PROCESS FOR THE PREPARATION OF 4-[(2S)-2-4-[5-CHLORO-2-(4-CHLORO-1H-1,2,3-TRIAZOL-1-YL)PHENYL]-5-METHOXY-2-OXOPYRIDINI-1(2H)-YLBUTANOYL]AMINO-2-FLUOROBENZAMIDE (I) OR 4-((2S)-2-[4-5-CHLORO-2-[4-(TRIFLUOROMETHYL)-1H-1,2,3-TRIAZOL-1-YL]PHENYL-5-METHOXY-2-OXOPYRIDINI-1(2H)-YL]BUTANOYL-AMINO)-2-FLUOROBENZAMIDE (II) AND INTERMEDIATE COMPOUNDS USEFUL IN THE PROCESS

Abstract

La presente se refiere a un proceso para preparar 4-{[(2S)-2-{4-[5-cloro-2-(4-cloro-1H-1,2,3-triazol-1-il)fenil]-5-metoxi-2-oxopirin-1(2H)-il}butanoil]amino}-2-fluorobenzamida (I) o 4-({(2S)-2-[4-(5-cloro-2-[4-(trifluorometil)-1H-1,2,3-triazol-1-il]fenil}-5-metoxi-2-oxopirin-1(2H)-il]butanoil}amino)-2-fluorobenzamida (II) a partir de 2,5-dimethoxypiridine (III), 1-(2-bromo-4-chlorophenyl)-4-chloro-1H-1,2,3-triazol (X-Cl) or 1-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazol (X-CF3), 4-amino-2-fluorbenzamida (XIII) y ácido (2R)-2-aminobutanoic acid (XVII).

Description

PROCESO DE PREPARACIÓN La presente invención se refiere a un proceso para preparar 4-{[(2S)-2-{4-[5-cloro-2-(4-cloro-1H1,2,3-triazol-1-yl)fenil]-5-metoxi-2-oxopyridin-1(2H)-il}butanoil]amino}-2-fluorobenzamida (I) o 4-({(2S)-2-[4-{5-cloro-2-[4-(trifluorometil)-1H1-l,2,3-triazol-1-yl]fenil}-5-metoxi-2-oxopyridinl(2H)-il]butanoil}amino)-2-fluorobenzamida (II) a partir de 2,5-dimethoxypyridine (III), l-(2-bromo4-chlorophenyl)-4-cIoro-lH-l,2,3-triazol (X-Cl) or l-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-lH1,2,3-triazol (X-CF3), 4-amino-2-fluorbenzamide (XIII) and (2R)-2-aminobutanoic acid (XVII). Los compuestos 4-{[(2S)-2-{4-[5-cloro-2-(4-cloro-lH-l,2,3-triazoI-l-il)fenil]-5-metoxi-2oxopirin-l(2H)-il}butanoil]amino}-2-fluorobenzamida (I) y 4-({(2S)-2-[4-{5-cloro-2-[4(trifluorometil)-lH-l,2,3-triazol-l-il]fenil}-5-metoxi-2-oxopirin-l(2H)-il]butanoil}-amino)-2fluorobenzamida (II) se conocen de WO 2017 / 005725 y corresponden a las fórmulas (I) y (II) The compounds in formulas (I) and (II) act as inhibitors of Factor Xla and due to this specific mechanism of action, they could cause safe and effective anticoagulation in vivo after oral administration. WO 2014 / 154794 and WO 2017 / 005725 describe a synthesis for preparing the compounds of formulas (I) and (II) in the gram range from 2,5-dimethoxypyridine (III), l-(2-bromo-4-chlorophenyl)-4-chloro-lH-l,2,3-triazole (X-Cl) or l-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-l H-1,2,3-triazole (X-CF3) respectively, 4-amino-2-fluorobenzamide (XIII) and terebutyl 2-bromobutanoate (VII) (Scheme 1). IF-2019-3 6281512-APN-ANP#INPI Page 1 of 30 BHC 17 1 041-FC Scheme 1 IUPAC chemical names of compounds(I) to (XIV-C1) / (XIV-CF3): 4-{[(2S)-2-{4-[5-chloro-2-(4-chloro-1 Η-1,2,3-triazol-1 -yl)phenyl]-5-methoxy-2-oxopyridin-1 (2H)yl}butanoyl]amino}-2-fluorobenzamida (I), 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5-methoxy-2-oxopyridinl(2H)-yl]butanoyl}amino)-2-fluorobenzamide (II), 2,5-dimethoxypyridine (III), (2,5-dimethoxipyridin-4-yl)boronic acid (IV), 4-bromo-2,5-dimethoxypyridine (V), 4-bromo-5-methoxipyridin-2( 1 H)-ona (VI), Tere-butyl 2-bromobutanoate (VII), 2-(4-bromo-5-methoxy-2-oxopyridin-l(2H)-yl)terebutyl butanoate (VIII), 2-[5-methoxy-2-oxo-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-l(2H)-yl]terebutyl butanoate (IX), l-(2-bromo-4-chlorophenyl)-4-chloro-l Hl ,2,3-triazol (X-CI), l-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-lH-l,2,3-triazol (X-CF3), 2-{4-[5-chloro-2-(4-chloro-1 Η-1,2,3-triazol-1 -yl)phenyl]-5-methoxy-2-oxopyridin-1 (2H)-i 1} terebutyl butanoate (XI-C1), 2-[4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-5-methoxy-2-oxopyridin-l(2H)yl]butanoate de tere-butyl (XI-CF3), IF-2019-36281512-APN-ANP#INPI Page 2 of 30 BHC 17 1 041-FC 2-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-5-methoxy-2-oxopyridin-1(2H)yl}butanoic acid (X1I-C1), 2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5-methoxy-2-oxopyridin-1(2H)yl]butanoic acid (XII-CF3), 4-amino-2-fluorobenzamida (XIII), 4-(2-{4-[5-chloro-2-(4-chloro-lH-1,2,3-triazol-l-yl)phenyl]-5-methoxy-2-oxopyridin- 1(2H)yl}butanamido)-2-fluorobenzamida (XIV-C1), 4-{2-[4-{5-chloro-2-[4-(trifluoromethyl)-4,5-dihydro-lH-l,2,3-triazol-l-yl]phenyl}-5-methoxy-2oxopyridin-l(2H)-yl]butanamido}-2-fluorobenzamida (XIV-CF3). The summary of the components of forms (I) and (II), mentioned in example 1, can be divided into three sections: a) Preparación de 2-{4-[5-cloro-2-(4-cloro-1H-1,2,3-triazol-1-yl)fenil]-5-metoxi-2-oxopyridinl(2H)-il}butanoato de tere-butilo (XI-C1) o 2-[4-{5-cloro-2-[4-(trifluorometil)-1H-1,2,3-triazol-1¡l]fenil}-5-metoxi-2-oxopyridin-1(2H)-il]butanoato de tere-butilo (XI-CF3) a partir de 2,5dimetoxipiridina (III) y l-(2-bromo-4-clorofenil)-4-cloro-1H-1,2,3-triazol (X-Cl) o l-(2-bromo-4clorofenil)-4-(trifluorometil)-lH-l,2,3-triazol (X-CF3) respectivamente a través de 2-[5-metoxi-2oxo-4-(4,4,5,5-tetrametil-l,3,2-dioxaborolan-2-il)piridin-l(2H)-il]butanoato de tere-butilo (IX). Scheme 2 b) Preparation of 4-(2-{4-[5-chloro-2-(4-chloro-lH-1,2,3-triazol-l-yl)phenyl]-5-methoxy-2-oxopyridinl(2H)-yl}butanamido)-2-fluorobenzamida (XIV-C1) or 4-{2-[4-{5-chloro-2-[4-(trifluoromethyl)-4,5dihydro-1 H-1,2,3-triazol-l-yl]phenyl}-5-methoxy-2-oxopyridin-l(2H)-yl]butanamido}-2- fluorobenzamida (XIV-CF3) starting from 2-{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)feml]-5methoxy-2-oxopyridin-1(2H)-yl}butanoate tere-butyl (XI-C1) or 2-[4-{5-chloro-2-[4IF-2019-3 6281512-APN-ANP#INPI Page 3 of 30 BHC 17 1 041-FC (trifluorometil)-lH-l,2,3-triazol-l-yl]fenil}-5-metoxi-2-oxopyridin-l(2H)-yl]butanoato de tercbutil (XI-CF3) respectively a través de ácido 2-{4-[5-cloro-2-(4-cloro-lH-l,2,3-triazol-lyl)fenil]-5-metoxi-2-oxopyridin-l(2H)-yl}butanoico (XII-CI) o ácido 2-[4-{5-cloro-2-[4(trifluorometil)-lH-l,2,3-triazol-l-yl]fenil}-5-metoxi-2-oxopyridin-l(2H)-yl]butanoico (XII-CF3) 5 respectively y 4-amino-2-fluorobenzamida (XIII). Scheme 3 c) Separation of the two enantiomers of 4-(2-{4-[5-chloro-2-(4-chloro-lH-l,2,3-triazol-l-il)fenil]-5-metoxi-2-oxopiridin-l(2H)-il}butanamido)-2-fluorobenzamide (XIV-C1) 0 4-{2-[4-{5-chloro-2-[4-(trifluorometil)-4,5-dihydro-1H-1,2,3-triazol-1-i I]fenil}-5-metoxi-2-oxopiridin-1 (2H)-il]butanamido}-2-fluorobenzamide (XIV-CF3) to obtain the simple enantiomers 4-{[(2S)-2{4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1 -il)fenil]-5-metoxi-2-oxopiridin-1 (2H)il}butanoil]amino}-2-fluorobenzamida (I) 0 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluorometil)-lH-l,2,3triazol-l-il]fenil}-5-metoxi-2-oxopiridin-l(2H)-il]butanoil}amino)-2-fluorobenzamida (II) respectivamente. IF-2019-3 6281512-APN-ANP#INPI Page 4 of 30 BHC 17 1 041-FC For industrial implementation and production of larger quantities, the preparation processes and route described in WO 2014 / 154794 and WO 2017 / 005725 are suitable only for a very limited scope. The route is lengthy (9 linear steps) and requires tedious monitoring and purification processes, resulting in a low overall yield. The major disadvantage is that the sequence provides material only in racemic form as a compound of formula (XIV-C1) / (XIV-CF3) and requires separation by chiral chromatography to produce the desired simple enantiomers of the compound of formula (1) / (11). The sequence of synthetic steps as described in WO 2014 / 154794 and WO 2017 / 005725 makes the development of an asymmetric version using the same intermediates virtually impossible.The literature indicates that installing a stereocenter between a pyridone ring and an ester, as in compounds with formulas (VIII), (IX), and (XI-C1) / (XI-CF3), is a difficult task due to the high tendency for racemization at this position in the molecule (PS Dragovich et al., J. Med. Chem., 2003, 46, 4572). Furthermore, there is clear evidence that under conditions of deprotection or amide coupling, a stereocenter at a highly acidic position is very susceptible to racemization (L. Chen et al., Organic Process Research & Development, 2006, 10, 838). The need for chiral separation not only represents an economically unfavorable process but also makes the production of the Active Pharmaceutical Ingredient (API) a time-consuming undertaking. Therefore, a new synthetic route was surprisingly found that