Preparative process

Abstract

The present invention relates to a process for preparing (4S)-24-chloro-4-ethyl-73-fluoro-35- methoxy-32,5-dioxo-14-(trifluoromethyl)-32H-6-aza-3(4,1)-pyridina-1(1)-[1,2,3]triazola- 2(1,2),7(1)-dibenzenaheptaphane-74-carboxamide (I) from 2,5-dimethoxypyridine (II), 1-(2-bromo- 4-chlorophenyl)-4-(trifluoromethyl)-1H-1,2,3-triazole (IV), 4-amino-2-fluorbenzamide (IX) and (2R)-2-bromobutanoic acid - N-cyclohexylcyclohexanamine (XI).

Description

[0001] BHC 24 1 041 FC

[0002] - 1 -

[0003] Preparative process

[0004] The present invention relates to a process for preparing (4S)-24-chloro-4-ethyl-73-fluoro-35- mcthoxy-32.5-dioxo- l4-(trifluoromcthyl)-32 / / -6-aza-3(4. 1 )-pyridina- l ( l )-| 1.2.3 |triazola- 2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (I) from 2,5 -dimethoxypyridine (II), l-(2-bromo- 4-chlorophenyl)-4-(trifluoromethyl)-lH-l,2,3-triazole (IV), 4-amino-2-fluorbenzamide (IX) and (2R)-2 -bromobutanoic acid - N-cyclohexylcyclohexanamine (XI).

[0005] Compound of the formula (I), (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 74-carboxamide (INN: Asundexian), also named as 4-({(2S)-2-[4-{5-chloro-2-[4-(trifluoromethyl)- lH-l,2,3-triazol-l-yl]phenyl}-5-methoxy-2-oxopyridin-l(2H)-yl]butanoyl}amino)-2-fluorobenz- amide, is known from W02017 / 005725 and has the following formula:

[0006] The compound of the formula (I) acts as inhibitors for the Factor Xia and owing to this specific mechanism of action, might lead in vivo after oral administration to a safe and efficient anticoagulation.

[0007] WO2022 / 189279 describes the crystalline forms of the compound of the formula (I), amongst other the crystalline modification I.

[0008] WO2014 / 154794 and W02017 / 005725 describe a synthesis for preparing the compound of the formula (I) in the gram range starting from 2,5 -dimethoxypyridine, l-(2-bromo-4-chlorophenyl)-4- (trifhroromethyl)-lH-l,2,3-triazole, 4-amino-2 -fluorobenzamide and tert-butyl 2-bromobutanoate.

[0009] For industrial implementation and the production of larger kilogram amounts, the preparative processes and route described in WO2014 / 154794 and W02017 / 005725 are suitable to only a very limited extent. The route is lengthy (9 linear steps) and requires tedious work-up and purification procedures, resulting in a low overall yield. The biggest drawback is that the sequence provides the compound of the formula (I) only in racemic form and needs to be separated via a chiral chromatography to produce the desired single enantiomers of the compound of the formula (I). The necessity of a chiral separation represents not only an economically unfavourable process, but also makes the production of the Active Pharmaceutical Ingredient (API) a time-consuming endeavour. BHC 24 1 041 FC

[0010] WO2019 / 175043 describes a synthesis for preparing the compound of the formula (I) in the gram range starting from 2,5 -dimethoxypyridine (II), l-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)- lH-l,2,3-triazole (IV), 4-amino-2-fluorobenzamide (IX) and (2R)-2-aminobutanoic acid (VII).

[0011] IUPAC Chemical names of the compounds (I), (XV) and (XVI):

[0012] S-enantiomer: (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifhioromethyl)-32H-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (I)

[0013] R-enantiomer: (4R)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (XV)

[0014] Racemic compound (a 1: 1 mixture of R-enantiomer and S -Enantiomer as a homogeneous solid phase): (4)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-

[0015] 3(4,1) -pyridina- 1(1)-[1,2,3 ]triazola-2( 1 ,2) ,7( 1 ) -dibenzenaheptaphane -74-carboxamide (XVI)

[0016] For industrial implementation and the production of larger kilogram amounts, the preparative processes and route described in WO2019 / 175043 have limitations (Scheme 1):

[0017] The reaction of (2,5-dimethoxypyridin-4-yl)boronic acid (III) and l-(2-bromo-4-chlorophenyl)-4- (trifluoromethyl)-lH-l,2,3-triazole (IV) requires slowly dosing of the compound of the formula (III) to avoid the formation of a side product by reaction of a second molecule of the compound of the formula (III) with the chloride in the phenyl ring of the already formed 4-{5-chloro-2-[4- (trifluoromethyl) - 1 H- 1 ,2, 3 -triazol- 1 -yl] phenyl } -2, 5 -dimethoxypyridine (V) .

[0018] The demethylation of 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-2,5- dimethoxypyridine (V) requires handling of large excess of lithium chloride and solid p-toluene sulfonic acid. Lithium chloride is an expensive chloride source. p-Toluene sulfonic acid forms hard blocks during storage and is therefore difficult to charge into a reaction vessel on large scale.

[0019] Coupling of (2R)-2-bromobutanoic acid (VIII) with 4-amino-2-fluorobenzamide (IX) is accompanied by formation of impurities, namely a nitrile analogue of the compound of the formula (X) on large scale using the described process parameters.

[0020] The compound of the formula (I) is initially isolated as amorphous material of low quality which has to be purified by recrystallization as compound of the formula (XII) (acetone solvate of the BHC 24 1 041 FC

[0021] - 3 - compound of the formula (I)).

[0022] The compound of the formula (XV) (R-enantiomer) is removed as compound of the formula (XVI) (racemic compound) on the last step by filtration of a supersaturated ethanol solution. There is the risk that the compound of the formula (I) (S -enantiomer) will crystallize before the compound of the formula (XVI) (racemic compound) can be removed. Due to the low solubility of the crystalline compound of the formula (I) in ethanol it cannot be dissolved by simple reheating of the suspension which is a serious risk for commercial production.

[0023] The isolated amorphous form of the compound of the formula (I) is hygroscopic and less stable than the crystalline modification I of the compound of the formula (I). Scheme 1

[0024] IUPAC Chemical names of the compounds (I) to (X):

[0025] (4.S)-24-chloro-4-cthyl-72-fluoro-32-mcthoxy-32.5-dioxo- l4-(trifliioromcthyl)-32 / / -6-aza-3(4. 1 )- pyridina- 1 ( l)-[ 1 ,2,3]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane-74-carboxamide (I), BHC 24 1 041 FC

[0026] - 4 -

[0027] 2,5 -dimethoxypyridine (II),

[0028] (2,5-dimethoxypyridin-4-yl)boronic acid (III),

[0029] 1 -(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)- 1H- 1 ,2,3-triazole (IV),

[0030] 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-2,5-dimethoxypyridine (V), 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-5-methoxypyridin-2(lH)-one

[0031] (VI),

[0032] (2R)-2 -aminobutanoic acid (VII),

[0033] (2R)-2 -bromobutanoic acid (VIII),

[0034] 4-amino-2 -fluorobenzamide (IX), 4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (X).

[0035] Thus a new synthetic route has surprisingly been found that allows to provide the desired compound of the formula (I) as crystalline compound in high enantiomeric excess (ee) and excellent quality. The new synthetic route solves the disadvantages of WO2014 / 154794, W02017 / 005725 and WO2019 / 175043 and is feasible for multi-kilo manufacturing of the compound of the formula (I) (Scheme 2).

[0036] Scheme 2 BHC 24 1 041 FC

[0037] - 5 -

[0038] IUPAC Chemical names of the compounds (XI) and (XII):

[0039] (2R)-2 -bromobutanoic acid - N-cyclohexylcyclohexanamine (XI), (4S)-24-chloro-4-ethyl-73-fhioro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4, 1)- pyridina- 1 ( l)-[ 1 ,2,3]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane-74-carboxamide acetone (XII) .

[0040] Comparison of synthetic sequences: a) Compound of the formula (II) to compound of the formula (V) via compound of the formula (III) (described in WO2019 / 175043) versus compound of the formula (II) to compound of the formula (V) via compound of the formula (III) (present invention)

[0041] Compound of the formula (II) to compound of the formula (V) via compound of the formula (III) (described in WQ2019 / 175043)

[0042] In the first step 2,5-dimethoxypyridine (II) is transformed to (2,5-dimethoxypyridin-4-yl)boronic acid (III).

[0043] The obtained (2,5-dimethoxypyridin-4-yl)boronic acid (III) is directly coupled with l-(2-bromo-4- chlorophenyl)-4-(trifluoromethyl)-lH-l,2,3-triazole (IV) to give 4-{5-chloro-2-[4-(trifluoro- methyl)-lH-l,2,3-triazol-l-yl]phenyl}-2,5-dimethoxypyridine (V). The cross-coupling reaction is performed with the Pd-catalyst system Pd(Amphos)2C12 with sodium carbonate as base and tert- amyl-alcohol as solvent. A solution of (2,5-dimethoxypyridin-4-yl)boronic acid (III) is slowly added to the reaction mixture to avoid the undesired reaction of a second molecule of the compound of the formula (III) with the chloride in the phenyl ring of the compound of the formula (V).

