Method for preparing gadolinium contrast agent

Abstract

The present invention relates to a process for the preparation of gadolinium chelates of formula (I) or stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof. Furthermore, the present invention relates to crystalline forms of the gadolinium chelate of formula (I), to a process for preparing said crystalline forms, as well as to intermediate compounds in the synthesis of gadolinium chelate of formula (I) and / or to crystalline forms thereof and to their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or to mixtures thereof. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the subject matter characterized in the patent claims, namely a process for preparing a gadolinium chelate of formula (I) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

[0002]

[0003] Furthermore, the present invention relates to a crystalline form of a gadolinium chelate of formula (I), a process for preparing said crystalline form, and intermediate compounds in the synthesis of a gadolinium chelate of formula (I), and / or its crystalline form and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof. Background Art

[0004] Gd-based contrast agents play a vital role in diagnosis using magnetic resonance imaging (MRI) techniques. One such Gd-based contrast agent is a compound of formula (I), which is described in WO2016 / 193190 (BAYER AG). However, the synthetic methods for preparing compounds of formula (I) described in the prior art, while producing the desired product, contain several obstacles that are unfavorable for large-scale synthesis.

[0005]

[0006] For example, the manufacture of the compound of formula (II), i.e. the 4-nitrophenol ester of carboxylic acid (IV), described in the prior art (WO 2001051095 A2) is hardly amenable to scale-up on a metric ton scale. This is based on the fact that the route involves the formation of the pyridinium salt of carboxylic acid (IV) in water using highly toxic pyridine, which is then isolated by freeze drying (WO 2001051095 A2, 21d, p. 44). Thereafter, in pure pyridine, the salt is reacted with an excess of bis(4-nitrophenol) carbonate to give, after a long reaction time of 3 days, the corresponding activated ester of formula (II), which is isolated by filtration and then washed with highly toxic chemicals pyridine and dichloromethane.

[0007]

[0008] In addition, the preparation of the compounds of formula (I) by the fragment coupling of the tetraamines of formula (III) or their salts and the activated esters (II) has only been described by carrying out the reaction at high dilution and using a large excess of the valuable intermediate of formula (II). When distilling most of the high-boiling solvent dimethyl sulfoxide, which requires low pressure and high temperature, the crude material is precipitated by adding a large excess of ethyl acetate, thus complicating its large-scale production. After removing low-molecular impurities by diafiltration / ultrafiltration in an aqueous solution, the retentate is lyophilized and chromatographically separated to obtain an amorphous solid. Overall, the yield of this sequence is low. High dilution, excess reagents, and cumbersome procedures (i.e., chromatography and lyophilization) are the most likely factors contributing to the high cost and low efficiency of this method.

[0009] Accordingly, there is a need to provide a method for preparing compounds of general formula (I) which:

[0010] - is reliable and scalable,

[0011] - is cost-effective and provides a high overall yield,

[0012] - includes a reliable and scalable method for preparing compounds of formula (II),

[0013] - enables the compounds of general formula (I) to be provided as crystalline materials with high chemical purity, thus facilitating compliance with the necessary regulatory requirements for clinical trials and market supply,

[0014] - tames and allows monitoring of the strong hygroscopicity of the compounds of general formula (I), thus facilitating their handling for analytical purposes and for pharmaceutical manufacturing, and at the same time allowing the residual ethanol level to be maintained in accordance with regulatory requirements.

[0015] Surprisingly, a method has now been found, which forms the basis of the present invention, that allows the preparation of compounds of general formula (I) and overcomes the disadvantages of the previously described methods. Furthermore, the present invention also relates to novel crystalline forms of the gadolinium chelates of formula (I), methods for preparing said crystalline forms, and intermediate compounds in the synthesis of the gadolinium chelates of formula (I) and / or their crystalline forms.

[0016] In addition, it has surprisingly been found that, in the context of the present invention, it is possible

[0017] - to develop a one-pot protocol for reacting compounds of formula (IV) to compounds of formula (II) which avoids the use of the highly toxic and environmentally harmful solvent pyridine and includes the isolation of the compounds of formula (IV) as crystalline materials. This is a process that requires a delicate balance of the different variables involved in the reaction.

[0018] - To provide a method for preparing a compound of formula (II), which is carried out in such a way that it allows for a reduction in the equivalents in the reaction subsequent to the compound of formula (I) and the reaction is carried out at a higher (much higher) concentration. Surprisingly, this protocol enables the separation of the compound of formula (I) as a crude material into a well-performing solid without distilling the high-boiling solvent dimethyl sulfoxide.

[0019] - To prepare the compound of formula (I) as a crude material with high purity (i.e., a purity of at least 50% (w / w) and preferably at least 70% (w / w)) and a very small amount of residual organic solvent.

[0020] - To prepare a crystalline form of the compound of formula (I), thereby avoiding the use of cumbersome, expensive, and inefficient preparative HPLC and enabling the production of the title compound with high chemical purity and in crystalline form.

[0021] - To separate different solid forms of the compound of formula (I) by well-defined parameters and conditions, thereby providing a reliable and controllable method for its manufacture and handling. Summary of the Invention

[0022] The present invention relates to a method for preparing a gadolinium chelate of formula (I), and a crystalline form of the gadolinium chelate of formula (I), a method for preparing the crystalline form, and intermediate compounds and / or their crystalline forms in the synthesis of the gadolinium chelate of formula (I).

[0023] Definitions

[0024] The term "substituted" means that one or more hydrogen atoms on a specified atom or group are replaced by a group selected from the specified groups, provided that the normal valence of the specified atom in the existing situation is not exceeded. Combinations of substituents and / or variables are allowed.

[0025] The term "optionally substituted" means that the number of substituents can be equal to or different from zero.

[0026] When a group in the compounds of the present invention is substituted, unless otherwise specified, the group may be mono-substituted or multi-substituted by substituents. Within the scope of the present invention, the meanings of all groups that occur repeatedly are independent of each other. The groups in the compounds of the present invention may be substituted by one, two, or three identical or different substituents, especially by one substituent.

[0027] If the composite substituent consists of more than one part, such as (C 1 -C 3 -alkoxy)-(C 2 -C 6 -alkyl)-, the position of a given part can be at any suitable position in the composite substituent, i.e., C 1 -C 3-The alkoxy moiety may be attached to the C of the (C 1 -C 3 -alkoxy)-(C 2 -C 6 -alkyl)-group at any carbon atom of the C 2 -C 6 -alkyl moiety. A hyphen at the beginning or end of such a complex substituent indicates the point of attachment of the complex substituent to the remainder of the molecule.

[0028] When used in this specification, the term "comprising" includes "consisting of".

[0029] If any item is referred to herein as "as mentioned herein", it means that it can be mentioned anywhere in this document.

[0030] In the context of the present invention, the term "relative humidity" may be defined as the humidity calculated according to the following formula

[0031]

[0032] where pw represents the partial pressure of water and pwL represents the vapor pressure of water in the liquid phase.

[0033] The relative humidity as a function of temperature and vapor pressure is shown, for example, in Thermische Trennverfahren–Grundlagen, Auslegung, Apparate by Klaus Sattler (K. Sattler, Thermische Trennverfahren–Grundlagen, Auslegung, Apparate, Wiley-VCH, Weinheim, Germany, 2nd edition, 1995, p. 415).

[0034] In a "liquid-gas" system, the water molecules in the gas phase are in equilibrium with the water molecules in the liquid phase. The concentration of water molecules in the gas phase is represented by the partial pressure of water. At 100% water atmosphere, the partial pressure of water is equal to the total pressure. In the case of a mixture of water and another gas component (e.g., nitrogen), the partial pressure of water is equal to the total pressure multiplied by the mole fraction of water in the gas phase (Dalton's law). The vapor pressure of water in the liquid phase is a temperature-dependent property of the substance.

[0035] In the "solid-gas" system, the water molecules in the gas phase are in equilibrium with the water molecules absorbed / adsorbed in / on the solid phase. The concentration of water molecules in the gas phase is expressed as the water partial pressure. In an atmosphere of 100% water, the water partial pressure is equal to the total pressure. In a mixture of water and another gas component (such as nitrogen), the water partial pressure is equal to the total pressure multiplied by the mole fraction of water in the gas phase (Dalton's law). The vapor pressure of water in the solid phase is a temperature-dependent property of the substance. The relative humidity set in "dynamic vapor sorption" and in the production process refers to water in the "liquid-gas" system.

[0036] The terms mentioned in this document have the following meanings:

[0037] The term "halogen atom" refers to a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.

[0038] The term "C 1 -C 6 -alkyl" refers to a straight-chain or branched-chain, saturated, monovalent hydrocarbon radical group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl or 1,3-dimethylbutyl groups or their isomers. In particular, the group has 1, 2, 3 or 4 carbon atoms ("C 1 -C 4 -alkyl"), such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl groups, more specifically 1, 2 or 3 carbon atoms ("C 1 -C 3 -alkyl"), such as methyl, ethyl, n-propyl or isopropyl groups.

[0039] The term "C 1 -C 3 -haloalkyl" refers to a straight-chain or branched-chain, saturated, monovalent hydrocarbon radical group, where the term "C 1 -C 3 -alkyl" is as defined above, and where one or more hydrogen atoms are identically or differently replaced by halogen atoms. In particular, the halogen atom is a fluorine atom. The C 1 -C 3-Halogenoalkyl groups are, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoropropan-2-yl.

[0040] The term "C 2 -C 6 -hydroxyalkyl" means a straight-chain or branched-chain, saturated, monovalent hydrocarbon radical group, where the term "C 2 -C 6 -alkyl" is as defined above, and where one, two or three hydrogen atoms are replaced by hydroxy groups, for example 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropan-2-yl, 2,3-dihydroxypropyl, 1,3-dihydroxypropan-2-yl, 1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl groups.

[0041] The term "C 1 -C 3 -alkoxy" means a straight-chain or branched-chain, saturated, monovalent group of the formula (C 1 -C 3 -alkyl)-O-, where the term "C 1 -C 3 -alkyl" is as defined above, for example: methoxy, ethoxy, n-propoxy or isopropoxy groups.

[0042] The term "C 3 -C 6 -cycloalkyl" means a saturated, monovalent, monocyclic or bicyclic hydrocarbon ring containing 3, 4, 5 or 6 carbon atoms ("C 3 -C 6 -cycloalkyl"). The C 3 -C 6 -cycloalkyl groups are, for example, monocyclic hydrocarbon rings (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups).

[0043] As used herein, the term "C 1 -C 6 ", for example in the definition of "C 1 -C 6 -alkyl" in context, means an alkyl group having a limited number of 1 to 6 carbon atoms (i.e., 1, 2, 3, 4, 5 or 6 carbon atoms).

[0044] Furthermore, as used herein, the term "C 3 -C 6 ", for example as used herein, in the context of "C 3 -C 6In the definition of "-cycloalkyl", it refers to a cycloalkyl group having 3 to 6 limited carbon atoms (i.e., 3, 4, 5, or 6 carbon atoms).

[0045] When a range of values is given, the range includes each value and sub-range within the range.

[0046] For example:

[0047] "C 1 -C 6 "includes C 1 、C 2 、C 3 、C 4 、C 5 、C 6 、C 1 -C 6 、C 1 -C 5 、C 1 -C 4 、C 1 -C 3 、C 1 -C 2 、C 2 -C 6 、C 2 -C 5 、C 2 -C 4 、C 2 -C 3 、C 3 -C 6 、C 3 -C 5 、C 3 -C 4 、C 4 -C 6 、C 4 -C 5 and C 5 -C 6 ;

[0048] "C 1 -C 4 "includes C 1 、C 2 、C 3 、C 4 、C 1 -C 4 、C 1 -C 3 、C 1 -C 2 、C 2 -C 4 、C 2 -C 3and C 3 -C 4 ;

[0049] "C 1 -C 3 "contains C 1 、C 2 、C 3 、C 1 -C 3 、C 1 -C 2 and C 2 -C 3 ;

[0050] "C 2 -C 6 "contains C 2 、C 3 、C 4 、C 5 、C 6 、C 2 -C 6 、C 2 -C 5 、C 2 -C 4 、C 2 -C 3 、C 3 -C 6 、C 3 -C 5 、C 3 -C 4 、C 4 -C 6 、C 4 -C 5 and C 5 -C 6 ;

[0051] "C 3 -C 6 "contains C 3 、C 4 、C 5 、C 6 、C 3 -C 6 、C 3 -C 5 、C 3 -C 4 、C 4 -C 6 、C 4 -C 5 and C 5 -C 6 。

[0052] The compounds of the present invention may contain one or more asymmetric centers, depending on the position and nature of the various substituents desired. Symmetric carbon atoms may exist in the (R) or (S) configuration, which can result in a racemic mixture in the case of a single asymmetric center and a mixture of diastereomers in the case of multiple asymmetric centers. In some cases, asymmetry may also exist due to restricted rotation about a given bond, such as the central bond adjacent to two substituted aromatic rings of a specified compound.

[0053] In the context of the present invention, the compounds of formula (I) may exist in different stereoisomeric forms, i.e., diastereoisomeric and / or enantiomeric forms, since it contains four asymmetric centers (marked with * below):

[0054]

[0055] Those skilled in the art will understand that the compounds of formula (I) may exist in different configurations (i.e., (R,R,R,R), (S,S,S,S), (R,S,S,S), (S,R,R,R), (S,S,R,R)) in pure form or as a mixture of two or more different configurations. Preferably, the compounds of formula (I) prepared according to the method of the present invention are obtained as a mixture of diastereomers. More preferably, the compounds of formula (I) prepared according to the method of the present invention are obtained as a mixture of (S,S,R,R), (S,R,R,R)+(R,S,S,S) and (R,R,R,R)+(S,S,S,S) diastereomers in a ratio of 60:30:10 to 30:60:10, more preferably in a ratio of 50:40:10 to 40:50:10. Even more preferably, the compounds of formula (I) prepared according to the method of the present invention are obtained as a mixture of (S,S,R,R), (S,R,R,R)+(R,S,S,S) and (R,R,R,R)+(S,S,S,S) diastereomers in a ratio of 30:60:10 to 75:25:0, or in a ratio of 40:55:5 to 65:35:0.

[0056] Preferably, the compounds are those that produce more desirable biological activity. The isolated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. The purification and separation of these materials can be accomplished by standard techniques known in the art.

[0057] Optical isomers can be obtained by resolving a racemic mixture according to conventional methods, for example by forming diastereomeric salts or covalent diastereomers using an optically active acid or base. Examples of suitable acids are tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid and camphorsulfonic acid. The mixture of diastereomers can be separated into their individual diastereomers by methods known in the art based on their physical and / or chemical differences, for example by chromatography or fractional crystallization. The optically active base or acid is then liberated from the separated diastereomeric salt. Different methods for separating optical isomers involve the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatization, which is optimally selected to maximize enantiomeric separation. Suitable chiral HPLC columns are manufactured by Daicel, such as Chiracel OD and Chiracel OJ, etc., all of which are conventionally selectable. Enzymatic separation with or without derivatization is also useful. The optically active compounds of the present invention can also be obtained by chiral synthesis using optically active starting materials.

[0058] To limit isomers of different types from each other, reference is made to Part E of the IUPAC rules (Pure Appl Chem 45, 11 - 30, 1976).

[0059] The present invention includes all possible stereoisomers of the compounds of the present invention, which are either a single stereoisomer or any mixture of said stereoisomers in any ratio (e.g., R - or S - isomers). The separation of a single stereoisomer of the compounds of the present invention (e.g., a single enantiomer or a single diastereomer) can be achieved by any suitable prior art method (e.g., chromatography, especially chiral chromatography).

[0060] The present invention also relates to useful forms of the compounds disclosed herein, such as metabolites, hydrates, solvates, salts (especially pharmaceutically acceptable salts) and co - precipitates.

[0061] The compounds of the present invention can exist as hydrates, or as solvates, or as mixtures thereof (i.e., mixed hydrates and / or mixed solvates), especially when the compounds of the present invention contain polar solvents, especially water, methanol or ethanol, for example as a structural element of the compound lattice. The amount of the polar solvent (especially water) can be present in stoichiometric or non - stoichiometric ratios. In the case of stoichiometric solvates, for example, hydrates, half -,, mono -,, sesqui -,, di -,, tri -,, tetra -,, penta - etc. solvates or hydrates are possible respectively. The present invention includes all such hydrates or solvates or mixtures thereof (i.e., mixed hydrates and / or mixed solvates).

[0062] In addition, the compounds of the present invention may exist in the form of salts. The salts may be inorganic or organic addition salts, particularly any pharmaceutically acceptable inorganic or organic addition salts commonly used in pharmacy.

[0063] The term "pharmaceutically acceptable salts" refers to relatively non-toxic inorganic or organic acid addition salts of the compounds of the present invention. See, for example, S.M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19. The production of particular neutral salts is described in US 5,560,903.

[0064] Pharmaceutically acceptable salts of the compounds according to the present invention include inorganic acid salts and carboxylates, such as, but not limited to, hydrochloride, sulfate, phosphate, acetate, propionate, lactate, tartrate, malate, citrate, fumarate, maleate, aspartate, and glutamate.

[0065] Those skilled in the art will further recognize that the acid addition salts of the claimed compounds can be prepared by reacting the compounds with a suitable inorganic or organic acid via any of a variety of known methods.

[0066] The present invention includes all possible salts of the compounds of the present invention, either as a single salt or as any mixture of said salts in any proportion.

[0067] In this context, particularly in the experimental section, for the synthesis of the intermediates and examples of the present invention, when the compounds are mentioned in the form of salts with the corresponding bases or acids, the exact stoichiometric composition of the salt forms obtained by the respective preparation and / or purification methods is, in most cases, unknown.

[0068] This similarly applies to the case of synthesis intermediates or example compounds or their salts obtained by the described preparation and / or purification methods as solvates, such as hydrates, with an unknown stoichiometric composition (if defined). Detailed Description of the Invention

[0070] Separation of the Compounds of Formula (I)

[0071] According to a first aspect, the present invention relates to a method for separating a compound of general formula (I),

[0072]

[0073] or its stereoisomers, tautomers, N-oxides, hydrates, solvates or its salts, or mixtures thereof, the method comprising

[0074] (i) providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent,

[0075] (ii) Removing water from the mixture provided in (i),

[0076] (iii) Adding a second organic solvent,

[0077] (iv) Optionally adding a third organic solvent,

[0078] (v) Separating the compound of formula (I).

[0079] In a further embodiment of the first aspect, the present invention relates to a method for preparing the compound of formula (I) above or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, the method comprising

[0080] (i) Providing a mixture comprising the compound of formula (I), water and at least a first organic solvent,

[0081] (ii) Removing water from the mixture provided in (i),

[0082] (iii) Adding a second organic solvent,

[0083] (iv) Adding a third organic solvent,

[0084] (v) Separating the compound of formula (I).

[0085] In a further embodiment of the first aspect, the present invention relates to a method for preparing the compound of formula (I) above or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, the method comprising

[0086] (i) Providing a mixture comprising the compound of formula (I), water and at least a first organic solvent,

[0087] (ii) Removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% by weight (w / w),

[0088] (iii) Adding a second organic solvent,

[0089] (iv) Adding a third organic solvent,

[0090] (v) Separating the compound of formula (I).

[0091] In a further embodiment of the first aspect, the present invention relates to a method for preparing the compound of formula (I) above or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, the method comprising

[0092] (i) Provide a mixture comprising a compound of formula (I), water, and at least a first organic solvent,

[0093] (ii) Remove water from the mixture provided in (i),

[0094] (iii) Add a second organic solvent, wherein the second organic solvent is a C 1 -C 4 alcohol,

[0095] (iv) Add a third organic solvent,

[0096] (v) Isolate the compound of formula (I).

[0097] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of formula (I) above or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof, the method comprising

[0098] (i) Provide a mixture comprising a compound of formula (I), water, and at least a first organic solvent,

[0099] (ii) Remove water from the mixture provided in (i),

[0100] (iii) Add a second organic solvent, wherein the second organic solvent is a C 1 -C 4 alcohol,

[0101] (iv) Add a third organic solvent, wherein the third organic solvent is acetone

[0102] (v) Isolate the compound of formula (I).

[0103] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of formula (I) above or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof, the method comprising

[0104] (i) Provide a mixture comprising a compound of formula (I), water, and at least a first organic solvent, wherein the at least first organic solvent is DMSO,

[0105] (ii) Remove water from the mixture provided in (i),

[0106] (iii) Add a second organic solvent, wherein the second organic solvent is a C 1 -C 5 alcohol,

[0107] (iv) Add a third organic solvent, wherein the third organic solvent is acetone

[0108] (v) Separated (I) compound.

[0109] In a further embodiment of the first aspect, the present invention relates to a method for preparing the above general formula (I) compound or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, the method comprising

[0110] (i) providing a mixture comprising a compound of formula (I), water and at least a first organic solvent,

[0111] (ii) removing water from the mixture provided in (i),

[0112] (iii) adding a second organic solvent, wherein the second organic solvent is an alcohol selected from ethanol, n-propanol and isopropanol,

[0113] (iv) adding a third organic solvent, wherein the third organic solvent is acetone

[0114] (v) separating the compound of formula (I).

[0115] In a further embodiment of the first aspect, the present invention relates to a method for preparing the above general formula (I) compound or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, the method comprising

[0116] (i) providing a mixture comprising a compound of formula (I), water and at least a first organic solvent, wherein the at least first organic solvent is DMSO,

[0117] (ii) removing water from the mixture provided in (i),

[0118] (iii) adding a second organic solvent, wherein the second organic solvent is an alcohol selected from ethanol, n-propanol and isopropanol,

[0119] (iv) adding a third organic solvent, wherein the third organic solvent is acetone

[0120] (v) separating the compound of formula (I).

[0121] In a further embodiment of the first aspect, the present invention relates to a method for preparing the above general formula (I) compound or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, the method comprising

[0122] (i) providing a mixture comprising a compound of formula (I), water and at least a first organic solvent,

[0123] (ii) removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% by weight (w / w),

[0124] (iii) Add a second organic solvent, wherein the second organic solvent is an alcohol selected from ethanol, n-propanol, and isopropanol,

[0125] (iv) Add a third organic solvent, wherein the third organic solvent is acetone

[0126] (v) Isolate the compound of formula (I).

[0127] In a further embodiment of the first aspect, the present invention relates to a method for preparing the above-mentioned compound of formula (I) or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, the method comprising

[0128] (i) Providing a mixture comprising the compound of formula (I), water, and at least a first organic solvent,

[0129] (ii) Removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% by weight (w / w),

[0130] (iii) Adding a second organic solvent, wherein the second organic solvent is ethanol,

[0131] (iv) Adding a third organic solvent, wherein the third organic solvent is acetone,

[0132] (v) Isolate the compound of formula (I).

[0133] In a further embodiment of the first aspect, the present invention relates to a method for preparing the above-mentioned compound of formula (I) or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, the method comprising

[0134] (i) Providing a mixture comprising the compound of formula (I), water, and at least a first organic solvent, wherein the at least first organic solvent is DMSO,

[0135] (ii) Removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% by weight (w / w),

[0136] (iii) Adding a second organic solvent, wherein the second organic solvent is ethanol,

[0137] (iv) Adding a third organic solvent, wherein the third organic solvent is acetone,

[0138] (v) Isolate the compound of formula (I).

[0139] Step (i) of the method according to the invention comprises providing a mixture comprising a compound of formula (I), water and at least a first organic solvent. Preferably, the at least first organic solvent is DMSO. More preferably, the mixture comprising the compound of formula (I), water and at least a first organic solvent is a mixture obtained in a reaction which results in the formation of the compound of formula (I).

[0140] In step (ii), water is removed from the mixture provided in step (i). Preferably, water is removed from the mixture until the water content of the mixture is between 10% and 20% by weight (w / w).

[0141] In step (iii), a second organic solvent is added to the mixture. Preferably, the second organic solvent is an alcohol selected from ethanol, n-propanol and isopropanol. More preferably, the second organic solvent is ethanol.