addresses most of the challenges of the previous processes described earlier in Scheme 1. The route described in Scheme 5 is much shorter, with only 4 steps in the longest linear sequence (6 in total). Higher yields are obtained for the individual steps, resulting in a higher overall yield for the entire sequence. The route is convergent, allowing the synthetic steps to be performed in parallel and optimizing time management. More importantly, the new route follows an asymmetric strategy and provides the desired compound of formula (1) / (11) in high enantiomeric excess (ee) without relying on costly and time-consuming chiral separation by HPLC or SFC. IF-2019-3 6281512-APN-ANP#INPI Page 5 of 30 BHC 17 1 041-FC Scheme 5 LDA, BiOiPr)·.. -505C then AoOH, 75¾. «1% Isomer NsNO¿, HjSOj KB? 83% TjF. pirkfca 85¾ Tetramethylguankfin 2-F'OH: Acetone 4:1 N / OS1 >73% IUPAC chemical names of the compounds (XV-Cl) / (XV-CF3) to (XIX): 4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1 -yl)phenyl]-2,5-dimethoxy-pyridine (XV-C1) 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-2,5-dimethoxypyridine (XV-CF3) 4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1 -yl)phenyl]-5-methoxipyridin-2( 1 H)-ona (XVI-C1) 4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5-methoxypyridin-2(1H)-one (XVI-CF3) IF-2019-3 6281512-APN-ANP#INPI Page 6 of 30 BHC 17 1 041-FC (2R)-2-aminobutanoic acid (XVII) (2R)-2-bromobutanoic acid (XVIII) 4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamida (XIX) The compound of formula (II) can be converted into its respective solvates by treatment with the corresponding solvents. The solvates are, for example, isopropyl acetate, tetrahydrofuran, and acetone, resulting in the compound 4-({(2S)-2-[4-{5-chloro-2-[4-(tnfluoromethyl)lH-1,2,3-triazol-l-yl]phenyl}-5-methoxy-2-oxopiridin-l(2H)-yl]butanoyl}-amino)-2-fluorobenzamide isopropyl acetate (Ha), 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-lH-1,2,3-triazol-l-yl]phenyl}5-methoxy-2-oxopiridin-l(2H)-yl]butanoyl}-amino)-2-fluorobenzamide tetrahydrofuran (Ilb), and 4({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-5-methoxy-2-oxopyridinl(2H)-yl]butanoyl}-amino)-2-fluorobenzamide acetone (Ilc) respectively. Explanation of the figures: Figure 1: XRPD graph of the compound of formula (Ha). Figure 2: XRPD graph of the compound in formula (Ilb). Figure 3: XRPD graph of the compound in the formula (lie). Figure 4: DSC graph of the compound of formula (lia). Figure 5: DSC graph of the compound of formula (Ilb). Figure 6: DSC graph of the compound in the formula (lie). Figure 7: Micrograph of the compound with formula (Ha). Figure 8: Micrograph of the compound of formula (Ilb). Figure 9: Micrograph of the compound in formula (lie). In the case of the synthesis intermediates and working examples of the invention described hereinafter, any compound specified as a solvate is generally a solvate of unknown exact stoichiometric composition, obtained by the respective preparation and / or purification process. Unless specified in more detail, additions and structural formulas, such as “isopropyl acetate,” “tetrahydrofuran,” or “acetone,” should therefore not be understood in a stoichiometric sense in the case of such solvates, but rather be merely descriptive with respect to the components forming the solvate present in the present IF-2019-3 6281512-APN-ANP#INPI Page 7 of 30 BHC 17 1 041-FC Solvates with a 1:1 stoichiometric compound-to-solvent composition are preferred. Comparison of synthetic sequences: a) Compound of formula (III) to compound of formula (XI-C1) / (XI-CF3) through compound of formula (IX) (described in WO 2017 / 005725) versus compound of formula (III) to compound of formula (XV1-C1) / (XVI-CF3) (present invention) Compound of formula (III) to compound of formula (XI-CI) / (XI-CF3) via compound of formula (IX) (described in WO 2017 / 005725) The sequence described in WO 2017 / 005725 and in part in WO 2014 / 154794 begins with a lithiation-borylation sequence of 2,5-dimethoxypyridine (III) to provide (2,5-dimethoxypyridin-4-yl)boronic acid (IV), and in the next step the boron group on the pyridine ring is replaced by a bromide to give 4-bromo-2,5-dimethoxypyridine (V). 4-Bromo-2,5-dimethoxypyridine (V) is then demethylated to give 4-bromo-5-methoxypyridin-2(1H)-one (VI) which is N-alkylated with tere-butyl 2-bromobutanoate (VII) to give tere-butyl 2-(4-bromo-5-methoxy-2-oxopiridin-1(2H)-yl)butanoate (VIII). In the compound of formula (VIII) a pinacol boronic ester is installed in a Pd-catalyzed borylation reaction to obtain terebutyl 2-[5-methoxy-2-oxo-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-l(2H)-yl]butanoate (IX).The compound of formula (IX) is then coupled with l-(2-bromo-4-chlorophenyl)-4-chlorolH-l,2,3-triazole (X-Cl) / l-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-lH-l,2,3-triazole (X-CF3) to obtain the intermediate Tere-butyl 2-{4-[5-chloro-2-(4-chloro-lH-l,2,3-triazol-l-yl)phenyl]-5-methoxy-2-oxopyridinl(2H)-yl}butanoate (XI-C1) / Tere-butyl 2-[4-{5-chloro-2-[4-(trifluoromethyl)-IH-l,2,3-triazol-lyl]phenyl}-5-methoxy-2-oxopyridin-l(2H)-yl]butanoate (XI-CF3). Although the sequence allows completion of the target compound of formula (1) / (11), it has some disadvantages for the preparation of the molecules on a larger scale. The installation of the bromide on pyridine (compound of formula (V)) via a boronic acid (compound of formula (IV)) is a low-yield and relatively uneconomical procedure, especially since another boronic ester is then installed in the same position in the sequence for the preparation of the compound of formula (IX).Furthermore, the use of a reagent (Bis)pinacolatodiboron in the step from compound (VIII) to compound (IX) and the catalyst Pd(dppf)Cl2 in the transformations from compound (VIII) to compound (IX) and from compound (IX) to compound (XI-C1) / (XI-CF3) make the sequence relatively expensive. Likewise, the sequence requires the unfavorable solvents DMF and dioxane in the transformations from compound (V) to compound (XIC1) / (XI-CF3). Copper bromide for the preparation of compound (V) would also present disposal problems after industrialization. Page 8 of 30 BHC 17 1 041-FC Compound of formula (III) to compound of formula (XVI-Cl) / (XVI-CFx) (present invention) The sequence described in the present invention radically reduces the sequence length and associated problems through the use of different synthetic intermediates and more advantageous reaction conditions. The first transformation of 2,5-dimethoxypyridine(III) to (2,5-dimethoxypyridin-4-yl)boronic acid(IV) remains the same with improved yield due to better reaction conditions and follow-up procedures. Unlike the reaction conditions described above, the transformation can now be carried out at -60°C instead of 78°C, which is advantageous for the industrialization of the process. Furthermore, for product quality and yield, it is beneficial to prepare the lithium diisopropylamide directly on-site rather than using a commercially available lithium diisopropylamide solution.After the reaction is completed, it is inactivated with a mixture of acetic acid and water, and the remaining organic solvent is removed under vacuum at temperatures not exceeding 70°C (product stability). The obtained (2,5-dimethoxypyridin-4-yl)boronic acid (IV) is directly coupled with l-(2-bromo4-chlorophenyl)-4-chloro-lH-l,2,3-triazole (X-Cl) / l-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-lH1,2,3-triazole (X-CF3) to provide without going through another step of boronic ester / bromination facility. The cross-coupling reaction is carried out under robust and reliable conditions with a Pd catalyst system based in a solvent that allows for an efficient tracking and coupling process, removing the remaining palladium and resulting in convenient crystallization of the target compound from the tracking mixture in excellent quality. The key to this improved tracking procedure is the change of the Pd catalyst system to Pd(Amphos)2Cl2(AS Guram, et al., Organic Letters, 2006, 8, 1787), implementation of a dosing strategy and change of reaction solvent from THF to tert-amyl-alcohol. The reaction works well with various Pd catalyst