Improved process for producing an elinzanetant precursor

Abstract

The present invention relates to a new and improved process for producing the intermediate of the synthesis of 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2- methylphenyl)-6-[(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,1-c][1,4]oxazin- 8(1H)-yl]pyridin-3-yl}-N,2-dimethylpropanamide (elinzanetant), namely the direct precursor with a protective group attached to the hydroxy group of the 7-(hydroxymethyl)hexahydropyrazino moiety within the structure of elinzanetant. The invention also relates to compositions comprising the compound of Formula (II) with increased purity, in particular with respect to the impurities of Formula (VI) and Formula (VII). Furthermore, the invention relates to a process for manufacturing elinzanetant or a salt thereof, the process comprising the new and improved process for producing the intermediate.

Description

[0001] New PCT Application Bayer Consumer Care AG Our Ref: BHC243010 WO Improved Process for producing an elinzanetant precursor The present invention relates to a new and improved process for producing a central intermediate of 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6- [(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]pyridin-3-yl}- N,2-dimethylpropanamide (elinzanetant), namely the direct precursor with a protective group attached to the hydroxy group of the 7-(hydroxymethyl)hexahydropyrazino moiety within the structure of elinzanetant. The invention also relates to compositions comprising the compound of Formula (II) with increased purity, in particular with respect to the impurities of Formula (VI) and Formula (VII). Furthermore, the invention relates to a process for manufacturing elinzanetant or a salt thereof, the process comprising the new and improved process for producing the intermediate. Background of the Invention The compound 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)-6- [(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]pyridin-3-yl}- N,2-dimethylpropanamide (herein also referred to by its INN: elinzanetant) is being developed for treatment of different diseases and conditions (WO 2007 / 028654 A1), including sex-hormone dependent diseases and disorders (WO 2016 / 184829 A1). Elinzanetant is a dual neurokinin-1 (NK-1) receptor antagonist and neurokinin-3 (NK- 3) receptor antagonist (also referred to as dual NK-1 / NK-3 receptor antagonists). Elinzanetant is the compound of Formula (I): (I). The prior-art production of elinzanetant comprises the compound of Formula (IIa) as a central intermediate and precursor before obtaining the final product; see WO 2021 / 094247 A1: (IIa). In WO 2021 / 094247 A1 the production of the compound of Formula (IIa) is performed by a palladium-catalyzed Buchwald-Hartwig C-N cross-coupling of the compound of Formula (IVa) with the compound of Formula (Va) in the presence of sodium tert- butoxide as a base. The compound of Formula (IVa) is obtained by conversion of its di-oxalate salt of Formula (IIIa) into the free base. The Buchwald-Hartwig C-N cross- coupling in the prior art is performed using Bis(tri-tert-butylphosphine) palladium(0) (see WO 2021 / 094247, Example 6). For medicinal products, it is necessary to safeguard that the products have a minimum proportion of impurities. Further, the presence of impurities leads to reduced quality of the product and to a loss of yield. Further, cumbersome crystallization processes may be needed to deplete the impurities, but that are accompanied by a loss of yield. Palladium forms a variety of ionic, coordination, and organopalladium compounds, typically with oxidation states of Pd0or Pd2+. Palladium compounds are frequently used as catalysts in cross-coupling reactions. To generate the active catalyst, which comprises of a palladium coordinated to one or more ligands, e.g. phosphines, two typical pathways are known. Either a palladium precursor is mixed with the ligand to form the catalytically active palladium complex in-situ, or a precatalyst is used. Precatalyst are already preformed palladium and ligand complexes. Typically, a homogenous Pd catalyst consists of two mono-dentate ligands or one bidentate ligand and a palladium atom two which said ligand(s) is / are coordinated. See also Negishi, E.-i. (2002). Background for Part II. In Handbook of Organopalladium Chemistry for Organic Synthesis, E.-i. Negishi (Ed.).; and Tsuji, J. (2004). The Basic Chemistry of Organopalladium Compounds. In Palladium Reagents and Catalysts, J. Tsuji (Ed.) The inventors of the present invention have found that the use of bis(tri-tert- butylphosphine) palladium as the catalyst in the Buchwald-Hartwig C-N cross-coupling of the compounds of Formula (IV) and Formula (V) results in the formation of undesired impurities, e.g. the compounds of Formula (VI) and / or Formula (VII) and / or Formula (VIII): Two impurities, the compound of Formula (VI) and the compound of Formula (VII), result from a competitive reaction to the actual C-N cross-coupling. Without being bound by hypothesis, impurity of the Formula (VI) originates from competing C-O coupling with the tert-butoxide. Without being bound by hypothesis, the inventors assume that the catalysts used in the prior art for this reaction by their low chemoselectivity mediate a reaction between sodium tert-butoxide, which is present as a base, with the chloropyridine of the compound of Formula (V) to form the tert-butyl ether (VI), whereas traces of water present (such as during reaction), may lead to the corresponding hydroxy compound of Formula (VII). The compound of Formula (VIII) is generated through competing proto dehalogenation. Other bases are described in the literature for Buchwald-Hartwig cross-coupling reactions. However, in the prior art alkoxide bases have been described as favorable for the palladium catalyzed C-N cross-coupling reaction to produce the compound of Formula (IIa); see WO 2021 / 094247 A1, Paola A. Forero-Cortés and Alexander M. Haydl Organic Process Research & Development 201923 (8), 1478-1483, Paula Ruiz- Castillo and Stephen L. Buchwald Chemical Reviews 2016116 (19), 12564-12649; and B.T. Ingoglia et al. / Tetrahedron 75 (2019) 4199-4211). The process of the prior art including the impurities obtained by the low chemoselectivity of the Pd catalyst is exemplified as follows: Hence, there is a need for the provision of an improved process for the synthesis of a compound of Formula (II) with a reduction in the proportion of impurities in the product, such as the impurities of the compounds of Formulas (VI) and / or (VII) and / or (VIII). In particular, there is a great need for a more efficient and economically more favorable process that allows the production of elinzanetant or a salt thereof or a compound of Formula (II) with an increased yield and purity. Further, there is a need for the provision of such method suited for use in a ton scale synthesis suitable for the pharmaceutical industry. Summary of the Invention The inventors of the present invention now have unexpectedly found that the above- mentioned needs are fulfilled by the use of a palladium catalyst that comprises a ligand of Formula (A) (A); wherein groups Z are independently from each other t-Bu, adamantyl, phenyl or - C4-C7-cycloalkyl; 2 wherein R1is or -O-C1-C3-alkyl; and 2 wherein R and from each other a C1-C3-alkyl. Such catalyst provides for the following unexpected superior effects in the process according to the invention: • significantly higher N-selectivity allowing the production of a compound of Formula (II), the direct precursor of elinzanetant, in a form as pure as possible, • lowering the amount of catalyst needed for the production while maintaining or even increasing yield and purity with respect to the identified impurities and providing for a complete conversion of the educts. Accordingly, a subject-matter of the present invention is a process for producing the compound of Formula (II), comprising the step of with the compound of wherein PG is a protective group; wherein X is a halogen or -O-SO2-R4; wherein R4is selected from the group consisting of alkyl, fluoroalkyl, optionally substituted phenyl, and optionally substituted naphthyl; and wherein the reaction is conducted in the presence of a Pd catalyst comprising a ligand of Formula (A) wherein groups Z are independently from each other selected from the group consisting of t-Bu, adamantyl, phenyl, and -C4-C7-cycloalkyl; 2 wherein R1is or -O-C1-C3-alkyl; and 2 wherein R and from each other a C1-C3-alkyl. A further subject-matter of the present invention is the use of a Pd catalyst or Pd precatalyst comprising a ligand of Formula (A), or of a Pd precursor in combination with a ligand of Formula (A) Z (A), in a process for producing a compound of Formula (II): wherein PG is a wherein groups Z are independently from each other selected from the group consisting of t-Bu, adamantyl, phenyl, and -C4-C7-cycloalkyl; 2 R N wherein R13 is R or -O-C1-C3-alkyl; and wherein R2and R3are independently from each other a C1-C3-alkyl. Yet a further subject-matter is the use of a Pd catalyst or Pd precatalyst comprising a ligand of Formula (A), or of a Pd precursor in combination with a ligand of Formula (A): Z in a process for manufacturing elinzanetant or a salt thereof; wherein groups Z are independently from each other selected from the group consisting of t-Bu, adamantyl, phenyl, and -C4-C7-cycloalkyl; and 2 wherein R1is or -O-C1-C3-alkyl; and 2 wherein R and from each other a C1-C3-alkyl. The invention also pertains to a process for manufacturing elinzanetant or a salt thereof, comprising process for producing the compound of Formula (II) as disclosed herein. The invention also pertains to a composition comprising a compound of Formula (II) obtainable by a method for producing or use of a Pd catalyst or a Pd precatalyst according to the present disclosure. Figure Legend Figure 1: Visualization of the selectivity factors S for Examples 2a, 2b, 2c, and 2d. Detailed Description The