure 3, the second method involved the construction of uracil derivative 2g from the reaction of compound 2f with t-Boc-(1R)-amino-2-amino-1-phenylethane acetate. Subsequently, compound 2g was alkylated with 2-fluoro-6-trifluoromethylbenzyl bromide to give compound 2h, which is also represented by compound F in scheme 1 in Figure 1 and compound 1f in scheme 2 in Figure 2.

[0008] PCT Patent Application No. 2019 / 112968A1 discloses an alternative route for the preparation of elagolix and its intermediates, as shown by Scheme 4 in Figure 4. To avoid the formation of potential genotoxic by-products, such as methanesulfonic acid, this route involves a Mitsunobu reaction, via C-N bond coupling of compound X with N-Boc-D-phenylglycinol.

[0009] Notwithstanding the above methods, a need exists for the development of improved methods for the preparation of elagolix sodium. The present disclosure addresses this need and provides related benefits as well. Summary of the Invention

[0010] In one aspect, the present invention provides a compound of formula VII: [ka] or a salt thereof, the method comprising: 1) A compound of formula V: [ka] and a compound of formula IV: [ka] and one or more coupling agents in a first solvent to form a mixture; and 2) treating the mixture with an acid to provide a compound of formula VII or a salt thereof; R in the formula 1 is hydrogen, methanesulfonic acid, or p-toluenesulfonic acid; and R 2 and R 3 are independently hydrogen, substituted or unsubstituted C 1-8 Alkyl, or substituted or unsubstituted C 6-12 It is aryl.

[0011] In another aspect, the present invention provides elagolix of formula I: [ka] or a pharmaceutically acceptable salt thereof, the method comprising: 1) A compound of formula V: [ka] and a compound of formula IV: [ka] and one or more coupling agents in a first solvent to form a mixture; 2) Treating the mixture with acid and neutralizing to produce a compound of formula VII: [ka] Provide; 3) contacting the compound of Formula VII with ethyl 4-halobutyrate and a third base in a fourth solvent to produce a compound of Formula VIII: [ka] form; and 4) treating the compound of Formula VIII with a fourth base in a fifth solvent to provide Elagolix of Formula I or a pharmaceutically acceptable salt thereof; R in the formula 1 is hydrogen, methanesulfonic acid, or p-toluenesulfonic acid; and R 2 and R 3 are independently hydrogen, substituted or unsubstituted C 1-8 Alkyl, or substituted or unsubstituted C 6-12 It is aryl. [Brief explanation of the drawings]

[0012] [Figure 1] A scheme for preparing elagolix sodium as disclosed in U.S. Patent No. 7,056,927 B2.

[0013] [Figure 2] 1 is a scheme of a first approach for preparing elagolix sodium as disclosed in U.S. Patent No. 8,765,948 B2.

[0014] [Figure 3] 1 is a scheme of a second approach for preparing an intermediate of elagolix sodium as disclosed in U.S. Patent No. 8,765,948 B2.

[0015] [Figure 4] Scheme for preparing an intermediate of elagolix sodium, as disclosed in PCT Publication WO / 2019 / 112968A1. DETAILED DESCRIPTION OF THE INVENTION

[0016] I. Overview The present invention provides an improved method for preparing elagolix and its intermediates. Compared to the prior art, the present invention is suitable for large-scale production, avoids the use of potentially genotoxic substances, and can be carried out under mild conditions. The coupling reaction of the present invention utilizes N-benzylidene-D-phenylglycinol (compound of Formula IVa), in which the benzylidene group at the N atom has less steric hindrance than the tert-butoxycarbonyl (Boc) group of N-Boc-D-phenylglycinol. This steric difference has been found to affect the N-alkylation / O-alkylation ratio of the imide (compound of Formula V). When N-Boc-D-phenylglycinol (disclosed in WO 2019 / 112968 A1) is used, the reaction produces O-alkylated by-products in amounts of 8-10%. In the present invention, when N-benzylidene-D-phenylglycinol is used, the O-alkylated by-products were not observed. Furthermore, deprotection of the N-benzylidene group to generate the NH group is effected under mild conditions by treatment with acid at room temperature. In comparison, deprotection of the N-Boc group is carried out at 60° C. as described in the prior art.

[0017] II. Definition "Alkyl" refers to a straight-chain or branched, saturated, aliphatic radical having the number of carbon atoms indicated (i.e., C 1-8 means 1 to 8 carbons). Alkyl means any number of carbons, e.g., C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 For example, C 1-8 Alkyl includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl and the like.

[0018] "Aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups can contain any suitable number of ring atoms, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, and 6-10, 6-12, or 6-14 membered rings. Aryl groups can be monocyclic, fused to bicyclic or tricyclic groups, or linked by bonds to form biaryl groups. Representative aryl groups are phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl, which has a methylene linking group. Some aryl groups have 6-12 membered rings, for example, phenyl, naphthyl, or biphenyl. Other aryl groups have 6-10 membered rings, for example, phenyl or naphthyl. Some other aryl groups have 6 membered rings, for example, phenyl. Aryl groups can be substituted or unsubstituted.

[0019] "OMs" means methanesulfonic acid; and "OTs" means p-toluenesulfonic acid.