[0044] Compound of the formula (II) to compound of the formula (V) via compound of the formula (III) (present invention)

[0045] The first transformation of 2,5-dimethoxypyridine (II) to (2,5-dimethoxypyridin-4-yl)boronic acid (III) remains the same.

[0046] The obtained (2,5-dimethoxypyridin-4-yl)boronic acid (III) is directly coupled with l-(2-bromo-4- chlorophenyl)-4-(trifluoromethyl)-lH-l,2,3-triazole (IV) to give 4-{5-chloro-2-[4-(trifluoro- methyl)-lH-l,2,3-triazol-l-yl]phenyl}-2,5-dimethoxypyridine (V). The cross-coupling reaction is in the present invention is performed with the Pd-catalyst system [l,l'-bis(di-tert- butylphosphino)ferrocene]dichloropalladium(II) (Pd(dtbpf)C12) with potassium carbonate as base and a mixture of tetrahydrofuran and water as solvent. The advantage of the Pd-catalyst system Pd(dtbpf)C12 is the better suited activity. In contrast to the previously described reaction conditions the coupling can now be conducted at lower temperature, which represents an advantage for the industrialization of the process. Slowly dosing of (2,5-dimethoxypyridin-4-yl)boronic acid (III) to avoid the reaction of a second molecule of the compound of the formula (III) with the chloride in BHC 24 1 041 FC

[0047] - 6 - the phenyl ring of the compound of the formula (V) is no longer necessary. All reaction partners can be charged directly into the reaction vessel. The new reaction conditions yield 4-{5-chloro-2- [4-(trifluoro-methyl)-lH-l,2,3-triazol-l-yl]phenyl}-2,5-dimethoxypyridine (V) in improved quality of typically > 99area% and improved yield of > 90%.

[0048] Good results are obtained using the Pd-catalyst system Pd(dtbpf)C12 in a ratio of 0.3 mol% to 1.5 mol%, preferably at a ratio of 0.5 mol% to 1.1 mol% and very preferably at a ratio of 0.7 mol% based on the compound of the formula (IV).

[0049] The respective base potassium carbonate is used as a solution in water. The base is used in a ratio of from 1 to 3 molar equivalents based on the compound of the formula (IV) with preference for a ratio of 1.3 to 2.0 molar equivalents and with particular preference for a ratio of 1.5 molar equivalents.

[0050] (2,5-Dimethoxypyridin-4-yl)boronic acid (III) is used in a ratio of 0.9 to 1.1 molar based on the compound of the formula (IV). Preferably it is used at a ratio of 0.95 to 1.05 molar equivalents and very preferably it is used at a ratio of 1.0 molar equivalents based on the compound of the formula (IV).

[0051] The reaction temperature is preferably > 55 °C with a particular preference for the temperature range from 62°C to 65 °C (reflux temperature of the reaction mixture). b) Compound of the formula (V) to compound of the formula (VI) (described in WO2019 / 175043) versus compound of the formula (V) to compound of the formula (VI) (present invention)

[0052] Compound of the formula (V) to compound of the formula (VI) (described in WQ2019 / 175043)

[0053] The obtained compound of the formula (V) is directly used in a demethylation reaction that selectively removes one of the two methyl groups (the methyl group in neighborhood to the nitrogen) to obtain the pyridone which is the compound of the formula (VI). The demethylation is performed with 5 molar equivalents of lithium chloride and 1.8 molar equivalents of p-toluene sulfonic acid based on the compound of the formula (V). Solid p-toluene sulfonic acid is difficult to handle on larger scale because it forms solid blocks during storage and is therefore difficult to charge into the reaction vessel. Lithium chloride is not cheap as other chloride sources, e.g. hydrogen chloride, due to high demand of lithium salts worldwide.

[0054] Compound of the formula (V) to compound of the formula (VI) (present invention)

[0055] In the present invention the obtained compound of the formula (V) is also directly used in a demethylation reaction that selectively removes one of the two methyl groups (the methyl group in neighborhood to the nitrogen) to obtain the pyridone which is the compound of the formula (VI). The demethylation is performed under very advantageous conditions with inexpensive concentrated BHC 24 1 041 FC

[0056] - 7 - hydrogen chloride solution in a solvent. Hydrogen chloride solution is cheaper and easier to handle in multi-kilogram scale than solid lithium chloride and solid p-toluene sulfonic acid and thus an advantage during scale-up.

[0057] Preferably concentrated aqueous hydrogen chloride solution is used. Hydrogen chloride is used in a ratio of 3 to 7 molar based on the compound of the formula (V). Preferably it is used at a ratio of 4 to 6 molar equivalents and very preferably it is used at a ratio of 5 molar equivalents based on the compound of the formula (V). Alternatively, hydrogen chloride solution in other solvents, e.g. 2- propanol, can be used. This solution can be made in situ from acetyl chloride and 2-propanol to avoid the handling of gaseous hydrogen chloride or stability issues with commercial solution.

[0058] The demethylation reaction is performed in polar and high boiling solvents such as alcohols. Since a reaction temperature of > 75 °C is necessary, alcohols with > 3 carbon atoms are required, for example 2-propanol or 1 -propanol. Preferably 2-propanol is used.

[0059] The preferred temperature range for the demethylation is between 75°C and 120°C. The choice of 2-propanol as solvent allows for a very convenient work-up procedure. Simple addition of water at reflux temperature and cooling to lower temperatures results in precipitation of the compound of the formula (VI) in excellent quality and yield. c) Compound of the formula (VIII) to compound of the formula (X) (described in WO2019 / 175043) versus compound of the formula (XI) to compound of the formula (X) (present invention)

[0060] Compound of the formula (VIII) to compound of the formula (X) (described in WQ2019 / 175043)

[0061] The enantiomerically pure (2R)-2-bromobutanoic acid (VIII) is coupled to 4-amino-2- fluorobenzamide (IX) to yield 4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (X). The coupling works in this case with the TsP / pyridine coupling system (J. R. Dunetz, et al., Org. Lett., 2011, 13, 5048) as coupling reagents. Preferred is the use of 1.5 molar equivalents of T3P and 1.1 molar equivalents of pyridine. The preferred reaction temperature is 15 °C to 30°C, the particularly preferred reaction temperature is 22°C. Due to the solubility properties of the compound of the formula (X) tetrahydrofuran is particularly useful as a solvent.

[0062] Compound of the formula (XI) to compound of the formula (X) (present invention)

[0063] The enantiomerically pure (2R)-2-bromobutanoic acid - N-cyclohexylcyclohexanamine (XI) is coupled to 4-amino-2-fluorobenzamide (IX) to yield 4-{[(2R)-2-bromobutanoyl]amino}-2- fluorobenzamide (X). The coupling works in the present invention also with the TsP / pyridine coupling system (J. R. Dunetz, et al., Org. Lett., 2011, 13, 5048) as coupling reagents, but at a lower temperature and with less pyridine. The lower temperature during reaction and quench of excess T3P avoids the formation of impurities, namely the formation of the respective nitrile of the compound of the formula (X). The nitrile is formed by dehydration of the terminal amide group BHC 24 1 041 FC

[0064] - 8 - with excess T3P.

[0065] In the process preference is given to using from 1.1 to 2.2 molar equivalents of T3P and 0.1 to 1.0 molar equivalents of pyridine while the reaction is performed in a temperature range between minus 10°C and +10°C. Preferred is the use of 1.2 to 1.8 molar equivalents of T3P, particularly preferred is the use of 1.5 molar equivalents of T3P. Preferred is the use of 0.2 to 0.4 molar equivalents of pyridine, particularly preferred is the use of 0.3 molar equivalents of pyridine. The preferred reaction temperature is -5 °C to +5 °C, the particularly preferred reaction temperature is 0°C. Due to the solubility properties of the compound of the formula (X) tetrahydrofuran is particularly useful as a solvent.

[0066] The reagent T3P can be used directly as commercially available solutions, e.g. in ethyl acetate.

[0067] The (2R)-2 -bromobutanoic acid - N-cyclohexylcyclohexanamine (XI) is a solid and can be stored at room temperature without loss of enantiomeric purity. The salt can be directly used in the coupling reaction. Dicyclohexylamine forms salts with the hydrolysis products of T3P, e.g. propylphosphonic acid, as by-products of the reaction. The salts are easily removed by simply washing the isolated compound of the formula (X) with a mixture of tetrahydrofuran and water. d) Coupling of compound of the formula (VI) with compound of the formula (X) to compound of the formula (I) (described in WO2019 / 175043) versus coupling of compound of the formula (VI) with compound of the formula (X) via compound of the formula (XII) to compound of the formula (I) (present invention) of the formula (X) to compound of the formula

[0068] The compound of the formula (VI) and the compound of the formula (X) are coupled in a base mediated N-alkylation reaction to the compound of the formula (I). The best results are obtained using N,N,N’,N’ -tetramethylguanidine as base and a l:4-mixture of acetone and 2 -propanol as solvent at 20°C. The ratio of N-alkylation over undesired O-alkylation is 9: 1 to 10: 1. During workup the reaction mixture is dosed into cooled water and amorphous compound of the formula (I) precipitates. The amorphous compound of the formula (I) contains a high amount of side products, namely unwanted O-alkylated product and N,N,N’,N’ -tetramethylguanidine hydrobromide. It also contains a significant amount of the compound of the formula (XV) which is formed by epimerization due to the basic reaction conditions. The enantiomeric purity is between 92.5 and 96.5% S-enantiomer (85%ee to 93%ee). Filtration of the amorphous compound of the formula (I) has to be done at lower temperature to avoid the formation of a glass like material during isolation which will block the filter. Due to the low quality of the isolated amorphous compound of the formula (I), it is then crystallized from acetone and water and the acetone solvate (compound of the formula (XII)) is isolated. This step removes most of the impurities, but the enantiomeric purity is BHC 24 1 041 FC

