Patent Description:
Orilissa is the first FDA-approved oral pill specifically developed for women with moderate to severe endometriosis pain in over a decade.

<CIT> discloses the preparation of elagolix sodium as shown by Scheme <NUM> in <FIG>. The preparation involved the construction of compound C from <NUM>-fluoro-<NUM>-(trifluoromethyl)benzonitrile via an intramolecular cyclization, followed by introduction of Br at C5 position to give compound D. Compound D was alkylated with N-Boc-D-phenylglycinol at N3 position via a Mitsunobu reaction to afford compound E. Subsequently, compound E was reacted with <NUM>-fluoro-<NUM>-methoxyphenylboronic acid in the presence of a Pd catalyst to undergo a Suzuki coupling reaction, followed by a de-Boc reaction to obtain compound F. The NH<NUM> group in compound F was alkylated with ethyl <NUM>-bromobutyrate to give compound G. Finally, elagolix sodium was obtained by the hydrolysis of compound G with NaOH.

<CIT> discloses two approaches for the general preparation of elagolix sodium and its intermediates, as shown by Scheme <NUM> in <FIG> and Scheme <NUM> in <FIG>, respectively. As shown in <FIG>, the first approach involved the introduction of iodo (I) instead of bromo (Br) at C5 position, followed by a Suzuki reaction with <NUM>-fluoro-<NUM>-methoxyphenylboronic acid to give compound 1d. Compound 1f was obtained via the treatment of compound 1d with compound 1e under basic conditions, followed by de-Boc reaction. Subsequently, the NH<NUM> group in compound 1f was alkylated with ethyl <NUM>-bromobutyrate to give compound <NUM>. After hydrolysis under basic conditions, elagolix sodium was obtained. As shown in <FIG>, the second approach involved the construction of uracil derivative <NUM> from the reaction of compound 2f with t-Boc-(1R)-amino-<NUM>-amino-<NUM>-phenylethane acetate salt. Subsequently, compound <NUM> could be alkylated with <NUM>-fluoro-<NUM>-trifluoromethylbenzyl bromide to give compound <NUM>. Compound <NUM> in Scheme <NUM> of <FIG> is also represented by compound F in Scheme <NUM> of <FIG> and compound 1f in Scheme <NUM> of <FIG>.

<CIT>A1 discloses an alternative route for the preparation of elagolix and its intermediates, as shown by Scheme <NUM> in <FIG>. In order to avoid the formation of potential genotoxic byproduct, such as methansulfonic acid, this route involved a Mitsunobu reaction to undergo a C-N bond coupling of compound X with N-Boc-D-phenylglycinol.

Despite the above described processes, there remains a need for the development of improved processes for the preparation of elagolix sodium. The present disclosure addresses this need and provides related advantages as well.

<CIT>, <CIT>, and <CIT> disclose different processes for producing elagolix.

The present invention is set forth in the appended claims. In one aspect, the present invention provides a process for preparing a compound of formula VII:
<CHM>
or a salt thereof, according to claim <NUM>.

In another aspect, the present invention provides a process for preparing elagolix of formula VII
or a pharmaceutically acceptable salt thereof, according to claim <NUM>.

The present invention provides improved processes for the preparation of elagolix and intermediates thereof. As compared to prior art, the present invention is suitable for a large-scale production, avoiding the use of potential genotoxic substances and can be performed under mild conditions. The coupling reaction of the present invention utilizes N-benzylidene-D-phenylglycinol (the compound of formula IVa), in which the benzylidene group at the N atom has less steric hindrance than the tert-butoxycarbonyl (Boc) group ofN-Boc-D-phenylglycinol. This steric difference is found to affect the ratio of N-alkylation/O-alkylation of the imide (the compound of formula V). When N-Boc-D-phenylglycinol (disclosed in <CIT>) is used, the reaction produces an O-alkylated side product in an amount of <NUM>∼<NUM>%. In the present invention, the O-alkylated side product is not observed when N-benzylidene-D-phenylglycinol is used. Furthermore, the deprotection of N-benzylidene group to generate the NH<NUM> group is achieved under mild conditions by treatment with an acid at room temperature. As comparison, the deprotection of the N-Boc group is performed at <NUM>, as described in prior art.