[0020] "Salt" refers to an acid or base salt of a compound used in the methods of the present disclosure. Useful salts of the present disclosure include, but are not limited to, phosphate, sulfate, chloride, bromide, carbonate, nitrate, acetate, methanesulfonate, sodium, potassium, and calcium salts. Examples of pharmaceutically acceptable salts include mineral acid salts (such as hydrochloric acid, hydrobromic acid, and phosphoric acid), organic acid salts (such as acetic acid, propionic acid, glutamic acid, and phosphoric acid), quaternary ammonium salts (such as methyl iodide and ethyl iodide), and alkali metal or alkaline earth metal salts (such as sodium, potassium, and calcium). Pharmaceutically acceptable salts are understood to be non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Macl Publishing Company, Easton, Pa., 1985, incorporated herein by reference.

[0021] "Base" refers to a functional group that deprotonates water to produce hydroxide ions. Bases useful in the present disclosure include organic and inorganic bases. Exemplary organic bases, as defined herein, include tertiary amines, aromatic amine bases, and amidine-based compounds. Exemplary inorganic bases, as defined herein, include alkali bicarbonates, alkali carbonates, and alkali hydroxides.

[0022] "First base," "second base," etc., refer to bases as defined above and described in the embodiments of the present invention. The base naming conventions are used solely for clarity purposes in the relevant steps of the processes described herein, and they are not required to be in numerical order. Some bases may be absent in selected embodiments of the present invention as disclosed herein. Those of skill in the art will understand the meaning of these naming conventions ("first base," "second base") within the context of the use of the terms in the embodiments and claims herein.

[0023] A "tertiary amine" is a compound having the formula N(R), where the R group can be, among others, alkyl, aryl, heteroalkyl, heteroaryl, or two R groups together can form an N-linked heterocycloalkyl. The R groups can 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).

[0024] "Aromatic amine base" refers to an N-containing 5- to 10-membered heteroaryl compound or a tertiary amine having the formula N(R)3, where at least one R group is aryl or heteroaryl. Aromatic amine bases useful in the present application include, but are not limited to, pyridine, lutidine (e.g., 2,6-lutidine, 3,5-lutidine, and 2,3-lutidine), collidine (e.g., 2,3,4-collidine, 2,3,5-collidine, 2,3,6-collidine, 2,4,5-collidine, 2,4,6-collidine, and 3,4,5-collidine), 4-dimethylaminopyridine, imidazole, dimethylaniline, and diethylaniline.

[0025] As used herein, "amidine-based compounds" refers to a class of compounds that includes, but is not limited to, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN).

[0026] "Alkali bicarbonate" is a compound consisting of an alkali metal cation and a bicarbonate anion (HCO3 - Alkali carbonates useful in the present disclosure include lithium bicarbonate (LiHCO), sodium bicarbonate (NaHCO), potassium bicarbonate (KHCO), and cesium bicarbonate (CsHCO).

[0027] "Alkali carbonate" is a compound of alkali metal cation and carbonate anion (CO3 2- ) is a class of compounds that includes alkali carbonates useful in the present disclosure. 2- ), sodium carbonate (Na2CO3), potassium carbonate (K2CO3), and cesium carbonate (Cs2CO3).

[0028] "Alkali hydroxide" refers to a compound of an alkali metal cation and a hydroxide anion (OH - Alkali hydroxides useful in this disclosure include lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium hydroxide (CsOH), and calcium hydroxide (Ca(OH)).

[0029] "Contacting" refers to the process of bringing at least two different species into contact so that they can react. However, it is understood that the resulting reaction product may be produced directly from the reaction between the added reagents or from an intermediate from one or more added reagents that may be produced in the reaction mixture.

[0030] "Deprotecting" means removing a protecting group (e.g., a benzylidene group at the N atom of a compound of Formula VI) using one or more chemicals or substances to restore the functional group (e.g., an -NH group) to its original state.

[0031] "Solvent" means a liquid capable of dissolving a substance, e.g., a solute. Solvents can be polar or nonpolar, protic or aprotic. Polar solvents typically have a dielectric constant greater than about 5 or a dipole moment greater than about 1.0, and 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 a proton available for removal, e.g., a hydroxy or carboxy group. Aprotic solvents lack such a group. Representative polar protic solvents include alcohols (e.g., methanol, ethanol, propanol, isopropanol, etc.), acids (e.g., formic acid, acetic acid, etc.), and water. Representative polar aprotic solvents include dichloromethane, chloroform, tetrahydrofuran, diethyl ether, acetone, ethyl acetate, dimethylformamide, dimethylacetamide, acetonitrile, and dimethyl sulfoxide. Representative non-polar solvents include alkanes (pentane, hexane, etc.), cycloalkanes (cyclopentane, cyclohexane, etc.), benzene, toluene, diethyl ether, and 1,4-dioxane. Other solvents are useful in the present invention.

[0032] "First solvent," "second solvent," etc. refer to solvents as defined above and described in the embodiments of the present invention. The solvent naming conventions are used solely for purposes of clarity in the relevant steps of the processes as described herein, and they are not required to be in numerical order. Some solvents may be absent in selected embodiments of the present invention as disclosed herein. Those skilled in the art will understand the meaning of these naming conventions ("first solvent," "second solvent") within the context of the use of the terms in the embodiments and claims.