invention and its subject-matter are further defined by the disclosure and the embodiments herein. As used herein, “eq.” or “eq” are used interchangeably herein and refer to the molar equivalent of a molecule or atoms, per molecule or atom of a reference compound. In an embodiment, “eq.” may also be expressed as mol%. In an embodiment, 0.01 eq. equals 1 mol% as compared to the molar amount of the reference compound. A “protective group” (also referred to as “protecting group”) as used herein is a reversibly formed derivative of an existing functional group in a molecule. The protective group is temporarily attached to decrease reactivity so that the protected functional group does not react under synthetic conditions to which the molecule is subjected in one or more steps. “Elinzanetant” as used herein refers the respective INN. In an embodiment, elinzanetant refers to 2-[3,5-bis(trifluoromethyl)phenyl]-N-{4-(4-fluoro-2-methylphenyl)- 6-[(7S,9aS)-7-(hydroxymethyl)hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]pyridin-3- yl}-N,2-dimethylpropanamide. In an embodiment, elinzanetant refers to the compound of formula (I). Salts of elinzanetant refers to the any suitable salt of elinzanetant, in particular to a pharmaceutically acceptable salt. In an embodiment the salt of elinzanetant is selected from the group consisting of hydrochloride, besylate (benzenesulfonate), and tosylate (4-methyl benzenesulfonate). The inventors have unexpectedly found that the process of preparing a compound of Formula (II) can be conducted to reduce the proportion of impurities in the product while maintaining or even increasing yield and providing for a complete conversion of the educts, even with reduced amounts of catalyst, when a compound of Formula (IV) and a compound of Formula (V) are reacted in the presence of a Pd catalyst comprising a ligand of Formula (A). As will be understood by the skilled person when considering the present disclosure, the ligand, typically two ligands, coordinate the palladium atom. The inventors surprisingly could attribute a certain ligand group (the ligands of Formula (A)) to provide for improvements as outlined herein in the processes and uses according to the present disclosure. In an embodiment the ligand is of Formula (A) wherein groups Z are independently from each other selected from the group consisting of t-Bu, adamantyl, phenyl, and -C4-C7-cycloalkyl; and 2 wherein R1is or -O-C1-C3-alkyl; and 2 wherein R and from each other a C1-C3-alkyl. In an embodiment groups Z are independently from each other t-Bu or -cyclohexyl. In an embodiment Z is phenyl. In an embodiment Z is adamantyl. In an embodiment Z is t-Bu. In an embodiment Z is cyclohexyl. In an embodiment R1is -O-methyl. In an embodiment R1is -O-ethyl. In an embodiment R1is -O-propyl. 2 In an embodiment R1is R , and wherein R2and R3are independently from each other a C1-C3-alkyl. In an embodiment R2and R3are both methyl. 2 R N In an embodiment Z is t-Bu, and R13 is R and R2and R3are both methyl. In an embodiment the ligand is 4-(di-tert-butylphosphino)-N,N-dimethylaniline (Aphos, also referred to as amphos herein). In an embodiment, 4-(di-tert-butylphosphino)-N,N- dimethylaniline refers to a ligand of Formula (A1) -Bu (A1). In an embodiment Z is cyclohexyl, and R1is and R2and R3are both methyl. In an embodiment the ligand is 4-(dicyclohexylphosphino)-N,N-dimethylaniline (CAS: 40438-64-0). In an embodiment, the ligand is the ligand of Formula (A2) (A2). In an embodiment Z is phenyl, and R1is and R2and R3are both methyl. In an embodiment the ligand is 4-(diphenylphosphino)-N,N-dimethylaniline (CAS: 739- 58-2; (PPh2)(PhNMe2)). In an embodiment, the ligand is the ligand of Formula (A3) (A3). In an embodiment the Pd catalyst comprises two ligands. In an embodiment the Pd catalyst comprises two ligands of Formula (A1). In another embodiment Pd catalyst comprises two ligands of Formula (A2). In another embodiment the Pd catalyst comprises two ligands of Formula (A3). “Pd catalyst” in connection with the present disclosure refers to a catalytically active species comprising a Pd atom. Typically, a Pd catalyst consists of two mono-dentate ligands or one bidentate ligand and a palladium atom two which said ligand(s) is / are coordinated. In an embodiment the term refers to a Pd atom coordinated by one or two ligands of Formula (A). In an embodiment the term refers to a Pd atom coordinated by two ligands of Formula (A). In an embodiment the term refers to a Pd atom coordinated by a ligand of Formula (A1). In an embodiment the term refers to a Pd atom coordinated by two ligands of Formula (A1). In an embodiment the term refers to a Pd atom coordinated by a ligand of Formula (A2). In an embodiment the term refers to a Pd atom coordinated by two ligands of Formula (A2). In an embodiment the term refers to a Pd atom coordinated by a ligand of Formula (A3). In an embodiment the term refers to a Pd atom coordinated by two ligands of Formula (A3). In an embodiment the Pd catalyst is selected from the group consisting of Pd(Aphos)2(CAS: 1233717-68-4), bis[(dicyclohexyl)(4- (dimethylaminophenyl)phosphine)]palladium (Pd(A-caPhos)2), and bis[(4- (dimethylamino)phenyl)(diphenyl)phosphine)]palladium (Pd[(PPh2)(PhNMe2)]2). In an embodiment the Pd catalyst is the catalyst of Formula (B1) In an embodiment the Pd catalyst is the catalyst of Formula (B2) (B2). In an embodiment the Pd catalyst is the catalyst of Formula (B3) (B3). The Pd catalyst may be added to, or be formed in situ in the reaction by different means. It can be added as a Pd precatalyst in which the Pd atom is coordinated by the ligand(s). The Pd catalyst may also be formed in situ from a Pd precursor and the respective stoichiometric amounts of the ligand. ”Pd precatalyst” in an embodiment refers to a Pd(II) or Pd(0) atom coordinated by a ligand of Formula (A), and optionally one or more stabilizing anion (such as chloride, bromide, acetate or trifluoroacetate) and / or organic ligand to be exchanged by a ligand according to the present invention (such as acetylacetone, dibenzylideneacetone (dba), crotyl, allyl, or cinnamyl). In an embodiment the Pd catalyst according to the present disclosure is added as a Pd precatalyst comprising one or more ligands of Formula (A). In an embodiment the Pd catalyst according to the present disclosure is added as a Pd precatalyst comprising one or more ligands of Formula (A1). In an embodiment the Pd catalyst according to the present disclosure is added as a Pd precatalyst comprising one or more ligands of Formula (A2). In an embodiment the Pd catalyst according to the present disclosure is added as a Pd precatalyst comprising one or more ligands of Formula (A3). In an embodiment the Pd catalyst is added as a Pd precatalyst selected from the group consisting of Pd(APhos)2Cl2 (CAS: 887919-35-9), Pd(APhos)2Br2 (CAS: 2548682-79- 5), Pd(APhos)2 (CAS: 1233717-68-4), APhos Pd(allyl)Cl (CAS: 1235509-04-2), APhos Pd(crotyl)Cl (CAS: 1334497-06-1), APhos Pd(cinnamyl)Cl (CAS: 1323137-09-2), Aphos Pd-G2 (CAS: 2169976-34-3), Aphos Pd-G3 (CAS: 1820817-64-8), Aphos Pd- G4 (CAS: 2812444-73-6), Pd(A-caPhos)2Cl2 (CAS: 945375-77-9), A-caPhos Pd-G3 (CAS:2730016-91-6), and [(PPh2)(PhNMe2)]2PdCl2. The Pd catalyst may also be formed from a suitable Pd precursor, optionally as a salt, in combination with a ligand of Formula (A), optionally as a salt, in the desired stoichiometric amounts. When referring herein to the combination of a Pd precursor and a ligand of Formula (A) the use of respective salts shall be meant to be included. In an embodiment the Pd catalyst according to the present disclosure is formed from a Pd precursor and one or more ligands of Formula (A). In an embodiment the Pd catalyst according to the present disclosure is formed from a Pd precursor and g one or more ligands of Formula (A1). In an embodiment the Pd catalyst according to the present disclosure is formed from a Pd precursor and one or more ligands of Formula (A2). In an embodiment the Pd catalyst according to the present disclosure is formed from a Pd precursor and one or more ligands of Formula (A3). In an embodiment the Pd catalyst according to the present disclosure is formed from a combination of APhos (CAS: 932710-63-9) or A-caPhos (CAS: 40438-64-0]), (PPh2)PhNMe2(CAS: 739-58-2), or a combination thereof; and a Pd precursor selected from the group consisting of Pd(OAc)2 (CAS: 3375-31-3), Pd(OPiv)2 (CAS: 106224-36-6), Pd(Oi-Bu)2 (CAS: 61261-73-2), Pd(acetylacetonate)2 (CAS: 14024-61- 4), [Pd(crotyl)Cl]2(CAS: 12081-22-0), [Pd(cinnamyl)Cl]2(CAS: 12131-44-1), [PdCl(allyl)]2 (CAS: 12012-95-2), PdCl2 (CAS: 7647-10-1), PdCl2(1,5-cyclooctadiene) (CAS: 12107-56-1), PdCl2 (PhCN)2 (CAS: 14220-64-5), PdCl2 (CH3CN)2 (CAS: 14592- 56-4), PdBr2(CAS: 13444-94-5), PdBr2(1,5-cyclooctadiene) (CAS: 12145-47-0), [Pd(CH3CN)4](BF4)2(CAS: 21797-13-7), Pd(dba)2(CAS: 32005-36-0), Pd2(dba)3•CHCl3 (CAS: 52522-40-4) and Pd2(dba)3 (CAS: 51364-51-3), or combinations thereof. In an embodiment the Pd catalyst according to the present disclosure is formed from a combination of APhos or A-caPhos, or a combination thereof; and a Pd precursor selected from the group consisting of Pd(OAc)2, Pd(acetylacetonate)2, and Pd2(dba)3. In an embodiment the Pd catalyst according to the present disclosure is formed from a combination of APhos or A-caPhos, or a combination thereof; and Pd(OAc)2. In an embodiment the Pd catalyst according to the present disclosure is formed from a combination of APhos; and a Pd precursor selected from the group consisting of Pd(OAc)2, Pd(OPiv)2, Pd(OiBu)2, Pd(acetylacetonate)2, [Pd(crotyl)Cl]2, [Pd(cinnamyl)Cl]2, [PdCl(allyl)]2, PdCl2, PdCl2(1,5-cyclooctadiene), Pd(dba)2, and Pd2(dba)3, or combinations thereof. In an embodiment the Pd catalyst according to the present disclosure is formed from a combination of APhos and a Pd precursor selected from the group consisting of Pd(OAc)2,Pd(acetylacetonate)2, and Pd2(dba)3. In an embodiment the Pd catalyst according to the present disclosure is formed from a combination