Method for preparing fezolinetant

Abstract

The present invention relates to a method for obtaining fezolinetant which allows said product to be obtained with a high purity and enantiomeric excess by means of using trifluoromethanesulfonic acid. The present invention also relates to the trifluoromethanesulfonic acid salt of fezolinetant and to the use of said salt in obtaining fezolinetant.

Description

[0001] DESCRIPTION

[0002] Method for preparing fezolinetant

[0003] Field of the invention

[0004] The present invention relates to a method for obtaining fezolinetant. The present invention also relates to the trifluoromethanesulfonic acid salt of fezolinetant, to the compound ((5R)-4-(4- fluorobenzoyl)-5-methyl-3,5-dihydro-2 / 7-pyrazin-6-yl)trifluoromethanesulfonate, and to the use of said compounds in obtaining fezolinetant.

[0005] Background of the invention

[0006] Fezolinetant is a selective non-hormonal neurokinin 3 (NK3) receptor antagonist. It blocks the binding of neurokinin B (NKB) to the kisspeptin / neurokinin B / dynorphin (KNDy) neuron, which is thought to restore the balance of KNDy neuronal activity in the hypothalamic thermoregulatory center. Fezolinetant is approved for use in the treatment of moderate to severe vasomotor symptoms (SVM), or hot flushes, associated with menopause.

[0007] Fezolinetant, also known by its IIIPAC name (4-fluorophenyl)-[(8R)-8-methyl-3-(3-methyl- 1 ,2,4-thiadiazol-5-yl)-6,8-dihydro-5 / 7-[1 ,2,4]triazolo[4,3-a]pyrazin-7-yl]methanone or as (R)-(4- fluorophenyl)(8-methyl-3-(3-methyl-1 ,2,4-thiadiazol-5-yl)-5,6-dihydro-[1 ,2,4]triazolo[4,3- a]pyrazin-(8 / - / )-yl)methanone, has the chemical structure shown below

[0008] Patent document WO 2014 / 154895 A1 generally describes obtaining compounds of the fezolinetant family according to the synthesis route shown below:

[0009] The above method applied to obtaining fezolinetant could be exemplified with the following scheme, which coincides with the method described by Hoveyda et al. [ACS Med Chem Lett., Patent document WO 2016 / 046398 A1 discloses another method for obtaining fezolinetant by means of a modified chiral synthesis route. As described in said document, the synthesis of fezolinetant according to the state of the art (reference is made particularly to patent document WO 2011 / 121137 A1), by first reacting (R)-3-methylpiperazin-2-one protected with a tert- butoxycarbonyl group with Et3OBF4 and subsequently reacting same with a carbohydrazide derivative and cycling, represent reaction steps particularly susceptible to racemization. To that end, obtaining the intermediates and products with a high quiral purity is feasible but not reproducible. The solution proposed in WO2016 / 046398A1 is the synthesis route shown below:

[0010] Patent document US 2021 / 0094955 A1 discloses obtaining salts of fezolinetant with various acids and use thereof as active ingredients in pharmaceutical compositions for preventing and / or treating NK3 receptor-related diseases. Nevertheless, it is not mentioned that the obtained salts can be used to increase the chemical or quiral purity of the compound fezolinetant.

[0011] In view of the above, there is a need to provide novel methods for obtaining fezolinetant that yield the product with a high chemical and / or enantiomeric purity, particularly greater than that of the methods described in the state of the art.

[0012] Summary of the invention

[0013] The inventors have found a novel method for obtaining fezolinetant which allows said product to be obtained with a high purity and enantiomeric excess. This method involves reacting (R)-3-methylpiperazin-2-one, with the optionally protected amino group, with trifluoromethanesulfonic acid anhydride to yield a new intermediate in the synthesis of fezolinetant, which is the compound ((5R)-4-(4-fluorobenzoyl)-5-methyl-3,5-dihydro-2 / 7- pyrazin-6-yl)trifluoromethanesulfonate. Furthermore, in this method, after obtaining fezolinetant, said compound is transformed into the corresponding trifluoromethanesulfonic acid salt of fezolinetant and then converted back to fezolinetant. The inventors have discovered that this set of reaction steps allows fezolinetant to be obtained with a high purity and enantiomeric excess, as shown in the examples.

[0014] To that end, in a first aspect, the present invention relates to a method for preparing fezolinetant which comprises: a) reacting a compound of formula (I) with a compound of formula (II)

[0015] 0 R^X

[0016] (II) to obtain a compound of formula (III)

[0017] (HI), wherein R is selected from the group consisting of 4-fluorophenyl, -OCH2Ph, and tert- butoxyl, and X is: i) Cl when R is 4-fluorophenyl or -OCH2Ph, or ii) -O-C(=O)-O-tert-butyl when R is tert- butoxy I; b) reacting the compound of formula (III) with trifluoromethanesulfonic acid anhydride, adding 3-methyl-1 ,2,4-thiadiazole-5-carbohydrazide, and subjecting the obtained mixture to heating at a temperature of at least 40°C in the presence of an alcohol solvent to obtain a compound of formula (IV)

[0018] (IV), wherein R’ is selected from the group consisting of 4-fluorobenzoyl, -C(=O)-OCH2Ph, and H; when R’ is 4-fluorobenzoyl in the compound of formula (IV) obtained in step b), the method is continued with step e), dispensing with steps c) and d); c) when R’ is -C(=O)-OCH2Ph in the compound of formula (IV) obtained in step b), reacting said compound of formula (IV) with a hydrogen source to obtain a compound of formula (IV) wherein R’ is H, and reacting said compound of formula (IV) wherein R’ is H with 4- fluorobenzoyl chloride to obtain a compound of formula (IV) wherein R’ is 4-fluorobenzoyl; d) when R’ is H in the compound of formula (IV) obtained in step b), reacting said compound of formula (IV) with 4-fluorobenzoyl chloride to obtain a compound of formula (IV) wherein R’ is 4-fluorobenzoyl; e) reacting the compound of formula (IV) wherein R’ is 4-fluorobenzoyl obtained in steps b), c), or d) with trifluoromethanesulfonic acid to obtain the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) f) treating the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) with a basic medium to obtain fezolinetant of formula (IVa)

[0019]

[0020] In a second aspect, the invention relates to the trifluoromethanesulfonic acid salt of fezolinetant of formula (V)

[0021] In a third aspect, the invention relates to a compound of formula (VI) wherein R is selected from the group consisting of 4-fluorophenyl, -OCH2Ph, and tert-butoxyl.

[0022] In a fourth aspect, the invention relates to the use of the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) as defined in the second aspect or of the compound of formula (VI) as defined in the third aspect in a method for preparing fezolinetant of formula (I a)

[0023] Description of the Figures

[0024] Figure 1 shows the X-ray powder diffractogram of the trifluoromethanesulfonic acid salt of fezolinetant.

[0025] Figure 2 shows the X-ray powder diffractogram of fezolinetant.

