Method for preparing gadolinium contrast agent

Abstract

The present invention relates to a method for preparing a gadolinium chelate compound of formula (I) or its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof. Furthermore, the present invention relates to the crystalline form of the gadolinium chelate of formula (I), a method for preparing the crystalline form, and intermediate compounds in the synthesis of the gadolinium chelate compound of formula (I) and / or its crystalline form, as well as stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof.

Description

[Technical Field]

[0001] The present invention relates to the claims characterized by the following: a method for preparing a gadolinium chelate compound of formula (I) or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof. [ka]

[0002] Furthermore, the present invention relates to the crystalline form of the gadolinium chelate of formula (I), a method for preparing the crystalline form, and intermediate compounds in the synthesis of the gadolinium chelate compound of formula (I) and / or its crystalline form, as well as stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, or mixtures thereof. [Background technology]

[0003] Gd-based contrast agents play a crucial role in diagnostics using magnetic resonance imaging (MRI) techniques. One such Gd-based agent is the compound of formula (I) described in International Publication No. 2016 / 193190 (BAYER AG). However, the synthetic methods for preparing the compound of formula (I) described in the prior art, while yielding the desired product, involve several obstacles that make its synthesis on a large scale detrimental. [ka]

[0004] For example, the preparation of the compound of formula (II), namely the 4-nitrophenol ester (IV) of the carboxylic acid, as described in the prior art (International Publication No. 2001051095 A2), cannot be modified for scaling up on a metric ton scale. This is based on the fact that this route involves using highly toxic pyridine in water to form the pyridinium salt (IV) of the carboxylic acid, followed by isolation by freeze-drying (International Publication No. 2001051095 A2, 21d, p.44). Subsequently, the salt is reacted with an excess of bis(4-nitrophenol) carbonate in neat pyridine, yielding the corresponding activated ester of formula (II) after a long reaction time of 3 days, which is isolated by filtration, followed by washing with the highly toxic chemicals pyridine and dichloromethane. [ka]

[0005] Furthermore, the fragmentation of the tetraamine of formula (III) or a salt thereof with the activated ester (II) is described only in terms of preparation of the compound of formula (I) using a large excess of the precious intermediate of formula (II) at high dilution. Regarding the distillation of most of the high-boiling point solvent dimethyl sulfoxide, a method requiring low pressure and high temperature, the addition of a large excess of ethyl acetate caused precipitation of the crude material, thus complicating large-scale production. After removing low molecular weight impurities by dialysate / ultrafiltration in aqueous solution, the concentrated water was lyophilized and subjected to chromatography to obtain an amorphous solid. Overall, the yield of the sequence was low. High dilution, excess reagents, and cumbersome procedures, namely chromatography and lyophilization, are the most likely factors explaining the high cost and near-inefficiency of the method.

[0006] Therefore, there is an unmet need to provide a method for preparing a compound of general formula (I) that satisfies the following conditions: -Large-scale, reliable, and correctable, - High cost-effectiveness and high overall yield, -Includes a reliable and scalable method for producing the compound of formula (II), - This makes it possible to provide compounds of general formula (I) as crystalline substances of high chemical purity, thus facilitating compliance with necessary regulatory requirements for clinical trials and market supply. - To enable and regulate the monitoring of the strong hygroscopic properties of compounds of general formula (I), thereby facilitating transport and handling for analytical purposes and pharmaceutical manufacturing, while simultaneously maintaining residual ethanol levels in accordance with regulatory requirements.

[0007] Remarkably, a method has been found that enables the preparation of compounds of general formula (I) and overcomes the aforementioned drawbacks of the aforementioned methods, which constitutes the basis of the present invention. Furthermore, the present invention also relates to novel crystalline forms of gadolinium chelates of formula (I), methods for preparing said crystalline forms, and intermediate compounds in the synthesis of gadolinium chelate compounds of formula (I) and / or their crystalline forms.

[0008] Furthermore, surprisingly, in the context of the present invention, It has been found that it is possible to develop a one-pot protocol for reacting the compound of formula (IV) with the compound of formula (II), which involves isolating the compound of formula (IV) as a crystalline material, and avoids the use of pyridine, a highly toxic and environmentally harmful solvent. This method requires a precise balance of the various variables involved in the reaction. -It was found that it is possible to provide a method for producing the compound of formula (II) in a manner that allows for a reduction in the equivalent amount with the compound of formula (I) in subsequent reactions, as well as a method that allows the reaction to be carried out at (much) higher concentrations. Surprisingly, this protocol allows for the isolation of the compound of formula (I) as a well-behaving solid as a crude substance without the need for distillation of the high-boiling solvent dimethyl sulfoxide. -It was found that the compound of formula (I) can be prepared as a crude substance with a very small amount of residual organic solvent, in high purity, i.e., at least 50% (w / w), preferably at least 70% (w / w). -It was found that the compound of formula (I) can be prepared in crystalline form, thereby avoiding the cumbersome, expensive, and inefficient use of preparative HPLC, and enabling the production of the title compound in high chemical purity and crystalline form. -It was found that it is possible to isolate the compound of formula (I) in different solid states accessible by clearly defined parameters and conditions, thereby providing a reliable and controllable method for its production and handling. [Overview of the project] [Means for solving the problem]

[0009] The present invention relates to a gadolinium chelate compound of formula (I), a method for preparing the crystalline form of the gadolinium chelate of formula (I), a method for preparing the crystalline form, and intermediate compounds in the synthesis of the gadolinium chelate compound of formula (I) and / or its crystalline form.