of APhos and Pd(OAc)2. In an embodiment the Pd catalyst according to the present disclosure is formed from a combination of A-caPhos and a Pd precursor selected from the group consisting of Pd(OAc)2, Pd(OPiv)2, Pd(OiBu)2, Pd(acetylacetonate)2, [Pd(crotyl)Cl]2, [Pd(cinnamyl)Cl]2, [PdCl(allyl)]2, PdCl2, PdCl2(1,5-cyclooctadiene), Pd(dba)2, and Pd2(dba)3, or combinations thereof. In an embodiment the Pd catalyst according to the present disclosure is formed from a combination of A-caPhos and a Pd precursor selected from the group consisting of Pd(OAc)2,Pd(acetylacetonate)2, and Pd2(dba)3. In an embodiment the Pd catalyst according to the present disclosure is formed from a combination of A-caPhos and Pd(OAc)2. In an embodiment the Pd catalyst according to the present disclosure is formed from a combination of (PPh2)PhNMe2 (CAS: 739-58-2),and a Pd precursor selected from the group consisting of Pd(OAc)2(CAS: 3375-31-3), Pd(OPiv)2(CAS: 106224-36-6), Pd(OiBu)2 (CAS: 61261-73-2), Pd(acetylacetonate)2 (CAS: 14024-61-4), [Pd(crotyl)Cl]2 (CAS: 12081-22-0) , [Pd(cinnamyl)Cl]2 (CAS: 12131-44-1), [PdCl(allyl)]2 (CAS: 12012-95-2), PdCl2(CAS: 7647-10-1), PdCl2(1,5-cyclooctadiene) (CAS: 12107- 56-1), Pd(dba)2 (CAS: 32005-36-0), and Pd2(dba)3 (CAS: 51364-51-3), or combinations thereof. In an embodiment the Pd catalyst according to the present disclosure is formed from a combination of (PPh2)PhNMe2and a Pd precursor selected from the group consisting of Pd(OAc)2,Pd(acetylacetonate)2, and Pd2(dba)3. In an embodiment the Pd catalyst according to the present disclosure is formed from a combination of (PPh2)PhNMe2and Pd(OAc)2. In an embodiment, the Pd catalyst is added as Pd(amphos)2Cl2of Formula (B) (B). In an embodiment, the Pd catalyst is added (A-caPhos)2PdCl2of Formula (C) In an embodiment, the Pd catalyst is added [(PPh2)(PhNMe2)]2PdCl2 of Formula (D) In an embodiment, the compounds of Formula (IV) and Formula (V) in the presence of the Pd catalyst are reacted in a solvent selected from the group consisting of substituted arenes (such as toluene, xylene and its isomers, mesitylene, ethyl benzene, trifluoro toluene), ethereal solvents (such as 1,4 dioxane, dibutyl ether (Bu2O), tetrahydrofurane (THF), 2-methyltetrahydrofuran (2-MeTHF), 1,2- Dimethoxyethane (DME), tert-butyl methyl ether (MTBE), methyl cyclopentyl ether, anisol), protic solvents (such as tert-butanol (t-BuOH), 2-methyl-2-butanol (t-AmOH), water and mixtures of them), a polar aprotic solvent (such as dimethyl sulfoxide (DMSO), sulfolane, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), and 1-methyl-2-pyrrolidinone (NMP)), or mixtures thereof. In an embodiment, the solvent is selected from the group selected from the group consisting of toluene, xylene and its isomers, mesitylene, ethyl benzene, and trifluoro toluene. In an embodiment, the solvent is toluene. In an embodiment, the compounds of Formula (IV) and Formula (V) in the presence of the Pd catalyst are reacted in the presence of a base. In an embodiment, the base is selected from the group consisting of alkoxide bases (such as sodium tert-butoxide, sodium tert-pentoxide, sodium methoxide, sodium ethoxide, sodium iso-propoxide, potassium tert-butoxide), cesium carbonate, potassium carbonate, potassium phosphate, lithium hexamethyl disilazane, sodium hexamethyl disilazane, potassium hexamethyl disilazane, phosphazines, amidines, and guanidines (such as 8- diazabicyclo[5.4.0]-undec-7-ene (DBU), 7-Methyl-1,5,7-triazabicyclo(4.4.0)dec-5-ene (MTBD), diisopropyl ethyl amine (DIPEA), 1,5-Diazabicyclo(4.3.0)non-5-en (DBN), diethyl phosphazine, 1,1,3,3-Tetramethylguanidine). In an embodiment, the base is sodium tert-butoxide. In an embodiment, compounds of Formula (IV) and Formula (V) in the presence of the Pd catalyst are reacted in a solvent and in the presence of a base. In an embodiment, compounds of Formula (IV) and Formula (V) in the presence of the Pd catalyst are reacted in toluene as the solvent and in the presence of a base. In an embodiment, compounds of Formula (IV) and Formula (V) in the presence of the Pd catalyst are reacted in a solvent and in the presence of sodium tert-butoxide. In an embodiment, compounds of Formula (IV) and Formula (V) in the presence of the Pd catalyst are reacted in toluene and in the presence of sodium tert-butoxide. The reaction may be performed under atmospheric pressure or under supra- atmospheric pressure. In an embodiment, the reaction is conducted at a temperature of between 60°C to 150°C. In an embodiment, the reaction is conducted at a temperature of between 70°C to 150°C. In an embodiment, the reaction is conducted at a temperature of between 80°C to 150°C. In an embodiment, the reaction is conducted at a temperature of between 80°C to 150°C and at a pressure of between 1 bar and 6 bar. In an embodiment, the reaction is conducted at a temperature of between 80°C to 150°C and at a pressure of between 1 bar and 2.5 bar. In an embodiment, the reaction is conducted at a reaction time between 1 h and 18 h. In an embodiment, the reaction is conducted at a reaction time between 2 h and 10 h. In an embodiment, the reaction is conducted at a reaction time between 2 h and 6 h. In an embodiment, the base is present in an amount in the range from 1.1 eq. to 2.0 eq., such as from 1.1 eq. to 1.5 eq. such as from 1.3 eq. to 1.4 eq. In relation to the amounts of the base, “eq.” refers to a compound of Formula (V) as the reference compound. The disclosure relates to a process for producing a compound of Formula (II): wherein PG is a The inventors have unexpectedly found that by the use of a Pd catalyst according to the present disclosure, the amount of Pd for catalysis can be drastically reduced while maintaining or even increasing the yield of the reaction and purity of the product, in particular with respect to the herein identified impurities. The skilled person will recognize that the amount of a catalyst to be added in a reaction is specified as equivalent (eq, or eq.). In an embodiment eq. in relation to the Pd catalyst refers to the molar equivalent of Pd atoms per reference compound. In an embodiment, the reference compound is a compound of Formula (IV). In an embodiment the reference molecule is the molecule of a compound of Formula (V). In an embodiment of the method according to the present disclosure, the Pd catalyst is present in an amount of 0.0075 eq or more of a compound of Formula (V). In an embodiment of the method according to the present disclosure, the Pd catalyst is present in a stoichiometric amount of from 0.0075 eq to 0.15 eq of a compound of Formula (V). In an embodiment of the method according to the present disclosure, the Pd catalyst is present in an amount of from 0.0075 eq to 0.10 eq of a compound of Formula (V). In an embodiment of the method according to the present disclosure, the Pd catalyst is present in an amount of from 0.0075 eq to 0.02 eq of a compound of Formula (V). The compound of Formula (V) according to the present disclosure is (V); wherein X is a halogen or -O-SO2-R4; and wherein R4is selected from the group consisting of alkyl, fluoroalkyl, optionally substituted phenyl, and optionally substituted naphthyl. R4in an embodiment is a C1-C3-alkyl. R4in an embodiment is a C1-C4-fluoroalkyl. R4in an embodiment is phenyl, optionally substituted by one or two substituents independently selected from the group consisting of C1-C3-alkyl, C1-C3-alkoxy, a halogen, and a nitro group. R4in an embodiment is naphthyl, optionally substituted by one or two substituents independently selected from the group consisting of C1-C3-alkyl, C1-C3-alkoxy, a halogen, and a nitro group. In an embodiment X is a halogen. In an embodiment X is selected from the group consisting of Cl, Br, and I. In one embodiment X is Cl. In an embodiment the compound of Formula (V) is the Compound of Formula (Va): (Va). The disclosure relates to a process for producing a compound of Formula (II): (II), wherein PG is a protective group. The skilled person will recognize that PG may be any suited protective group. In one embodiment, PG is a hydroxyl protective group (see e.g. Wuts, P.G.M. and Greene, T.W. (2006). Protection for the Hydroxyl Group, Including 1,2- and 1,3-Diols. In Greene's Protective Groups in Organic Synthesis (eds P.G.M. Wuts and T.W. Greene). In an embodiment PG is selected from the group consisting of a silyl-protective group (such as trimethylsilyl (TMS), triethylsilyl (TES); dimethylisopropylsilyl (IPDMS), Diethylisopropylsilyl (DEIPS); Triisopropylsilyl (TIPS), t-Butyldimethylsilyl (TBDMS), t- Butyldiphenylsilyl (TBDPS)); an acyl protecting group (such as acetyl, pivaloyl, benzoyl, p-methoxybenzoyl (PMB)); an acetal protecting group (such as methoxymethyl ether (MOM), benzyloxymethyl ether (BOM), 2-methoxyethoxymethyl ether (MEM), tetrahydropyranyl ether (THP); and an ether protecting group (such as allyl, trityl, benzyl, p-methoxybenzyl, t-butyl, Isopropenyl, diphenylmethyl). In an embodiment PG is selected from benzyl or TBDMS. In an embodiment PG is benzyl. In an embodiment PG is benzyl. In an embodiment the compound of Formula (II) is the compound of Formula (IIa): (IIa). In an embodiment in the process for producing a compound of Formula (II), the compound of Formula (IV) is reacted as disclosed herein, the compound of Formula (IV) having the following structure. O wherein PG is a protective group. The skilled person will recognize that, depending on the desired protective group in a compound of Formula (II), the respective protective group in the compound of Formula (IV) may be chosen accordingly. Hence, in one embodiment, PG is a hydroxyl protective group (see e.g. Wuts, P.G.M. and Greene, T.W. (2006). Protection for the Hydroxyl Group, Including 1,2- and 1,3-Diols. In Greene's Protective Groups in Organic Synthesis (eds P.G.M. Wuts and T.W. Greene). In an embodiment PG is selected from the group consisting of a silyl-protective group (such as trimethylsilyl (TMS), triethylsilyl (TES); dimethylisopropylsilyl (IPDMS), Diethylisopropylsilyl (DEIPS); Triisopropylsilyl (TIPS), t-Butyldimethylsilyl (TBDMS), t-Butyldiphenylsilyl (TBDPS)); an acyl protecting group (such as acetyl, pivaloyl, benzoyl, p-methoxybenzoyl (PMB)); an acetal protecting group (such as methoxymethyl ether (MOM), benzyloxymethyl ether (BOM), 2-methoxyethoxymethyl ether (MEM), tetrahydropyranyl ether (THP); and an ether protecting group (such as allyl, trityl, benzyl, p-methoxybenzyl, t-butyl, Isopropenyl, diphenylmethyl). In an embodiment PG is selected from benzyl or TBDMS. In an embodiment PG is benzyl. In an embodiment, the compound of Formula (IV) is present in an amount in the range from 1.0 eq. to 2.0 eq., such as from 1.0 eq. to 1.5 eq. such as from 1.0 eq. to 1.2 eq. In relation to the amounts of the compound of Formula (IV), “eq.” refers to a compound of Formula (V) as the reference compound. In an embodiment the compound of Formula (II) is the compound of Formula (IVa): (IVa). In an embodiment, the present disclosure relates to a process for producing the compound of Formula (IIa), comprising the step with the compound of Formula (IVa); wherein X is a halogen or -O-SO2-R4; and wherein R4is selected from the group consisting of alkyl, fluoroalkyl, optionally substituted phenyl and optionally substituted naphthyl; and wherein the reaction is conducted in the presence of a Pd catalyst comprising a ligand of Formula (A) Z wherein groups Z are independently from each other t-But or -C4-C7-cycloalkyl; and 2 wherein R1is or -O-C1-C3-alkyl; and wherein R2 and from each other C1-C3-alkyl. The disclosure in an embodiment also relates to a process for producing the compound of Formula (IIa), (IIa), comprising the step of reacting the compound of Formula (Va) CF3with the compound of Formula (IVa); wherein the reaction is conducted in the presence of a Pd catalyst comprising a ligand of Formula (A) Z wherein groups Z are independently from each other t- Bu, adamantyl, phenyl, or -C4- C7-cycloalkyl; and 2 R N 3 wherein R1is R or -O-C1-C3-alkyl; and wherein R2and R3are independently from each other a C1-C3-alkyl. The disclosure in an embodiment also relates to a process for producing the compound of Formula (IIa), comprising the step CF3with the compound of Formula (IVa); wherein the reaction is conducted in the presence of a Pd catalyst comprising a ligand of Formula (A1) -Bu (A1). The compound of Formula (IV) may be added to the reaction of the method in any suitable form. In one embodiment, the compound of Formula (IV) is added to the reaction as a free base. In an embodiment the compound of Formula (IV) is obtained as a free base from a salt of the compound of Formula (IV). The salt of the compound of Formula (IV) is in an embodiment selected from the group consisting of a dioxalate salt, acetate, benzoate, succinate, phthalate, propionate, citrate, tartrate, tosylate, besylate, mesylate, hydrochloride, hydrobromide, phosphate, and sulfate. In an embodiment the salt of the compound of Formula (IV) is an oxalate salt. In an embodiment, the salt of the compound of Formula (IV) the dioxalate salt. In an embodiment the compound of Formula (IV) is obtained as a free base from a salt of Formula (III) (III), wherein PG is a protective group. Depending on the desired properties, the protective group may be chosen. The embodiments and disclosure of the protective group as disclosed herein also apply the protective group (PG) of a salt of a compound of Formula (IV) and to the salt of Formula (III). In one embodiment, PG is a hydroxyl protective group (see e.g. Wuts, P.G.M. and Greene, T.W. (2006). Protection for the Hydroxyl Group, Including 1,2- and 1,3-Diols. In Greene's Protective Groups in Organic Synthesis (eds P.G.M. Wuts and T.W. Greene). In an embodiment PG is selected from the group consisting of a silyl- protective group (such as trimethylsilyl (TMS), triethylsilyl (TES); dimethylisopropylsilyl (IPDMS), Diethylisopropylsilyl (DEIPS); Triisopropylsilyl (TIPS), t-Butyldimethylsilyl (TBDMS), t-Butyldiphenylsilyl (TBDPS)); an acyl protecting group (such as acetyl, pivaloyl, benzoyl, p-methoxybenzoyl (PMB)); an acetal protecting group (such as methoxymethyl ether (MOM), benzyloxymethyl ether (BOM), 2-methoxyethoxymethyl ether (MEM), tetrahydropyranyl ether (THP); and an ether protecting group (such as allyl, trityl, benzyl, p-methoxybenzyl, t-butyl, Isopropenyl, diphenylmethyl). In an embodiment PG is selected from benzyl or TBDMS. In an embodiment PG is benzyl. In an embodiment, PG is benzyl and the salt of the compound of Formula (IV) is provided as the dioxalate salt of Formula (IIIa) (IIIa). Method for Manufacturing elinzanetant As disclosed herein, the compound of Formula (II) is the precursor of elinzanetant. Accordingly, the present invention is useful for the manufacturing of elinzanetant or a salt thereof. Hence, in one embodiment the present disclosure relates to a method for manufacturing elinzanetant or a salt thereof, the method comprising the method for producing a compound of Formula (II) as disclosed. The embodiments as disclosed herein for the method for producing a compound of Formula (II) apply mutatis mutandis. The method for manufacturing of elinzanetant or a salt thereof in one embodiment comprises the step of converting the compound of Formula (II) into elinzanetant. The conversion in one embodiment comprises cleaving off the protective group from the rest of the molecule. This cleavage may be performed by methods and conditions known by those of skill in the art (see e.g. Wuts, P.G.M. and Greene, T.W. (2006). Protection for the Hydroxyl Group, Including 1,2- and 1,3-Diols. In Greene's Protective Groups in Organic Synthesis (eds P.G.M. Wuts and T.W. Greene)) and may be dependent on the protective group present in the compound of Formula (II). In one embodiment, the conversion is performed under reductive or acidic conditions. In an embodiment the conversion of the compound of Formula (II) is performed as disclosed in WO 2021 / 094247 A1. Use The present disclosure also relates to the use of a Pd catalyst or Pd precatalyst comprising a ligand of Formula (A), or a Pd precursor in combination with a ligand of Formula (A) in a process for producing a compound of Formula (II), or in a process for manufacturing elinzanetant or a salt thereof. The embodiments for the Pd catalyst, the Pd precatalyst, the ligand of Formula (A), the Pd precursor in combination with a ligand of Formula (A) and the processes as disclosed herein also apply to the use of a Pd catalyst or Pd precatalyst or a Pd precursor in combination with a ligand of Formula (A) according to the disclosure. Compositions The inventors have shown that by the teaching herein it is possible to obtain the compound of Formula (II) in higher purity as compared to the method disclosed in the prior art. In particular, the amounts of the compounds of Formula (IV) and Formula (V) are drastically reduced. Thus, the present disclosure is allowing for obtaining compositions comprising the Formula (II) in an increased purity. The present disclosure, hence, in an embodiment also relates to a composition obtainable by a method for producing the compound of Formula (II) or a method for manufacturing elinzanetant according to the disclosure herein. In an embodiment the disclosure relates to a composition comprising elinzanetant or a salt thereof, wherein the composition is obtainable by a method for manufacturing elinzanetant or a salt thereof according to the present disclosure. In an embodiment, the disclosure relates to a composition comprising a compound of Formula (II), wherein the composition is obtainable by a method for producing a compound of Formula (II) according to the present invention. In an embodiment, the disclosure relates to a composition comprising a compound of Formula (II), wherein the composition comprises a compound of Formula (VI) in an amount relative to the compound of Formula (II) of less than 0.005:1 (compound of Formula (VI): compound of Formula (II)). In an embodiment, the disclosure relates to a composition comprising a compound of Formula (II), wherein the composition comprises a compound of Formula (VI) in an amount relative to the compound of Formula (II) of less than 0.0005:1 (compound of Formula (VI): compound of Formula (II)). In an embodiment, the disclosure relates to a composition comprising a compound of Formula (II), wherein the composition comprises a compound of Formula (VII) in an amount relative to the compound of Formula (II) of less than 0.02:1 (compound of Formula (VII): compound of Formula (II)). In an embodiment, the disclosure relates to a composition comprising a compound of Formula (II), wherein the composition comprises a compound of Formula (VII) in an amount relative to the compound of Formula (II) of less than 0.0005:1 (compound of Formula (VII): compound of Formula (II)). In an embodiment, the invention relates to a composition comprising a compound of Formula (II), wherein the composition comprises a compound of Formula (VI) and a compound of Formula (VII) in an amount relative to the compound of Formula (II) of less than 0.03:1 (sum of compounds of Formula (VI) and Formula (VII): compound of Formula (II)). In an embodiment, the invention relates to a composition comprising a compound of Formula (II), wherein the composition comprises a compound of Formula (VI) and a compound of Formula (VII) in an amount relative to the compound of Formula (II) of less than 0.015:1 (sum of compounds of Formula (VI) and Formula (VII): compound of Formula (II)). The embodiments and disclosure regarding the compounds of Formula (II) as disclosed herein also apply to the respective compounds in the compositions according to the present disclosure. In an embodiment of the compositions, the compound of Formula (II) is the compound of Formula (IIa). In an embodiment, the compound of Formula (VI) is (VI). In an embodiment, the compound of Formula (VII) is CF3 (VII). The present invention and its embodiments are further exemplified by the following, non-limiting Examples and Figures.