[0142] In step (iv), a third organic solvent is added to the mixture. Preferably, the third organic solvent is selected from acetone, methyl ethyl ketone and methyl tert-butyl ether. More preferably, the third organic solvent is acetone. After adding the third organic solvent, a solid comprising the compound of formula (I) as a crude material is preferably obtained after step (iv). Additional and / or optional steps such as percolation, ultrafiltration, nanofiltration, extraction, treatment with activated carbon, solvent evaporation, treatment with exchange resins, treatment with ion exchange resins, etc. may be necessary and can be carried out after adding the third organic solvent in step (iv) and before separation in step (v), or they may be included as part of the separation process in step (v).

[0143] In step (v), the compound of formula (I) is separated. Preferably, the compound of formula (I) is separated as a solid. In the context of the present invention, the separation of the compound of formula (I) may optionally include additional steps such as percolation, ultrafiltration, nanofiltration, extraction, treatment with activated carbon, solvent evaporation, treatment with exchange resins, treatment with ion exchange resins, etc. In a particularly preferred embodiment, the compound of formula (I) is separated in step (v) by a method comprising percolation / ultrafiltration in water.

[0144] In a further embodiment of the first aspect, the present invention relates to a method for preparing the above general formula (I) compound or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, the method comprising

[0145] (i) providing a mixture comprising a compound of formula (I), water and at least a first organic solvent,

[0146] (ii) removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% by weight (w / w),

[0147] (iii) Add a second organic solvent, wherein the second organic solvent is an alcohol selected from ethanol, n-propanol, and isopropanol,

[0148] (iv) Add a third organic solvent, wherein the third organic solvent is acetone

[0149] (v) Separate the compound of formula (I) by a method including percolation, ultrafiltration, or using an ion exchange resin.

[0150] In a further embodiment of the first aspect, the present invention relates to a method for preparing the compound of formula (I) above or its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures thereof, the method comprising

[0151] (i) Provide a mixture comprising the compound of formula (I), water, and at least a first organic solvent, wherein the at least first organic solvent is DMSO,

[0152] (ii) Remove water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% by weight (w / w),

[0153] (iii) Add a second organic solvent, wherein the second organic solvent is ethanol,

[0154] (iv) Add a third organic solvent, wherein the third organic solvent is acetone,

[0155] (v) Separate the compound of formula (I) by a method including percolation, ultrafiltration, or using an ion exchange resin.

[0156] Crystalline Forms I and II of the Compound of Formula (I)

[0157] Surprisingly, it has been found that the compound of formula (I) exists in crystalline form (i.e., as crystalline material, i.e., as a crystalline solid). Accordingly, the present invention relates to the compound of formula (I) in crystalline form (i.e., as crystalline material, i.e., as a crystalline solid). It has been found that the compound of formula (I) can exist in at least two crystalline forms, I and II, in pure form or as a mixture in any proportion thereof.

[0158] The crystalline forms of the compound of formula (I) can be characterized by analytical methods well-known in the pharmaceutical industry for the characterization of solids. Such methods include, 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 vapor sorption (DVS). The crystalline forms of the compound of formula (I) can be characterized by one of the above methods or by combining two or more of them. Specifically, the crystalline forms of the compound of formula (I) can be characterized by one of the following embodiments or by combining two or more of the following embodiments.

[0159] Crystalline Form I of the compound of formula (I)

[0160] Crystalline Form I of the compound of formula (I) is characterized in that when measured at room temperature with Cu-Kα radiation having a wavelength of 0.15419 nm 1 it has a powder X-ray diffraction pattern having reflections at 2-θ angles including: (6.8 ± 0.2)°, (9.1 ± 0.2)°, and (11.4 ± 0.2)°. Preferably, Crystalline Form I of the compound of formula (I) is characterized in that when measured at room temperature with Cu-Kα radiation having a wavelength of 0.15419 nm 1 it has a powder X-ray diffraction pattern having reflections at 2-θ angles including: (6.8 ± 0.2)°, (9.1 ± 0.2)°, (10.1 ± 0.2)°, (11.4 ± 0.2)°, and (12.0 ± 0.2)°. Preferably, Crystalline Form I of the compound of formula (I) is characterized in that when measured at room temperature with Cu-Kα radiation having a wavelength of 0.15419 nm 1 it has a powder X-ray diffraction pattern having reflections at 2-θ angles including: (6.8 ± 0.2)°, (9.1 ± 0.2)°, (10.1 ± 0.2)°, (11.4 ± 0.2)°, (12.0 ± 0.2)°, (14.4 ± 0.2)°, and (23.5 ± 0.2)°. Preferably, Crystalline Form I of the compound of formula (I) is characterized in that when measured at room temperature with Cu-Kα radiation having a wavelength of 0.15419 nm 1 it has a powder X-ray diffraction pattern having reflections at 2-θ angles including: (6.8 ± 0.2)°, (9.1 ± 0.2)°, (10.1 ± 0.2)°, (11.4 ± 0.2)°, (12.0 ± 0.2)°, (13.6 ± 0.2)°, (14.4 ± 0.2)°, (17.2 ± 0.2)°, (23.5 ± 0.2)°, and (29.0 ± 0.2)°.

[0161] Alternatively or additionally, crystalline Form I of the compound of formula (I) is characterized by having, when measured at room temperature with Cu-Kα1 radiation having a wavelength of 0.15419 nm, substantially the same powder X-ray diffraction pattern as shown in Figure 3 of the present invention.

[0162] Alternatively or additionally, crystalline Form I of the compound of formula (I) is characterized by having a Fourier transform infrared spectrum comprising bands at the following wavenumbers when measured at room temperature using a diamond ATR cell: (1083 ± 2) cm -1 、(1383 ± 2) cm -1 and (1594 ± 2) cm -1 . Preferably, crystalline Form I of the compound of formula (I) is characterized by having a Fourier transform infrared spectrum comprising peaks at the following wavenumbers when measured at room temperature using a diamond ATR cell: (713 ± 2) cm -1 、(1083 ± 2) cm -1 、(1383 ± 2) cm -1 、(1557 ± 2) cm -1 and (1594 ± 2) cm -1 . Preferably, crystalline Form I of the compound of formula (I) is characterized by having a Fourier transform infrared spectrum comprising bands at the following wavenumbers when measured at room temperature using a diamond ATR cell: (494 ± 2) cm -1 、(564 ± 2) cm -1 、(713 ± 2) cm -1 、(1083 ± 2) cm -1 、(1383 ± 2) cm -1 、(1557 ± 2) cm -1 and (1594 ± 2) cm -1 . Preferably, crystalline Form I of the compound of formula (I) is characterized by having a Fourier transform infrared spectrum comprising bands at the following wavenumbers when measured at room temperature using a diamond ATR cell: (494 ± 2) cm -1 、(564 ± 2) cm -1 、(713 ± 2) cm -1 、(935 ± 2) cm -1 、(1083 ± 2) cm -1 、(1383 ± 2) cm -1 、(1557 ± 2) cm -1 、(1594 ± 2) cm -1 、(1661 ± 2) cm -1 and (3313 ± 2) cm -1 .

[0163] Alternatively, the crystalline Form I of the compound of formula (I) is characterized in that, when measured at room temperature using a diamond ATR cell, it has a Fourier transform infrared spectrum substantially the same as that shown in Figure 4 of the present invention.

[0164] Alternatively or additionally, the crystalline Form I of the compound of formula (I) is characterized in that, when measured at room temperature using a laser at a wavelength of 1064 nm, it has a Raman spectrum comprising peaks at the following wave numbers: (938 ± 2) cm -1 , (1460 ± 2) cm -1 and (2890 ± 2) cm -1 . Preferably, the crystalline Form I of the compound of formula (I) is characterized in that, when measured at room temperature using a laser at a wavelength of 1064 nm, it has a Raman spectrum comprising bands at the following wave numbers: (387 ± 2) cm -1 , (834 ± 2) cm -1 , (938 ± 2) cm -1 , (1460 ± 2) cm -1 and (2890 ± 2) cm -1 . Preferably, the crystalline Form I of the compound of formula (I) is characterized in that, when measured at room temperature using a laser at a wavelength of 1064 nm, it has a Raman spectrum comprising peaks at the following wave numbers: (387 ± 2) cm -1 , (834 ± 2) cm -1 , (938 ± 2) cm -1 , (1305 ± 2) cm -1 , (1460 ± 2) cm -1 , (2890 ± 2) cm -1 and (2965 ± 2) cm -1 . Preferably, the crystalline Form I of the compound of formula (I) is characterized in that, when measured at room temperature using a laser at a wavelength of 1064 nm, it has a Raman spectrum comprising peaks at the following wave numbers: (387 ± 2) cm -1 , (834 ± 2) cm -1 , (938 ± 2) cm -1 , (1241 ± 2) cm -1 , (1305 ± 2) cm -1 , (1393 ± 2) cm -1 , (1422 ± 2) cm -1 , (1460 ± 2) cm -1 , (2890 ± 2) cm -1 and (2965 ± 2) cm -1 .

[0165] Alternatively, crystalline Form I of the compound of formula (I) is characterized by having a Raman spectrum that is substantially the same as that shown in Figure 5 of the present invention when measured at room temperature with a laser at a wavelength of 1064 nm.

[0166] Crystalline Form II of the compound of formula (I)

[0167] Crystalline Form II of the compound of formula (I) is characterized by having a powder X-ray diffraction pattern comprising reflections at the following 2-θ angles when measured at room temperature with Cu-Kα 1 radiation having a wavelength of 0.15419 nm: (10.2 ± 0.2)°, (10.8 ± 0.2)°, and (11.3 ± 0.2)°. Preferably, crystalline Form II of the compound of formula (I) is characterized by having a powder X-ray diffraction pattern comprising reflections at the following 2-θ angles when measured at room temperature with Cu-Kα 1 radiation having a wavelength of 0.15419 nm: (7.3 ± 0.2)°, (10.2 ± 0.2)°, (10.8 ± 0.2)°, (11.3 ± 0.2)°, and (13.3 ± 0.2)°. Preferably, crystalline Form II of the compound of formula (I) is characterized by having a powder X-ray diffraction pattern comprising reflections at the following 2-θ angles when measured at room temperature with Cu-Kα 1 radiation having a wavelength of 0.15419 nm: (7.1 ± 0.2)°, (7.3 ± 0.2)°, (10.2 ± 0.2)°, (10.8 ± 0.2)°, (11.3 ± 0.2)°, (13.3 ± 0.2)°, and (15.1 ± 0.2)°. Preferably, crystalline Form II of the compound of formula (I) is characterized by having a powder X-ray diffraction pattern comprising reflections at the following 2-θ angles when measured at room temperature with Cu-Kα 1 radiation having a wavelength of 0.15419 nm: (5.4 ± 0.2)°, (7.1 ± 0.2)°, (7.3 ± 0.2)°, (10.2 ± 0.2)°, (10.8 ± 0.2)°, (11.3 ± 0.2)°, (13.3 ± 0.2)°, (14.8 ± 0.2)°, (15.1 ± 0.2)°, and (15.6 ± 0.2)°.

[0168] Alternatively, crystalline Form II of the compound of formula (I) is characterized by having a powder X-ray diffraction pattern that is substantially the same as that shown in Figure 8 of the present invention when measured at room temperature with Cu-Kα1 radiation having a wavelength of 0.15419 nm.

[0169] Alternatively or additionally, crystalline Form II of the compound of formula (I) is characterized by a Fourier transform infrared spectrum having bands at the following wave numbers when measured at room temperature using a diamond ATR cell: (1082 ± 2) cm -1 、(1380 ± 2) cm -1 and (1596 ± 2) cm -1 。Preferably, crystalline Form II of the compound of formula (I) is characterized by a Fourier transform infrared spectrum having bands at the following wave numbers when measured at room temperature using a diamond ATR cell: (716 ± 2) cm -1 、(1082 ± 2) cm -1 、(1380 ± 2) cm -1 、(1557 ± 2) cm -1 and (1596 ± 2) cm -1 。Preferably, crystalline Form II of the compound of formula (I) is characterized by a Fourier transform infrared spectrum having bands at the following wave numbers when measured at room temperature using a diamond ATR cell: (495 ± 2) cm -1 、(716 ± 2) cm -1 、(1082 ± 2) cm -1 、(1316 ± 2) cm -1 、(1380 ± 2) cm -1 、(1557 ± 2) cm -1 and (1596 ± 2) cm -1 。Preferably, crystalline Form II of the compound of formula (I) is characterized by a Fourier transform infrared spectrum having bands at the following wave numbers when measured at room temperature using a diamond ATR cell: (495 ± 2) cm -1 、(716 ± 2) cm -1 、(933 ± 2) cm -1 、(1082 ± 2) cm -1 、(1316 ± 2) cm -1 、(1380 ± 2) cm -1 、(1557 ± 2) cm -1 、(1596 ± 2) cm -1 、(1660 ± 2) cm -1 and (3291 ± 2) cm -1 。

[0170] Alternatively, crystalline Form II of the compound of formula (I) is characterized by having a Fourier transform infrared spectrum that is substantially the same as that shown in Figure 9 of the present invention when measured at room temperature using a diamond ATR cell.

[0171] Alternatively or additionally, crystalline Form II of the compound of formula (I) is characterized by a Raman spectrum having bands at wavenumbers including the following when measured at room temperature with a laser at a wavelength of 1064 nm: (935 ± 2) cm -1 、(1472 ± 2) cm -1 and (2888 ± 2) cm -1 。Preferably, crystalline Form II of the compound of formula (I) is characterized by a Raman spectrum having bands at wavenumbers including the following when measured at room temperature with a laser at a wavelength of 1064 nm: (390 ± 2) cm -1 、(833 ± 2) cm -1 、(935 ± 2) cm -1 、(1472 ± 2) cm -1 and (2888 ± 2) cm -1 。Preferably, crystalline Form II of the compound of formula (I) is characterized by a Raman spectrum having bands at wavenumbers including the following when measured at room temperature with a laser at a wavelength of 1064 nm: (390 ± 2) cm -1 、(833 ± 2) cm -1 、(935 ± 2) cm -1 、(1277 ± 2) cm -1 、(1472 ± 2) cm -1 、(2888 ± 2) cm -1 and (2951 ± 2) cm -1 。Preferably, crystalline Form II of the compound of formula (I) is characterized by a Raman spectrum having bands at wavenumbers including the following when measured at room temperature with a laser at a wavelength of 1064 nm: (390 ± 2) cm -1 、(833 ± 2) cm -1 、(935 ± 2) cm -1 、(1244 ± 2) cm -1 、(1277 ± 2) cm -1 、(1390 ± 2) cm -1 、(1429 ± 2) cm -1 、(1472 ± 2) cm -1 、(2888 ± 2) cm -1 and (2951 ± 2) cm -1 。

[0172] Alternatively, crystalline Form II of the compound of formula (I) is characterized by having a Raman spectrum that is substantially the same as that shown in Figure 10 of the present invention when measured at room temperature with a laser at a wavelength of 1064 nm.

[0173] Separation of the compound of formula (I) in crystalline form I

[0174] In step (v), the compound of formula (I) is separated. In the context of the present invention, step (v) can be understood as part of a broader method (which also includes steps (i), (ii), (iii) and (iv)) and an independent method (which includes the individual sub-steps (v-1) to (v-3) described below), resulting in the separation of the compound of formula (I), preferably resulting in the selective separation of the compound of formula (I) in crystalline form I or crystalline form II.

[0175] In a preferred embodiment, the separation of the compound of formula (I) in step (v) comprises the following steps:

[0176] (v-1) Provide an aqueous mixture comprising the compound of formula (I),

[0177] (v-2) Add an organic solvent,

[0178] (v-3) Dry the solid obtained in (v-2).

[0179] In a further preferred embodiment, the separation of the compound of formula (I) in step (v) comprises the following steps:

[0180] (v-1) Provide an aqueous mixture comprising the compound of formula (I),

[0181] (v-2) Add an organic solvent selected from ethanol, n-propanol, isopropanol or a mixture thereof,

[0182] (v-3) Dry the solid obtained in (v-2).

[0183] In a further preferred embodiment, the separation of the compound of formula (I) in step (v) comprises the following steps:

[0184] (v-1) Provide an aqueous mixture comprising the compound of formula (I),

[0185] (v-2) Add ethanol,

[0186] (v-3) Dry the solid obtained in (v-2).

[0187] In step (v-1), an aqueous mixture containing the compound of formula (I) is provided. Preferably, the only solvent in the aqueous mixture containing the compound of formula (I) is water. Preferably, the compound of formula (I) is completely dissolved in the aqueous mixture. Thus, preferably, in step (v-1), the aqueous mixture containing the compound of formula (I) is an aqueous solution of the compound of formula (I) in water. In order to achieve complete dissolution of the compound of formula (I) and / or obtain an aqueous mixture or aqueous solution of the compound of formula (I) suitable for separating crystalline form I or crystalline form II, processes such as filtration, diafiltration, ultrafiltration, nanofiltration, treatment with ion exchange resins may be required. Preferably, the content of the compound of formula (I) in the aqueous mixture provided in step (v-1) is in the range of 30% to 70% by weight (w / w), more preferably in the range of 40% to 60% by weight (w / w), and even more preferably in the range of 45% to 55% by weight (w / w).

[0188] In step (v-2), an organic solvent selected from ethanol, n-propanol, and isopropanol or a mixture thereof is added to the mixture provided in step (v-1). Preferably, the solvent is ethanol or isopropanol or a mixture thereof. More preferably, the solvent is ethanol. Preferably, the organic solvent is added until the water content of the mixture is in the range of 5% to 25% by weight (w / w), more preferably in the range of 7% to 20% by weight (w / w).

[0189] In a further preferred embodiment, the separation of the compound of formula (I) in step (v) comprises the following steps:

[0190] (v-1) Provide a mixture containing the compound of formula (I) in water,

[0191] (v-2) Add ethanol,

[0192] (v-3) Dry the solid obtained in (v-2).

[0193] In a further preferred embodiment, the separation of the compound of formula (I) in step (v) comprises the following steps:

[0194] (v-1) Provide a solution of the compound of formula (I) in water,

[0195] (v-2) Add ethanol,

[0196] (v-3) Dry the solid obtained in (v-2).

[0197] In step (v-2), the organic solvent is preferably added at a temperature of 45°C to 75°C, more preferably at a temperature of 50°C to 70°C, and even more preferably at a temperature of 55°C to 65°C. Particularly preferably, ethanol is added, which is carried out at the temperature as described above. After adding the organic solvent, the water content of the mixture is preferably in the range of 5% to 25% by weight (w / w), more preferably in the range of 7% to 20% by weight (w / w).

[0198] After adding the organic solvent in step (v-2), a solid is obtained, which is dried in step (v-3).

[0199] In one embodiment, the compound of formula (I) is separated as a crystalline material, i.e., a solid in crystalline form (Form I), in step (v), which is characterized in that when measured at room temperature with Cu-Kα radiation having a wavelength of 0.15419 nm 1 it has a powder X-ray diffraction pattern with reflections at 2-θ angles including: (6.8 ± 0.2)°, (9.1 ± 0.2)°, (10.1 ± 0.2)°, (11.4 ± 0.2)°, and (12.0 ± 0.2)°.

[0200] In one embodiment, the solid is dried at a relative humidity of 18% to 70%, preferably 30% to 65%, thereby obtaining the compound of formula (I) in crystalline form I. Thus, step (v-3) includes drying the solid produced in step (v-2) at a relative humidity of 18% to 70%, preferably 30% to 65%, to obtain the compound of formula (I) in crystalline form I. Additionally or alternatively, step (v-3) includes drying the solid produced in step (v-2) at a relative humidity of 18% to 70%, preferably 30% to 65%, to obtain the compound of formula (I) in crystalline form I, which compound of formula (I) in crystalline form I includes reflections at the following 2-θ angles when measured at room temperature with Cu-Kα radiation having a wavelength of 0.15419 nm 1 : (6.8 ± 0.2)°, (9.1 ± 0.2)°, (10.1 ± 0.2)°, (11.4 ± 0.2)°, and (12.0 ± 0.2)°. Preferably, the drying process is carried out for a time of 1 h to 48 h at the above relative humidity.

[0201] In a preferred embodiment, step (v) includes separating the compound of formula (I) in crystalline form I by

[0202] (v-1) providing an aqueous mixture comprising the compound of formula (I),

[0203] (v-2) adding ethanol,

[0204] (v-3) Dry the solid obtained in (v-2) at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0205] In a further preferred embodiment, step (v) comprises separating the compound of formula (I) in crystalline form I by:

[0206] (v-1) Provide an aqueous solution of the compound of formula (I),

[0207] (v-2) Add ethanol,

[0208] (v-3) Dry the solid obtained in (v-2) at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0209] In a further preferred embodiment, step (v) comprises separating the compound of formula (I) in crystalline form I by:

[0210] (v-1) Provide an aqueous mixture comprising the compound of formula (I), wherein the compound of formula (I) is in the range of 30% to 70% by weight (w / w), more preferably in the range of 40% to 60% by weight (w / w), even more preferably in the range of 45% to 55% by weight (w / w),

[0211] (v-2) Add ethanol,

[0212] (v-3) Dry the solid obtained in (v-2) at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0213] In a further preferred embodiment, step (v) comprises separating the compound of formula (I) in crystalline form I by:

[0214] (v-1) Provide an aqueous mixture comprising the compound of formula (I), wherein the compound of formula (I) is in the range of 30% to 70% by weight (w / w), more preferably in the range of 40% to 60% by weight (w / w), even more preferably in the range of 45% to 55% by weight (w / w),

[0215] (v-2) Add ethanol until the water content of the mixture is in the range of 5% to 25% by weight (w / w), more preferably in the range of 7% to 20% by weight (w / w),

[0216] (v-3) Dry the solid obtained in (v-2) at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0217] In a further preferred embodiment, step (v) comprises separating the compound of formula (I) in crystalline form I by:

[0218] (v-1) Provide an aqueous mixture comprising a compound of formula (I), wherein the compound of formula (I) is in the range of 30% to 70% by weight (w / w), more preferably in the range of 40% to 60% by weight (w / w), and most preferably in the range of 45% to 55% by weight (w / w).

[0219] (v-2) Add ethanol until the water content of the mixture is in the range of 5% to 25% by weight (w / w), more preferably in the range of 7% to 20% by weight (w / w).

[0220] (v-3) Dry the solid obtained in (v-2) for a time of 1 h to 48 h at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0221] In a further preferred embodiment, step (v) comprises separating the compound of formula (I) in crystalline form I by:[

[0222] (v-1) Provide an aqueous solution of a compound of formula (I), wherein the compound of formula (I) is in the range of 30% to 70% by weight (w / w), more preferably in the range of 40% to 60% by weight (w / w), and most preferably in the range of 45% to 55% by weight (w / w).

[0223] (v-2) Add ethanol until the water content of the mixture is in the range of 5% to 25% by weight (w / w), more preferably in the range of 7% to 20% by weight (w / w).

[0224] (v-3) Dry the solid obtained in (v-2) for a time of 1 h to 48 h at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0225] Separation of the compound of formula (I) in crystalline form II

[0226] In a further embodiment, in step (v), the compound of formula (I) is separated as a crystalline material, i.e., a solid in crystalline form (form II), which is characterized in that when measured at room temperature with Cu-Kα radiation having a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern with reflections at 2-θ angles including the following: (7.3 ± 0.2)°, (10.2 ± 0.2)°, (10.8 ± 0.2)°, (11.3 ± 0.2)°, and (13.3 ± 0.2)°. 1 (7.3 ± 0.2)°, (10.2 ± 0.2)°, (10.8 ± 0.2)°, (11.3 ± 0.2)°, and (13.3 ± 0.2)°.

[0227] In a further embodiment, the solid is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then further dried by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached, whereby a compound of formula (I) in crystalline form II is obtained.

[0228] Thus, step (v-3) comprises first drying the solid produced in step (v-2) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then subjecting it to a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached, whereby a compound of formula (I) in crystalline form II is obtained.

[0229] Additionally or alternatively, step (v-3) comprises first drying the solid produced in step (v-2) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then subjecting it to a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached, whereby a compound of formula (I) in crystalline form II is obtained, which compound of formula (I) in crystalline form II comprises reflections at the following 2-θ angles when measured at room temperature with Cu-Kα 1 radiation of wavelength 0.15419 nm: (7.3 ± 0.2)°, (10.2 ± 0.2)°, (10.8 ± 0.2)°, (11.3 ± 0.2)° and (13.3 ± 0.2)°.