[0010] definition The term "substituted" means that one or more hydrogen atoms on a specified atom or group are replaced by those selected from the indicated group, provided that the valency does not exceed the normal valency of the specified atom in the context in which it exists. Substituents and / or variable combinations are permitted.

[0011] The term "optionally substituted" means that the number of substituents may be equal to or different from zero.

[0012] When a group in a compound according to the present invention is substituted, unless otherwise specified, the group may be monosubstituted or polysubstituted with one or more substituents. Within the scope of the present invention, the meaning of all repeating groups is independent of one another. A group in a compound according to the present invention may be substituted with one, two, or three identical or different substituents, in particular one substituent.

[0013] In the case of a composite substituent composed of two or more parts, for example (C1~C3-alkoxy)-(C2~C6-alkyl)-, the position of a given part can be any suitable position on the composite substituent, i.e., the C1~C3-alkoxy part can be bonded to any carbon atom of the C2~C6-alkyl part of the (C1~C3-alkoxy)-(C2~C6-alkyl)- group. The first or last hyphen of such a composite substituent indicates the bond site between the composite substituent and the rest of the molecule.

[0014] The term "including" as used herein includes "consisting of".

[0015] If any item is referred to as “referred to herein” within the text, it means that it may be referred to anywhere in the text.

[0016] In the context of this invention, the term "relative humidity" can be defined as humidity calculated according to the following formula.

number

[0017] Relative humidity as a function of temperature and vapor pressure is shown, for example, in Klaus Sattler's *Thermische Trennverfahren-Grundlagen, Auslegung, Apparate* (K. Sattler, *Thermische Trennverfahren-Grundlagen, Auslegung, Apparate*, Wiley-VCH, Weinheim, Germany, 2nd Edition, 1995, p. 415).

[0018] In a liquid-gas system, water molecules in the gas phase are in equilibrium with water molecules in the liquid phase. The concentration of water molecules in the gas phase is expressed as water pressure. In a 100% water atmosphere, water pressure is equal to the total pressure. In the case of a mixture of water and another gaseous component (e.g., nitrogen), water pressure is equal to the total pressure multiplied by the mole fraction of water in the gas phase (Dalton's Law). The water vapor pressure in the liquid phase is temperature-dependent.

[0019] In a "solid-gas" system, water molecules in the gas phase are in equilibrium with water molecules absorbed / adsorbed in the solid phase. The concentration of water molecules in the gas phase is expressed as water pressure. In a 100% water atmosphere, water pressure is equal to the total pressure. In the case of a mixture of water and another gaseous component (e.g., nitrogen), water pressure is equal to the total pressure multiplied by the mole fraction of water in the gas phase (Dalton's Law). The water vapor pressure in the solid phase is temperature-dependent. The relative humidity set in "dynamic vapor sorption" and manufacturing methods refers to water in a "liquid-gas" system.

[0020] The terms used in this text have the following meanings:

[0021] The term "halogen atom" means fluorine, chlorine, bromine, or iodine atoms, and in particular fluorine, chlorine, or bromine atoms.

[0022] The term "C1-C6-alkyl" means a linear or branched saturated monovalent hydrocarbon 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, neo-pentyl, 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 group, or their isomers. In particular, the group is a group having 1, 2, 3, or 4 carbon atoms ("C1-C4-alkyl"), for example, a methyl, ethyl, propyl, isopropyl, butyl, sec-butylisobutyl, or tert-butyl group, and more particularly, a group having 1, 2, or 3 carbon atoms ("C1-C3-alkyl"), for example, a methyl, ethyl, n-propyl, or isopropyl group.

[0023] The term "C1-C3-haloalkyl" means a linear or branched saturated monovalent hydrocarbon group in which the term "C1-C3-alkyl" is as defined above, and one or more hydrogen atoms are replaced identically or differently by halogen atoms. In particular, the halogen atom is a fluorine atom. Examples of the C1-C3-haloalkyl groups are fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, or 1,3-difluoropropane-2-yl.

[0024] The term "C2-C6-hydroxyalkyl" is defined above as "C2-C6-alkyl," and refers to a linear or branched saturated monovalent hydrocarbon group in which one, two, or three hydrogen atoms are replaced by a hydroxyl group, such as 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-methylpropyl, and 2-hydroxy-2-methylpropyl groups.

[0025] The term "C1-C3-alkoxy" refers to a linear or branched saturated monovalent group of the formula (C1-C3-alkyl)-O-, as defined above, such as a methoxy, ethoxy, n-propoxy, or isopropoxy group.