[0026] Detailed Description of the Invention

[0027] In a first aspect, the present invention relates to a method for preparing fezolinetant which comprises: a) reacting a compound of formula (I) with a compound of formula (II) 0 R^X

[0028] (H) to obtain a compound of formula wherein R is selected from the group consisting of 4-fluorophenyl, -OCH2Ph, and tert-butoxyl, and X is: i) Cl when R is 4-fluorophenyl or -OCH2Ph, or ii) -O-C(=O)-O-tert- butyl when R is tert-butoxyl; b) reacting the compound of formula (III) with trifluoromethanesulfonic acid anhydride, adding 3-methyl-1 ,2,4-thiadiazole-5-carbohydrazide, and subjecting the obtained mixture to heating at a temperature of at least 40°C in the presence of an alcohol solvent to obtain a compound of formula (IV) wherein R’ is selected from the group consisting of 4-fluorobenzoyl, -C(=O)-OCH2Ph, and H; when R’ is 4-fluorobenzoyl in the compound of formula (IV) obtained in step b), the method is continued with step e), dispensing with steps c) and d); c) when R’ is -C(=O)-OCH2Ph in the compound of formula (IV) obtained in step b), c1) reacting said compound of formula (IV) with a hydrogen source to obtain a compound of formula (IV) wherein R’ is H, and c2) reacting said compound of formula (IV) wherein R’ is H with 4-fluorobenzoyl chloride to obtain a compound of formula (IV) wherein R’ is 4-fluorobenzoyl; d) when R’ is H in the compound of formula (IV) obtained in step b), reacting said compound of formula (IV) with 4-fluorobenzoyl chloride to obtain a compound of formula (IV) wherein R’ is 4-fluorobenzoyl; e) reacting the compound of formula (IV) wherein R’ is 4-fluorobenzoyl obtained in steps b), c), or d) with trifluoromethanesulfonic acid to obtain the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) and f) treating the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) with a basic medium to obtain fezolinetant of formula (IVa)

[0029] The first step of the method, step a), is to react a compound of formula (I) with a compound of formula (II)

[0030] 0 R^X

[0031] (II) to obtain a compound of formula (III) wherein R is selected from the group consisting of 4-fluorophenyl, -OCH2Ph, and tert-butoxyl, and X is: i) Cl when R is 4-fluorophenyl or -OCH2Ph, or ii) -O-C(=O)-O-tert-butyl when R is tert- butoxy I.

[0032] The compound of formula (I) is (R)-3-methylpiperazin-2-one.

[0033] In one embodiment, in step a) of the method, R is 4-fluorophenyl and X is Cl in the compound of formula (II). Therefore, in this embodiment, step a) of the method is to react (R)-3- methylpiperazin-2-one of formula (I) with 4-fluorobenzoyl chloride (Ila) (compound of formula (II) wherein R is 4-fluorophenyl and X is Cl) to yield (R)-4-(4-fluorobenzoyl)-3-methylpiperazin- 2-one (Illa), i.e. , a compound of formula (III) wherein R is 4-fluorophenyl.

[0034] Preferably, the molar ratio of (R)-3-methylpiperazin-2-one of formula (I) with respect to 4- fluorobenzoyl chloride (compound of formula (II) wherein R is 4-fluorophenyl and X is Cl) is 1 :1 to 1 :1.5, more preferably 1 :1 to 1 :1.2, even more preferably 1 :1 to 1 :1.1.

[0035] In another embodiment, in step a) of the method, R is -OCH2Ph and X is Cl in the compound of formula (II). Therefore, in this embodiment, step a) of the method is to react (R)-3- methylpiperazin-2-one of formula (I) with benzyl chloroformate (lib) (compound of formula (II) wherein R is -OCH2Ph and X is Cl) to yield (R)-benzyl 2-methyl-3-oxopiperazine-1 -carboxylate (111 b), i.e., a compound of formula (III) wherein R is -OCH2Ph.

[0036] Preferably, the molar ratio of (R)-3-methylpiperazin-2-one of formula (I) with respect to benzyl chloroformate (compound of formula (II) wherein R is -OCH2Ph and X is Cl) is 1 :1 to 1 :1.5, more preferably 1 :1 to 1 :1.3, even more preferably 1 :1 to 1 :1.2. In another embodiment, in step a) of the method, R is tert-butoxyl and X is -O-C(=O)-O-tert- butyl in the compound of formula (II). Therefore, in this embodiment, step a) of the method is to react (R)-3-methylpiperazin-2-one of formula (I) with di-tert-butyl dicarbonate (He) (compound of formula (II) wherein R is tert-butoxyl and X is -O-C(=O)-O-tert-butyl) to yield (R)-tert-butyl 2-methyl-3-oxopiperazine-1-carboxylate (lllc), i.e. , a compound of formula (III) wherein R is tert- butoxy I.

[0037] Preferably, the molar ratio of (R)-3-methylpiperazin-2-one of formula (I) with respect to di-tert- butyl dicarbonate (lie) (compound of formula (II) wherein R is tert-butoxyl and X is -O-C(=O)- O-tert-butyl) is 1 :1 to 1 :1.5, more preferably 1 :1 to 1 :1.3, even more preferably 1 :1 to 1 :1.2.

[0038] Preferably, the compound of formula (II) is 4-fluorobenzoyl chloride (Ila) (compound of formula (II) wherein R is 4-fluorophenyl and X is Cl), and the compound of formula (III) is (R)-4-(4- fluorobenzoyl)-3-methylpiperazin-2-one (Illa) (compound of formula (III) wherein R is 4- fluorophenyl).

[0039] Preferably, step a) is performed in the presence of a base.

[0040] The term “base” refers to an organic or inorganic compound, a substance which is capable of accepting a proton (from an acid).

[0041] Preferably, the base used in step a) is a tertiary amine; more preferably, the base is selected from the group consisting of N-methylmorpholine, triethylamine, and a mixture thereof.

[0042] In a more preferred embodiment, the molar ratio of (R)-3-methylpiperazin-2-one of formula (I) with respect to the base in step a) is 1 :1 to 1 :1.5, more preferably 1 :1 to 1 :1.3, even more preferably 1 :1 to 1 :1.2.

[0043] Preferably, step a) is performed in the presence of an aprotic polar organic solvent. The term “aprotic polar organic solvent” refers to a liquid compound which lacks acidic protons (such as hydroxyl groups, for example) and is polar, i.e. , it has a dielectric constant of at least 5. Examples of aprotic polar organic solvents are dichloromethane, tetrahydrofuran, 2- methyltetrahydrofuran, among others.

[0044] Preferably, the aprotic polar organic solvent of step a) is selected from the group consisting of dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, and a mixture thereof, more preferably dichloromethane.

[0045] Preferably, step a) is performed at a temperature of -5 to 25°C.

[0046] The compound of formula (III) obtained in step a) can be isolated from the reaction medium by means of conventional methods in the art, such as extraction, washing, solvent removal, filtration, crystallization, and a combination thereof.

[0047] In a particular embodiment, the compound of formula (III) is crystallized in a mixture of ethyl acetate and methyl tert-butyl ether.

[0048] The next step of the method, step b), is to react the compound of formula (III) with trifluoromethanesulfonic acid anhydride, adding 3-methyl-1 ,2,4-thiadiazole-5-carbohydrazide, and subjecting the obtained mixture to heating at a temperature of at least 40°C in the presence of an alcohol solvent to obtain a compound of formula (IV)

[0049] (IV), wherein R’ is selected from the group consisting of 4-fluorobenzoyl, -C(=O)-OCH2Ph, and H.

[0050] The compound of formula (III) is the compound that has been described above for step a). To that end, in the compound of formula (III) R is selected from the group consisting of 4-fluorophenyl, -OCH2Ph, and tert-butoxyl, preferably 4-fluorophenyl. In the compound of formula (IV), R’ is selected from the group consisting of 4-fluorobenzoyl, -C(=O)-OCH2Ph, and H, preferably 4-fluorobenzoyl.