[0230] In some cases, the formation of crystalline material is observed during the second drying process at low relative humidity, which is not related to form I and form II. Figure 33 The X-ray powder diffraction pattern of this material is shown in. This crystalline form may or may not form during the first and / or second drying process, and if it forms, it may form in different amounts and be accompanied by other species, such as crystalline form II of the compound of formula (I), depending on the specific conditions in each case. Nevertheless, adjusting the relative humidity of the second drying process until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached ensures a reliable conversion to crystalline form II of the compound of formula (I) and the preparation of crystalline form II of the compound of formula (I).

[0231] Preferably, the first drying process is carried out for a time of 0.5 h to 24 h at the above relative humidity, and the second drying process is carried out for a time of 0.5 h to 48 h at the above relative humidity.

[0232] In a preferred embodiment, step (v) comprises separating the compound of formula (I) in crystalline form II by:

[0233] (v-1) providing an aqueous mixture comprising the compound of formula (I),

[0234] (v-2) adding ethanol,

[0235] (v-3) drying the solid obtained in (v-2) first at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then carrying out a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

[0236] In a preferred embodiment, step (v) comprises separating the compound of formula (I) in crystalline form II by:

[0237] (v-1) providing an aqueous solution of the compound of formula (I),

[0238] (v-2) adding ethanol,

[0239] (v-3) drying the solid obtained in (v-2) first at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then carrying out a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

[0240] In a further preferred embodiment, step (v) comprises separating the compound of formula (I) in crystalline form II by:

[0241] (v-1) providing an aqueous mixture comprising the compound of formula (I), wherein the compound of formula (I) is in the range of 30% to 70% by weight (w / w), more preferably in the range of 40% to 60% by weight (w / w), even more preferably in the range of 45% to 55% by weight (w / w),

[0242] (v-2) adding ethanol,

[0243] (v-3) drying the solid obtained in (v-2) first at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then carrying out a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

[0244] In a further preferred embodiment, step (v) comprises separating the compound of formula (I) in crystalline form II by:

[0245] (v-1) Provide an aqueous mixture containing a compound of formula (I), wherein the compound of formula (I) is in the range of 30% to 70% by weight (w / w), more preferably in the range of 40% to 60% by weight (w / w), and even more preferably in the range of 45% to 55% by weight (w / w).

[0246] (v-2) Add ethanol until the water content of the mixture is in the range of 5% to 25% by weight (w / w), more preferably in the range of 7% to 20% by weight (w / w).

[0247] (v-3) First dry the solid obtained in (v-2) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then carry out a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

[0248] In a further preferred embodiment, step (v) comprises separating the compound of formula (I) in crystalline form II by:

[0249] (v-1) Provide an aqueous solution of a compound of formula (I), wherein the compound of formula (I) is in the range of 30% to 70% by weight (w / w), more preferably in the range of 40% to 60% by weight (w / w), and even more preferably in the range of 45% to 55% by weight (w / w).

[0250] (v-2) Add ethanol until the water content of the mixture is in the range of 5% to 25% by weight (w / w), more preferably in the range of 7% to 20% by weight (w / w).

[0251] (v-3) First dry the solid obtained in (v-2) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then carry out a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

[0252] In a further preferred embodiment, step (v) comprises separating the compound of formula (I) in crystalline form II by:

[0253] (v-1) Provide an aqueous mixture containing a compound of formula (I), wherein the compound of formula (I) is in the range of 30% to 70% by weight (w / w), more preferably in the range of 40% to 60% by weight (w / w), and even more preferably in the range of 45% to 55% by weight (w / w).

[0254] (v-2) Ethanol is added until the water content of the mixture is in the range of 5% to 25% by weight (w / w), more preferably in the range of 7% to 20% by weight (w / w).

[0255] (v-3) The solid obtained in (v-2) is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16% for a period of 0.5 h to 24 h, and then a second drying process is carried out for a period of 0.5 h to 48 h by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

[0256] Method for preparing crystalline Form I of the compound of formula (I)

[0257] The present invention provides a method for selectively preparing the crystalline Form I of the compound of formula (I). The details of the method according to the above steps (i) to (iv) are applicable to the method described herein, and the details of the method according to the above steps (v-1) to (v-3) are also applicable to the separation of the crystalline Form I of the compound of formula (I).

[0258] In a preferred embodiment of the first aspect, the present invention relates to a method for preparing the above general formula (I) compound or its stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof, the method comprising

[0259] (i) providing a mixture comprising the compound of formula (I), water and at least a first organic solvent,

[0260] (ii) removing water from the mixture provided in (i),

[0261] (iii) adding a second organic solvent,

[0262] (iv) adding a third organic solvent,

[0263] (v) separating the compound of formula (I) in crystalline Form I by a method comprising:

[0264] (v-1) providing an aqueous mixture comprising the compound of formula (I),

[0265] (v-2) adding ethanol,

[0266] (v-3) drying the solid obtained in (v-2) at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0267] In a preferred embodiment of the first aspect, the present invention relates to a method for preparing the above general formula (I) compound or its stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof, the method comprising

[0268] (i) Providing a mixture comprising a compound of formula (I), water and at least a first organic solvent,

[0269] (ii) Removing water from the mixture provided in (i),

[0270] (iii) Adding a second organic solvent,

[0271] (iv) Adding a third organic solvent,

[0272] (v) Separating the compound of formula (I) in crystalline form I by a method comprising:

[0273] (v-1) Providing an aqueous solution of the compound of formula (I),

[0274] (v-2) Adding ethanol,

[0275] (v-3) Drying the solid obtained in (v-2) at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0276] In another preferred embodiment of the first aspect, the present invention relates to a method for preparing the compound of general formula (I) above or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, the method comprising

[0277] (i) Providing a mixture comprising a compound of formula (I), water and at least a first organic solvent,

[0278] (ii) Removing water from the mixture provided in (i),

[0279] (iii) Adding a second organic solvent,

[0280] (iv) Adding a third organic solvent,

[0281] (v) Separating the compound of formula (I) in crystalline form I by a method comprising:

[0282] (v-1) Providing an aqueous mixture comprising the compound of formula (I),

[0283] (v-2) Adding ethanol,

[0284] (v-3) Drying the solid obtained in (v-2) at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0285] In a further embodiment of the first aspect, the present invention relates to a method for preparing the compound of general formula (I) above or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, the method comprising

[0286] (i) Provide a mixture comprising a compound of formula (I), water and at least a first organic solvent,

[0287] (ii) Remove water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% by weight (w / w),

[0288] (iii) Add a second organic solvent, wherein the second organic solvent is an alcohol selected from ethanol, n-propanol and isopropanol,

[0289] (iv) Add a third organic solvent, wherein the third organic solvent is acetone,

[0290] (v) Isolate the compound of formula (I) in crystalline form I by a method comprising

[0291] (v-1) Provide an aqueous mixture comprising a compound of formula (I),

[0292] (v-2) Add ethanol,

[0293] (v-3) Dry the solid obtained in (v-2) at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0294] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of formula (I) above or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, the method comprising

[0295] (i) Provide a mixture comprising a compound of formula (I), water and at least a first organic solvent,

[0296] (ii) Remove water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% by weight (w / w),

[0297] (iii) Add a second organic solvent, wherein the second organic solvent is ethanol,

[0298] (iv) Add a third organic solvent, wherein the third organic solvent is acetone,

[0299] (v) Isolate the compound of formula (I) in crystalline form I by a method comprising

[0300] (v-1) Provide an aqueous mixture comprising a compound of formula (I),

[0301] (v-2) Add ethanol,

[0302] (v-3) Dry the solid obtained in (v-2) at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0303] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of the above general formula (I) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, the method comprising

[0304] (i) providing a mixture comprising a compound of formula (I), water and at least a first organic solvent, wherein the at least first organic solvent is DMSO,

[0305] (ii) removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% by weight (w / w),

[0306] (iii) adding a second organic solvent, wherein the second organic solvent is ethanol,

[0307] (iv) adding a third organic solvent, wherein the third organic solvent is acetone,

[0308] (v) separating the compound of formula (I) in crystalline form I by a method comprising

[0309] (v-1) providing an aqueous mixture comprising a compound of formula (I),

[0310] (v-2) adding ethanol,

[0311] (v-3) drying the solid obtained in (v-2) at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0312] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of the above general formula (I) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, the method comprising

[0313] (i) providing a mixture comprising a compound of formula (I), water and at least a first organic solvent, wherein the at least first organic solvent is DMSO,

[0314] (ii) removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% by weight (w / w),

[0315] (iii) adding a second organic solvent, wherein the second organic solvent is ethanol,

[0316] (iv) adding a third organic solvent, wherein the third organic solvent is acetone,

[0317] (v) separating the compound of formula (I) in crystalline form I by a method comprising

[0318] (v-1) Provide an aqueous mixture comprising a compound of formula (I).

[0319] (v-2) Add ethanol.

[0320] (v-3) Dry the solid obtained in (v-2) at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0321] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of formula (I) above or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, the method comprising

[0322] (i) Provide a mixture comprising a compound of formula (I), water and at least a first organic solvent, wherein the at least first organic solvent is DMSO.

[0323] (ii) Remove water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% by weight (w / w).

[0324] (iii) Add a second organic solvent, wherein the second organic solvent is ethanol.

[0325] (iv) Add a third organic solvent, wherein the third organic solvent is acetone.

[0326] (v) Isolate the compound of formula (I) in crystalline form I by a method comprising

[0327] (v-1) Provide an aqueous solution of a compound of formula (I).

[0328] (v-2) Add ethanol.

[0329] (v-3) Dry the solid obtained in (v-2) at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0330] A method for preparing crystalline form II of a compound of formula (I)

[0331] The present invention provides a method for selectively preparing crystalline form II of a compound of formula (I). The details of the method according to the above steps (i) to (iv) apply to the method described herein, and the details of the method according to the above steps (v-1) to (v-3) also apply to the isolation of crystalline form II of the compound of formula (I).

[0332] Thus, in a further preferred embodiment of the first aspect, the present invention relates to a method for preparing a compound of formula (I) above or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, the method comprising

[0333] (i) Provide a mixture comprising a compound of formula (I), water and at least a first organic solvent,

[0334] (ii) Remove water from the mixture provided in (i),

[0335] (iii) Add a second organic solvent,

[0336] (iv) Add a third organic solvent,

[0337] (v) Isolate the compound of formula (I) in crystalline form II by a method comprising:

[0338] (v-1) Provide an aqueous mixture comprising a compound of formula (I),

[0339] (v-2) Add ethanol,

[0340] (v-3) First dry the solid obtained in (v-2) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then perform a second drying by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

[0341] Thus, in a further preferred embodiment of the first aspect, the present invention relates to a method for preparing a compound of formula (I) above or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, the method comprising

[0342] (i) Provide a mixture comprising a compound of formula (I), water and at least a first organic solvent,

[0343] (ii) Remove water from the mixture provided in (i),

[0344] (iii) Add a second organic solvent,

[0345] (iv) Add a third organic solvent,

[0346] (v) Isolate the compound of formula (I) in crystalline form II by a method comprising:

[0347] (v-1) Provide an aqueous solution of a compound of formula (I),

[0348] (v-2) Add ethanol,

[0349] (v-3) First, dry the solid obtained in (v-2) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then perform a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

[0350] Thus, in a further preferred embodiment of the first aspect, the present invention relates to a method for preparing the above-mentioned compound of general formula (I) or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, said method comprising

[0351] (i) providing a mixture comprising a compound of formula (I), water and at least a first organic solvent,

[0352] (ii) removing water from the mixture provided in (i),

[0353] (iii) adding a second organic solvent,

[0354] (iv) adding a third organic solvent,

[0355] (v) separating the compound of formula (I) in crystalline form II by a method comprising:

[0356] (v-1) providing an aqueous mixture comprising a compound of formula (I),

[0357] (v-2) adding ethanol,

[0358] (v-3) First, dry the solid obtained in (v-2) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then perform a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

[0359] In a further embodiment of the first aspect, the present invention relates to a method for preparing the above-mentioned compound of general formula (I) or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, said method comprising

[0360] (i) providing a mixture comprising a compound of formula (I), water and at least a first organic solvent,

[0361] (ii) removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% by weight (w / w),

[0362] (iii) adding a second organic solvent, wherein the second organic solvent is an alcohol selected from ethanol, n-propanol and isopropanol,

[0363] (iv) Add a third organic solvent, wherein the third organic solvent is acetone

[0364] (v) Isolate the compound of formula (I) in crystalline form II by a method comprising:

[0365] (v-1) Provide an aqueous mixture comprising the compound of formula (I),

[0366] (v-2) Add ethanol,

[0367] (v-3) First dry the solid obtained in (v-2) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then carry out a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

[0368] In a further embodiment of the first aspect, the present invention relates to a method for preparing the above general formula (I) compound or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, said method comprising

[0369] (i) Provide a mixture comprising the compound of formula (I), water and at least a first organic solvent,

[0370] (ii) Remove water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% by weight (w / w),

[0371] (iii) Add a second organic solvent, wherein the second organic solvent is ethanol,

[0372] (iv) Add a third organic solvent, wherein the third organic solvent is acetone,

[0373] (v) Isolate the compound of formula (I) in crystalline form II by a method comprising:

[0374] (v-1) Provide an aqueous mixture comprising the compound of formula (I),

[0375] (v-2) Add ethanol,

[0376] (v-3) First dry the solid obtained in (v-2) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then carry out a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

[0377] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of the above general formula (I) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, the method comprising

[0378] (i) providing a mixture comprising a compound of formula (I), water and at least a first organic solvent, wherein the at least first organic solvent is DMSO,

[0379] (ii) removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% by weight (w / w),

[0380] (iii) adding a second organic solvent, wherein the second organic solvent is ethanol,

[0381] (iv) adding a third organic solvent, wherein the third organic solvent is acetone,

[0382] (v) separating the compound of formula (I) in crystalline form II by a method comprising

[0383] (v-1) providing an aqueous mixture comprising a compound of formula (I),

[0384] (v-2) adding ethanol,

[0385] (v-3) first drying the solid obtained in (v-2) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then performing a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

[0386] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of the above general formula (I) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, the method comprising

[0387] (i) providing a mixture comprising a compound of formula (I), water and at least a first organic solvent, wherein the at least first organic solvent is DMSO,

[0388] (ii) removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% by weight (w / w),

[0389] (iii) adding a second organic solvent, wherein the second organic solvent is ethanol,

[0390] (iv) adding a third organic solvent, wherein the third organic solvent is acetone,

[0391] (v) Separating the compound of formula (I) in crystalline form II by a method comprising:

[0392] (v-1) Providing an aqueous solution of the compound of formula (I),

[0393] (v-2) Adding ethanol,

[0394] (v-3) First drying the solid obtained in (v-2) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16% for a period of 0.5 h to 24 h, and then carrying out a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached for a period of 0.5 h to 48 h.

[0395] In a further embodiment of the first aspect, the present invention relates to a method for preparing the compound of the above general formula (I) or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof, the method comprising

[0396] (i) Providing a mixture comprising the compound of formula (I), water and at least a first organic solvent,

[0397] (ii) Removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% by weight (w / w),

[0398] (iii) Adding a second organic solvent, wherein the second organic solvent is an alcohol selected from ethanol, n-propanol and isopropanol,

[0399] (iv) Adding a third organic solvent, wherein the third organic solvent is acetone

[0400] (v) Separating the compound of formula (I) in crystalline form II by a method comprising:

[0401] (v-1) Providing an aqueous mixture comprising the compound of formula (I),

[0402] (v-2) Adding ethanol,

[0403] (v-3) First drying the solid obtained in (v-2) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16% for a period of 0.5 h to 24 h, and then carrying out a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25%

[0404] to 70%, more preferably 30% to 70% is reached for a period of 0.5 h to 48 h.

[0405] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of the above general formula (I) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, the method comprising

[0406] (i) providing a mixture comprising a compound of formula (I), water and at least a first organic solvent,

[0407] (ii) removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% by weight (w / w),

[0408] (iii) adding a second organic solvent, wherein the second organic solvent is ethanol,

[0409] (iv) adding a third organic solvent, wherein the third organic solvent is acetone,

[0410] (v) separating the compound of formula (I) in crystalline form II by a method comprising

[0411] (v-1) providing an aqueous mixture comprising a compound of formula (I),

[0412] (v-2) adding ethanol,

[0413] (v-3) first drying the solid obtained in (v-2) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16% for a period of 0.5 h to 24 h, and then carrying out a second drying process for a period of 0.5 h to 48 h by adjusting the relative humidity until a final value of 18% to 70%, preferably 25%

[0414] to 70%, more preferably 30% to 70% is reached.

[0415] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of the above general formula (I) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, the method comprising

[0416] (i) providing a mixture comprising a compound of formula (I), water and at least a first organic solvent, wherein the at least first organic solvent is DMSO,

[0417] (ii) removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% by weight (w / w),

[0418] (iii) adding a second organic solvent, wherein the second organic solvent is ethanol,

[0419] (iv) Add a third organic solvent, wherein the third organic solvent is acetone,

[0420] (v) Isolate the compound of formula (I) in crystalline form II by a method comprising:

[0421] (v-1) Provide an aqueous mixture comprising the compound of formula (I),

[0422] (v-2) Add ethanol,

[0423] (v-3) First dry the solid obtained in (v-2) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16% for a time of 0.5 h to 24 h, and then carry out a second drying process for a time of 0.5 h to 48 h by adjusting the relative humidity until a final value of 18% to 70%, preferably 25%

[0424] to 70%, more preferably 30% to 70% is reached.

[0425] Crystallization of form I of the compound of formula (I)

[0426] The present invention also provides a method for preparing crystalline form I of the compound of formula I, i.e., the crystalline form I of the compound of formula I is characterized in that when measured at room temperature with Cu-Kα 1 radiation having a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern with reflections at 2-θ angles including: (6.8 ± 0.2)°, (9.1 ± 0.2)°, (10.1 ± 0.2)°, (11.4 ± 0.2)° and (12.0 ± 0.2)°.

[0427] Thus, in one embodiment, the present invention provides a method for preparing crystalline form I of the compound of formula (I)

[0428]

[0429] The method comprises:

[0430] (i) Provide an aqueous mixture comprising the compound of formula (I),

[0431] (ii) Add an organic solvent,

[0432] (iii) Dry the solid obtained in (ii) at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0433] In a further embodiment, the present invention provides a method for preparing crystalline form I of the above-mentioned compound of formula (I), the method comprising:

[0434] (i) Provide an aqueous mixture comprising the compound of formula (I),

[0435] (ii) adding an organic solvent selected from ethanol, n-propanol, and isopropanol or a mixture thereof

[0436] (iii) drying the solid obtained in (ii) at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0437] In a further embodiment, the present invention provides a method for preparing crystalline Form I of the above compound of formula (I), the method comprising:

[0438] (i) providing an aqueous mixture comprising the compound of formula (I)

[0439] (ii) adding ethanol

[0440] (iii) drying the solid obtained in (ii) at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0441] In step (i), an aqueous mixture comprising the compound of formula (I) is provided. Preferably, the only solvent in the aqueous mixture comprising the compound of formula (I) is water. Preferably, the compound of formula (I) is completely dissolved in the aqueous mixture. Thus, preferably, in step (i), the aqueous mixture comprising the compound of formula (I) is an aqueous solution of the compound of formula (I) in water. In order to achieve complete dissolution of the compound of formula (I) and / or obtain an aqueous mixture or aqueous solution of the compound of formula (I) suitable for separating crystalline Form I or crystalline Form II, processes such as filtration, diafiltration, ultrafiltration, nanofiltration, treatment with an ion exchange resin may be required. Preferably, the content of the compound of formula (I) in the aqueous mixture provided in step (i) is in the range of 30% to 70% by weight (w / w), more preferably in the range of 40% to 60% by weight (w / w), even more preferably in the range of 45% to 55% by weight (w / w).

[0442] In step (ii), an organic solvent is added to the mixture provided in step (i). Preferably, the organic solvent is selected from ethanol, n-propanol, and isopropanol or a mixture thereof. Preferably, the solvent is ethanol or isopropanol or a mixture thereof. More preferably, the solvent is ethanol. Preferably, the organic solvent is added until the water content of the mixture is in the range of 5% to 25% by weight (w / w), more preferably in the range of 7% to 20% by weight (w / w).

[0443] In step (ii), the organic solvent is preferably added at a temperature of 45°C to 75°C, more preferably at a temperature of 50°C to 70°C, even more preferably at a temperature of 55°C to 65°C. Particularly preferably, ethanol is added, which is carried out at the temperature as described above. After adding the organic solvent, the water content of the mixture is preferably in the range of 5% to 25% by weight (w / w), more preferably in the range of 7% to 20% by weight (w / w).

[0444] After adding the organic solvent in step (ii), a solid is obtained, which is dried in step (iii) at a relative humidity of 18% to 70%, preferably 30% to 65%, thereby obtaining the compound of formula (I) in crystalline form I. Thus, step (iii) comprises drying the solid produced in step (ii) at a relative humidity of 18% to 70%, preferably 30% to 65%, to obtain the compound of formula (I) in crystalline form I. Additionally or alternatively, step (iii) comprises drying the solid produced in step (ii) at a relative humidity of 18% to 70%, preferably 30% to 65%, to obtain the compound of formula (I) in crystalline form I, which compound of formula (I) in crystalline form I comprises reflections at the following 2-θ angles when measured with Cu-Kα 1 radiation having a wavelength of 0.15419 nm at room temperature: (6.8 ± 0.2)°, (9.1 ± 0.2)°, (10.1 ± 0.2)°, (11.4 ± 0.2)° and (12.0 ± 0.2)°. Preferably, the drying process is carried out for a time of 1 h to 48 h at the above relative humidity.

[0445] In a preferred embodiment, the present invention provides a method for preparing crystalline form I of the above-mentioned compound of formula (I), the method comprising:

[0446] (i) providing an aqueous mixture comprising the compound of formula (I),

[0447] (ii) adding ethanol,

[0448] (iii) drying the solid obtained in (ii) at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0449] In a preferred embodiment, the present invention provides a method for preparing crystalline form I of the above-mentioned compound of formula (I), the method comprising:

[0450] (i) providing an aqueous solution of the compound of formula (I),

[0451] (ii) adding ethanol,

[0452] (iii) drying the solid obtained in (ii) at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0453] In a further preferred embodiment, the present invention provides a method for preparing crystalline Form I of the above compound of formula (I), the method comprising:

[0454] (i) providing an aqueous mixture comprising the compound of formula (I), wherein the compound of formula (I) is in the range of 30% to 70% by weight (w / w), more preferably in the range of 40% to 60% by weight (w / w), even more preferably in the range of 45% to 55% by weight (w / w),

[0455] (ii) adding ethanol,

[0456] (iii) drying the solid obtained in (ii) at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0457] In a further preferred embodiment, the present invention provides a method for preparing crystalline Form I of the above compound of formula (I), the method comprising:

[0458] (i) providing an aqueous mixture comprising the compound of formula (I), wherein the compound of formula (I) is in the range of 30% to 70% by weight (w / w), more preferably in the range of 40% to 60% by weight (w / w), even more preferably in the range of 45% to 55% by weight (w / w),

[0459] (ii) adding ethanol until the water content of the mixture is in the range of 5% to 25% by weight (w / w), more preferably in the range of 7% to 20% by weight (w / w),

[0460] (iii) drying the solid obtained in (ii) at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0461] In a further preferred embodiment, the present invention provides a method for preparing crystalline Form I of the above compound of formula (I), the method comprising:

[0462] (i) providing an aqueous solution of the compound of formula (I), wherein the compound of formula (I) is in the range of 30% to 70% by weight (w / w), more preferably in the range of 40% to 60% by weight (w / w), even more preferably in the range of 45% to 55% by weight (w / w),

[0463] (ii) adding ethanol until the water content of the mixture is in the range of 5% to 25% by weight (w / w), more preferably in the range of 7% to 20% by weight (w / w),

[0464] (iii) Dry the solid obtained in (ii) at a relative humidity of 18% to 70%, preferably 30% to 65%.