[0026] The term "C3-C6-cycloalkyl" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring ("C3-C6-cycloalkyl") containing 3, 4, 5, or 6 carbon atoms. The C3-C6-cycloalkyl group is, for example, a monocyclic hydrocarbon ring, such as a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.

[0027] As used in this text, the term "C1-C6" refers to an alkyl group having a finite number of carbon atoms, i.e., 1 to 6 carbon atoms, in the context of the definition of "C1-C6-alkyl," for example.

[0028] Furthermore, as used herein, the term "C3-C6" as used in the text, for example, in the context of the definition of "C3-C6-cycloalkyl," means a cycloalkyl group having a finite number of carbon atoms, i.e., 3 to 6 carbon atoms, i.e., 3, 4, 5, or 6 carbon atoms.

[0029] Given a range of values, the range includes each value and subranges within that range.

[0030] for example: "C1~C6" means C1, C2, C3, C4, C5, C6, C1~C6, C1~C5, C1~C4, C1~C3, C1~C2, C2~C6 , C2~C5, C2~C4, C2~C3, C3~C6, C3~C5, C3~C4, C4~C6, C4~C5 and C5~C6; "C1~C4" encompasses C1, C2, C3, C4, C1~C4, C1~C3, C1~C2, C2~C4, C2~C3, and C3~C4; "C1~C3" encompasses C1, C2, C3, C1~C3, C1~C2, and C2~C3; "C2~C6" means C2, C3, C4, C5, C6, C2~C6, C2~C5, C2~C4, C2~C3, C3~C6, C3~C 5、 It includes C3-C4, C4-C6, C4-C5, and C5-C6; "C3~C6" is C3, C4, C5, C6, C3~C6, C3~C5, C3~C 4、 This includes C4-C6, C4-C5, and C5-C6.

[0031] The compounds of the present invention may contain one or more chiral centers, depending on the position and properties of various desired substituents. The chiral carbon atom may exist in a (R) or (S) configuration, which may result in a racemic mixture in the case of a single chiral center and a diastereomer mixture in the case of multiple chiral centers. In certain examples, asymmetry may exist because rotation around a given bond, for example, a central bond joining two substituted aromatic rings of a particular compound, is restricted.

[0032] In the context of the present invention, the compound of formula (I) contains four chiral centers (marked * below) and can therefore exist in different stereoisomers, i.e., diastereomers and / or enantiomers. [ka]

[0033] Those skilled in the art will understand that the compound of formula (I) may exist in either a pure form or as a mixture of two or more different compositions, in different compositions, namely (R,R,R,R), (S,S,S,S,), (R,S,S,S), (S,R,R,R), and (S,S,R,R). Preferably, the compound of formula (I) prepared according to the method of the present invention is obtained as a mixture of diastereomers. More preferably, the compound of formula (I) prepared according to the method of the present invention is 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), in a ratio of 60:30:10 to 30:60:10, more preferably in a ratio of 50:40:10 to 40:50:10. More preferably, the compound of formula (I) prepared according to the method of the present invention is 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 40:55:5 to 65:35:0.

[0034] Preferred compounds are those that yield more desirable biological activity. Isolated, pure or partially purified isomers and stereoisomers or racemic or diastereomer mixtures of the compounds of the present invention are also within the scope of the present invention. Purification and separation of such substances can be achieved by standard techniques known in the art.

[0035] Optical isomers can be obtained by conventional methods of racemic mixture separation, for example, by the formation of diastereoisomer salts or covalent diastereomers using optically active acids or bases. Examples of suitable acids include tartaric acid, diacetyltartaric acid, ditoluyltartaric acid, and camphorsulfonic acid. The mixture of diastereoisomers can be separated into individual diastereomers based on their physical and / or chemical differences by methods known in the art, such as chromatography or fractional crystallization. The optically active base or acid is then liberated from the separated diastereomer salts. Another method for separating optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatization, which may be selected to maximize the separation of enantiomers. Suitable chiral HPLC columns are manufactured by Daicel, and include, for example, Chiracel OD and Chiracel OJ, among many others, all of which are routinely 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.

[0036] To distinguish between different isomers, IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976) is referred to.

[0037] The present invention comprises all possible stereoisomers of the compounds of the present invention as a single stereoisomer or as any mixture of the stereoisomers in any ratio, for example, R- or S-isomers. Isolation of a single stereoisomer of the compounds of the present invention, for example, a single enantiomer or a single diastereomer, can be achieved by any suitable prior art method, for example, chromatography, in particular chiral chromatography.

[0038] The present invention also relates to useful forms of the compounds disclosed herein, such as metabolites, hydrates, solvates, salts, particularly pharmaceutically acceptable salts, and coprecipitations.

[0039] The compounds of the present invention can exist as hydrates, solvates, or mixtures thereof, i.e., mixed hydrates and / or mixed solvates, especially when the compounds of the present invention contain, for example, a polar solvent, particularly water, methanol, or ethanol, as structural elements of the compound's crystal lattice. The amount of the polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios. In the case of stoichiometric solvates, for example, hydrates, semi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, pent-, etc., solvates, or hydrates, respectively. The present invention encompasses all such hydrates or solvates or mixtures thereof, i.e., mixed hydrates and / or mixed solvates.