[0033] III. DESCRIPTION OF EMBODIMENTS In one aspect, the present invention provides a compound of formula VII: [ka] or a salt thereof, the method comprising: 1) A compound of formula V: [ka] and a compound of formula IV: [ka] and one or more coupling agents in a first solvent to form a mixture; and 2) treating the mixture with an acid to provide a compound of formula VII or a salt thereof; R in the formula 1 is hydrogen, methanesulfonic acid, or p-toluenesulfonic acid; and R 2 and R 3 are independently hydrogen, substituted or unsubstituted C 1-8 Alkyl, or substituted or unsubstituted C 6-12 It is aryl.

[0034] In some embodiments, the mixture comprises a compound of formula VI: [ka]

[0035] In some embodiments, R 1 When is hydrogen, step 1) is carried out under Mitsunobu conditions.

[0036] In some embodiments, R 1 is hydrogen; R 2 and R 3 are independently hydrogen, substituted or unsubstituted C 1-8 Alkyl, or substituted or unsubstituted C 6-12 In some embodiments, R 1 is hydrogen; R2 is hydrogen; and R 3 is a substituted or unsubstituted C 6-12 In some embodiments, R 1 is hydrogen; R 2 is hydrogen; and R 3 is phenyl. In some embodiments, R 1 is hydrogen; R 2 and R 3 are substituted and unsubstituted C 1-8 In some embodiments, R 1 is hydrogen; R 2 and R 3 Each R is methyl. 1 is hydrogen; R 2 is a substituted or unsubstituted C 1-8 alkyl; and R 3 is a substituted or unsubstituted C 6-12 In some embodiments, R 1 is hydrogen; R 2 is methyl; and R 3 is phenyl.

[0037] Mitsunobu conditions include an azodicarboxylic acid compound and triphenylphosphine. In one embodiment, the one or more coupling agents in step 1) are a combination of diethyl azodicarboxylate (DEAD) and triphenylphosphine, a combination of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine, a combination of tetraisopropyl azodicarboxamide (TIPA) and triphenylphosphine, a combination of azodicarbonyldipiperidine (ADDP) and triphenylphosphine, or a combination of bis(2,2,2-trichloroethyl) azodicarboxylate (TCEAD) and triphenylphosphine. In one embodiment, the one or more coupling agents in step 1) are a combination of diethyl azodicarboxylate (DEAD) and triphenylphosphine or a combination of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine. In one embodiment, the one or more coupling agents in step 1) are a combination of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine.

[0038] The first solvent under Mitsunobu conditions can be an aprotic solvent or a nonpolar solvent, as defined herein. In some embodiments, the first solvent is dimethylformamide (DMF), dichloromethane (DCM), toluene, dimethylacetamide (DMAc), isopropyl acetate (IPAc), acetonitrile, tetrahydrofuran (THF), or a mixture thereof. In some embodiments, the first solvent comprises tetrahydrofuran (THF).

[0039] Generally, the Mitsunobu reaction (i.e., step 1) can be carried out at any suitable temperature. In some embodiments, the Mitsunobu reaction is carried out at a temperature between 0°C and 50°C. In some embodiments, the Mitsunobu reaction is carried out at a temperature between 15°C and 30°C. In some embodiments, the Mitsunobu reaction is carried out at room temperature.

[0040] In some embodiments, R 1 When Ms is methanesulfonic acid (Ms) or p-toluenesulfonic acid (Ts), step 1) is carried out under nucleophilic conditions.

[0041] In some embodiments, R 1 is methanesulfonic acid (Ms); R 2 and R 3 are independently hydrogen, substituted or unsubstituted C 1-8 Alkyl, or substituted or unsubstituted C 6-12 In some embodiments, R 1 is methanesulfonic acid (Ms); R 2 is hydrogen; and R 3 is a substituted or unsubstituted C 6-12 In some embodiments, R 1 is methanesulfonic acid (Ms); R 2 is hydrogen; and R 3 is phenyl. In some embodiments, R 1 is methanesulfonic acid (Ms); R 2 and R 3 Each R is methyl. 1 is methanesulfonic acid (Ms); R 2 is a substituted or unsubstituted C 1-8 alkyl; and R 3 is a substituted or unsubstituted C 6-12 In some embodiments, R 1 is methanesulfonic acid (Ms); R 2 is methyl; and R 3 is phenyl.

[0042] In some embodiments, R 1 is p-toluenesulfonic acid (Ts); R 2 and R 3 are independently hydrogen, substituted or unsubstituted C 1-8 Alkyl, or substituted or unsubstituted C 6-12 In some embodiments, R 1 is p-toluenesulfonic acid (Ts); R 2 is hydrogen; and R 3 is a substituted or unsubstituted C 6-12 In some embodiments, R1 is p-toluenesulfonic acid (Ts); R 2 is hydrogen; and R 3 is phenyl. In some embodiments, R 1 is p-toluenesulfonic acid (Ts); and R 2 and R 3 are substituted and unsubstituted C 1-8 In some embodiments, R 1 is p-toluenesulfonic acid (Ts); R 2 and R 3 Each R is methyl. 1 is p-toluenesulfonic acid (Ts); R 2 is a substituted or unsubstituted C 1-8 alkyl; and R 3 is a substituted or unsubstituted C 6-12 In some embodiments, R 1 is p-toluenesulfonic acid (Ts); R 2 is methyl; and R 3 is phenyl.