[0465] In a further preferred embodiment, the present invention provides a method for preparing crystalline Form I of the above-mentioned compound of formula (I), the method comprising:

[0466] (i) Providing an aqueous mixture comprising a compound of formula (I), wherein the compound of formula (I) is in the range of 30% to 70% by weight (w / w), more preferably in the range of 40% to 60% by weight (w / w), even more preferably in the range of 45% to 55% by weight (w / w),

[0467] (ii) Adding ethanol until the water content of the mixture is in the range of 5% to 25% by weight (w / w), more preferably in the range of 7% to 20% by weight (w / w),

[0468] (iii) Drying the solid obtained in (ii) at a relative humidity of 18% to 70%, preferably 30% to 65% for a period of 1 to 48 h.

[0469] Crystallization of Form II of the compound of formula (I)

[0470] The present invention also provides a method for preparing crystalline Form II of the compound of formula (I), i.e., the crystalline Form II of the compound of formula (I) is characterized in that when measured at room temperature with Cu-Kα 1 radiation having a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern including reflections at the following 2-θ angles: (7.3 ± 0.2)°, (10.2 ± 0.2)°, (10.8 ± 0.2)°, (11.3 ± 0.2)° and (13.3 ± 0.2)°.

[0471] Thus, in one embodiment, the present invention provides a method for preparing crystalline Form II of the compound of formula (I)

[0472]

[0473] The method comprising:

[0474] (i) Providing an aqueous mixture comprising a compound of formula (I),

[0475] (ii) Adding an organic solvent,

[0476] (iii) First, dry the solid obtained in (ii) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then conduct a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

[0477] In a further embodiment, the present invention provides a method for preparing the crystalline form II of the above - mentioned compound of formula (I), the method comprising:

[0478] (i) Providing an aqueous mixture comprising the compound of formula (I),

[0479] (ii) Adding an organic solvent selected from ethanol, n - propanol, and isopropanol or a mixture thereof,

[0480] (iii) First, dry the solid obtained in (ii) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then conduct a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

[0481] In a further embodiment, the present invention provides a method for preparing the crystalline form II of the above - mentioned compound of formula (I), the method comprising:

[0482] (i) Providing an aqueous mixture comprising the compound of formula (I),

[0483] (ii) Adding ethanol,

[0484] (iii) First, dry the solid obtained in (ii) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then conduct a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

[0485] In a further embodiment, the present invention provides a method for preparing the crystalline form II of the above - mentioned compound of formula (I), the method comprising:

[0486] (i) Providing an aqueous solution of the compound of formula (I),

[0487] (ii) Adding ethanol,

[0488] (iii) First, dry the solid obtained in (ii) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then conduct a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

[0489] In step (i), an aqueous mixture containing the compound of formula (I) is provided. Preferably, the only solvent in the aqueous mixture containing the compound of formula (I) is water. Preferably, the compound of formula (I) is completely dissolved in the aqueous mixture. Thus, preferably, in step (i), the aqueous mixture containing the compound of formula (I) is an aqueous solution of the compound of formula (I) in water. In order to achieve complete dissolution of the compound of formula (I) and / or to obtain an aqueous mixture or aqueous solution of the compound of formula (I) suitable for separating crystalline form I or crystalline form II, processes such as filtration, diafiltration, ultrafiltration, nanofiltration, treatment with ion exchange resins may be required. Preferably, the content of the compound of formula (I) in the aqueous mixture provided in step (i) is in the range of 30% to 70% by weight (w / w), more preferably in the range of 40% to 60% by weight (w / w), even more preferably in the range of 45% to 55% by weight (w / w).

[0490] In step (ii), an organic solvent is added to the mixture provided in step (i). Preferably, the organic solvent is selected from ethanol, n-propanol, and isopropanol or a mixture thereof. Preferably, the solvent is ethanol or isopropanol or a mixture thereof. More preferably, the solvent is ethanol. Preferably, the organic solvent is added until the water content of the mixture is in the range of 5% to 25% by weight (w / w), more preferably in the range of 7% to 20% by weight (w / w).

[0491] In step (ii), the organic solvent is preferably added at a temperature of 45°C to 75°C, more preferably at a temperature of 50°C to 70°C, even more preferably at a temperature of 55°C to 65°C. Particularly preferably, ethanol is added, which is carried out at the temperature as described above. After adding the organic solvent, the water content of the mixture is preferably in the range of 5% to 25% by weight (w / w), more preferably in the range of 7% to 20% by weight (w / w).

[0492] After adding the organic solvent in step (ii), a solid is obtained, which is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16% in step (iii), and then further dried by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached, thereby obtaining the compound of formula (I) in crystalline form II.

[0493] Thus, step (iii) comprises first drying the solid produced in step (ii) at a relative humidity of from 0% to 25%, preferably from 2% to 18%, more preferably from 5% to 16%, and then carrying out a second drying process by adjusting the relative humidity until a final value of from 18% to 70%, preferably from 25% to 70%, more preferably from 30% to 70% is reached, to obtain the compound of formula (I) in crystalline form II.

[0494] Alternatively or additionally, step (iii) comprises first drying the solid produced in step (ii) at a relative humidity of from 0% to 25%, preferably from 2% to 18%, more preferably from 5% to 16%, and then carrying out a second drying process by adjusting the relative humidity until a final value of from 18% to 70%, preferably from 25% to 70%, more preferably from 30% to 70% is reached, to obtain the compound of formula (I) in crystalline form II, which compound of formula (I) in crystalline form II comprises reflections at the following 2-θ angles when measured at room temperature with Cu-Kα 1 radiation of wavelength 0.15419 nm: (7.3 ± 0.2)°, (10.2 ± 0.2)°, (10.8 ± 0.2)°, (11.3 ± 0.2)° and (13.3 ± 0.2)°.

[0495] Preferably, the first drying process is carried out for a time of from 0.5 h to 24 h at the above relative humidity, and the second drying process is carried out for a time of from 0.5 h to 48 h at the above relative humidity.

[0496] In a preferred embodiment, the present invention provides a process for preparing crystalline form II of the above compound of formula (I), which process comprises:

[0497] (i) providing an aqueous mixture comprising the compound of formula (I),

[0498] (ii) adding ethanol,

[0499] (iii) first drying the solid obtained in (ii) at a relative humidity of from 0% to 25%, preferably from 2% to 18%, more preferably from 5% to 16%, and then carrying out a second drying process by adjusting the relative humidity until a final value of from 18% to 70%, preferably from 25% to 70%, more preferably from 30% to 70% is reached.

[0500] In a further preferred embodiment, the present invention provides a process for preparing crystalline form II of the above compound of formula (I), which process comprises:

[0501] (i) Provide an aqueous mixture comprising a compound of formula (I), wherein the compound of formula (I) is in the range of 30% to 70% by weight (w / w), more preferably in the range of 40% to 60% by weight (w / w), even more preferably in the range of 45% to 55% by weight (w / w).

[0502] (ii) Add ethanol.

[0503] (iii) First dry the solid obtained in (ii) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then perform a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

[0504] In a further preferred embodiment, the present invention provides a method for preparing the crystalline form II of the above-mentioned compound of formula (I), the method comprising:

[0505] (i) Provide an aqueous mixture comprising a compound of formula (I), wherein the compound of formula (I) is in the range of 30% to 70% by weight (w / w), more preferably in the range of 40% to 60% by weight (w / w), even more preferably in the range of 45% to 55% by weight (w / w).

[0506] (ii) Add ethanol until the water content of the mixture is in the range of 5% to 25% by weight (w / w), more preferably in the range of 7% to 20% by weight (w / w).

[0507] (iii) First dry the solid obtained in (ii) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then perform a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

[0508] In a further preferred embodiment, the present invention provides a method for preparing the crystalline form II of the above-mentioned compound of formula (I), the method comprising:

[0509] (i) Provide an aqueous solution of a compound of formula (I), wherein the compound of formula (I) is in the range of 30% to 70% by weight (w / w), more preferably in the range of 40% to 60% by weight (w / w), even more preferably in the range of 45% to 55% by weight (w / w).

[0510] (ii) Add ethanol until the water content of the mixture is in the range of 5% to 25% by weight (w / w), more preferably in the range of 7% to 20% by weight (w / w).

[0511] (iii) First, dry the solid obtained in (ii) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then perform a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

[0512] In a further preferred embodiment, the present invention provides a method for preparing crystalline form II of the compound of formula (I) above, the method comprising:

[0513] (i) Provide an aqueous mixture comprising the compound of formula (I), wherein the compound of formula (I) is in the range of 30% to 70% by weight (w / w), more preferably in the range of 40% to 60% by weight (w / w), and most preferably in the range of 45% to 55% by weight (w / w).

[0514] (ii) Add ethanol until the water content of the mixture is in the range of 5% to 25% by weight (w / w), more preferably in the range of 7% to 20% by weight (w / w).

[0515] (iii) First, dry the solid obtained in (ii) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16% for a time of 0.5 h to 24 h, and then perform a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached for a time of 0.5 h to 48 h.

[0516] Preparation of the compound of formula (I) from the compound of formula (II)

[0517] In a further embodiment, the present invention relates to a method for preparing the compound of formula (I), which comprises

[0518] (i-1) Provide the compound of formula (II) or its stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof.

[0519]

[0520] (i-2) And react the compound of formula (II) with the compound of formula (III) or its salt.

[0521]

[0522] As described in the first aspect, step (i) of the method for preparing the above-mentioned compound of general formula (I) or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, comprises providing a mixture comprising the compound of formula (I), water and at least a first organic solvent. According to a further aspect, the said providing in step (i) comprises

[0523] (i-1) providing a compound of formula (II) or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof,

[0524]

[0525] (i-2) and reacting the compound of formula (II) with a compound of formula (III) or its salt

[0526]

[0527] Accordingly, a further embodiment of the present invention relates to a method for preparing the above-mentioned compound of general formula (I) or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, said method comprising

[0528] (i) providing a mixture comprising the compound of formula (I), water and at least a first organic solvent by a method comprising:

[0529] (i-1) providing a compound of formula (II) or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof,

[0530]

[0531] (i-2) and reacting the compound of formula (II) with a compound of formula (III) or its salt

[0532]

[0533] (ii) removing water from the mixture provided in (i),

[0534] (iii) adding a second organic solvent,

[0535] (iv) adding a third organic solvent,

[0536] (v) separating the compound of formula (I).

[0537] In step (i-1), a compound of formula (II) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof is provided. Preferably, the compound of formula (II) is provided as a solid in step (i-1). More preferably, in step (i-1), the compound of formula (II) is provided as a crystalline solid (i.e., a crystalline form). More preferably, the compound of formula (II) is provided as a crystalline solid in crystalline form I. More preferably, the compound of formula (II) is provided as a crystalline solid in crystalline form I as described below. More preferably, the compound of formula (II) is provided as a crystalline solid in crystalline form I, wherein crystalline form I is characterized in that: when measured at room temperature with Cu-Kα 1 radiation having a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern having reflections at 2-θ angles including the following: (8.0 ± 0.2)°, (9.0 ± 0.2)°, and (12.8 ± 0.2)°.

[0538] Accordingly, a further embodiment of the present invention relates to a method for preparing a compound of the above general formula (I) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, the method comprising

[0539] (i) providing a mixture comprising a compound of formula (I), water and at least a first organic solvent by a method comprising

[0540] (i-1) providing a compound of formula (II) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof as a solid, preferably as a crystalline solid,

[0541]

[0542] (i-2) and reacting the compound of formula (II) with a compound of formula (III) or a salt thereof

[0543]

[0544] (ii) removing water from the mixture provided in (i),

[0545] (iii) adding a second organic solvent,

[0546] (iv) adding a third organic solvent,

[0547] (v) separating the compound of formula (I).

[0548] Accordingly, a further embodiment of the present invention relates to a method for preparing a compound of the above general formula (I) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, the method comprising

[0549] (i) A mixture comprising a compound of formula (I), water and at least a first organic solvent is provided by a method comprising the following:

[0550] (i-1) A compound of formula (II) or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, is provided as a solid, preferably as a crystalline solid in crystalline form I.

[0551]

[0552] (i-2) And the compound of formula (II) is reacted with a compound of formula (III) or a salt thereof.

[0553]

[0554] (ii) Water is removed from the mixture provided in (i).

[0555] (iii) A second organic solvent is added.

[0556] (iv) A third organic solvent is added.

[0557] (v) The compound of formula (I) is separated.

[0558] In the context of the present invention, providing a mixture comprising the above-mentioned compound of formula (I), water and at least a first organic solvent in step (i) by providing a compound of formula (II) and reacting the compound of formula (II) with a compound of formula (III) can be applied to any embodiment of the present invention including the above-mentioned or following step (i).

[0559] In the context of the present invention, step (i) of the method according to the present invention comprises providing a mixture comprising a compound of formula (I), water and at least a first organic solvent, which is achieved by providing a compound of formula (II) and reacting the compound of formula (II) with a compound of formula (III).

[0560] The reaction of the compound of formula (II) with the compound of formula (III) is preferably carried out in water or in an organic solvent. If the reaction is carried out in an organic solvent, the organic solvent is selected from dimethyl sulfoxide, methylimidazole, dimethylacetamide, sulfolane and N-methylpyrrolidone. More preferably, the organic solvent used for the reaction between the compound of formula (II) and the compound of formula (III) is the same as the at least first organic solvent used in step (i) of the method of the present invention. Most preferably, the organic solvent used for the reaction between the compound of formula (II) and the compound of formula (III) is dimethyl sulfoxide (DMSO).

[0561] The reaction of the compound of formula (II) with the compound of formula (III) is preferably carried out in the presence of a base. Such a base is preferably an organic base, more preferably a tertiary amine base. More preferably, the base is a tertiary amine base selected from triethylamine, tributylamine and N,N-diisopropylethylamine. Most preferably, the base is N,N-diisopropylethylamine. Such a base is preferably used in an excess amount. Preferably, the excess base ranges from 4.2 to 8.0 equivalents relative to the amount of the compound of formula (III).

[0562] The reaction of the compound of formula (II) with the compound of formula (III) is preferably carried out at a temperature of 20 °C to 60 °C. To ensure smooth conversion, the temperature is preferably in the range of 40 °C to 60 °C, more preferably in the range of 45 °C to 55 °C.

[0563] The reaction of the compound of formula (II) with the compound of formula (III) is preferably carried out using an excess of the compound of formula (II) in chemical equivalents. Preferably, the excess compound of formula (II) ranges from 4.0 to 6.0 equivalents, more preferably from 4.0 to 4.6 equivalents.

[0564] After the reaction of the compound of formula (II) with the compound of formula (III), water is added to the reaction mixture before separating the compound of formula (I). Preferably, water is added to the mixture obtained from the reaction of the compound of formula (II) with the compound of formula (III) in step (i-2), and then the mixture is treated with a base (preferably an inorganic base such as sodium hydroxide), neutralized with an inorganic acid (such as hydrochloric acid), and optionally extracted with an organic solvent. The preferred organic solvent for optional extraction is methyl tert-butyl ether (MTBE). Thus, preferably, before step (ii), water is added to the mixture obtained from the reaction of the compound of formula (II) with the compound of formula (III) in step (i-2), and then the mixture is treated with a base (preferably an inorganic base such as sodium hydroxide), neutralized with an inorganic acid (such as hydrochloric acid), and optionally extracted with an organic solvent. If an extraction step is included, in the separation of the compound of formula (I), the aqueous phase will undergo step (ii).

[0565] Regarding steps (ii), (iii), (iv) and (v), it should be understood that these steps can be carried out according to the method for preparing the compound of formula (I) of the present invention - including steps (v-1), (v-2) and (v-3) - as described throughout this document.

[0566] Crystalline Forms I, II and III of the Compound of Formula (II)

[0567] In the above step (i-1), a compound of formula (II) or its stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or a mixture thereof is provided. Preferably, in step (i-1), the compound of formula (II) is provided as a solid. More preferably, in step (i-1), the compound of formula (II) is provided as a crystalline solid (i.e., crystalline form).

[0568] Crystalline Form I of the compound of formula (II) is characterized in that when measured at room temperature with Cu-Kα radiation having a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern including reflections at 2-θ angles as follows: (8.0 ± 0.2)°, (9.0 ± 0.2)°, and (12.8 ± 0.2)°. Preferably, Crystalline Form I of the compound of formula (II) is characterized in that when measured at room temperature with Cu-Kα 1 radiation having a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern including reflections at 2-θ angles as follows: (8.0 ± 0.2)°, (9.0 ± 0.2)°, (11.7 ± 0.2)°, (12.8 ± 0.2)°, and (14.9 ± 0.2)°. Preferably, Crystalline Form I of the compound of formula (II) is characterized in that when measured at room temperature with Cu-Kα 1 radiation having a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern including reflections at 2-θ angles as follows: (8.0 ± 0.2)°, (9.0 ± 0.2)°, (10.4 ± 0.2)°, (11.7 ± 0.2)°, (12.8 ± 0.2)°, (14.9 ± 0.2)°. Preferably, Crystalline Form I of the compound of formula (II) is characterized in that when measured at room temperature with Cu-Kα 1 radiation having a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern including reflections at 2-θ angles as follows: (8.0 ± 0.2)°, (9.0 ± 0.2)°, (10.4 ± 0.2)°, (11.7 ± 0.2)°, (12.8 ± 0.2)°, (14.9 ± 0.2)°, and (17.4 ± 0.2)°. Preferably, Crystalline Form I of the compound of formula (II) is characterized in that when measured at room temperature with Cu-Kα 1 radiation having a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern including reflections at 2-θ angles as follows: (8.0 ± 0.2)°, (9.0 ± 0.2)°, (10.4 ± 0.2)°, (11.7 ± 0.2)°, (12.8 ± 0.2)°, (14.9 ± 0.2)°, (17.4 ± 0.2)°, (22.7 ± 0.2)°, (23.0 ± 0.2)°, and (28.3 ± 0.2)°.

[0569] Alternatively, Crystalline Form I of the compound of formula (II) is characterized in that when measured at room temperature with Cu-Kα 1 radiation having a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern substantially the same as that shown in Figure 18 of the present invention.

[0570] Alternatively or additionally, crystalline Form I of the compound of formula (II) is characterized by a Fourier transform infrared spectrum having bands at the following wavenumbers when measured at room temperature using a diamond ATR cell: (1085 ± 2) cm -1 、(1343 ± 2) cm -1 and (1598 ± 2) cm -1 。Preferably, crystalline Form I of the compound of formula (II) is characterized by a Fourier transform infrared spectrum having bands at the following wavenumbers when measured at room temperature using a diamond ATR cell: (715 ± 2) cm -1 、(1085 ± 2) cm -1 、(1343 ± 2) cm -1 、(1522 ± 2) cm -1 and (1598 ± 2) cm -1 。Preferably, crystalline Form I of the compound of formula (II) is characterized by a Fourier transform infrared spectrum having bands at the following wavenumbers when measured at room temperature using a diamond ATR cell: (715 ± 2) cm -1 、(1085 ± 2) cm -1 、(1343 ± 2) cm -1 、(1390 ± 2) cm -1 、(1522 ± 2) cm -1 、(1598 ± 2) cm -1 and (1688 ± 2) cm -1 。Preferably, crystalline Form I of the compound of formula (II) is characterized by a Fourier transform infrared spectrum having bands at the following wavenumbers when measured at room temperature using a diamond ATR cell: (715 ± 2) cm -1 、(1085 ± 2) cm -1 、(1154 ± 2) cm -1 、(1343 ± 2) cm -1 、(1390 ± 2) cm -1 、(1522 ± 2) cm -1 、(1557 ± 2) cm -1 、(1598 ± 2) cm -1 、(1688 ± 2) cm -1 and (1779 ± 2) cm -1 。

[0571] Alternatively, crystalline Form I of the compound of formula (II) is characterized by having a Fourier transform infrared spectrum that is substantially the same as that shown in Figure 19 of the present invention when measured at room temperature using a diamond ATR cell.

[0572] Alternatively or additionally, crystalline Form I of the compound of formula (II) is characterized by a Raman spectrum having bands at wavenumbers including the following when measured at room temperature with a laser at a wavelength of 1064 nm: (1111 ± 2) cm -1 、(1346 ± 2) cm -1 and (1594 ± 2) cm -1 。Preferably, crystalline Form I of the compound of formula (II) is characterized by a Raman spectrum having bands at wavenumbers including the following when measured at room temperature with a laser at a wavelength of 1064 nm: (1111 ± 2) cm -1 、(1213 ± 2) cm -1 、(1346 ± 2) cm -1 、(1594 ± 2) cm -1 and (2884 ± 2) cm -1 。Preferably, crystalline Form I of the compound of formula (II) is characterized by a Raman spectrum having bands at wavenumbers including the following when measured at room temperature with a laser at a wavelength of 1064 nm: (374 ± 2) cm -1 、(865 ± 2) cm -1 、(1111 ± 2) cm -1 、(1213 ± 2) cm -1 、(1346 ± 2) cm -1 、(1594 ± 2) cm -1 and (2884 ± 2) cm -1 。Preferably, crystalline Form I of the compound of formula (II) is characterized by a Raman spectrum having bands at wavenumbers including the following when measured at room temperature with a laser at a wavelength of 1064 nm: (374 ± 2) cm -1 、(865 ± 2) cm -1 、(1111 ± 2) cm -1 、(1213 ± 2) cm -1 、(1346 ± 2) cm -1 、(1396 ± 2) cm -1 、(1463 ± 2) cm -1 、(1594 ± 2) cm -1 、(2884 ± 2) cm -1 and (2987 ± 2) cm -1 。

[0573] Alternatively, crystalline Form I of the compound of formula (II) is characterized by having a Raman spectrum that is substantially the same as that shown in Figure 20 of the present invention when measured at room temperature with a laser at a wavelength of 1064 nm.

[0574] Alternatively or additionally, crystalline Form I of the compound of formula (II) is characterized by having a differential scanning calorimetry curve as shown in Figure 21 the present invention.

[0575] Alternatively or additionally, crystalline Form I of the compound of formula (II) is characterized by having a TGA curve as shown in Figure 22 the present invention.

[0576] Crystalline Form II of the compound of formula (II) is characterized in that, when measured at room temperature using Cu-Kα 1 radiation with a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern comprising reflections at the following 2-θ angles: (6.6 ± 0.2)°, (10.3 ± 0.2)°, and (11.1 ± 0.2)°. Preferably, crystalline Form II of the compound of formula (II) is characterized in that, when measured at room temperature using Cu-Kα 1 radiation with a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern comprising reflections at the following 2-θ angles: (6.6 ± 0.2)°, (10.3 ± 0.2)°, (11.1 ± 0.2)°, (11.5 ± 0.2)°, and (11.7 ± 0.2)°. Preferably, crystalline Form II of the compound of formula (II) is characterized in that, when measured at room temperature using Cu-Kα 1 radiation with a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern comprising reflections at the following 2-θ angles: (6.0 ± 0.2)°, (6.6 ± 0.2)°, (10.3 ± 0.2)°, (11.1 ± 0.2)°, (11.5 ± 0.2)°, (11.7 ± 0.2)°, and (12.2 ± 0.2)°. Preferably, crystalline Form II of the compound of formula (II) is characterized in that, when measured at room temperature using Cu-Kα 1 radiation with a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern comprising reflections at the following 2-θ angles: (6.0 ± 0.2)°, (6.6 ± 0.2)°, (8.3 ± 0.2)°, (10.3 ± 0.2)°, (11.1 ± 0.2)°, (11.5 ± 0.2)°, (11.7 ± 0.2)°, (12.2 ± 0.2)°, (12.6 ± 0.2)°, and (13.0 ± 0.2)°.

[0577] Alternatively, crystalline Form II of the compound of formula (II) is characterized in that, when measured at room temperature using Cu-Kα 1 radiation with a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern substantially the same as that shown in Figure 23 the present invention.