[0051] When R is 4-fluorophenyl in the compound of formula (III), R’ is 4-fluorobenzoyl in the compound of formula (IV), which compound corresponds to the fezolinetant of formula (IVa).

[0052] Therefore, in one embodiment, R is 4-fluorophenyl, X is Cl, and R’ is 4-fluorobenzoyl.

[0053] When R is -OCH2Ph in the compound of formula (III), R’ is -C(=O)-OCH2Ph in the compound of formula (IV), which corresponds with the structure of the compound of formula (IVb).

[0054] Therefore, in another embodiment, R is -OCH2Ph, X is Cl, and R’ is -C(=O)-OCH2Ph.

[0055] When R is tert-butoxyl in the compound of formula (III), R’ is H in the compound of formula

[0056] (IV), which corresponds with the structure of the compound of formula (IVc). Therefore, in another embodiment, R is tert-butoxyl, X is -O-C(=O)-O-tert-butyl, and R’ is H.

[0057] The reaction of the compound of formula (III) with trifluoromethanesulfonic acid anhydride of step b) yields a new intermediate in the synthesis of fezolinetant which is the compound of formula (VI) wherein R is selected from the group consisting of 4-fluorophenyl, -0CH2Ph, and tert-butoxyl.

[0058] Particularly, the reaction of the compound of formula (III) wherein R is 4-fluorophenyl with trifluoromethanesulfonic acid anhydride of step b) yields a new intermediate in the synthesis of fezolinetant which is the compound of formula (Via)

[0059] Preferably, the reaction of the compound of formula (III) with trifluoromethanesulfonic acid anhydride of step b) is performed in the presence of an aprotic polar organic solvent, as defined above, more preferably dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, or a mixture thereof, even more preferably dichloromethane.

[0060] Preferably, in step b), the reaction of the compound of formula (III) with trifluoromethanesulfonic acid anhydride is performed in the presence of a base. The term base is as defined above. Preferably, the base is a tertiary amine, more preferably the base is selected from the group consisting of triethylamine, diisopropylethylamine, and a mixture thereof, more preferably triethylamine.

[0061] Preferably, the reaction of the compound of formula (III) with trifluoromethanesulfonic acid anhydride of step b) is performed at a temperature of -25 to -10°C. In a preferred embodiment, the molar ratio of the compound of formula (III) with respect to the trifluoromethanesulfonic acid anhydride of step b) is 1 :1 to 1 :2, preferably 1 :1.3 to 1 :1.7, more preferably 1 :1.5 to 1 :1.6.

[0062] In step b), after reacting the compound of formula (III) with trifluoromethanesulfonic acid anhydride, 3-methyl-1 ,2,4-thiadiazole-5-carbohydrazide is added, and the mixture is subjected to heating at a temperature of at least 40°C in the presence of an alcohol solvent.

[0063] Preferably, the heating of step b) is at a temperature of at least 50°C, more preferably 60 to 110°C, more preferably 65 to 100°C, more preferably 70 to 90°C, even more preferably 75 to 85°C.

[0064] The “alcohol solvent” of step b) refers to an alkanol, i.e. , a linear or branched alkyl bound to a hydroxyl group, preferably of 1 to 6 carbon atoms, preferably of 2 to 4 carbon atoms, more preferably 2 or 3 carbon atoms, most preferably 3 carbon atoms. Examples of alkanols are methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol. In a preferred embodiment, the alcohol solvent of step b) is selected from the group consisting of isopropanol, n-propanol, ethanol, and mixtures thereof, more preferably isopropanol.

[0065] In a preferred embodiment, the molar ratio of the compound of formula (III) with respect to the 3-methyl-1 ,2,4-thiadiazole-5-carbohydrazide of step b) is 1 :1 to 1 :1.5, preferably 1 :1 to 1 :1.3, more preferably 1 :1.1 to 1 :1.25.

[0066] Preferably, the compound of formula (IV) obtained in step b) is not isolated from the reaction medium and the next step of the method is carried out directly, particularly when the next step of the method is step e), i.e., when in the compound of formula (IV) R’ is 4-fluorobenzoyl, i.e., the compound is fezolinetant of formula (IVa).

[0067] In the event of wishing to isolate the compound of formula (IV) from the reaction medium, it can be done by means of conventional methods in the art, such as extraction, washing, solvent removal, filtration, crystallization, and a combination thereof.

[0068] The next steps of the method are steps c), d), e), and f). Depending on the nature of group R’ in the compound of formula (IV) obtained in step b), step c), step d), or neither of steps c) and d) will be performed. Step e) will be performed directly (when R’ is 4-fluorobenzoyl in the compound of formula (IV) obtained in step b), i.e., when fezolinetant of formula (IVa) is obtained in step b)). Steps d) and e) will be performed (when R’ is H in the compound of formula (IV) obtained in step b), i.e. , when the compound of formula (IVc) is obtained in step b)). Steps c) and e) will be performed (when R’ is -C(=O)-OCH2Ph in the compound of formula (IV) obtained in step b), i.e., when the compound of formula (IVb) is obtained in step b)). After step e), step f) will be performed in all cases.

[0069] Step c) is only performed when R’ is -C(=O)-OCH2Ph in the compound of formula (IV) obtained in step b), i.e., when the compound of formula (IVb) has been obtained in step b). Step c) comprises sub-steps c1) and c2).

[0070] In step c1), said compound of formula (IV) wherein R’ is -C(=O)-OCH2Ph (i.e., the compound of formula (IVb)) is reacted with a hydrogen source to obtain a compound of formula (IV) wherein R’ is H (i.e., the compound of formula (IVc)).

[0071] This reaction is well known by one skilled in the art as it relates to the deprotection of a carboxybenzyl group.

[0072] The term “hydrogen source” refers to H2 or any substance capable of generating H2 in the reaction medium, such as hydrazine, cyclohexene, or dihydronaphthalene, preferably H2.

[0073] Preferably, H2 is used as the hydrogen source of step c1). Furthermore, the reaction is preferably performed in the presence of a palladium-based catalyst, such as palladium on carbon, for example.

[0074] Preferably, step c1) is performed in the presence of an alcohol solvent, as defined above, preferably an alcohol containing 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 carbon atom.

[0075] Preferably, step c1) is performed at a temperature of 20 to 25°C.

[0076] After step c1) has ended, the product with the deprotected amino group, i.e., a compound of formula (IV) wherein R’ is H (i.e., the compound of formula (IVc)), can be isolated from the reaction medium by means of conventional methods in the art, such as extraction, washing, solvent removal, filtration, crystallization, and a combination thereof. Step c2) is then performed to transform the compound of formula (IV) wherein R’ is H (i.e. , the compound of formula (I c)) into a compound of formula (IV) wherein R’ is 4-fluorobenzoyl (i.e., the compound of formula (IVa) or fezolinetant). This step c2) is the same as step d) described below.

[0077] The next step of the method is step d). This step is only performed when R’ is H in the compound of formula (IV) (i.e., in the compound of formula (IVc)). To that end, it is performed when a compound of formula (IV) wherein R’ is H (i.e., the compound of formula (IVc)) has been obtained directly in step b) and also when step c1) of transitioning from a compound of formula (IV) wherein R’ is -C(=O)-OCH2Ph (i.e., the compound of formula (IVb)) to a compound of formula (IV) wherein R’ is H (i.e., the compound of formula (IVc)) has been performed and, therefore, a compound of formula (IV) wherein R’ is H (i.e., the compound of formula (IVc)) has also been obtained.

