Crystalline salt of macropa-(OCH2ch2)-PH-ncs

Abstract

The present disclosure relates to the trifluoroacetic salt of a compound of formula (I), a crystalline form thereof, a process for its preparation and its use.

Description

[0001]BHC243021 FC CRYSTALLINE SALT OF MACROPA-(OCH2CH2)-PH-NCS FIELD The present disclosure relates to the items characterized in the patent claims, i.e. to the trifluoroacetic salt of a compound of formula (I), a crystalline form thereof, a process for its 5 preparation and its use. BACKGROUND 1. Introduction The macrocyclic chelator macropa (6-[[16-[(6-carboxypyridin-2-yl)methyl]-1,4,10,13-tetraoxa- 7,16-diazacyclooctadec-7-yl]methyl]pyridine-2-carboxylic acid) has been investigated due to 10 its radionuclide-binding properties and its potential application in conjugates with small molecules, monoclonal antibodies or other targeting moieties which can be useful for radiotherapy (see, for example: McDevitt et al., Pharmaceuticals 2024, 17(1), 76, https: / / doi.org / 10.3390 / ph17010076 and Mamat et al., Inorg. Chem. 2023, 62(50), 20699, https: / / doi.org / 10.1021 / acs.inorgchem.3c01983). One of the ways of incorporating the 15 chelating moiety into a drug conjugate is by coupling a macropa derivative comprising an isothiocyanate moiety such as macropa-(OCH2CH2)-Ph-NCS of formula (I) with an amino group of the desired targeting moiety via a thiourea group. - 1 - BHC243021 FC 2. Description of the prior art, problem to be solved and its solution WO2020 / 106886 describes the synthesis of macropa-(OCH2CH2)-Ph-NCS of formula (I) comprising a final activation step of macropa-(OCH2CH2)-Ph-NH2 of formula (II) using di-2- pyridyl-thionocarbonate in a mixture of water and acetonitrile in the presence of triethylamine 5 followed by direct purification by chromatography (Scheme 1). Scheme 1 The conversion of macropa-(OCH2CH2)-Ph-NH2 in a mixture of water and acetonitrile – even without the use of a base – is a rapid reaction. However, due to the degradation of macropa- 10 (OCH2CH2)-Ph-NCS under the isothiocyanate-forming reaction conditions, immediate purification of the product is essential. Further, alkaline aqueous conditions accelerate the hydrolysis of the isothiocyanate, but very few alternatives to the use of aqueous solutions are possible in view of the low solubility of macropa-(OCH2CH2)-Ph-NH2 in non-aqueous solvents. 15 The most prominent degradation product is the symmetrical bis-macropa thiourea (Scheme 2) which results from the addition of the initial hydrolysis product macropa-(OCH2CH2)-Ph-NH2 to the remaining macropa-(OCH2CH2)-Ph-NCS. Therefore, direct purification by chromatography, i.e., reversed phase chromatography, is essential. Isolated macropa- (OCH2CH2)-Ph-NCS is obtained as an amorphous material upon lyophilization / freeze drying. - 2 - BHC243021 FC Scheme 2 The isolated amorphous macropa-(OCH2CH2)-Ph-NCS has a poor stability and undergoes a rapid decline in quality upon storage at room temperature. Further, amorphous macropa- 5 (OCH2CH2)-Ph-NCS is still insufficiently stable upon storage at < -18°C. Indeed, the main degradation product, i.e., the symmetrical bis-macropa-thiourea already forms during the freeze-drying (lyophilization) of the chromatography product fractions. Finally, amorphous materials tend to be generally hygroscopic and therefore the risk for degradation is intrinsic. This is especially worrying in the case of macropa-(OCH2CH2)-Ph-NCS, which is particularly 10 sensitive to hydrolysis, thus severely complicating its use in the preparation of conjugates suitable for pharmaceutical application. For an application in antibody conjugation, for example, it is highly desirable and advantageous that such a material be water-soluble in order to avoid the use of organic cosolvents during the conjugation reaction. The use of organic cosolvents in antibody conjugations is a known risk 15 for antibody aggregation and antibody aggregates represent a known immunogenicity risk. In addition, purely aqueous processes have a significantly lower potential of contamination via leachables & extractables. Thus, the synthesis of macropa-(OCH2CH2)-Ph-NCS disclosed in the prior art is therefore not suited and highly disadvantageous for scale-up and therefore for the purposes of producing 20 and supplying the large quantities of material that the manufacturing of a commercial product (e.g., a radionuclide-containing conjugate) requires. The stability issues of amorphous macropa-(OCH2CH2)-Ph-NCS are of particular concern from a logistical perspective, since they would be a limiting factor constraining the reliable preparation and delivery of any macropa-containing drug product across countries and / or continents. - 3 - BHC243021 FC Thus, there is an unmet need to provide macropa-(OCH2CH2)-Ph-NCS which is sufficiently stable over long periods of time such that it allows its reliable use in the development and manufacture of drug products. Further, there is an unmet need to provide processes leading to stable forms of macropa-(OCH2CH2)-Ph-NCS which are suitable for scale-up and which 5 can reliably provide sufficient quantities of the material for the production and delivery of any macropa-containing drug product. In particular, there is an unmet need for a robust and reproducible process that allows for the manufacture of a stable form of macropa-(OCH2CH2)- Ph-NCS in a scale which is suitable to deliver a high-quality material that is sufficiently stable for prolonged storage and to supply the market demands of macropa-containing conjugates 10 such as conjugates with monoclonal antibodies, small molecules or peptidic moieties. The present disclosure solves these issues by providing (i) the trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NCS of formula (I), (ii) a crystalline form of the trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NCS of formula (I) as well as (iii) processes for the preparation of both the trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NCS of formula (I) and of a 15 crystalline form of the trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NCS of formula (I). It has surprisingly been found that the use of trifluoroacetic acid is advantageous in solubilizing macropa-(OCH2CH2)-Ph-NH2, i.e., the most suitable starting material for the preparation of macropa-(OCH2CH2)-Ph-NCS of formula (I) even in solvents which would typically lead to the formation of carbamate byproducts (alcohols) while at the same time providing a salt and 20 particularly a crystalline salt of macropa-(OCH2CH2)-Ph-NCS of formula (I) which can be easily prepared under mild reaction conditions and conveniently isolated in good yields. It has surprisingly been found that the trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NCS of formula (I) and particularly the crystalline form of the trifluoroacetic acid salt of macropa- (OCH2CH2)-Ph-NCS of formula (I) of the present disclosure display a significantly enhanced 25 stability and a remarkable reduction and / or absence of hygroscopicity in comparison to the amorphous lyophilizate of the free base of macropa-(OCH2CH2)-Ph-NCS. In addition, the stable forms of macropa-(OCH2CH2)-Ph-NCS of the present disclosure show an increased solubility in water which is advantageous for conjugation, particularly for antibody and peptide conjugation. 30 Further, the processes for the preparation of the trifluoroacetic acid salt of macropa- (OCH2CH2)-Ph-NCS of formula (I) and of the crystalline form of the trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NCS of formula (I) are suitable for scale-up and deliver the stable forms of macropa-(OCH2CH2)-Ph-NCS of formula (I) in high quantities and good yields. Further, the processes of the present disclosure avoid the use of aqueous conditions in the - 4 - BHC243021 FC preparation of the stable forms of macropa-(OCH2CH2)-Ph-NCS of formula (I), thus reducing the risk of hydrolysis and of the formation of undesired by-products. Despite the low solubility of the starting material macropa-(OCH2CH2)-Ph-NH2 of formula (II) in non-aqueous solvents, the processes of the present disclosure can be carried out avoiding the use of aqueous media 5 and strike the balance between ensuring a sufficient solubility of the starting material and avoiding the formation of undesired by-products due to the reactivity of the isothiocyanate group in macropa-(OCH2CH2)-Ph-NCS. Further, it has surprisingly been found that the trifluoroacetic salt, preferably the tris- trifluoroacetic salt of the starting material macropa-(OCH2CH2)-Ph-NH2 of formula (II) can be 10 isolated in crystalline form in good yields, thus providing a high-purity material which can be then converted directly into the trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NCS of formula (I), preferably the crystalline trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NCS of formula (I). The isolation of the tris-trifluoroacetic salt of the starting material macropa- (OCH2CH2)-Ph-NH2 of formula (II), preferably in crystalline form, is also advantageous 15 because it provides a material which is stable and easy to handle, thus facilitating the logistics around the provision of the trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NCS of formula (I) and especially of the crystalline trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NCS of formula (I). The provision of crystalline macropa-(OCH2CH2)-Ph-NH2 of formula (II), i.e., crystalline 20 material of the free base of macropa-(OCH2CH2)-Ph-NH2 of formula (II), is also surprising and advantageous because it provides a material which is easy to handle and convenient to convert either into the trifluoroacetic salt, preferably the tris-trifluoroacetic salt, more preferably the crystalline tris-trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NH2 of formula (II) or into the trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NCS of formula (I), preferably the 25 crystalline trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NCS of formula (I). - 5 - BHC243021 FC DESCRIPTION The present disclosure relates to the trifluoroacetic acid salt of a compound of formula (I), 5 to a crystalline form of the trifluoroacetic acid salt of a compound of formula (I), to processes for the preparation of the trifluoroacetic acid salt of a compound of formula (I) and for the preparation of a crystalline form of the trifluoroacetic acid salt of a compound of formula (I) and to the use of the trifluoroacetic acid salt of a compound of formula (I) and of a crystalline form of the trifluoroacetic acid salt of a compound of formula (I). Further, the present disclosure10 relates to the trifluoroacetic acid salt of a compound of formula (II), particularly to its tris- trifluoroacetic salt and more particularly to its tris-trifluoroacetic acid salt as a crystalline material, as well as to a process for its preparation and its use in the preparation of a crystalline form of the trifluoroacetic acid salt of a compound of formula (I). Further, the present disclosure relates to the compound of formula (II) in crystalline form, i.e. to crystalline material of macropa-15 (OCH2CH2)-Ph-NH2 of formula (II), and in particular to crystalline forms of macropa- (OCH2CH2)-Ph-NH2 of formula (II). DEFINITIONS In the context of the present disclosure, the compound of formula (I) - 6 - BHC243021 FC may also be referred to as macropa-(OCH2CH2)-Ph-NCS. In the context of the present disclosure, the compound of formula (II) 5 may also be referred to as macropa-(OCH2CH2)-Ph-NH2. In the context of the present disclosure, the term “the trifluoroacetic acid salt of a compound of formula (I)” or “a trifluoroacetic acid salt of a compound of formula (I)” refers to a salt comprising 10 one molar equivalent of the compound of formula (I) and two molar equivalents of trifluoroacetic - 7 - BHC243021 FC acid, i.e., to the bis-trifluoroacetate salt of the compound of formula (I), i.e. to macropa- (OCH2CH2)-Ph-NCS x 2 TFA as depicted below: In the context of the present disclosure, the term “the crystalline trifluoroacetic acid salt of a 5 compound of formula (I)” or “a crystalline trifluoroacetic acid salt of a compound of formula (I)” refers to a crystalline salt comprising one molar equivalent of the compound of formula (I) and two molar equivalents of trifluoroacetic acid, i.e., to the crystalline bis-trifluoroacetate salt of the compound of formula (I), i.e., to crystalline macropa-(OCH2CH2)-Ph-NCS x 2 TFA, i.e. to a (the) crystalline form of macropa-(OCH2CH2)-Ph-NCS x 2 TFA as depicted below: 10 In the context of the present disclosure, the term “the trifluoroacetic acid salt of a compound of formula (II)” or “a trifluoroacetic acid salt of a compound of formula (II)” refers to a salt - 8 - BHC243021 FC comprising one molar equivalent of the compound of formula (II) and more than one, preferably three molar equivalents of trifluoroacetic acid, i.e., to the trifluoroacetate, preferably the tris- trifluoroacetate salt of the compound of formula (II), i.e. to macropa-(OCH2CH2)-Ph-NH2 x 3 TFA as depicted below: 5 In the context of the present disclosure, the term “the crystalline trifluoroacetic acid salt of a compound of formula (II)” or “a crystalline trifluoroacetic acid salt of a compound of formula (II)” refers to a crystalline salt comprising one molar equivalent of the compound of formula (II) and more than one, preferably three molar equivalents of trifluoroacetic acid, i.e., to the 10 crystalline trifluoroacetate, preferably the crystalline tris-trifluoroacetate salt of the compound of formula (II), i.e., to crystalline macropa-(OCH2CH2)-Ph-NH2 x 3 TFA, i.e. to a (the) crystalline form of macropa-(OCH2CH2)-Ph-NH2 x 3 TFA as depicted below: - 9 - BHC243021 FC The term “substituted” means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated 5 atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and / or variables are permissible. The term “optionally substituted” means that the number of substituents can be equal to or different from zero. When groups in the compounds according to the invention are substituted, it is possible for 10 said groups to be mono-substituted or poly-substituted with substituent(s), unless otherwise specified. Within the scope of the present invention, the meanings of all groups which occur repeatedly are independent from one another. It is possible that groups in the compounds according to the invention are substituted with one, two or three identical or different substituents, particularly with one substituent. 15 The term “comprising” when used in the specification includes “consisting of” and “consisting essentially of”. If within the present disclosure any item is referred to as “as mentioned herein”, it means that it may be mentioned anywhere in the present disclosure. In the context of the present disclosure, the term “room temperature” refers to a temperature 20 in the range of from 20 to 25°C, preferably to a temperature of 23°C. The term “C1-C3”, as used in the present disclosure, e.g. in the context of the definition of “C1-C3 alcohol” means an alkyl group having a finite number of carbon atoms of 1 to 3, i.e.1, - 10 - BHC243021 FC 2 or 3 carbon atoms. The term “C1-C3 alcohol” as used within the present disclosure refers to a linear or branched alkyl chain having 1, 2 or 3 carbon atoms where at least one hydrogen atom is replaced with a hydroxy (OH) group. The term “C5-C7 alkane” as used in the present disclosure, refers to a linear or branched alkyl 5 chain having 5, 6 or 7 carbon atoms. The term “C3-C5 alcohol”, as used in the present disclosure, refers to a linear or branched alkyl chain having 3, 4 or 5 carbon atoms where at least one hydrogen atom is replaced with a hydroxy (OH) group. The term “fluorinated C2-C3 alcohol” as used in the present disclosure, refers to an alkyl chain 10 having 2 or 3 carbon atoms where at least one hydrogen atom is replaced with a hydroxy (OH) group and where at least one further hydrogen atom is replaced with a fluorine atom. The term “C2-C5” fluorinated alcohol containing at least three fluorine atoms”, as used in the present disclosure, refers to a linear or branched alkyl chain having 2, 3, 4 or 5 carbon atoms where at least one hydrogen atom is replaced with a hydroxy (OH) group and where at least 15 three further hydrogen atoms are replaced with fluorine atoms. DETAILED DESCRIPTION The present disclosure relates to the trifluoroacetic acid salt of a compound of formula (I), - 11 - BHC243021 FC In one embodiment, the trifluoroacetic acid salt of a compound of formula (I) is in amorphous form. Crystalline form of the trifluoroacetic acid salt of a compound of formula (I) In a further embodiment, the trifluoroacetic acid salt of a compound of formula (I) is crystalline. 