"Alkyl" refers to a straight or branched, saturated, aliphatic radical having the number of carbon atoms indicated (i.e., C<NUM>-<NUM> means one to eight carbons). Alkyl can include any number of carbons, such as C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM>, C<NUM>-<NUM> and C<NUM>-<NUM>. For example, C<NUM>-<NUM> 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, etc..

"Aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups can include any suitable number of ring atoms, such as, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM> or <NUM> ring atoms, as well as from <NUM> to <NUM>, <NUM> to <NUM>, or <NUM> to <NUM> ring members. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by a bond to form a biaryl group. Representative aryl groups include phenyl, naphthyl and biphenyl. Other aryl groups include benzyl, having a methylene linking group. Some aryl groups have from <NUM> to <NUM> ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have from <NUM> to <NUM> ring members, such as phenyl or naphthyl. Some other aryl groups have <NUM> ring members, such as phenyl. Aryl groups can be substituted or unsubstituted.

"OMs" refers to methanesulfonate; and "OTs" refers to p-toluenesulfonate.

"Salt" refers to acid or base salts of the compounds used in the methods of the present disclosure. Salts useful in the present disclosure include, but are not limited to, phosphate, sulfate, chloride, bromide, carbonate, nitrate, acetate, methanesulfonate, sodium, potassium, and calcium salts. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, and the like) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid and the like) salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like) salts, and alkaline metal or alkaline earth metal salts (sodium, potassium, calcium, and the like). It is understood that the pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in <NPL>, which is incorporated herein by reference.

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

"First base", "second base", and so on refer to a base as defined above and described in embodiments of the present invention. The base naming conventions are used solely for the purpose of clarity in relevant steps of the process as described herein and they are not required to be in a numerical order. Some bases may be absent in selected embodiments of the present invention as described herein. One skilled in the art will understand the meaning of these base naming conventions ('first base', 'second base') within the context of the term's use in the embodiments and claims herein.

"Tertiary amine" refers to a compound having formula N(R)<NUM> wherein the R groups can be alkyl, aryl, heteroalkyl, heteroaryl, among others, or two R groups together form a A-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, <NUM>,<NUM>-bis(dimethylamino)naphthalene, quinuclidine, and <NUM>,<NUM>-diazabicylo[<NUM>. <NUM>]-octane (DABCO).

"Aromatic amine base" refers to a N-containing <NUM>- to <NUM>-membered heteroaryl compound or a tertiary amine having formula N(R)<NUM> wherein at least one R group is an aryl or heteroaryl. Aromatic amine bases useful in the present application include, but are not limited to, pyridine, lutidines (e.g., <NUM>,<NUM>-lutidine, <NUM>,<NUM>-lutidine, and <NUM>,<NUM>-lutidine), collidines (e.g., <NUM>,<NUM>,<NUM>-collidine, <NUM>,<NUM>,<NUM>-collidine, <NUM>,<NUM>,<NUM>-collidine, <NUM>,<NUM>,<NUM>-collidine, <NUM>,<NUM>,<NUM>-collidine, and <NUM>,<NUM>,<NUM>-collidine), <NUM>-dimethylaminopyridine, imidazole, dimethylaniline, and diethylaniline.

"Amidine-based compounds" herein refers to a class of chemical compounds that include, but are not limited to, <NUM>,<NUM>-diazabicyclo[<NUM>. <NUM>]undec-<NUM>-ene (DBU) and <NUM>,<NUM>-diazabicyclo [<NUM>. <NUM>] non-<NUM> -en (DBN).

"Alkali bicarbonate" refers to a class of chemical compounds which are composed of an alkali metal cation and the hydrogencarbonate anion (HCO<NUM>-). Alkali carbonates useful in the present disclosure include lithium bicarbonate (LiHCO<NUM>), sodium bicarbonate (NaHCO<NUM>), potassium bicarbonate (KHCO<NUM>), and cesium bicarbonate (CsHCO<NUM>).

"Alkali carbonate" refers to a class of chemical compounds which are composed of an alkali metal cation and the carbonate anion (CO<NUM><NUM>-). Alkali carbonates useful in the present disclosure include lithium carbonate (Li<NUM>CO<NUM>), sodium carbonate (Na<NUM>CO<NUM>), potassium carbonate (K<NUM>CO<NUM>), and cesium carbonate (Cs<NUM>CO<NUM>).