[0002] EXAMPLES Abbreviations h hour g gram mg milligram min minute(s) °C Degree(s) Celsius mL milliliter mmol millimole mol mole Table 1: Pd catalyst source (Pd catalysts, Pd precatalysts, Pd precursors / ligand combination) used: CAS No. of No. Pd catalyst source Ligand Ligand Structure t-Bu t-Bu P 1 Pd(PtBu t-Bu 3)2(Pd-116) 932710-63-9 t-Bu Pd(Aphos)2Cl2(Pd- N P 2 132) 932710-63-9t-But-Bu N P 3 Pd(OAc)2 / Aphos 932710-63-9t-But-Bu N P 4 [Pd(crotyl)Cl]2 / Aphos 932710-63-9t-But-Bu [Pd(cinnamyl)Cl]2 / Apho N P 5 s 932710-63-9t-But-Bu N P 6 Aphos Pd-G3 932710-63-9t-Bu7 (A-caPhos)2PdCl2932710-63-9 Pd(OAc)2 / (PPh2)(PhNMe2)739-58-2P(Cy3)Pd-G32622-14-2Pd(OAc)2 / tBuXantphos 856405-77-1Pd(OAc)2 / DPEPhos 166330-10-5Pd(OAc)2 / tBuDavePho s224311-49-3Pd(OAc)2 / Johnphos224311-51-7Pd(OAc)2 / Cy-Johnphos247940-06-3Pd(OAc)2 / MePhos251320-86-2Pd(OAc)2 / DTBPF84680-95-5 P Fe P PdCl2(dcypf) 146960-90-9 P Fe P Pd(OAc)2 / dcypf 146960-90-9 Pd(OAc)2 / N-Xantphos 261733-18-0 Pd(OAc)2 / Xantphos161265-03-8Pd(OAc)2 / BINAP 98327-87-8Pd(OAc)2 / P(o-OMe-phenyl)34731-65-1Pd(OAc)2 / P(p-CF3-phenyl)313406-29-6 Pd(OAc)2 / Tri(2-furyl)phosphine 5518-52-5Pd(dppf)Cl212150-46-8Pd(OAc)2 / dppf 12150-46-8t-Bu P t-Bu Fe P t-Bu Pd(DTBPF)Cl284680-95-5t-BuPd(OAc)2 / P(o-tol)3 163-58-2Pd(OAc)2 / Davephos213697-53-1Pd(OAc)2 / TrixiePhos255836-67-0 Analytical methods: Determination of purity of compound of Formula (IIa) and quantification of impurities HPLC method A The HPLC method A is used to determine the purity of N-[6-[(7S,9aS)-7- (benzyloxymethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-4-(4- fluoro-2-methyl-phenyl)-3-pyridyl]-2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl- propanamide (compound of Formula (IIa)) and the content of the precursor 2-[3,5- bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-3-pyridyl]-N,2- dimethyl-propanamide (compound of Formula (Va)) as well as of the potential by- products APhos, toluene, N-[4-(4-fluoro-2-methyl-phenyl)-6-hydroxy-3-pyridyl]-N,2- dimethyl-2-[3-methyl-5-(trifluoromethyl)phenyl]propanamide (VII), N-[4-(4-fluoro-2- methyl-phenyl)-3-pyridyl]-N,2-dimethyl-2-[3-methyl-5- (trifluoromethyl)phenyl]propanamide (compound of Formula (VIII)), and N-[6-tert- butoxy-4-(4-fluoro-2-methyl-phenyl)-3-pyridyl]-N,2-dimethyl-2-[3-methyl-5- (trifluoromethyl)phenyl]propanamide (compound of Formula (VI)). For the content determination of the main component and the by-products a calibration solution of the compound of Formula (IIa) at a concentration level of 0.3 mg / mL is used. Stationary phase: Phenomenex YMC Meteoric Core C18 BIO (150 mm, 3.0 mm ID, 2.7 μm particle size); mobile phase A: 0.63 g ammonium formate + 90 μL formic acid / 1 L water (ca. pH 4.20); mobile phase B: acetonitrile; sample solution: water / acetonitrile (50 / 50 (v / v)); UV detection at 260 nm (relative response factors (RRF) were determined and applied if necessary); oven temperature: 35°C; injection volume: 5.0 μL; sampler temperature: 20 °C; Flow-rate: 0,8 mL / min; linear gradient after 1 minute isocratic run at 25% B in two steps: 25% B à 68% B (10 min), 2 minutes holding time at 68% B; 68% B à 95% B (7 min), 7 minutes holding time at 95% B; relevant potential impurities: APhos at RRT (relative retention time) 0.22 (RT=3.4 min), toluene at RRT 0.40 (RT=6.7 min), compound of Formula (VII) at RRT 0.55 (RT=9.2 min), compound of Formula (VIII) at RRT 0.68 (RT=11.4 min; RRF 2.51), compound of Formula (Va) at RRT 0.83 (RT=13.9 min; RRF 2.47), compound of Formula (VI) at RRT 1.04 (RT=17.4 min; RRF 4.10), compound of Formula (IIa) at RRT 1.00 (RT=16.7 min). For the calculation of the purity the compound of Formula (IIa), the peak areas originating from APhos, and toluene are not included. In addition to the classical UV detection, a mass spectrometric detector in routinely used to assign the detected species: Waters QDa; mass spectrometric parameters: Target: 10 points / sec; Modus: Advanced; MS Scan positive (m / z 250-1100); Data: Centroid; Cone Voltage: 15 V; Gain: 1; Capillary: 0.8 kV; Probe: 600 °C. HPLC method B The HPLC method B is used to determine the purity of N-[6-[(7S,9aS)-7- (benzyloxymethyl)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-4-(4- fluoro-2-methyl-phenyl)-3-pyridyl]-2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl- propanamide (compound of Formula (IIa)) and the content of the precursor 2-[3,5- bis(trifluoromethyl)phenyl]-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-3-pyridyl]-N,2- dimethyl-propanamide (compound of Formula (Va)) as well as of the potential, toluene, N-[4-(4-fluoro-2-methyl-phenyl)-6-hydroxy-3-pyridyl]-N,2-dimethyl-2-[3-methyl-5- (trifluoromethyl)phenyl]propanamide (VII), N-[4-(4-fluoro-2-methyl-phenyl)-3-pyridyl]- N,2-dimethyl-2-[3-methyl-5-(trifluoromethyl)phenyl]propanamide (compound of Formula (VIII)), and N-[6-tert-butoxy-4-(4-fluoro-2-methyl-phenyl)-3-pyridyl]-N,2- dimethyl-2-[3-methyl-5-(trifluoromethyl)phenyl]propanamide (compound of Formula (VI)). Stationary phase: Waters BEH C18 (50 mm, 2.1 mm ID, 1.7 μm particle size); mobile phase A: 0.03% trifluoroacetic acid in 90% water, 10% acetonitrile); mobile phase B: 0.03% trifluoroacetic acid in 100% acetonitrile; sample solution: water / acetonitrile (20 / 80 (v / v));UV detection at 210 nm; oven temperature: 50°C; injection volume: 0.2 μL; Flow-rate: 0,7 mL / min; linear gradient in one steps: 1% B à 95% B (2 min), 0.25 minutes holding time at 95% B; relevant potential impurities: toluene at RRT 0.76 (RT=1.28 min), compound of Formula (VIII) at RRT 0.94 (RT=1.58 min), compound of Formula (Va) at RRT 1.15 (RT=1.94 min), compound of Formula (VI) at RRT 1.28 (RT=2.15 min), compound of Formula (IIa) at RRT 1.00 (RT=1.68 min). For the calculation of the purity the compound of Formula (IIa), the peak areas originating from toluene is not included. Determination of S (Selectivity factor) A comparison of the different catalysts with respect to their selectivity was carried out. Therefore, the amount of O secondary components compound of Formula (VI) and compound of Formula (VII)) resulting from the O selectivity was compared with the amount of the actually wanted product (compound of Formula (IIa)) (N-selective). The different reaction behavior of various Pd catalysts with regard to N versus O selectivity can be described by a selectivity factor S, as is commonly used in the literature. The selectivity S can be determined as the ratio of the rate constant k, S = k(N) / k(O). To do this in practice, divide the HPLC area percentage of the product (IIa) by the sum of the O secondary components ((VI) and (VII)) considering the respective relative response factors as specified above in the description HPLC method A. The selectivity factor (S) was determined after the respective reaction according to the following formula: As the amounts the respective integrals multiplied with