[0043] The nucleophilic condition includes a first base. In some embodiments, one or more coupling agents in step 1) is a first base. As defined herein, the first base can be an organic base or an inorganic base. In some embodiments, the first base is an inorganic base. In some embodiments, the first base is an alkali carbonate. In some embodiments, the first base is lithium carbonate (Li2CO3 2- ) sodium carbonate (Na2CO3), potassium carbonate (K2CO3), and cesium carbonate (Cs2CO3), or a combination thereof. In some embodiments, the first base is potassium carbonate (K2CO3).

[0044] Under nucleophilic conditions, the first solvent can be an aprotic solvent or a nonpolar solvent, as defined herein. In some embodiments, the first solvent is dimethylformamide (DMF), dichloromethane (DCM), toluene, dimethylacetylamide (DMAc), isopropyl acetate (IPAc), acetonitrile, tetrahydrofuran (THF), or a mixture thereof. In some embodiments, the first solvent comprises dimethylformamide (DMF).

[0045] Generally, the nucleophilic reaction (i.e., step 1) can be carried out at any suitable temperature. In some embodiments, the nucleophilic reaction is carried out at a temperature between 0°C and 100°C. In some embodiments, the nucleophilic reaction is carried out at a temperature between 20°C and 70°C. In some embodiments, the nucleophilic reaction is carried out at a temperature of about 55°C.

[0046] In some embodiments, step 2) comprises: 2a) treating the mixture with an acid in a second solvent to provide a salt of the compound of formula VII.

[0047] In some embodiments, step 2) comprises: 2a) treating the mixture with an acid in a second solvent to provide a salt of the compound of Formula VII; and 2b) neutralizing the salt of the compound of formula VII with a second base in a third solvent comprising water to provide the compound of formula VII.

[0048] In some embodiments, the acid is hydrochloric acid (HCl) or methanesulfonic acid. In some embodiments, the acid is an aqueous solution of HCl or methanesulfonic acid. In some embodiments, the acid is an aqueous solution of HCl. In some embodiments, the acid is methanesulfonic acid.

[0049] In some embodiments, the salt of the compound of formula VII is its HCl salt.

[0050] The second solvent for deprotection (i.e., step 2a) can be an aprotic solvent or a nonpolar solvent, as defined herein. In certain embodiments, the second solvent is dimethylformamide (DMF), dichloromethane (DCM), toluene, dimethylacetamide (DMAc), isopropyl acetate (IPAc), acetonitrile, tetrahydrofuran (THF), or a mixture thereof. In certain embodiments, the second solvent comprises toluene. In certain embodiments, the second solvent comprises isopropyl acetate (IPAc).

[0051] Generally, the deprotection reaction (i.e., step 2a) can be carried out at any temperature. In some embodiments, the deprotection reaction is carried out at 0°C to 80°C. In some embodiments, the deprotection reaction is carried out at 20°C to 70°C. In some embodiments, when the acid is an aqueous solution of HCl, the deprotection reaction is carried out at room temperature, between 15°C and 30°C. In some embodiments, when the acid is methanesulfonic acid, the deprotection reaction is carried out at a temperature of about 60°C.

[0052] The second base in step 2b) can be an inorganic base as defined herein. In some embodiments, the second base can be an inorganic base. In some embodiments, the second base is an alkali carbonate. In some embodiments, the second base is sodium carbonate (NaCO) or potassium carbonate (KCO). In some embodiments, the second base is potassium carbonate (KCO).

[0053] The third solvent for neutralization (i.e., step 2b) can include water. In some embodiments, the third solvent includes water. In some embodiments, the neutralization step occurs in an aqueous solution containing a salt of the compound of Formula VII.

[0054] Generally, the neutralization reaction (i.e., step 2b) can be carried out at any suitable temperature. In some embodiments, the neutralization reaction is carried out at a temperature between 0°C and 50°C. In some embodiments, the neutralization reaction is carried out at a temperature between 15°C and 30°C.

[0055] In some embodiments, steps 1) and 2) are carried out in one pot. In some embodiments, steps 1) and 2a) are carried out in one pot. In some embodiments, steps 1), 2a), and 2b) are carried out in one pot. In some embodiments, the compound of formula VI is used directly in step 2) without separation. In some embodiments, the compound of formula VI is used directly in step 2a) without separation. In some embodiments, a salt of the compound of formula VII is used directly in step 2b) without separation.

[0056] In some embodiments, the compound of formula VI is isolated prior to step 2). In some embodiments, the compound of formula VI is isolated prior to step 2a). In some embodiments, the salt of the compound of formula VII is isolated prior to step 2b).

[0057] In one embodiment, the present invention provides a compound of formula VII: [ka] The present invention provides a method for preparing a compound comprising: 1) A compound of formula V: [ka] and a compound of formula IV: [ka] and one or more coupling agents in a first solvent to form a mixture; 2a) treating the mixture with an acid in a second solvent to provide a salt of the compound of Formula VII; and 2b) neutralizing the salt of the compound of formula VII with a second base in a third solvent comprising water to provide a compound of formula VII; R in the formula 1 , R 2 , and R 3 is as defined and described herein, and steps 1), 2a), and 2b) are described herein.

[0058] In one embodiment, the present invention provides a compound of formula VII: [ka] The present invention provides a method for preparing a salt of 1) A compound of formula V: [ka] and a compound of formula IV: [ka] and one or more coupling agents in a first solvent to form a mixture; and 2a) treating the mixture with an acid in a second solvent to provide a salt of the compound of formula VII; R in the formula 1 , R 2 , and R 3 is as defined and described herein, and steps 1) and 2a) are described herein.