[0069] - 9 - not improved. The isolated acetone solvate (compound of the formula (XII)) is then dissolved in ethanol and an insoluble material remains. This insoluble material is a l: l-mixture of the compound of the formula (XV) (R-enantiomer) and the compound of the formula (XVI). The compound of the formula (XVI) crystallizes as racemic compound, named Modification A. The modification A of the racemic compound of the formula (XVI) can be characterized by TGA, DSC, IR, Raman, XRPD and Single Crystal Diffraction (Figures 1 to 7). The compound of the formula (XVI) is insoluble in most organic solvents. Filtration of the ethanol suspension removes the compound of the formula (XVI) and thereby the unwanted compound of the formula (XV) efficiently. The clear ethanol filtrate is dosed into water and the compound of the formula (I) precipitates now as amorphous material with a high enantiomeric purity (S-enantiomer). As described in WO2022 / 189279, crystalline solvent-free forms of the compound of the formula (I) have been found. The crystalline modification I of the compound of the formula (I) is the thermodynamically stable form below the melting point. A serious disadvantage for scale-up of the process described in WO2019 / 175043 is the low solubility of the crystalline modification I of the compound of the formula (I) in ethanol. The ethanol solution is supersaturated, and presence of seeding crystals of crystalline modification I of the compound of the formula (I) can induce crystallization of the compound of the formula (I) prior to the removal of the compound of the formula (XVI). Once crystallized, crystalline modification I of the compound of the formula (I) cannot be dissolved again by simple heating of the suspension and direct removal of the compound of the formula (XVI) by filtration is not easily possible anymore. This is an inherent danger during long manufacturing campaigns.

[0070] Additionally, the crystalline modification I of the compound of the formula (I) shows beneficial properties over the amorphous form of the compound of the formula (I) with regards to hygroscopicity and thermal stability. Therefore, a manufacturing process suitable for manufacturing of the crystalline modification I of the compound of the formula (I) is needed.

[0071] Coupling of compound of the formula (VI) with compound of the formula (X) via compound of the formula (XII) to compound of the formula (I) (present invention)

[0072] In the present invention the compound of the formula (VI) and the compound of the formula (X) are coupled in a base mediated N-alkylation reaction to the intermediate compound of the formula (XII) and in a second step the compound of the formula (XII) is transformed to compound of the formula (I). The compound of the formula (I) is isolated as crystalline modification I.

[0073] N,N, N’, A ’-tetramethylguanidine is the preferred base for the reaction and a mixture of acetone and water is used as solvent. Preferable, the acetone contains 5w% to 35w% of water, more preferably I0w% to 20w%, and most preferably 16w% to 19w%. The reaction temperature is 10°C to 30°C, preferable 15°C to 25°C, and most preferably 18°C to 20°C. The amount of N,N,N’,N’- tetramethylguanidine is 1 to 2 molar equivalents in respect to the compound of the formula (VI) BHC 24 1 041 FC

[0074] - 10 - preferable 1.1 to 1.5 eq, most preferably 1.2 eq in respect to the compound of the formula (VI). The excess of N,N, N’, V ’-tetramethylguanidine is quenched with acetic acid to avoid epimerization during work-up. Water and seeding crystals (mixture of the compound of the formula (XII) and the compound of the formula (XVI)) are added and the acetone solvate (compound of the formula (XII)) crystallizes directly from the reaction mixture. It is easily isolated by filtration. The chemical purity of the acetone solvate (compound of the formula (XII)) is high. The unwanted O-alkylated product and N,N,N’, A ’-tetramethylguanidine hydrobromid is removed with the mother liquor. If needed, the quality can be further improved by as simple and high yielding recrystallization from acetone and water. The acetone solvate (compound of the formula (XII)) still contains the compound of the formula (XV) as impurity. The content of the compound of the formula (XV) crystallizes with the compound of the formula (I) in the form of the compound of the formula (XVI). When the acetone solvate (compound of the formula (XII)) is dissolved in acetonitrile, the compound of the formula (XVI) remains as insoluble solid and is removed by fdtration. In contrast to ethanol, the solubility of the crystalline modification I of the compound of the formula (I) in acetonitrile is so high at a temperature above room temperature, that crystallized compound of the formula (I) can be redissolved by simple reheating of a suspension. Thus, there is no danger during manufacturing in multi-kilo scale that the compound of the formula (XVI) cannot be removed due the premature crystallization of the compound of the formula (I). After removal of the compound of the formula (XVI) by filtration, diisopropyl ether and seeding crystals (compound of the formula (I) as crystalline modification I) are added to the acetonitrile solution of the compound of the formula (I) and the compound of the formula (I) crystallizes as crystalline modification I. Alternatively, acetonitrile can be substituted by methanol. In combination with methanol, disopropylether and water can be used as antisolvent in the crystallization of the compound of the formula (I). Especially the use of methanol and water is attractive for commercial manufacturing due to the low price compared to acetonitrile and diisopropyl ether.

[0075] The present invention covers a process for preparing 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3- triazol-l-yl]phenyl}-2,5-dimethoxypyridine (V), characterized in that (2,5-dimethoxypyridin-4- yl)boronic acid (III) is reacted with l-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)-lH-l,2,3- triazole (IV) in the presence of Pd(dtbpf)C12 with a base in a solvent.

[0076] The present invention covers a process for preparing 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3- triazol-l-yl]phenyl}-5-methoxypyridin-2(lH)-one (VI) by reaction of 4-{5-chloro-2-[4- (trifhioromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-2,5-dimethoxypyridine (V) with concentrated hydrogen chloride solution in a solvent.

[0077] The present invention covers a process for preparing 4-{[(2R)-2-bromobutanoyl]amino}-2- fluorobenzamide (X), characterized in that (2R)-2-bromobutanoic acid - N-cyclohexyl- cyclohexanamine (XI) is reacted with 4-amino-2-fluorobenzamide (IX) in the presence of BHC 24 1 041 FC

[0078] - 11 -

[0079] TsP / pyridine in a solvent.

[0080] The present invention covers a process for preparing (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-

[0081] 32.5-dioxo- l4-(trifluoromcthyl)-32 / / -6-aza-3(4. l )-pyridina- l ( l )-| 1.2.3 |triazola-2( l .2).7( I )- dibenzenaheptaphane-74-carboxamide acetone (XII), characterized in that 4-{5-chloro-2-[4- (trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-5-methoxypyridin-2(lH)-one (VI) is reacted with 4-{[(2R)-2-bromobutanoyl]amino}-2 -fluorobenzamide (X) in the presence of a base in a solvent.

[0082] The present invention covers a process for preparing (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-

[0083] 32.5-dioxo- l4-(trifluoromcthyl)-32 / / -6-aza-3(4. l )-pyridina- l ( l )-| 1.2.3 |triazola-2( l .2).7( I )- dibenzenaheptaphane-74-carboxamide (I), characterized in that (4S)-24-chloro-4-ethyl-73-fluoro-35- mcthoxy-32.5-dioxo- l4-(trifluoromcthyl)-32 / / -6-aza-3(4. 1 )-pyridina- l ( l )-| 1.2.3 |triazola- 2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide acetone (XII) is converted to the compound of the formula (I). The compound of the formula (I) is isolated as crystalline modification I.

[0084] The present invention covers a process for preparing (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-

[0085] 32.5-dioxo- l4-(trifluoromcthyl)-32 / / -6-aza-3(4. l )-pyridina- l ( l )-| 1.2.3 |triazola-2( l .2).7( I )- dibenzenaheptaphane-74-carboxamide (I), characterized in that i.) in the first step, (2,5-dimethoxypyridin-4-yl)boronic acid (III) is reacted with l-(2-bromo-

[0086] 4-chlorophenyl)-4-(trifluoromethyl)-lH-l,2,3-triazole (IV) in the presence of a Pd(dtbpf)C12 with a base in a solvent to form 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3- triazol- 1 -yl] phenyl} -2, 5 -dimethoxypyridine (V), ii.) in the second step, 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-2,5- dimethoxypyridine (V) is reacted with concentrated hydrogen chloride solution in a solvent to form 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-5-methoxy- pyridin-2(lH)-one (VI), iii.) in the third step, 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-5- methoxypyridin-2(lH)-one (VI) is reacted with 4-{[(2R)-2-bromobutanoyl]amino}-2- fluorobenzamide (X) in the presence of a base in a solvent to form (4.S)-24-chloro-4-cthyl- 73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4, 1 )-pyridina-l( 1 )- [ 1 ,2,3]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane-74-carboxamide acetone (XII), iv.) in the fourth step, (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-

[0087] (trifluoromethyl)-32H-6-aza-3(4, l)-pyridina-l( l)-[ l,2,3]triazola-2(l,2),7( l)-dibenzena- heptaphane-74-carboxamide acetone (XII) is converted to the compound of the formula (I).