5 Thus, in a further embodiment, the present disclosure relates to the trifluoroacetic acid salt of a compound of formula (I) in crystalline form, i.e., to a crystalline form of the trifluoroacetic acid salt of a compound of formula (I), i.e., to a crystalline form of the trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NCS of formula (I). The crystalline form of the trifluoroacetic acid salt of a compound of formula (I) may be 10 characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing solids. Such methods comprise but are not limited to powder X-ray diffraction (PXRD / XRPD), Fourier transform Infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and dynamic vapour sorption (DVS). The crystalline form of the trifluoroacetic acid salt of a compound of formula (I) may be 15 characterized by one of the aforementioned methods or by combining two or more of them. In particular, crystalline form of the trifluoroacetic acid salt of a compound of formula (I) may be characterized by one of the following embodiments or by combining two or more of the following embodiments. The crystalline form of the trifluoroacetic acid salt of a compound of formula (I) is characterized 20 by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (10.1 ± 0.2)°, (20.7 ± 0.2)° and (25.5 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. Preferably, the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) is characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.8 ± 0.2)°, (10.1 ± 0.2)°, (20.2 ± 25 0.2)°, (20.7 ± 0.2)° and (25.5 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. Preferably, the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) is characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.8 ± 0.2)°, (10.1 ± 0.2)°, (17.2 ± 0.2)°, (20.2 ± 0.2)°, (20.7 ± 0.2)°, (21.5 ± 0.2)° and (25.5 ± 0.2)°, when measured at room 30 temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. Preferably, the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) is characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.8 ± 0.2)°, (9.4 ± 0.2)°, (10.1 ± 0.2)°, (11.0 ± 0.2)°, (17.2 ± 0.2)°, (20.2 ± 0.2)°, (20.7 ± 0.2)°, (21.5 ± 0.2)°, (21.9 ± 0.2)° and (25.5 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation 35 having a wavelength of 0.15419 nm. - 12 - BHC243021 FC Alternatively or additionally, the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) is characterized by having a powder X-ray diffractogram essentially the same as displayed in Figure 1 (top or bottom) of the present invention, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. 5 Alternatively or additionally, the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) is characterized by having a Fourier transform Infrared spectrum comprising bands at wavenumbers of (720 ± 2) cm-1, (1114 ± 2) cm-1, and (1170 ± 2) cm-1, when measured at room temperature with a diamond ATR cell. Preferably, the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) is characterized by having a Fourier 10 transform Infrared spectrum comprising peaks at wavenumbers of (720 ± 2) cm-1, (1036 ± 2) cm-1, (1114 ± 2) cm-1, (1170 ± 2) cm-1 and (1345 ± 2) cm-1, when measured at room temperature with a diamond ATR cell. Preferably, the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) is characterized by having a Fourier transform Infrared spectrum comprising bands at wavenumbers of (720 ± 2) cm-1, (835 ± 2) cm-1, (1036 ± 2) cm- 15 1, (1114 ± 2) cm-1, (1170 ± 2) cm-1, (1345 ± 2) cm-1 and (1673 ± 2) cm-1, when measured at room temperature with a diamond ATR cell. Preferably, the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) is characterized by having a Fourier transform Infrared spectrum comprising bands at wavenumbers of (720 ± 2) cm-1, (779 ± 2) cm-1, (835 ± 2) cm- 1, (1036 ± 2) cm-1, (1114 ± 2) cm-1, (1170 ± 2) cm-1, (1345 ± 2) cm-1, (1404 ± 2) cm-1, (1573 20 ± 2) cm-1 and (1673 ± 2) cm-1, when measured at room temperature with a diamond ATR cell. Preferably, the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) is characterized by having a Fourier transform Infrared spectrum comprising bands at wavenumbers of (720 ± 2) cm-1, (779 ± 2) cm-1, (835 ± 2) cm-1, (1036 ± 2) cm-1, (1114 ± 2) cm-1, (1170 ± 2) cm-1, (1345 ± 2) cm-1, (1404 ± 2) cm-1, (1573 ± 2) cm-1, (1673 ± 2) cm-1, 25 (1754 ± 2) cm-1 and (2124 ± 2) cm-1 when measured at room temperature with a diamond ATR cell. Alternatively, the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) is characterized by having a Fourier transform Infrared spectrum essentially the same as displayed in Figure 4 of the present invention, when measured at room temperature with a 30 diamond ATR cell. Process for the preparation of the trifluoroacetic acid salt of a compound of formula (I) The present disclosure also relates to a process for the preparation of the trifluoroacetic acid salt of a compound of formula (I). A compound of formula (II) - 13 - BHC243021 FC (II), i.e., macropa-(OCH2CH2)-Ph-NH2, is a suitable starting material for the preparation of the trifluoroacetic acid salt of a compound of formula (I). Any form of macropa-(OCH2CH2)-Ph- 5 NH2 of formula (II) can be used as a starting material as long as it is suitable for the preparation of the trifluoroacetic acid salt of a compound of formula (I). Macropa-(OCH2CH2)-Ph-NH2 of formula (II) (i.e., the free base of macropa-(OCH2CH2)-Ph-NH2 of formula (II)) can be used in amorphous or crystalline form. If used as a free base for the preparation of the trifluoroacetic acid salt of a compound of formula (I), macropa-(OCH2CH2)-Ph-NH2 of formula (II) is 10 preferably used in crystalline form. Suitable examples of macropa-(OCH2CH2)-Ph-NH2 of formula (II) as a crystalline material are described in the Experimental Section. For the preparation of the trifluoroacetic acid salt of a compound of formula (I), the compound of formula (II) is first converted to the compound of formula (I). This conversion can be carried out in any suitable solvent or solvent mixture. Preferably, the conversion of the compound of 15 formula (II) to the compound of formula (I) is carried out in a solvent or solvent mixture comprising water, acetonitrile, dichloromethane, tetrahydrofurane, 1-methoxy-2-propanol, sulfolane, acetic acid, dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, dimethyl formamide, 1-propanol, 2-propanol, 1-butanol, 2-butanol, hexafluoro-2-propanol and trifluoroethanol or a mixture of two or more thereof. Preferably, the conversion of the compound 20 of formula (II) to the compound of formula (I) is carried out in a solvent mixture comprising an organic solvent and water. When the conversion of the compound of formula (II) to the compound of formula (I) is carried out in a solvent mixture comprising an organic solvent and water, the organic solvent is preferably selected from acetonitrile, tetrahydrofurane, 1- methoxy-2-propanol, sulfolane, acetic acid, dimethylacetamide, dimethyl sulfoxide, N-methyl25 pyrrolidone, dimethyl formamide, 1-propanol, 2-propanol, 1-butanol, 2-butanol, hexafluoro-2- - 14 - BHC243021 FC propanol and trifluoroethanol or a mixture of two or more thereof. More preferably, the conversion of the compound of formula (II) to the compound of formula (I) is carried out in a mixture of water and acetonitrile. The conversion of the compound of formula (II) to the compound of formula (I) is preferably 5 carried out in the absence of water. More preferably, the conversion of the compound of formula (II) to the compound of formula (I) is carried out in a solvent or solvent mixture comprising acetonitrile, dichloromethane, tetrahydrofurane, dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, dimethyl formamide, 1-methoxy-2-propanol, 1-propanol, 2- propanol, 1-butanol, 2-butanol, hexafluoro-2-propanol and trifluoroethanol or a mixture of two 10 or more thereof. More preferably, the conversion of the compound of formula (II) to the compound of formula (I) is carried out in an organic solvent selected from acetonitrile, dichloromethane, tetrahydrofurane, dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, dimethyl formamide, 1-methoxy-2-propanol, 1-propanol, 2-propanol, 1-butanol, 2- butanol, hexafluoro-2-propanol and trifluoroethanol or a mixture of two or more thereof. More 15 preferably, the conversion of the compound of formula (II) to the compound of formula (I) is carried out in an organic solvent selected from dimethylacetamide, dimethyl sulfoxide, N- methyl pyrrolidone, dimethyl formamide, 1-methoxy-2-propanol and hexafluoro-2-propanol or a mixture of two or more thereof. More preferably, the conversion of the compound of formula (II) to the compound of formula (I) is carried out in an organic solvent selected from acetonitrile, 20 2-propanol and hexafluoro-2-propanol or a mixture of two or more thereof. More preferably, the conversion of the compound of formula (II) to the compound of formula (I) is carried out in 2-propanol or in a mixture of 2-propanol and hexafluoro-2-propanol. Depending on the nature of the compound of formula (II) employed, additional reagents (e.g. a base such as an amine base, a tertiary amine base such as triethylamine, 25 diisopropylethylamine and the like or a heterocyclic base such as pyridine) may be necessary for the conversion of the compound of formula (II) to the compound of formula (I). Any isothiocyanate-forming reagent can be used as long as it is suitable for the conversion of the amino group in the compound of formula (II) into the isothiocyanate group in the compound of formula (I). Preferably, the isothiocyanate-forming group is an aryl or heteroaryl 30 thionocarbonate, an aryl or heteroaryl thiocarbonyl compound or thiophosgene. More preferably, the isothiocyanate-forming group is an aryl or heteroaryl thionocarbonate, thiocarbonyldiimidazol (di-1H-imidazol-1-ylmethanethione), bis(1H-1,2,4-triazol-1- yl)methanethione, bis(1H-benzotriazol-1-yl)methanethione or thiophosgene. More preferably, the isothiocyanate-forming group is bis(2-pyridyl)thionocarbonate, thiocarbonyldiimidazol (di-35 1H-imidazol-1-ylmethanethione), bis(1H-1,2,4-triazol-1-yl)methanethione, bis(1H- - 15 - BHC243021 FC benzotriazol-1-yl)methanethione or thiophosgene. More preferably, the isothiocyanate-forming group is bis(2-pyridyl)thionocarbonate (CAS-No.: 96989-50-3). The process can be carried out at any suitable temperature which allows for the conversion of the amine group in the compound of formula (II) to the isothiocyanate group in the compound 5 of formula (I). Preferably, the reaction is carried out at a temperature of from 20°C to 40°C. More preferably the reaction is carried out at room temperature. Once formed, the compound of formula (I) can be converted in situ to its trifluoroacetic acid salt, i.e., the trifluoroacetic acid salt of the compound of formula (I) by the addition of trifluoroacetic acid. Preferably, the trifluoroacetic acid salt of a compound of formula (I) is 10 formed by purification by reversed-phase chromatography with at least one eluent comprising trifluoroacetic acid. In one embodiment, the present disclosure relates to a process for the preparation of the trifluoroacetic acid salt of a compound of formula (I) comprising i. providing a compound of formula (II) in a solvent or solvent mixture comprising water, 15 acetonitrile, dichloromethane, tetrahydrofurane, 1-methoxy-2-propanol, sulfolane, acetic acid, dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, dimethyl formamide, 1-propanol, 2-propanol, 1-butanol, 2-butanol, hexafluoro-2-propanol and trifluoroethanol or a mixture of two or more thereof, ii. reacting the compound of formula (II) with a isothiocyanate-forming reagent to form a 20 compound of formula (I), iii. purifying the compound of formula (I) by reversed-phase chromatography, wherein at least one eluent comprises trifluoroacetic acid, iv. isolating the trifluoroacetic acid salt of a compound of formula (I). Process for the preparation of the crystalline form of the trifluoroacetic acid salt of a 25 compound of formula (I) The present disclosure also relates to a process for the preparation of the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) described supra. The process for the preparation of the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) comprises the reaction of a compound of formula (II) with an 30 isothiocyanate-forming reagent in the presence of trifluoroacetic acid. Any isothiocyanate-forming reagent can be used as long as it is suitable for the conversion of the amino group in the compound of formula (II) into the isothiocyanate group in the compound of formula (I). Preferably, the isothiocyanate-forming group is an aryl or heteroaryl - 16 - BHC243021 FC thionocarbonate, an aryl or heteroaryl thiocarbonyl compound or thiophosgene. More preferably, the isothiocyanate-forming group is an aryl or heteroaryl thionocarbonate, thiocarbonyldiimidazol (di-1H-imidazol-1-ylmethanethione), bis(1H-1,2,4-triazol-1- yl)methanethione, bis(1H-benzotriazol-1-yl)methanethione or thiophosgene. More preferably, 5 the isothiocyanate-forming group is bis(2-pyridyl)thionocarbonate, thiocarbonyldiimidazol (di- 1H-imidazol-1-ylmethanethione), bis(1H-1,2,4-triazol-1-yl)methanethione, bis(1H- benzotriazol-1-yl)methanethione or thiophosgene. More preferably, the isothiocyanate-forming group is bis(2-pyridyl)thionocarbonate (CAS-No.: 96989-50-3). The process for the preparation of the crystalline form of the trifluoroacetic acid salt of a 10 compound of formula (I) is preferably carried out in a solvent or solvent mixture comprising an alcohol, preferably in a solvent or solvent mixture comprising an alcohol having at least 3 carbon atoms to avoid the formation of thiocarbamate byproducts resulting from the reaction with the isothiocyanate group in the compound of formula (I). Preferably the process is carried out in a solvent or solvent mixture comprising a C3-C5 alcohol, i.e., an alcohol having three to 15 five carbon atoms. Preferably the process is carried out in a C2-C5 fluorinated alcohol containing at least three fluorine atoms. Preferably the process is carried out in a solvent mixture comprising a C3-C5 alcohol and a C2-C5 fluorinated alcohol containing at least three fluorine atoms. Preferably, the process for the preparation of the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) is carried out in a solvent or solvent mixture 20 comprising an alcohol selected from 1-methoxy-2-propanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, hexafluoro-2-propanol and trifluoroethanol or a mixture of two or more thereof. More preferably, the process for the preparation of the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) is carried out in 2-propanol or in a mixture of 2-propanol and hexafluoro-2-propanol. More preferably, the process for the preparation of the crystalline form 25 of the trifluoroacetic acid salt of a compound of formula (I) is carried out in a 3:1 (v / v) mixture of 2-propanol and hexafluoro-2-propanol. The process for the preparation of the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) comprises the use of trifluoroacetic acid. Without being bound by theory and depending on the solvent used for the conversion of the compound of formula (II) 30 to the compound of formula (I), the use of trifluoroacetic acid is presumed to increase the solubility of the starting material, i.e., the compound of formula (II) and, at the same time, to stabilize the compound of formula (I) as a trifluoroacetic acid salt. Preferably, the reaction is carried out using 2 to 10 molar equivalents of trifluoroacetic acid, more preferably using 2 to 8 molar equivalents of trifluoroacetic acid, more preferably using 3 to 5 molar equivalents of 35 trifluoroacetic acid. More preferably, the reaction is carried out using 3 molar equivalents of trifluoroacetic acid. - 17 - BHC243021 FC The process can be carried out at any suitable temperature which leads to the formation of the crystalline form of the trifluoroacetic acid salt of a compound of formula (I). Preferably, the reaction is carried out at a temperature of from 20°C to 50°C, more preferably at a temperature of from 25°C to 45°C. 5 The temperature of the reaction may be adjusted depending on the amount of trifluoroacetic acid used. Higher temperatures may be needed when larger amounts of trifluoroacetic acid are used. Preferably, the reaction is carried out using 3 molar equivalents of trifluoroacetic acid at a temperature of from 25°C to 30°C or using 8 molar equivalents of trifluoroacetic acid at a temperature of from 35 to 45°C. More preferably, the reaction is carried out using 3 molar 10 equivalents of trifluoroacetic acid at a temperature of from 25°C to 30°C. More preferably, the reaction is carried out using 8 molar equivalents of trifluoroacetic acid at a temperature of from 35 to 45°C. Preferably, the starting material, i.e., the compound of formula (II) is suspended and / or dissolved in the solvent or solvent mixture in the presence of the corresponding amount of 15 trifluoroacetic acid at a suitable temperature before the isothiocyanate-forming reagent is added. Upon forming, the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) may precipitate from the reaction mixture as a crystalline solid. Optionally, a further solvent or solvent mixture different from that in which the reaction (i.e., the reaction of a compound of 20 formula (II) with an isothiocyanate-forming reagent in the presence of trifluoroacetic acid) has been carried out may be added once the reaction is complete to induce or complete the crystallization of the crystalline form of the trifluoroacetic acid salt of a compound of formula (I). Preferably, precipitation as a crystalline solid of the trifluoroacetic acid salt of a compound of formula (I) ensues and the further solvent or solvent mixture different from that in which the 25 reaction has been carried out is added to complete the crystallization of the crystalline form of the trifluoroacetic acid salt of a compound of formula (I). In one preferred embodiment, the reaction is carried out in a solvent or solvent mixture which does not require the addition of a further solvent or solvent mixture to induce or complete the crystallization of the crystalline form of the trifluoroacetic acid salt of a compound of formula 30 (I). Preferably, the reaction is carried out in 2-propanol without the addition of a further solvent or solvent mixture to induce or complete the crystallization of the crystalline form of the trifluoroacetic acid salt of a compound of formula (I). If a further solvent or solvent mixture different from that in which the reaction has been carried out is added to induce or complete the crystallization of the crystalline form of the trifluoroacetic 35 acid salt of a compound of formula (I), said solvent or solvent mixture preferably comprises a - 18 - BHC243021 FC solvent selected from a C3-C5 alcohol, a C5-C7 alkane and an ether or a mixture of two or more thereof. If a further solvent or solvent mixture different from that in which the reaction has been carried out is added to induce or complete the crystallization of the crystalline form of the trifluoroacetic acid salt of a compound of formula (I), said solvent or solvent mixture preferably 5 comprises a solvent selected from 2-propanol, tetrahydrofurane, 2-methyl tetrahydrofurane, methyl tert-butyl ether (MTBE) or a mixture of two or more thereof. If a further solvent or solvent mixture different from that in which the reaction has been carried out is added to induce or complete the crystallization of the crystalline form of the trifluoroacetic acid salt of a compound of formula (I), said solvent or solvent mixture more preferably comprises 2-propanol or methyl 10 tert-butyl ether. More preferably, the reaction is carried out in a solvent mixture comprising a C2-C5 fluorinated alcohol containing at least three fluorine atoms and a further solvent or solvent mixture different from that in which the reaction has been carried out is added to induce or complete the crystallization of the crystalline form of the trifluoroacetic acid salt of a compound of formula (I). More preferably, the reaction is carried out in a solvent mixture 15 comprising a C3-C5 alcohol and a C2-C5 fluorinated alcohol containing at least three fluorine atoms and methyl tert-butyl ether is added to induce or complete the crystallization of the crystalline form of the trifluoroacetic acid salt of a compound of formula (I). More preferably, the reaction is carried out in a solvent mixture comprising a C2-C5 fluorinated alcohol containing at least three fluorine atoms and a further solvent selected from 2-propanol or 20 methyl tert-butyl ether is added to induce or complete the crystallization of the crystalline form of the trifluoroacetic acid salt of a compound of formula (I). More preferably, the reaction is carried out in a mixture of 2-propanol and hexafluoro-2-propanol and a further solvent is added to induce or complete the crystallization of the crystalline form of the trifluoroacetic acid salt of a compound of formula (I). More preferably, the reaction is carried out in a 3:1 (v / v) mixture of 25 2-propanol and hexafluoro-2-propanol and and methyl tert-butyl ether is added to induce or complete the crystallization of the crystalline form of the trifluoroacetic acid salt of a compound of formula (I). Optionally, the reaction mixture may be seeded with the crystalline trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NCS (i.e., the crystalline trifluoroacetic acid salt of the compound of 30 formula (I)) to induce or complete crystallization of the crystalline form of the trifluoroacetic acid salt of a compound of formula (I). In one embodiment, the present disclosure relates to a process for the preparation of a crystalline form of the trifluoroacetic acid salt of a compound of formula (I) comprising i. providing a compound of formula (II) in a solvent or solvent mixture comprising a C3- 35 C5 alcohol, - 19 - BHC243021 FC ii. adding trifluoroacetic acid, iii. reacting the compound of formula (II) with a isothiocyanate-forming reagent, iv. isolating the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) from the reaction mixture. 5 In a further embodiment, the present disclosure relates to a process for the preparation of a crystalline form of the trifluoroacetic acid salt of a compound of formula (I) characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.8 ± 0.2)°, (9.4 ± 0.2)°, (10.1 ± 0.2)°, (11.0 ± 0.2)°, (17.20 ± 0.2)°, (20.2 ± 0.2)°, (20.7 ± 0.2)°, (21.5 ± 0.2)°, (21.9 ± 0.2)° and (25.5 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 10 radiation having a wavelength of 0.15419 nm, said process comprising i. providing a compound of formula (II) in a solvent or solvent mixture comprising a C3- C5 alcohol, ii. adding trifluoroacetic acid, iii. reacting the compound of formula (II) with a isothiocyanate-forming reagent, 15 iv. isolating the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) from the reaction mixture. In a further embodiment, the present disclosure relates to a process for the preparation of a crystalline form of the trifluoroacetic acid salt of a compound of formula (I) comprising i. providing a compound of formula (II) in an alcohol selected from 1-propanol, 2- 20 propanol, 1-butanol, 2-butanol, hexafluoro-2-propanol and trifluoroethanol or a mixture of two or more thereof, ii. adding 2 to 8 molar equivalents of trifluoroacetic acid, iii. reacting the compound of formula (II) with a isothiocyanate-forming reagent, iv. isolating the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) 25 from the reaction mixture. In a further embodiment, the present disclosure relates to a process for the preparation of a crystalline form of the trifluoroacetic acid salt of a compound of formula (I) characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.8 ± 0.2)°, (9.4 ± 0.2)°, (10.1 ± 0.2)°, (11.0 ± 0.2)°, (17.20 ± 0.2)°, (20.2 ± 0.2)°, (20.7 ± 0.2)°, (21.5 ± 30 0.2)°, (21.9 ± 0.2)° and (25.5 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm, said process comprising - 20 - BHC243021 FC i. providing a compound of formula (II) in an alcohol selected from 1-propanol, 2- propanol, 1-butanol, 2-butanol, hexafluoro-2-propanol and trifluoroethanol or a mixture of two or more thereof, ii. adding 2 to 8 molar equivalents of trifluoroacetic acid, 5 iii. reacting the compound of formula (II) with a isothiocyanate-forming reagent, iv. isolating the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) from the reaction mixture. In a further embodiment, the present disclosure relates to a process for the preparation of a crystalline form of the trifluoroacetic acid salt of a compound of formula (I) comprising10 i. providing a compound of formula (II) in an alcohol selected from 1-propanol, 2- propanol, 1-butanol, 2-butanol, hexafluoro-2-propanol and trifluoroethanol or a mixture of two or more thereof, ii. adding 2 to 8 molar equivalents of trifluoroacetic acid, iii. reacting the compound of formula (II) with a isothiocyanate-forming reagent at a 15 temperature of from 20°C to 50°C, iv. isolating the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) from the reaction mixture. In a further embodiment, the present disclosure relates to a process for the preparation of a crystalline form of the trifluoroacetic acid salt of a compound of formula (I) characterized by 20 having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.8 ± 0.2)°, (9.4 ± 0.2)°, (10.1 ± 0.2)°, (11.0 ± 0.2)°, (17.20 ± 0.2)°, (20.2 ± 0.2)°, (20.7 ± 0.2)°, (21.5 ± 0.2)°, (21.9 ± 0.2)° and (25.5 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm, said process comprising i. providing a compound of formula (II) in an alcohol selected from 1-propanol, 2- 25 propanol, 1-butanol, 2-butanol, hexafluoro-2-propanol and trifluoroethanol or a mixture of two or more thereof, ii. adding 2 to 8 molar equivalents of trifluoroacetic acid, iii. reacting the compound of formula (II) with a isothiocyanate-forming reagent at a temperature of from 20°C to 50°C, 30 iv. isolating the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) from the reaction mixture. - 21 - BHC243021 FC In a further embodiment, the present disclosure relates to a process for the preparation of a crystalline form of the trifluoroacetic acid salt of a compound of formula (I) comprising i. providing a compound of formula (II) in a solvent mixture comprising a C3-C5 alcohol and a C2-C5 fluorinated alcohol containing at least three fluorine atoms, 5 ii. adding 2 to 8 molar equivalents of trifluoroacetic acid, iii. reacting the compound of formula (II) with a isothiocyanate-forming reagent at a temperature of from 20°C to 50°C, iv. isolating the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) from the reaction mixture. 10 In a further embodiment, the present disclosure relates to a process for the preparation of a crystalline form of the trifluoroacetic acid salt of a compound of formula (I) characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.8 ± 0.2)°, (9.4 ± 0.2)°, (10.1 ± 0.2)°, (11.0 ± 0.2)°, (17.20 ± 0.2)°, (20.2 ± 0.2)°, (20.7 ± 0.2)°, (21.5 ± 0.2)°, (21.9 ± 0.2)° and (25.5 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 15 radiation having a wavelength of 0.15419 nm, said process comprising i. providing a compound of formula (II) in a solvent mixture comprising a C3-C5 alcohol and a C2-C5 fluorinated alcohol containing at least three fluorine atoms, ii. adding 2 to 8 molar equivalents of trifluoroacetic acid, iii. reacting the compound of formula (II) with a isothiocyanate-forming reagent at a 20 temperature of from 20°C to 50°C, iv. isolating the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) from the reaction mixture. In a further embodiment, the present disclosure relates to a process for the preparation of a crystalline form of the trifluoroacetic acid salt of a compound of formula (I) comprising 25 i. providing a compound of formula (II) in a solvent mixture comprising a C3-C5 alcohol and a C2-C5 fluorinated alcohol containing at least three fluorine atoms, ii. adding 2 to 8 molar equivalents of trifluoroacetic acid, iii. reacting the compound of formula (II) with a isothiocyanate-forming reagent at a temperature of from 20°C to 50°C, 30 iv. isolating the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) from the reaction mixture, - 22 - BHC243021 FC wherein step (iv) comprises the addition of a further solvent or solvent mixture different from that in which the reaction in step (iii) is carried out, said solvent or solvent mixture preferably comprising a solvent selected from 2-propanol, tetrahydrofurane, 2-methyl tetrahydrofurane, methyl tert-butyl ether (MTBE) or a mixture of two or more thereof, more preferably wherein 5 the further solvent is methyl tert-butyl ether (MTBE). In a further embodiment, the present disclosure relates to a process for the preparation of a crystalline form of the trifluoroacetic acid salt of a compound of formula (I) characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.8 ± 0.2)°, (9.4 ± 0.2)°, (10.1 ± 0.2)°, (11.0 ± 0.2)°, (17.20 ± 0.2)°, (20.2 ± 0.2)°, (20.7 ± 0.2)°, (21.5 ± 10 0.2)°, (21.9 ± 0.2)° and (25.5 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm, said process comprising i. providing a compound of formula (II) in a solvent mixture comprising a C3-C5 alcohol and a C2-C5 fluorinated alcohol containing at least three fluorine atoms, ii. adding 2 to 8 molar equivalents of trifluoroacetic acid, 15 iii. reacting the compound of formula (II) with a isothiocyanate-forming reagent at a temperature of from 20°C to 50°C, iv. isolating the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) from the reaction mixture, wherein step (iv) comprises the addition of a further solvent or solvent mixture different from 20 that in which the reaction in step (iii) is carried out, said solvent or solvent mixture preferably comprising a solvent selected from 2-propanol, tetrahydrofurane, 2-methyl tetrahydrofurane, methyl tert-butyl ether (MTBE) or a mixture of two or more thereof, more preferably wherein the further solvent is methyl tert-butyl ether (MTBE). In a further embodiment, the present disclosure relates to a process for the preparation of a 25 crystalline form of the trifluoroacetic acid salt of a compound of formula (I) comprising i. providing a compound of formula (II) in an alcohol selected from 1-propanol, 2- propanol, 1-butanol, 2-butanol, hexafluoro-2-propanol and trifluoroethanol or a mixture of two or more thereof, ii. adding 3 molar equivalents of trifluoroacetic acid, 30 iii. reacting the compound of formula (II) with a isothiocyanate-forming reagent at a temperature of from 25°C to 30°C, iv. isolating the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) from the reaction mixture. - 23 - BHC243021 FC In a further embodiment, the present disclosure relates to a process for the preparation of a crystalline form of the trifluoroacetic acid salt of a compound of formula (I) characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.8 ± 0.2)°, (9.4 ± 0.2)°, (10.1 ± 0.2)°, (11.0 ± 0.2)°, (17.20 ± 0.2)°, (20.2 ± 0.2)°, (20.7 ± 0.2)°, (21.5 ± 5 0.2)°, (21.9 ± 0.2)° and (25.5 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm, said process comprising i. providing a compound of formula (II) in an alcohol selected from 1-propanol, 2- propanol, 1-butanol, 2-butanol, hexafluoro-2-propanol and trifluoroethanol or a mixture of two or more thereof, 10 ii. adding 3 molar equivalents of trifluoroacetic acid, iii. reacting the compound of formula (II) with a isothiocyanate-forming reagent at a temperature of from 25°C to 30°C, iv. isolating the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) from the reaction mixture. 