"Alkali hydroxide" refers to a class of chemical compounds which are composed of an alkali metal cation and the hydroxide anion (OH-). Alkali hydroxides useful in the present disclosure include lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium hydroxide (CsOH), and calcium hydroxide (Ca(OH)<NUM>).

"Contacting" refers to the process of bringing into contact at least two distinct species such that they can react. It should be appreciated, however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.

"Deprotecting" refers to remove the protecting group (e.g., the benzylidene group at the N-atom of a compound of formula VI) using one or more chemicals or agents so that the functional group (e.g., -NH<NUM> group) is restored to its original state.

"Solvent" refers to a substance, such as a liquid, capable of dissolving a solute. Solvents can be polar or non-polar, protic or aprotic. Polar solvents typically have a dielectric constant greater than about <NUM> or a dipole moment above about <NUM>, and non-polar solvents have a dielectric constant below about <NUM> or a dipole moment below about <NUM>. Protic solvents are characterized by having a proton available for removal, such as by having a hydroxy or carboxy group. Aprotic solvents lack such a group. Representative polar protic solvents include alcohols (methanol, ethanol, propanol, isopropanol, etc.), acids (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 (pentanes, hexanes, etc.), cycloalkanes (cyclopentane, cyclohexane, etc.), benzene, toluene, diethyl ether, and <NUM>,<NUM>-dioxane. Other solvents are useful in the present invention.

"First solvent", "second solvent", and so on refer to a solvent as defined above and described in embodiments of the present invention. The solvent naming conventions are used solely for the purpose of clarity in steps of the process as described herein and they are not required to be in a numerical order. Some solvents may be absent in selected embodiments of the present invention as described herein. One skilled in the art will understand the meaning of these solvent naming conventions (e.g., `first solvent', 'second solvent') within the context of the term's use in the embodiments and claims herein.

In one aspect, the present invention provides a process for preparing a compound of formula VII:
<CHM>
or a salt thereof, the process including:.

wherein R<NUM> is hydrogen, methanesulfonate, or p-toluenesulfonate; and
R<NUM> and R<NUM> are independently hydrogen, substituted or unsubstituted C<NUM>-<NUM> alkyl, or substituted or unsubstituted C<NUM>-<NUM> aryl.

According to the present invention, the mixture includes a compound of formula VI:
<CHM>.

In some embodiments, when R<NUM> is hydrogen, step <NUM>) is conducted under Mitsunobu conditions.

In some embodiments, R<NUM> is hydrogen; R<NUM> and R<NUM> are independently hydrogen, substituted or unsubstituted C<NUM>-<NUM> alkyl, or substituted or unsubstituted C<NUM>-<NUM> aryl. In some embodiments, R<NUM> is hydrogen; R<NUM> is hydrogen; and R<NUM> is substituted or unsubstituted C<NUM>-<NUM> aryl. In some embodiments, R<NUM> is hydrogen; R<NUM> is hydrogen; and R<NUM> is phenyl. In some embodiments, R<NUM> is hydrogen; R<NUM> and R<NUM> are each substituted or unsubstituted C<NUM>-<NUM> alkyl. In some embodiments, R<NUM> is hydrogen; R<NUM> and R<NUM> are each methyl. In some embodiments, R<NUM> is hydrogen; R<NUM> is substituted or unsubstituted C<NUM>-<NUM> alkyl; and R<NUM> is substituted or unsubstituted C<NUM>-<NUM> aryl. In some embodiments, R<NUM> is hydrogen; R<NUM> is methyl; and R<NUM> is phenyl.

Mitsunobu conditions include an azodicarboxylate compound and triphenylphosphine. In some embodiments, the one or more coupling agents in step <NUM>) are a combination of diethyl azodicarboxylate (DEAD) and triphenylphosphine, a combination of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine, a combination of tetraisopropylazodicarboxamide (TIPA) and triphenylphosphine , a combination of azodicarbonyldipiperidine (ADDP) and triphenylphosphine, or a combination of bis(<NUM>,<NUM>,<NUM>-trichloroethyl) azodicarboxylate (TCEAD) and triphenylphosphine. In some embodiments, the one or more coupling agents in step <NUM>) are a combination of diethyl azodicarboxylate (DEAD) and triphenylphosphine or a combination of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine. In some embodiments, the one or more coupling agents in step <NUM>) are a combination of diisopropyl azodicarboxylate (DIAD) and triphenylphosphine.