[0078] In step d) and / or in step c2), said compound of formula (IV) wherein R’ is H (i.e., the compound of formula (IVc)) is reacted with 4-fluorobenzoyl chloride to obtain a compound of formula (IV) wherein R’ is 4-fluorobenzoyl (i.e., the compound of formula (IVa) or fezolinetant).

[0079] Preferably, step d) and / or step c2) is performed in the presence of a base. The base is as defined above. Preferably, the base of step d) and / or of step c2) is a tertiary amine, more preferably N-methylmorpholine.

[0080] Preferably, step d) and / or step c2) is performed in the presence of an aprotic polar organic solvent, as defined above, more preferably the aprotic polar organic solvent is dichloromethane.

[0081] In a preferred embodiment, the molar ratio of the compound of formula (IV) wherein R’ is H (i.e., the compound of formula (IVc)) with respect to 4-fluorobenzoyl chloride of step d) and / or of step c2) is 1 :1 to 1 :1.5, preferably 1 :1 to 1 :1.2, more preferably 1 :1 to 1 :1.1.

[0082] Preferably, step d) and / or step c2) is performed at a temperature of 0 to 5°C.

[0083] After step d) and / or step c2) have ended, the obtained product, i.e., a compound of formula (IV) wherein R’ is 4-fluorobenzoyl (i.e., the compound of formula (IVa) or fezolinetant), can be isolated from the reaction medium by means of conventional methods in the art, such as extraction, washing, solvent removal, filtration, crystallization, and a combination thereof. Therefore, when a compound of formula (IV) wherein R’ is 4-fluorobenzoyl, i.e., the compound of formula (IVa) or fezolinetant, has been obtained in step b), the synthesis method comprises performing step e) after having performed step b), i.e., steps c) and d) are not performed, as shown in the synthesis scheme below:

[0084] When a compound of formula (IV) wherein R’ is H, i.e., the compound of formula (IVc), has been obtained in step b), the synthesis method comprises performing step d) before performing step e), as shown in the synthesis scheme below:

[0085] Step b)

[0086] Finally, when a compound of formula (IV) wherein R’ is -C(=O)-OCH2Ph, i.e., the compound of formula (IVb), has been obtained in step b), the synthesis method comprises performing step c) before performing step e), according to the synthesis scheme shown below:

[0087] Step b)

[0088] The next step of the method is step e) of reacting the compound of formula (IV) wherein R’ is 4-fluorobenzoyl (i.e., the compound of formula (IVa) orfezolinetant) obtained in steps b), c), or d) with trifluoromethanesulfonic acid to obtain the trifluoromethanesulfonic acid salt of fezolinetant of formula (V)

[0089] Preferably, step e) is performed in the presence of an alcohol type solvent. The alcohol type solvent is as defined above, preferably isopropanol, n-propanol, ethanol, and mixtures thereof, more preferably isopropanol.

[0090] In a preferred embodiment, the molar ratio of the compound of formula (IV) wherein 4-fluorobenzoyl (i.e., the compound of formula (IVa) or fezolinetant) of step e) with respect to the trifluoromethanesulfonic acid of step e) is 1 :1.5 to 1 :2, preferably 1 :1.5 to 1 :1.8, more preferably 1 :1.5 to 1 :1.6.

[0091] Preferably, step e) is performed at a temperature greater than 40°C, more preferably at a temperature greater than 50°C, more preferably 60 to 110°C, more preferably 65 to 100°C, more preferably 70 to 90°C, even more preferably 75 to 85°C.

[0092] The trifluoromethanesulfonic acid salt of fezolinetant of formula (V) obtained in step e) can be isolated from the reaction medium by means of conventional methods in the art, such as extraction, washing, solvent removal, filtration, crystallization, and a combination thereof, preferably by means of filtration and washing.

[0093] The trifluoromethanesulfonic acid salt of fezolinetant of formula (V) obtained in step e) is a new salt of fezolinetant and has the advantage of achieving a further purification of fezolinetant.

[0094] The next step of the method is step f) of treating the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) with a basic medium to obtain fezolinetant of formula (IVa)

[0095] (IVa).

[0096] The expression “basic medium” refers to any substance or mixture of substances capable of neutralizing the trifluoromethanesulfonic acid of the trifluoromethanesulfonic acid salt of fezolinetant to yield fezolinetant (free base).

[0097] Preferably, the basic medium of step f) is a basic aqueous solution; more preferably, said basic aqueous solution is selected from the group consisting of sodium bicarbonate aqueous solution, potassium bicarbonate aqueous solution, sodium carbonate aqueous solution, potassium carbonate aqueous solution, and mixtures thereof; even more preferably sodium bicarbonate aqueous solution.

[0098] Preferably, step f) is performed at a temperature of 20 to 25°C.

[0099] After step f) has ended, the obtained fezolinetant can be isolated from the reaction medium by means of conventional methods in the art, such as extraction, washing, solvent removal, filtration, crystallization, and a combination thereof, preferably filtration and washing.

[0100] As explained above, the method of the invention yields two new compounds, the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) and the compound of formula (VI).

[0101] To that end, in a second aspect, the invention relates to the trifluoromethanesulfonic acid salt of fezolinetant of formula (V)

[0102] Preferably, said trifluoromethanesulfonic acid salt of fezolinetant is in solid form, more preferably in crystalline solid form.

[0103] In a particular embodiment, the trifluoromethanesulfonic acid salt of fezolinetant is characterized in that it has an X-ray powder diffractogram measured with CuKa radiation comprising peaks at 8.1 ° 20, 8.7° 20, 11.0° 20, 13.6° 20, 17.3° 20, 18.9° 20, 19.7° 20, 22.4° 20, all with a margin of error of ± 0.2° 20.

[0104] In another embodiment, the trifluoromethanesulfonic acid salt of fezolinetant is characterized in that it has an X-ray powder diffractogram measured with CuKa radiation essentially such as that of Figure 1 .

[0105] The X-ray diffractograms can be recorded using a powder diffraction system with a copper anode emitting CuKa radiation with a wavelength of 1.54 A, particularly, following the method described in the examples.

[0106] In another embodiment, the trifluoromethanesulfonic acid salt of fezolinetant is characterized in that it has a differential scanning calorimetry (DSC) diagram comprising an exothermic peak having a threshold temperature of about 236.8°C ± 2°C.

[0107] The differential scanning calorimetry diagram can be obtained as described in the examples.

[0108] The threshold temperature or “onset T” refers to the temperature resulting from extrapolating the baseline before the onset of the transition and the baseline during energy absorption (tangent of the curve). It can be calculated as defined in standard DIN ISO 11357-1 :2016(E).

[0109] In a third aspect, the invention relates to a compound of formula (VI) wherein R is selected from the group consisting of 4-fluorophenyl, -OCH2Ph, and tert-butoxyl.

[0110] In a preferred embodiment, R is 4-fluorophenyl and the compound has the formula (Via)

[0111] In a fourth aspect, the invention relates to the use of the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) as defined in the second aspect or of the compound of formula (VI) wherein R is selected from the group consisting of 4-fluorophenyl, -OCH2Ph, and tert-butoxyl as defined in the third aspect in a method for preparing fezolinetant of formula (IVa)

[0112] (IVa). In the context of the present invention, the terms “about” and “around” in reference to a value refer to any value that is comprised in the interval defined by the value ±10% of said value, preferably ±5% of said value.

[0113] Illustrative examples showing the features and advantages of the invention are described below. However, they should not be interpreted as being limiting of the object of the invention as defined in the claims.