15 In a further embodiment, the present disclosure relates to a process for the preparation of a crystalline form of the trifluoroacetic acid salt of a compound of formula (I) comprising i. providing a compound of formula (II) in an alcohol selected from 1-propanol, 2- propanol, 1-butanol, 2-butanol, hexafluoro-2-propanol and trifluoroethanol or a mixture of two or more thereof, 20 ii. adding 2 to 8 molar equivalents of trifluoroacetic acid, iii. reacting the compound of formula (II) with a isothiocyanate-forming reagent selected from an aryl or heteroaryl thionocarbonate, thiocarbonyldiimidazol (di-1H-imidazol-1- ylmethanethione), bis(1H-1,2,4-triazol-1-yl)methanethione, bis(1H-benzotriazol-1- yl)methanethione and thiophosgene, preferably wherein the isothiocyanate-forming25 group is selected from bis(2-pyridyl)thionocarbonate, thiocarbonyldiimidazol (di-1H- imidazol-1-ylmethanethione), bis(1H-1,2,4-triazol-1-yl)methanethione, bis(1H- benzotriazol-1-yl)methanethione and thiophosgene at a temperature of from 20°C to 50°C, iv. isolating the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) 30 from the reaction mixture. In a further embodiment, the present disclosure relates to a process for the preparation of a crystalline form of the trifluoroacetic acid salt of a compound of formula (I) characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.8 ± 0.2)°, - 24 - BHC243021 FC (9.4 ± 0.2)°, (10.1 ± 0.2)°, (11.0 ± 0.2)°, (17.20 ± 0.2)°, (20.2 ± 0.2)°, (20.7 ± 0.2)°, (21.5 ± 0.2)°, (21.9 ± 0.2)° and (25.5 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm, said process comprising i. providing a compound of formula (II) in an alcohol selected from 1-propanol, 2- 5 propanol, 1-butanol, 2-butanol, hexafluoro-2-propanol and trifluoroethanol or a mixture of two or more thereof, ii. adding 2 to 8 molar equivalents of trifluoroacetic acid, iii. reacting the compound of formula (II) with a isothiocyanate-forming reagent selected from an aryl or heteroaryl thionocarbonate, thiocarbonyldiimidazol (di-1H-imidazol-1-10 ylmethanethione), bis(1H-1,2,4-triazol-1-yl)methanethione, bis(1H-benzotriazol-1- yl)methanethione and thiophosgene, preferably wherein the isothiocyanate-forming group is selected from bis(2-pyridyl)thionocarbonate, thiocarbonyldiimidazol (di-1H- imidazol-1-ylmethanethione), bis(1H-1,2,4-triazol-1-yl)methanethione, bis(1H- benzotriazol-1-yl)methanethione and thiophosgene at a temperature of from 20°C to 15 50°C, iv. isolating the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) from the reaction mixture. In a further embodiment, the present disclosure relates to a process for the preparation of a crystalline form of the trifluoroacetic acid salt of a compound of formula (I) comprising20 i. providing a compound of formula (II) in a 3:1 (v / v) mixture of 2-propanol and hexafluoro- 2-propanol. ii. adding 2 to 8 molar equivalents of trifluoroacetic acid, iii. reacting the compound of formula (II) with a isothiocyanate-forming reagent at a temperature of from 20°C to 50°C, 25 iv. isolating the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) from the reaction mixture. In a further embodiment, the present disclosure relates to a process for the preparation of a crystalline form of the trifluoroacetic acid salt of a compound of formula (I) characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.8 ± 0.2)°, 30 (9.4 ± 0.2)°, (10.1 ± 0.2)°, (11.0 ± 0.2)°, (17.20 ± 0.2)°, (20.2 ± 0.2)°, (20.7 ± 0.2)°, (21.5 ± 0.2)°, (21.9 ± 0.2)° and (25.5 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm, said process comprising - 25 - BHC243021 FC i. providing a compound of formula (II) in a 3:1 (v / v) mixture of 2-propanol and hexafluoro- 2-propanol. ii. adding 2 to 8 molar equivalents of trifluoroacetic acid, iii. reacting the compound of formula (II) with a isothiocyanate-forming reagent at a 5 temperature of from 20°C to 50°C, iv. isolating the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) from the reaction mixture. It is to be understood that the present invention relates also to any combination of the embodiments described above. 10 The present disclosure covers methods of preparing compounds of the present disclosure, said methods comprising the steps as described in the Experimental Section herein. In a further embodiment, the present disclosure covers the use of a compound of formula (II) for the preparation of a trifluoroacetic acid salt of a compound of formula (I). 15 In a further embodiment, the present disclosure covers the use of a compound of formula (II) for the preparation of a crystalline form of the trifluoroacetic acid salt of a compound of formula (I). In a further embodiment, the present disclosure covers the use of a compound of formula (II) for the preparation of a crystalline form of the trifluoroacetic acid salt of a compound of formula 20 (I) characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.8 ± 0.2)°, (9.4 ± 0.2)°, (10.1 ± 0.2)°, (11.0 ± 0.2)°, (17.20 ± 0.2)°, (20.2 ± 0.2)°, (20.7 ± 0.2)°, (21.5 ± 0.2)°, (21.9 ± 0.2)° and (25.5 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. In a further embodiment, the present disclosure covers the use of the trifluoroacetic acid salt 25 of a compound of formula (I) and / or the use of the the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) for the preparation of a conjugate. In a further embodiment, the present disclosure covers the use of the trifluoroacetic acid salt of a compound of formula (I) and / or the use of the the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) for the preparation of a conjugate of formula (III) - 26 - BHC243021 FC wherein L is an optional linking moiety and T is a targeting moiety. In a further embodiment, the present disclosure covers the use of the trifluoroacetic acid salt 5 of a compound of formula (I) and / or the use of the the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.8 ± 0.2)°, (9.4 ± 0.2)°, (10.1 ± 0.2)°, (11.0 ± 0.2)°, (17.20 ± 0.2)°, (20.2 ± 0.2)°, (20.7 ± 0.2)°, (21.5 ± 0.2)°, (21.9 ± 0.2)° and (25.5 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm 10 for the preparation of a conjugate of formula (III) - 27 - BHC243021 FC wherein L is an optional linking moiety and T is a targeting moiety. In a further embodiment, the present disclosure covers the use of the trifluoroacetic acid salt 5 of a compound of formula (I) and / or the use of the the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.8 ± 0.2)°, (9.4 ± 0.2)°, (10.1 ± 0.2)°, (11.0 ± 0.2)°, (17.20 ± 0.2)°, (20.2 ± 0.2)°, (20.7 ± 0.2)°, (21.5 ± 0.2)°, (21.9 ± 0.2)° and (25.5 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm 10 for the preparation of a conjugate of formula (III) - 28 - BHC243021 FC wherein L is an optional linking moiety and T is a targeting moiety comprising an antibody, an antibody fragment (e.g., an antigen-binding fragment), a binding moiety, a binding peptide, a 5 binding polypeptide (such as a selective targeting oligopeptide containing up to 50 amino acids), a binding protein, an enzyme, a nucleobase-containing moiety (such as an oligonucleotide, DNA or RNA vector, or aptamer), or a lectin. In a further embodiment, the present disclosure covers the use of the trifluoroacetic acid salt of a compound of formula (I) and / or the use of the the crystalline form of the trifluoroacetic acid 10 salt of a compound of formula (I) characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.8 ± 0.2)°, (9.4 ± 0.2)°, (10.1 ± 0.2)°, (11.0 ± 0.2)°, (17.20 ± 0.2)°, (20.2 ± 0.2)°, (20.7 ± 0.2)°, (21.5 ± 0.2)°, (21.9 ± 0.2)° and (25.5 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm for the preparation of a conjugate of formula (III) - 29 - BHC243021 FC wherein L is an optional linking moiety and T is a targeting moiety selected from an antibody, an antibody fragment (e.g., an antigen-binding fragment), a binding moiety, a binding peptide, 5 a binding polypeptide (such as a selective targeting oligopeptide containing up to 50 amino acids), a binding protein, an enzyme, a nucleobase-containing moiety (such as an oligonucleotide, DNA or RNA vector, or aptamer), or a lectin. In a further embodiment, the present disclosure covers the use of the trifluoroacetic acid salt of a compound of formula (I) and / or the use of the the crystalline form of the trifluoroacetic acid 10 salt of a compound of formula (I) characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.8 ± 0.2)°, (9.4 ± 0.2)°, (10.1 ± 0.2)°, (11.0 ± 0.2)°, (17.20 ± 0.2)°, (20.2 ± 0.2)°, (20.7 ± 0.2)°, (21.5 ± 0.2)°, (21.9 ± 0.2)° and (25.5 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm for the preparation of a conjugate of formula (IIIa) - 30 - BHC243021 FC wherein L is an optional linking moiety and T is a targeting moiety selected from an antibody, an antibody fragment (e.g., an antigen-binding fragment), a binding moiety, a binding peptide, 5 a binding polypeptide (such as a selective targeting oligopeptide containing up to 50 amino acids), a binding protein, an enzyme, a nucleobase-containing moiety (such as an oligonucleotide, DNA or RNA vector, or aptamer), or a lectin and [M] is a radiation-emitting radionuclide, preferably an alpha-emitting radionuclide, preferably an alpha-emitting radionuclide selected from actinium-225 (225Ac3+), radium-223, (223Ra2+), bismuth-213 10 (213Bi3+), lead-212 (212Pb2+ and / or 212Pb4+), terbium-149 (149Tb3+), fermium-255 (255Fm3+), thorium-227 (227Th4+), thorium-226 (226Th4+), astatine-211 (211At+), astatine- 217 (217At+), or uranium-230, more preferably 225Ac3+. Trifluoroacetic salt of a compound of formula (II) The present disclosure also relates to a trifluoroacetic salt of a compound of formula (II), 15 preferably to the tris-trifluoroacetic salt of a compound of formula (II), more preferably to the crystalline tris-trifluoroacetic salt of a compound of formula (II). The tris-trifluoroacetic salt of a compound of formula (II) is depicted below: - 31 - BHC243021 FC Thus, the present disclosure also relates to a trifluoroacetic salt of macropa-(OCH2CH2)-Ph- NH2 of formula (II), preferably to the tris-trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2 of formula (II), more preferably to the crystalline tris-trifluoroacetic salt of macropa- 5 (OCH2CH2)-Ph-NH2 of formula (II). The tris-trifluoroacetic salt, preferably the crystalline tris-trifluoroacetic acid salt of macropa- (OCH2CH2)-Ph-NH2 of formula (II) can be prepared by providing macropa-(OCH2CH2)-Ph- NH2 and reacting it with an excess of trifluoroacetic acid in a suitable solvent. Macropa- (OCH2CH2)-Ph-NH2 of formula (II) can be provided as a starting material in any form as long 10 as it is suitable for the preparation of the tris-trifluoroacetic acid salt, preferably the crystalline tris-trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NH2 of formula (II). The free base of macropa-(OCH2CH2)-Ph-NH2 of formula (II) can be provided in amorphous or crystalline form. For the preparation of the tris-trifluoroacetic salt, preferably the crystalline tris-trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NH2 of formula (II), it is preferred that the free base of 15 macropa-(OCH2CH2)-Ph-NH2 of formula (II) is used in amorphous, i.e., non-crystalline form as the starting material. Preferably, more than 3 molar equivalents of trifluoroacetic acid is used; more preferably, 3 to 10 molar equivalents of trifluoroacetic acid is used; more preferably, 5 molar equivalents of trifluoroacetic acid is used. The reaction can be carried out in any suitable solvent; preferably, 20 the solvent is a C1-C3 alcohol or a fluorinated C2-C3 alcohol; more preferably, the solvent is ethanol, 2-propanol, HFIP or trifluoroethanol or a mixture of two or more thereof. The tris- trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2 may precipitate spontaneously from the reaction mixture. Preferably, the tris-trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2 - 32 - BHC243021 FC precipitates spontaneously from the reaction mixture as a crystalline material. If necessary, a further solvent may be added to induce precipitation / crystallization. Preferred solvents are tetrahydrofurane, 2-methyl tetrahydrofurane, and methyl tert-butyl ether (MTBE) or a mixture of two or more thereof. More preferably, the further solvent added to induce the 5 precipitation / crystallization of the tris-trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2 is MTBE. Concurrently or additionally to the addition of a further solvent, seeding material, i.e., a crystalline trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2, preferably the crystalline tris- trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2, may be added to induce crystallization of the crystalline tris-trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2. 10 In a preferred embodiment, the crystalline tris-trifluoroacetic salt of macropa-(OCH2CH2)-Ph- NH2 is prepared by reacting the free base of macropa-(OCH2CH2)-Ph-NH2 with an excess of trifluoroacetic acid ranging of from 3 to 10 equivalents of trifluoroacetic acid, preferably 5 equivalents of trifluoroacetic acid in a C1-C3 alcohol or a C2-C3 fluorinated alcohol or a mixture of two or more thereof optionally followed by the addition of a suitable additional solvent 15 selected from tetrahydrofurane, 2-methyl tetrahydrofurane, and methyl tert-butyl ether (MTBE) or a mixture of two or more thereof and optionally adding seeding material of a crystalline trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2. If used, the preferred additional suitable solvent is MTBE. If used, the preferred seeding material is the crystalline bis-trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2 or the crystalline tris-trifluoroacetic salt of macropa-20 (OCH2CH2)-Ph-NH2. More preferably, the crystalline tris-trifluoroacetic salt of macropa- (OCH2CH2)-Ph-NH2 is used as seeding material. Preferably, an additional suitable solvent and seeding material are added to obtain the crystalline tris-trifluoroacetic salt of macropa- (OCH2CH2)-Ph-NH2. In a preferred embodiment, the present disclosure relates to a process for the preparation of 25 the crystalline tris-trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2, said process comprising: i) providing the free base of macropa-(OCH2CH2)-Ph-NH2, ii) reacting the free base of macropa-(OCH2CH2)-Ph-NH2 with an excess of trifluoroacetic acid in a suitable solvent, 30 wherein the amount of trifluoroacetic acid used is in the range of from 3 to 10 molar equivalents, preferably 5 molar equivalents, and wherein the solvent is selected from a C1-C3 alcohol or a fluorinated C2-C3 alcohol or a mixture of two or more thereof, preferably wherein the solvent is ethanol, 2-propanol, HFIP or trifluoroethanol or a mixture of two or more thereof, - 33 - BHC243021 FC iii) optionally adding a suitable additional solvent selected from tetrahydrofurane, 2- methyl tetrahydrofurane, and MTBE or a mixture of two or more thereof, preferably wherein the optional suitable additional solvent is MTBE, iv) optionally adding a crystalline trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2 5 as seeding material, preferably wherein the seeding material is the crystalline bis- trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2 or the crystalline tris- trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2, more preferably wherein the seeding material is the crystalline tris-trifluoroacetic salt of macropa-(OCH2CH2)- Ph-NH2. 