The first solvent under Mitsunobu conditions can be an aprotic solvent or a non-polar 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 mixtures thereof. In some embodiments, the first solvent includes tetrahydrofuran (THF).

In general, the Mitsunobu reaction (i.e., step <NUM>)) can be performed at any suitable temperature. In some embodiments, the Mitsunobu reaction is conducted at a temperature of from <NUM> to <NUM>. In some embodiments, the Mitsunobu reaction is conducted at a temperature of from <NUM> to <NUM>. In some embodiments, the Mitsunobu reaction is conducted at room temperature.

In some embodiments, when R<NUM> is methanesulfonate (Ms) or p-toluenesulfonate (Ts), step <NUM>) is conducted under nucleophilic conditions.

In some embodiments, R<NUM> is methanesulfonate (Ms); R<NUM> and R<NUM> are independently hydrogen, substituted or unsubstituted C<NUM>-<NUM> alkyl, or substituted or unsubstituted C<NUM>-<NUM> aryl. In some embodiments, R<NUM> is methanesulfonate (Ms); R<NUM> is hydrogen; and R<NUM> is substituted or unsubstituted C<NUM>-<NUM> aryl. In some embodiments, R<NUM> is methanesulfonate (Ms); R<NUM> is hydrogen; and R<NUM> is phenyl. In some embodiments, R<NUM> is methanesulfonate (Ms); R<NUM> and R<NUM> are each substituted or unsubstituted C<NUM>-<NUM> alkyl. In some embodiments, R<NUM> is methanesulfonate (Ms); R<NUM> and R<NUM> are each methyl. In some embodiments, R<NUM> is methanesulfonate (Ms); R<NUM> is substituted or unsubstituted C<NUM>-<NUM> alkyl; and R<NUM> is substituted or unsubstituted C<NUM>-<NUM> aryl. In some embodiments, R<NUM> is methanesulfonate (Ms); R<NUM> is methyl; and R<NUM> is phenyl.

In some embodiments, R<NUM> is p-toluenesulfonate (Ts); R<NUM> and R<NUM> are independently hydrogen, substituted or unsubstituted C<NUM>-<NUM> alkyl, or substituted or unsubstituted C<NUM>-<NUM> aryl. In some embodiments, R<NUM> is p-toluenesulfonate (Ts); R<NUM> is hydrogen; and R<NUM> is substituted or unsubstituted C<NUM>-<NUM> aryl. In some embodiments, R<NUM> is p-toluenesulfonate (Ts); R<NUM> is hydrogen; and R<NUM> is phenyl. In some embodiments, R<NUM> is p-toluenesulfonate (Ts); R<NUM> and R<NUM> are each substituted or unsubstituted C<NUM>-<NUM> alkyl. In some embodiments, R<NUM> is p-toluenesulfonate (Ts); R<NUM> and R<NUM> are each methyl. In some embodiments, R<NUM> is p-toluenesulfonate (Ts); R<NUM> is substituted or unsubstituted C<NUM>-<NUM> alkyl; and R<NUM> is substituted or unsubstituted C<NUM>-<NUM> aryl. In some embodiments, R<NUM> is p-toluenesulfonate (Ts); R<NUM> is methyl; and R<NUM> is phenyl.

The nucleophilic conditions include a first base. In some embodiments, the one or more coupling agents in step <NUM>) are a first base. The first base can be an organic or inorganic base, as defined herein. 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 (U<NUM>CO<NUM>), sodium carbonate (Na<NUM>CO<NUM>), potassium carbonate (K<NUM>CO<NUM>), and cesium carbonate (Cs<NUM>CO<NUM>), or combinations thereof. In some embodiments, the first base is potassium carbonate (K<NUM>CO<NUM>).

The first solvent under nucleophilic conditions can be an aprotic solvent or a non-polar 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 mixtures thereof. In some embodiments, the first solvent includes dimethylformamide (DMF).

In general, the nucleophilic reaction (i.e., step <NUM>)) can be performed at any suitable temperature. In some embodiments, the nucleophilic reaction is conducted at a temperature of from <NUM> to <NUM>. In some embodiments, the nucleophilic reaction is conducted at a temperature of from <NUM> to <NUM>. In some embodiments, the nucleophilic reaction is conducted at a temperature of about <NUM>.