[0578] Alternatively or additionally, crystalline Form II of the compound of formula (II) is characterized by a Fourier transform infrared spectrum having bands at the following wave numbers when measured at room temperature using a diamond ATR cell: (1085 ± 2) cm -1 , (1346 ± 2) cm -1 and (1612 ± 2) cm -1 . Preferably, crystalline Form II of the compound of formula (II) is characterized by a Fourier transform infrared spectrum having bands at the following wave numbers when measured at room temperature using a diamond ATR cell: (713 ± 2) cm -1 , (1085 ± 2) cm -1 , (1321 ± 2) cm -1 , (1346 ± 2) cm -1 and (1612 ± 2) cm -1 . Preferably, crystalline Form II of the compound of formula (II) is characterized by a Fourier transform infrared spectrum having peaks at the following wave numbers when measured at room temperature using a diamond ATR cell: (713 ± 2) cm -1 , (1085 ± 2) cm -1 , (1153 ± 2) cm -1 , (1321 ± 2) cm -1 , (1346 ± 2) cm -1 , (1612 ± 2) cm -1 and (1774 ± 2) cm -1 . Preferably, crystalline Form II of the compound of formula (II) is characterized by a Fourier transform infrared spectrum having bands at the following wave numbers when measured at room temperature using a diamond ATR cell: (713 ± 2) cm -1 , (1085 ± 2) cm -1 , (1153 ± 2) cm -1 , (1213 ± 2) cm -1 , (1321 ± 2) cm -1 , (1346 ± 2) cm -1 , (1521 ± 2) cm -1 , (1612 ± 2) cm -1 , (1683 ± 2) cm -1 and (1774 ± 2) cm -1 .

[0579] Alternatively, crystalline Form II of the compound of formula (II) is characterized by having a Fourier transform infrared spectrum that is substantially the same as that shown in Figure 24 of the present invention when measured at room temperature using a diamond ATR cell.

[0580] Alternatively or additionally, crystalline Form II of the compound of formula (II) is characterized by having a Raman spectrum comprising peaks at the following wavenumbers when measured at room temperature with a laser at a wavelength of 1064 nm: (1335 ± 2) cm -1 , (1348 ± 2) cm -1 and (1592 ± 2) cm -1 . Preferably, crystalline Form II of the compound of formula (II) is characterized by having a Raman spectrum comprising peaks at the following wavenumbers when measured at room temperature with a laser at a wavelength of 1064 nm: (1111 ± 2) cm -1 , (1335 ± 2) cm -1 , (1348 ± 2) cm -1 , (1592 ± 2) cm -1 and (2935 ± 2) cm -1 . Preferably, crystalline Form II of the compound of formula (II) is characterized by having a Raman spectrum comprising bands at the following wavenumbers when measured at room temperature with a laser at a wavelength of 1064 nm: (864 ± 2) cm -1 , (1461 ± 2) cm -1 , (1111 ± 2) cm -1 , (1335 ± 2) cm -1 , (1348 ± 2) cm -1 , (1592 ± 2) cm -1 and (2935 ± 2) cm -1 . Preferably, crystalline Form II of the compound of formula (II) is characterized by having a Raman spectrum comprising bands at the following wavenumbers when measured at room temperature with a laser at a wavelength of 1064 nm: (864 ± 2) cm -1 , (1461 ± 2) cm -1 , (1111 ± 2) cm -1 , (1215 ± 2) cm -1 , (1295 ± 2) cm -1 , (1335 ± 2) cm -1 , (1348 ± 2) cm -1 , (1592 ± 2) cm -1 , (2885 ± 2) cm -1 and (2935 ± 2) cm -1 .

[0581] Alternatively, crystalline Form II of the compound of formula (II) is characterized by having a Raman spectrum that is substantially the same as that shown in Figure 25 of the present invention when measured at room temperature with a laser at a wavelength of 1064 nm.

[0582] Alternatively or additionally, crystalline Form II of the compound of formula (II) is characterized by having a differential scanning calorimetry curve as shown in Figure 26 the present invention.

[0583] Alternatively or additionally, crystalline Form II of the compound of formula (II) is characterized by having a TGA curve as shown in Figure 27 the present invention.

[0584] Crystalline Form III of the compound of formula (II) is characterized in that when measured at room temperature using Cu-Kα 1 radiation with a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern comprising reflections at the following 2-θ angles: (5.8 ± 0.2)°, (10.2 ± 0.2)°, and (11.1 ± 0.2)°. Preferably, crystalline Form III of the compound of formula (II) is characterized in that when measured at room temperature using Cu-Kα 1 radiation with a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern comprising reflections at the following 2-θ angles: (5.8 ± 0.2)°, (9.6 ± 0.2)°, (10.2 ± 0.2)°, (11.1 ± 0.2)°, and (11.3 ± 0.2)°. Preferably, crystalline Form III of the compound of formula (II) is characterized in that when measured at room temperature using Cu-Kα 1 radiation with a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern comprising reflections at the following 2-θ angles: (5.6 ± 0.2)°, (5.8 ± 0.2)°, (9.6 ± 0.2)°, (10.2 ± 0.2)°, (11.1 ± 0.2)°, (11.3 ± 0.2)°, and (12.1 ± 0.2)°. Preferably, crystalline Form III of the compound of formula (II) is characterized in that when measured at room temperature using Cu-Kα 1 radiation with a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern comprising reflections at the following 2-θ angles: (5.6 ± 0.2)°, (5.8 ± 0.2)°, (7.7 ± 0.2)°, (9.6 ± 0.2)°, (10.2 ± 0.2)°, (11.1 ± 0.2)°, (11.3 ± 0.2)°, (12.1 ± 0.2)°, (13.0 ± 0.2)°, and (14.3 ± 0.2)°.

[0585] Alternatively, crystalline Form III of the compound of formula (II) is characterized in that when measured at room temperature using Cu-Kα 1 radiation with a wavelength of 0.15419 nm, it has a powder X-ray diffraction pattern that is substantially the same as that shown in Figure 28 the present invention.

[0586] Alternatively or additionally, crystalline Form III of the compound of formula (II) is characterized by a Fourier transform infrared spectrum having bands at the following wave numbers when measured at room temperature using a diamond ATR cell: (1083 ± 2) cm -1 , (1329 ± 2) cm -1 and (1607 ± 2) cm -1 . Preferably, crystalline Form III of the compound of formula (II) is characterized by a Fourier transform infrared spectrum having bands at the following wave numbers when measured at room temperature using a diamond ATR cell: (1083 ± 2) cm -1 , (1291 ± 2) cm -1 , (1329 ± 2) cm -1 , (1521 ± 2) cm -1 and (1607 ± 2) cm -1 . Preferably, crystalline Form III of the compound of formula (II) is characterized by a Fourier transform infrared spectrum having bands at the following wave numbers when measured at room temperature using a diamond ATR cell: (1083 ± 2) cm -1 , (1131 ± 2) cm -1 , (1291 ± 2) cm -1 , (1329 ± 2) cm -1 , (1347 ± 2) cm -1 , (1521 ± 2) cm -1 and (1607 ± 2) cm -1 . Preferably, crystalline Form III of the compound of formula (II) is characterized by a Fourier transform infrared spectrum having bands at the following wave numbers when measured at room temperature using a diamond ATR cell: (709 ± 2) cm -1 , (1083 ± 2) cm -1 , (1131 ± 2) cm -1 , (1291 ± 2) cm -1 , (1329 ± 2) cm -1 , (1347 ± 2) cm -1 , (1521 ± 2) cm -1 , (1607 ± 2) cm -1 , (1688 ± 2) cm -1 and (1777 ± 2) cm -1 .

[0587] Alternatively, crystalline Form III of the compound of formula (II) is characterized by having a Fourier transform infrared spectrum that is substantially the same as that shown in Figure 29 of the present invention when measured at room temperature using a diamond ATR cell.

[0588] Alternatively or additionally, crystalline Form III of the compound of formula (II) is characterized by a Raman spectrum having bands at wavenumbers including the following when measured at room temperature with a laser at a wavelength of 1064 nm: (1113 ± 2) cm -1 、(1332 ± 2) cm -1 and (1350 ± 2) cm -1 。Preferably, crystalline Form III of the compound of formula (II) is characterized by a Raman spectrum having bands at wavenumbers including the following when measured at room temperature with a laser at a wavelength of 1064 nm: (1113 ± 2) cm -1 、(1295 ± 2) cm -1 、(1332 ± 2) cm -1 、(1350 ± 2) cm -1 and (1592 ± 2) cm -1 。Preferably, crystalline Form III of the compound of formula (II) is characterized by a Raman spectrum having bands at wavenumbers including the following when measured at room temperature with a laser at a wavelength of 1064 nm: (864 ± 2) cm -1 、(1113 ± 2) cm -1 、(1295 ± 2) cm -1 、(1332 ± 2) cm -1 、(1350 ± 2) cm -1 、(1592 ± 2) cm -1 and (2932 ± 2) cm -1 。Preferably, crystalline Form III of the compound of formula (II) is characterized by a Raman spectrum having bands at wavenumbers including the following when measured at room temperature with a laser at a wavelength of 1064 nm: (864 ± 2) cm -1 、(1113 ± 2) cm -1 、(1215 ± 2) cm -1 、(1295 ± 2) cm -1 、(1332 ± 2) cm -1 、(1350 ± 2) cm -1 、(1463 ± 2) cm -1 、(1592 ± 2) cm -1 、(2883 ± 2) cm -1 and (2932 ± 2) cm -1 。

[0589] Alternatively, crystalline Form III of the compound of formula (II) is characterized by a Raman spectrum that is substantially the same as that shown in Figure 30 of the present invention when measured at room temperature with a laser at a wavelength of 1064 nm.

[0590] Alternatively or additionally, crystalline Form III of the compound of formula (II) is characterized by having a differential scanning calorimetry curve as shown in Figure 31 of the present invention.

[0591] Alternatively or additionally, crystalline Form III of the compound of formula (II) is characterized by having a TGA curve as shown in Figure 32 of the present invention.

[0592] Process for preparing the crystalline form of the compound of formula (II)

[0593] In a further aspect, the present invention relates to a process for preparing the crystalline form of the compound of formula (II), the process comprising

[0594] (a) providing a compound of formula (IV)

[0595]

[0596] (b) reacting the compound of formula (IV) with p-nitrophenol in the presence of a coupling agent

[0597] (c) and isolating the crystalline form of the compound of formula (II).

[0598] In a preferred embodiment, the compound of formula (II) is isolated in the crystalline form as described above. In a preferred embodiment, the compound of formula (II) is isolated in crystalline Form I as described above and characterized.

[0599] In a preferred embodiment, the compound of formula (II) is isolated in a crystalline form which, when measured at room temperature with Cu-Kα 1 radiation having a wavelength of 0.15419 nm, has a powder X-ray diffraction pattern comprising reflections at the following 2-θ angles: (8.0 ± 0.2)°, (9.0 ± 0.2)°, (11.7 ± 0.2)°, (12.8 ± 0.2)° and (14.9 ± 0.2)°.

[0600] In a preferred embodiment, the compound of formula (II) is isolated in a crystalline form which, when measured at room temperature with Cu-Kα 1 radiation having a wavelength of 0.15419 nm, has a powder X-ray diffraction pattern substantially the same as that shown in Figure 18 of the present invention.

[0601] In a preferred embodiment, the compound of formula (II) is isolated in a crystalline form which, when measured at room temperature with a diamond ATR cell, has a Fourier transform infrared spectrum comprising bands at the following wave numbers: (715 ± 2) cm-1 、(1085±2)cm -1 、(1343±2)cm -1 、(1522±2)cm -1 and (1598±2)cm -1 .

[0602] In a preferred embodiment, the compound of formula (II) is isolated in a crystalline form characterized by having Figure 19 Essentially the same Fourier transform infrared spectrum as shown in .

[0603] In a preferred embodiment, the compound of formula (II) is isolated in a crystalline form characterized by a Raman spectrum having a band at the following wavenumbers: (1111±2) cm -1 、(1213±2)cm -1 、(1346±2)cm -1 、(1594±2)cm -1 and (2884±2)cm -1 .

[0604] In a preferred embodiment, the compound of formula (II) is isolated in a crystalline form characterized by having Figure 20 Essentially the same Raman spectrum shown in .

[0605] In a preferred embodiment, the compound of formula (II) is isolated in a crystalline form characterized by having Figure 21 The differential scanning calorimetry curve is shown in .

[0606] In a preferred embodiment, the compound of formula (II) is isolated in a crystalline form characterized by having a TGA curve as shown in Figure 222 of the present invention.

[0607] In a preferred embodiment, the reaction of the compound of formula (IV) with p-nitrophenol in the presence of a coupling agent in step (b) is preferably carried out in an organic solvent or in a mixture of organic solvents. Preferably, the organic solvent is acetonitrile, formamide, tetrahydrofuran, 2-methyltetrahydrofuran or a mixture thereof. More preferably, the reaction of the compound of formula (IV) with p-nitrophenol in the presence of a coupling agent in step (b) is carried out in a mixture of acetonitrile and formamide or in a mixture of tetrahydrofuran and formamide. More preferably, the solvent mixture for the reaction of the compound of formula (IV) with p-nitrophenol comprises acetonitrile and formamide in a ratio by weight (w / w) of 2:1 to 5:1, preferably 2.3:1 to 4.0:1 by weight (w / w).

[0608] In a preferred embodiment, the reaction of the compound of formula (IV) with p-nitrophenol in step (d) is carried out in the presence of a coupling agent, preferably the coupling agent is selected from DIC (N,N-diisopropylcarbodiimide), DCC (N,N-dicyclohexylcarbodiimide), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) and CDI (carbonyldiimidazole). Preferably, the reaction is carried out using DIC (N,N-diisopropylcarbodiimide) as the coupling agent. Preferably, before adding the coupling agent, the mixture of the compound of formula (IV) and p-nitrophenol in a suitable or preferred organic solvent or solvent mixture is stirred for a time of 0.5 h to 5 h, more preferably 1 h to 3 h. Preferably, before adding the coupling agent, the mixture of the compound of formula (IV) and p-nitrophenol in a suitable or preferred organic solvent or solvent mixture is stirred at a temperature of -5 °C to 5 °C, more preferably at -3 °C to 3 °C. Even more preferably, before adding the coupling agent, the mixture of the compound of formula (IV) and p-nitrophenol in a suitable or preferred organic solvent or solvent mixture is stirred at a temperature of -5 °C to 5 °C for 0.5 h to 5 h. Even more preferably, before adding the coupling agent, the mixture of the compound of formula (IV) and p-nitrophenol in a suitable or preferred organic solvent or solvent mixture is stirred at a temperature of -3 °C to 3 °C for 1 h to 3 h.

[0609] In a preferred embodiment, in step (d), the reaction of the compound of formula (IV) with p-nitrophenol in the presence of a coupling agent is preferably carried out at a temperature of 15 °C to 40 °C, more preferably at 20 °C to 26 °C.

[0610] In a preferred embodiment, in step (d), the reaction of the compound of formula (IV) with p-nitrophenol in the presence of a coupling agent is preferably carried out for 6 h to 72 h, more preferably 10 h to 43 h, most preferably 12 h to 19 h.

[0611] In a preferred embodiment, in step (d), the reaction of the compound of formula (IV) with p-nitrophenol in the presence of a coupling agent is preferably carried out at a temperature of 15 °C to 40 °C, more preferably 20 °C to 26 °C and continues for 6 h to 72 h, more preferably 10 h to 43 h, most preferably 12 h to 19 h.

[0612] In a preferred embodiment, the separation of the compound of formula (IV) in step (e) comprises adding a mixture of water and an organic solvent selected from tetrahydrofuran and acetonitrile or a mixture thereof to the reaction mixture. Preferably, the organic solvent is acetonitrile.

[0613] Preferably, the amount of water in the mixture of added water and organic solvent is selected such that the final water content of the entire reaction mixture is in the range of 0% to 6% by weight (w / w), more preferably in the range of 2% to 5% (w / w) by weight.

[0614] In a preferred embodiment, the present invention relates to a method for preparing a crystalline form of a compound of formula (II), the method comprising

[0615] (a) providing a compound of formula (IV)

[0616]

[0617] (b) reacting the compound of formula (IV) with p-nitrophenol in the presence of a coupling agent, wherein the compound of formula (IV) and p-nitrophenol are stirred, and then the coupling agent is added to the reaction mixture

[0618] (c) and isolating the crystalline form of the compound of formula (II).

[0619] In a preferred embodiment, the present invention relates to a method for preparing a crystalline form of a compound of formula (II), the method comprising

[0620] (a) providing a compound of formula (IV)

[0621]

[0622] (b) reacting the compound of formula (IV) with p-nitrophenol in the presence of the coupling agent N,N-diisopropylcarbodiimide, wherein the compound of formula (IV) and p-nitrophenol are stirred, and then the coupling agent is added to the reaction mixture

[0623] (c) and isolating the crystalline form of the compound of formula (II).

[0624] In a preferred embodiment, the present invention relates to a method for preparing a crystalline form of a compound of formula (II), the method comprising

[0625] (a) providing a compound of formula (IV)

[0626]

[0627] (b) reacting the compound of formula (IV) with p-nitrophenol in the presence of a coupling agent, wherein the compound of formula (IV) and p-nitrophenol are stirred for 0.5 h to 5 h, preferably 1 h to 3 h, and then the coupling agent is added to the reaction mixture,

[0628] (c) and isolating the crystalline form of the compound of formula (II).

[0629] In a preferred embodiment, the present invention relates to a method for preparing a crystalline form of a compound of formula (II), the method comprising

[0630] (a) providing a compound of formula (IV)

[0631]

[0632] (b) reacting the compound of formula (IV) with p-nitrophenol in the presence of a coupling agent N,N-diisopropylcarbodiimide, wherein the compound of formula (IV) and p-nitrophenol are stirred for 0.5 h to 5 h, preferably 1 h to 3 h, and then the coupling agent is added to the reaction mixture,

[0633] (c) and isolating the crystalline form of the compound of formula (II).

[0634] In a preferred embodiment, the present invention relates to a method for preparing a crystalline form of a compound of formula (II), the method comprising

[0635] (a) providing a compound of formula (IV)

[0636]

[0637] (b) reacting the compound of formula (IV) with p-nitrophenol in the presence of a coupling agent, wherein the compound of formula (IV) and p-nitrophenol are stirred at a temperature of -3 °C to 3 °C for 0.5 h to 5 h, preferably 1 h to 3 h, and then the coupling agent is added to the reaction mixture,

[0638] (c) and isolating the crystalline form of the compound of formula (II).

[0639] In a preferred embodiment, the present invention relates to a method for preparing a crystalline form of a compound of formula (II), the method comprising

[0640] (a) providing a compound of formula (IV)

[0641]

[0642] (b) reacting the compound of formula (IV) with p-nitrophenol in the presence of a coupling agent, wherein the compound of formula (IV) and p-nitrophenol are stirred at a temperature of -3 °C to 3 °C for 0.5 h to 5 h, preferably 1 h to 3 h, and then the coupling agent is added to the reaction mixture,

[0643] (c) and isolating the crystalline form of the compound of formula (II), which is characterized in that when at room temperature with a wavelength of 0.15419 nm Cu-Kα 1When measured by radiation, the powder X-ray diffraction pattern has reflections at 2-θ angles including: (8.0 ± 0.2)°, (9.0 ± 0.2)°, and (12.8 ± 0.2)°.

[0644] In a preferred embodiment, the present invention relates to a method for preparing a crystalline form of a compound of formula (II), the method comprising

[0645] (a) providing a compound of formula (IV)

[0646]

[0647] (b) reacting the compound of formula (IV) with p-nitrophenol in the presence of a coupling agent N,N-diisopropylcarbodiimide, wherein the compound of formula (IV) and p-nitrophenol are stirred at a temperature of -3°C to 3°C for 0.5 h to 5 h, preferably 1 h to 3 h, and then the coupling agent is added to the reaction mixture,

[0648] (c) and isolating the crystalline form of the compound of formula (II), the crystalline form being characterized in that when measured at room temperature with Cu-Kα radiation having a wavelength of 0.15419 nm, 1 the powder X-ray diffraction pattern has reflections at 2-θ angles including: (8.0 ± 0.2)°, (9.0 ± 0.2)°, and (12.8 ± 0.2)°.

[0649] In a preferred embodiment, the present invention relates to a method for preparing a crystalline form of a compound of formula (II), the method comprising

[0650] (a) providing a compound of formula (IV)

[0651]

[0652] (b) reacting the compound of formula (IV) with p-nitrophenol in the presence of a coupling agent, wherein the compound of formula (IV) and p-nitrophenol are stirred at a temperature of -3°C to 3°C for 0.5 h to 5 h, preferably 1 h to 3 h, and then the coupling agent is added to the reaction mixture,

[0653] (c) and isolating the crystalline form of the compound of formula (II), the crystalline form being characterized in that when measured at room temperature with Cu-Kα radiation having a wavelength of 0.15419 nm, 1When performing radiation measurement, the powder X-ray diffraction pattern has reflections at the following 2-θ angles: (8.0 ± 0.2)°, (9.0 ± 0.2)°, and (12.8 ± 0.2)°, where separation involves using a mixture of water and an organic solvent. Preferably, the organic solvent is acetonitrile, such that the final water content of the entire reaction mixture is in the range of 0% to 6% by weight (w / w), more preferably in the range of 2% to 5% by weight (w / w).

[0654] It should be understood that the present invention also relates to any combination of the above embodiments.

[0655] More specifically, the present invention encompasses the intermediate compounds disclosed in the Examples section below herein.

[0656] General synthesis

[0657] The compounds of formulas (III) and (IV) according to the method of the present invention can be prepared as described in the literature.

[0658] The compound of formula (III) can be prepared from pentaerythritol tetrabromide according to W. Hayes, et al., Tetrahedron 59 (2003), 7983–7996.

[0659] The compound of formula (IV) can be prepared starting from 1,4,7,10-tetraazacyclododecane as described in DE 19652386, Schering AG. Description of the drawings

[0660] Figure 1 Relative humidity as a function of temperature and vapor pressure

[0661] Figure 2 X-ray powder diffraction spectrum of the compound of formula (I) - amorphous material

[0662] Figure 3 X-ray powder diffraction spectrum of the compound of formula (I) - Form I

[0663] Figure 4 IR spectrum of the compound of formula (I) - Form I

[0664] Figure 5 Raman spectrum of the compound of formula (I) - Form I

[0665] Figure 6 DSC curve of the compound of formula (I) - Form I

[0666] Figure 7 TGA curve of the compound of formula (I) - Form I

[0667] Figure 8X-ray powder diffraction spectrum of the compound of formula (I) - Form II

[0668] Figure 9 IR spectrum of the compound of formula (I) - Form II

[0669] Figure 10 Raman spectrum of the compound of formula (I) - Form II

[0670] Figure 11 DSC curve of the compound of formula (I) - Form II

[0671] Figure 12 TGA curve of the compound of formula (I) - Form II

[0672] Figure 13 DVS isotherm diagram of the transformation of the crystalline forms (Form I to Form II) of the compound of formula (I) 50 - 0 - 90 - 50 at 20 °C

[0673] Figure 14 DVS isotherm diagram of the transformation of the crystalline forms (Form I to Form II) of the compound of formula (I) 50 - 0 - 50 at 20 °C

[0674] Figure 15 DVS isotherm diagram of the transformation of the crystalline forms (Form I to Form II) of the compound of formula (I) 50 - 0 - 50 at 40 °C

[0675] Figure 16 . Asymmetric part of the unit cell of enantiomer 1 of the compound of formula (I)

[0676] Figure 17 . Asymmetric part of the unit cell of enantiomer 3 of the compound of formula (I)

[0677] Figure 18 . X-ray powder diffraction spectrum of the compound of formula (II) - Form I

[0678] Figure 19 . IR spectrum of the compound of formula (II) - Form I

[0679] Figure 20 . Raman spectrum of the compound of formula (II) - Form I

[0680] Figure 21 . DSC curve of the compound of formula (II) - Form I

[0681] Figure 22 . TGA curve of the compound of formula (II) - Form I

[0682] Figure 23 . X-ray powder diffraction spectrum of the compound of formula (II) - Form II

[0683] Figure 24 IR spectrum of the compound of formula (II) - Form II

[0684] Figure 25 Raman spectrum of the compound of formula (II) - Form II

[0685] Figure 26 DSC curve of the compound of formula (II) - Form II

[0686] Figure 27 TGA curve of the compound of formula (II) - Form II

[0687] Figure 28 X-ray powder diffraction spectrum of the compound of formula (II) - Form III

[0688] Figure 29 IR spectrum of the compound of formula (II) - Form III

[0689] Figure 30 Raman spectrum of the compound of formula (II) - Form III

[0690] Figure 31 DSC curve of the compound of formula (II) - Form III

[0691] Figure 32 TGA curve of the compound of formula (II) - Form III

[0692] Figure 33 X-ray powder diffraction spectrum of the transient crystalline form of the compound of formula (I) during the second drying process in the preparation of the crystalline form II of the compound of formula (I).