[0114] Examples

[0115] Materials and methods

[0116] Ultra-High Resolution Liquid Chromatography

[0117] The chemical purity of the obtained products was analyzed by means of the ultra-high resolution liquid chromatography technique in a WatersAcquity model apparatus provided with a photodiode detector, a mass detector, and a thermostatted oven for the column. A BEH C18 Acquity column (1.7 pm, 2.1 x 100 mm) and mobile phases A (50 mM of ammonium formate, pH 4.8 in water), B (acetonitrile), and C (water) were used with the following analysis conditions:

[0118] Flow rate: 0.5 mL / min

[0119] Column temperature: 45°C

[0120] Wavelength: 220 nm

[0121] Injection volume: 1 pL

[0122] Diluent: Mobile phase A / Mobile phase B (1 :1)

[0123] Gradient:

[0124] The optical purity of the obtained products was analyzed by means of the ultra-high resolution liquid chromatography technique in a Waters Acquity model apparatus provided with a photodiode director, a mass detector, and a thermostaic oven for the column. A Chiralpak IA column (4.6 x 250 mm x 5 pm) and mobile phases A (0.1 % diethylamine in hexane) and B (ethanol) were used with the following analysis conditions:

[0125] Flow rate: 1 mL / min

[0126] Column temperature: 25°C

[0127] Wavelength: 280 nm for fezolinetant and trifluoromethanesulfonic acid salt of fezolinetant and 230 nm for the rest of the compounds Injection volume: 1 L

[0128] Diluent: Mobile phase A / Mobile phase B (75:25)

[0129] Gradient: Isocratic

[0130] Acquisition time: 20 minutes

[0131] Differential Scanning Calorimetry (DSC)

[0132] DSC analysis was performed in a Mettler Toledo 822e apparatus with STARe SW15 software, using the following parameters: heating range of 30 to 300°C with a ramp of 10°C / min and an N2 flow of 50 mL / min. The measurement is taken with a closed perforated capsule.

[0133] X-ray Crystallography (XRPD)

[0134] XRPD analysis was performed using a BRLIKER D2 PHASER X-ray powder diffractometer equipped with a copper anode. The radiation used is CuKa with a wavelength of 1.54 A. The following scan parameters were used: 3-50 degrees 20, continuous scan, ratio: 5.6 degrees / minute.

[0135] Nuclear Magnetic Resonance Analysis

[0136] Proton nuclear magnetic analysis (1H-NMR) and13C-NMR analysis were performed in a 400 MHz Brucker Avance III spectrometer. The chemical shifts were referenced to the DMSO-d6 signal (2.49 ppm for proton and 39.5 ppm for carbon).

[0137] Example 1. Obtaining ( / ?)-4-(4-fluorobenzoyl)-3-methylpiperazin-2-one (Illa)

[0138] 100.0 g (876.0 mmol) of (R)-3-methylpiperazin-2-one (I) were mixed with 1000 mL of dichloromethane at the temperature of about 20°C. The reaction mass was cooled at the temperature of about 0°C and 98.2 mL (893.6 mmol) of N-methylmorpholine and then 103.5 mL (876.0 mmol) of 4-fluorobenzoyl chloride (Ila) were added very slowly. The resulting reaction mixture was kept under stirring for 1 hour at the temperature of between 0 and 5°C.

[0139] Thereafter, 438 mL of a 1 N aqueous HCI solution were added slowly. The two resulting phases were separated, and the organic phase was washed with 418.1 mL of an 8 % wt aqueous NaHCOs solution. The solvent was removed from the organic phase resulting from the subsequent treatment by means of vacuum distillation, and 195 mL of ethyl acetate were added to the solid thus obtained. The resulting mixture was heated at the reflux temperature and kept under stirring for 10 minutes, obtaining a perfect solution. 195 mL of methyl tert-butyl ether were added, observing slight turbidity in the reaction mixture. It was cooled slowly at the temperature of between 5 and 10°C and kept under stirring for 2 hours at said temperature. The resulting solid was filtered, successively washed with two fractions of 100 mL of methyl tert-butyl ether each, and dried in a vacuum oven at the temperature of about 40°C to obtain 172.17 g (83.2% yield, 99.95% purity by means of HPLC, and 99.46% enantiomeric excess) of a white solid corresponding to (R)-4-(4-fluorobenzoyl)-3-methylpiperazin-2-one (Illa).

[0140] Example 2. Obtaining the trifluoromethanesulfonic acid salt of (R)-(4-fluorophenyl)(8- methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone (trifluoromethanesulfonic acid salt of fezolinetant)

[0141] 20.0 g (84.7 mmol) of (F?)-4-(4-fluorobenzoyl)-3-methylpiperazin-2-one (Illa) were mixed with 230 mL of dichloromethane at the temperature of about 20°C. The reaction mass was cooled at the temperature of about -15°C, and 18.3 mL (131.2 mmol) of triethylamine were added, keeping the reaction mass under stirring for 10 minutes at the indicated temperature. 22.2 mL (131.2 mmol) of trifluoromethanesulfonic acid anhydride were added very slowly, maintaining the indicated temperature, and the obtained reaction mass was kept under stirring for 10 minutes. Finally, 16.07 g (101.6 mmol) of 3-methyl-1 ,2,4-thiadiazole-5-carbohydrazide also at the temperature of about -15°C were added slowly, and the obtained reaction mass was kept under stirring for 10 minutes at the mentioned temperature. The temperature of the reaction mass was left to evolve to about 20°C and kept under stirring at said temperature for 1 hour.

[0142] Thereafter, the solvent was removed by means of vacuum distillation, and 200 mL of isopropanol were added. The resulting reaction mass was heated to the reflux temperature and kept under stirring for 16 hours.

[0143] Thereafter, an optical purity of about 98.5% is observed in the reaction crude by means of UHPLC for (F?)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1 ,2,4-thiadiazol-5-yl)-5,6-dihydro- [1 ,2,4]triazolo[4,3-a]pyrazin-7(8 / - / )-yl)methanone. The reaction mass was cooled to the temperature of about 50°C, and 12.0 mL (135.4 mmol) of trifluoromethanesulfonic acid were added slowly. The reaction mixture was heated at the reflux temperature and kept under stirring for 10 minutes at said temperature. It was then cooled slowly at the temperature of about 20°C, the resulting solid was filtered, successively washed with two fractions of 20 mL of isopropanol each, and dried in a vacuum oven at the temperature of about 40°C to obtain 20.36 g (47.3% yield, 99.84% purity by means of HPLC, and 99.88% enantiomeric excess) of a white solid corresponding to the trifluoromethanesulfonic acid salt of (R)-(4-fluorophenyl)(8- methyl-3-(3-methyl-1 ,2,4-thiadiazol-5-yl)-5,6-dihydro-[1 ,2,4]triazolo[4,3-a]pyrazin-7(8 / - / )- yl)methanone.

[0144] 1H-NMR (d6-DMSO, 400 MHz) b(ppm): 12.16 (broad s, 1 H), 7.59 (dd, 2H), 7.35-7.29 (m, 2 H), 5.73 (broad s, 1 H), 4.70-4.68 (d, 1 H), 4.30 (m, 1 H), 3.65 (m, 1 H) 2.68 (s, 3H), 1.61 (d, 3H).

[0145] 13C-NMR (d6-DMSO, 400 MHz) b(ppm): 174.8, 174.1 , 169.2, 163.3 (d), 154.6, 145.4, 132.1 (d), 130.0 (d, 2C), 121.1 (d), 116.1 (d, 2C), 62.5, 45.3 (2C), 25.9, 19.1.