In some embodiments, step <NUM>) includes:
2a) treating the mixture with an acid in a second solvent to provide the salt of the compound of formula VII.

In some embodiments, step <NUM>) includes:.

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.

In some embodiments, the salt of the compound of formula VII is a HCl salt thereof.

The second solvent for deprotection (i.e., step 2a)) can be an aprotic solvent or a non-polar solvent as defined herein. In some embodiments, the second solvent is dimethylformamide (DMF), dichloromethane (DCM), toluene, dimethylacetamide(DMAc), isopropyl acetate (IPAc), acetonitrile, tetrahydrofuran (THF), or mixtures thereof. In some embodiments, the second solvent includes toluene. In some embodiments, the second solvent includes isopropyl acetate (IPAc).

In general, the deprotection reaction (i.e., step 2a)) can be performed at any suitable temperature. In some embodiments, the deprotection reaction is conducted at a temperature of from <NUM> to <NUM>. In some embodiments, the deprotection reaction is conducted at a temperature of from <NUM> to <NUM>. In some embodiments, when the acid is an aqueous solution of HCl, the deprotection reaction is conducted at a room temperature of from <NUM> to <NUM>. In some embodiments, when the acid is methanesulfonic acid, the deprotection reaction is conducted at a temperature of about <NUM>.

The second base in step 2b) can be an inorganic base as defined herein. In some embodiments, the second base is an inorganic base. In some embodiments, the second base is an alkali carbonate. In some embodiments, the second base is sodium carbonate (Na<NUM>CO<NUM>) or potassium carbonate (K<NUM>CO<NUM>). In some embodiments, the second base is potassium carbonate (K<NUM>CO<NUM>).

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 takes place in an aqueous solution including the salt of the compound of formula VII.

In general, the neutralization reaction (i.e., step 2b)) can be performed at any suitable temperature. In some embodiments, the neutralization reaction is conducted at a temperature of from <NUM> to <NUM>. In some embodiments, the neutralization reaction is conducted at a temperature of from <NUM> to <NUM>.

In some embodiments, steps <NUM>) and <NUM>) are conducted in one-pot. In some embodiments, steps <NUM>) and 2a) are conducted in one-pot. In some embodiments, steps <NUM>), 2a), and 2b) are conducted in one-pot. In some embodiments, the compound of formula VI is used directly in step <NUM>) without isolation. In some embodiments, the compound of formula VI is used directly in step 2a) without isolation. In some embodiments, the salt of the compound of formula VII is used directly in step 2b) without isolation.

In some embodiments, the compound of formula VI is isolated prior to step <NUM>). 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).

In some embodiments, the present invention provides a process for preparing a compound of formula VII:
<CHM>
the process including:.

wherein R<NUM>, R<NUM>, and R<NUM> are defined and described herein; and steps <NUM>), 2a), and 2b) are described herein.

In some embodiments, the present invention provides a process for preparing a salt of a compound of formula VII:
<CHM>
the process including:.

wherein R<NUM>, R<NUM>, and R<NUM> are defined and described herein; and steps <NUM>) and 2a) are described herein.

In some embodiments, the mixture includes a compound of formula VI:
<CHM>.

In another aspect, the present invention provides a process for preparing elagolix of formula I:
<CHM>
or a pharmaceutically acceptable salt thereof, the process including:.

In some embodiments, R<NUM>, R<NUM>, and R<NUM> are described above.

In some embodiments, steps 2a) and 2b) as described above.

In some embodiments, the ethyl <NUM>-halobutyrate in step <NUM>) is ethyl <NUM>-bromobutyrate.

The third base in step <NUM>) can be an organic or 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).

The fourth solvent for step <NUM>) can be an aprotic solvent or a non-polar 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 mixtures thereof. In some embodiments, the fourth solvent includes dimethylacetamide (DMAc).

In general, step <NUM>) can be performed at any suitable temperature. In some embodiments, the step <NUM>) reaction mixture can be at a temperature of from <NUM> to <NUM>. In some embodiments, the step <NUM>) reaction mixture can be at a temperature of from <NUM> to <NUM>. In some embodiments, the step <NUM>) reaction reaction mixture can be at a temperature of about <NUM>.