[0088] Synthesis sequences of the invention:

[0089] The compound of the formula (II) is converted to the compound of the formula (III).

[0090] The compound of the formula (III) is reacted with the compound of the formula (IV) to give the BHC 24 1 041 FC

[0091] - 12 - compound of the formula (V).

[0092] The compound of the formula (V) is converted to the compound of the formula (VI).

[0093] The compound of the formula (XI) is reacted with the compound of the formula (IX) to give the compound of the formula (X).

[0094] The compound of the formula (VI) is reacted with the compound of the formula (X) to give the compound of the formula (XII).

[0095] The compound of the formula (XII) is converted to the compound of the formula (I).

[0096] Abbreviations and acronyms

[0097] AcOH acetic acid aq. aqueous wt% percent by weight area% percent by area

[0098] % of th. percent of theory conv. conversion equiv. equivalent min minutes h hours mg milligram g gram

[0099] 1 litre ml millilitre

[0100] DSC differential scanning calorimetry

[0101] ESI electron spray ionisation

[0102] HPLC high pressure (performance) liquid chromatography

[0103] IR infrared spectroscopy

[0104] SFC supercritical fluid chromatography br broad s singlet d doublet t triplet q quartet ppm parts per million m multiplet

[0105] Hz hertz BHC 24 1 041 FC

[0106] M molar

[0107] Examp. example

[0108] DIC A'.A'-diisopropylcarbodiimidc

[0109] EDC l-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0110] EtOH ethanol

[0111] EtOAc ethyl acetate LDA lithium N-isopropylpropan-2-aminide Pd(Amphos)2C12 Bis[(dicyclohexyl)(4-dimethylaminophenyl)phosphine]palladium(II)- chloride

[0112] Pd(dtbpf)Cl2[1,1 '-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) p-TsOH p-toluene sulfonic acid t-amyl-OH ter-amylalcohol, also known as 2-methylbutan-2-ol T3P propylphosphonic anhydride THF tetrahydrofuran

[0113] TGA thermogravimetric analysis

[0114] XRPD X-ray powder diffraction

[0115] (a / a) area / area

[0116] (v / v) volume / volume (w / w) weight / weight

[0117] Rt retention time

[0118] If the term “the compound of the formula ( . . . .)” is used this term can be replaced by the IUPAC name of the compound of the formula The IUPAC names of the compounds are mentioned above.

[0119] In the context of the present invention, the term "enantiomerically pure" is to be understood as meaning 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 here 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%)]

[0120] Alternatively, to the enantiomeric excess the chiral purity can be reported as enantiomeric purity.

[0121] The enantiomeric purity is calculated as: enantiomeric purity = [EA(area%) x 100%] / [EA(area%)+EB(area%)]

[0122] (EA: major enantiomer, EB: minor enantiomer)

[0123] In the case of the synthesis intermediates and working examples of the invention described BHC 24 1 041 FC

[0124] - 14 - hereinafter, any compound specified in the form of a solvate is generally a solvate of unknown exact stoichiometric composition, as obtained by the respective preparation and / or purification process. Unless specified in more detail, additions to names and structural formulae, such as “acetone” should not therefore be understood in a stoichiometric sense in the case of such solvates, but have merely descriptive character with regard to the solvate -forming components present therein.

[0125] Preferred are solvates with a stoichiometric composition of compound to solvent 1: 1.

[0126] HPLC and UPLC methods:

[0127] UHPLC method for 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-2,5- dimethoxypyridine (V):

[0128] Column: Waters Acquity BEHShield RP18 3.0 mm x 100 mm, 1.7 pm, mobile phase A: 10 mM phosphate buffer pH 3 (e.g. 1.15 g NH4H2PO4 + 155 pl H3PO4 (85%ig) / 11 water), mobile phase B: acetonitrile / methanol 1 / 1 (v / v), gradient: 0.00 min 5% B, 2.00 min 5% B, 10.00 min 40% B, 24.00 min 51% B, 35.00 min 80% B, 38.00 min 80% B, oven 51°C, flow rate 0.85 ml / min, UV detection 210 nm.

[0129] HPLC for 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-5-methoxypyridin- 2(lH)-one (VI):

[0130] Column: Waters Xbridge BEH Shield RP18 3.0 mm x 100 mm, 2.5 pm, mobile phase A: 10 mM phosphate buffer pH 3 (e.g. 1.15 g NH4H2PO4 + 155 pl H3PO4 (85%ig) / 11 water), mobile phase B: acetonitrile / methanol 1 / 1 (v / v), gradient: 0.00 min 20% B, 2.00 min 20% B, 4.00 min 40.0% B, 10.00 min 40.0% B, 18.00 min 80% B, 25.00 min 80% B, oven 30°C, flow rate 0.40 ml / min, UV detection 220 nm.

[0131] UHPLC for 4-{[(2R)-2 -bromobutanoyl] amino} -2 -fluorobenzamide (X):

[0132] Column: Waters Acquity UPLC HSS PFP 1.8pm, 3.0 mm x 100 mm, 1.8 pm, mobile phase A: water and 0.08 vol% formic acid, mobile phase B: acetonitrile / methanol 65 / 35 (v / v), gradient: 0 min 10% B, 1 min 10% B, 12.50 min 37% B, 20 min 90% B, 23 min 90% B, oven 28°C, flow rate 0.8 ml / min, UV detection 270 nm. chiral HPLC for 4- { [(2R)-2 -bromobutanoyl] amino} -2 -fluorobenzamide (X):

[0133] Column: Chiralpak IA 4.6 mm x 250 mm, 5 pm, mobile phase A: n-heptane, ethanol and diethylamine (93%:7%:0.4%, v / v / v), isocratic - gradient: 0.00 min 0% B, oven 40°C, flow rate 4.00 ml / min, UV detection 270 nm, sample solvent ethanol + 0.4% diethylamine.

[0134] UHPLC for (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (I) and (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4,l)- BHC 24 1 041 FC

[0135] - 15 - pyridina- 1 ( l)-[ 1 ,2,3]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane-74-carboxamide acetone (XII)

[0136] Column: YMC Triart C18 3.0mm x 100 mm, 1.9 pm, mobile phase A: water and 0.1% formic acid, mobile phase B: acetonitrile, gradient: 0.00 min 5% B, 2.00 min 5% B, 9.00 min 42% B, 11.50 min 42% B, 20 min 64% B, 23 min 90% B, 30 min 90% B, oven 28°C, flow rate 0.60 ml / min, UV detection 262 nm. chiral HPLC for (4.S')-24-chloro-4-cthyl-73-fluoro-3 -mcthoxy-32.5-dioxo- l4-(trifliioromcthyl)-32 / / - 6-aza-3 (4, 1 )-pyridina- 1 ( 1 )-[ 1 ,2,3]triazola-2( 1 ,2) ,7( 1 )-dibenzenaheptaphane-74-carboxamide (I) and (4S)-24-chloro-4-ethyl-73-fhioro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4,l)- pyridina- 1 ( l)-[ 1 ,2,3]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane-74-carboxamide acetone (XII)

[0137] Column: Chiralpak IC 4.6 mm x 250 mm, 5 pm, mobile phase A: n-heptane, 2-propanol and diethylamine (70%:30%:0.1%, v / v / v), isocratic - gradient: 0.00 min 0% B, oven 40°C, flow rate 3.00 ml / min, UV detection 262 nm, sample solvent ethanol.

[0138] Alternative chiral HPLC for (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 74-carboxamide (I)

[0139] Column: Daicel Chiralpak IA (SFC) 3 mm x 150 mm, 3 pm, mobile phase A: carbondioxide, mobile phase B: methanol, isocratic 85% A, 15% B, oven 40°C, flow rate 2.0 ml / min, UV detection 260 nm, sample solvent methanol.

[0140] Working Examples

[0141] Synthesis of 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyll-2,5-dimethoxy- pyridine (V)

[0142] Variation 1

[0143] 232.2 kg of tetrahydrofuran were mixed with 150 of water, and 31.8 kg of potassium carbonate and stirred at 20°C for 20 minutes. 28.4 kg of (2,5-dimethoxypyridin-4-yl)boronic acid (III) were added and stirring was continued for 10 min. 50 kg of l-(2-bromo-4-chlorophenyl)-4-(trifluoromethyl)- lH-l,2,3-triazole (IV) were added, followed by inertisation of the mixture via three vacuum (200 mbar) / nitrogen cycles. 1 kg of Pd(dtbpf)C12-catalst was added and the inertisation procedure was repeated. The jacket temperature was increased to 80°C to bring the mixture to a reflux temperature. The mixture was stirred under these conditions for 3 h. 255 kg of a 9.8% w / w solution of '-acctyl cysteine in water were added, keeping the temperature of the reaction mixture above 63°C. After the addition the mixture qas stirred under reflux for 1 h and then cooled to a temperature of 20°C. The lower aqueous phase was discarded. 330 kg of a 8.5% w / w solution of N- acetyl cysteine in water were added and the jacket temperature was increased to 90°C. Solvent was BHC 24 1 041 FC

[0144] - 16 - distilled off at atmospheric pressure until the inner temperature reached 80°C. The mixture was cooled to 70°C and 20 kg of 2-methylbutan-2-ol were added followed by 178 kg of ethanol. Stirring was continued at 70°C for 1 h, followed by addition of 500 g of 4-{5-chloro-2-[4- (trifhioromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-2,5-dimethoxy-pyridine (V) seed crystals and further stirring for 1 h. Additional 95 kg of ethanol were added, followed by 50 kg of water, keeping the temperature at 70°C. The suspension was slowly cooled to 20°C and stirred for 3 h at that temperature. The suspension was filtered via centrifuge and the filter cake washed with a mixture consisting of 55.9% water, 39.6% ethanol, and 4.5% w / w 2-methylbutan-2-ol. The filter cake was dried under vacuum to obtain 53.1 kg (90.2% yield) of 4-{5-chloro-2-[4- (trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-2,5-dimethoxy-pyridine (V) with an assay of 99.4%.