10 The crystalline form of the tris-trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2 of formula (II) may be characterized by analytical methods well known in the field of the pharmaceutical industry for characterizing solids. Such methods comprise but are not limited to powder X-ray diffraction (PXRD / XRPD), Fourier transform Infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and dynamic vapour sorption 15 (DVS). The crystalline form of the tris-trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2 of formula (II) may be characterized by one of the aforementioned methods or by combining two or more of them. In particular, the crystalline form of the tris-trifluoroacetic salt of macropa- (OCH2CH2)-Ph-NH2 of formula (II) may be characterized by one of the following embodiments or by combining two or more of the following embodiments. 20 In one embodiment, the crystalline form of the tris-trifluoroacetic salt of macropa-(OCH2CH2)- Ph-NH2 of formula (II) is characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (20.1 ± 0.2)°, (20.4 ± 0.2)° and (21.6 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. 25 Preferably, the crystalline form of the tris-trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2 of formula (II) is characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (10.0 ± 0.2)°, (19.1 ± 0.2)°, (20.1 ± 0.2)°, (20.4 ± 0.2)° and (21.6 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. Preferably, the crystalline form of the tris-trifluoroacetic salt of macropa- 30 (OCH2CH2)-Ph-NH2 of formula (II) is characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (10.0 ± 0.2)°, (11.6± 0.2)°, (19.1 ± 0.2)°, (19.6 ± 0.2)°, (20.1 ± 0.2)°, (20.4 ± 0.2)° and (21.6 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. Preferably, the crystalline form of the tris-trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2 of formula (II) is characterized by 35 having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (7.1 ± 0.2)°, - 34 - BHC243021 FC (10.0± 0.2)°, (11.6 ± 0.2)°, (13.4 ± 0.2)°, (19.1± 0.2)°, (19.6 ± 0.2)°, (20.1 ± 0.2)°, (20.4 ± 0.2)°, (21.6 ± 0.2)° and (23.6 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. Alternatively or additionally, the crystalline form of the tris-trifluoroacetic salt of macropa- 5 (OCH2CH2)-Ph-NH2 of formula (II) is characterized by having a powder X-ray diffractogram essentially the same as displayed in Figure 10 of the present invention, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. In another embodiment, the crystalline form of the tris-trifluoroacetic salt of macropa- 10 (OCH2CH2)-Ph-NH2 of formula (II) is characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (8.2 ± 0.2)°, (20.6 ± 0.2)° and (21.2 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. Preferably, the crystalline form of the tris-trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2 of formula (II) is characterized by having a powder X-ray diffractogram comprising reflections 15 at 2-Theta angles of (6.5 ± 0.2)°, (8.2 ± 0.2)°, (18.6 ± 0.2)°, (20.6 ± 0.2)° and (21.2 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. Preferably, the crystalline form of the tris-trifluoroacetic salt of macropa- (OCH2CH2)-Ph-NH2 of formula (II) is characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.0 ± 0.2)°, (6.5± 0.2)°, (8.2 ± 0.2)°, (17.0± 0.2)°,20 (18.6 ± 0.2)°, (20.6 ± 0.2)° and (21.2 ± 0.2)°, when measured at room temperature with Cu- Kalpha1 radiation having a wavelength of 0.15419 nm. Preferably, the crystalline form of the tris-trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2 of formula (II) is characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.0 ± 0.2)°, (6.5± 0.2)°, (8.2 ± 0.2)°, (16.5± 0.2)°, (17.0 ± 0.2)°, (18.6 ± 0.2)°, (20.6 ± 0.2)°, (21.2 ± 0.2)°, 25 (22.1 ± 0.2)° and (24.3 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. Alternatively or additionally, the crystalline form of the tris-trifluoroacetic salt of macropa- (OCH2CH2)-Ph-NH2 of formula (II) is characterized by having a powder X-ray diffractogram essentially the same as displayed in Figure 11 of the present invention, when measured at 30 room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. The provision of the tris-trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2 of formula (II), preferably of the crystalline tris-trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2 of formula (II) is advantageous because it allows for the convenient and direct preparation of the 35 trifluoroacetic acid salt of the compound of formula (I) macropa-(OCH2CH2)-Ph-NCS, - 35 - BHC243021 FC preferably of the crystalline trifluoroacetic acid salt of the compound of formula (I) macropa- (OCH2CH2)-Ph-NCS. The isolation of tris-trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2 of formula (II), preferably of the crystalline tris-trifluoroacetic salt of macropa-(OCH2CH2)-Ph- NH2 of formula (II) and its use in the preparation of the trifluoroacetic acid salt of the compound 5 of formula (I) macropa-(OCH2CH2)-Ph-NCS, preferably of the crystalline trifluoroacetic acid salt of the compound of formula (I) macropa-(OCH2CH2)-Ph-NCS allows for a more convenient, reliable and flexible process in the preparation of the trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NCS of formula (I), preferably of the crystalline trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NCS of formula (I), since the starting material can be 10 prepared, stored, handled and used in a predictable and projectable manner, particularly and preferably when the starting material is the crystalline tris-trifluoroacetic salt of macropa- (OCH2CH2)-Ph-NH2 of formula (II) which is used to prepare the crystalline trifluoroacetic acid salt of the compound of formula (I) macropa-(OCH2CH2)-Ph-NCS. The trifluoroacetic acid salt of the compound of formula (I) macropa-(OCH2CH2)-Ph-NCS, 15 preferably the crystalline trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NCS of formula (I) can be prepared from the tris-trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2 of formula (II), preferably from the crystalline tris-trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2 of formula (II) reliably and conveniently by reacting the latter with an isothiocyanate-forming reagent in a suitable solvent. The isothiocyanate-forming reagent, the solvent, the reaction 20 conditions and the isolation are similar to those described for the preparation of the trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NCS of formula (I) and / or of the crystalline trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NCS of formula (I), supra, and may include the optional use of small amounts of seeding material to facilitate the isolation of the crystalline trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NCS of formula (I). If employed, the25 seeding material is preferably the crystalline trifluoroacetic acid salt of macropa-(OCH2CH2)- Ph-NCS of formula (I) which is used in an amount ranging of from 0.5 to 5 mol%, more preferably of from 0.5 to 2 mol%, even more preferably of from 0.5 to 1.5 mol%. Thus, the present disclosure further comprises a process for the preparation of the trifluoroacetic acid salt, preferably the crystalline trifluoroacetic acid salt of a compound of 30 formula (I) comprising i. providing a trifluoroacetic acid salt, preferably a tris-trifluoroacetic acid salt, more preferably a crystalline tris-trifluoroacetic acid salt of the compound of formula (II) in a solvent or solvent mixture comprising water, acetonitrile, dichloromethane, tetrahydrofurane, 1-methoxy-2-propanol, sulfolane, acetic acid, dimethylacetamide, 35 dimethyl sulfoxide, N-methyl pyrrolidone, dimethyl formamide, 1-propanol, 2-propanol, - 36 - BHC243021 FC 1-butanol, 2-butanol, hexafluoro-2-propanol and trifluoroethanol or a mixture of two or more thereof, ii. reacting the trifluoroacetic acid salt, preferably the tris-trifluoroacetic acid salt, more preferably the crystalline tris-trifluoroacetic acid salt of the compound of formula 5 (II) with a isothiocyanate-forming reagent to form the trifluoroacetic acid salt, preferably the crystalline trifluoroacetic acid salt of a compound of formula (I), iii. isolating the trifluoroacetic acid salt, preferably the crystalline trifluoroacetic acid salt of a compound of formula (I), wherein the process does not comprise the use of trifluoroacetic acid. 10 In a preferred embodiment, the process above-described employs the tris-trifluoroacetic acid salt of the compound of formula (II) to prepare the trifluoroacetic acid salt of the compound of formula (I). In a particularly preferred embodiment, the process above-described employs the crystalline tris-trifluoroacetic acid salt of the compound of formula (II) to prepare the crystalline 15 trifluoroacetic acid salt of the compound of formula (I). DESCRIPTION OF THE FIGURES Figure 1 displays the powder X-ray diffractogram (XRD) of two samples of the crystalline form of the trifluoroacetic acid salt of the compound of formula (I) macropa-(OCH2CH2)-Ph-NCS prepared according to Examples 2d (top) and 2a (bottom). 20 Figure 2 displays the DSC (top) and TGA (bottom) curves of a sample of the crystalline form of the trifluoroacetic acid salt of the compound of formula (I) macropa-(OCH2CH2)-Ph-NCS prepared according to Example 2a. Figure 3 displays the DSC (top) and TGA (bottom) curves of a sample of the crystalline form of the trifluoroacetic acid salt of the compound of formula (I) macropa-(OCH2CH2)-Ph-NCS 25 prepared according to Example 2d. Figure 4 displays the infrared spectrum of a sample of the crystalline form of the trifluoroacetic acid salt of the compound of formula (I) macropa-(OCH2CH2)-Ph-NCS prepared according to Example 2a. Figure 5 displays the powder X-ray diffractogram (XRD) of the crystalline form of the 30 trifluoroacetic acid salt of the compound of formula (I) macropa-(OCH2CH2)-Ph-NCS prepared according to Example 2b. - 37 - BHC243021 FC Figure 6 displays the powder X-ray diffractogram (XRD) of the crystalline form of the trifluoroacetic acid salt of the compound of formula (I) macropa-(OCH2CH2)-Ph-NCS prepared according to Example 2c. Figure 7 displays the DSC (top) and TGA (bottom) curves of a sample of the crystalline form 5 of the trifluoroacetic acid salt of the compound of formula (I) macropa-(OCH2CH2)-Ph-NCS prepared according to Example 2c. Figure 8 displays the DSC (top) and TGA (bottom, exo-mode) curves of a sample of the crystalline trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NCS obtained using the crystalline tris-trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NH2 as the starting material (example 10 2k). Figure 9 displays the powder X-ray diffractogram (XRD) of the crystalline bis-trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NH2 of formula (II) prepared according to example 3b (top) and to example 3a (middle: from the isolated material; bottom: from the material in suspension). 15 Figure 10 displays the powder X-ray diffractogram (XRD) of the crystalline tris-trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NH2 of formula (II) prepared according to example 3c. Figure 11 displays the powder X-ray diffractogram (XRD) of the crystalline tris-trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NH2 of formula (II) prepared according to example 3d. Figure 12 displays the DSC (top) and TGA (bottom, exo-mode) curves of the crystalline tris- 20 trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NH2 prepared according to example 3c. Figure 13 displays the powder X-ray diffractogram (XRD) of crystalline macropa-(OCH2CH2)- Ph-NH2 of formula (II) prepared according to example 4a (bottom), 4b (middle) and 4c (top). Figure 14 displays the DSC (top) and TGA (bottom, exo-mode) curves of crystalline macropa- (OCH2CH2)-Ph-NH2 prepared according to example 4b. 25 EXPERIMENTAL SECTION Chemical names were generated using the ACD / Name software from ACD / Labs. In some cases generally accepted names of commercially available reagents were used in place of ACD / Name generated names. The following table 1 lists the abbreviations used in this paragraph and in the Examples section 30 as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person. - 38 - BHC243021 FC Table 1. Abbreviations - 39 - BHC243021 FC Other abbreviations have their meanings customary per se to the skilled person. The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way. The example testing experiments described herein serve to illustrate the present invention and 5 the invention is not limited to the examples given. Experimental section - general part All reagents for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art. 10 macropa-(OCH2CH2)-Ph-NH2 was prepared according to the synthesis described in WO2020 / 106886. The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no 15 purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be removed by trituration using a suitable solvent. In some cases, the compounds may be purified by chromatography. In some cases, the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and / or on-line electrospray ionization 20 mass spectrometer in combination with a suitable prepacked reverse phase column and - 40 - BHC243021 FC eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia. NMR Spectra The multiplicities of proton signals in1H NMR spectra given in the following paragraphs reflect 5 the observed signal form and do not take into account any higher-order signal phenomena. As a rule, the chemical shift data refers to the center of the signal in question. In the case of wide multiplets, a range is specified. Signals hidden by solvent or water were either assigned tentatively or are not listed. Strongly broadened signals - e.g. caused by rapid rotation of molecular moieties or by interchanging protons - have also been assigned tentatively (often 10 referred to as a broad multiplet or broad singlet) or are not shown. The1H-NMR data of selected compounds are listed in the form of1H-NMR peaklists. Therein, for each signal peak the δ value in ppm is given, followed by the signal intensity, reported in round brackets. The δ value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: δ1 (intensity1), δ2 (intensity2), 15 ... , δi (intensityi), ... , δn (intensityn). The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the 20 spectrum, are shown. A1H-NMR peaklist is similar to a classical1H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical1H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of the particular target compound, peaks of impurities,13C satellite peaks, and / or spinning sidebands. The peaks of stereoisomers, and / or peaks of impurities are 25 typically displayed with a lower intensity compared to the peaks of the target compound (e.g., with a purity of >90%). Such stereoisomers and / or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify a reproduction of the manufacturing process on the basis of "by-product fingerprints". An expert who calculates the peaks of the target compound by known methods (MestReC, ACD simulation, or by use of 30 empirically evaluated expectation values), can isolate the peaks of the target compound as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical1H-NMR interpretation. A detailed description of the reporting of NMR data in the form of peaklists can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (cf. http: / / www.researchdisclosure.com / searching-disclosures, 35 Research Disclosure Database Number 605005, 2014, 01 Aug 2014). In the peak picking - 41 - BHC243021 FC routine, as described in the Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be adjusted between 1% and 4%. However, depending on the chemical structure and / or depending on the concentration of the measured compound it may be reasonable to set the parameter "MinimumHeight" <1%. 