[0040] Furthermore, the compounds of the present invention may exist in the form of salts. The salts may be either inorganic or organic addition salts, in particular any pharmaceutically acceptable inorganic or organic addition salt commonly used in pharmaceuticals.

[0041] The term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic acid addition salt of the compound of the present invention. See, for example, SMBerge et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19. The specific preparation of the neutral salt is described in U.S. Patent No. 5,560,903.

[0042] pharmaceutically acceptable salts of the compounds according to the present invention include salts of mineral acids and carboxylic acids, for example, but not limited to, salts of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, aspartic acid, and glutamic acid.

[0043] Those skilled in the art will further recognize that an acid addition salt of the claimed compound can be prepared by the reaction of the compound with a suitable inorganic or organic acid via one of several known methods.

[0044] The present invention comprises all possible salts of the compounds of the present invention, either as a single salt or as any mixture of the salts in any ratio.

[0045] In this text, particularly in the experimental section, when a compound is referred to as a salt form with a corresponding base or acid in relation to the synthesis of intermediates and examples of the present invention, the exact stoichiometric composition of the salt form obtained by each preparation and / or purification step is, in most cases, unknown.

[0046] This also applies when synthetic intermediates, example compounds, or salts thereof are obtained by preparation and / or purification steps as solvates, such as hydrates, of an unknown stoichiometric composition (if defined). [Modes for carrying out the invention]

[0047] Isolation of the compound of formula (I) According to the first aspect, the present invention relates to a compound of general formula (I), [ka] or a method for isolating a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent, (ii) The step of removing water from the mixture provided in (i), (iii) The step of adding a second organic solvent, (iv) Depending on the case, the step of adding a third organic solvent, (v) Steps to isolate the compound of formula (I) and This includes methods.

[0048] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent, (ii) The step of removing water from the mixture provided in (i), (iii) The step of adding a second organic solvent, (iv) The step of adding a third organic solvent, (v) Steps to isolate the compound of formula (I) and This includes methods.

[0049] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent, (ii) The step of removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% (by weight) (w / w), (iii) The step of adding a second organic solvent, (iv) The step of adding a third organic solvent, (v) Steps to isolate the compound of formula (I) and This includes methods.

[0050] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent, (ii) The step of removing water from the mixture provided in (i), (iii) A step of adding a second organic solvent, wherein the second organic solvent is a C1-C4 alcohol, (iv) The step of adding a third organic solvent, (v) Steps to isolate the compound of formula (I) and This includes methods.

[0051] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent, (ii) The step of removing water from the mixture provided in (i), (iii) A step of adding a second organic solvent, wherein the second organic solvent is a C1-C4 alcohol, (iv) A step of adding a third organic solvent, wherein the third organic solvent is acetone, (v) Steps to isolate the compound of formula (I) and This includes methods.

[0052] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least one first organic solvent, wherein the at least one first organic solvent is DMSO. (ii) The step of removing water from the mixture provided in (i), (iii) A step of adding a second organic solvent, wherein the second organic solvent is a C1-C5 alcohol, (iv) A step of adding a third organic solvent, wherein the third organic solvent is acetone, (v) Steps to isolate the compound of formula (I) and This includes methods.

[0053] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent, (ii) The step of removing water from the mixture provided in (i), (iii) A step of adding a second organic solvent, wherein the second organic solvent is an alcohol selected from the list consisting of ethanol, n-propanol and isopropanol, (iv) A step of adding a third organic solvent, wherein the third organic solvent is acetone, (v) Steps to isolate the compound of formula (I) and This includes methods.

[0054] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of 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. (ii) The step of removing water from the mixture provided in (i), (iii) A step of adding a second organic solvent, wherein the second organic solvent is an alcohol selected from the list consisting of ethanol, n-propanol and isopropanol, (iv) A step of adding a third organic solvent, wherein the third organic solvent is acetone, (v) Steps to isolate the compound of formula (I) and This includes methods.

[0055] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent, (ii) The step of removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% (by weight) (w / w), (iii) A step of adding a second organic solvent, wherein the second organic solvent is an alcohol selected from the list consisting of ethanol, n-propanol and isopropanol, (iv) A step of adding a third organic solvent, wherein the third organic solvent is acetone, (v) Steps to isolate the compound of formula (I) and This includes methods.

[0056] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent, (ii) The step of removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% (by weight) (w / w), (iii) A step of adding a second organic solvent, wherein the second organic solvent is ethanol, (iv) A step of adding a third organic solvent, wherein the third organic solvent is acetone, (v) Steps to isolate the compound of formula (I) and This includes methods.

[0057] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least one first organic solvent, wherein the at least one first organic solvent is DMSO. (ii) The step of removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% (by weight) (w / w), (iii) A step of adding a second organic solvent, wherein the second organic solvent is ethanol, (iv) A step of adding a third organic solvent, wherein the third organic solvent is acetone, (v) Steps to isolate the compound of formula (I) and This includes methods.