The fourth base in step <NUM>) 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)<NUM>). In some embodiments, the fourth base is sodium hydroxide (NaOH) or calcium hydroxide (Ca(OH)<NUM>). In some embodiments, the fourth base is sodium hydroxide (NaOH).

The fifth solvent for step <NUM>) can be an alcohol, water, or combinations thereof. In some embodiments, the fifth solvent includes ethanol and water.

In general, step <NUM>) can be performed at any suitable temperature. In some embodiments, the step <NUM>) reaction mixture is at a temperature of from <NUM> to <NUM>. In some embodiments, the step <NUM>) reaction mixture is at a temperature of from <NUM> to <NUM>.

In some embodiments, the pharmaceutically acceptable salt of elagolix of formula I is a sodium salt. In some embodiments, the elagolix of formula I is elagolix sodium.

In some embodiments, steps <NUM>) and <NUM>) are conducted in one-pot. In some embodiments, steps <NUM>) to <NUM>) are conducted in one-pot.

In some embodiments, elagolix sodium is isolated as a solid.

To a suitable reactor, the compound of formula II (<NUM>) and acetic acid (<NUM>) were added at room temperature. The resulting clear solution was added N-iodosuccinimide (<NUM>). The mixture was heated to <NUM> and stirred for <NUM> hours. Upon completion, the suspension was added water (<NUM>) slowly and then cooled to room temperature. The slurry was stirred at room temperature for <NUM> hours, followed by filtration. The wet cake was washed with water (<NUM>) twice and then dried in vacuo at <NUM> to afford crude compound of formula III. Crude compound of formula III and MeOH (<NUM>) was charged to a suitable reactor. The slurry mixture was heated to reflux and stirred for <NUM> hour. After reflux, the slurry was cooled to room temperature and stirred for <NUM> hour, followed by filtration. The wet cake was washed with pre-cooled MeOH (<NUM>) and then dried in vacuo at <NUM> to afford the compound of formula III (<NUM>, <NUM>% yield).

To a suitable reactor, the compound of formula III (<NUM>), <NUM>-fluoro-<NUM>-methoxyphenylboronic acid (<NUM>), acetone (<NUM>) were charged. KOH (<NUM>) in water (<NUM>) was added. The resulting mixture was degassed for <NUM>. The mixture was heated to <NUM>, followed by addition of PdCl<NUM>(dtbpf) (<NUM>). The reaction was heated to <NUM> and stirred for <NUM> hrs. Upon completion, the reaction was cooled to room temperature. Celite (<NUM>) was added. The mixture was stirred for <NUM> hr, followed by filtration. The Celite cake was washed with a mixture solution of KOH (<NUM>)/acetone (<NUM>)/water (<NUM>). The filtrate was added slowly to another flask containing THF (<NUM>)/AcOH (<NUM>)/water (<NUM>) at <NUM>. After addition, the resulting slurry was cooled to room temperature and then stirred for <NUM> hr. The slurry was filtered through a Buchner funnel to afford a wet cake. The wet cake was washed with water/MeOH (v/v = <NUM>/<NUM>, <NUM>) twice, followed by MeOH (<NUM>) twice. The wet cake was dried at NMT <NUM> in vacuo to give the compound of formula V (<NUM>, <NUM>% yield).

To a suitable reactor, the compound of formula V (<NUM>), N-benzylidene-D-phenylglycinol (<NUM>), PPh<NUM> (<NUM>) and THF (<NUM>) were added, followed by addition of DIAD (<NUM>). The reaction was stirred at room temperature for <NUM> hours. Upon completion, the reaction was quenched with water (<NUM>) and then stirred for <NUM>. The resulting mixture concentrated via solvent-swap with toluene (<NUM>) to <NUM> vol. 3N HCl (<NUM>) was added. The resulting mixture was stirred at room temperature for <NUM> hour. Upon completion, MeOH (<NUM>) was added. The solution was washed with n-heptane (<NUM>) for three times, followed by concentration via solvent-swap with toluene to <NUM> vol. The solution was neutralized with K<NUM>CO<NUM> (<NUM>) in water (<NUM>). The aqueous layer was extracted with toluene (<NUM>). The combined organic layers were extracted with <NUM>% H<NUM>PO<NUM> (<NUM>) twice. The aqueous layer was washed with IPAc (<NUM>) twice. The aqueous layer was neutralized with K<NUM>CO<NUM> (<NUM>) in water (<NUM>). The resulting solution was extracted with IPAc (<NUM>). The organic layer was washed with water (<NUM>) and then recrystallized with IPAc/n-heptane to give the compound of formula VII (<NUM>, <NUM>% yield).