systems such as Pd(OAc)2 / PPh3, Pd(Amphos)2Cl2, or precatalyst systems. Particularly good results are obtained using Pd(Amphos)2Cl2 as the Pd catalyst system. The Pd catalyst system is used in a ratio of 0.5 mol% to 5 mol%, preferably at a ratio of 0.7 mol% to 1.3 mol%, and most preferably at a ratio of 1 mol%, depending on the compound of formula (X-Cl) / (XCF3). Several inorganic bases can be used as a base in this process. Particular preference is given to bases such as potassium phosphate, potassium hydrogen phosphate, sodium carbonate, or potassium carbonate, with sodium carbonate being especially preferred. The respective base is used as a solution in water. The base is used in a ratio of 2 to 4 molar equivalents depending on the compound. Page 9 of 30 BHC 17 1 041-FC formula (X-C1) / (X-CF3) with preference for a ratio of 2.5 to 3.5 molar equivalents and with particular preference for a ratio of 3 molar equivalents. (2,5-Dimethoxypyridin-4-yl)boronic(IV) acid is used in a molar ratio of 1.0 to 1.5. Preferably, it is used in a molar ratio of 1.2 to 1.4 molar equivalents based on the compound of formula (X-Cl), and very preferably in a molar ratio of 1.2 molar equivalents based on the compound of formula (X-Cl). Preferably, it is used in a molar ratio of 1.05 to 1.15 molar equivalents based on the compound of formula (X-CF3), and very preferably in a molar ratio of 1.07 molar equivalents based on the compound of formula (XCF3). Several high-boiling organic solvents, such as alcohols or tetrahydrofuran, can be used as solvents. The preferred alcohols are 2-propanol, 1-propanol, 1-butanol, or tert-amyl alcohol (2-methyl-2-butanol), with tert-amyl alcohol (2-methyl-2-butanol) being the preferred choice. The use of tert-amyl alcohol (2-methyl-2-butanol) in a 1.10 (m / v) ratio based on the compound of formula (X-C1) / (X-CF3) is particularly preferred. tert-amyl alcohol (2-methyl-2-butanol) is especially useful because it provides excellent conversion rates, resulting in a short reaction time, and allows for high reaction temperatures and good phase separations of aqueous phases during monitoring. The reaction temperature is preferably in the range of 55°C to 100°C with particular preference for the temperature range of 63°C to 67°C for the compound of formula (XV-C1) and 93°C to 97°C for the compound of formula (XV-CF3). To avoid the formation of by-products, namely second coupling of the compound of formula (XV-C1) / (XV-CF3) with another molecule of the compound of formula (IV) through the chloride in the phenyl ring, a dosing strategy is used. A slow addition of (2,5-dimethoxypyridin-4-yl)boronic(IV) acid to the active catalytic system (Pd catalyst system with compound of formula (X-C1) / (X-CF3)) is chosen to ensure selectivity for the coupling of (2,5-dimethoxypyridin-4-yl)boronic(IV) acid with the bromide in the compound of formula (X-C1) / (X-CF3) over the undesired secondary coupling with the primary coupling product involving the reaction with the chloride in the pheno ring of the compound of formula (XV-C1) / (XVCF3). The dosage of a solution of the compound of formula (IV) and the base in water is carried out over a time interval of 0.5 to 5 hours, and preferably between 1 and 4 hours. Particularly advantageous is the addition of the above specified mixture in 2 to 3 hours, preferably 2.5 hours, for the preparation of the compound of formula (XV-C1) and in 3 to 4 hours, preferably 4 hours, for the preparation of the compound of formula (XV-CF3). IF-2019-3 6281512-APN-ANP#INPI Page 10 of 30 BHC 17 1 041-FC The compound obtained from the formula (XV-C1) / (XV-CF3) is used directly in a demethylation reaction that selectively removes one of the two methyl groups (the methyl group closest to the nitrogen) to yield pyridone, which is the compound of formula (XVI-CI) / (XVI-CF3). The demethylation is carried out under very advantageous conditions using readily available lithium chloride and ptoluenesulfonic acid. The demethylation reaction is performed in polar, high-boiling solvents such as alcohols or ethylene glycol. Because a reaction temperature > 75°C is required, alcohols with > 3 carbon atoms are necessary, for example, 2-propanol, 1-propanol, 1-butanol, or tert-amyl alcohol (2-methyl-2-butanol). The preferred temperature range for demethylation is between 75°C and 120°C. The use of 2-propanol at reflux temperature is particularly preferred for the reaction. This choice of solvent allows for a very convenient monitoring procedure.The simple addition of water at reflux temperature and cooling to lower temperatures results in the precipitation of the compound of formula (XVI-C1) / (XVI-CF3) in excellent quality and yield. The synthetic steps described represent a significant shortcut in the overall synthesis of the comparable synthetic intermediates, the compound of formula (XI-C1) / (XI-CF3) and the compound of formula (XVI-C1) / (XVI-CF3). In both formulas, the triazole couples to the pyridone core and is necessary to complete the assembly of the benzamide structural entity. In other words, both intermediates, the compound of formula (XI-CI) / (X1-CF3) and the compound of formula (XVI-C1) / (XVI-CF3), are only one synthetic step away from forming the structure of the intermediate containing all the structural elements of the final target compound of formula (1) / (11). While the synthetic route described in WO 2017 / 005725 requires 6 steps with an overall yield of 9.3%, the synthetic route of the present invention requires only 3 steps with an overall yield of 47%. b) Compound of formula (XI-C1) / (XI-CF3) to compound of formula (XIVC1) / (XIVCF3) (described in WO 2017 / 005725) versus compound of formula (XVI-C1) / (XVI-CF3) to compound of formula (1) / (11) (present invention) Compound of formula (XI-C1) / (XI-CF3) to compound of formula (XIV-C1) / (XIV-CF3) (described in WO 2017 / 005725) In WO 2017 / 005725, the intermediate compound of formula (XI-C1) / (XI-CF3) proceeds in a linear sequence to the racemic version of the target compound of formula (XVIC1) / (XVI-CF3). Therefore, the 1 / 2-butyl ester of the compound of formula (XI-C1) / (XI-CF3) is converted by hydrolysis of the acid ester to the carboxylic acid of the compound of formula (XII-C1) / (XII-CF3) using 4M hydrogen chloride in dioxane. The compound of formula (XIIC1) / (XII-CF3) is then coupled with 4-amino-2-fluorobenzamide (XIII) to provide the compound of formula (XIV-C1) / (XIV-CF3). The deprotection of the tere.-butyl esterIFa5roe^a3°6^°8βΤ2-ΑΡτί-ΑΝΡ#Π4ΡΙ Page 11 of 30 BHC 17 1 041-FC sequence, since no additional bonds are formed in the final compound. One of the major drawbacks of the entire synthesis is that the starting product of the sequence described in WO 2017 / 005725, the compound of formula (XIV-C1) / (XIV-CF3), is completely racemic, and the chances of obtaining enantiomerically pure material with this sequence are very limited (see the precedence of the literature mentioned above). Compound of the formula (XVI-CD / (XV1-CF3) to the compound of formula (1) / (11) (present invention) In the present invention, the entire eastern portion of the compound of formula (1) / (11), which is the compound of formula (XIX), is prepared separately and coupled to the compound of formula (XVICI) / (XVI-CF3) in the final step, which adds a high level of convergence to the synthetic strategy. To obtain high levels of enantiomeric purity, the final step needs to proceed as a pure SN2 reaction with complete stereocenter inversion to form the enantiomerically pure R-stereoisomer 4-{[(2R)-2-bromobutanoyl]amino}2-fluorobenzamide (XIX) of formula (1) / (11). The preparation of 4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (XIX) starts from (2R)-2-aminobutanoic acid (XVII) which is readily converted to (2R)-2-bromobutanoic acid (XVIII) with potassium bromide and sodium nitrite in aqueous sulfuric acid (H. Rapoport, et al., J. Org. Chem., 1986, 51, 1713). Enantiomerically pure (2R)-2-bromobutanoic acid (XVIII) is then coupled to 4-amino-2-fluorobenzamide (XIII) to provide 4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (XIX), which, together with pyridone, the compound of formula (XVI-C1) / (XVI-CF3), is the direct precursor