[0145] Variation 2

[0146] A reaction vessel was charged with 8.9 kg of tetrahydrofuran, 6.0 kg of water, 1.27 kg of potassium carbonate, 1.12 kg of (2,5-dimethoxypyridin-4-yl)boronic acid (III) and 2.0 kg of l-(2-bromo-4- chlorophenyl)-4-(trifluoromethyl)-lH-l,2,3-triazole (IV) under nitrogen atmosphere. 0.028 kg of [l,l'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) were added. The resulting mixture was heated up and stirred at reflux for three hours. A solution of 1.0 kg of N-acetylcysteine in 9.2 kg of water was slowly added. The mixture was stirred at reflux for one hour and then cooled to 40°C. The layers were separated, and the aqueous layer was discarded. A solution of 0.40 kg of N- acetylcysteine in 12.0 kg of water was added to the organic layer and the resulting mixture was heated up. Volatiles were distilled off until an internal temperature of approximately 82°C was reached. The mixture was cooled to an internal temperature of 70°C and 0.81 kg of 2-methylbutan- 2-ol was added., followed by 7.11 kg of ethanol. The suspension was stirred for an additional hour at 70°C and was then cooled to 20°C within four hours. The suspension was fdtered and the collected solids were washed with a mixture of water and ethanol (ratio 1: 1 (v / v)). The product was dried under reduced pressure at 50°C to obtain 2.12 kg (90% yield) of 4-{5-chloro-2-[4- (trifhroromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-2,5-dimethoxy-pyridine (V) with an assay of 98.4%.

[0147] Synthesis of 4-f5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]Dhenyl}-5-methoxy- pyridin-2(lH)-one (VI)

[0148] Variation 1

[0149] 157 kg of isopropanol and 25 kg of 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l- yl]phenyl} -2, 5-dimethoxy -pyridine (V) were mixed at 20°C. 32.9 kg of concentrated hydrochloric acid (37.5% w / w in water) were dosed in and the intake pipe was rinsed into the reactor using 15 kg of isopropanol. The temperature was increased to 105 °C and the mixture was stirred at that temperature for 24 h. 250 kg of hot water (88°C) were dosed into the refluxing mixture and stirring BHC 24 1 041 FC

[0150] - 17 - was continued under these conditions for 2 h. The temperature was decreased to 20°C and the suspension was fdtered via centrifuge and the filter cake was washed with a 1: 1.9 w / w mixture of isopropanol and water. The filter cake was dried under vacuum to obtain 22.4 kg (93% yield) of 4- {5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-5-methoxypyridin-2(lH)-one (VI) with an assay of 100%.

[0151] Variation 2

[0152] 5.1 g of acetic chloride were added to 40 ml of 2-propanol at 0°C to 5°C. The mixture is stirred at 0°C for 1 h. 5 g of 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-2,5- dimethoxy-pyridine (V) were added and the used funnel was washed with 4 ml of 2-porpanol. The resulting mixture was heated up to 80°C and stirred overnight. 62.5 g of water were added within 2 h. The mixture was cooled to room temperature and stirred for 1 h. The suspension was filtered, and the product washed three times with 10 ml of a mixture of 2 -propanol-water (2:3 v / v). The product was dried in vacuum. 4.7 g of 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l- yl]phenyl}-5-methoxypyridin-2(lH)-one (VI) were isolated (97% yield) with a purity of 99.6%.

[0153] Synthesis of 4-f[(2R)-2-bromobutanoyl]aminoI-2-fluorobenzamide (X)

[0154] 61.4 kg of tetrahydrofuran were mixed with 14.5 kg of 4-amino-2-fluorobenzamid (IX) and cooled to a temperature of 0°C. 36.0 kg of (2R)-2-bromobutanoic acid - N-cyclohexylcyclohexanamine (XI) were added thereto, followed by 2.2 kg of pyridine. Residues in the intake lines were rinsed into the reactor using 3 kg of tetrahydrofuran. 89.8 kg of T3P (50% solution in ethyl acetate) are dosed into the reactor, keeping the temperature between -5 and +5°C. Residues in the intake lines were rinsed into the reactor using 10 kg of tetrahydrofuran. The mixture was stirred at 0°C for 120 minutes. 36 g of water were dosed into the mixture, keeping the temperature between -5 and +5°C. The temperature was increased to 50°C and 109 kg of water were added. 145 g of 4-{[(2R)-2- bromobutanoyl]amino}-2-fluorobenzamide (X) seed crystals were added and the mixture was stirred for 30 minutes. The temperature was decreased to 30°C and solvent was evaporated from the suspension at 250 mbar and 80°C of jacket temperature, until an inner temperature of 50°C was reached. The this point 78 kg of water and 17.4 kg of tetrahydrofuran were added and the suspension was cooled to 20°C followed by stirring for 1 h at this temperature. The suspension was fdtered and the fdter cake was re -suspended and washed 4 times, each time using a mixture of 62 kg of water and 10.9 kg of tetrahydrofuran. The fdter cake was dried under vacuum to obtain 25.2 kg (88.4% yield) of 4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (X) with an assay of 100% and an enantiomeric purity of 99.79% of S-enantiomer.

[0155] Synthesis of -24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)- 6-aza-3(4,l)-Dyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheDtaDhane-74-carboxamide acetone (XII) BHC 24 1 041 FC

[0156] - 18 -

[0157] Variation 1

[0158] 165 kg of acetone and 21 kg of water were mixed at 22°C. 10.3 kg of tetramethylguanidin were added, followed by 27.5 kg of 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-5- methoxypyridin-2(lH)-one (VI) and 24.7 kg of 4-{[(2R)-2-bromobutanoyl]amino}-2-fluoro- benzamide (X). The mixture was stirred for 18 h at 22°C. 1.3 kg of acetic acid were added while the temperature was kept at 20°C. The temperature was increased to 50°C and 144 kg of water were added at this temperature. 300 g of (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo- l4-(trifluoromcthyl)-32 / / -6-aza-3(4. l )-pyridina- l ( l )-| l .2.3 |triazola-2( l .2).7( l )-dibcnzcna- heptaphane-74-carboxamide acetone (XII) seed crystals (enantiomeric purity 95.8% S-enantiomer) were added and the mixture was stirred at 50°C for 3 h. The mixture is cooled to 35°C and additional 300 g of (4S)-24-chloro-4-ethyl-73-fhioro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)- 32H-6-aza-3(4, l)-pyridina-l( l)-[ l,2,3]triazola-2(l,2),7(l)-dibenzena-heptaphane-74-carboxamide acetone (XII) seed crystals (enantiomeric purity 95.8% S-enantiomer) are added. The mixture was cooled to 5 °C. The temperature was increased again to 20°C before being lowered again slowly to 5°C. The suspension was stirred at that temperature for 3 h and then filtered. The filter cake was washed twice, each time using a 5 °C cold mixture of 17 kg acetone and 22 kg of water. The filter cake was dried under vacuum to obtain 38.3 kg (79.3% yield) of (4S)-24-chloro-4-ethyl-73-fluoro- 35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4, 1 )-pyridina-l( 1 )-[ 1,2,3 ]triazola- 2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide acetone (XII) with an assay of 92.0% (4.S)-24- chloro-4-ethyl-73-fhioro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4, 1 )-pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (I) (purity 99.87area%) and 7.80w% acetone. Enantiomeric purity: 96.3% of S-enantiomer.

[0159] Variation 2

[0160] To a mixture of 10 g of 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-5- methoxy-pyridin-2(lH)-one (VI) and 9 g of 4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (X) were added 60 g of acetone, 13.7 g of water and 4.060 ml of N,N,N, N -tetramethylguanidine. The resulting mixture is stirred at 18°C for 18 hours. 0.463 ml of acetic acid were added and the mixture is heated up to 50°C. 46.3 g of water were added, followed by 123 mg of (4.S)-24-chloro-4- ethyl-73-fhioro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4, l)-pyridina-l( 1)- [l,2,3]triazola-2(l,2),7(l)-dibenzena-heptaphane-74-carboxamide acetone (XII) seed crystals (enantiomeric purity 96.2% S-enantiomer). The mixture is stirred at 50°C for 3 hours, then cooled to 35°C. Additional 123 mg of (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3]triazola-2( 1 ,2),7( l)-dibenzena-heptaphane- 74-carboxamide acetone (XII) seed crystals (enantiomeric purity 96.2% S-enantiomer) were added. The mixture was stirred at 35 °C for 1 h and then cooled to 5 °C and stirred overnight. The suspension was filtered and the product was washed twice with 16 ml of a cold 1: 1 -mixture (v / v) of BHC 24 1 041 FC

[0161] - 19 - acetone and water. (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)- 32H-6-aza-3 (4, 1 )-pyridina- 1 ( 1 )-[ 1 ,2,3]triazola-2( 1 ,2),7( 1 )-dibenzenaheptaphane-74-carboxamide acetone (XII) was dried in vacuum at 50°C to yield 14.09 g (80.2% yield) (assay 92.7w% (4.S)-24- chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4, 1 )-pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (I), acetone 7.5w%. Enantiomeric purity: 97.52% of S-enantiomer.