[0146] XRPD: 8.1 ° 20, 8.7° 20, 11.0° 20, 13.6° 20, 17.3° 20, 18.9° 20, 19.7° 20, 22.4° 20, all with a margin of error of ± 0.2° 20. The X-ray powder diffractogram of the compound is shown in Figure 1.

[0147] The differential scanning calorimetry (DSC) spectrum of the compound comprises an endothermal peak having a threshold temperature of about 236.8°C.

[0148] Example 3. Obtaining ( / ?)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)- 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (fezolinetant)

[0149] 76.43 g (150.3 mmol) of the trifluoromethanesulfonic acid salt of (R)-(4-fluorophenyl)(8-methyl- 3-(3-methyl-1 ,2,4-thiadiazol-5-yl)-5,6-dihydro-[1 ,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone obtained by means of the methodology described in Example 2 were mixed with 382 mL of water at the temperature of about 20°C. A 10 % wt aqueous NaHCCh solution was added until obtaining a stable pH of about 8, maintaining the indicated temperature, and the resulting mixture was kept under stirring for 1 hour. The resulting solid was filtered, successively washed with two fractions of 35 mL of water each, and dried in a vacuum oven at the temperature of about 45°C to obtain 52.51 g (97.5% yield, 99.97% purity by means of HPLC, and 99.94% enantiomeric excess) of a white solid corresponding to (R)-(4- fluorophenyl)(8-methyl-3-(3-methyl-1 ,2,4-thiadiazol-5-yl)-5,6-dihydro-[1 ,2,4]triazolo[4,3- a]pyrazin-7(8 / - / )-yl)methanone. XRPD: 9.3° 20, 9.9° 20, 12.0° 20, 13.5° 20, 14.9° 20, 15.7° 20, 16.8° 20, 18.6° 20, 19.1° 20, 19.8° 20, 20.1° 20, 21.8° 20, 22.5° 20, 24.2° 20, 25.4° 20, 27.5° 20, and 28.9° 20, all with a margin of error of ± 0.2° 20. The X-ray powder diffractogram of the compound is shown in Figure 2.

[0150] The differential scanning calorimetry (DSC) spectrum of the compound comprises an endothermal peak having a threshold temperature of about 169.1 °C.

[0151] Example 4. Obtaining ( / ?)-tert-butyl 2-methyl-3-oxopiperazine-1 -carboxylate (lllc)

[0152] 5 g (43.75 mmol) of (R)-3-methylpiperazin-2-one and 6.8 mL (48.25 mmol) of triethylamine were mixed with 25 mL of dichloromethane at the temperature of about 20°C. The obtained solution was cooled at the temperature of about 0°C, and 11.0 g (50.25 mmol) of di-tert-butyl dicarbonate (lie) were added. The temperature of the reaction mixture was left to evolve to about 20°C, and the obtained solution was kept under stirring for 1 hour at said temperature.

[0153] Thereafter, the reaction mixture was successively washed with 15 mL of a 1 N aqueous HCI solution and 15 of a saturated aqueous NaCI solution. The solvent was removed from the organic phase by means of vacuum distillation, and the resulting solid was crystallized in a mixture of 15 mL of methyl tert-butyl ether and 10 mL of ethyl acetate to obtain 8.35 g (89.0% yield, 99.01% purity by means of HPLC, and 99.89% enantiomeric excess) of a white solid corresponding to (R)-tert-butyl 2-methyl-3-oxopiperazine-1-carboxylate (lllc).

[0154] Example 5. Obtaining (R)-benzyl 2-methyl-3-oxopiperazine-1 -carboxylate (lllb) 5 g (43.75 mmol) of (R)-3-methylpiperazin-2-one (I) and 6.8 mL (48.25 mmol) of triethylamine were mixed with 25 mL of dichloromethane at the temperature of about 20°C. The obtained solution was cooled at the temperature of about 0°C, and 7.2 mL (50.44 mmol) of benzyl chloroformate (lib) were added. The temperature of the reaction mixture was left to evolve to about 20°C, and the obtained solution was kept under stirring for 1 hour at said temperature.

[0155] Thereafter, the reaction mixture was successively washed with 15 mL of a 1 N aqueous HCI solution and 15 of a saturated aqueous NaCI solution. The solvent was removed from the organic phase by means of vacuum distillation, and the resulting solid was crystallized in a mixture of 25 mL of methyl tert-butyl ether and 15 mL of ethyl acetate to obtain 7.36 g (67.7% yield, 99.15% purity by means of HPLC, and 99.91% enantiomeric excess) of a white solid corresponding to (R)-benzyl 2-methyl-3-oxopiperazine-1-carboxylate (I lib).

[0156] Example 6. Obtaining the trifluoromethanesulfonic acid salt of (R)-(4-fluorophenyl)(8- methyl-3-(3-methyl-1 ,2,4-thiadiazol-5-yl)-5,6-dihydro-[1 ,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone (trifluoromethanesulfonic acid salt of fezolinetant) 2 g (9.34 mmol) of (R)-tert-butyl 2-methyl-3-oxopiperazine-1-carboxylate (lllc) obtained by means of the methodology described in Example 4 were mixed with 20 mL of dichloromethane at the temperature of about 20°C. The reaction mass was cooled at the temperature of about -15°C, and 2.0 mL (14.35 mmol) of triethylamine were added, keeping the reaction mass under stirring for 5 minutes at the indicated temperature. 2.4 mL (14.21 mmol) of trifluoromethanesulfonic acid anhydride were added very slowly, maintaining the indicated temperature, and the obtained reaction mass was kept under stirring for 10 minutes. Then 1.8 g (11.38 mmol) of 3-methyl-1 ,2,4-thiadiazole-5-carbohydrazide also at the temperature of about -15°C were added slowly, and the obtained reaction mass was kept under stirring for 5 minutes at the mentioned temperature. The temperature of the reaction mass was left to evolve to about 20°C and kept under stirring at said temperature for 1 hour.

[0157] Thereafter, the solvent was removed by means of vacuum distillation, and 20 mL of isopropanol were added. The resulting reaction mass was heated to the reflux temperature and kept under stirring for 16 hours.

[0158] Thereafter, the solvent was removed by means of vacuum distillation to obtain a solid residue to which 20 mL of dichloromethane were added. The reaction mass was cooled at the temperature of about 0°C, and 2.1 mL (19.1 mmol) of / V-methylmorpholine and then 1.1 mL (9.32 mmol) of 4-fluorobenzoyl chloride were added very slowly. The resulting reaction mixture was kept under stirring for 1 hour at the temperature of between 0 and 5°C.

[0159] Thereafter, 5 mL of a 1 N aqueous HCI solution were added slowly. The two resulting phases were separated, and the organic phase was washed with 5 mL of an 8 wt% aqueous NaHCCh solution. The solvent was removed from the organic phase resulting from the subsequent treatment by means of vacuum distillation, 20 mL of isopropanol were added, and the reaction mixture was heated at a temperature of about 50°C. Then 1.3 mL (14.7 mmol) of trifluoromethanesulfonic acid were added slowly. The reaction mixture was heated at the reflux temperature and kept under stirring for 10 minutes at said temperature. It was then cooled slowly at the temperature of about 20°C, the resulting solid was filtered, successively washed with two fractions of 5 mL of isopropanol each, and dried in a vacuum oven at the temperature of about 40°C to obtain 1.92 g (40.4% yield, 99.81 % purity by means of HPLC, and 99.88% enantiomeric excess) of a white solid corresponding to the trifluoromethanesulfonic acid salt of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1 ,2,4-thiadiazol-5-yl)-5,6-dihydro-

[0160] [1 ,2,4]triazolo[4,3-a]pyrazin-7(8 / - / )-yl)methanone. The X-ray powder diffractogram (XRPD) and the differential scanning calorimetry (DSC) spectrum of the obtained compound coincide with those of the compound obtained following the experimental methodology described in Example 2.