for the preparation of the compound of formula (1) / (11). The coupling works in the case of the carboxylic acid with carbodiimides, such as EDC or DIC, or with the T3P / pyridine coupling system applied here (JR Dunetz, et al., Org. Lett., 2011, 13, 5048) as coupling reagents, optionally via carboxylic acid chloride in the presence of a base, e.g., triethylamine. The procedure developed for coupling based on T3P / pyridine as a reagent system proves to be particularly useful and allows amide formation without any racemization at the chiral center of the compound of formula (XIX) during the reaction or follow-up.In this process, preference is given to using 1.1 to 2.2 molar equivalents of T3P and 0.5 to 3.5 molar equivalents of pyridine while the reaction is carried out within a temperature range of 0°C to 40°C. The use of 1.2 to 1.8 molar equivalents of T3P is preferred, with 1.5 molar equivalents being particularly preferred. The use of 0.8 to 2.5 molar equivalents of pyridine is also preferred, with 1.1 molar equivalents being particularly preferred. The preferred reaction temperature is 15°C to 30°C, with 22°C being the particularly preferred temperature. Page 12 of 30 BHC 17 1 041-FC solubility of the compound of formula (XIX) tetrahydrofuran is particularly useful as a solvent. For the present invention, a carefully developed follow-through procedure involving the addition of water and seeding allows the crystallization of the compound of formula (XIX) from the follow-through mixture to achieve excellent quality and yield without erosion of enantioselectivity. Therefore, it is necessary to avoid counterhalide ions from washing solutions, such as aqueous sodium chloride and aqueous ammonium chloride solutions. The follow-through procedure is carried out as follows. In the first step, water is added, preferably in a ratio of 1:8 to 1:12 (w / v) depending on the compound of formula (XVIII), more preferably in a ratio of 1:10 (w / v). The mixture is then seeded with the compound of formula (XIX), and more water is added, preferably in a ratio of 1:4 to 1:8 (w / v) depending on the compound of formula (XVIII), more preferably in a ratio of 1:6 (w / v).The removal of tetrahydrofuran by vacuum distillation results in an easy-to-filter suspension containing the compound of formula (XIX) in high yield and excellent quality. Finally, the compound of formula (XIX) and the compound of formula (XVI-C1) / (XVI-CF3) are coupled in a base-mediated N-alkylation reaction. The challenge of this transformation is to find reaction conditions that are simultaneously optimal with respect to conversion (time and yield), N / O-alkylation selectivity, and enantioselectivity. The base needs to have a pKa > 13 in water and is preferably a nonionic organic base. Weaker bases result in no conversion or insufficient conversion, while stronger ionic bases are also inferior in terms of conversion, enantioselectivity, and N / O-alkylation selectivity. The best results are obtained with strong nonionic organic bases such as amidine, guanidine, or phosphazene bases. Preferred nonionic organic bases are 1,8diazabicyclo[5.4.0]undec-7-ene, Ν,Ν,Ν,Ν-tetramethylguanidine and 2-tert-butylimino-2-dietolaminol,3-dimethylperhydro-l,3,2-diazaphosphorine.The base N,N,N,N,N-tetramethylguanidine is particularly preferred because it is affordable and mediates the reaction with good conversion rates, as well as good enantioselectivity and N / O-alkylation selectivity. Furthermore, N,N,N,N-tetramethylguanidine is miscible in water, which allows for easy removal during aqueous monitoring. The base is used in a ratio of 0.8 to 5 molar equivalents depending on the compound of formula (XVI-C1) / (XVI-CF3), with a preferred ratio of 1.1 to 3 molar equivalents. A range of 1.2 to 1.6 molar equivalents depending on the compound of formula (XVI-C1) / (XVI-CF3) is particularly preferred. As a solvent, various pure organic solvents or mixtures can be used with one or the other advantage, for example in N / O-alkylation selectivity or enantioselectivity or yield or IF-2019-3 6281512-APN-ANP#INPI Page 13 of 30 BHC 17 1 041-FC conversion time. Alcohols provide very good N / O-alkylation selectivity. Preferably good results are obtained with tert-butanol, 1-butanol, or 2-propanol. However, these solvents are unsatisfactory in terms of solubility and conversion. None of these reactions is completed in 50 hours. The reaction time exceeds 50 hours, and in several cases, it is not fully completed. In contrast, polar non-protic solvents such as tetrahydrofuran, N,N-dimethylformamide, dioxane, or acetone result in complete conversion in less than 3 hours, but suffer from poor N-alkylation selectivity over unwanted O-alkylation. Consequently, solvent mixtures are used to combine the good conversions observed with the more polar non-protic solvents with the high enantioselectivity and N / O-alkylation selectivity observed with alcohols.While several mixtures of the solvents mentioned above work, the combination of acetone and 1-butanol or acetone and 2-propanol is preferred. The mixture of acetone and 2-propanol is particularly preferred. The mixture is used in a range of 1:2 to 1:9 acetone / 2-propanol, with a 1:3 to 1:5 acetone / 2-propanol ratio being particularly preferred. The reaction temperature range is between 0°C and 60°C to obtain reasonable conversions. However, at the upper end of this temperature range, the enantioselectivities obtained are generally unsatisfactory. Reactions at the lower end of the described temperature range require longer conversion times, which are also detrimental to the enantioselectivities obtained. Therefore, a preferred temperature range is identified as between 15°C and 25°C, with a particularly preferred range being between 18°C ​​and 23°C. In summary, a mixture of a protic solvent (i.e., an alcohol) and a polar non-protic solvent at moderate temperatures (15°C to 25°C) is preferred for achieving good overall conversion and good enantioselectivity and N / O-alkylation selectivity. The best results are obtained with 1:4 mixtures of acetone and alcohols at a reaction temperature of 20°C. The compound of formula (1) / (11) is obtained in amorphous form with high ee values ​​of 85%ee to 93%ee after filtration and evaporation of the solvents. Furthermore, the preferred N-alkylation over the undesirable O-alkylation is achieved at an N-alkylation to O-alkylation ratio of 9:1 to 10:1. c) Compound of formula (XIV-C1) / (XIV-CF3) to compound of formula (1) / (11) through chiral separation (described in WO 2017 / 005725) versus enrichment of the desired enantiomer of the compound of formula (1) / (11) (present invention) Compound of formula (XIV-C1) / (XIV-CF3) to compound of formula (1) / (11) via chiral splitting (described in WO 2017 / 005725) The preparation of the compound of formula (1) / (11) described in WO 2017 / 005725 is based on the separation of the two enantiomers of the racemic compound Page 14 of 30 BHC 17 1 041-FC via chiral supercritical fluid chromatography (SFC). This represents a very expensive and time-consuming procedure that is not suitable for large-scale production of the compound of formula (1) / (11). This is particularly true because cycle times in a standard laboratory SFC are already very short (3–4 g eutomer / day / machine). Furthermore, half of the material produced is the undesired enantiomer and cannot be used immediately, but needs to be exposed to racemization and SFC separation conditions again. Enrichment of the desired enantiomer of the compound of formula (1) / (11) (present invention) In contrast, the procedure described in the present invention shows an easy and scalable way to achieve the enrichment of the desired enantiomer to ee values ​​of >99%ee. The enantiomerically pure compound of formula (1) / (11) is present in an amorphous solid state, whereas the racemic material of the compound of formula (1) / (11) (which is herein the same as the compound of formula (XIV-C1) / (XIV-CF3)) is crystalline with much lower solubility in organic solvents. The organic solvent is ethyl acetate, dichloromethane, methanol, 2-propanol, acetone, and mixtures thereof, most preferably ethyl acetate.According to this