their respective relative response factors of the HPLC analysis of the compounds of Formulas (IIa), (VI) and (VII) were used. Example 1 Catalyst Screening All reactions conducted were carried out in anhydrous toluene (~18 volumes related to compound of Formula (Va)) inside a nitrogen filled glove box. Compound of Formula (Va)) (150 mg, 1.00 eq.) was weighed into a reaction tube fitted with a stir bar. The compound of Formula (IVa) (93 mg, 1.26 eq.) was dissolved in anhydrous toluene (1 ml) and charged to the reaction tube. The Pd-precursor (0.02 eq.) and ligand (ratio based on ligand structure) were stirred at 50 °C for 30 minutes in anhydrous toluene (0.5 ml) in a separate reaction tube prior to transferring to the starting material followed by the addition of sodium tert-butoxide (47 mg, 1.75 eq.) at 25 °C. Then the reaction mixture was heated to 85 °C. The hydrolysis of the compound of Formula (VI) and the compound of Formula (Va) to the compound of Formula (VII) was excluded by the rigorous exclusion of moisture through the use of an inert atmosphere in a glovebox. Accordingly, only the compound of Formula (VI) was used as impurity for the calculation of the selectivity factor. HPLC analysis was performed in accordance with HPLC Method B. Results: The following amounts of the Product (compound of Formula (IIa)), Impurities (compound of Formula VI), and the De-halo-ArC (compound of Formula (VIII) were detected, and the selectivity factor was calculated based on the amount of compound of Formula (VI) as impurity, according to the following Formula: amount of compound of Formula IIaS of the compound of Formula VITable 2: Product and Impurities using different Pd catalyst, Pd precatalyst, Pd precursors / Ligands Product of Compound Compound Formula of Formula of Formula No. Pd-catalyst source (IIa) (%) (VI) (%) (VIII) (%) S 1 Pd(PtBu3)283.7 3.6 0.5 23.3 2 Pd(Aphos)2Cl289.6 0.1 0.4 896.0 3 Pd(OAc)2 / APhos 91.6 0.6 0.0 152.7 4 [Pd(crotyl)Cl]2 / APhos 91.6 0.2 0.4 458.0 5 [Pd(cinnamyl)Cl]2 / APhos 91.1 0.4 0.4 227.8 6 APhos Pd-G3 91.1 0.5 0.0 182.2 7 (A-caPhos)2PdCl287.3 0.1 2.1 873.0 8Pd(OAc)2 / (PPh2)(PhNMe2)85.6 0.8 2.6 107.09 P(Cy3)Pd-G3 60.1 4.9 17.6 12.3 10 Pd(OAc)2 / tBuXantphos 11.6 5.0 0.8 2.3 11 Pd(OAc)2 / DPEPhos 11.0 5.1 0.8 2.2 12 Pd(OAc)2 / tBuDavePhos 15.2 6.2 0.7 2.5 13 Pd(OAc)2 / Johnphos 21.9 12.6 0.6 1.7 14 Pd(OAc)2 / Cy-Johnphos 59.6 22.9 0.4 2.6 15 Pd(OAc)2 / MePhos 73.9 12.9 0.4 5.7 16 Pd(OAc)2 / DTBPF 77.6 7.7 1.1 10.1 17 PdCl2(dcypf) 76.1 9.5 1.6 8.0 18 Pd(OAc)2 / Dcypf 80.0 4.3 1.1 18.6 19 Pd(OAc)2 / N-Xantphos 84.3 4.2 0.6 20.1 20 Pd(OAc)2 / Xantphos 82.5 3.9 1.0 21.2 21 Pd(OAc)2 / BINAP 77.6 7.0 1.4 11.1 22 Pd(OAc)2 / P(o-OMe)322.7 5.6 1.0 4.1 Pd(OAc)2 / P(p- 23 CF3phenyl)324.8 5.5 0.6 4.5 Pd(OAc)2 / Tri(2- 24 furyl)phosphine 3.1 7.5 0.2 0.4 25 Pd(dppf)Cl263.4 5.3 0.9 12.0 26 Pd(OAc)2 / Dppf 62.6 4.2 0.8 14.9 27 Pd(DTBPF)Cl241.3 40.4 0.3 1.0 28 Pd(OAc)2 / P(o-tol)338.0 7.3 0.9 5.2 29 Pd(OAc)2 / Davephos 74.0 13.2 0.4 5.6 30 Pd(OAc)2 / TrixiePhos 22.1 10.4 0.1 2.1 The use of a Pd-precursor and the respective ligands is indicated by the use of “ / ” in the name. Example 2 Catalysts according to the present invention were tested for their ability to effectively catalyze the reaction. All experiments were carried out as disclosed in WO 2021 / 094247 A1, Example 6, Preparation 2 using 10 g of the compound of Formula (Va) and either the catalyst of prior art (Pd-catalyst source No. 1) or a catalyst according to the present disclosure (Pd-catalyst source No. 2). The stoichiometry of the Pd catalysts were varied. Either 0.1 eq. was used as in the prior art or a reduced amount of 0.015 eq. The following catalysts and amounts of catalysts were used and compared: 0.1 eq. Pd-catalyst source No.2 (Example 2a); 0.1 eq. Pd-catalyst source No.1 (Example 2b); 0.015 eq. Pd-catalyst source No.2 (Example 2c); and 0.015 eq. Pd-catalyst source No.1 (Example 2d); A conversion control was carried out after 3 hours using HPLC Method A. The controls confirmed that the starting material (compound of Formula (Va)) was almost completely converted. The detailed description was as follows: Example 2a Synthesis of N-[6-[(7S,9aS)-7-(benzyloxymethyl)-3, 4,6,7,9,9a- hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-4-(4-fluoro-2-methyl-phenyl)-3- pyridyl]-2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-propanamide (compound of Formula (IIa)) using 0.1 eq. Pd-catalyst source No.2 To 133.5 g of a solution of the compound of Formula (IVa) in toluene (= 10.461 g (23.645 mmol)) were added 10.00 g (18.77 mmol) of the compound of Formula (Va), 3.156 g (32.840 mmol) sodium tert-butoxide, 1,329 g (1.88 mmol = 0.1 eq.) Pd-source No.2 and 20 ml toluene, and the mixture was heated to 80°C (inner temperature) for 3 h. After 3 h a sample was taken and analyzed by HPLC: Starting material (compound of Formula (Va)): complete conversion compound of Formula (IIa): 94.27% compound of Formula (VI): 0.39 % compound of Formula (VII): 0.10 % Selectivity factor S: 192.38 Example 2b Synthesis of N-[6-[(7S,9aS)-7-(benzyloxymethyl)-3, 4,6,7,9,9a- hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-4-(4-fluoro-2-methyl-phenyl)-3- pyridyl]-2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-propanamide (compound of Formula (IIa)) using 0.1 eq of Pd-catalyst source No.1 To 133.5 g of a solution of the compound of Formula (IVa) in toluene (= 10.461 g (23.645 mmol)) were added 10.00 g (18.77 mmol) of the compound of Formula (Va), 3.156 g (32.840 mmol) sodium tert-butoxide, 959.0 mg (1.88 mmol = 0.1 eq.) Pd- source No. 1 and 20 ml toluene, and the mixture was heated to 80°C (inner temperature) for 3 h. After 3 h a sample was taken and analyzed by HPLC: Starting material (compound of Formula (Va)): complete conversion compound of Formula (IIa): 95.66 % compound of Formula (VI)): 3.06 % compound of Formula (VII): 0.71 % Selectivity factor S: 25.37 Example 2c Synthesis of N-[6-[(7S,9aS)-7-(benzyloxymethyl)-3, 4,6,7,9,9a- hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-4-(4-fluoro-2-methyl-phenyl)-3- pyridyl]-2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-propanamide (compound of Formula (IIa)) using 0.015 eq of Pd-catalyst source No.2 To 133.5 g of a solution of the compound of Formula (IVa) in toluene (= 10.461 g (23.645 mmol)) were added 10.00 g (18.77 mmol) of the compound of Formula (Va), 3.156 g (32.840 mmol) sodium tert-butoxide, 199.0 mg (0.281 mmol = 0.015 eq.) Pd-catalyst source No.2 and 20 ml toluene, and the mixture was heated to 80°C (inner temperature) for 3 h. After 3 h a sample was taken and analyzed by HPLC: Starting material (compound of Formula (Va)): complete conversion compound of Formula (IIa): 98.75% compound of Formula (VI): 0.11 % compound of Formula (VII): 0.06 % Selectivity factor S: 580.88 Example 2d Synthesis of N-[6-[(7S,9aS)-7-(benzyloxymethyl)-3, 