[0161] Example 7. Obtaining ( / ?)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)- 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (fezolinetant)

[0162] 5.0 g (9.83 mmol) of the trifluoromethanesulfonic acid salt of (R)-(4-fluorophenyl)(8-methyl-3- (3-methyl-1 ,2,4-thiadiazol-5-yl)-5,6-dihydro-[1 ,2,4]triazolo[4,3-a]pyrazin-7(8 / - / )-yl)methanone obtained by means of the methodology described in section 5.6 were mixed with 25 mL of water at the temperature of about 20°C. A 10 % wt aqueous NaHCCh solution was added until obtaining a stable pH of about 8, maintaining the indicated temperature, and the resulting mixture was kept under stirring for 1 hour. The resulting solid was filtered, successively washed with two fractions of 5 mL of water each, and dried in a vacuum oven at the temperature of about 45°C to obtain 3.41 g (96.8% yield, 99.91% purity by means of HPLC, and 99.92% enantiomeric excess) of a white solid corresponding to (R)-(4-fluorophenyl)(8-methyl-3-(3- methyl-1 ,2,4-thiadiazol-5-yl)-5,6-dihydro-[1 ,2,4]triazolo[4,3-a]pyrazin-7(8 / - / )-yl)methanone.

[0163] The X-ray powder diffractogram (XRPD) and the differential scanning calorimetry (DSC) spectrum of the obtained compound coincide with those of the compound obtained following the experimental methodology described in Example 3.

[0164] Example 8. Obtaining the trifluoromethanesulfonic acid salt of (R)-(4-fluorophenyl)(8- methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)methanone (trifluoromethanesulfonic acid salt of fezolinetant)

[0165]

[0166] 2 g (8.06 mmol) of (R)-benzyl 2-methyl-3-oxopiperazine-1 -carboxylate obtained by means of the methodology described in Example 5 were mixed with 20 mL of dichloromethane at the temperature of about 20°C. The reaction mass was cooled at the temperature of about -15°C, and 1.7 mL (12.20 mmol) of triethylamine were added, keeping the reaction mass under stirring for 5 minutes at the indicated temperature. 2.0 mL (12.12 mmol) of trifluoromethanesulfonic acid anhydride were added very slowly, maintaining the indicated temperature, and the obtained reaction mass was kept under stirring for 10 minutes. Then 1 .53 g (9.67 mmol) of 3-methyl-1 ,2,4-thiadiazole-5-carbohydrazide also at the temperature of about -15°C were added slowly, and the obtained reaction mass was kept under stirring for 5 minutes at the mentioned temperature. The temperature of the reaction mass was left to evolve to about 20°C and kept under stirring at said temperature for 1 hour. Thereafter, the solvent was removed by means of vacuum distillation, and 20 mL of isopropanol were added. The resulting reaction mass was heated to the reflux temperature and kept under stirring for 18 hours. Thereafter, the reaction mass was cooled to the temperature of about 20°C, and triethylamine was added slowly until obtaining a pH value of between 7 and 8. The solvent was removed from the reaction mixture by means of vacuum distillation, and the obtained residue was dissolved in 10 mL of ethyl acetate and 10 mL of water. The organic phase thus obtained was separated, and the solvent was removed by means of vacuum distillation. The solid thus obtained was mixed with 20 mL of methanol, and 0.10 g of 5% Pd / C were added. Two successive sequences of inertization with a vacuum and N2 were performed, and finally the internal pressure of the flask was adjusted to about 5 bar with H2 atmosphere. The resulting mixture was kept under stirring for 18 hours at a temperature of between 20 and 25°C and about 5 bar of H2 pressure.

[0167] Thereafter, the reaction mixture was depressurized and filtered through a diatomaceous earth filter which was then washed with two fractions of 10 mL of methanol each. The solvent was removed by means of vacuum distillation to obtain a solid residue to which 20 mL of dichloromethane were added. The reaction mass was cooled at the temperature of about 0°C, and 0.9 mL (8.19 mmol) of / V-methylmorpholine and then 1.0 mL (8.46 mmol) of 4- fluorobenzoyl chloride were added very slowly. The resulting reaction mixture was kept under stirring for 1 hour at the temperature of between 0 and 5°C.

[0168] Thereafter, 5 mL of a 1 N aqueous HCI solution were added slowly. The two resulting phases were separated, and the organic phase was washed with 5 mL of an 8 wt% aqueous NaHCCh solution. The solvent was removed from the organic phase resulting from the subsequent treatment by means of vacuum distillation, 20 mL of isopropanol were added, and the reaction mixture was heated at the temperature of about 50°C. Then 1.1 mL (12.4 mmol) of trifluoromethanesulfonic acid were added slowly. The reaction mixture was heated at the reflux temperature and kept under stirring for 5 minutes at said temperature. It was then cooled slowly at the temperature of about 20°C, the resulting solid was filtered, successively washed with two fractions of 5 mL of isopropanol each, and dried in a vacuum oven at the temperature of about 40°C to obtain 1.80 g (43.9% yield, 99.74% purity by means of HPLC, and 99.91% enantiomeric excess) of a white solid corresponding to the trifluoromethanesulfonic acid salt of (R)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1 ,2,4-thiadiazol-5-yl)-5,6-dihydro-

[0169] [1 ,2,4]triazolo[4,3-a]pyrazin-7(8 / - / )-yl)methanone. The X-ray powder diffractogram (XRPD) and the differential scanning calorimetry (DSC) spectrum of the obtained compound coincide with those of the compound obtained following the experimental methodology described in Example 2.

[0170] Example 9. Obtaining ( / ?)-(4-fluorophenyl)(8-methyl-3-(3-methyl-1,2,4-thiadiazol-5-yl)- 5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)methanone (fezolinetant)

[0171] 5.0 g (9.83 mmol) of the trifluoromethanesulfonic acid salt of (R)-(4-fluorophenyl)(8-methyl-3- (3-methyl-1 ,2,4-thiadiazol-5-yl)-5,6-dihydro-[1 ,2,4]triazolo[4,3-a]pyrazin-7(8 / - / )-yl)methanone obtained by means of the methodology described in Example 8 were mixed with 25 mL of water at the temperature of about 20°C. A 10 % wt aqueous NaHCCh solution was added until obtaining a stable pH of about 8, maintaining the indicated temperature, and the resulting mixture was kept under stirring for 1 hour. The resulting solid was filtered, successively washed with two fractions of 5 mL of water each, and dried in a vacuum oven at the temperature of about 45°C to obtain 3.45 g (97.9% yield, 99.90% purity by means of HPLC, and 99.92% enantiomeric excess) of a white solid corresponding to (R)-(4-fluorophenyl)(8-methyl-3-(3- methyl-1 ,2,4-thiadiazol-5-yl)-5,6-dihydro-[1 ,2,4]triazolo[4,3-a]pyrazin-7(8 / - / )-yl)methanone.