principle of different solubility of the desired enantiomerically pure compound of formula (1) / (11) and the racemic material of the compound of formula (1) / (11), the product with ee values ​​of 85%ee to 93%ee (as mentioned above) is dissolved in a defined quantity of refluxed and stirred ethyl acetate. A ratio of compound of formula (1) / (11) to ethyl acetate of 1:1 to 1:10 (m / m) is preferred, with particular preference given to a ratio of compound of formula (1) / (11) to ethyl acetate of 1.2 to 1.5 (m / m). The less soluble crystalline racemic compound of formula (1) / (11) forms a suspension, while the desired enantiomerically pure amorphous material of the compound of formula (1) / (11) dissolves in the organic solvent. Hot filtration separates the crystalline racemate from the additionally enantio-enriched single enantiomer.Through racemate formation, the unwanted enantiomer is removed from the product, resulting in ee values ​​>99%ee. This means that the enantiomerically pure compound of formula (1) / (11) (ee values ​​>99%ee) is obtained by heating the compound of formula (1) / (11) with ee values ​​from 85%ee to 93%ee under reflux in an organic solvent, preferably ethyl acetate, followed by filtration. Evaporation of the solvent from the filtrate yields the enantiomerically pure compound of formula (1) / (11) (ee values ​​>99%ee), which is further purified by normal-phase column chromatography to remove other chemical impurities. These other chemical impurities are byproducts generated during the reaction. In an alternative procedure, the purification of the crude product of the compound of formula IF-2019-3 6281512-APN-ANP#INPI Page 15 of 30 BHC 17 1 041-FC (1) / (11) is obtained by crystallization of the enantiomerically enriched compound of formula (1) / (11) as a solvate. The respective solvent for the solvate is ethyl acetate, isopropyl acetate, tetrahydrofuran, or acetone, preferably acetone. As a solvate, the crystalline phases of the enantiomerically enriched compound of formula (1) / (11), and in particular the enantiomerically enriched compound of formula (II), can be obtained, allowing for the efficient removal of organic by-products still present in the crude product of the compound of formula (1) / (11). The advantage of solvates is therefore that a purification step can be carried out through solvate crystallization. Crystals formed as solvates, particularly compounds of formula (Ha), (Ilb), and (He), dissolve better in organic solvents than racemic crystals of the compound of formula (II) as such. Therefore, the crystals formed as solvates are dissolved in an organic solvent such as ethanol, followed by filtration of the remaining racemic crystals of the compound of formula (II), resulting in a solution containing the compound of formula (II) with an ee enrichment. The compound of formula (II) with ee values ​​>99 / oee is isolated by slowly dosing the solution into cold water and subsequent filtration. The advantage of using solvates is that by-products can be purged from the compound of formula (II) using the solvates, and this can be combined with the subsequent ee enrichment achieved by removing the crystalline racemate. Enantiomerically enriched compound means a compound with preferably ee values ​​of 85%ee to 93%ee, but enantiomeric purity may also be below ee values ​​of 85%ee or above ee values ​​of 93%ee for this purification step. In general, the new synthetic route described in the present invention is more efficient, economical, and time-optimized for manufacturing kilogram quantities of the compound of formula (1) / (11). The longest linear sequence consists of four synthetic steps, and the overall yield of the six steps combined is 20% to 25%. Furthermore, the synthesis of the present invention requires fewer steps for introducing and removing protecting groups that do not directly contribute to tracking the compound of formula (1) / (11). La presente invención también abarca un proceso para preparar 4-{[(2S)-2-{4-[5-cloro-2-(4-clorolH-l,2,3-triazol-l-il)fenil]-5-metoxi-2-oxopirin-l(2H)-il}butanoil]amino}-2-fluorobenzamida (I) o 4-({(2S)-2-[4-{5-cloro-2-[4-(trifluorometil)-lH-l,2,3-triazol-l-il]fenil}-5-metoxi-2-oxopirinl(2H)-il]butanoil}-amino)-2-fluorobenzamida (II), caracterizado porque respectivamente 4-[5cloro-2-(4-cloro-1H-1,2,3-triazol-1-yl)fenil]-5-methoxypyridin-2(1H)-ona (XVI-C1) o 4-{5-cloro-2[4-(trifluorometil)-1H-1,2,3-triazol-1-yl]fenil}-5-methoxypyridin-2(1H)-ona (XVI-CF3) se hace reaccionar con 4-{[(2R)-2-bromobutanoil]amino}-2-fluorobenzamida (XIX) en presencia de una base en un solvente y el compuesto de la fórmula (1) o (II) 2-APN-ANP#INPI Page 16 of 30 BHC 17 1 041-FC The present invention also encompasses a process for preparing 4-{[(2R)-2-bromobutanoyl]amino}2-fluorobenzamide (XIX) by reaction of (2R)-2-bromobutanoic acid (XVIII) with 4-amino-2-fluorobenzamide (XIII). The present invention also encompasses a process for preparing 4-{5-chloro-2-[4-(trifluoromethyl)lH-l,2,3-triazol-l-yl]phenyl}-5-methoxypyridin-2(lH)-one (XVI-CF3) by reaction of 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-2,5-dimethoxypyridine (XV-CF3) with lithium chloride and β-toluenesulfonic acid in a solvent. The present invention also encompasses a process for preparing 4-{5-chloro-2-[4-(trifluoromethyl)lH-l,2,3-triazol-l-yl]phenyl}-2,5-dimethoxypyridine (XV-CF3) by reaction of (2,5-dimethoxypyridin-4-yl)boronic acid (IV) with l-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-lH-l,2,3-triazol (X-CF3) in the presence of a Pd catalyst system with a base in a solvent. La presente invención también abarca un proceso para preparar 4-[5-cloro-2-(4-cloro-lH-l,2,3triazol-l-il)fenil]-5-metoxipiridin-2(lH)-ona (XVI-C1) por reacción de 4-[5-cloro-2-(4-cIoro-lHl,2,3-triazol-l-il)fenil]-2,5-dimetoxi-piridina (XV-C1) con cloruro de litio y ácido ptoluenosulfónico en un solvente. La presente invención también abarca un proceso para preparar 4-[5-cloro-2-(4-cloro-1H-1,2,3triazol-l-il)feniI]-2,5-dimetoxi-piridina (XV-CI) por reacción de ácido (2,5-dimetoxipiridin-4il)borónico (IV) con l-(2-bromo-4-clorofenil)-4-cloro-lH-l,2,3-triazol (X-Cl) en presencia de un sistema catalizador de Pd con una base en un solvente. The present invention also involves a process to prepare 4-{[(2S)-2-{4-[5-chloro-2-(4-chlorolH-l,2,3-triazol-l-yl)phenyl]-5-methoxi-2-oxopyridin-l(2H)-yl}butanoyl]amino}-2-fluorobenzamida (I), characterized Therefore, in the first step, (2,5-dimethoxipyridin-4-yl)boronic acid (IV) is reacted with 1(2-bromo-4-chlorophenyl)-4-chloro-lH-l,2,3-triazol (X-Cl) in the presence of a Pd catalyst system with a base in a solvent to form 4-[5-chloro-2-(4-chloro- 1H-1,2,3triazol-l-il)fenil]-2,5-dimetoxi-piridina (XV-CI), ii .) en el segundo paso, 4-[5-cloro-2-(4-cloro-lH-l,2,3-triazol-l-il)fenil]-2,5-dimetoxi-piridina (XV-CI) se hace reaccionar con cloruro de litio y ácido / 2-toluenesulfónico en un solvente para formar 4-[5-cloro-2-(4-cloro-lH-l,2,3-triazol-l-il)fenil]-5-metoxipiridin-2(lH)-ona (XVI-C1), iii .In the third step, 4-[5-chloro-2-(4-chloro-lH-l,2,3-triazol-l-yl)phenyl]-5-methoxypyridin-2(lH)one (XVI-C1) is reacted with 4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (XIX) in the presence of a base in a solvent and the compound of formula (I) is subsequently isolated. IF-2019-36281512-APN-ANP#INPI. Page 17 of 30 BHC 17 1 041-FC The present invention also encompasses a process for preparing 4-({(2S)-2-[4-{5-chloro-2-[4(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5-methoxy-2-oxopiridin-1(2H)-yl]butanoyl}-amino)-2-fluorobenzamide (II), characterized in that i.) in the first step, (2,5-dimethoxypyridin-4-yl)boronic acid (IV) is reacted with 1(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (X-CF3) in the presence of a Pd catalyst system with a base in a solvent to form 4-{5-chloro-2-[4(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl 1}-2,5-dimethoxypyridine (XV-CF3), ii.) In the second step, 4-{5-chloro-2-[4-(trifluoromethyl)-lH-1,2,3-triazol-l-yl]phenyl}-2,5-dimethoxypyridine (XV-CF3) is reacted with lithium chloride and ptoluenesulfonic acid in a solvent to form 4-{5-chloro-2-[4-(trifluoromethyl)-lH-1,2,3-triazol-l-yl]phenyl}-5-methoxypyridin-2(lH)-one (XVI-CF3), ii.) In the third step, 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-5-methoxypyridin-2(lH)-one (XVI-CF3) is reacted with 4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (XIX) in the presence of a base in a solvent and the compound of formula (II) is subsequently isolated. The present invention also encompasses a process for preparing 4-({(2S)-2-[4-{5-chloro-2-[4(trifluoromethyl)-1 H-1,2,3-triazol-1 -yl]phenyl}-5-methoxy-2-oxopiridin-1 (2H)-yl]butanoyl} -amino)-2-fluorobenzamide (II), characterized in that the subsequent isolation is carried out through 4-({(2S)2-[4- {5-chloro-2-[4-(trifluoromethyl 1)-1 H-1,2,3-triazol-1 -yljpheni I} -5-methoxy-2-oxopiridin-1 (2H)yl]butanoyl}-amino)-2-fluorobenzamide acetone (Ilc). Synthesis sequences of the invention: The compound of formula (XVII) becomes the compound of formula (XVIII). The compound of formula (XVIII) is reacted with the compound of formula (XIII) to provide the compound of formula (XIX). The compound of formula (III) becomes the compound of formula (IV). The compound of formula (IV) is reacted with the compound of formula (X-Cl) to provide the compound of formula (XV-C1). The compound of formula (IV) is reacted with the compound of formula (X-CF3) to provide the compound of formula (XV-CF3). The compound of formula (XV-C1) becomes the compound of formula (XVI-C1). The compound of formula (XV-CF3) becomes the compound of formula (XVI-CF3). IF-2019-36281512-APN-ANP#INPI Page 18 of 30 BHC 17 1 041-FC The compound of formula (XVI-C1) is reacted with the compound of formula (XIX) to provide the compound of formula (I). The compound of formula (XVI-CF3) is reacted with the compound of formula (XIX) to provide the compound of formula (II). The present invention also encompasses 4-[5-chloro-2-(4-chloro-lH-l,2,3-triazol-l-yl)phenyl]-2,5dimethoxy-pyridine of the formula (XV-C1). The present invention also encompasses 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}2,5-dimethoxy-pyridine of the formula (XV-CF3). The present invention also encompasses 4-[5-chloro-2-(4-chloro-lH-l,2,3-triazol-l-yl)phenyl]-5-methoxypyridin-2(lH)-one of the formula (XVI-CI). The present invention also encompasses 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}15-5-methoxy-pyridin-2(1H)-one of the formula IF-2019-3 6281512-APN-ANP#INPI Page 19 of 30 BHC 17 1 041-FC The present invention also includes 4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamida from the formula (XIX). La presente invención también abarca 4-({(2S)-2-[4-{5-cloro-2-[4-(trifluorometil)-lH-l;2,3triazol-l-il]fenil}-5-metoxi-2-oxopirin-l(2H)-il]butanoil}-amino)-2-fluorobenzamida acetato de isopropilo de la fórmula X isopropyl acetate (lia). La presente invención también abarca 4-({(2S)-2-[4-{5-cloro-2-[4-(trifluorometil)-lH-l,2,3 triazol-l-il]fenil}-5-metoxi-2-oxopirin-l(2H)-il]butanoil}-amino)-2-fluorobenzamida tetrahidrofurano de la fórmula IF-2019-3 6281512-APN-ANP#INPI Page 20 of 30 BHC 17 1 041-FC X tetrahydrocrano (lib). The present invention also encompasses 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3triazol-l-yl]phenyl}-5-methoxy-2-oxopyridin-l(2H)-yl]butanoyl}-amino)-2-fluorobenzamide acetone of the formula IF-2019-3 6281512-APN-ANP#INPI Page 21 of 30 BHC 17 1 041-FC Examples Abbreviations and acronyms Pd(amphos)2Ch Bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II) chloride % wt percent wt percent % ar percent ar percent % of t. percent of theory corr. correlated uncorr. uncorrected min minutes h hours mg milligram g gram kg kilogram liter mi milliliter ESI electrospray ionization GC gas chromatography HPLC high-performance liquid chromatography (yield) SFC supercritical fluid chromatography Br broad s singlet d doublet t triplet spt quin septet quintet ppm parts per million m multiplet Hz hertz M molar EDC l-ethyl-3-(3-dimethylaminopropyl)carbodiimide DIC Lαβ'-diisopropylcarbodiimide T3P propylphosphonic anhydride THF tetrahydrofuran (m / m) mass / mass (m / v) mass / volume XRPD Powder X-ray Diffraction IF-2019-36281512-APN-ANP#INPI Page 22 of 30 BHC 17 1 041-FC DSC Differential Scanning Calorimetry The term “the compound of formula (XVI-C1) / (XVI-CF3)” means that the compound of formula (XVI-C1) or the compound of formula (XVI-CFs) is used according to the synthetic route to the compound of formula (1) containing a chlorine substituent or the compound of formula (II) containing a trifluoromethyl substituent. The same applies to the other terms meaning the compound of formula (X-C1) / (X-CF3), (XI-C1) / (XI-CF3), (XIIC1) / (XII-CF3), (XIV-C1) / (XIV-CF3), (XV-C1) / (XV-CF3), (XVI-C1) / (XVI-CF3), and (1) / (11), as well as whether the chemical names of the compounds are used. If the term “the compound of formula (....)” is used, this term may be replaced by the IUPAC name of the compound of formula (....). The IUPAC names of the compounds are mentioned above. The racemic material of the compound of formula (1) / (11) is hereby the same as the compound of formula (XIV-C1) / (X1V-CF3). In the context of the present invention, the term enantiomerically pure shall be understood to mean that the compound in question, with respect to the absolute configuration of the chiral center, is present in an enantiomeric excess of more than 95%, preferably more than 97%. The enantiomeric excess, ee, is calculated herein by evaluating the corresponding HPLC chromatogram on a chiral phase using the formula below: ee = [EA(area%) - EB(area%)] x 100% / [EA(area%) + EB(area%)] (Ea: major enantiomer, EB: minor enantiomer) Work examples Synthesis of (2,5-dimethoxypyridin-4-yl)boronic (IV) acid 66.9 g (661.1 mmol) of MV-diisopropylamine was dissolved in 380 g of THF and cooled to -60°C. 395.2 mL (632.4 mmol) of w-butyllithium (1.6 M in hexane) was added over 45 min while the temperature was maintained below -50°C. The mixture was stirred at 60°C for another 15 min. Then, 80 g (574.9 mmol) of 2,5-dimethoxypyridine was added over 45 min while the temperature was maintained between -50 and -60°C. After the addition was complete, the addition funnel was washed with an additional 10 mL of THF. The reaction mixture was stirred at 60°C for 2 h, after which 118.9 g (632.4 mmol) of triisopropyl borate was added over a period of 30 min. The addition funnel was then rinsed again with 10 mL of THF. The reaction mixture was heated to 20°C and stirred for 30 min. IF-2019-3 6281512-APN-ANP#INPI Page 23 of 30 BHC 17 1 041-FC A mixture of acetic acid (106 g) and water (602 g) was then added over a period of 15 min, and the mixture was stirred for another 30 min. The organic solvents (650 g) were then evaporated in a vacuum (300 mbar) at a maximum temperature of 70°C, and the resulting suspension was cooled to 20°C and filtered. The product cake was washed with cold water (three 100 mL washes) and dried at 40°C for approximately 16 hours under reduced pressure in a drying oven. Yield: 78.6 g (75% of theoretical). MS (ESI+): m / z =184,1 [M+H]+; Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 8.15 (br s, 2H), 7.80 (s, 1H), 6.76 (s, 1H), 3.78 (d, 6H). Synthesis of 4-[5-chloro-2-(4-chloro-lH-l,2,3-triazol-l-yl)phenyl]-2,5-dimethoxy-pyridine (XV-Cp 5 g (17.1 mmol) of l-(2-bromo-4-chlorophenyl)-4-chloro-lH-l,2,3-triazole (X-Cl) and 121 mg (0.17 mmol) Pd(amphos)2Cl2 were suspended in 40.3 g of erc-amyl alcohol. The reaction mixture was heated to 65°C and a mixture of 5.4 g (51.2 mmol) sodium carbonate and 3.8 g (20.5 mmol) of (2,5-dimethoxypyridin-4-yl)boronic (IV) acid in water (35 mL) was added over 1 h. The reaction mixture was stirred at 65°C for another 5 h until complete consumption of the triazole (X-Cl) was observed. Then 0.8 g (5.1 mmol) of N-acetylcysteine ​​was added and the mixture was stirred for another 30 min before adding 8 mL of water. The mixture was cooled to 8°C for 40 min and the resulting suspension was filtered. The filter cake was washed with cold ethanol (twice, 4 mL) and water (twice, 5 mL) before being dried at 50°C for about 15 hours under reduced pressure in a drying oven. Yield: 4.46 g (74% of theoretical value). MS (ESI+): m / z = 351.0 [M+H]+; 'H-NMR (400MHz, DMSO-dó): δ [ppm] = 8,56 (s, 1H), 7,68 - 7,79 (m, 4H), 6,79 (s, 1H), 3,76 3,85 (s, 3H), 