[0058] 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. Preferably, the at least first organic solvent is DMSO. More preferably, the mixture comprising a compound of formula (I), water, and at least a first organic solvent is a mixture obtained from a reaction resulting in the formation of a compound of formula (I).

[0059] 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).

[0060] In step (iii), a second organic solvent is added to the mixture. Preferably, the second organic solvent is an alcohol selected from the list consisting of ethanol, n-propanol, and isopropanol. More preferably, the second organic solvent is ethanol.

[0061] In step (iv), a third organic solvent is added to the mixture. Preferably, the third organic solvent is selected from the list consisting of acetone, methyl-ethyl-ketone, and methyl-tert-butyl ether. More preferably, the third organic solvent is acetone. After the addition of the third organic solvent, preferably a solid containing the compound of formula (I) as a crude substance is obtained after step (iv). Additional and / or optional steps such as dialysis filtration, ultrafiltration, nanofiltration, extraction, treatment with activated carbon, solvent evaporation, exchange resin treatment, and ion exchange resin treatment may be required and may be performed after the addition of the third organic solvent in step (iv) and before isolation in step (v), or they may be included as part of the isolation process in step (v).

[0062] In step (v), the compound of formula (I) is isolated. Preferably, the compound of formula (I) is isolated as a solid. In the context of the present invention, the isolation of the compound of formula (I) may optionally include additional steps such as dialysis filtration, ultrafiltration, nanofiltration, extraction, treatment with activated carbon, solvent evaporation, exchange resin treatment, and ion exchange resin treatment. In a particularly preferred embodiment, the compound of formula (I) is isolated in step (v) by a method including dialysis filtration / ultrafiltration in water.

[0063] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent, (ii) The step of removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% (by weight) (w / w), (iii) A step of adding a second organic solvent, wherein the second organic solvent is an alcohol selected from the list consisting of ethanol, n-propanol and isopropanol, (iv) A step of adding a third organic solvent, wherein the third organic solvent is acetone, (v) The step of isolating the compound of formula (I) by a method including diafiltration, ultrafiltration or the use of an ion exchange resin. This includes methods.

[0064] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of 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. (ii) The step of removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% (by weight) (w / w), (iii) A step of adding a second organic solvent, wherein the second organic solvent is ethanol, (iv) A step of adding a third organic solvent, wherein the third organic solvent is acetone, (v) The step of isolating the compound of formula (I) by a method including diafiltration, ultrafiltration or the use of an ion exchange resin. This includes methods.

[0065] Crystalline forms I and II of the compound of formula (I) Surprisingly, the compound of formula (I) was found to exist in crystalline form, i.e., as a crystalline substance, i.e., as a crystalline solid. Therefore, the present invention relates to the compound of formula (I) in crystalline form, i.e., as a crystalline substance, i.e., as a crystalline solid. It was found that the compound of formula (I) can exist in at least two crystalline forms I and II, either in pure form or in mixtures thereof in any ratio.

[0066] The crystalline form of the compound of formula (I) can be characterized by analytical methods well known in the pharmaceutical industry for characterizing 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 form of the compound of formula (I) can be characterized by one of the aforementioned methods or by a combination of two or more of them. In particular, the crystalline form of the compound of formula (I) can be characterized by one of the following embodiments or by a combination of two or more of the following embodiments.

[0067] Crystalline form I of the compound of formula (I) Crystalline form I of the compound of formula (I) is characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (6.8±0.2)°, (9.1±0.2)°, and (11.4±0.2)° when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm. Preferably, crystalline form I of the compound of formula (I) is characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (6.8±0.2)°, (9.1±0.2)°, (10.1±0.2)°, (11.4±0.2)°, and (12.0±0.2)° when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm. Preferably, crystalline form I of the compound of formula (I) is characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (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)° when measured at room temperature using Cu-Kα1 radiation having a wavelength of 0.15419 nm. Preferably, crystalline form I of the compound of formula (I) is characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (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)° when measured at room temperature using Cu-Kα1 radiation having a wavelength of 0.15419 nm.

[0068] Alternatively, the crystalline form I of the compound of formula (I) is characterized in that, when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm, it has essentially the same powder X-ray diffraction pattern as that shown in Figure 3 of the present invention.

[0069] Alternatively, the crystalline form I of the compound of formula (I) is (1083 ± 2) cm³ when measured at room temperature using a diamond ATR cell. -1 , (1383±2)cm -1 , and (1594±2)cm -1Characterized by having a Fourier transform infrared spectrum including a band at the wavenumber. Preferably, when the crystalline form I of the compound of formula (I) is 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 having a Fourier transform infrared spectrum including a peak at the wavenumber of (1594±2) cm -1 . Preferably, when the crystalline form I of the compound of formula (I) is measured at room temperature using a diamond ATR cell, (494±2) cm -1 , (564±2) cm -1 , (713±2) cm -1 , (1083±2) cm D -1 , (1383±2) cm -1 , (1557±2) cm -1 and having a Fourier transform infrared spectrum including a band at the wavenumber of (1594±2) cm -1 . Preferably, when the crystalline form I of the compound of formula (I) is 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 having a Fourier transform infrared spectrum including a band at the wavenumber of (3313±2) cm -1 .