4,6,7,9,9a- hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-4-(4-fluoro-2-methyl-phenyl)-3- pyridyl]-2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-propanamide (compound of Formula (IIa)) using 0.015 eq of Pd-catalyst source No.1 To 133.5 g of a solution of the compound of Formula (IVa) in toluene (= 10.461 g (23.645 mmol)) were added 10.00 g (18.77 mmol) of the compound of Formula (Va), 3.156 g (32.840 mmol) sodium tert-butoxide, 144.0 mg (0.281 mmol = 0.015 eq.) Pd- source No. 1 and 20 ml toluene, and the mixture was heated to 80°C (inner temperature) for 3 h. After 3 h a sample was taken and analyzed by HPLC: Starting material (compound of Formula (Va)): complete conversion compound of Formula (IIa): 94,93 % compound of Formula (VI): 0.7 % compound of Formula (VII): 2.41 % Selectivity factor S: 30.52 Summary and Conclusion The results of Example 2 are summarized in Table 3 and Figure 1. Table 3: Pd-source Example No. (eq.) compounds % Selectivity factor S compound of Formula (IIa) 94.27 compound of Formula (VI) 0.39 2a 2 (0.1) 192.38 compound of Formula (VII) 0.1 Sum of compounds of Formulas (VI) and (VII) 0.49 compound of Formula (IIa) 95.66 compound of Formula (VI) 0.71 2b 1 (0.1) 25.37 compound of Formula (VII) 3.06 Sum of compounds of Formulas (VI) and (VII) 3.77 compound of Formula (IIa) 98.75 compound of Formula (VI) 0.11 2c 2 (0.015) 580.88 compound of Formula (VII) 0.06 Sum of compounds of Formulas (VI) and (VII) 0.17 2d 1 (0.015)compound of Formula(IIa) 94.93 30.52 of Formula These results show that a Pd catalyst according to the present invention surprisingly allows for a significantly increased N / O selectivity, even though used in 6.25 times smaller quantities as compared to Pd catalyst as used in the prior art. By these surprising results on the selectivity of the Pd catalyst according to the invention in the synthesis of the compound, it is possible to decrease the total amount of Pd catalyst in the reaction while maintaining or even increasing the yield and purity of the desired product. Even more surprisingly, the high N / O selectivity of the catalyst according to the invention becomes even more apparent with particularly small amounts of catalyst. Example 3 To investigate the possibility of further reducing the amount of catalyst while maintaining the full conversion of a compound of Formula (V) and the N / O selectivity, the experiments as disclosed in Example 2 were performed with further reduced amounts of the respective catalysts as follows: 0.01 eq. Pd-catalyst source No.2 (Example 3a); 0.01 eq. Pd-catalyst source No.1 (Example 3b); 0.0075 eq. Pd-catalyst source No.2 (Example 3c); and 0.0075 eq. Pd-catalyst source No.1(Example 3d); Example 3a Synthesis of N-[6-[(7S,9aS)-7-(benzyloxymethyl)-3, 4,6,7,9,9a- hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-4-(4-fluoro-2-methyl-phenyl)-3- pyridyl]-2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-propanamide (compound of Formula (IIa)) using 0.01 eq of Pd-catalyst source No.2 To 133.5 g of a solution of the compound of Formula (IVa) in toluene (= 10.461 g (23.645 mmol)) were added 10.00 g (18.77 mmol) of the compound of Formula (Va), 3.156 g (32.840 mmol) sodium tert-butoxide, 132.87 mg (0.188 mmol = 0.010 eq.) Pd- source No. 2 and 20 ml toluene, and the mixture was heated to 80°C (inner temperature) for 3 h. After 3 h a sample was taken and measured by HPLC: Starting material (compound of Formula (Va)): complete conversion compound of Formula (IIa): 99.34 % compound of Formula (VI): 0.09 % compound of Formula (VII): 0.05 % Selectivity factor S: 697.6 Example 3b Synthesis of N-[6-[(7S,9aS)-7-(benzyloxymethyl)-3, 4,6,7,9,9a- hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-4-(4-fluoro-2-methyl-phenyl)-3- pyridyl]-2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-propanamide (compound of Formula (IIa)) using 0.01 eq of Pd-catalyst source No.1 To 68.2 g of a solution of the compound of Formula (IVa) in toluene (= 5.23 g (11.82 mmol)) were added 5.00 g (9.38 mmol) of the compound of Formula (Va), 1.750 g (16.42 mmol) sodium tert-butoxide, 47.95 mg (0.094 mmol = 0.010 eq.) Pd-source No. 1 and 20 ml toluene, and the mixture was heated to 80°C (inner temperature) for 3 h. After 3 h a sample was taken and analyzed by HPLC: Starting material (compound of Formula (Va)): >20% starting material incomplete conversion Product and impurities were not determined because of the incomplete conversion. Hence, the selectivity factor was not applicable. Example 3c Synthesis of N-[6-[(7S,9aS)-7-(benzyloxymethyl)-3, 4,6,7,9,9a- hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-4-(4-fluoro-2-methyl-phenyl)-3- pyridyl]-2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-propanamide (compound of Formula (IIa)) using 0.0075 eq of Pd-catalyst source No.2 To 68.2 g of a solution of the compound of Formula (IVa) in toluene (= 5.23 g (11.82 mmol)) were added 5.00 g (9.38 mmol) of the compound of Formula (Va), 1.58 g (16.42 mmol) sodium tert-butoxide, 46.51 mg (0.066 mmol = 0.0075 eq.) Pd-source No.2 and 10 ml toluene, and the mixture was heated to 80°C (inner temperature) for 3 h. After 3 h a sample was taken and analyzed by HPLC: Starting material (compound of Formula (Va)): complete conversion compound of Formula (IIa): 98.98 % compound of Formula (VI): 0.1 % compound of Formula (VII): 0.21 % Selectivity factor S: 316 Example 3d Synthesis of N-[6-[(7S,9aS)-7-(benzyloxymethyl)-3, 4,6,7,9,9a- hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-4-(4-fluoro-2-methyl-phenyl)-3- pyridyl]-2-[3,5-bis(trifluoromethyl)phenyl]-N,2-dimethyl-propanamide (compound of Formula (IIa)) using 0.0075 eq of Pd-source No.1 To 68.2 g of a solution of the compound of Formula (IVa) in toluene (= 5.23 g (11.82 mmol)) were added 5.00 g (9.38 mmol) of the compound of Formula (Va), 1.58 g (16.42 mmol) sodium tert-butoxide, 33.57 mg (0.066 mmol = 0.0075 eq.) Pd-source No.1 and 10 ml toluene, and the mixture was heated to 80°C (inner temperature) for 3 h. After 3 h a sample was taken and analyzed by HPLC: Starting material (compound of Formula (Va)): >20% starting material incomplete conversion Product and impurities were not determined because of the incomplete conversion. Hence, the selectivity factor was not applicable. Summary and Conclusion The results of Example 3 are summarized in the following table: Selectivity factor S Eq. Pd-Catalyst Pd-catalyst source No.1 Pd-catalyst source No.2 0.015 23.25 896 0.010 n.c.r 697.6 0,0075 n.c.r 316.3 Surprisingly, the Pd catalyst used in the prior art already at an amount of 0.01 eq. does not show complete conversion, while a Pd catalyst according to the present disclosure still shows full conversion even at 0.0075 with a very high N / O selectivity of S being 316.3, which is more than ten times higher than for the Pd catalyst used in the prior art at 0.1 eq or 0.015 eq.