3,44 (s, 3H). Synthesis of 4-(5-chloro-2-í4-(trifluoromethyl)-lH-l<2,3-triazol-l-yl]phenyl}-215-dimethoxy-pyridine (XV-CF3) g (15.3 mmol) of l-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-lH-l,2,3-triazole (X-CF3) and 108 mg (0.15 mmol) Pd(amphos)2Cl2 were suspended in 40.3 g of erc-amyl-alcohoL. The reaction mixture was heated to 85°C and a mixture of 4.8 g (45.9 mmol) sodium carbonate and 3.6 g (19.9 mmol) of (2,5-dimethoxypyridin-4-yl)boronic acid (IV) in Water (35 mL) was added over 3 h. The reaction mixture was stirred at 85°C for another 1 h until the triazole (X-CF3) was completely consumed. Then, 0.8 g (5.1 mmol) of N-acetylcysteine ​​was added and stirred for another 30 min, before distilling 40 mL of i.e., erc-amyl alcohol and adding 20 mL of ethanol. The mixture was cooled to 2°C for 120 min and stirred for another 1 h. The resulting suspension was then filtered. The filter cake was washed with cold ethanol (three times, 3 mL) and water (twice, 5 mL), before being dried at 50°C. IF-2019-3 6281512-APN-ANP#INPI Page 24 of 30 BHC 17 1 041-FC was dried for approximately 15 hours under reduced pressure in a drying oven. Yield: 3.62 g (62% of theoretical value). MS (ES1+): m / z = 385.1 [M+H]+; Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 9.14 (s, 1H), 7.82 (s, 2H), 7.73 (s, 2H), 6.84 (s, 1H), 3.81 (s,3H), 3.38 (s, 3H). Synthesis of 4-[5-chloro-2-(4-chloro-lH-l,2,3-triazol-l-yl)phenyl]-5-methoxypyridin-2(lH)-one (XVL Cl) 9.0 g (25.6 mmol) of 4-[5-chloro-2-(4-chloro-1H-1,2,3-triazol-1-yl)phenyl]-2,5-dimethoxypyridine (XVCl), 5.4 g (128.1 mmol) of lithium chloride, and 1.8 g (46.4 mmol) of toluene sulfocic acid were dissolved in 60 mL of 2-propanol and stirred under reflux for approximately 16 h until the starting material was completely consumed. Then, 120 mL of water was added over 60 min, and the mixture was cooled to 10°C over another 60 min. The suspension was filtered, and the filter cake was washed with water (three 20 mL washes). It was then dried at 50°C for a further 15 h under reduced pressure in a drying oven. Yield: 7.46 g (86% of theoretical value). MS (ESI+): m / z=337,0 [M+H]+; Synthesis of 4-(5-chloro-2-[4-(trifluoroniethyl)-lH-l,2,3-triazol-l-illphenyl}-5-methoxy-pyridine-. 2(lH)-one (XVI-CF3) 7.0 g (18.2 mmol) of 4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-1]feml}-2,5-dimethoxypyridine (XV-CF3), 3.9 g (91.0 mmol) of lithium chloride, and 6.3 g (32.9 mmol) of ptoluene sulfonic acid were dissolved in 60 mL of 2-propanol and stirred under reflux for approximately 16 h until the starting material was completely consumed. Then, 120 mL of water was added over 60 min, and the mixture was cooled to 10°C over another 60 min. The suspension was filtered, and the filter cake was washed with water (three 20 mL washes). It was then dried at 50°C for a further 15 h under reduced pressure in a drying oven. Yield: 6.58 g (97% of theoretical value). MS (ESI+): m / z = 371.0 [M+H]+; Ή-NMR (400MHz, DMSO-d6): δ [ppm] = 11.21 (br s, 1H), 9.18 (s, 1H), 7.81 (s, 2H), 7.72 (s, 1H), 6.95 (s, 1H), 6.41 (s, 1H), 3.23 (s, 3H). Synthesis of (2R)-2-bromobutanoic acid (XVIII) In a stirred container, 150 g (1454.6 mmol) of (2R)-2-aminobutanoic (XVII) acid and 605.8 g (5091.1 mmol) of potassium bromide were dissolved in 809 g of 2.5 M aqueous sulfuric acid. IF-2019-3 6281512-APN-ANP#INPI Page 25 of 30 The BHC 17 1 041-FC mixture was cooled to -10°C and an aqueous solution of 150.4 g (2181.9 mmol) of sodium nitrite in 150 mL of water was added over 30 min. The reaction mixture was then stirred at 0°C for 18 h. After heating the reaction temperature to 20°C, the reaction mixture was extracted with ethyl acetate (three 500 mL volumes) and the organic layer was concentrated under vacuum to obtain the title compound. Yield: 193.9 g (80% of theoretical yield). MS (ES1+): m / z = 166.0 [M+H]+; Ή-NMR (500MHz, DMSO-d6): δ [ppm] = 4.28 (dd, 1H), 1.98 - 2.07 (m, 1H), 1.83 - 1.94 (m, 1H), 0.97 (t, 3H). Synthesis of 4-{|(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (XIX) 5.0 g (32.4 mmol) of 4-amino-2-fluorobenzamide (CHIP) was suspended in THF (50 mL) and cooled to 0°C. Then, 5.9 g (35.6 mmol) of (2R)-2-bromobutanoic (XVIII) acid and 2.8 g (35.6 mmol) of pyridine were added, preceded by the addition of 31.0 g (48.6 mmol) of a 50% T3P solution in ethyl acetate over 20 min. The mixture was stirred for 10 min and then heated to 22°C. The mixture was stirred for a further 3 h until the starting materials were completely consumed. Then, 60 g of water were added over 45 min, and seed crystals were added. Dosing was stopped for 30 min, and then another 40 g of water were added over 15 min. The mixture was distilled to remove the solvent until an internal temperature of 40°C was reached at a vacuum of 300 mbar. It was then cooled to room temperature and filtered. The filter cake was washed with cold water (10 mL) and dried at 50°C for approximately 16 hours under reduced pressure in a drying oven. Yield: 8.4 g (85% of theoretical). MS (ESI+): m / z = 303.0 [M+H]+; 'H-NMR (400MHz, DMSO-d6): δ [ppm] = 10.70 (s, 1H), 7.70 (t, 1H), 7.62 - 7.67 (m, 1H), 7.55 (s, 1H), 7.52 (brs, 1H), 7.35 (dd, 1H),4.46 (t, 1H), 2.10 (spt, 1H), 1.95 (dquin, 1H), 0.96 (t, 3H). Síntesis de 4-ÍK2S)-2-(4-15-cloro-2-(4-cloro-1H-1,2,3-triazol-1-yl)fenil]-5-metoxi-2-oxopindiii2 l(2H)-il}butanoillamino}-2-fluorobenzamida (I) 10.0 g (30 mmol) of 4-[5-chloro-2-(4-chloro-2,3-dihydro-lH-l,2,3-triazol-l-yl)phenyl]-5-methoxypyridin2(lH)-one (XVI-CI) was dissolved in 2-propanol (85 mL) and acetone (21 mL) at 22°C and 10.3 g (90 mmol) of N,N,N,N-tetramethylguanidine was added. After stirring for 15 min at 22°C, 9.89 g (33 mmol) of 4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (XIX) was added and the mixture was stirred for 16 h. The reaction mixture was then filtered and ethyl acetate (125 mL) was added. The organic layer was washed with a saturated aqueous solution of ammonium chloride (125 mL) and a saturated aqueous solution of sodium chloride (125 mL). The organic layer was then concentrated under vacuum. The residue was dissolved in ethyl acetate (140 mL), stirred for 30 min, and filtered. The filtrate was IF-2019-3 6281512-APN-ANP#INPI Page 26 of 30 BHC 17 1 041-FC was concentrated under vacuum and purified by column chromatography (silica gel, hexane / acetone gradient). Yield: 12.5 (75% of theoretical). MS (ESI+): m / z = 558,1 [M]+; 'H-NMR (400MHz, DMSO-dó): δ [ppm] = 10.78 (s, 1H), 8.62 (s, 1H), 7.62 - 7.81 (m, 5H), 7.53 (br d, 2H), 7.39 (dd, 1H), 7.18 (s, 1H), 6.48 (s, 1H), 5.54 (dd, 1H), 3.32 (s, 3H), 2.02 - 2.19 (m, 2H), 0.82 (t, 3H). Synthesis of 4-({(2S)-2-14-{5-chloro-2-[4-(trifluorometil)-lH-l,2,3-triazol-l-il]fenil}-5-metoxi-2:oxopiridin-l(2H)-illbutanoiBamino)-2-fluorobenzamida (II) 10.0 g (27 mmol) of 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-5-methoxy-pyridin2(lH)-one (XVI-CF3) was dissolved in 2-propanol (85 mL) and acetone (21 mL) at 22°C and 9.2 g (81 mmol) of Ύ,MMN-tetramethylguanidine was added. After stirring for 15 min at 22°C, 9.0 g (30 mmol) of 4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (XIX) was added and the mixture was stirred for 16 h. The reaction mixture was then filtered and ethyl acetate (125 mL) was added. The organic layer was washed with 125 mL of saturated aqueous ammonium chloride solution and 125 mL of saturated aqueous sodium chloride solution. The organic layer was concentrated under vacuum. The residue was dissolved in 140 mL of ethyl acetate, stirred for 30 min, and filtered. The filtrate was concentrated under vacuum and purified by column chromatography (silica gel, hexane / acetone gradient). Yield: 11.1 g (70% of theoretical). MS (ESI+): m / z = 593.1 [M]+; 'H-NMR (400MHz, DMSO-d6): δ [ppm] = 10,77 (br s, 1H), 9,13 (s, 1H), 7,58 - 7,95 (m, 5H), 7,53 (brd, 2H), 7,37 (dd, 1H), 7,14 (s, 1H), 6,54 (s, 1H), 5,53 (br dd, 1H), 3,26 (s, 3H), 2,02 - 2,22 (m, 2H), 0,79 (t, 3H). Método alternativo: 25.0 g (67 mmol) of 4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenyl}-5-methoxy-pyridin2(1H)-one (XVI-CF3) was dissolved in 2-propanol (125 mL) and acetone (31.4 mL) at 22°C and 11.6 g (101 mmol) of N,LζN,N-tetramethylguanidine was added. After stirring for 15 min at 