[0059] In some embodiments, the mixture comprises a compound of formula VI: [ka]

[0060] In some embodiments, the salt of the compound of formula VII is its HCl salt.

[0061] In another aspect, the present invention provides elagolix of formula I: [ka] or a pharmaceutically acceptable salt thereof, the method comprising: 1) A compound of formula V: [ka] and a compound of formula IV: [ka] and one or more coupling agents in a first solvent to form a mixture; 2) Treating the mixture with an acid and neutralizing to produce a compound of formula VII: [ka] Provide; 3) contacting the compound of Formula VII with ethyl 4-halobutyrate and a third base in a fourth solvent to produce a compound of Formula VIII: [ka] and 4) treating the compound of Formula VIII with a fourth base in a fifth solvent to provide Elagolix of Formula I or a pharmaceutically acceptable salt thereof; R in the formula 1 is hydrogen, methanesulfonic acid, or p-toluenesulfonic acid; and R 2 , and R 3 are independently hydrogen, substituted or unsubstituted C 1-8 Alkyl, or substituted or unsubstituted C 6-12 It is aryl.

[0062] In some embodiments, the mixture comprises a compound of formula VI: [ka]

[0063] In some embodiments, R 1 , R 2 , and R 3 is as above.

[0064] In some embodiments, step 2) comprises: 2a) treating the mixture with an acid in a second solvent to provide a salt of the compound of Formula VII; and 2b) treating the salt of the compound of formula VII with a second base in a third solvent comprising water to provide the compound of formula VII.

[0065] In some embodiments, steps 2a) and 2b) are as described above.

[0066] In some embodiments, the salt of the compound of formula VII is its HCl salt.

[0067] In some embodiments, the ethyl 4-halobutyrate in step 3) is ethyl 4-bromobutyrate.

[0068] The third base in step 3) can be an organic base or an inorganic base, as defined herein. In some embodiments, the third base is an organic base. In some embodiments, the third base is a tertiary amine. In some embodiments, the third base is triethylamine, tri-n-butylamine, N,N-diisopropylethylamine, N-methylpyrrolidine, N-methylmorpholine, dimethylaniline, or diethylaniline. In some embodiments, the third base is N,N-diisopropylethylamine (DIPEA).

[0069] The fourth solvent in step 3) can be an aprotic solvent or a nonpolar solvent, as defined herein. In some embodiments, the fourth solvent is dimethylformamide (DMF), dichloromethane (DCM), toluene, dimethylacetamide (DMAc), isopropyl acetate (IPAc), acetonitrile, tetrahydrofuran (THF), or a mixture thereof. In some embodiments, the fourth solvent comprises dimethylacetamide (DMAc).

[0070] Generally, step 3) can be carried out at any suitable temperature. In some embodiments, the step 3) reaction mixture can be at a temperature of 0°C to 100°C. In some embodiments, the step 3) reaction mixture can be at a temperature of 20°C to 70°C. In some embodiments, the step 3) reaction mixture can be at a temperature of about 55°C.

[0071] The fourth base in step 4) can be an inorganic base as defined herein. In some embodiments, the fourth base is an alkali hydroxide. In some embodiments, the fourth base is sodium hydroxide (NaOH), potassium hydroxide (KOH), or calcium hydroxide (Ca(OH)). In some embodiments, the fourth base is sodium hydroxide (NaOH) or calcium hydroxide (Ca(OH)). In some embodiments, the fourth base is sodium hydroxide (NaOH).

[0072] The fifth solvent in step 4) can be an alcohol, water, or a combination thereof. In some embodiments, the fifth solvent comprises ethanol and water.

[0073] Generally, step 4) can be carried out at any suitable temperature. In some embodiments, the step 4) reaction mixture is at a temperature between 0°C and 50°C. In some embodiments, the step 4) reaction mixture is at a temperature between 15°C and 30°C.

[0074] In some embodiments, the pharmaceutically acceptable salt of elagolix of formula I is the sodium salt. In some embodiments, the elagolix of formula I is elagolix sodium.

[0075] In some embodiments, steps 1) and 2) are carried out in one pot. In some embodiments, steps 1) and 2a) are carried out in one pot. In some embodiments, steps 1), 2a), and 2b) are carried out in one pot. In some embodiments, the compound of formula VI is used directly in step 2) without separation. In some embodiments, the compound of formula VI is used directly in step 2a) without separation. In some embodiments, a salt of the compound of formula VII is used directly in step 2b) without separation.

[0076] In some embodiments, the compound of formula VI is isolated prior to step 2). In some embodiments, the compound of formula VI is isolated prior to step 2a). In some embodiments, the salt of the compound of formula VII is isolated prior to step 2b).

[0077] In some embodiments, steps 3) and 4) are carried out in one pot. In some embodiments, steps 1) through 4) are carried out in one pot.