Claims

New PCT Application Bayer Consumer Care AG Our Ref: BHC243010 WO Claims 1. A process for producing a compound of Formula (II), comprising the step(V) with the compound ofO wherein PG is a protective group;wherein X is a halogen or -O-SO2-R4; wherein R4is selected from the group consisting of alkyl, fluoroalkyl, optionally substituted phenyl and optionally substituted naphthyl; and wherein the reaction is conducted in the presence of a Pd catalyst comprising a ligand of Formula (A)Z(A); wherein groups Z are independently from each other selected from the group consisting of t-Bu, adamantyl, phenyl, and -C4-C7-cycloalkyl; and 2 wherein R1is or -O-C1-C3-alkyl; andwherein R2and from each other a C1-C3-alkyl.

2. The process according to claim 1, wherein groups Z are independently from each other t-But, phenyl or -cyclohexyl. 2 R N he process according to claim 1 or 2, wherein R13 3. T is R , and wherein R2and R3are independently from each other a C1-C3-alkyl.

4. The process according to any one of claims 1 to 3, wherein R2and R3are both methyl.

5. The process according to any one of claims 1 to 4, wherein X is -O-SO2-R4; and wherein R4is selected from the group consisting of C1-C3-alkyl, C1-C4- fluoroalkyl, phenyl, and naphthyl, said phenyl and naphthyl groups being optionally substituted by one or two substituents independently selected from the group consisting of C1-C3- alkyl, C1-C3-alkoxy, a halogen, and a nitro group.

6. The process according to any one of claims 1 to 5, wherein the Pd catalyst is selected from the group consisting of Pd(A-caPhos)2, Pd(Aphos)2,and Pd[(PPh2)(PhNMe2)]2.

7. The use according to any one of claims 1 to 6, wherein the Pd catalyst is:added as a Pd precatalyst selected from the group consisting of Pd(APhos)2Cl2, Pd(APhos)2Br2, Pd(APhos)2, APhos Pd(allyl)Cl, APhos Pd(crotyl)Cl, APhos Pd(cinnamyl)Cl, Aphos Pd-G2, Aphos Pd-G3, and Aphos Pd-G4, Pd(A-caPhos)2Cl2, A-caPhos Pd-G3, and [(PPh2)(PhNMe2)]2PdCl2; or formed from a combination APhos or A-caPhos or a combination thereof; and a Pd precursor selected from the group consisting of Pd(OAc)2, Pd(OPiv)2, Pd(Oi-Bu)2, Pd(acetylacetonate)2, [Pd(crotyl)Cl]2, [Pd(cinnamyl)Cl]2, [PdCl(allyl)]2, PdCl2, PdCl2(1,5-cyclooctadiene), PdCl2(PhCN)2, PdCl2(CH3CN)2, PdBr2, PdBr2(1,5-cyclooctadiene), [Pd(CH3CN)4](BF4)2, Pd(dba)2, Pd2(dba)3•CHCl3 and Pd2(dba)3 , or combinations thereof.

8. The process according to any one of claims 1 to 7, wherein the Pd catalyst is formed by the addition of Pd(amphos)2Cl2 of Formula (B)9. The process according to any one of claims 1 to 7, wherein the Pd catalyst is formed by the addition of (A-caPhos)2PdCl2of Formula (C)10. The process according to any one of claims 1 to 9, wherein the Pd catalyst is present in a stoichiometric amount of 0.0075 eq or more.

11. The process according to any one of claims 1 to 4 and 6 to 10, wherein X is halogen.

12. The process according to claim 11, wherein X is Cl.

13. The process according to any one of claims 1 to 12, wherein the compound of Formula (IV) is obtained as a free base from a dioxalate salt of Formula (III) in the presence of a base(III).

14. The process according to any one of claims 1 to 13, wherein the protective group PG is selected from the group consisting of a silyl-protective group (such as trimethylsilyl (TMS), triethylsilyl (TES); dimethylisopropylsilyl (IPDMS), Diethylisopropylsilyl (DEIPS); Triisopropylsilyl (TIPS), t-Butyldimethylsilyl (TBDMS), t-Butyldiphenylsilyl (TBDPS)); an acyl protecting group (such as acetyl, pivaloyl, benzoyl, p-methoxybenzoyl (PMB)); an acetal protecting group (such as methoxymethyl ether (MOM), benzyloxymethyl ether (BOM), 2- methoxyethoxymethyl ether (MEM), tetrahydropyranyl ether (THP); and an ether protecting group (such as allyl, trityl, benzyl, p-methoxybenzyl, t-butyl, Isopropenyl, diphenylmethyl).

15. The process according to any one of claims 1 to 14, wherein the protective group PG is benzyl.

16. A process for manufacturing elinzanetant or a salt thereof, comprising the process for producing according to any one of claims 1 to 15.

17. The process for manufacturing according to claim 16, comprising the step of converting the obtained compound of Formula (II) into elinzanetant.

18. Use of a Pd catalyst comprising a ligand of Formula (A)Z(A), in a process for producing a compound of Formula (II):; wherein PG is a protective group; wherein groups Z are independently from each other selected from the group consisting of t-Bu, adamantyl, phenyl, and -C4-C7-cycloalkyl; and 2 R N 1 3 wherein R is R or -O-C1-C3-alkyl; and wherein R2and R3are independently from each other a C1-C3-alkyl.

19. Use of a Pd catalyst comprising a ligand of Formula (A) Zin a process for manufacturing elinzanetant or a salt thereof; wherein groups Z are independently from each other selected from the group consisting of t-Bu, adamantyl, phenyl, and -C4-C7-cycloalkyl; and 2 R N rein R13 whe is R or -O-C1-C3-alkyl; andwherein R2and R3are independently from each other a C1-C3-alkyl.

20. The use according to claim 18 or 19, wherein the Pd catalyst is Pd(amphos)2.

21. The use according to any one of claims 18 to 20, wherein the Pd catalyst is: added as a Pd precatalyst selected from the group consisting of Pd(APhos)2Cl2, Pd(APhos)2Br2, Pd(APhos)2, APhos Pd(allyl)Cl, APhos Pd(crotyl)Cl, APhos Pd(cinnamyl)Cl, Aphos Pd-G2, Aphos Pd-G3, and Aphos Pd-G4, Pd(A-caPhos)2Cl2 (CAS: 945375-77-9) and A-caPhos Pd- G3 (CAS:2730016-91-6); or formed from a combination APhos or A-caPhos or a combination thereof; and a Pd precursor selected from the group consisting of Pd(OAc)2, Pd(OPiv)2, Pd(Oi-Bu)2, Pd(acetylacetonate)2, [Pd(crotyl)Cl]2, [Pd(cinnamyl)Cl]2, [PdCl(allyl)]2, PdCl2, PdCl2(1,5-cyclooctadiene), PdCl2(PhCN)2, PdCl2(CH3CN)2, PdBr2, PdBr2(1,5-cyclooctadiene), [Pd(CH3CN)4](BF4)2, Pd(dba)2, Pd2(dba)3•CHCl3 and Pd2(dba)3 , or combinations thereof.

22. A composition comprising a compound of Formula (II) obtainable by a method according to any one of claims 1 to 15 or by the use according to any one of claims 18, 20, or 21.

23. A composition comprising a compound of Formula (II), wherein the composition comprises the compound of Formula (VI)in an amount relative to the compound of Formula (II) of less than 0.005:1 (compound of Formula (VI): compound of Formula (II)).

24. A composition comprising a compound of Formula (II), wherein the composition comprises the compound of Formula (VII) CF3in an amount relative to the compound of Formula (II) of less than 0.02:1 (compound of Formula (VII): compound of Formula (II)).

25. A composition comprising a compound of Formula (II), wherein the composition comprises the compound of Formula (VI) and compound of Formula (VII) in an amount relative to the compound of Formula (II) of less than 0.03:1 (sum of compounds of Formula (VI) and (VII): compound of Formula (II)).

26. A composition according to any one of claims 22 to 25, wherein the compound of Formula (II) is the compound of Formula (IIa).

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