22°C, 22.5 g (74 mmol) of 4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (XIX) was added and the mixture was stirred for 16 h. The reaction mixture was then slowly added to cold water (0°C) (661 mL). The crude product was precipitated and filtered. The crude product was then suspended in acetone (125 mL) and stirred for 30 min. Water (98.5 g) was then added over 4 h, the mixture was seeded, and stirred for a further 18 h. The resulting acetone solvate was filtered, dried, and redissolved in ethanol (108 mL) at 22°C. The mixture was stirred for 30 min, filtered, and the filtrate was slowly dosed into cold water (5°C, 427 g). The resulting suspension was filtered, and the cake of IF-2019-3 6281512-APN-ANP#INPI Page 27 of 30 BHC 17 1 041-FC filtrate was washed and dried at 60°C for 16 ha under reduced pressure in a drying oven. Yield: 24.4 g (61% of theoretical value). Isolation of 4-(í(2S)-2-[4-{5-cIoro-2-I4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl|phenyl}-5zmethoxy-2-oxoDiridin-l(2H)-illbutanoyl)amino)-2-fluorobenzamide isopropyl acetate (Ha) 46.9 mg of amorphous solid 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazo11-yl]feml}-5-methoxy-2-oxopiridin-1(2H)-yl]butanoyl}amino)-2-fluorobenzamide (II) was weighed into a glass vial and 100 pL of isopropyl acetate was added. The vial was sealed and the contents were stirred with a magnetic stir bar at 25°C. Crystalline particle formation occurred after approximately 1 week of stirring. The resulting suspension was air-dried overnight and the resulting solid was used for further experiments. Subsequently, 198.6 mg of amorphous solid 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-lyl]phenyl}-5-methoxy-2-oxopiridin-1(2H)-yl]butanoyl}amino)-2-fluorobenzamide (II) was weighed into a glass vial, and 600 µL of isopropyl acetate was added. The vial was sealed, and the contents were stirred with a magnetic stir bar at 25°C for 30 minutes. A small amount (approximately 5 mg) of the previously isolated solid (as described in the preceding paragraph) was added to the resulting solution as a seed. The contents were further stirred at 25°C, and complete crystallization was observed within one minute. The resulting suspension was dried on a clay square overnight. Figure I shows the XRPD of the solid resulting from the compound of formula (lia), Figure 4 its DSC and Figure 7 its microscopic image. Isolation of 4-(i(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-5-methoxy-2-oxoDÍridin-l(2H)-ylbutanoyl)amino)-2-fluorobenzamide tetrahydrofuran (Ilb) 53.9 mg of amorphous solid 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]feml}-5-methoxy-2-oxopiridin-l(2H)-yl]butanoyl}amino)-2-fluorobenzamide (II) was weighed into a glass vial and 50 pL of THF was added. The vial was sealed and the contents were stirred with a magnetic stir bar at 25°C. Crystalline particle formation occurred after approximately 1 week of stirring. The resulting suspension was air-dried overnight and the resulting solid was used for further experiments. Subsequently, 198.5 mg of amorphous solid 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-lyl]phenyl}-5-methoxy-2-oxopiridin-1(2H)-yl]butanoyl}amino)-2-fluorobenzamide (II) was weighed into a glass vial and 600 pL of THF was added. The vial was sealed and the contents were stirred with a magnetic stir bar at 25°C for 30 minutes. A small amount (approximately 5 mg) of the previously isolated solid (as described in the preceding paragraph) was added to the resulting solution as a seed. The contents were further stirred at 25°C and complete crystallization was observed within 30 minutes. The resulting suspension was dried on a clay square. IF-2019-3 6281512-APN-ANP#INPI Page 28 of 30 BHC 17 1 041-FC overnight. Figure 2 shows the XRPD of the resulting solid from the compound of formula (lib), Figure 5 its DSC and Figure 8 its microscopic image. Isolation of 4-(K2S)-2-í4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}z5zmethoxy-2-oxoDIridin-l(2H)-illbutanoyl}amino)-2-fluorobenzamide acetone (lie) 50.5 mg of amorphous solid 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]feml}-5-methoxy-2-oxopiridin-l(2H)-yl]butanoyl}amino)-2-fluorobenzamide (II) was weighed into a glass vial and 50 pL of acetone was added. The vial was sealed and the contents were stirred with a magnetic stir bar at 25°C. Crystalline particle formation occurred after approximately 1 week of stirring. The resulting suspension was air-dried overnight and the resulting solid was used for further experiments. Subsequently, 203.9 mg of amorphous solid 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)-1H-1,2,3-triazol-lyl]phenyl}-5-methoxy-2-oxopiridin-1(2H)-yl]butanoyl}amino)-2-fluorobenzamide (II) was weighed into a glass vial and 600 pL of acetone was added. The vial was sealed and the contents were stirred with a magnetic stir bar at 25°C for 30 minutes. A small amount (approximately 5 mg) of the previously isolated solid (as described in the preceding paragraph) was added to the resulting solution as a seed. The contents were further stirred at 25°C, and complete crystallization was observed within one minute. The resulting suspension was dried on a clay square overnight. Figure 3 shows the XRPD of the solid resulting from the compound of formula (11c), Figure 6 its DSC and Figure 9 its microscopic image. X-ray diffractometry X-ray powder diffraction (XRPD) data were recorded on a Bruker D2 PHASER diffractometer with a LynxEye detector using Cu Kai,2 (1.5418 Å) radiation. All samples were measured at room temperature. Data were collected in horizontal Bragg-Brentano (Θ / 2Θ) geometry between 3.00149 and 40.0046° (20) in 0.0264119° steps at 0.5 s step-1 intervals. The X-ray tube operated at 30 kV and 10 mA. Differential scanning calorimetry (DSC) Differential scanning calorimetry (DSC) was performed using a Mettler Toledo DSC 2, calibrated with an indium standard. The calorimeter cell was purged with nitrogen at a rate of 100 mL min⁻¹. Approximately 5–10 mg of each sample was measured in an aluminum crucible. The temperature program was set in the range of 25–260°C (for isopropyl acetate and tetrahydrofuran solvates) or in the range of 25–250°C (for acetone solvate), at a heating rate of 5°C min⁻¹. The data were processed using the Mettler Toledo Star System. IF-2019-3 6281512-APN-ANP#INPI Page 29 of 30 BHC 17 1 041-FC X-ray powder diffraction (XRPD) data of the compounds of formulas (lia), (Ilb). and (Hcl Reflections (2Θ maximum, °) _________________________ Compound of formula (Ha) (Isopropyl acetate solvate) Compound of formula (Ilb) (Tetrahydrofuran solvate) Compound of formula (lie) (Acetone solvate) 7.6 7.6 7.7 8.0 8.0 8.1 10.3 10.3 8.9 11.9 11.2 10.5 12.4 13.1 11.1 ________________________ 13.4 13.7 11.9 13.7 14.5 13.5 15.6 16.0 13.8 16.1 16.4 15.0 16.8 16.9 15.6 17.3 17.3 16.3 18.0 18.1 16.7 18.8 19.4 17.2 20.1 20.0 17.6 21.2 21.1 18.0 22.1 22.3 19.0 23.2 23.0 20.1 24.2 24.0 21.4 24.7 26.0 22.2 26.0 26.9 23.3 26.9 27.5 23.8 27.6 28.8 24.6 28.4 30.2 25.0 29.5 25.4 30.1 25.8 29.4

Claims

1. Proceso para preparar 4-{[(2S)-2-{4-[5-cloro-2-(4-cloro-1H-1,2,3-triazol-1-yl)fenil]-5-metoxi-2-oxopirin-1(2H)-il}butanoil]amino}-2-fluorobenzamida (I) o 4-({(2S)-2-[4-{5-cloro-2-[4-(trifluorometil)-1H-1,2,3-triazol-1-il]fenil}-5-metoxi-2-oxopirin-1(2H)-il]butanoil}-amino)-2-fluorobenzamida (II), caracterizado porque respectivamente 4-[5-cloro-2-(4-cloro-1H-1,2,3-triazol-1-yl)phenyl]-5-methoxypyridin-2(1H)-ona (XVI-Cl) o 4-{5-cloro-2-[4-(trifluorometil)-1H-1,2,3-triazol-1-yl]phenyl}-5-methoxypyridin-2(1H)-ona (XVI-CF3) se hace reaccionar con 4-{[(2R)-2-bromobutanoil]amino}-2-fluorobenzamida (XIX) en presencia de 1,8-diazabiciclo[5.4.0]undec-7-ene, N,N,N,N-tetramethylguanidine or 2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diazaphosphorine as in a mixture of a protonic solvent and a polar non-protonic solvent, wherein the protonic solvent is tert-butanol, 1-butanol or 2-propanol and the polar non-protonic solvent is tetrahydrofuran, N,N-dimethylformamide, dioxane or acetone, at a temperature between 0°C and 60°C and the compound of formula (I) or (II) is subsequently isolated by filtration and evaporation of the solvents. 13 Claims follow.