5 Analytical Methods LC-MS Method 1: System MS: Waters TOF instrument; System UPLC: Waters Acquity I-CLASS; Column: Waters Acquity UPLC HSS T3, 2.1 x 150 mm, 1.8 µm; Eluent A: 1 L Water + 0.100 mL 99% trifluoroacetic acid, Eluent B: 1 L Acetonitrile + 0.100 10 mL 99% trifluoroacetic acid; Gradient: 0.0 min 5% B → 1 min 5% B → 13 min 95% B → 15 min 95% B; Oven: 50°C; Flow: 0.60 mL / min; UV-Detection: 210 nm. HPLC Method 2a: System UPLC: Agilent 1290 Infinity I; Column: Waters Acquity HSS Peptide T3 15 C18; 2.1 x 100 mm, 1.8 µm; Eluent A: 0.1% TFA in water; Eluent B: 0.085% TFA in acetonitrile; Gradient: 0.0 min → 2.0 min 8% B → 12.0 min 50% B → 15.0 min 50% B → 15.1 min 80% B → 18.0 min 80% B → 18.1 min 8% B → 23.0 min 8% B; Oven: 50°C; Flow: 0.8 mL / min; UV-Detection 225 nm. 20 Method 2b: System UPLC: Agilent 1290 Infinity I; Column: Waters Acquity HSS Peptide T3 C18; 2.1 x 100 mm, 1.8 µm; Eluent A: 0.1% TFA in water; Eluent B: 0.085% TFA in acetonitrile; Gradient: 0.0 min → 2.0 min 0% B → 12.0 min 50% B → 15.0 min 50% B → 15.1 min 80% B → 18.0 min 80% B → 18.1 min 0% B → 23.0 min 0% B; Oven: 60°C; Flow: 0.9 mL / min; UV-Detection 225 nm. 25 Method 3a: System HPLC: Agilent 1100; Column: Agilent Zorbax SB-Aq; 3.0 x 150 mm, 3.5 µm; Eluent A: Water; Eluent B: Acetonitrile; Gradient: 0.0 min 5% B → 20.0 min 80% B; Oven: 45°C; Flow: 0.5 mL / min; UV-Detection 210 nm. 30 Method 3b: System HPLC: Agilent 1260 Infinity; Column: Agilent Zorbax SB-Aq; 3.0 x 150 mm, 3.5 µm; Eluent A: Water; Eluent B: Acetonitrile; Gradient: 0.0 min 5% B → 20.0 min 80% B; Oven: 45°C; Flow: 0.5 mL / min; UV-Detection 210 nm. XRD - 42 - BHC243021 FC X-ray powder diffraction (XRPD) data were recorded on a STOE STADI P diffractometer using monochromatized CuK^^-radiation, a position sensitive detector, at generator settings of 40 kV and 40 mA. The samples were collected in transition mode, being prepared as a thin layer between two foils. The scanning range was between 2 ° and 40 ° 2 theta with a 0.5° step at 15 5 sec / step. DSC 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. 3 – 10 mg of each sample was placed into an aluminum crucible and heated at a rate of 20 °C.min -1 from -10 °C 10 to either 230°C, or to 20 - 30 K above the highest melting point or to the beginning of decomposition. TGA Thermogravimetric analysis (TGA) was performed with a Mettler Toledo TGA / DSC 3+. The instrument was purged with nitrogen gas at a flow rate of 50 ml.min-1. Approximately 5 – 8 mg 15 of each sample was placed into an aluminum crucible with piercing lid and heated at a heating rate of 10 °C.min -1 from 25 °C to 20 - 30 K above the highest melting point or to the beginning of decomposition. IR IR measurements were performed with a Bruker alpha spectrometer in the attenuated total 20 reflectance (ATR) geometry. No sample preparation was performed, and each individual measurement consisted of 32 scans. DVS Water sorption isotherms were determined using a Hiden IGAsorp gravimetric sorption analyzer.10 – 20 mg of sample was equilibrated at 0 % RH / 25°C and the weight recorded. 25 The isotherm was then recorded by changing the humidity in steps of 10 % and 5 %. The equilibrium criterion was set to a relative mass change of dm / dt = 0.0005 mg / min. Synthesis of the Examples Example 1: Preparation of the amorphous trifluoroacetic salt of macropa-(OCH2CH2)- Ph-NCS (trifluoroacetic acid salt of the compound of formula (I) - 43 - BHC243021 FC 3.00 g (4.49 mmol) macropa-(OCH2CH2)-Ph-NH2 was suspended in 24 mL acetonitrile. After addition of 7.2 ml water a turbid solution formed. After addition of 1.15 g (4.94 mmol) di-2- pyridyl thionocarbonate (O,O-dipyridin-2-yl carbonothioate) at room temperature a clear 5 solution formed. HPLC control (method 3a) confirmed complete conversion after 10 min.90 mL water was added and the reaction mixture was purified by reversed phase chromatography at 400 g Kromasil C18-100-16 with stepwise change of the eluent composition: 400 mL fractions – eluent A: water + 0.1 % TFA; eluent B: acetonitrile (Table 2) Table 2 - 44 - BHC243021 FC Product containing fractions (5b1, 6 and 7) were combined and immediately freeze-dried. 4.0 g (95 % of theory) of lyophilisate was isolated. 5 5 batches were produced at 3 g-scale and with one re-purification batch of mixed fractions combined by dissolution in water and freeze-drying to obtain a homogenized batch of 19.10 g product (91 % of theoretical value) as a nearly white lyophilisate. Purity by HPLC, method 2a: 99.2 area-%; Rt: 10.02 min Assay free macropa-(OCH2CH2)-Ph-NCS: 69.1 wt.-% 10 TFA by ion-chromatography: 28.10 wt.-% (theoretical value: 24.3 wt.-%) Stability study (Table 3) Table 3 1 Fraction 5 was split into 2 sub-fractions a and b to separate from impurities.. - 45 - BHC243021 FC Example 2: Preparation of the crystalline trifluoroacetic salt of macropa-(OCH2CH2)- Ph-NCS (crystalline trifluoroacetic acid salt of the compound of formula (I) Example 2a 80.0 g (0.12 mol) of macropa-(OCH2CH2)-Ph-NH2 was suspended in 0.80 L 2-propanol 5 and 73.8 mL trifluoroacetic acid (0.96 mol) was added. The mixture was warmed to 40°C to give a solution after 10 min.36.2 g (0.16 mol) di-2-pyridyl thionocarbonate was added to the mixture and stirring was continued overnight. The resulting suspension was cooled to room temperature and diluted with 0.80 mL methyl-tert-butyl ether (MTBE). The product was isolated by filtration. The filter cake was rinsed 4 times with 80 mL MTBE / 2- 10 propanol (1:1 v / v), each. After drying in vacuum at 30°C 92.5 g (82 % of theoretical yield) was obtained as a white to off-white solid. Purity by HPLC, method 2a: 96.7 area-%; Rt: 9.33 min Impurity at RRT: 0.972, method 2a: 0.59 area-%; Rt: 9.10 min 15 Assay “free macropa-(OCH2CH2)-Ph-NCS”: 73.8 wt.-% TFA by ion-chromatography: 21.8 wt.-% (theoretical value: 24.3 wt.-%) -- measured at re- release. 201H-NMR (D2O; 500 MHz) δ [ppm] = 3.13 (m, 2H), 3.58 (m, 4H), 3.63 (m, 12 H), 3.89 (m, 8H), 4.47 (m, 2H), 4.63 (s, 2H), 4.74 (s, *), 7.18 (m, 2H)**, 7.23 (m, 1H), 7.33 (m, 2H), 7.47 (m, 1H), 7.71 (m, 1H), 7.98 (m, 1H), 8.08 (m, 1H). * Significant overlap with the signal resulting from measurement in deuterium-oxide. 2 Identified later as macropa-(OCH2CH2)-phenyl -2-propyl-thiocarbamate. - 46 - BHC243021 FC ** A shift of this 2H-signal of the phenylene-moiety is observed between batches. The assumed root-cause is a different protonation status of the NCS-group under TFA-acidic conditions in D2O. XRPD (2Theta): 6.8°, 9.4°, 10.1°, 11.0°, 17.2°, 20.2°, 20.7°, 21.5°, 21.9°, 25.5°, Figure 1 5 (top). DSC / TGA: Figure 2 IR: Figure 4 DVS analysis confirmed the stability of the sample product (crystalline trifluoroacetic salt of macropa-(OCH2CH2)-Ph-NCS, i.e., the crystalline trifluoroacetic acid salt of the compound of 10 formula (I)). LC-HRMS (method 1): Rt = 5.70 min (98 %); MS (ESIpos): m / z = 710.2883 (M+H)+. Stability study (Table 4) Table 4 15 Example 2b Following the crystallization process of Example 2a from 5.0 g macropa-(OCH2CH2)-Ph-NH2 6.5 g (93 % of theoretical yield) of the crystalline trifluoroacetic acid salt of a compound of formula (I) was obtained. XRPD analysis confirmed the same crystalline form as in Example 2a. 20 Purity by HPLC, method 2a: 96.9 area-%; Rt: 9.42 min Impurity at RRT: 0.973, method 2a: 0.57 area-%; Rt: 9.18 min Assay “free macropa-(OCH2CH2)-Ph-NCS”: 71.7 wt.-% TFA by ion-chromatography: 22.3 wt.-% 3 Identified later as macropa-(OCH2CH2)-phenyl -2-propyl-thiocarbamate. - 47 - BHC243021 FC The1NMR showed the 2H-signal of the phenylene-moiety located at 7.24 ppm. 1H-NMR (D2O; 500 MHz) δ [ppm] = 3.15 (t, 2H), 3.54 (m, 4H), 3.61 (m, 12 H), 3.87 (m, 8H), 4.50 (t, 2H*), 4.60 (s, 2H*), 4.72 (s, 2H*), 7.22 (m, 1H), 7.24 (m, 2H), 7.36 (m, 2H), 7.51 (m, 1H), 7.70 (m, 1H), 8.01 (m, 1H), 8.07 (m, 1H). 5 Example 2c The process outlined above (Example 2a, Example 2b) was repeated in a GMP-laboratory in a larger scale. A glass-reactor was charged with 137.2 g (92.7 mL; 1.20 mol) trifluoroacetic acid and 788 g (1.0 L) 2-propanol and 100 g (0.15 mol) macropa-(OCH2CH2)-Ph-NH2 was added. The10 suspension was heated to 38°C and an almost clear solution formed.44.8 g (0.19 mol) di-2- pyridyl thionocarbonate was added and stirred at 38°C overnight (22:30 h). The reaction mixture was cooled to 22°C and diluted with 740 g (1.0 L) MTBE. After 12 min at 19°C the product was isolated by filtration. The filter cake was rinsed 4 times with MTBE / 2-propanol (1:1 v / v) approx.100 mL each and dried in vacuum at 30°C. 15 123 g (88 % of theoretical yield) of the crystalline product was obtained as a light-yellow solid. XRPD analysis confirmed the same crystalline form as in Example 2a. Purity by HPLC, method 2a: 94.7 area-%, Rt: 9.46 min Impurity at RRT: 0.974, method 2a: 2.50 area-%; Rt: 9.20 min 20 Assay “free macropa-(OCH2CH2)-Ph-NCS”: 69.7 wt.-% TFA by ion-chromatography: 23.7 wt.-% (theoretical value: 24.3 wt.-%). Main impurity*: 2.5 area-%, RT = 9.20 min 4 Identified as macropa-(OCH2CH2)-phenyl -2-propyl-thiocarbamate. - 48 - BHC243021 FC XRPD and DSC / TGA analysis confirmed the crystalline form of the product (i.e., the crystalline trifluoroacetic acid salt of the compound of formula (I)). LC-HRMS (method 1): Rt = 5.80 min (89 %); MS (ESIpos): m / z = 710.2866 (M+H)+. 5 Example 2d To a mixture of 752 mL (590 g) 2-propanol and 253 mL (403 g) hexafluoro-2-propanol (HFIP) was added 51.2 g (34.6 mL, 0.45 mol) trifluoroacetic acid and 100 g (0.15 mol) macropa- (OCH2CH2)-Ph-NH2. The mixture was stirred at 23°C and an almost clear solution was formed.52.2 g (0.22 mol) di-2-pyridyl thionocarbonate was added, followed by addition of 0.7 g 10 (0.7 mmol) seed crystals of crystalline macropa-(OCH2CH2)-Ph-NCS bis TFA salt. The reaction mixture was stirred at 23°C for 6:20 h. 1.11 kg (1.5 L) MTBE was added, and the suspension was stirred at 20°C overnight, i.e.17:30 h. The product was isolated by filtration. The filter cake was rinsed three times with MTBE / 2-propanol (3:2 v / v) approx.125 mL each and once with 93 g (125 mL) MTBE. The product was dried in vacuum at 30°C.133 g (95 % 15 of theoretical value) of crystalline, white product was obtained. Purity by HPLC, method 2b 98.8 area-%; Rt: 9.36 min Impurity at RRT: 0.985, method 2b: 0.14 area-%; Rt: 9.16 min Assay “free macropa-(OCH2CH2)-Ph-NCS”: 74.2 wt.-% 5 Identified as macropa-(OCH2CH2)-phenyl -2-propyl-thiocarbamate. - 49 - BHC243021 FC TFA by ion-chromatography: 23.3 wt.-% (theoretical value: 24.3 wt.-%). DSC-TGA: Figure 3 1H-NMR (D2O; 500 MHz) δ [ppm] = 3.11 (m, 2H), 3.58 (m, 4H), 3.63 (m, 12 H), 3.90 (m, 5 8H), 4.45 (m), 4.64 (s), 4.75 (s), 7.14 (m, 2H), 7.23 (m, 1H), 7.31 (m, 2H), 7.45 (m, 1H), 7.72 (m, 1H), 7.98 (m, 1H), 8.06 (m, 1H). Example 2e A series of experiments with varying equivalents of the activation reagent were performed: 50 mg (0.075 mmol) macropa-(OCH2CH2)-Ph-NH2 was suspended in 0.5 mL 2-propanol and 10 46 µL (0.6 mmol) trifluoroacetic acid was added. The mixture was warmed to 40°C and a clear solution formed after 10 min. The corresponding amount of di-2-pyridyl thionocarbonate was added (s. table) followed by seeding with a small amount of crystalline macropa-(OCH2CH2)- Ph-NCS bis TFA salt. The mixture was stirred at 40°C overnight and the results are summarized in Table 5. 15 Table 5 HPLC method: 3a - 50 - BHC243021 FC Example 2f – Effect of different amounts of trifluoroacetic acid: 50 mg (0.075 mmol) macropa-(OCH2CH2)-Ph-NH2 was suspended in 0.5 mL 2-propanol and various amounts of trifluoroacetic acid were added (see table below). The mixtures were stirred at room temperature and after 30 min gave clear solutions. 35 mg (0.15 mmol) di-2-pyridyl 5 thionocarbonate was added followed by seeding with a small amount of crystalline macropa- (OCH2CH2)-Ph-NCS bis TFA salt. The reaction mixtures were stirred at room temperature overnight (20h). The results of the in-process controls by HPLC are summarized in Table 6. Table 6 The byproduct at Rt: 13.5 / 13.6 min was identified as a mixture of the two regioisomeric mono- 10 2-propyl-esters of product macropa-(OCH2CH2)-Ph-NCS. HPLC method: 3a - 51 - BHC243021 FC Example 2g – Effect of different solvents for the preparation of the crystalline trifluoroacetic salt of a compound of formula (I): 50 mg scale; 0.5 mL solvent, room temperature; 3 eq. TFA; 1.5 eq thionocarbonate reagent 50 mg (0.075 mmol) macropa-(OCH2CH2)-Ph-NH2 was suspended each in 0.5 mL various 5 solvents (see table below) and 17 µL (0.23 mmol) trifluoroacetic acid was added to each reaction mixture. The mixtures were stirred at room temperature and after 1 h gave clear solutions except for 2-methyl-1-propanol where a small quantity of undissolved material remained.26 mg (0.11 mmol) di-2-pyridyl thionocarbonate was added to each reaction mixture which were all clear solutions followed by seeding with a small amount of crystalline macropa- 10 (OCH2CH2)-Ph-NCS bis TFA salt which did not dissolve. The reaction mixtures were stirred at room temperature overnight (20h) and precipitation occured. The results of the in-process controls by HPLC are summarized in Table 7. Table 7 - 52 - BHC243021 FC HPLC method: 3a 0.5 mL MTBE was added to each of the reaction mixtures and stirring was continued at room temperature for 1 h. The product was isolated by filtration. The filter cake was rinsed two times with 0.25 mL of 2-propanol / MTBE (1:1 v / v) each. After drying in vacuum at 30°C the product 5 was obtained in the yields and HPLC-purities depicted in Table 8. Table 8 HPLC-controls: Method 3a. Example 2h – Solvent effects in the (attempted) preparation of the crystalline trifluoroacetic salt of a compound of formula (I) 10 1. Methanol To 50 mg (0.075 mmol) macropa-(OCH2CH2)-Ph-NH2 was added 0.5 mL methanol and 46 µL (0.6 mmol) trifluoroacetic acid. The mixture was warmed to 40°C and a clear solution formed. 23 mg (0.10 mmol) di-2-pyridyl thionocarbonate was added and a small amount of seeds of crystalline macropa-(OCH2CH2)-Ph-NCS bis TFA salt was added. The seeds 15 dissolved. The reaction mixture was stirred overnight (20h) at 40°C and remained a clear solution. HPLC control (method: 3a) revealed a complex mixture with 40.6 area-% product, 5.6 area-% bis-macropa-thiourea and an unknown impurity with 29.9 area-%. The latter was - 53 - BHC243021 FC identified subsequently as the corresponding methanol-adduct, i.e. the macropa-(OCH2CH2)- phenyl-methyl-thiocarbamate. 2. Ethanol To 50 mg (0.075 mmol) macropa-(OCH2CH2)-Ph-NH2 was added 0.5 mL ethanol and 46 µL 5 (0.6 mmol) trifluoroacetic acid. The mixture was warmed to 40°C and a clear solution formed. 23 mg (0.10 mmol) di-2-pyridyl thionocarbonate was added and a small amount of seeds of crystalline macropa-(OCH2CH2)-Ph-NCS bis TFA salt was added. The seeds dissolved. The reaction mixture was stirred overnight (20h) at 40°C and remained a clear solution. HPLC control (method 3a) revealed a complex mixture with 56.7 area-% product, 0.9 area-% bis- 10 macropa-thiourea and an unknown impurity with 17.3 area-%. The latter was identified subsequently as the corresponding ethanol-adduct, i.e. the macropa-(OCH2CH2)-phenyl- ethyl-thiocarbamate. 3. Dimethylacetamide 20 mg (0.02 mmol) macropa-(OCH2CH2)-Ph-NH2 tris trifluoroacetate was dissolved in 0.16 15 mL DMA.4.6 mg (0.02 mmol) di-2-pyridyl thionocarbonate was added and the reaction solution was stirred at room temperature overnight. HPLC controls (method 3a) after 10 min, 30 min and overnight reaction time revealed incomplete conversion with approximately 54 – 57 area-% of product and a significant amount of symmetrical bis-macropa-thiourea byproduct formed besides other impurities. 20 4. Mixtures of 2-propanol and dimethylacetamide (DMA) 50 mg (0.075 mmol) macropa-(OCH2CH2)-Ph-NH2 was dissolved in 0.5 mL of the following solvent mixtures: 0.45 mL 2-propanol and 0.05 mL DMA (sample a, Example 2h-1) 0.40 mL 2-propanol and 0.10 mL DMA (sample b, Example 2h-2) 25 0.35 mL 2-propanol and 0.15 mL DMA (sample c, Example 2h-3) To each solution 17 µL (0.225 mmol) trifluoroacetic acid was added. After stirring for 30 min at room temperature 26 mg (0.112 mmol) di-2-pyridyl thionocarbonate, each, was added to the clear solutions, directly followed by seeding with a small amount of crystalline macropa- (OCH2CH2)-Ph-NCS bis TFA salt. The seeds did not dissolve. The reaction mixtures were 30 stirred overnight at room temperature. 