[0172] The X-ray powder diffractogram (XRPD) and the differential scanning calorimetry (DSC) spectrum of the obtained compound coincide with those of the compound obtained following the experimental methodology described in Example 3.

Claims

CLAIMS1 . Method for preparing fezolinetant which comprises: a) reacting a compound of formula (I)with a compound of formula (II)0 R^X(II) to obtain a compound of formulawherein R is selected from the group consisting of 4-fluorophenyl, -OCH2Ph, and tert-butoxyl, and X is: i) Cl when R is 4-fluorophenyl or -OCH2Ph, or ii) -O-C(=O)-O-tert- butyl when R is tert-butoxyl; b) reacting the compound of formula (III) with trifluoromethanesulfonic acid anhydride, adding 3-methyl-1 ,2,4-thiadiazole-5-carbohydrazide, and subjecting the obtained mixture to heating at a temperature of at least 40°C in the presence of an alcohol solvent to obtain a compound of formula (IV)wherein R’ is selected from the group consisting of 4-fluorobenzoyl, -C(=O)-OCH2Ph, and H; when R’ is 4-fluorobenzoyl in the compound of formula (IV) obtained in step b), the method is continued with step e), dispensing with steps c) and d)c) when R’ is -C(=0)-0CH2Ph in the compound of formula (IV) obtained in step b), c1) reacting said compound of formula (IV) with a hydrogen source to obtain a compound of formula (IV) wherein R’ is H, and c2) reacting said compound of formula (IV) wherein R’ is H with 4-fluorobenzoyl chloride to obtain a compound of formula (IV) wherein R’ is 4-fluorobenzoyl; d) when R’ is H in the compound of formula (IV) obtained in step b) or in step c), reacting said compound of formula (IV) with 4-fluorobenzoyl chloride to obtain a compound of formula (IV) wherein R’ is 4-fluorobenzoyl; e) reacting the compound of formula (IV) wherein R’ is 4-fluorobenzoyl obtained in steps b), c), or d) with trifluoromethanesulfonic acid to obtain the trifluoromethanesulfonic acid salt of fezolinetant of formula (V)and f) treating the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) with a basic medium to obtain fezolinetant of formula (IVa)2. Method for preparing fezolinetant according to claim 1 , wherein R is 4-fluorophenyl, X is Cl, and R’ is 4-fluorobenzoyl.

3. Method for preparing fezolinetant according to claim 1 , wherein R is -OCH2Ph, X is Cl, and R’ is -C(=O)-OCH2Ph.

4. Method for preparing fezolinetant according to claim 1 , wherein R is tert-butoxyl, X is -O- C(=O)-O-tert-butyl, and R’ is H.

5. Method for preparing fezolinetant according to any of the preceding claims, wherein step a) is performed in the presence of a base.

6. Method for preparing fezolinetant according to claim 5, wherein the base is selected from the group consisting of N-methylmorpholine, triethylamine, and a mixture thereof.

7. Method for preparing fezolinetant according to any of the preceding claims, wherein step a) is performed in the presence of an aprotic polar organic solvent.

8. Method for preparing fezolinetant according to claim 7, wherein the aprotic polar organic solvent is dichloromethane.

9. Method for preparing fezolinetant according to any of the preceding claims, wherein step a) is performed at a temperature of -5 to 25°C.

10. Method for preparing fezolinetant according to any one of the preceding claims, wherein the reaction of the compound of formula (III) with trifluoromethanesulfonic acid anhydride of step b) is performed in the presence of a base.

11. Method for preparing fezolinetant according to claim 10, wherein the base is selected from the group consisting of triethylamine, diisopropylethylamine, and a mixture thereof.

12. Method for preparing fezolinetant according to any one of the preceding claims, wherein the reaction of the compound of formula (III) with trifluoromethanesulfonic acid anhydride of step b) is performed in the presence of an aprotic polar organic solvent.

13. Method for preparing fezolinetant according to claim 12, wherein the aprotic polar organic solvent is dichloromethane.

14. Method for preparing fezolinetant according to any one of the preceding claims, wherein the reaction of the compound of formula (III) with trifluoromethanesulfonic acid anhydride of step b) is performed at a temperature of -25 to -10°C.

15. Method for preparing fezolinetant according to any one of the preceding claims, wherein the heating of step b) is at a temperature of 60 to 110°C.

16. Method for preparing fezolinetant according to any one of the preceding claims, wherein the alcohol solvent of step b) is selected from the group consisting of isopropanol, n-propanol, ethanol, and mixtures thereof.

17. Method for preparing fezolinetant according to any one of the preceding claims, wherein step e) is performed at a temperature of 60 to 110°C.

18. Method for preparing fezolinetant according to any one of the preceding claims, wherein step e) is performed in the presence of an alcohol type solvent.

19. Method for preparing fezolinetant according to claim 18, wherein the alcohol solvent of step e) is selected from the group consisting of isopropanol, n-propanol, ethanol, and mixtures thereof.

20. Method for preparing fezolinetant according to any one of the preceding claims, wherein the basic medium of step f) is a basic aqueous solution.

21. Method for preparing fezolinetant according to claim 20, wherein the basic aqueous solution is selected from the group consisting of sodium bicarbonate aqueous solution, potassium bicarbonate aqueous solution, sodium carbonate aqueous solution, potassium carbonate aqueous solution, and mixtures thereof.

22. Method for preparing fezolinetant according to any one of claims 1 , 3, and 5-21 , wherein the hydrogen source of step c) is H2.

23. Method for preparing fezolinetant according to any one of claims 1 and 3-22, wherein step d) and / or step c2) is performed in the presence of a base.

24. Method for preparing fezolinetant according to claim 23, wherein the base is N- methylmorpholine.

25. Method for preparing fezolinetant according to any one of claims 1 and 3-24, wherein step d) and / or step c2) is performed in the presence of an aprotic polar organic solvent.

26. Method for preparing fezolinetant according to claim 25, wherein the aprotic organic solvent is dichloromethane.

27. Trifluoromethanesulfonic acid salt of fezolinetant of formula (V)28. Trifluoromethanesulfonic acid salt of fezolinetant according to claim 27 in solid form.

29. Trifluoromethanesulfonic acid salt of fezolinetant according to claim 27 or 28, characterized in that it has an X-ray powder diffractogram measured with CuKa radiation comprising peaks at 8.1 ° 20, 8.7° 20, 11.0° 20, 13.6° 20, 17.3° 20, 18.9° 20, 19.7° 20, 22.4° 20, all with a margin of error of ± 0.2° 20.

30. Trifluoromethanesulfonic acid salt of fezolinetant according to any of claims 27 to 29, characterized in that it has an X-ray powder diffractogram measured with CuKa radiation essentially such as that of Figure 1.

31. Trifluoromethanesulfonic acid salt of fezolinetant according to any of claims 27 to 30, characterized in that it has a differential scanning calorimetry (DSC) diagram comprising an exothermic peak having a threshold temperature of about 236.8°C ± 2°C32. Compound of formula (VI)(VI), wherein R is selected from the group consisting of 4-fluorophenyl, -OCFkPh, and tert-butoxyl.

33. Compound of formula (VI) according to claim 32, wherein R is 4-fluorophenyl.

34. Use of the trifluoromethanesulfonic acid salt of fezolinetant of formula (V) according to any one of claims 27 to 31 or of the compound of formula (VI), wherein R is selected from the group consisting of 4-fluorophenyl, -OCH2Ph, and tert-butoxyl, according to claim 32 or 33, in a method for preparing fezolinetant of formula (IVa)

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