[0693] Figure 34a Determination of sample solution 1 of the compound of formula (II) by hydrolysis to 4-nitrophenol (HPLC-UV method b).

[0694] Figure 34b Determination of sample solution 2 of the compound of formula (II) by hydrolysis (hydrolysis) to 4-nitrophenol (HPLC-UV method b).

[0695] Figure 35a Determination of the SST solution of the compound of formula (II) by derivatization to the benzylamide derivative of the compound of formula (IV) (HPLC-UV method c).

[0696] Figure 35b SST solution of the compound of formula (IV) in the compound of formula (II) (HPLC-UV method c-1).

[0697] Figure 36aSST solution 1 of the crude compound of formula (I) (HPLC-UV method d-1).

[0698] Figure 36b SST solution 2 of the crude compound of formula (I) (HPLC-UV method d-1).

[0699] Figure 36c SST solution of the compound of formula (I) (HPLC-UV method d-1).

[0700] Figure 37 HPLC chromatogram of the crude compound of formula (I) in the separated material, Example 2 (HPLC-UV method d-1).

[0701] Figure 38 HPLC chromatogram of the compound of formula (I) in the separated material, Example 4 (HPLC-UV method d-1).

[0702] Figure 39 HPLC chromatogram of the compound of formula (I) in the separated material, Example 4.1 (HPLC-UV method d-1).

[0703] Experimental section

[0704] Abbreviations

[0705]

[0706]

[0707] Materials and instruments

[0708] Unless otherwise stated, the chemicals used for synthetic work are of reagent grade quality and are used as received.

[0709] All reagents for which the synthesis is not described in the experimental section are commercially available, or are known compounds, or can be formed from known compounds by known methods by those skilled in the art.

[0710] Instrument settings for XRPD measurement (compound of formula (I), amorphous)

[0711] X-ray powder diffraction (XRPD) data were recorded on a Panalytical X-Pert PRO diffractometer using CuK α radiation (position-sensitive detector) with a generator setting of 40 kV and 40 mA. Samples were collected in transmission mode and prepared as a thin layer between two foils. The scanning range was between 2° and 38° 2θ, with a step size of 0.013° at 25 seconds / step.

[0712] Instrument settings for XRPD measurements (compounds of formula (I), crystalline forms I and II, including transient crystalline forms)

[0713] X-ray powder diffraction (XRPD) data were recorded on a STOE STADIP diffractometer using monochromated CuKα1 radiation (position-sensitive detector) with a generator setting of 40 kV and 40 mA. Samples were collected in the transition mode and prepared as thin layers between two foils. The scanning range was between 2° and 38° 2θ with a step size of 0.2° at 15 s / step.

[0714] Instrument settings for XRPD measurements (compounds of formula (II), crystalline forms I, II and III)

[0715] X-ray powder diffraction (XRPD) data were recorded on a STOE STADIP diffractometer using monochromated CuKα1 radiation (position-sensitive detector) with a generator setting of 40 kV and 40 mA. Samples were collected in the transition mode and prepared as thin layers between two foils. The scanning range was between 2° and 40° 2θ with a step size of 0.5° at 15 s / step.

[0716] Instrument settings for SCD measurements (diastereomer 1 of the compound of formula (I))

[0717] The crystallographic data of diastereomer 1 of the compound of formula (I) and the figures depicting thermal ellipsoids and structure numbers are shown in Table 4 and Figure 16 Colorless crystals were obtained by dissolving 100 mg of diastereomer 1 of the compound of formula (I) (see Example 5) in 150 mg of water at 60 °C, slowly adding 700 mg of ethanol, and finally slowly diffusing ethanol vapor into the solution at 60 °C.

[0718] Single-crystal X-ray diffraction data were collected on a Rigaku Oxford Diffraction XtaLAB Synergy-S diffractometer equipped with a birefringent source (Cu at zero), a HyPix-6000HE detector, and an Oxford Cryosystems Cobra cooling device. Data were collected using CuKα radiation. The structure was solved and refined using the Shelx program suite, and OLEX2 was used as an interface to view the structure and generate figures. Unless otherwise stated, hydrogen atoms attached to carbon were geometrically placed and allowed to refine using riding isotropic displacement parameters. Hydrogen atoms attached to heteroatoms were located in the difference Fourier synthesis map and allowed to refine freely with isotropic displacement parameters. The asymmetric unit was found to contain 1 / 4 of diastereomer 1 of the compound of formula (I), where the fully occupied Gd 3+The ion coordinates with the ligand. It also contains one fully occupied water molecule, one fully occupied EtOH molecule, and two partially occupied EtOH molecules, each refined to an occupancy of 75% and 80% (see Figure x). The molecule of the compound of formula (I) contains four Gd ligand units, and the central carbon atom (C21) is in a special position (inversion rotation). The crystal structure belongs to the enantiomorphic space group I-4, and the inversion rotation symmetry element -4 means that the sample of the compound of formula (I) under study (Example 5) is actually the R,S,R,S (or S,R,S,R) diastereomer, thus confirming the structure of diastereomer 1 of the compound of formula (I).

[0719] Instrument settings for SCD measurements (diastereomer 3 of the compound of formula (I))

[0720] The crystallographic data of diastereomer 3 of the compound of formula (I) and the figures depicting the thermal ellipsoids and the structure numbering are shown in Table 5 and Figure 17 in. Colorless crystals were obtained by dissolving 50 mg of diastereomer 3 of the compound of formula (I) (see Example 7) in 36 mg of water at 60 °C, slowly adding 100 mg of ethanol, and finally slowly diffusing isopropanol vapor into the solution at 60 °C.

[0721] Single-crystal X-ray diffraction data were collected on a Rigaku Oxford Diffraction XtaLAB Synergy-S diffractometer equipped with a dual-bounce source (Cu at zero), a HyPix-6000HE detector, and an Oxford Cryosystems Cobra cooling device. Data were collected using CuKα. The structure was solved and refined using the Shelx program suite, and OLEX2 was used as the interface to view the structure and generate the figures. Unless otherwise stated, hydrogen atoms attached to carbon were geometrically placed and allowed to be refined with isotropic displacement parameters. Hydrogen atoms attached to heteroatoms were located in the difference Fourier synthesis map and allowed to be freely refined with isotropic displacement parameters. The asymmetric unit was found to contain one molecule of diastereomer 3 of the compound of formula (I) (see Figure 17)。In the crystal structure, there is a large amount of diffuse electron density corresponding to severely disordered and partially occupied solvent molecules, which is located in the large voids between adjacent molecules of the diastereomer 3 of the compound of formula (I). This diffuse electron density was removed during structure refinement using the Olex2 implementation of the Platon Squeeze routine. This method significantly improved the final model and enabled the least-squares refinement to converge. Due to the highly diffuse nature of the electron density, all hydrogen atoms located on heteroatoms were refined as riding on their parent atoms at the calculated positions (AFIX 47). In the structure, a disordered carboxylate group was modeled at two sites and refined in a ratio of 0.60:0.40. In the structure, all stereocenters (C15, C36, C45, C76) of 50% of the molecules of the compound of formula (I) are of the R configuration, and the other 50% are of the S configuration (centrosymmetric space group P21 / n). This means that the crystal structure of the sample of the compound of formula (I) (Example 7) contains an equimolar mixture of the (R,R,R,R) and (S,S,S,S) diastereomers and confirms the diastereomer 3 of the compound of structural formula (I).

[0722] Instrument settings for IR measurement

[0723] IR measurements were carried out using a Bruker α spectrometer in the attenuated total reflection (ATR) geometry. No sample preparation was performed, and each individual measurement consisted of 32 scans.

[0724] Instrument settings for Raman measurement

[0725] Raman measurements were carried out using a Bruker MultiRAM spectrometer. No sample preparation was performed, and each individual measurement consisted of 64 scans using a laser power of 300 mW.

[0726] Instrument settings for TGA measurement (crystalline forms I and I of the compound of formula (I))

[0727] Thermogravimetric analysis (TGA) was carried out using a Mettler Toledo TGA / DSC 3+. The instrument was purged with nitrogen at a flow rate of 50 ml.min -1 . Approximately 3–10 mg of each sample was placed in an aluminum crucible and heated from 25 °C to 350 °C at a heating rate of 10 °C.min -1 .

[0728] Instrument settings for TGA measurement (crystalline forms I, II, and III of the compound of formula (II))

[0729] Thermogravimetric analysis (TGA) was carried out using a Mettler Toledo TGA / DSC 3+. The instrument was purged with nitrogen at a flow rate of 10 or 20 ml.min -1Purge with a flow rate. Place approximately 1–15 mg of each sample in an aluminum or alumina crucible and heat from 25 °C at a heating rate of 10 °C / min -1 until reaching the target temperature

[0730] Instrument settings for DSC measurement

[0731] Differential scanning calorimetry (DSC) was performed using a Mettler Toledo DSC3+. The calorimeter was purged with nitrogen at a flow rate of 50 ml / min. Place 3–10 mg of each sample in an aluminum crucible and heat from -10 °C to 250 °C at a rate of 20 °C / min -1 Purge with a flow rate. Place 3–10 mg of each sample in an aluminum crucible and heat from -10 °C to 250 °C at a rate of 20 °C / min -1 until reaching the target temperature

[0732] Instrument settings for DVS measurement (crystalline forms I and II of the compound of formula (I))

[0733] The water adsorption isotherm was determined using a Surface Measurement Systems Ltd DVS1 gravimetric sorption analyzer. 10–20 mg of the sample was equilibrated at 50% relative humidity and the weight was recorded. Then, the isotherm was recorded by changing the humidity in 10% steps. The equilibrium criterion was set as a relative mass change of dm / dt = 0.002% / min

[0734] Analysis method

[0735] HPLC chromatography

[0736] HPLC-UV method a:

[0737] Instrument: Agilent Series 1260, pump: G1312B, autosampler: G1329B, degasser: G4225A, column oven: G1316C, detector: G1314F; detection wavelength: 198 nm, bandwidth: 8 nm; data rate: 40 Hz; column temperature: 40 °C, column: YMC Triart Phenyl C18 100 mm x 3 mm, 3 μm, eluent A: aqueous solution of 0.1 wt-% formic acid; eluent B: acetonitrile, flow rate: 1.20 mL / min; gradient (A): 0 min: 98%; 1 min: 98%; 9 min: 20%; 11 min: 20%; equilibration time: 3 min, injection volume: 10 μL

[0738] HPLC-UV method b: (Determination of the content of the compound of formula (II))

[0739] Evaluated by hydrolysis to 4-nitrophenol, sample preparation protocol:

[0740] Sample solution 1: Dissolve approximately 0.2 mg / mL of the sample in a mixture of 85% acetonitrile + 15% water (v / v). The sample must be dissolved directly before analysis only (maximum duration between sample dissolution and injection: 15 min).

[0741] Sample solution 2: Dissolve approximately 0.2 mg / mL of the sample in 50% of the required volume of 14 mmol / L disodium hydrogen phosphate solution and shake at 50 °C for 2 h. After cooling, fill to volume (use the sample solution within 24 h when stored at room temperature).

[0742] The content determination of the compound of formula (II) is indirectly determined by the 4-nitrophenol content after sample hydrolysis (direct determination is not possible due to the inherent instability of the compound of formula (II) in aqueous medium / HPLC conditions). The analysis is evaluated by external standard calibration against a 4-nitrophenol standard. Determine the 4-nitrophenol content of sample solution 1 (before hydrolysis) and sample solution 2 (after hydrolysis). Subsequently, subtract the 4-nitrophenol content determined for sample solution 1 from the 4-nitrophenol content determined for sample solution 2. The difference is used for the determination calculation of the compound of formula (II). The determination of the compound of formula (II) is back-calculated based on a factor considering the molecular weight fraction of the compound of formula (II) relative to 4-nitrophenol.

[0743] HPLC-UV parameters:

[0744] Instrument: e.g., Agilent Series 1290, detection wavelength: 316 nm, bandwidth: 6 nm; data rate: 10 Hz; column temperature: 40 °C, column: Acquity BEH Phenyl 100 mm x 3 mm, 1.7 μm, eluent A: 10 mmol / L ammonium phosphate buffer, pH 2.4 to 1 L; eluent B: acetonitrile, flow rate: 1.0 mL / min; gradient: 0 min: 0% B; 1.0 min: 0% B; 9.0 min: 50% B; 11.0 min: 75% B; 11.5 min: 0% B; 15.0 min: 0% B; equilibration time: included in the gradient, injection volume: 1 μL.

[0745] HPLC-UV method b-2 (Determination of formamide in the compound of formula (II))

[0746] Sample solution: Dissolve approximately 5 mg of the sample in B / A (see HPLC-UV parameters) 9 / 1 in a 50 mL volumetric flask and make up to volume. Use a formamide reference standard and evaluate the multi-level calibration by appropriate linear regression.

[0747] HPLC-UV parameters

[0748] Instrument: such as Agilent series 1290; Detection wavelength: 195 nm; Bandwidth: 4 nm; Data rate: 10 Hz; Column temperature: 40 °C, Column: Nucleodur HILIC, 125 mm x 4.6 mm, 3 μm, isocratic, 10% A / 90% B; A: 5 mM ammonium phosphate buffer pH 2.4, B: acetonitrile; Flow rate: 1 mL / min; Run time: 5 min; Injection volume: 20 μL

[0749] HPLC-UV method c (Determination of the compound of formula (II) by the benzamide derivative of the compound of formula (IV)):

[0750] Evaluation was carried out by derivatizing the compound of formula (II) into the benzamide derivative of formula (IV). Sample preparation protocol:

[0751] Derivatization reagent: benzylamine in DMSO (e.g., 1.75 μL / 1 mL)

[0752] Preparation of blank reaction solution: Pipette 2 mL of the derivatization reagent into a small reaction vessel and stir at 40 °C on a temperature-controlled magnetic block for 30 min.

[0753] Preparation of blank solution: Dilute 90 μL of the blank reaction solution with 1410 μL of water.

[0754] Preparation of sample reaction solution: Prepare a sample solution of approximately 10 mg / mL using the derivatization reagent as the solvent (e.g., weigh 20 mg of the substance into a small reaction vessel, add 2 mL of the derivatization reagent), and stir at 40 °C on a temperature-controlled magnetic block for 30 min for complete reaction.

[0755] Preparation of sample solution: Dilute 90 μL of the sample reaction solution with 1410 μL of water (sample concentration is approximately 0.6 mg / mL)

[0756] Analytical evaluation was carried out by external standard calibration against the benzylamide derivative standard of the compound of formula (IV). The determination of the compound of formula (II) was calculated based on the factor considering the molecular weight fraction of the benzylamide derivative of the compound of formula (IV) relative to the compound of formula (II).

[0757] HPLC-UV parameters:

[0758] Instrument: e.g., Agilent Series 1260; Detection wavelength: 200 nm; Bandwidth: 4 nm; Data rate: 5 Hz; Column temperature: 25 °C; Column: Waters Atlantis Premier BEH C18AX, 100 mm x 4.6 mm, 2.5 μm; Eluent A: Aqueous solution of 0.1% formic acid + 0.5% acetonitrile, Eluent B: Aqueous solution of 0.1% formic acid and 30% acetonitrile; Flow rate: 1.0 mL / min; Gradient: 0 min: 0% B, 2.0 min: 0% B; 14.0 min: 40% B; 23.0 min: 100% B; 30.0 min: 100% B, Equilibration time: 5 min at 0% B; Injection volume: 5 μL.

[0759] HPLC-UV method c-1 (i.e., the compound of formula (IV) in the compound of formula (II)):

[0760] Evaluation from the derivatization solution of HPLC-UV method c, Sample preparation protocol:

[0761] Preparation of blank reaction solution: The same as "HPLC method c (new, determination)".

[0762] Preparation of blank solution: Dilute the blank reaction solution 1:1 with water.

[0763] Preparation of sample reaction solution: The same as "HPLC method c (new, determination)".

[0764] Preparation of sample solution: Dilute the sample reaction solution 1:1 with water (using a sample concentration of approximately 5 mg / mL).

[0765] HPLC-UV parameters:

[0766] Same as HPLC method c

[0767] HPLC method d-1:

[0768] Instrument: e.g., Agilent Series 1290, Detection wavelength: 198 nm, Bandwidth: 4 nm; Data rate: 5 Hz; Column temperature: 35 °C, Column: Acquity BEH Phenyl 100 mm x 3 mm, 1.7 μm, Eluent A: 30 mL acetonitrile, made up to 1 L with 10 mmol / L ammonium phosphate aqueous buffer (pH 2.4); Eluent B: 600 mL acetonitrile + 400 mL ammonium phosphate aqueous buffer (pH 2.4), Flow rate: 0.4 mL / min; Gradient: 0 min: 100% A; 2.0 min: 100% A; 32.0 min: 93.0% A; 37.0 min: 0% A; 47.0 min: 0% A; Equilibration time: 5 min, Injection volume: 5 μL.

[0769] HPLC method d-2 (Alternative method to d-1):

[0770] Instrument: Agilent 1260 or 1290; Detection wavelength: 200 nm, Bandwidth: 6 nm; Data rate: 10 Hz; Column temperature: 20 °C, Column: YMC Triart C18 150 mm x 3 mm, 3 μm, Aqueous potassium phosphate buffer: 1.36 g potassium hydrogen phosphate + 640 μL phosphoric acid (85%) made up to 1 L with water; Eluent A: 99% aqueous potassium phosphate buffer + 1% acetonitrile v / v; Eluent B: 35% aqueous potassium phosphate buffer + 65% acetonitrile v / v, Flow rate: 0.4 mL / min; Gradient: 0 min: 100% A, 27.0 min: 95% A, 37.0 min: 50% A, 50 min: 0% A; 60 min: 0%; Equilibration time: at least 10 min, Injection volume: 10 μL.

[0771] HPLC method e:

[0772] Instrument: Agilent Series 1260, Pump: G1312B, Autosampler: G1329B, Degasser: G4225A, Column oven: G1316C, Detector: G1314F; Detection wavelength: 200 nm, Bandwidth: 6 nm; Data rate: 10 Hz; Column temperature: 20 °C, Column: YMC Triart C18 150 mm x 3 mm, 3 μm, 1.36 g potassium hydrogen phosphate + 640 μL phosphoric acid (85%) made up to 1 L with water; Eluent A: 99% aqueous potassium phosphate buffer + 1% acetonitrile v / v; Eluent B: 95% aqueous potassium phosphate buffer + 5% acetonitrile v / v, Flow rate: 0.4 mL / min; Gradient: 0 min: 100% A, 27.0 min: 95% A, 37.0 min: 50% A, 50 min: 0% A; 60 min: 0%; Equilibration time: at least 10 min, Injection volume: 10 μL.

[0773] Determination of Residual Solvents

[0774] Content of formamide (Method a; GC):

[0775] Instrument: Agilent GC HP 7890A or GC HP 7890B, Autosampler: Agilent GC Headspace Sampler 7693, Injection Temperature: 220 °C, Injection Volume: 0.5 μL; Detection Temperature: 300 °C; Data Rate: 10 Hz; Column: Rxi-624Sil MS 22m x 0.18mm x 1μm, Column Flow Rate: 0.7 mL / min, Split Flow Rate: 3.5 mL / min, Split Ratio: 5; Septum: SLGFocus-Liner Part Number 092219; Analytical Method: 50 °C, Initial Time 2.0 min, Heating Rate 10 °C / min to 150 °C, Heating Rate 70 °C / min to 250 °C, Hold Time 2.57 min; Carrier Gas: Hydrogen.

[0776] Determination of residual solvent content (i.e., ethanol) by GC-Head-Space (Method a)

[0777] Instrument: Agilent GC HP 7890A or similar instrument, Autosampler: Perkin-Elmer HS 40XL Sampler or Agilent GC Headspace Sampler 7697A, Injection Temperature: 160 °C, Injection Volume: 80 μL; Detection Temperature: 300 °C; Data Rate: 20 Hz; Column: Rxi-624 Sil MS 20m x 0.18mm x 1μm, Column Flow Rate: 1.2 mL / min, Split Flow Rate: 21.6 mL / min, Split Ratio: 18; Septum: Transfer Septum Agilent Part Number 18740-80200; Analytical Method: 40 °C, Initial Time 4.5 min, Heating Rate 14 °C / min to 70 °C, Heating Rate 90 °C / min to 220 °C, Hold Time 1.69 min; Carrier Gas: Hydrogen.

[0778] Ethanol content (Method b)

[0779] Headspace gas chromatography based on USP<467>.

[0780] Determination of water content

[0781] Water content (Method a):

[0782] Instrument: 870KF-Titrino Plus, Metrohm AG, Herisau, Switzerland; Solvent: Solvent for volumetric determination of water content according to Karl-Fischer; Titrant: - Titrant 5.

[0783] Water content (Method b):

[0784] According to Pharm.Eur. 2.5.32 (Karl-Fischer method; coulometric method)

[0785] Example 1 - Synthesis of the compound of formula (II)

[0786] Synthesis of gadolinium 2,2’,2”-[10-(1-{2-(4-nitrophenoxy)-2-oxoethyl)amino}-1-oxopropan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl]triacetate

[0787] Reaction scheme

[0788]

[0789] Charge 4-nitrophenol (0.994 kg, CAS: 100 - 02 - 7, purchased from Amarjyot Chemical Corporation, India) into a 36 L reactor and add acetonitrile (11.0 kg). Stir the mixture at 25 °C (jacket temperature) for 15 min to obtain a clear solution, and add gadolinium 10-[4-carboxy-1-methyl-2-oxo-3-azetidinyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (2.25 kg, CAS: 208252 - 78 - 2, see DE 19652386, Schering AG, supplied as the dihydrate, 5.6 wt-% water) as a solid. Rinse the source container and the addition funnel with acetonitrile (1.29 kg). Stir the mixture at 25 °C (jacket temperature) for another 15 min, then cool to 0 °C (internal temperature). Add formamide (4.21 kg), rinse the pipeline with acetonitrile (0.890 kg), and stir the mixture at this temperature for 3 h. Then add a solution of N,N-diisopropylcarbodiimide (0.676 kg, CAS: 693 - 13 - 0, purchased from Kemilabs, Hungary) in acetonitrile (0.670 kg) within 8 min. Rinse the source container and the pipeline with acetonitrile (0.630 kg). Warm the mixture to 23 °C (internal temperature), then stir for 19 h. Add a solution of acetonitrile (4.56 kg) and water (0.810 kg), and stir the mixture for 3 h. Filter the mixture and wash the product with acetonitrile (three times, 3.51 kg, 3.99 kg, 3.51 kg). Dry the solid under reduced pressure and at elevated temperature to obtain the title compound (2.33 kg, 87%), which is a colorless to slightly yellow crystalline solid.

[0790] Analysis

[0791] HPLC (method a), R t : 4.23 min.

[0792] HPLC (Method b), R t : 4.52 min.

[0793] Determination (Method b): 78.3 wt-%

[0794] Mass spectrometry:

[0795]

[0796] Formamide (Method b): 11.9 wt-%

[0797] Water (Method b): 2.2 wt-%

[0798] Solid form: Form I

[0799] The following examples were carried out analogously to those described above:

[0800]

[0801]

[0802] ** Different addition order: Charge 4-nitrophenol and gadolinium 10-[4-carboxy-1-methyl-2-oxo-3-azetidinyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid into the reactor; then add acetonitrile to obtain a suspension, which is carried out as described above.

[0803] *** Add 1 wt-% gadolinium 2,2’,2”-[10-(1-{2-(4-nitrophenoxy)-2-oxoethyl)amino}-1-oxopropan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl]triacetate (Form I) seeds to the reaction after adding formamide.