[0070] Alternatively, the crystalline form I of the compound of formula (I) is characterized by having a Fourier transform infrared spectrum that is essentially the same as that shown in FIG. 4 of the present invention when measured at room temperature using a diamond ATR cell.

[0071] Alternatively, the crystalline form I of the compound of formula (I) is (938±2) cm² when measured at room temperature using a laser with a wavelength of 1064 nm. -1 , (1460±2)cm -1 and (2890±2)cm -1 It is characterized by having a Raman spectrum that includes a peak at a wavenumber. Preferably, the crystalline form I of the compound of formula (I) is (387±2)cm when measured at room temperature using a laser with a wavelength of 1064 nm. -1 , (834±2)cm -1 , (938±2)cm -1 , (1460±2)cm -1 and (2890±2)cm -1 It is characterized by having a Raman spectrum that includes a band at a wavenumber. Preferably, the crystalline form I of the compound of formula (I) is (387±2)cm when measured at room temperature using a laser with a wavelength of 1064 nm. -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 It is characterized by having a Raman spectrum that includes a peak at a wavenumber. Preferably, the crystalline form I of the compound of formula (I) is (387±2)cm when measured at room temperature using a laser with a wavelength of 1064 nm. -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 It is characterized by having a Raman spectrum that includes a peak at a certain wavenumber.

[0072] Alternatively, the crystalline form I of the compound of formula (I) is characterized in that, when measured at room temperature using a laser with a wavelength of 1064 nm, it has essentially the same Raman spectrum as that shown in Figure 5 of the present invention.

[0073] Crystalline form II of the compound of formula (I) Crystalline form II of the compound of formula (I) is characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (10.2±0.2)°, (10.8±0.2)°, and (11.3±0.2)° when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm. Preferably, crystalline form II of the compound of formula (I) is characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (7.3±0.2)°, (10.2±0.2)°, (10.8±0.2)°, (11.3±0.2)°, and (13.3±0.2)° when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm. Preferably, the crystalline form II of the compound of formula (I) is characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (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)° when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm. Preferably, the crystalline form II of the compound of formula (I) is characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (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)° when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm.

[0074] Alternatively, the crystalline form II of the compound of formula (I) is characterized in that, when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm, it has essentially the same powder X-ray diffraction pattern as that shown in Figure 8 of the present invention.

[0075] Alternatively, the crystalline form II of the compound of formula (I) is (1082 ± 2) cm² when measured at room temperature using a diamond ATR cell. -1 , (1380±2)cm -1 and (1596±2)cm -1 It is characterized by having a Fourier transform infrared spectrum that includes a band at a wavenumber. Preferably, the crystalline form II of the compound of formula (I) is (716±2) cm when measured at room temperature using a diamond ATR cell. -1 , (1082±2)cm -1 , (1380±2)cm -1 , (1557±2)cm -1 and (1596±2)cm -1 It is characterized by having a Fourier transform infrared spectrum that includes a band at a wavenumber. Preferably, the crystalline form II of the compound of formula (I) is (495±2) cm when measured at room temperature using a diamond ATR cell. -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 It is characterized by having a Fourier transform infrared spectrum that includes a band at a wavenumber. Preferably, the crystalline form II of the compound of formula (I) is (495±2) cm when measured at room temperature using a diamond ATR cell. -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 It is characterized by having a Fourier transform infrared spectrum that includes a band at the wavenumber.

[0076] Alternatively, crystalline form II of the compound of formula (I) is characterized by having an essentially identical Fourier transform infrared spectrum to that shown in FIG. 9 of the present invention when measured at room temperature using a diamond ATR cell.

[0077] Alternatively or additionally, crystalline form II of the compound of formula (I) has a Raman spectrum containing bands at wavenumbers of (935 ± 2) cm -1 , (1472 ± 2) cm -1 and (2888 ± 2) cm -1 when measured at room temperature using a laser with a wavelength of 1064 nm. Preferably, crystalline form II of the compound of formula (I) has a Raman spectrum containing bands at wavenumbers of (390 ± 2) cm -1 , (833 ± 2) cm -1 , (935 ± 2) cm -1 , (1472 ± 2) cm -1 and (2888 ± 2) cm -1 when measured at room temperature using a laser with a wavelength of 1064 nm. Preferably, crystalline form II of the compound of formula (I) has a Raman spectrum containing bands at wavenumbers of (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 when measured at room temperature using a laser with a wavelength of 1064 nm. Preferably, crystalline form II of the compound of formula (I) has a Raman spectrum containing bands at wavenumbers of (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 -1and (2951±2)cm -1 It is characterized by having a Raman spectrum that includes a band at a wavenumber.

[0078] Alternatively, the crystalline form II of the compound of formula (I) is characterized in that, when measured at room temperature using a laser with a wavelength of 1064 nm, it has essentially the same Raman spectrum as that shown in Figure 10 of the present invention.