[0162] Variation 3

[0163] To a mixture of 10 g of 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-5- methoxy-pyridin-2(lH)-one (VI) and 9 g of 4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (X) were added 60 g of acetone, 11.4 g of water and 4.061 ml of N,N,N,N -tetramethylguanidine. The resulting mixture is stirred at 20°C for 18 hours. 0.463 ml of acetic acid were added and the mixture is heated up to 50°C. 48.6 g of water were added, followed by 123 mg of (4.S)-24-chloro-4- ethyl-73-fhioro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4, l)-pyridina-l( 1)- [l,2,3]triazola-2(l,2),7(l)-dibenzena-heptaphane-74-carboxamide acetone (XII) seed crystals (enantiomeric purity 96.2% S-enantiomer). The mixture is stirred at 50°C for 3 hours, then cooled to 35°C. Additional 123 mg of (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifhioromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3]triazola-2( 1 ,2),7( l)-dibenzena-heptaphane- 74-carboxamide acetone (XII) seed crystals (enantiomeric purity 96.2% S-enantiomer) were added. The mixture was stirred at 35 °C for 1 h and then cooled to 5 °C and stirred overnight. The suspension was filtered and the product was washed twice with 16 ml of a cold 1: 1 -mixture (v / v) of acetone and water. (45)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)- 32H-6-aza-3 (4, 1 )-pyridina- 1 ( 1 )-[ 1 ,2,3]triazola-2( 1 ,2),7( 1 )-dibenzenaheptaphane-74-carboxamide acetone (XII) was dried in vacuum at 50°C to yield 13.96 g (79.5% yield) of acetone solvate crude (assay 93.09w% (4S)-24-chloro-4-ethyl-73-fhioro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H- 6-aza-3 (4, 1 )-pyridina- 1 ( 1 )-[ 1 ,2,3]triazola-2( 1 ,2),7( 1 )-dibenzenaheptaphane-74-carboxamide (I), enantiomeric purity 97.26% S-enantiomer)

[0164] Crystallization of -24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)- 32J7-6-aza-3(4,l)-Dyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheDtaDhane-74- carboxamide acetone (XII)

[0165] 94 kg of acetone were mixed with 94 kg of water and 37.5 kg of (4.S')-24-chloro-4-cthyl-73-fluoro- 35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4, 1 )-pyridina-l( 1 )-[ 1,2,3 ]triazola- 2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide acetone (XII) were added to this mixture. The temperature was increased to 50°C and the mixture was stirred for 1 h at that temperature, before it was lowered to 35°C. 130 g of (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane- 74-carboxamide acetone (XII) seed crystals were added and stirring was continued at 35 °C for 1 h, BHC 24 1 041 FC

[0166] - 20 - followed by lowering of the temperature to 0°C. The suspension was filtered using a centrifuge. The filter cake was washed using a 0°C cold mixture of acetone and water (1: 1 v / v, 209 kg in total). The product was dried under vacuum to obtain 35.6 kg (95% yield) of (4.S)-24-chloro-4- ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4, l)-pyridina-l( 1)- [l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide acetone (XII) with an assay of 92.5% (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza- 3(4,1) -pyridina- 1(1)-[1,2,3 ]triazola-2( 1 ,2) ,7( 1 ) -dibenzenaheptaphane -74-carboxamide (I) (purity 99.99area%) and 8.06w% acetone. Enantiomeric purity: 96.0% of S-enantiomer.

[0167] Synthesis of -24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)- 6-aza-3(4,l)-Dyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheDtaDhane-74-carboxamide 01

[0168] Variation 1

[0169] 2723 g of (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza- 3(4,1) -pyridina- 1(1)-[1,2,3 ]triazola-2( 1 ,2) ,7( 1 ) -dibenzenaheptaphane -74-carboxamide acetone (XII) (enantiomeric purity: 93.8% of S-enantiomer; acetone content: 7.46%) was suspended in 4080 g of acetonitrile. The mixture was heated to 80°C, stirred for 2 hours, cooled down to 20°C and stirred for 30 minutes. The suspension containing the compound of the formula (XVI) was filtered. The filter cake was washed with 1090 g of a 1: 1 (w:w) mixture of acetonitrile and diisopropyl ether. The filtrate was heated to 60°C and held at this temperature. Subsequently, 9370 g of diisopropyl ether was dosed in, while the temperature of the solution was held at 60°C. To the resulting solution, 71 g of (4S)-24-chloro-4-ethyl-73-fhioro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H- 6-aza-3 (4, 1 )-pyridina- 1 ( 1 )-[ 1 ,2,3]triazola-2( 1 ,2),7( 1 )-dibenzenaheptaphane-74-carboxamide (I) seeds (crystalline modification I) were added and the mixture was stirred at a temperature of 60 °C for a period of 17.5 hours. To the resulting suspension 5720 g of diisopropyl ether was added. The final suspension was cooled down to 20°C, stirred for 30 minutes and isolated by filtration. The crystallization vessel was rinsed with 6260 g of diisopropyl ether, and the rinse was used to wash the filter cake. The wet product (4236 g) was dried under vacuum. 2219 g of dry (4.S)-24-chloro-4- ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4, 1) -pyridina- 1( 1)- [l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (I) (crystalline modification I, yield: 84. 1%) was isolated with an enantiomeric purity of 99.9% S-enantiomer.

[0170] Analytical data of (4.S)-24-chloro-4-cthyl-73-fliioro-3 -mcthoxy-32.5-dioxo-l4-(trifliioromcthyl)-32 / / -6- aza-3(4, l)-pyridina- 1( l)-[ l,2,3]triazola-2( 1 ,2),7( l)-dibenzenaheptaphane-74-carboxamide (I) are mentioned in WO2014 / 154794.

[0171] Variation 2

[0172] 96.4 g of (4.S)-24-chloro-4-cthyl-73-fluoro-3 -mcthoxy-32.5-dioxo- l4-(trifliioromcthyl)-32 / / -6-aza- BHC 24 1 041 FC

[0173] - 21 -

[0174] 3(4,1) -pyridina- 1(1)-[1,2,3 ]triazola-2( 1 ,2) ,7( 1 ) -dibenzenaheptaphane -74-carboxamide acetone (XII) (enantiomeric purity: 95.2% of S-enantiomer; acetone content: 7.43%) was suspended in 114.6 g of acetonitrile. The suspension was heated to 80°C and upon gentle boiling, 23.7 g of distillate was collected. The resulting mixture was stirred for 2 h, cooled down to 20°C and fdtered to separate the compound of the formula (XVI). The solid residue was washed with 20 g of acetonitrile and the liquid fractions were combined. 10.0 g of the compound of the formula (XVI) was isolated after drying in vacuum.

[0175] 50 g of the combined liquid fractions from above (concentration approximately 37.5 %wt) were heated up to 60°C and afterwards, 75 g of diisopropyl ether was added during 60 minutes, while maintaining the solution temperature at 60°C. To the resulting solution 600 mg of (4.S)-24-chloro-4- ethyl-73-fhioro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4, 1) -pyridina- 1( 1)- [l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (I) seeds (crystalline modification I) were added, and the resulting mixture was stirred for 10 hours. To the resulting suspension, an additional 25 g of diisopropyl ether was added during 60 minutes, while maintaining the solution temperature at 60°C. The final suspension was cooled down to 20°C in 120 minutes. After 68 hours of stirring at 20°C, the solid was isolated by filtration, washed with 50 g of diisopropyl ether and dried in vacuum to obtain 17.2 g of (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromcthyl)-32 / / -6-aza-3(4. l)-pyridina- 1 ( l)-[ 1 ,2,3]triazola-2( 1 ,2),7( 1) -dibenzenaheptaphane - 74-carboxamide (I) (crystalline modification I, yield: 91.7%).

[0176] Variation 3

[0177] 197 g of (4.S)-24-chloro-4-cthyl-73-fluoro-3 -mcthoxy-32.5-dioxo- l4-(trifliioromcthyl)-32 / / -6-aza- 3(4,1) -pyridina- 1(1)-[1,2,3 ]triazola-2( 1 ,2) ,7( 1 ) -dibenzenaheptaphane -74-carboxamide acetone (XII) (enantiomeric purity: 94.3% of S-enantiomer) was suspended in 591 g of acetonitrile. The suspension was heated to 80°C and stirred for 2 hours. The resulting mixture was cooled down to 20°C and filtered to separate the compound of the formula (XVI) (27.2 g of dry solid).