[0078] In some embodiments, the elagolix sodium is isolated as a solid. [Example]

[0079] Example 1: Preparation of Compounds of Formula III [ka] To a suitable reactor, the compound of formula II (90.0 g) and acetic acid (900 mL) were added at room temperature. To the resulting clear solution, N-iodosuccinimide (80.4 g) was added. The mixture was heated to 50°C and stirred for 8 hours. Upon completion, the suspension was slowly added to water (2250 mL) and then cooled to room temperature. The slurry was stirred at room temperature for 2 hours and then filtered. The wet cake was washed twice with water (540 mL) and then vacuum dried at 60°C to obtain the crude compound of formula III. The crude compound of formula III and MeOH (225 mL) were added to a suitable reactor. The slurry mixture was heated to reflux and stirred for 1 hour. After refluxing, the slurry was cooled to room temperature and stirred for 1 hour, then filtered. The wet cake was washed with pre-chilled MeOH (90 mL) and subsequently dried under vacuum at 60° C. to give the compound of formula III (115.38 g, 90.5% yield).

[0080] Example 2: Preparation of Compound of Formula V [ka] To a suitable reactor was added the compound of Formula III (20.00 g), 2-fluoro-3-methoxyphenylboronic acid (10.29 g), and acetone (22 mL). KOH (10.62 g) in water (76 mL) was added. The resulting mixture was degassed for 30 minutes. The mixture was heated to 40°C, followed by the addition of PdCl(dtbpf) (0.0432 g). The reaction was heated to 45°C and stirred for 2.5 hours. Upon completion, the reaction was cooled to room temperature. Celite (5.01 g) was added. The mixture was stirred for 1 hour and then filtered. The Celite cake was washed with a mixture of KOH (1.53 g), acetone (10.4 mL), and water (30 mL). The filtrate was slowly added to another flask containing THF (60 mL), AcOH (30.2 mL), and water (20 mL) at 60°C. The slurry was filtered through a Buchner funnel to obtain a wet cake. The wet cake was washed twice with water / MeOH (v / v = 2 / 3, 50 mL) followed by two washes with MeOH (64 mL). The wet cake was dried under vacuum at NMT 50°C to provide the compound of formula V (17.89 g, 88.4% yield).

[0081] Example 3: Preparation of Compound of Formula VII [ka] To a suitable reactor was added the compound of formula V (5.00 g), N-benzylidene-D-phenylglycinol (4.63 g), PPh3 (6.15 g), and THF (75 mL), followed by DIAD (4.74 g). The reaction was stirred at room temperature for 2 hours. Upon completion, the reaction was quenched with water (10 mL) and subsequently stirred for 10 minutes. The resulting mixture was concentrated six-fold (by volume) via a solvent swap with toluene (30 mL). 3N HCl (11.7 mL) was added. The resulting mixture was stirred for 1 hour at room temperature. Upon completion, MeOH (30 mL) was added. The solution was washed three times with n-heptane (30 mL) and subsequently concentrated six-fold (by volume) via a solvent swap with toluene (30 mL). The solution was neutralized with K2CO3 (8.12 g) in water (42.5 mL). The aqueous phase was extracted with toluene (25 mL). The combined organic phase was extracted twice with 10% H3PO4 (50 mL). The aqueous phase was washed twice with IPAc (50 mL). The aqueous phase was neutralized with K2CO3 (16.28 g) dissolved in water (25 mL). The resulting solution was extracted with IPAc (42.5 mL). The organic phase was washed with water (15 mL) and subsequently recrystallized with IPAc / n-heptane to give the compound of formula VII (5.89 g, 92.2% yield).

[0082] Example 4: Preparation of Compound of Formula VII [ka] To a suitable reactor was added the compound of formula V (3.00 g), N-isopropylidene-D-phenylglycinol (2.54 g), PPh3 (3.69 g), and THF (45 mL), followed by DIAD (2.90 g). The reaction was stirred at room temperature for 2 hours. Upon completion, the reaction was quenched with water (6 mL) and subsequently stirred for 10 minutes. The resulting mixture was concentrated 6-fold (by volume) via a solvent swap with toluene (18 mL). MsOH (0.91 mL) was added. The resulting mixture was stirred at 60 °C for 1 hour. Upon completion, a solution of K2CO3 (3.89 g) in water (25.5 mL) was added at 30 °C. Toluene (15 mL) was added to the mixture, and the phases were separated. The aqueous phase was extracted with toluene (15 mL). The combined organic phases were extracted twice with 10% H3PO4 (30 mL). The combined aqueous phase was washed twice with IPAc (30 mL). The aqueous phase was neutralized with KCO (9.76 g) dissolved in water (15 mL). The resulting solution was extracted with IPAc (25.5 mL). The organic phase was washed with water (9 mL) and subsequently recrystallized with IPAc / n-heptane to give the compound of formula VII (3.45 g, 89.9% yield).

[0083] Example 5: Preparation of Compound of Formula VII [ka] To a suitable reactor was added the compound of formula V (3.00 g), [(2R)-2-[(E)-benzylideneamino]-2-phenyl-ethyl]methanesulfonic acid (3.44 g), K2CO3 (2.43 g), and DMF (20 mL). The reaction was stirred at 55 °C. Upon completion, IPAc (24 mL) and water (28.5 mL) were added to the reactor. The organic phase was washed with water (16 mL). 3N HCl (0.78 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. Upon completion, MeOH (18 mL) was added. The solution was washed three times with n-heptane (18 mL) and subsequently concentrated six-fold (by volume) via a solvent swap with toluene. The solution was neutralized with K2CO3 (4.87 g) dissolved in water (25.5 mL). The aqueous phase was extracted with toluene (15 mL). The combined organic phase was extracted twice with 10% H3PO4 (30 mL). The aqueous phase was washed twice with IPAc (30 mL). The aqueous phase was neutralized with K2CO3 (9.77 g) dissolved in water (15 mL). The resulting solution was extracted with IPAc (25.5 mL). The organic phase was washed with water (9 mL) followed by recrystallization from IPAc / n-heptane to give the compound of formula VII (3.23 g, 84.1% yield).