[0079] Isolation of the compound of formula (I) in crystalline form I In step (v), the compound of formula (I) is isolated. In the context of the present invention, step (v) can also be understood as part of a broader method comprising steps (i), (ii), (iii), and (iv), as well as the individual substeps (v-1) to (v-3) described herein which result in the isolation of the compound of formula (I), preferably in crystalline form I or crystalline form II.

[0080] In a preferred embodiment, the isolation of the compound of formula (I) in step (v) is performed in the following steps: (v-1) The step of providing an aqueous mixture containing a compound of formula (I), (v-2) The step of adding an organic solvent, (v-3) The step of drying the solid obtained in (v-2) and Includes.

[0081] In a more preferred embodiment, the isolation of the compound of formula (I) in step (v) is performed in the following steps: (v-1) The step of providing an aqueous mixture containing a compound of formula (I), (v-2) Adding an organic solvent selected from the group consisting of ethanol, n-propanol, and isopropanol, or a mixture thereof, (v-3) The step of drying the solid obtained in (v-2) and Includes.

[0082] In a more preferred embodiment, the isolation of the compound of formula (I) in step (v) is performed in the following steps: (v-1) The step of providing an aqueous mixture containing a compound of formula (I), (v-2) The step of adding ethanol, (v-3) The step of drying the solid obtained in (v-2) and Includes.

[0083] In step (v-1), an aqueous mixture containing the compound of formula (I) is provided. Preferably, the sole 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. Therefore, 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. To achieve complete dissolution of the compound of formula (I) and / or to obtain an aqueous mixture or aqueous solution suitable for isolating the compound of formula (I) in crystalline form I or crystalline form II, processes such as filtration, diafiltration, ultrafiltration, nanofiltration, and 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% (on a weight basis) (w / w), more preferably 40% to 60% (on a weight basis) (w / w), and even more preferably 45% to 55% (on a weight basis) (w / w).

[0084] In step (v-2), an organic solvent selected from the group consisting of 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 7% to 20% (by weight) (w / w).

[0085] In a more preferred embodiment, the isolation of the compound of formula (I) in step (v) is performed in the following steps: (v-1) A step of providing a mixture containing a compound of formula (I) in water, (v-2) The step of adding ethanol, (v-3) The step of drying the solid obtained in (v-2) and Includes.

[0086] In a more preferred embodiment, the isolation of the compound of formula (I) in step (v) is performed in the following steps: (v-1) The step of providing an aqueous solution of the compound of formula (I) in water, (v-2) The step of adding ethanol, (v-3) The step of drying the solid obtained in (v-2) and Includes.

[0087] In step (v-2), the organic solvent is added at a temperature of preferably 45°C to 75°C, more preferably 50°C to 70°C, and more preferably 55°C to 65°C. Addition of ethanol at the above temperatures is particularly preferred. After the addition of the organic solvent, the water content of the mixture is preferably in the range of 5% to 25% (by weight) (w / w), more preferably 7% to 20% (by weight) (w / w).

[0088] When the organic solvent is added in step (v-2), a solid is obtained, which is then dried in step (v-3).

[0089] In one embodiment, the compound of formula (I) is isolated in step (v) as a crystalline solid, i.e., a crystalline form (Form I) characterized by having a powder X-ray diffraction pattern including reflections at 2θ angles of (6.8±0.2)°, (9.1±0.2)°, (10.1±0.2)°, (11.4±0.2)° and (12.0±0.2)° when measured at room temperature using Cu-Kα1 radiation having a wavelength of 0.15419 nm.

[0090] In one embodiment, the solid is dried at a relative humidity of 18% to 70%, preferably 30% to 65%, to obtain the compound of formula (I) in crystalline form I. Therefore, step (v-3) includes drying the solid obtained from 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. Furthermore, step (v-3) includes drying the solid obtained from 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 includes reflections at 2θ angles of (6.8±0.2)°, (9.1±0.2)°, (10.1±0.2)°, (11.4±0.2)°, and (12.0±0.2)° when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm. Preferably, the drying process is carried out at the above relative humidity for 1 to 48 hours.

[0091] In a preferred embodiment, step (v) is as follows: (v-1) A step of providing an aqueous mixture containing a compound of formula (I), (v-2) Step of adding ethanol, (v-3)(v-2) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%. This includes the isolation of the compound of formula (I) in crystalline form I.

[0092] In a more preferred embodiment, step (v) is as follows: (v-1) A step of providing an aqueous solution of the compound of formula (I), (v-2) Step of adding ethanol, (v-3)(v-2) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%. This includes the isolation of the compound of formula (I) in crystalline form I.

[0093] In a more preferred embodiment, step (v) is as follows: (v-1) A step of providing an aqueous mixture containing a compound of formula (I) in the range of 30% to 70% (by weight) (w / w), more preferably 40% to 60% (by weight) (w / w), and even more preferably 45% to 55% (by weight) (w / w), (v-2) Step of adding ethanol, (v-3)(v-2) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%. This includes the isolation of the compound of formula (I) in crystalline form I.