[0178] 70 g of the filtrate (concentration: 21.4 %wt) was heated up to 60°C and afterwards, 181.5 g of water was added during 30 minutes, while maintaining the solution temperature at 60°C. To the resulting solution 70 mg of (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromcthyl)-32 / / -6-aza-3(4. l)-pyridina- 1 ( l)-[ 1 ,2,3]triazola-2( 1 ,2),7( 1) -dibenzenaheptaphane - 74-carboxamide (I) seeds (crystalline modification I) were added, and the resulting mixture was stirred for 69 hours. The final suspension was cooled down to 20°C in 180 minutes. After 1 h of stirring at 20°C, the solid was isolated by filtration, washed with 35 g of water and dried in vacuum at 50°C to obtain 13.2 g of (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromcthyl)-32 / / -6-aza-3(4. l)-pyridina- 1 ( l)-[ 1 ,2,3]triazola-2( 1 ,2),7( 1) -dibenzenaheptaphane - 74-carboxamide (I) (crystalline modification I, yield: 88.1%). BHC 24 1 041 FC

[0179] - 22 -

[0180] Variation 4

[0181] 20.0 g of (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza- 3(4,1) -pyridina- 1(1)-[1,2,3 ]triazola-2( 1 ,2) ,7( 1 ) -dibenzenaheptaphane -74-carboxamide (I)

[0182] (crystalline modification I) was suspended in 37.0 g of methanol and the mixture was heated to reflux temperature and the resulting solution was cooled down and kept at 55°C. To the clear solution, 56 g of diisopropyl ether was dosed during 60 minutes, while maintaining a temperature of 54°C.

[0183] To the resulting solution 200 mg of (45)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromcthyl)-32 / / -6-aza-3(4. l)-pyridina- 1 ( l)-[ 1 ,2,3]triazola-2( 1 ,2),7( 1) -dibenzenaheptaphane - 74-carboxamide (I) seeds (crystalline modification I) were added, and the resulting mixture was stirred at 54°C overnight. To the resulting suspension, an additional 55 g of diisopropyl ether were added during 60 minutes, while maintaining the solution temperature at 54°C. The final suspension was stirred for an additional 2 hours at 54°C. Afterwards, 40 g of the liquid phase were removed by distillation at atmospheric pressure. The resulting suspension was diluted with 40 g of diisopropyl ether, which was added during 20 minutes while maintaining an internal temperature of 55 °C. The so-obtained suspension was stirred at 55°C for additional 2 hours and cooled down to 20°C in 120 minutes. After overnight stirring at 20°C, the solid was isolated by filtration, washed with 70 g of diisopropyl ether and dried in vacuum to obtain 18.44 g of (4.S')-24-chloro-4-cthyl-73-fluoro-3 - methoxy-32,5-dioxo- l4-(trifluoromethyl)-32H-6-aza-3(4, l)-pyridina- 1 ( l)-[ 1 ,2,3]triazola- 2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (I) (crystalline modification I, yield: 92.2%).

[0184] Variation 5

[0185] 34.9 g of (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza- 3(4,1) -pyridina- 1(1)-[1,2,3 ]triazola-2( 1 ,2) ,7( 1 ) -dibenzenaheptaphane -74-carboxamide acetone (XII) (assay 93.0w% (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6- aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (I), enantiomeric purity 96.38%) was suspended in 42.7 g of methanol. The suspension was stirred at room temperature for 3 hours. The compound of the formula (XVI) containing solids were separated by centrifugation. 5 g methanol were used for material transfer. This solution was transferred to a laboratory reactor using 5.6 g of methanol to achieve a (4.S)-24-chloro-4-cthyl-73- fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4, 1 )-pyridina-l( 1 )-[ 1,2,3 ]triazola- 2(l,2),7(l)-dibenzenaheptaphane-74-carboxamide (I) content of 36% w / w and then heated to 60°C. 3 g of diisopropylether were added. 35.7 g of water were added over 40 minutes, followed by 300 mg of (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza- 3(4,1) -pyridina- 1(1)-[1,2,3 ]triazola-2( 1 ,2) ,7( 1 ) -dibenzenaheptaphane -74-carboxamide (I) seeds

[0186] (crystalline modification I), and the resulting mixture was stirred at 60°C for 5 h. To the resulting suspension, an additional 24.8 g of water were added during 47 minutes, and stirring was continued BHC 24 1 041 FC

[0187] - 23 - at 60°C for 1 h. The suspension was cooled down to 20°C in 120 minutes. The solid was isolated by fdtration, washed with 100 g of a 90: 10 w / w water / methanol mixture and dried in vacuum to obtain 27.4 g of (4.S')-24-chloro-4-cthyl-72-fluoro-32-mcthoxy-32.5-dioxo- l4-(trifliioromcthyl)-32 / / - 6-aza-3 (4, 1 )-pyridina- 1 ( 1 )-[ 1 ,2,3]triazola-2( 1 ,2),7( 1 )-dibenzenaheptaphane-74-carboxamide (I)

[0188] (crystalline modification I, yield: 87.6% based on content of S-enantiomer in used acetone solvate (compound of the formula (XII))).

[0189] Physical characterization of (4)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromethyl)-32J7-6-aza-3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzena- heptaphane-74-carboxamide (XVI)

[0190] The solid compound of formula (XVI) which was isolated in the described experiments crystallizes as crystalline racemic compound (i.e. a 1: 1 mixture of R-enantiomer and S-Enantiomer as a homogeneous solid phase) named modification A. Modification A was characterized:

[0191] Thermogravimetric analysis (TGA)

[0192] Thermogravimetric analysis (TGA) was performed with a Mettler Toledo TGA / DSC1. The instrument was purged with nitrogen gas at a flow rate 50 ml.min-1. Approximately 5 mg of the compound of formula (XVI) was placed into an aluminum crucible. The temperature range was 25 - 280°C at a heating rate of 10°C.min -1. TGA thermogram is shown in figure 1.

[0193] Differential scanning calorimetry (DSC)

[0194] Differential scanning calorimetry (DSC) was performed with a Mettler Toledo DSC3. The calorimeter was purged with nitrogen gas at a flow rate of 50 ml.min-1. Approximately 5 mg of the compound of formula (XVI) was placed into an aluminum crucible without sample preparation. The temperature range was -10 - 280°C at a heating rate of 20°C.min-l. The DSC thermogram is shown in figure 2.

[0195] Infrared spectroscopy

[0196] IR measurements were performed with a Bruker alpha spectrometer in the attenuated total reflectance (ATR) geometry. No sample preparation was performed, and each individual measurement consisted of 32 scans. IR spectrum is shown in figure 3.

[0197] Table 1 : Infrared spectroscopy of the compound of formula (XVI) BHC 24 1 041 FC

[0198] - 24 -

[0199] The compound of formula (XVI) was characterized by infrared spectroscopy which displays at least the following values of the band maxima (cm1): 443, 1025, 1134, preferably at least the following values of the band maxima (cm1): 443, 1025, 1048, 1171, 1134, more preferably at least the following values of the band maxima (cm1): 443, 1025, 1048, 1171, 1134, 1534, 1679, most preferably at least the following values of the band maxima (cm1): 443, 1025, 1048, 1171, 1134, 1193, 1278, 1534, 1679 and 3086.

[0200] Raman spectroscopy

[0201] Raman measurements were performed with a Bruker MultiRAM spectrometer. No sample preparation was performed, and each individual measurement consisted of 64 scans using a laser power of 300 mW. Raman spectrum is shown in figure 4.

[0202] Table 2: Raman spectroscopy of the compound of formula (XVI) BHC 24 1 041 FC

[0203] - 25 -

[0204] The compound of formula (XVI) was characterized by raman spectroscopy which displays at least the following values of the band maxima (cm1): 982, 1562, 1608, preferably at least the following values of the band maxima (cm1): 982, 1535, 1562, 1608, 1657, more preferably at least the following values of the band maxima (cm1): 982, 1251, 1281, 1535, 1562, 1608, 1657, most preferably at least the following values of the band maxima (cm1): 218, 982, 1193, 1251, 1281, 1332, 1535, 1562, 1608 and 1657.

[0205] X-ray powder diffraction (XRPD)

[0206] X-ray powder diffraction (XRPD) data were recorded on a STOE STADI P using monochromatized CuKai-radiation, a position sensitive detector, at generator settings of 40 kV and

[0207] 40 mA. The compound of formula (XVI) was collected in transition mode, being prepared as a thin layer between two foils. The scanning rage was between 2° and 40° 2 theta with a 0.5° step at 15 sec / step. X-ray powder diffractogram is shown in figure 5.

[0208] Table 3: X-ray powder diffraction (XRPD) of the compound of formula (XVI) BHC 24 1 041 FC

[0209] - 26 -

[0210] Modification A of the compound of formula (XVI) was characterized by X-Ray powder diffractogram (at 20 ± 5 °C and with Cu-K alpha 1 as radiation) which displays at least the following reflections: 12.4, 18.3, 25.1, preferably at least the following reflections: 12.4, 14.6, 15.7, 18.3, 25.1, more preferably at least the following reflections: 12.4, 14.6, 15.7, 18.3, 23.5, 24.5, 25.1, most preferably at least the following reflections: 6.6. 12.4, 13.6, 14.6, 15.7, 18.3, 23.5, 24.5, 25.1 and 27.2, each quoted as 20 value ± 0.2°.