To a suitable reactor, the compound of formula V (<NUM>), N-isopropylidene-D-phenylglycinol (<NUM>), PPh<NUM> (<NUM>) and THF (<NUM>) were added, followed by addition of DIAD (<NUM>). The reaction was stirred at room temperature for <NUM> hours. Upon completion, the reaction was quenched with water (<NUM>) and then stirred for <NUM>. The resulting mixture concentrated via solvent-swap with toluene (<NUM>) to <NUM> vol. MsOH (<NUM>) was added. The resulting mixture was stirred at <NUM> for <NUM> hour. Upon completion, K<NUM>CO<NUM> (<NUM>) in water (<NUM>) was added at NMT <NUM>. Toluene (<NUM>) was added to the mixture for phase separation. The aqueous layer was extracted with toluene (<NUM>). The combined organic layers were extracted with <NUM>% H<NUM>PO<NUM> (<NUM>) twice. The combined aqueous layer was washed with IPAc (<NUM>) twice. The aqueous layer was neutralized with K<NUM>CO<NUM> (<NUM>) in water (<NUM>). The resulting solution was extracted with IPAc (<NUM>). The organic layer was washed with water (<NUM>) and then recrystallized with IPAc/n-heptane to give the compound of formula VII (<NUM>, <NUM>% yield).

To a suitable reactor, the compound of formula V (<NUM>), [(2R)-<NUM>-[(E)-benzylideneamino]-<NUM>-phenyl-ethyl] methanesulfonate (<NUM>), K<NUM>CO<NUM> (<NUM>) and DMF (<NUM>) were added. The reaction was stirred at <NUM>. Upon completion, IPAc (<NUM>) and water (<NUM>) were charged to the reactor. The organic layer was washed with water (<NUM>). 3N HCl (<NUM>) was added. The resulting mixture was stirred at room temperature for <NUM> hour. Upon completion, MeOH (<NUM>) was added. The solution was washed with n-heptane (<NUM>) for three times, followed by concentration via solvent-swap with toluene to <NUM> vol. The solution was neutralized with K<NUM>CO<NUM> (<NUM>) in water (<NUM>). The aqueous layer was extracted with toluene (<NUM>). The combined organic layers were extracted with <NUM>% H<NUM>PO<NUM> (<NUM>) twice. The aqueous layer was washed with IPAc (<NUM>) twice. The aqueous layer was neutralized with K<NUM>CO<NUM> (<NUM>) in water (<NUM>). The resulting solution was extracted with IPAc (<NUM>). The organic layer was washed with water (<NUM>) and then recrystallized with IPAc/n-heptane to give the compound of formula VII (<NUM>, <NUM>% yield).

Claim 1:
A process for preparing elagolix of formula I:
<CHM>
or a pharmaceutically acceptable salt thereof, the process comprising:
<NUM>) contacting a compound of formula V:
<CHM>
with a compound of formula IV:
<CHM>
in a first solvent to form a mixture comprising a compound of formula VI:
<CHM>
wherein step <NUM>), when R<NUM> is hydrogen, is conducted under a Mitsunobu condition comprising one or more coupling agents; or step <NUM>), when R<NUM> is methanesulfonate, or p-toluenesulfonate, is conducted under a nucleophilic condition comprising a first base;
2a) treating the mixture with an acid in a second solvent; and 2b) neutralizing with a second base in a third solvent comprising water to provide a compound of formula VII:
<CHM>
<NUM>) contacting the compound of formula VII with ethyl <NUM>-halobutyrate and a third base in a fourth solvent to form a compound of formula VIII:
<CHM>
and
<NUM>) treating the compound of formula VIII with a fourth base in a fifth solvent to provide elagolix of formula I or the pharmaceutically acceptable salt thereof,
wherein R<NUM> is hydrogen, methanesulfonate, or p-toluenesulfonate; and
R<NUM> and R<NUM> are independently hydrogen, substituted or unsubstituted C<NUM>-<NUM> alkyl, or substituted or unsubstituted C<NUM>-<NUM> aryl.