0.5 mL MTBE was added to each suspension and stirring was continued for 1 h at room temperature. The product was isolated by filtration, two rinses with 0.25 mL of 2- propanol / MTBE (1:1 v / v), each and drying in vacuum at 30°C. - 54 - BHC243021 FC Slightly beige coloured products were obtained (Table 9). Table 9 HPLC-method: 2b 5. Hexafluoro-2-propanol 5 200 mg (0.30 mmol) macropa-(OCH2CH2)-Ph-NH2 was dissolved in 2.0 mL HFIP.76.5 mg (0.33 mmol) di-2-pyridyl thionocarbonate was added and the reaction mixture was stirred at room temperature. The HPLC control after 2:30 h showed 87 area-% of product. 5 mL 2- propanol and 185 µL (2.40 mmol) trifluoroacetic acid were added and the mixture was concentrated at 40°C and 60 mbar to a volume of approximately 2 mL.5 mL 2-propanol was 10 added and the volume reduced to 2 mL a second time. The solution was cooled to 0-5°C and seed crystals of the product were added. After stirring for 2 h at this temperature a thin suspension had formed. Additional 92 µL (1.2 mmol) trifluoroacetic acid was added and the mixture was stored at 2 – 8°C overnight. The precipitate was isolated by filtration and the filter- cake was rinsed twice with 0.5 mL 2-propanol each. After drying in vacuum at 30°C 175 mg 15 (62 % of theory) of crystalline product macropa-(OCH2CH2)-Ph-NCS bis TFA salt was obtained. The XRPD confirmed the same polymorphic form as described above. 6. THF To 20 mg (0.03 mmol) macropa-(OCH2CH2)-Ph-NH2 was added 0.20 mL THF and 18.5 µL (0.24 mmol) trifluoroacetic acid. After sonication for 10 min a solution formed.7.7 mg (0.033 20 mmol) di-2-pyridyl thionocarbonate was added and the reaction mixture was stirred at room temperature overnight. The HPLC control (method 3a) showed 86 area-% of product, 0.4 area- % of starting material and 3.2 area-% of bis-macropa-thiourea (HPLC method 3a). By addition of 0.2 mL MTBE the product was precipitated. However, due to the sticky resinous consistency isolation was not pursued. - 55 - BHC243021 FC Example 2i – Conversion of the amorphous trifluoroacetic salt of a compound of formula (I) (i.e., amorphous macropa-(OCH2CH2)-Ph-NCS) to the crystalline trifluoroacetic salt of a compound of formula (I) (i.e, amorphous macropa-(OCH2CH2)-Ph-NCS) by intermediary dissolution by addition of triethylamine 5 500 mg (0.53 mmol) macropa-(OCH2CH2)-Ph-NCS bis TFA (lyophilisate) was suspended in 5.0 mL 2-propanol and turned into a sticky consistency. The mixture was heated to 50°C and an oily residue was observed. Upon addition of 0.30 mL (2.13 mmol) triethylamine and stirring for 2 h at 40°C a solution formed.0.16 mL (2.13 mmol) trifluoroacetic acid was added and the mixture was cooled to 0°C within 2 h and precipitation occurred. After filtration, two rinses with 10 0.5 mL 2-propanol each and drying in vacuum at 30°C 427 mg (85 % of theory) of a crystalline white solid was obtained. The XRPD was in agreement with the polymorphic form described above. HPLC (method 3a): 97.1 area-%. Example 2j – Alternative Acids The following table summarizes a series of experiments using alternative acids to 15 trifluoroacetic acid. The generic procedure was: The starting material macropa-(OCH2CH2)-Ph-NH2 was suspended in the solvent and the corresponding acid was added. The mixture was stirred at the given temperature and the activation reagent di-2-pyridyl thionocarbonate was added. The reaction-mixture was stirred at the same temperature overnight. An in-process control by HPLC was performed and the 20 appearance of the reaction mixture was controlled (Table 10). - 56 - BHC243021 FC - 57 - BHC243021 FC - 58 - BHC243021 FC - 59 - BHC243021 FC Sol: solution, i.e., no (solid) precipitate P: product, area-% HPLC in-process control (method 3a) P1: product, area-% HPLC in-process control (method 2b) SM: starting material, area-% in-process control (method 3a) 5 BPs: significant amounts of byproducts X: Consistence not suitable for isolation (sticky, resinous, oily) - 60 - BHC243021 FC Y: suspension; work-up: addition of 0.5 mL MTBE, filtration, 2 rinses with 0.05 mL MTBE / 2-propanol (1:1, v / v): non-crystalline solid, 94.0 area-% product; 1.4 area-% starting material Z: addition of 2.0 mL MTBE and seeding led to “oiling out”. 5 * main component: formamide of the starting material. ** by LC-MS method 1. Example 2k: Preparation of the crystalline trifluoroacetic salt of macropa-(OCH2CH2)-Ph- NCS (crystalline trifluoroacetic acid salt of the compound of formula (I)) with utilization of the trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NH2. 10 To a mixture of 5 mL of 2-propanol and 1.7 mL hexafluoro-2-propanol (HFIP) was added 1.0 g (0.99 mmol) of the crystalline tris-trifluoroacetic acid salt of macropa-(OCH2CH2)-Ph-NH2 (example 3c) and stirred for 30 min at room temperature. For complete dissolution 0.3 mL hexafluoro-2-propanol was added. 345 mg (1.49 mmol) di-2-pyridyl thionocarbonate was added at room temperature, followed by addition of 10 mg (10.7 µmol) of macropa- 15 (OCH2CH2)-Ph-NCS crystalline seed-material. The reaction mixture was stirred for 6h at room temperature.10 mL of MTBE was slowly added, and the suspension was stirred at room temperature over-night. The product was isolated by filtration and the filter-cake was rinsed three times with 2 ml 2-propanol / methyl-tert-butyl ether (MTBE) (1:1.5 v / v), each. After drying in vacuum over-night at 30°C 900 mg (97 % of theoretical yield) was isolated as slightly beige 20 solid. Purity by HPLC, method 2a: 100 area-%; Rt: 9.59 min TFA by ion-chromatography: 24.9 wt.-% (theoretical value: 24.3 wt.-%). XRPD analysis confirmed the same crystalline form as in Example 2a. DSC* / TGA: Figure 8 (*exo-mode) 25 0.28 wt.-% of MTBE and 0.40 wt.-% 2-propanol were found as residual solvents. Example 3: Preparation of the crystalline trifluoroacetic salt of Macropa-(OCH2CH2)- Ph-NH2 tris TFA Salt - 61 - BHC243021 FC 100 mg (0.15 mmol) Macropa-(OCH2CH2)-Ph-NH2 was suspended in 1 mL ethanol. Upon 5 addition of 58 µL (0.75 mmol) trifluoroacetic acid a clear solution formed during stirring at room temperature. After overnight stirring 1 mL 2-propanol was added. No precipitation occurred. Upon addition of 1 mL MTBE the solution turned turbid. After stirring overnight, the suspension* contained a crystalline solid. After filtration and rinsing the filter cake with ethanol / MTBE (1:1 v / v) the solid was dried in vacuum overnight at 30°C to give 70 mg of a salt which by ion 10 chromatography (IC) showed a TFA content of 22.8 wt.-% (calculated value for a bis-TFA salt: 25.5 wt.-%) *This suspension was used to seed the subsequent experiment. XRPD (2Theta): see Figure 9 bottom (from suspension), Figure 9 middle (isolated). TFA by ion-chromatography: 22.8 wt.-% (theoretical value for bis-TFA salt: 25.5 wt.-%). 15 To 500 mg (0.75 mmol) Macropa-(OCH2CH2)-Ph-NH2 was added 5 mL ethanol. At room temperature 288 µL (3.74 mmol) trifluoroacetic acid was added. After stirring the clear solution overnight 2.5 mL MTBE was added, and the solution remained clear. To this solution 100 µL of the suspension from the preceding experiment was added and the thin suspension was 20 stirred at room temperature over 3 days. Slowly, additional 4 mL MTBE were added and stirred overnight. The suspension thickened significantly, was filtered and the filter cake rinsed with 1 mL of ethanol / MTBE (1:3 v / v). The obtained precipitate was dried in vacuum overnight at 30°C to give 460 mg of solid product. By IC a content of 24.4 wt.-% of TFA was found. - 62 - BHC243021 FC XRPD (2Theta): see Figure 9 top. TFA by ion-chromatography: 24.4 wt.-% (theoretical value for bis-TFA salt: 25.5 wt.-%). Example 3c - Seeding with isolated crystalline TFA salt: 50 ml Ethanol was added to 5.0 g (7.49 mmol) macropa-(OCH2CH2)-Ph-NH2. Upon addition 5 of 2.88 mL (37.4 mmol) trifluoroacetic acid a clear solution formed. This solution was stirred at room temperature over-night.50 mL MTBE was added and the resulting solution was seeded with 20 mg product of the preceding experiment. After stirring at room temperature for 2 h additional 20 mL MTBE was added followed by additional 5 mL after 2 h. The suspension became thicker. Addition of further 3 mL MTBE led to a slight oiling out but the precipitation 10 remained. Stirring overnight further thickened the suspension. Additional 20 mL MTBE was added over 30 min and stirred for 2 h. The precipitate was isolated by filtration and rinsing of the filter-cake with ethanol / MTBE (1:3 v / v). The product was dried in vacuum for 3 days at 30°C.6.2 g (82 % of theoretical yield) of a slightly beige solid was obtained. Purity by HPLC, method 2a: 100 area-%; Rt: 5.56 min 15 TFA by ion-chromatography: 36.5 wt.-% (theoretical value for tris-TFA salt: 33.9 wt.-%). XRPD (2Theta): 7.1°, 10.0°, 11.6°, 13.4°, 19.1°, 19.6°, 20.1°, 20.4°, 21.6°, 23.6°, Figure 10. DSC* / TGA: Figure 12 (*exo-mode) 0.1 wt.-% of MTBE was found as residual solvent. Example 3d - Crystallization from 2-propanol and seeding with crystalline TFA salt from 20 example 3c: To 500 mg (0.75 mmol) macropa-(OCH2CH2)-Ph-NH2 was added 5 mL 2-propanol. Upon addition of 288 µL (3.74 mmol) trifluoroacetic acid a clear solution formed at room temperature. After seeding with 5 mg (5 µmol) macropa-(OCH2CH2)-Ph-NH2 tris TFA and stirring at room temperature for 2 h a thick suspension formed.5 mL of MTBE was added and stirring at room 25 temperature was continued for 3h. The precipitate was filtered, and the filter-cake was rinsed with1 mL of 2-propanol / MTBE (1:3 v / v). After drying in vacuum at 30°C over-night 550 mg (69 % of theoretical yield) of a slightly beige solid material was isolated. XRPD (2Theta): 6.0°, 6.5°, 8.2°, 16.5°, 17.0°, 18.6°, 20.6°, 21.2°, 22.1°, 24.3°, Figure 11. TFA by ion-chromatography: 38.4 wt.-% (theoretical value for tris-TFA salt: 33.9 wt.-%). 30 5.0 wt.-% 2-propanol and 0.5 wt.-% of MTBE were found as residual solvents. Theoretical value for a mono 2-propanol solvate: 5.6 wt.-%. - 63 - BHC243021 FC Example 4: Preparation of crystalline Macropa-(OCH2CH2)-Ph-NH2 Example 4a To a mixture of 2-propanol (1.88 mL) and hexafluoro-2-propanol (0.63 mL) was added 250 mg of macropa-(OCH2CH2)-Ph-NH2 at room temperature. The material dissolved almost 5 completely and after 5 minutes precipitation occurred. The suspension was stirred at room temperature for 2 h. By XRPD of the suspension a crystalline solid phase was confirmed. Crystalline macropa-(OCH2CH2)-Ph-NH2 can be characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (7.0 ± 0.2)°, (10.0 ± 0.2)°, (17.7 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 10 0.15419 nm. Preferably, crystalline macropa-(OCH2CH2)-Ph-NH2 can be characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (7.0 ± 0.2)°, (10.0 ± 0.2)°, (10.6 ± 0.2)°, (17.7 ± 0.2)°, (19.6 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. Preferably, crystalline macropa-(OCH2CH2)-Ph-NH2 can be characterized by having a powder X-ray diffractogram 15 comprising reflections at 2-Theta angles of (7.0 ± 0.2)°, (10.0 ± 0.2)°, (10.6 ± 0.2)°, (13.9 ± 0.2)°, (17.7 ± 0.2)°, (19.6 ± 0.2)°, (20.1 ± 0.2)°, when measured at room temperature with Cu- Kalpha1 radiation having a wavelength of 0.15419 nm. Preferably, crystalline macropa- (OCH2CH2)-Ph-NH2 can be characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (7.0 ± 0.2)°, (8.5 ± 0.2)°, (10.0 ± 0.2)°, (10.6 ± 0.2)°, (13.9 ± 20 0.2)°, (17.7 ± 0.2)°, (19.6 ± 0.2)°, (20.1 ± 0.2)°, (24.0 ± 0.2)°, (25.4 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. Alternatively or additionally, crystalline macropa-(OCH2CH2)-Ph-NH2 can be characterized by having a powder X-ray diffractogram essentially the same as displayed in Figure 13 (bottom) of the present invention, when measured at room temperature with Cu-Kalpha1 radiation 25 having a wavelength of 0.15419 nm. XRPD (2Theta) (see Figure 13; bottom XRPD) Example 4b To a mixture of 2-propanol (7.5 mL) and hexafluoro-2-propanol (2.5 mL) was added 1000 mg of macropa-(OCH2CH2)-Ph-NH2 at room temperature. The material dissolved almost 30 completely and after 5 minutes a precipitation occurred. The suspension was stirred at room temperature for 4 h. The precipitate was isolated by filtration and the filter-cake was rinsed two times with 2 mL 2-propanol / MTBE (1:1 v / v) each, followed by a rinse with 2 mL of MTBE. After drying in vacuum overnight at 30°C 1160 mg of the product was isolated. By GC-headspace - 64 - BHC243021 FC 8.6 wt.-% of 2-propanol was detected, DSC-TGA indicated the additional presence of HFIP in the solid material. Crystalline macropa-(OCH2CH2)-Ph-NH2 can be characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (10.9 ± 0.2)°, (18.5 ± 0.2)°, (21.8 ± 5 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. Preferably, crystalline macropa-(OCH2CH2)-Ph-NH2 can be characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (10.9 ± 0.2)°, (14.5 ± 0.2)°, (18.5 ± 0.2)°, (19.9 ± 0.2)°, (21.8 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. Preferably, crystalline 10 macropa-(OCH2CH2)-Ph-NH2 can be characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.9 ± 0.2)°, (10.9 ± 0.2)°, (14.5 ± 0.2)°, (16.3 ± 0.2)°, (18.5 ± 0.2)°, (19.9 ± 0.2)°, (21.8 ± 0.2)°, when measured at room temperature with Cu- Kalpha1 radiation having a wavelength of 0.15419 nm. Preferably, crystalline macropa- (OCH2CH2)-Ph-NH2 can be characterized by having a powder X-ray diffractogram comprising 15 reflections at 2-Theta angles of (6.9 ± 0.2)°, (10.9 ± 0.2)°, (13.6 ± 0.2)°, (14.5 ± 0.2)°, (16.3 ± 0.2)°, (17.9 ± 0.2)°, (18.5 ± 0.2)°, (19.9 ± 0.2)°, (21.8 ± 0.2)°, (23.4 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. Alternatively or additionally, crystalline macropa-(OCH2CH2)-Ph-NH2 can be characterized by having a powder X-ray diffractogram essentially the same as displayed in Figure 13 (middle) 20 of the present invention, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. XRPD (2Theta) (see Figure 13; middle XRPD) DSC* / TGA: Figure 14 (*exo-mode) 25 Example 4c 1000 mg of macropa-(OCH2CH2)-Ph-NH2 was added to hexafluoro-2-propanol (2.5 mL) at room temperature. A small portion remained undissolved when 2-propanol (2.5 mL) was added and resulted in a precipitation. Additional hexafluoro-2-propanol (2.5 mL) was added to obtain a clear solution. After two successive additions of 2.5 mL 2-propanol, each, a precipitation 30 occurred. The suspension was stirred overnight at room temperature. MTBE (15 mL) was added to the mixture After stirring for 2 h at room temperature the precipitate was isolated by filtration. The filter-cake was rinsed with 2 mL 2-propanol / MTBE (1:1 v / v) twice and once with 2 mL MTBE. The product was dried in vacuum at 30°C overnight.1310 mg of solid material was obtained. By GC-headspace 3.9 wt.-% of 2-propanol and 0.3 wt.-% of MTBE were found. - 65 - BHC243021 FC The excess weight of the mass balance indicates a significant amount of HFIP in the crystalline solid. Crystalline macropa-(OCH2CH2)-Ph-NH2 can be characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (10.5 ± 0.2)°, (20.9 ± 0.2)°, (21.9 ± 5 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. Preferably, crystalline macropa-(OCH2CH2)-Ph-NH2 can be characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (10.5 ± 0.2)°, (13.5 ± 0.2)°, (18.5 ± 0.2)°, (20.9 ± 0.2)°, (21.9 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. Preferably, crystalline 10 macropa-(OCH2CH2)-Ph-NH2 can be characterized by having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (7.0 ± 0.2)°, (10.5 ± 0.2)°, (11.0 ± 0.2)°, (13.5 ± 0.2)°, (18.5 ± 0.2)°, (20.9 ± 0.2)°, (21.9 ± 0.2)°, when measured at room temperature with Cu- Kalpha1 radiation having a wavelength of 0.15419 nm. Preferably, crystalline macropa- (OCH2CH2)-Ph-NH2 can be characterized by having a powder X-ray diffractogram comprising 15 reflections at 2-Theta angles of (7.0 ± 0.2)°, (10.5 ± 0.2)°, (11.0 ± 0.2)°, (13.5 ± 0.2)°, (17.8 ± 0.2)°, (18.5 ± 0.2)°, (19.9 ± 0.2)°, (20.9 ± 0.2)°, (21.9 ± 0.2)°, (23.4 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. Alternatively or additionally, crystalline macropa-(OCH2CH2)-Ph-NH2 can be characterized by having a powder X-ray diffractogram essentially the same as displayed in Figure 13 (top) of 20 the present invention, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm. XRPD (2Theta): (Figure 13; top XRPD) - 66 -