[0804] **** Instead of adding a solution of acetonitrile and water, add these two components sequentially. Add water within 45 to 60 min.

[0805] § The actual yield was higher. Due to production line delays, not all materials could be separated.

[0806] $在 Moisture content of the mixture after adding all reagents, solvents and water: 3.2 wt-%

[0807] Example 2 - Synthesis of the crude compound of formula (I)

[0808] [4,10-Bis(carboxylate methyl)-7-{3,6,12,15-tetraoxo-16-[4,7,10-tris-(carboxylate methyl)-1,4,7,10-tetraazacyclododec-1-yl]-9,9-bis({[({2-[4,7,10-tris-(carboxylate methyl)-1,4,7,10-tetraazacyclododec-1-yl]propanoyl}amino)acetyl]-amino}methyl)-4,7,11,14-tetraazadec-2-yl}-1,4,7,10-tetraazacyclododec-1-yl]acetate

[0809] Reaction Scheme:

[0810]

[0811] Dimethyl sulfoxide (7.26 kg) was charged into a 26 L reactor. 2,2-Bis(aminomethyl)propane-1,3-diamine tetrahydrochloride (0.148 kg, see W. Hayes et al., Tetrahedron 2003, 59, 7983), and the mixture was stirred for 15 min. Gadolinium(III) tris[2,2',2''-[10-(1-{2-(4-nitrophenoxy)-2-oxoethyl)amino}-1-oxopropan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl]triacetate (2.20 kg | 77 wt-%) was added, and the mixture was stirred for 30 min. Subsequently, N,N-Diisopropylethylamine (0.303 kg) was added. The mixture was heated to 50 °C (internal temperature) and stirred for 4 h. The reaction was cooled to 23 °C and water (6.6 kg) was added slowly, keeping the internal temperature below 40 °C. The pH was adjusted to 12.5 by slowly adding aqueous sodium hydroxide solution (7.38 wt-%, 3.63 kg), and the mixture was stirred at 20 °C for 1 h. The pH was adjusted to 6.5–7.5 by slowly adding aqueous hydrochloric acid solution (10 wt-%, 2.1 kg). The mixture was washed successively with methyl tert-butyl ether (2 x 4.88 kg), and the organic layer of each wash was discarded. The aqueous layer was filtered and then concentrated under reduced pressure (50 mbar) until the internal temperature reached ~58 °C. The water content was determined by volumetric Karl-Fischer titration to be ~16 wt-%. The mixture was cooled to room temperature and ethanol (containing ~1% methyl ethyl ketone, 5.5 kg) was added. Subsequently, acetone (11 kg) was added over 2 h. The resulting suspension was stirred for 30 min and filtered. The resulting solid was washed with acetone (twice, 2.75 kg each time), and then dried under reduced pressure and at elevated temperature. The title compound was obtained as a colorless solid (2.13 kg, 155% based on the 2,2-bis(aminomethyl)propane-1,3-diamine tetrahydrochloride used, corrected assay 94%).

[0812] Typically, this material is determined to be 50 - 80%. In addition to the main impurities (compounds of formula (IV) derived from the compound of formula (II)) and other organic impurities, the material also contains inorganic salts such as sodium chloride, residual solvents such as dimethyl sulfoxide, formamide, and water.

[0813] Synthesis of the compound of formula (I) according to the proposed synthetic route results in a mixture of three isomer types: (RRRR / SSSS), (RRRS / SSSR), (RRSS), and their selective separation is described in Examples 5, 6, and 7. Considering the reaction mechanism, the statistical distribution of the isomers is expected to result in a ratio of ~1:5:4 (in terms of (RRRR / SSSS):(RRRS / SSSR):(RRSS)), which is roughly observable in the reaction mixture outlined for this batch.

[0814] Analysis:

[0815] Purity (area - %, method d - 1): 89.2%

[0816] HPLC determination (method d - 1): 60.6%

[0817] Diastereomeric distribution: Diastereomer 1 (R t : 20.3 min): 40.5%

[0818] Diastereomer 2 (R t : 20.9 min): 50.2%

[0819] Diastereomer 3 (R t : 22.4 min): 9.3%

[0820] Water (KF - Fischer, volumetric method, method a): 4 wt - %

[0821] The following examples are carried out similarly to the above; the ratio of the compound of formula (IV) / the compound of formula (III) is outlined below.

[0822]

[0823]

[0824] * The difference in the manufacturing method is that before adding dimethyl sulfoxide, the solid compound of formula (III) and the compound of formula (II) are charged into the reactor.

[0825] ** The reaction is carried out similarly to the above, but the treatment with aqueous sodium hydroxide solution and aqueous hydrochloric acid solution is not carried out.

[0826] *** The reaction is carried out similarly to the above, but the alkaline treatment after adding the aqueous sodium hydroxide solution is carried out at 50 °C and pH = 8.5

[0827] $ The reaction was carried out similarly to the above, but the alkaline treatment after adding the aqueous sodium hydroxide solution was carried out at 50 °C and pH = 9.5.

[0828] $$ The reaction was carried out similarly to the above, but triethylamine was used instead of diisopropylethylamine.

[0829] $$$ The reaction was carried out similarly to the above, but tributylamine was used instead of diisopropylethylamine.

[0830] $$$$ The reaction was carried out similarly to the above, but washing with tert-butyl methyl ether did not occur.

[0831] $$$$$ The reaction was carried out similarly to the above, but the alkaline treatment after adding the aqueous sodium hydroxide solution was carried out at 50 °C and pH = 9; washing with tert-butyl methyl ether did not occur.

[0832] § Distillation was carried out at 75 mbar until an internal temperature of 66 °C was reached. The water content was determined to be 16.9 wt-%.

[0833] Example 3: Synthesis of the compound of formula (I) | Aqueous solution: Synthesis of [4,10-bis(carboxymethyl)-7-{3,6,12,15-tetraoxo-16-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl]-9,9-bis({[({2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl]propanoyl}amino)acetyl]-amino}methyl)-4,7,11,14-tetraazadec-2-yl}-1,4,7,10-tetraazacyclododec-1-yl]acetate | Aqueous solution

[0834] Reaction scheme:

[0835]

[0836] The crude compound of formula (I) (32.5 kg, ~51 wt-% determined, 16.5 kg of the compound of formula (I)) was dissolved in water (190 kg) in a total of four portions. Each portion was filtered and stored in a container. Overall, the reactor and pipes were washed with water (14 kg). The mixture was transferred through a filter to a second reactor, and the container and pipes were rinsed with water (21 kg). A 2 kDa membrane (12 m 2 Surface, The solution was diafiltered using a filter (purchased from Satorius AG, Germany), and the water volume of the retentate was exchanged a total of seven times while keeping the mass in the retentate vessel constant. After completion, the mass of the retentate was concentrated by ultrafiltration, the mixture was stored in a vessel, and the system was rinsed with water. Overall, 127.9 kg of solution was obtained, which was determined to be ~12.2 wt-% of the compound of formula (I) (yield ~95%).

[0837] Analysis:

[0838] Purity (area-%, method d-1): 92.5%

[0839] Diastereomer content (area-%, method d-1):

[0840] Diastereomer 1 (R t : 20.7 min): 36.5 area-%

[0841] Diastereomer 2 (R t : 21.4 min): 46.0 area-%

[0842] Diastereomer 3 (R t : 23.1 min): 9.0 area-%

[0843] The following examples were carried out similarly to the above; the membrane size was adjusted to scale.

[0844]

[0845] **Due to the high purity of the crude compound of formula (I), only four cycles of diafiltration were carried out before concentrating the aqueous solution.

[0846] ***UF / DF was carried out at 40 °C.

[0847] $ Due to the high purity of the crude compound of formula (I), only five cycles of diafiltration were carried out before concentrating the aqueous solution.

[0848] $$ UF / DF was carried out at 35 °C.

[0849] $$$ Only three cycles of diafiltration were carried out

[0850] § The aqueous solution was collected in a vessel equipped with a level sensor instead of a balance. The solution was further processed. In addition, there was still retention in the pipes and vessels. Therefore, the yield was >95%.

[0851] Example 4. Synthesis of the compound of formula (I)

[0852] [4,10-bis(carboxymethyl)-7-{3,6,12,15-tetraoxo-16-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl]-9,9-bis({[({2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl]propanoyl}amino)acetyl]-amino}methyl)-4,7,11,14-tetraazadec-2-yl}-1,4,7,10-tetraazacyclododec-1-yl]acetate

[0853] Reaction Scheme:

[0854]

[0855] Transfer the solution of the compound of formula (I) in water (128 kg, determination: ~12.3 wt-%, ~15.7 kg of the compound of formula (I)) in the container to a 250 L reactor, and rinse the container and the pipeline with water (total 10.0 kg). Concentrate the resulting solution under reduced pressure (50–70 mbar) at a high temperature (jacket temperature: 75 °C) to obtain a solution of ~20 wt-% of the compound of formula (I) in water. Transfer the solution to a second reactor, and rinse the source reactor and the pipeline with water (5.2 kg). Add activated carbon (0.830 kg, Norit A Supra DAB type) and heat the mixture to 60 °C and stir for 1 h. Cool the mixture to 20 °C, then filter and transfer it to a third reactor. Wash the source reactor and the pipeline with water (12.4 kg). Concentrate the resulting aqueous solution under reduced pressure (50–70 mbar) and at a high temperature (jacket temperature: 75 °C) to obtain a solution of ~50 wt-% of the compound of formula (I) in water. Warm the mixture to 60 °C, and add ethanol (containing ~1% methyl ethyl ketone, 78.5 kg) within 2 h. Determine the water content of the mixture by volumetric Karl-Fischer titration to be ~13.5 wt-%. Stir the resulting suspension at this temperature for another 2 h, then cool it to 20 °C within 90 min. Stir the mixture for 15 min, filter and wash it with ethanol (containing ~1% methyl ethyl ketone, twice, 29.9 kg, 16.1 kg). Dry the resulting solid in a stirred Nutsch dryer under high temperature and reduced pressure. Transfer this material to an oven containing two trays filled with water. Equilibrate this material under reduced pressure (30 mbar) and at a slightly elevated temperature (36 °C, equal to ~50% relative humidity) for 20 h to obtain the title compound (14.7 kg, 94%, 83% assay corrected), which is a colorless crystalline solid.

[0856] Analysis:

[0857] HPLC purity (method d-1, area-%) : 99.8%

[0858] HPLC (Method d-1):

[0859] Diastereomeric distribution: Diastereomer 1 (R t : 20.1 min): 46.4%

[0860] Diastereomer 2 (R t : 20.7 min): 52.6%

[0861] Diastereomer 3 (R t : 22.3 min): 1.0%

[0862] Determination: 86.9 wt-%

[0863] Mass spectrometry [LC-MS, modified method d-1 using formic acid instead of phosphate buffer]:

[0864] The sum formula of the masses detected conforms to the diastereomers of the compound of formula (I)

[0865]

[0866] Water (Method b): 12.5 wt-%

[0867] Ethanol (Method b): <0.050 wt-%

[0868] Solid state: Mixture; Form II and Form I

[0869] Example 4.1: Selective production of Form II

[0870] A solution of the compound of formula (I) in water (8.6 kg, ~15.7 wt-%, ~1.35 kg of the compound of formula (I)) in a container was transferred to a 26 L reactor, and the pipeline was rinsed with a solution of the compound of formula (I) in water (1.05 kg, ~2.6 wt-%, ~0.027 kg of the compound of formula (I)). Activated carbon (0.059 kg, Norit SX Plus 20 type) was suspended in a solution of the compound of formula (I) in water (1.5 kg, ~2.6 wt-%, ~0.039 kg of the compound of formula (I)) and added to the mixture. The mixture was heated to 60 °C and stirred for 1 h. The mixture was cooled to 22 °C and then filtered. The source reactor and the filter were washed with water (1.35 kg). The resulting solution (11.9 kg) was transferred to a 50 L reactor and then concentrated under reduced pressure (75 mbar) and at a high temperature (jacket temperature: 80 °C) to obtain a solution of ~50 wt-% of the compound of formula (I) in water (collected distillate: 9.68 kg). The mixture was warmed to 60 °C and ethanol (containing ~1% methyl ethyl ketone, 6.8 kg) was added within 2 h. The water content of the mixture was determined by volumetric Karl-Fischer titration to be ~8 - 9 wt-%. The resulting suspension was stirred for an additional 2 h at this temperature and then cooled to 25 °C within 45 min. The mixture was stirred for 30 min, filtered, and washed with ethanol (containing ~1% methyl ethyl ketone, twice, 1.35 kg each time). The resulting solid was dried in a stirred Nutsch dryer at a high temperature (initial jacket temperature: 80 °C) and under reduced pressure (pump pressure: 20 mbar). When a pressure of 27 mbar (pressure in the dryer) and a product temperature of 47.5 °C were reached, steam was applied. § The material was dried at about 25–29 mbar (pressure in the dryer) and a product temperature of about 64–68 °C (equal to r.H. of ~9–12%) for 3 h. Drying was continued at 25–29 mbar (pressure in the dryer) in the presence of steam. The jacket temperature was lowered to 30 °C, and the product temperature was gradually lowered to a final product temperature of 30 °C (equal to r.H. of ~66%) within 4.5 h to obtain the title compound (1.2 kg, 89%, 78% corrected assay), which is a colorless crystalline solid.

[0871] § Steam is generated in a pressure reactor at a jacket temperature of 130 °C | 1200–1500 mbar, abs. The hot steam enters the nutsch dryer using a heating hose. The flow rate is controlled by a valve.

[0872] Analysis:

[0873] HPLC purity (method d-1, area-%) : 99.9%

[0874] HPLC (Method d-1):

[0875] Diastereomeric distribution: Diastereomer 1 (R t : 20.1 min): 46.7%

[0876] Diastereomer 2 (R t : 20.7 min): 52.3%

[0877] Diastereomer 3 (R t : 22.3 min): 1.1%

[0878] Determination: 87.2 wt-%.

[0879] Water (Method b): 13.2 wt-%

[0880] Ethanol (Method b): n.d.

[0881] Solid state: Form II

[0882] Example 4.2: Selective Manufacture of Crystalline Form I

[0883] A solution of the compound of formula (I) in water (15.2 kg, ~16.0 wt-%, ~2.43 kg of the compound of formula (I)) in a container was transferred to a 26 L reactor, and the pipeline was rinsed with a solution of the compound of formula (I) in water (3.05 kg, ~4.4 wt-%, ~0.134 kg of the compound of formula (I)). Activated carbon (0.106 kg, Norit A Supra DAB type) was suspended in a solution of the compound of formula (I) in water (1.6 kg, ~4.4 wt-%, ~0.070 kg of the compound of formula (I)) and added to the mixture. The mixture was heated to 60 °C and stirred for 1 h. The mixture was cooled to 22 °C and then filtered. The source reactor and the filter were washed with water (1.2 kg). The resulting solution (20.8 kg) was transferred to a 50 L reactor and then concentrated under reduced pressure (75 mbar) and at a high temperature (jacket temperature: 80 °C) to obtain a solution of ~50 wt-% of the compound of formula (I) in water (collected distillate: ~16 kg). The mixture was warmed to 60 °C, and ethanol (containing ~1% methyl ethyl ketone, 12 kg) was added over 2 h. The water content of the mixture was determined to be ~15 wt-% by volumetric Karl-Fischer titration. The resulting suspension was stirred for an additional 2 h at this temperature and then cooled to 25 °C over 45 min. The mixture was stirred for 30 min, filtered, and washed with ethanol (containing ~1% methyl ethyl ketone, twice, 2.4 kg each time). The wet material was dried in a stirred Nutsch dryer under water vapor §It was dried for 24 h in the presence of [[ID=]] at 29 - 32 mbar (pressure in the dryer) and a product temperature of 31 - 38 °C (equivalent to a r.H. of ~44 - 69 %). The final product temperature was 31 °C and the pressure was 29 mbar (pressure in the dryer, equivalent to a r.H. of ~65 %), giving the title compound (2.28 kg, 87 %, 71 % corrected assay). §§ , which is a colorless crystalline solid.

[0884] § Steam was generated in a pressure reactor at a jacket temperature of 130 °C | 1200 - 1500 mbar, abs. The hot steam entered the nutsch dryer using a heating hose. The flow rate was controlled by a valve.

[0885] §§ The actual yield was higher, but the stirred nutsch dryer could not be completely emptied. The remaining material was dissolved in water.

[0886] Analysis:

[0887] HPLC purity (method d - 1, area - %): >99 %

[0888] HPLC (method d - 1):

[0889] Diastereomer distribution: Diastereomer 1 (R t : 20.1 min): 48.7 %

[0890] Diastereomer 2 (R t : 20.7 min): 50.4 %

[0891] Diastereomer 3 (R t : 22.3 min): 0.9 %

[0892] Assay: 82.4 wt - %

[0893] Water (KF - Fischer, method b): 17.2 wt - %

[0894] Ethanol (method b): 0.222 wt - %

[0895] Solid state: Form I

[0896] The following examples were carried out analogously to the above examples. The drying | equilibration conditions were partly different from those above.

[0897]

[0898]

[0899] *The crystallization and separation procedures are slightly different: After concentration under vacuum, the mixture is cooled to room temperature. Then ethanol is added and the mixture is heated to 60 °C, causing the product to crystallize. The product is separated, washed with ethanol and dried under reduced pressure. Due to the ethanol level exceeding the specification limit (detected ~2 wt-%), the product was exposed to air for several hours, resulting in water absorption. The product was dried again under reduced pressure - but not in the presence of water - to obtain the final compound.

[0900] **Normalized yield. Not all wet products were equilibrated

[0901] ***The wet product was directly equilibrated in a glass drum dryer in the presence of water at a jacket temperature of 30 °C | product temperature of ~30 °C | pump pressure of 20 mbar (equivalent to a r.H. of ~48%). Due to technical settings, the pressure in the dryer was not measured.

[0902] ****Drying was carried out directly in a glass drum dryer in the presence of water. First, at a jacket temperature of 70 °C | product temperature of ~62 °C | pump pressure of 20 mbar (equivalent to a r.H. of ~9%) for 1.75 h, then at a jacket temperature of 30 °C | pump pressure of 20 mbar for 2.25 h (cooling) + 1.25 h (holding time), with a final product temperature of 29 °C (equivalent to a r.H. of ~50%). Due to technical settings, the pressure in the dryer was not measured.

[0903] § After reaching the required parameters, drying was carried out directly in a stirred nutsch dryer in the presence of water. First, at a jacket temperature of 80 °C | product temperature of 68–73 °C | pump pressure of 20 mbar | pressure in the dryer of ~32 mbar (equivalent to a r.H. of ~9–11%) for 4.5 h; then, at a jacket temperature of 31–40 °C | pump pressure of 20 mbar | pressure in the dryer of ~30 mbar for 5 h; the final product temperature was 31 °C (equivalent to a r.H. of ~67%).

[0904] §§ After reaching the required parameters, drying was carried out directly in a stirred nutsch dryer in the presence of water. First, at a jacket temperature of 72 °C | product temperature of 61–65 °C | pump pressure of 20 mbar | pressure in the dryer of 22–24 mbar (equivalent to a r.H. of 9–11%) for 3 h, then, at a jacket temperature of 30 °C | pump pressure of 20 mbar | pressure in the dryer of ~21 mbar for 4.5 h, with a final product temperature of 31 °C (equivalent to a r.H. of ~48%).

[0905] §§§After reaching the required parameters, drying is carried out directly in a stirred nutsch dryer in the presence of water. First, at a jacket temperature of 63 °C | a product temperature of 55–57 °C | a pump pressure of 20 mbar | a pressure in the dryer of 30–31 mbar (equivalent to a r.H. of 18–19%) for 3 h, then at a jacket temperature of 30 °C | a pump pressure of 20 mbar | a pressure in the dryer of ~28 mbar for 1.5 h, with a final product temperature of 38 °C (equivalent to a r.H. of ~43%) to obtain a mixture (Form I and Form II). Drying is continued in the presence of water, first at a jacket temperature of 72 °C | a product temperature of 60–63 °C | a pump pressure of 20 mbar | a pressure in the dryer of 27–31 mbar (equivalent to a r.H. of 12–15%) for 2 h, then at a jacket temperature of 30 °C | a pump pressure of 20 mbar | a pressure in the dryer of ~27 mbar for 2.5 h, with a final product temperature of 33 °C (equivalent to a r.H. of ~54%) to obtain Form II.

[0906] §§§§ After reaching the required parameters, drying is carried out directly in a stirred nutsch dryer in the presence of water. First, at a jacket temperature of 93–95 °C | a product temperature of 78–82 °C | a pump pressure of 21–24 mbar | a pressure in the dryer of 29–33 mbar (equivalent to a r.H. of 6–7%) for 3 h, then at a jacket temperature of 30 °C | a pump pressure of 20 mbar | a pressure in the dryer of ~27 mbar for 4 h, with a final temperature of 32 °C (equivalent to a r.H. of ~56%) to obtain a mixture (Form I and Form II). Drying is continued in the presence of water, first at a jacket temperature of 80 °C | a product temperature of 58–71 °C | a pump pressure of 20 mbar | a pressure in the dryer of 30–31 mbar (equivalent to a r.H. of 9–17%) for 3 h, subsequently at a jacket temperature of 30 °C | a pump pressure of 20 mbar | a pressure in the dryer of ~28 mbar for 2.5 h, with a final product temperature of 33 °C (equivalent to a r.H. of ~55%) to obtain Form II.

[0907] $ The equilibration is carried out in a stirred nutsch dryer. Water vapor is generated in a pressure reactor at a jacket temperature of 125–130 °C | 1200–1500 mbar, abs in pressure. The hot water vapor enters the nutsch dryer using a heating hose. The flow rate is controlled by a valve.

[0908] $$ The actual yield is higher, but the stirred nutsch dryer cannot be completely emptied. The remaining material is dissolved in water.

[0909] $$$After reaching the required parameters, drying is carried out directly in a glass drum dryer in the presence of water. First, at a jacket temperature of 65–68 °C | 54–63 °C in the dryer | with a pump pressure of 20 mbar (equivalent to a r.H. of ~9–13%) for 2 h, then at a jacket temperature of ~30 °C | with a pump pressure of 20 mbar for 3 h (cooling) + 2 h (holding time), and the final product temperature is 29 °C (equivalent to a r.H. of ~50%), obtaining a mixture (Form I and Form II). Due to the technical setup, the pressure in the dryer was not measured.

[0910] $$$$ The reaction was carried out similarly to the above, but crystallization was carried out by slowly adding a mixture of ethanol and isopropanol (w / w = 4:1) over 2 h. Accordingly, the separated wet product was washed with a mixture of ethanol and isopropanol (w / w = 4:1). Drying was not carried out in the presence of water vapor. In addition to ethanol, 0.16 wt-% isopropanol was detected. The solid form was not determined.

[0911] $$$$$ The reaction was carried out similarly to the above, but crystallization was carried out by slowly adding a mixture of ethanol and isopropanol (w / w = 3:2) over 2 h. Accordingly, the separated wet product was washed with a mixture of ethanol and isopropanol (w / w = 3:2). Drying was not carried out in the presence of water vapor. In addition to ethanol, 0.73 wt-% isopropanol was detected. The solid form was not determined.

[0912] # After complete addition of ethanol for crystallization, the water content was determined to be ~14 wt-% by volumetric Karl-Fischer titration. After reaching the required parameters (product temperature of 45 °C | pressure in the dryer < 40 mbar), drying was carried out in a stirred nutsch dryer in the presence of steam (~15 kg / h) with a jacket temperature until the product temperature reached 64 °C at 35 mbar (equivalent to a r.H. of ~15%), with a total exposure to steam of ~12 h. The jacket temperature was lowered to 38 °C, and drying was continued in the presence of steam until the product temperature reached 45 °C at 35 mbar in ~7 h (equivalent to a r.H. of ~35%). Throughout the process, steam was applied in a pressure range of ~30 to 45 mbar. At regular frequencies (~20 to 40 min), the steam was shut off for a period of ~8 min for cleaning of the steam filter to reduce the relative humidity. The actual yield was higher, but the stirred nutsch dryer could not be completely emptied. The remaining material was dissolved in water.