[0084] Example 6: Preparation of the compound of formula VIII and elagolix sodium [ka] To a suitable reactor was added the compound of Formula VII (3.00 g), ethyl 4-bromobutyrate (0.95 mL), and DMAc (4.5 mL). DIPEA (1.25 mL) was added. The resulting mixture was heated to 55°C overnight. Upon completion, the reaction was cooled to room temperature. IPAc (15 mL) and water (9 mL) were added. The resulting mixture was stirred for 10 minutes. The organic phase was washed with citric acid (0.31 g) in water (6 mL). The organic phase was extracted with H3PO4 (1.07 g) in 85% water (21 mL), followed by H3PO4 (0.44 g) in water (6 mL). The combined phosphoric acid phase was washed twice with IPAc (6 mL). IPAc (15 mL) was added to the aqueous solution. The mixture was neutralized with K2CO3 (3.05 g) in water (4.5 mL). The organic phase was subjected to a solvent swap with EtOH (15 mL) to obtain the compound of Formula VIII in EtOH solution. NaOH (0.44 g) in water (6 mL) was slowly added. The resulting mixture was stirred at room temperature for 2 hours. Upon completion, water (9 mL) was added. The mixture was stirred and then separated. MIBK (9 mL) was added to the aqueous phase. The resulting mixture was concentrated 10 times (by volume), followed by the addition of NaCl (4.5 g) and MIBK (21 mL). The resulting mixture was stirred at 25-30 °C and then phase separated. The organic phase was concentrated 3 times (by volume). The resulting suspension was filtered to remove the remaining NaCl solids. The filtrate was added to a well-stirred n-heptane solution (30 mL). The suspension was stirred for 2 hours. The suspension was filtered through a Buchner funnel followed by washing with n-heptane (6 mL). The wet cake was dried under vacuum at 70° C. to give elagolix sodium (2.39 g, 66.5% yield).

[0085] Although the foregoing invention has been described in detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will recognize that certain variations and modifications may be made within the scope of the appended claims. Additionally, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. In the event of a conflict between the present application and a reference provided herein, the present application shall control.

Claims

1. Formula I: 【Chemistry 1】 1. A process for preparing elagolix or a pharmaceutically acceptable salt thereof comprising: The method comprises: 1) To form a mixture: Compound of Formula V: 【Chemistry 2】 and a compound of formula IV: 【Transformation 3】 and one or more coupling agents in a first solvent, the one or more coupling agents (i) a combination of an azodicarboxylic acid compound and triphenylphosphine, or (ii) a first base which is an organic base or an inorganic base; the contacting, wherein the first solvent is an aprotic solvent or a nonpolar solvent; 2) A compound of formula VII: 【Chemistry 4】 treating said mixture with an acid and neutralizing to provide 3) A compound of formula VIII: 【Transformation 5】 contacting the compound of Formula VII with ethyl 4-halobutyrate and a third base in a fourth solvent to form the third base is an organic base or an inorganic base, the contacting, wherein the fourth solvent is an aprotic solvent or a nonpolar solvent; and 4) to provide elagolix of formula I or a pharmaceutically acceptable salt thereof, treating the compound of Formula VIII with an inorganic base in a fifth solvent; the treating, wherein the fifth solvent is an alcohol, water, or a combination thereof; A method comprising: In the formula R １ is hydrogen, methanesulfonic acid, or p-toluenesulfonic acid; and R ２ and R ３ are independently hydrogen, substituted or unsubstituted C １－８ Alkyl, or substituted or unsubstituted C ６－１２ The method according to claim 1, wherein the aryl is aryl.

2. 10. The method of claim 1, wherein the mixture comprises a compound of formula VI: 【Transformation 6】 10. The method of claim 1, comprising:

3. R １ is hydrogen; R ２ is hydrogen; and R ３ The method of claim 1 or 2, wherein is phenyl.

4. R １ is hydrogen; and R ２ and R ３ The method of claim 1 or 2, wherein each is methyl.

5. 5. The method of claim 3 or 4, wherein the one or more coupling agents in step 1) are a combination of diethyl azodicarboxylate (DEAD) and triphenylphosphine, or a combination of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine.

6. R １ is methanesulfonic acid; R ２ is hydrogen; and R ３ The method of claim 1 or 2, wherein is phenyl.

7. The one or more coupling agents in step 1) are the first base, 7. The method of claim 6, wherein the first base is an organic base or an inorganic base.

8. 8. The method of claim 7, wherein the first base is an inorganic base.

9. 9. The method of claim 8, wherein the inorganic base is one or more alkali carbonates.

10. 10. The method of claim 9, wherein the one or more alkali carbonates is potassium carbonate.

11. 11. The method of any one of claims 1 to 10, wherein the first solvent in step 1) is dimethylformamide, dichloromethane, toluene, dimethylacetamide, isopropyl acetate, acetonitrile, tetrahydrofuran, or a mixture thereof.

12. 5. The method of claim 3 or 4, wherein the first solvent in step 1) comprises tetrahydrofuran.

13. 7. The method of claim 6, wherein the first solvent in step 1) comprises dimethylformamide.