[0211] Single Crystal Diffraction of (4)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromethyl)- 6-aza-3(4,l)-pyridina-l(l)-[l,2,31triazola-2(l,2),7(l)-dibenzena- heptaphane-74-carboxamide (XVI)

[0212] Crystalline (4)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoro-methyl)-32H-6-aza- 3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzena-heptaphane-74-carboxamide (XVI) (30 mg) was dissolved in 0.15 ml DMSO at 50°C, followed by slow evaporation at ambient conditions to obtain crystals. The crystal structure was determined at 100(2) K. The crystallographic data of crystalline (4)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoro-methyl)-32H-6-aza- 3(4,l)-pyridina-l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzena-heptaphane-74-carboxamide (XVI) as well as a figure depicting the asymmetric unit and thermal ellipsoids, are shown in Table 4 and Figure 6.

[0213] Single crystal X-ray diffraction data were collected on a Rigaku Oxford Diffraction XtaLAB Synergy- S diffractometer equipped with a dualflex source (Cu at Zero), HyPix-6000HE detector and an Oxford BHC 24 1 041 FC

[0214] - 27 -

[0215] Cryosy stems Cobra cooling device. The data were collected using Cu Ka radiation. The structure was solved and refined using the Shelx suite of programs and OLEX2 was used as an interface to produce figures. Hydrogen atoms attached to carbon were placed geometrically and allowed to refine with a riding isotropic displacement parameter. Hydrogen atoms attached to a heteroatom were located in a difference Fourier synthesis map and were allowed to refine freely with an isotropic displacement parameter. The asymmetric unit was found to contain 1 fully ordered molecule of crystalline (4)-24- chloro-4-cthyl-73-fluoro-32-mcthoxy-32.5-dioxo- l4-(trifliioro-mcthyl)-32H-6-aza-3(4. 1 )-pyridina- l(l)-[l,2,3]triazola-2(l,2),7(l)-dibenzena-heptaphane-74-carboxamide (XVI) (Figure 6). The molecules crystallise in the monoclinic crystal system in the centrosymmetric space group I2 / a. The R and S enantiomers are present in a 1: 1 ratio. The final R1 is | I>2c(I) | = 5.90 %.

[0216] Table 4: Crystal data and structure refinement

[0217] Empirical formula C26H21CIF4N6O4

[0218] Formula weight 592.94

[0219] Temperature 100(2) K

[0220] Wavelength 1.54184 A

[0221] Crystal size 0.080 x 0.030 x 0.010 mm

[0222] Crystal system Monoclinic

[0223] Space group / 2 / a

[0224] Unit cell dimensions a = 14.9878(7) A a = 90° b = 18.0423(7) A P = 110.444(5) c = 20.4954(10) A y = 90°

[0225] Volume 5193.2(4) A3

[0226] Z 8

[0227] Density (calculated) 1.517 g / ml

[0228] Absorption coefficient 1.978 mm-1

[0229] F(000) 2432

[0230] Data collection method omega scans

[0231] Theta range for data collection 3.361 to 68.242°

[0232] Index ranges -18 < h < 18, -19 < k < 21, -24 < / < 22

[0233] Reflections collected 17757

[0234] Independent reflections 4727 [R(int) = 0.0415]

[0235] Coverage of independent reflections 99.6 %

[0236] Data / restraints / parameters 4727 / 0 / 384 Goodness-of-fit on31.050

[0237] Final R indices

[0238] 3783 data; I>2o(I) R1 = 0.0590, wR2 = 0.1641 BHC 24 1 041 FC

[0239] - 28 - all data R1 = 0.0728, wR2 = 0.1774

[0240] Largest diff. peak and hole 0.770 and -0.409 eA'3

[0241] A comparison of the simulated XRPD diffraction pattern of the single crystal structure collected at 100 K with the experimental bulk powder pattern from crystalline (4)-24-chloro-4-ethyl-73-fluoro-35- mcthoxy-32.5-dioxo- l4-(trifluoro-mcthyl)-32 / / -6-aza-3(4. 1 )-pyridina-l( l )-| l .2.3 |triazola-2( l.2).7( I )- dibenzena-heptaphane-74-carboxamide (XVI), collected at room temperature shows the patterns are mostly consistent, but as expected, show slight differences due to the difference in the collection temperatures and therefore differences in cell constants due to thermal expansion / contraction , as well as preferred orientation for the experimental pattern (figure 7).

[0242] Explanation of the figures:

[0243] Figure 1 : TGA Curve of the compound of the formula (XVI)

[0244] Figure 2: DSC Curve of the compound of the formula (XVI)

[0245] Figure 3 : IR spectrum of the compound of the formula (XVI)

[0246] Figure 4: Raman spectrum of the compound of the formula (XVI)

[0247] Figure 5 : X-ray powder diffraction (XRPD) of the compound of the formula (XVI)

[0248] Figure 6: A view of the asymmetric part of the unit cell of crystalline (4)-24-chloro-4-ethyl-73- fluoro-35-methoxy-32,5-dioxo-l4-(trifluoro-methyl)-32H-6-aza-3(4, 1 )-pyridina-l( 1 )-[ l,2,3]triazola- 2(l,2),7(l)-dibenzena-heptaphane-74-carboxamide (XVI). Anisotropic atomic displacement ellipsoids for the non -hydrogen atoms are shown at the 50% probability level. Hydrogen atoms are displayed with an arbitrarily small radius.

[0249] Figure 7: Simulated X-ray powder diffraction pattern (XRPD) from the single crystal structure collected at 100 K for the compound of the formula (XVI)

Claims

BHC 24 1 041 FC- 29 -Patent Claims1. Process for preparing (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromcthyl)-32 / / -6-aza-3(4. l )-pyridina- l ( l )-| l .2.3 |triazola-2( l .2).7( l )- dibenzenaheptaphane-74-carboxamide (I), characterized in that i.) in the first step, (2,5-dimethoxypyridin-4-yl)boronic acid (III) is reacted with l-(2- bromo-4-chlorophenyl)-4-(trifluoromethyl)-lH-l,2,3-triazole (IV) in the presence of a Pd(dtbpf)C12 with a base in a solvent to form 4-{5-chloro-2-[4-(trifhioromethyl)-lH- 1 ,2,3 -triazol- 1 -yl]phenyl } -2,5 -dimethoxypyridine (V), ii.) in the second step, 4-{5-chloro-2-[4-(trifhioromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-2,5 -dimethoxypyridine (V) is reacted with concentrated hydrogen chloride solution in a solvent to form 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-5- methoxy-pyridin-2(lH)-one (VI), iii.) in the third step, 4-{5-chloro-2-[4-(trifluoromethyl)-lH-l,2,3-triazol-l-yl]phenyl}-5- methoxypyridin-2(lH)-one (VI) is reacted with 4-{[(2R)-2-bromobutanoyl]amino}-2- fluorobenzamide (X) in the presence of a base in a solvent to form (4.S)-24-chloro-4- ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromethyl)-32H-6-aza-3(4,l)-pyridina- 1(1)-[1,2,3 ]triazola-2( 1 ,2), 7( 1 )-dibenzenaheptaphane -74-carboxamide acetone (XII) , iv.) in the fourth step, (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4-(trifluoromcthyl)-32 / / -6-aza-3(4. l )-pyridina- l ( l )-| l .2.3 |triazola-2( l .2).7( l )-dibcnzcna- heptaphane-74-carboxamide acetone (XII) is converted to the compound of the formula (I).

2. Process according to Claim 1, characterized in that the reaction in the first step is carried out using potassium carbonate as base and a mixture of tetrahydrofuran and water as solvent.

3. Process according to Claim 1 or 2, characterized in that the reaction in the second step is carried out using 2-propanol or 1 -propanol as solvent.

4. Process according to any of Claims 1 to 3, characterized in that the reaction in the third step is carried out using N,N,N’,N ’-tetramethylguanidine as base and a mixture of acetone and water as solvent.

5. Process according to any of Claims 1 to 4, characterized in that the compound of the formula (I) is isolated as crystalline modification I.

6. Process for preparing (4S)-24-chloro-4-ethyl-73-fluoro-35-methoxy-32,5-dioxo-l4- (trifluoromethyl)-32H-6-aza-3(4, l)-pyridina-l(l)-[ l,2,3]triazola-2( l,2),7(l)-dibenzena- heptaphane-74-carboxamide acetone (XII), characterized in that 4-{5-chloro-2-[4-BHC 24 1 041 FC- 30 -(trifluoromethyl)- 1H- 1 ,2,3 -triazol- 1 -yl]phenyl } -5 -methoxypyridin-2( lH)-one (VI) is reacted with 4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (X) in the presence of a base in a solvent.

7. Process according to Claim 6, characterized in that the reaction is carried out using N,N,N ’-tetramethylguanidine as base and a mixture of acetone and water as solvent.

8. Process for preparing 4-{[(2R)-2-bromobutanoyl]amino}-2-fluorobenzamide (X), characterized in that (2R)-2 -bromobutanoic acid - N-cyclohexyl-cyclohexanamine (XI) is reacted with 4-amino-2 -fluorobenzamide (IX) in the presence of T; P / pyridinc in a solvent.

9. Process according to Claim 8, characterized in that the reaction is carried out using tetrahydrofuran as solvent.

10. Process according to Claim 8 or 9, characterized in that 1.1 to 2.2 molar equivalents of T3P and 0.1 to 1.0 molar equivalents of pyridine are used and the reaction is performed in a temperature range between minus 10°C and +10°C.

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