[0913] ##After complete crystallization with the addition of ethanol, the water content was determined by volumetric Karl-Fischer titration to be 23 wt-%. After reaching the desired parameters (product temperature 45 °C | pressure in the dryer < 40 mbar), drying was carried out in a stirred nutsch dryer in the presence of steam (∼15 kg / h) at a jacket temperature until the product temperature reached 65 °C at 45 mbar (equivalent to r.H. ∼18 %), with a total exposure to steam of ∼500 min. The jacket temperature was reduced to 43 °C and drying was continued in the presence of steam until the product temperature reached 50 °C at 45 mbar (equivalent to r.H. ∼37 %) within ∼330 min. Throughout the process, steam was applied in a pressure range of ∼35 to 55 mbar. At fixed frequencies (approx. 20 to 40 min), the steam was shut off for a period of ∼8 min for cleaning of the steam filter to reduce the relative humidity. The actual yield was higher, but the stirred nutsch dryer could not be completely emptied. The remaining material was dissolved in water.

[0914] ### After reaching the desired parameters (product temperature 50 °C | pressure in the dryer < 50 mbar), drying was carried out in a stirred nutsch dryer in the presence of steam (∼15 kg / h) at a jacket temperature until the product temperature reached 65 °C at 45 mbar (equivalent to r.H. ∼18 %), with a total exposure to steam of ∼430 min. The jacket temperature was reduced to 43 °C and drying was continued in the presence of steam until the product temperature reached 50 °C at 45 mbar (equivalent to r.H. ∼37 %) within ∼300 min. Throughout the process, steam was applied in a pressure range of ∼40 to 55 mbar. At fixed frequencies (∼20 to 40 min), the steam was shut off for a period of ∼8 min for cleaning of the steam filter to reduce the relative humidity. The actual yield was higher, but the stirred Nutsch dryer could not be completely emptied. The remaining material was dissolved in water.

[0915] The isomers of the compound of formula (I) can be separated according to the method outlined below to obtain material for characterization purposes:

[0916] Example 5: Separation of the diastereomer 1 (RRSS) of the compound of formula (I)

[0917] Examples 5.1, 5.2 and 5.3 describe the enrichment of the material to diastereomer 1 of the compound of formula (I):

[0918] Example 5.1: The compound of formula (I) (38 g, obtained by crystallization as described above, HPLC purity > 99%, diastereomer 1 = ~50%, diastereomer 2 = ~48.5%, diastereomer 3 = 1%) was dissolved in water (38 mL). Ethanol (containing ~1% methyl ethyl ketone, 38 mL) was added and the mixture was heated to reflux. Additional ethanol (containing ~1% methyl ethyl ketone, 342 mL) was added in three portions and the mixture was refluxed for 4 h, cooled to room temperature and stirred for 18 h. The resulting precipitate was filtered off and washed with ethanol (containing ~1% methyl ethyl ketone, 10 mL) to give the wet product (50 g).

[0919] The wet product thus obtained was dissolved in water (50 mL). Ethanol (containing ~1% methyl ethyl ketone, 500 mL) was added and the mixture was heated to reflux for 2 h. The resulting suspension was cooled to room temperature, and the precipitate was filtered off and washed with ethanol (containing about 1% methyl ethyl ketone) to give the wet product (47 g).

[0920] The wet product thus obtained was dissolved in water (50 mL). Ethanol (containing about 1% methyl ethyl ketone, 500 mL) was added and the mixture was heated to reflux for 2 h. The resulting suspension was cooled to room temperature and stirred for 18 h. The precipitate was filtered off and washed with ethanol (containing ~1% methyl ethyl ketone) to give the wet product (42 g).

[0921] HPLC purity (method e, area-%) : > 99%

[0922] Diastereomer 1 = ~54%

[0923] Diastereomer 2 = ~46%

[0924] Diastereomer 3 = not detected.

[0925] The wet product thus obtained was dissolved in water (126 mL). Ethanol (containing ~1% methyl ethyl ketone, 230 mL) was added and the mixture was heated to reflux for 2 h. Since no crystallization was observed, additional ethanol (containing ~1% methyl ethyl ketone, 230 mL) was added and the mixture was heated to reflux for 2 h. The resulting suspension was cooled to room temperature and stirred for 18 h. The precipitate was filtered off and washed with ethanol (containing ~1% methyl ethyl ketone) to give the wet product (27 g).

[0926] HPLC purity (method e, area-%) : > 99%

[0927] Diastereomer 1 = ~69%

[0928] Diastereomer 2 = ~31%

[0929] Diastereomer 3 = not detected.

[0930] The wet product thus obtained was dissolved in water (126 mL). Ethanol (containing ~1% methyl ethyl ketone, 230 mL) was added, and the mixture was heated under reflux for 2 h. Since no crystallization was observed, additional ethanol (containing ~1% methyl ethyl ketone, 230 mL) was added, and the mixture was heated under reflux for 2 h. The resulting suspension was cooled to room temperature and stirred for 18 h. The precipitate was filtered and washed with ethanol (containing ~1% methyl ethyl ketone) to obtain a wet product, which was dried under reduced pressure and at a high temperature to obtain the compound of formula (I) (27 g, HODA 6004-2-9), which was a colorless solid.

[0931] HPLC purity (method e, area-%) : >99%

[0932] Diastereomer 1 = ~82%

[0933] Diastereomer 2 = ~18%

[0934] Diastereomer 3 = not detected.

[0935] Example 5.2. Similar to that described in Example 5.1, the compound of formula (I) (21.3 g obtained by crystallization as described above, HPLC purity >98%, diastereomer 1 = ~49%, diastereomer 2 = ~48%, diastereomer 3 = ~1%) was recrystallized repeatedly from a mixture of ethanol (containing ~1% methyl ethyl ketone) and water to obtain a colorless solid (7.1 g).

[0936] HPLC purity (method e, area-%) : >98%

[0937] Diastereomer 1 = ~87%

[0938] Diastereomer 2 = ~11%

[0939] Diastereomer 3 = not detected

[0940] Example 5.3. Similar to that described in Example 5.1, the compound of formula (I) (26 g of wet product obtained by crystallization as described above, HPLC purity >99%, diastereomer 1 = ~59%, diastereomer 2 = ~40%, diastereomer 3 = ~1%) was recrystallized repeatedly from a mixture of ethanol (containing ~1% methyl ethyl ketone) and water to obtain a colorless solid (18.8 g).

[0941] HPLC purity (method e, area-%) : >98%

[0942] Diastereomer 1 = ~77%

[0943] Diastereomer 2 = ~23%

[0944] Diastereomer 3 = not detected

[0945] Preparation of the title compound:

[0946] Combine the three batches described above and dissolve in water (100 mL). Add ethanol (containing ~1% methyl ethyl ketone, 500 mL) and reflux the mixture for 4 h. Cool the mixture to room temperature and stir for 1 h. Filter the suspension and wash the solid with ethanol (containing ~1% methyl ethyl ketone, 50 mL). Dry the residue under reduced pressure and at elevated temperature to obtain a mixture of diastereomers of the compound of formula (I), which is a colorless solid (41.6 g).

[0947] HPLC purity (method e, area-%) : >99%

[0948] Diastereomer 1 = ~81%

[0949] Diastereomer 2 = ~19%

[0950] Diastereomer 3 = not detected.

[0951] Dissolve this material (41.5 g) in water (120 mL). Add ethanol (containing ~1% methyl ethyl ketone, 420 mL), and reflux the mixture for 4 h. Cool the mixture to room temperature and stir for 1 h. Filter the suspension and wash the solid with ethanol (containing ~1% methyl ethyl ketone, 50 mL). Dry the residue under reduced pressure and at elevated temperature to obtain a mixture of diastereomers of the compound of formula (I) (36.5 g), which is a colorless solid.

[0952] HPLC purity (method e, area-%) : >99%

[0953] Diastereomer 1 = ~88%

[0954] Diastereomer 2 = ~12%

[0955] Diastereomer 3 = not detected.

[0956] Dissolve this material (36.5 g) in water (90 mL) and filter. Wash the filter with water (18 mL). Add ethanol (containing ~1% methyl ethyl ketone, 360 mL) and reflux the mixture for 4 h. Cool the mixture to room temperature and stir for 1 h. Filter the suspension and wash the solid with ethanol (containing ~1% methyl ethyl ketone, 50 mL). Dry the residue under reduced pressure and at elevated temperature to obtain the title compound (32.6 g).

[0957] Analysis:

[0958] Before analytical characterization, the material is equilibrated by storing in a desiccator over saturated potassium carbonate solution for at least 48 h.

[0959] HPLC purity (method d-2, area-%) : > 99.9%

[0960] HPLC (method d-2):

[0961] Diastereomeric distribution

[0962] Diastereomer D1: 94.1%

[0963] Diastereomer D2: 5.9%

[0964] Diastereomer D3: n.d.

[0965] Water content (method b): 11.2 wt-%

[0966] Residual ethanol: (method b) n.d.

[0967] Relaxivity R1 [in water]: 10.3 [L / (mmol*sec)]

[0968] Relaxivity R2 [in water]: 11.7 [L / (mmol*sec)]

[0969] Solubility data in water: >= 593 mg / mL

[0970] Solid state: Form II

[0971] The stereochemistry configuration and molecular structure were further verified by single crystal x-ray diffraction. For details, refer to the Instrument and Method section and Table 4 / Figure 16 .

[0972] Example 6. Separation of Diastereomers 2 (RRRS and SSSR) of the Compound of Formula (I)

[0973] Since the diastereomers 2 and 3 of the compound of formula (I) are more soluble in the crystallization media water and ethanol than the diastereomer 1 of the compound of formula (I), the mother liquors obtained by crystallization experiments carried out in a similar manner as described in Example 5 above to enrich the diastereomer 1 of the compound of formula (I) were combined and concentrated to dryness under reduced pressure and at elevated temperature.

[0974] A mixture of isomers (69.4 g) of the compound of formula (I) was dissolved in water (150 mL). Ethanol (containing ~1% methyl ethyl ketone, 250 mL) was added and the mixture was heated to reflux. Additional ethanol (containing ~1% methyl ethyl ketone, 250 mL) was added. Subsequently, 100 mL of the solvent was distilled off and the mixture was stirred at reflux for 2 h. The mixture was cooled to room temperature and stirred for 1 h. The suspension was filtered and the solid was washed with ethanol (containing ~1% methyl ethyl ketone, 70 mL). The residue was dried under reduced pressure and at elevated temperature to give a mixture of isomers (32.5 g) of the compound of formula (I), which was a colorless solid.

[0975] HPLC purity (method e, area-%) : >99%

[0976] Diastereomer 1 = ~25%

[0977] Diastereomer 2 = ~75%

[0978] Diastereomer 3 = not detected.

[0979] The mother liquor was concentrated to give a residue (36.7 g).

[0980] HPLC purity (method e, area-%) : >99%

[0981] Diastereomer 1 = not detected

[0982] Diastereomer 2 = ~92%

[0983] Diastereomer 3 = ~8%.

[0984] Ethanol (containing ~1% methyl ethyl ketone, 50 mL) was added to this material (36.7 g), and the mixture was stirred at 60 °C for 2 h to form a white suspension. The mixture was cooled to room temperature and stirred for 1 h. The suspension was filtered and the solid was dried under reduced pressure and at elevated temperature to give a mixture of isomers (25.4 g) of the compound of formula (I), which was a colorless solid.

[0985] HPLC purity (method d-2, area-%) : 98.7%

[0986] Diastereomer 1 = 1.9%

[0987] Diastereomer 2 = 95.3%

[0988] Diastereomer 3 = 1.6%.

[0989] To reduce the high ethanol content ( ~5 wt-%) of this material, it was stored in an ambient atmosphere for 24 h and then dried under reduced pressure and at elevated temperature to give the title compound (23.8 g).

[0990] Analysis:

[0991] Before analytical characterization, the material was equilibrated by storing it in a saturated potassium carbonate solution in a desiccator for at least 48 h.

[0992] HPLC purity (method d-2, area-%) : 99.4%

[0993] HPLC (method d-2):

[0994] Diastereomer distribution

[0995] Diastereomer D1: 1.9%

[0996] Diastereomer D2: 96.0%

[0997] Diastereomer D3: 1.6%.

[0998] Water content (Method b): 15.1 wt-%

[0999] Residual ethanol: (Method b) n.d.

[1000] Relaxivity R1 [in water]: 10.3 [L / (mmol*sec)]

[1001] Relaxivity R2 [in water]: 11.9 [L / (mmol*sec)]

[1002] Solubility in water >= 548 mg / mL

[1003] Solid state: Form II with amorphous content

[1004] Example 6.1

[1005] This example was carried out similarly to those described above. By repeated recrystallization and mother liquor combination, diastereomer 2 of the compound of formula (I) was obtained.

[1006] HPLC purity (Method d-1, area-%): 99.8%

[1007] HPLC (Method d-1):

[1008] Diastereomer distribution

[1009] Diastereomer D1: 4.6%

[1010] Diastereomer D2: 95.2%

[1011] Diastereomer D3: 0.05%.

[1012] Water content (Method a): 9.3 wt-%

[1013] Residual ethanol: (Method a) 0.2 wt-%

[1014] Example 7. Separation of Diastereomer 3 (RRRR and SSSS) of the Compound of Formula (I)

[1015] The mother liquor and washings from crystallization (performed on a 2.5 kg scale) similar to that described above were concentrated under reduced pressure to a highly viscous residue (∼2 - 3 L). The residue was divided into two parts, and ethanol (500 mL containing ∼1% methyl ethyl ketone) was added to each part. The mixture was concentrated at 60 °C under reduced pressure to give a syrupy material. Additional ethanol (1 L containing ∼1% methyl ethyl ketone) was added, and the mixture was concentrated under reduced pressure to give a mixture of crystalline material and amorphous aggregates. The crystalline material from both trials was separated manually (∼600 g) and not pursued further.

[1016] A portion of the remaining amorphous aggregates described above was dissolved in water (25 mL). Ethanol (1 L containing ∼1% methyl ethyl ketone) was added and the mixture was heated to reflux. Since no crystallization was observed, a seed material (5 g, wet product, purity (method e) = ∼99%, diastereomer 1 = ∼26%, diastereomer 2 = ∼70%, diastereomer 3 = ∼3%,) was added and the mixture was heated to reflux for 5 h, distilling off a total of 250 mL of solvent. The mixture was slowly cooled to room temperature and stirred for 72 h. The precipitate was filtered off and washed with ethanol (25 mL containing ∼1% methyl ethyl ketone). The filtrate was concentrated under reduced pressure and at elevated temperature. Acetone (1 L) was added to the resulting residue and the resulting suspension was stirred at room temperature for 1 h. The precipitate was filtered off, washed with acetone, and then dried under reduced pressure and at elevated temperature to give a colorless solid (207 g).

[1017] HPLC purity (method d - 2, area - %): 64.4%

[1018] Diastereomer 1 = 2.1%

[1019] Diastereomer 2 = 14.8%

[1020] Diastereomer 3 = 47.5%.

[1021] This material was dissolved in water (500 mL), and an ion - exchange resin (211 g, type MB6113, purchased from Merck KGaA, Germany) was added. The source container was rinsed with water (250 mL), and the mixture was stirred at room temperature for 3 h. The resin was filtered off and washed with water. The filtrate was concentrated under reduced pressure. Ethanol (250 mL containing ∼1% methyl ethyl ketone) was added to the resulting residue and the mixture was heated to 60 °C. Then, acetone (250 mL) was added and the mixture was stirred for 1 h to form a suspension. The mixture was allowed to cool to room temperature. The precipitate was filtered off, washed with acetone, and dried under reduced pressure and at elevated temperature to give a solid (71.5 g).

[1022] HPLC purity (method d - 2, area - %): 76.5%

[1023] Diastereomer 1 = 2.6%,

[1024] Diastereomer 2 = 19.4%

[1025] Diastereomer 3 = 54.5%.

[1026] This material was further purified by preparative HPLC

[1027] Instrument: Agilent 1260 Infinity series, pump: G1361A, autosampler: G2260A, fraction collector: G1364C, detector: G1315D; column: YMC Triart Actus C18, column size: 250x30mm, 5μm, bandwidth: 12nm, detection: DAD, wavelength: 210nm; flow rate: 36mL / min; eluent A: aqueous solution of 0.1% formic acid; eluent B: aqueous solution of 0.1% formic acid: acetonitrile = 9:1; gradient: isocratic, 65% A, 35% B.

[1028] A total of 140 runs were carried out with 0.2g of the material in 2mL of water.

[1029] The combined product containing fractions from chromatography was concentrated under reduced pressure and at elevated temperature (bath temperature: 60°C) to give a residue, which was then dissolved in water (50mL). Due to the formic acid generated by chromatographic separation, it showed a weakly acidic pH. An ion exchange resin (16g, type IRA 67, purchased from Merck KGaA, Germany) was added, and the mixture was stirred for 1h to adjust the pH to ~7. The resin was filtered off and washed with water. The filtrate was concentrated under reduced pressure and at elevated temperature to give a colorless foamy solid (13.1g)

[1030] Analysis:

[1031] Before analytical characterization, the material was equilibrated by storing it in a desiccator over saturated potassium carbonate solution for at least 48h.

[1032] HPLC purity (method d-2, area-%) : 96.2%

[1033] HPLC (method d-2):

[1034] Diastereomer distribution:

[1035] Diastereomer D1: <0.03%

[1036] Diastereomer D2: 0.4%

[1037] Diastereomer D3: 99.6%.

[1038] Moisture content (method b): 17.8wt-%

[1039] Residual ethanol: (Method b) n.d.

[1040] Relaxivity R1 [in water]: 10.3 [L / (mmol*sec)]

[1041] Relaxivity R2 [in water]: 11.8 [L / (mmol*sec)]

[1042] Solubility in water >= 565 mg / mL

[1043] Solid state: Amorphous

[1044] The retention time of the diastereomer 3 of the compound of formula (I) matches the retention time of the samples prepared by selective chemical synthesis described in Examples 3-1 and 3-2 of Patent EP3303307B1.

[1045] The stereochemistry configuration and molecular structure were further verified by single crystal x-ray diffraction. See the Instrument and Method section and Table 5 for details / Figure 17 .

[1046] Crystalline form

[1047] Crystalline forms of the compound of formula (I)

[1048]

[1049]

[1050] Table 1. XRPD data of crystalline form I and crystalline form II of the compound of formula (I)

[1051]

[1052]

[1053] Table 2. IR data of crystalline form I and II of the compound of formula (I)

[1054]

[1055]

[1056]

[1057] Table 3. Raman data of crystalline form I and II of the compound of formula (I)

[1058] Crystalline forms of the diastereomers of the compound of formula (I)

[1059] As described above, the compounds of formula (I) can exist in different configurations (i.e., (R,R,R,R) and (S,S,S,S) (diastereomer 3); (R,S,S,S) and (S,R,R,R) (diastereomer 2); (S,S,R,R) (meso form, diastereomer 1)) in pure form or as a mixture of two or more of these diastereomeric configurations.

[1060] The absolute configurations of diastereomers 1 and 3 of the compounds of formula (I) were determined by single crystal diffraction (SCD). For diastereomer 1, the asymmetric part of the unit cell is shown in Figure 16 . The crystal data and structure refinement are shown in Table 4. For diastereomer 3, the asymmetric part of the unit cell is shown in Figure 17 . The crystal data and structure refinement are shown in Table 5.

[1061]

[1062]

[1063] Table 4. Crystal data and structure refinement of diastereomer 1 of the compounds of formula (I).

[1064]

[1065]

[1066] Table 5. Crystal data and structure refinement of diastereomer 3 of the compounds of formula (I).

[1067] Crystalline forms of the compounds of formula (II)

[1068]

[1069]

[1070] Table 6. XRPD data of crystalline forms I, II and III of the compounds of formula (II)

[1071]

[1072]

[1073] Table 7. IR data of crystalline forms I, II and III of the compounds of formula (II)

[1074]

[1075]

[1076] Table 8. Raman data of crystalline forms I, II and III of the compounds of formula (II)

Claims

1. A method for separating a compound of general formula (I) or its stereoisomers, tautomers, N - oxides, hydrates, solvates or salts thereof or mixtures thereof, The method comprises (i) providing a mixture comprising a compound of formula (I), water and at least a first organic solvent, (ii) removing water from the mixture provided in (i), (iii) adding a second organic solvent, (iv) optionally adding a third organic solvent, (v) separating the compound of formula (I).

2. The method according to claim 1, wherein the second organic solvent in step (iii) is an alcohol selected from ethanol, n - propanol and isopropanol, and wherein the third organic solvent in step (iv) is acetone.

3. The method according to any one of claims 1 or 2, wherein the second organic solvent in step (iii) is ethanol.

4. The method according to any one of claims 1 to 3, wherein step (ii) comprises removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% by weight (w / w).

5. The method according to any one of claims 1 or 4, wherein the at least first organic solvent in step (i) is DMSO.

6. The method according to any one of claims 1 to 5, wherein the separation of the compound of formula (I) in step (v) comprises the following steps: (v - 1) providing an aqueous mixture comprising a compound of formula (I), (v - 2) adding an organic solvent, (v - 3) drying the solid obtained in (v - 2).

7. The method according to claim 6, wherein the organic solvent in (v - 2) is ethanol, and wherein the drying of the solid obtained in (v - 2) in (v - 3) is carried out at a relative humidity of 18% to 70%, preferably 30% to 65%.

8. The method according to any one of claims 6 or 7, wherein the organic solvent in (v - 2) is ethanol, and wherein the drying of the solid obtained in (v - 2) in (v - 3) is first carried out at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then a second drying process is carried out by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

9. Crystalline form I of the compound of formula (I), characterized in that When measured at room temperature using Cu-Kα radiation with a wavelength of 0.15419 nm 1 a powder X-ray diffraction pattern having reflections at 2-θ angles including the following: (6.8 ± 0.2)°, (9.1 ± 0.2)°, and (11.4 ± 0.2)°, preferably a powder X-ray diffraction pattern having reflections at 2-θ angles including the following: (6.8 ± 0.2)°, (9.1 ± 0.2)°, (10.1 ± 0.2)°, (11.4 ± 0.2)°, and (12.0 ± 0.2)°, more preferably a powder X-ray diffraction pattern having reflections at 2-θ angles including the following: (6.8 ± 0.2)°, (9.1 ± 0.2)°, (10.1 ± 0.2)°, (11.4 ± 0.2)°, (12.0 ± 0.2)°, (14.4 ± 0.2)°, and (23.5 ± 0.2)°.

10. Crystalline form II of the compound of formula (I), characterized in that When measured at room temperature with Cu-Kα radiation having a wavelength of 0.15419 nm 1 a powder X-ray diffraction pattern having reflections at 2-θ angles including those in the following: (10.2 ± 0.2)°, (10.8 ± 0.2)°, and (11.3 ± 0.2)°, preferably a powder X-ray diffraction pattern having reflections at 2-θ angles including those in the following: (7.3 ± 0.2)°, (10.2 ± 0.2)°, (10.8 ± 0.2)°, (11.3 ± 0.2)°, and (13.3 ± 0.2)°, more preferably a powder X-ray diffraction pattern having reflections at 2-θ angles including those in the following: (7.1 ± 0.2)°, (7.3 ± 0.2)°, (10.2 ± 0.2)°, (10.8 ± 0.2)°, (11.3 ± 0.2)°, (13.3 ± 0.2)°, and (15.1 ± 0.2)°.

11. A method for preparing crystalline form I of the compound of formula (I) according to claim 9 The method comprises: (i) providing an aqueous mixture comprising the compound of formula (I), (ii) adding an organic solvent, (iii) drying the solid obtained in (ii) at a relative humidity of 18% to 70%, preferably 30% to 65%.

12. A method for preparing crystalline form II of the compound of formula (I) according to claim 10 The method comprises: (i) providing an aqueous mixture comprising the compound of formula (I), (ii) adding an organic solvent, (iii) First, dry the solid obtained in (ii) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then perform a second drying process by adjusting the relative humidity until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached.

13. The method according to any one of claims 11 or 12, wherein the organic solvent in step (ii) is ethanol.

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