14. Step 2) is 2a) treating the mixture with an acid in a second solvent to provide a salt of the compound of formula VII; the treating, wherein the second solvent is an aprotic solvent or a nonpolar solvent; and 2b) neutralizing the salt of the compound of Formula VII with an inorganic base in a third solvent to provide the compound of Formula VII; 14. The method of any one of claims 1 to 13, comprising said neutralizing step wherein said third solvent is water.

15. 15. The method of claim 14, wherein the acid is HCl or methanesulfonic acid.

16. 16. The method of claim 14 or 15, wherein the second solvent is dimethylformamide, dichloromethane, toluene, dimethylacetamide, isopropyl acetate, acetonitrile, tetrahydrofuran, or a mixture thereof.

17. 17. The method of claim 16, wherein the second solvent comprises toluene or isopropyl acetate.

18. The method of claim 14, wherein the inorganic base in step 2b) is potassium carbonate.

19. The method according to any one of claims 1 to 18, wherein the ethyl 4-halobutyrate in step 3) is ethyl 4-bromobutyrate.

20. 20. The method of any one of claims 1 to 19, wherein the third base in step 3) is N,N-diisopropylethylamine.

21. 21. The method of any one of claims 1 to 20, wherein the fourth solvent in step 3) comprises dimethylacetamide.

22. 22. The method according to any one of claims 1 to 21, wherein the inorganic base in step 4) is sodium hydroxide or calcium hydroxide.

23. 23. The method of claim 22, wherein the inorganic base in step 4) is sodium hydroxide.

24. 24. The method of any one of claims 1 to 23, wherein the fifth solvent in step 4) comprises ethanol and water.

25. 10. The method of claim 1, wherein steps 1) and 2) are carried out in one pot.

26. 3. The method of claim 2, wherein the compound of formula VI is used directly in step 2) without isolation.

27. 10. The method of claim 1, wherein steps 3) and 4) are carried out in one pot.

28. Compound of Formula VII: 【Transformation 7】 Or a method for preparing a salt thereof, said method comprising: 1) To form a mixture: Compound of Formula V: 【Transformation 8】 and a compound of formula IV: 【Chemistry 9】 and one or more coupling agents in a first solvent, the one or more coupling agents (i) a combination of an azodicarboxylic acid compound and triphenylphosphine, or (ii) a first base which is an organic base or an inorganic base; the contacting, wherein the first solvent is an aprotic solvent or a nonpolar solvent; and 2) treating the mixture with an acid to provide the compound of formula VII or a salt thereof; A method comprising: In the formula R １ is hydrogen, methanesulfonic acid, or p-toluenesulfonic acid; and R ２ and R ３ are independently hydrogen, substituted or unsubstituted C １－８ Alkyl, or substituted or unsubstituted C ６－１２ The method according to claim 1, wherein the aryl is aryl.

29. The mixture comprises a compound of formula VI: 【Chemistry 10】 29. The method of claim 28, comprising:

30. R １ is hydrogen; R ２ is hydrogen; and R ３ 30. The method of claim 28 or 29, wherein is phenyl.

31. R １ is hydrogen; R ２ and R ３ 30. The method of claim 28 or 29, wherein each is methyl.

32. 32. The method of claim 30 or 31, wherein the one or more coupling agents are diethyl azodicarboxylate (DEAD) in combination with triphenylphosphine or diisopropyl azodicarboxylate (DIAD) in combination with triphenylphosphine.

33. R １ is methanesulfonic acid, R ２ is hydrogen, and R ３ 30. The method of claim 28 or 29, wherein is phenyl.

34. the one or more coupling agents are the first base; 34. The method of claim 33, wherein the first base is an organic base or an inorganic base.

35. 35. The method of claim 34, wherein the first base is an inorganic base.

36. 36. The method of claim 35, wherein the inorganic base is one or more alkali carbonates.

37. 37. The method of claim 36, wherein the one or more alkali carbonates is potassium carbonate.

38. 38. The method of any one of claims 28 to 37, wherein the first solvent is dimethylformamide, dichloromethane, toluene, dimethylacetamide, isopropyl acetate, acetonitrile, tetrahydrofuran, or a mixture thereof.

39. 32. The method of claim 30 or 31, wherein the first solvent comprises tetrahydrofuran.

40. 34. The method of claim 33, wherein the first solvent comprises dimethylformamide.

41. Step 2) is 2a) treating the mixture with an acid in a second solvent to provide a salt of the compound of formula VII; the treating, wherein the second solvent is an aprotic solvent or a nonpolar solvent; and 2b) neutralizing the salt of the compound of Formula VII with an inorganic base in a third solvent to provide the compound of Formula VII; 41. The method of any one of claims 28 to 40, comprising said neutralizing, wherein said third solvent is water.

42. 42. The method of claim 41, wherein the acid is HCl or methanesulfonic acid.

43. 43. The method of claim 41 or 42, wherein the second solvent is dimethylformamide, dichloromethane, toluene, dimethylacetamide, isopropyl acetate, acetonitrile, tetrahydrofuran, or a mixture thereof.

44. 44. The method of claim 43, wherein the second solvent comprises toluene or isopropyl acetate.

45. 42. The method of claim 41, wherein the inorganic base is potassium carbonate.

46. 30. The method of claim 29, wherein the compound of formula VI is used directly in step 2) without isolation.

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