Claims

BHC243021 FC ABSTRACT The present disclosure relat a compound of formula (I), a crystalline form thereof, a pro e. 5(I) 10 15 - 1 -i. providing a compound of formula (II) in a solvent or solvent mixture comprising water, acetonitrile, dichloromethane, tetrahydrofurane, 1-methoxy-2-propanol, sulfolane, acetic acid, dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, dimethyl formamide, 1-propanol, 2-propanol, 1-butanol, 2-butanol, hexafluoro-2-propanol and trifluoroethanol or a mixture of two or more thereof, ii. reacting the compound of formula (II) with a isothiocyanate-forming reagent to form a compound of formula (I), iii. purifying the compound of formula (I) by reversed-phase chromatography, wherein at least one eluent comprises trifluoroacetic acid, iv. isolating the trifluoroacetic acid salt of a compound of formula (I).

6. The process according to claim 5, wherein the solvent in step (i) is a mixture of water and acetonitrile.

7. A process for the preparation of a crystalline form of the trifluoroacetic acid salt of a compound of formula (I) according to any of claims 3 or 4 comprising i. providing a compound of formula (II) in a solvent or solvent mixture comprising a C3-C5 alcohol, ii. adding trifluoroacetic acid, iii. reacting the compound of formula (II) with a isothiocyanate-forming reagent, iv. isolating the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) from the reaction mixture.

8. The process according to claim 7, wherein the solvent or solvent mixture in step (i) comprises a C3-C5 alcohol selected from 1-propanol, 2-propanol, 1-butanol and 2- butanol and a C2-C5 fluorinated alcohol containing at least three fluorine atoms.

9. The process according to any of claims 7 or 8, wherein the solvent or solvent mixture in step (i) comprises a C3-C5 alcohol selected from 1-propanol, 2-propanol, 1-butanol and 2-butanol and a C2-C5 fluorinated alcohol containing at least three fluorine atoms selected from hexafluoro-2-propanol and trifluoroethanol.

10. The process according to any of claims 7 to 9, wherein the solvent or solvent mixture in step (i) is a 3:1 (v / v) mixture of 2-propanol and hexafluoro-2-propanol.

11. The process according to any of claims 7 to 10, wherein 2 to 8 molar equivalents of trifluoroacetic acid are added in step (ii) and / or wherein the reaction in step (iii) is carried out at a temperature of from 20 to 50°C.

12. The process according to any of claims 7 to 11 , wherein 3 molar equivalents of trifluoroacetic acid are added in step (ii) and wherein the reaction in step (iii) is carried out at a temperature of from 25 to 30°C.

13. The process according to any of claims 7 to 11 , wherein 8 molar equivalents of trifluoroacetic acid are added in step (ii) and wherein the reaction in step (iii) is carried out at a temperature of from 35 to 45°C.

14. The process according to any of claims 7 to 13, wherein step (iv) comprises the addition of a further solvent or solvent mixture different from that in which the reaction in step (iii) is carried out, said solvent or solvent mixture preferably comprising a solvent selected from 2-propanol, tetrahydrofurane, 2-methyl tetrahydrofurane, methyl tertbutyl ether (MTBE) or a mixture of two or more thereof, more preferably wherein the further solvent is methyl tert-butyl ether (MTBE).

15. Use of the trifluoroacetic acid salt of a compound of formula (I) according to any of claim 1 or 2 and / or use of the crystalline form of the trifluoroacetic acid salt of a compound of formula (I) according to any of claims 3 or 4 for the preparation of a conjugate of formula (III)wherein L is an optional linking moiety and T is a targeting moiety.

16. The trifluoroacetic salt of a compound of formula (II)comprising three molar equivalents of trifluoroacetic acid per molar equivalent of the compound of formula (II).

17. The trifluoroacetic salt of a compound of formula (I) according to claim 16 in crystalline form having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (20.1 ± 0.2)°, (20.4 ± 0.2)° and (21.6 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm.

18. The crystalline trifluoroacetic salt of a compound of formula (II) according to claim 16 having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (10.0 ± 0.2)°, (11.6± 0.2)°, (19.1 ± 0.2)°, (19.6 ± 0.2)°, (20.1 ± 0.2)°, (20.4 ± 0.2)° and (21.6 ± 0.2)°, preferably comprising reflections at 2-Theta angles of (7.1 ± 0.2)°, (10.0± 0.2)°, (11.6 ± 0.2)°, (13.4 ± 0.2)°, (19.1± 0.2)°, (19.6 ± 0.2)°, (20.1 ± 0.2)°, (20.4 ± 0.2)°, (21.6 ± 0.2)° and (23.6 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm.

19. The trifluoroacetic salt of a compound of formula (I) according to claim 16 in crystalline form having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (8.2 ± 0.2)°, (20.6 ± 0.2)° and (21.2 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm.

20. The crystalline trifluoroacetic salt of a compound of formula (II) according to claim 16 having a powder X-ray diffractogram comprising reflections at 2-Theta angles of (6.0 ± 0.2)°, (6.5± 0.2)°, (8.2 ± 0.2)°, (17.0± 0.2)°, (18.6 ± 0.2)°, (20.6 ± 0.2)° and (21 .2 ± 0.2)°, preferably comprising reflections at 2-Theta angles of (6.0 ± 0.2)°, (6.5± 0.2)°, (8.2 ± 0.2)°, (16.5± 0.2)°, (17.0 ± 0.2)°, (18.6 ± 0.2)°, (20.6 ± 0.2)°, (21.2 ± 0.2)°, (22.1 ± 0.2)°and (24.3 ± 0.2)°, when measured at room temperature with Cu-Kalpha1 radiation having a wavelength of 0.15419 nm.21 . A process for the preparation of the trifluoroacetic acid salt of a compound of formula (I) according to any of claims 1 or 2 or of the crystalline trifluoroacetic acid salt of a compound of formula (I) according to any of claims 3 or 4 comprising i. providing the tris-trifluoroacetic acid salt of the compound of formula (II) according to claim 16 or the crystalline tris-trifluoroacetic acid salt of the compound of formula (II) according to any of claims 17-20 in a solvent or solvent mixture comprising water, acetonitrile, dichloromethane, tetrahydrofurane, 1- methoxy-2-propanol, sulfolane, acetic acid, dimethylacetamide, dimethyl sulfoxide, N-methyl pyrrolidone, dimethyl formamide, 1-propanol, 2-propanol, 1- butanol, 2-butanol, hexafluoro-2-propanol and trifluoroethanol or a mixture of two or more thereof, ii. reacting the tris-trifluoroacetic acid salt of the compound of formula (II) or the crystalline tris-trifluoroacetic acid salt of the compound of formula (II) with a isothiocyanate-forming reagent to form the trifluoroacetic acid salt or the crystalline trifluoroacetic acid salt of a compound of formula (I), iii. isolating the trifluoroacetic acid salt or the crystalline trifluoroacetic acid salt of a compound of formula (I), wherein the process does not comprise the use of trifluoroacetic acid.

22. Use of the tris-trifluoroacetic salt of a compound of formula (II) according to any of claims 16 to 20 for the preparation of the trifluoroacetic acid salt of a compound of formula (I) according to any of claims 1 to 4.

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