[0094] In a more preferred embodiment, step (v) is as follows: (v-1) A step of providing an aqueous mixture containing a compound of formula (I) in the range of 30% to 70% (by weight) (w / w), more preferably 40% to 60% (by weight) (w / w), and even more preferably 45% to 55% (by weight) (w / w), (v-2) Adding ethanol until the water content of the mixture is in the range of 5% to 25% (by weight) (w / w), more preferably 7% to 20% (by weight) (w / w), (v-3)(v-2) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%. This includes the isolation of the compound of formula (I) in crystalline form I.

[0095] In a more preferred embodiment, step (v) is as follows: (v-1) A step of providing an aqueous mixture containing a compound of formula (I) in the range of 30% to 70% (by weight) (w / w), more preferably 40% to 60% (by weight) (w / w), and most preferably 45% to 55% (by weight) (w / w), (v-2) Adding ethanol until the water content of the mixture is in the range of 5-25% (by weight) (w / w), more preferably 7-20% (by weight) (w / w), (v-3)(v-2) The solid obtained in (v-2) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%, for 1 to 48 hours. This includes the isolation of the compound of formula (I) in crystalline form I.

[0096] In a more preferred embodiment, step (v) is as follows: (v-1) A step of providing an aqueous solution of the compound of formula (I) in the range of 30% to 70% (by weight) (w / w), more preferably 40% to 60% (by weight) (w / w), and most preferably 45% to 55% (by weight) (w / w), (v-2) Adding ethanol until the water content of the mixture is in the range of 5-25% (by weight) (w / w), more preferably 7-20% (by weight) (w / w), (v-3)(v-2) The solid obtained in (v-2) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%, for 1 to 48 hours. This includes the isolation of the compound of formula (I) in crystalline form I.

[0097] Isolation of the compound of formula (I) in crystalline form II In further embodiments, the compound of formula (I) is isolated in step (v) as a crystalline solid, i.e., a crystalline form (Form II) characterized by having a powder X-ray diffraction pattern including reflections at 2θ angles of (7.3±0.2)°, (10.2±0.2)°, (10.8±0.2)°, (11.3±0.2)° and (13.3±0.2)° when measured at room temperature using Cu-Kα1 radiation having a wavelength of 0.15419 nm.

[0098] 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, at which point the compound of formula (I) is obtained in crystalline form II.

[0099] Therefore, step (v-3) includes drying the solid obtained from step (v-2) by first drying it at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, followed by a second drying process in which the relative humidity is adjusted to a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%, thereby obtaining the compound of formula (I) in crystalline form II.

[0100] Furthermore, step (v-3) includes a step of first drying the solid obtained from step (v-2) at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, followed by a second drying process in which the relative humidity is adjusted to a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%, at which point a compound of formula (I) is obtained in crystalline form II, which includes reflections at 2θ angles of (7.3±0.2)°, (10.2±0.2)°, (10.8±0.2)°, (11.3±0.2)°, and (13.3±0.2)° when measured at room temperature using Cu-Kα1 radiation having a wavelength of 0.15419 nm.

[0101] In some cases, the formation of crystalline material was observed during the second drying process at a low relative humidity that could not be assigned to Form I and Form II. The X-ray powder diffraction pattern of this material is shown in Figure 33. This crystalline form may or may not be formed during the first and / or second drying process, and if formed, it may be formed in different amounts depending on the specific conditions in each case, simultaneously with other forms, e.g., crystalline form II of the compound of formula (I). Nevertheless, by 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, reliable conversion and preparation of crystalline form II of the compound of formula (I) is ensured.

[0102] Preferably, the first drying process is carried out at the above relative humidity for 0.5 to 24 hours, and the second drying process is carried out at the above relative humidity for 0.5 to 48 hours.

[0103] In a preferred embodiment, step (v) is as follows: (v-1) A step of providing an aqueous mixture containing a compound of formula (I), (v-2) Step of adding ethanol, (v-3)(v-2) 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%, and then dried by a second drying process, which involves adjusting the relative humidity until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%. This includes the isolation of the compound of formula (I) in crystalline form II.

[0104] In a preferred embodiment, step (v) is as follows: (v-1) A step of providing an aqueous solution of the compound of formula (I), (v-2) Step of adding ethanol, (v-3)(v-2) 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%, and then dried by a second drying process, which involves adjusting the relative humidity until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%. This includes the isolation of the compound of formula (I) in crystalline form II.

[0105] In a more preferred embodiment, step (v) is as follows: (v-1) A step of providing an aqueous mixture containing a compound of formula (I) in the range of 30% to 70% (by weight) (w / w), more preferably 40% to 60% (by weight) (w / w), and even more preferably 45% to 55% (by weight) (w / w), (v-2) Step of adding ethanol, (v-3)(v-2) 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%, and then dried by a second drying process, which involves adjusting the relative humidity until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%. This includes the isolation of the compound of formula (I) in crystalline form II.

[0106] In a more preferred embodiment, step (v) is as follows: (v-1) A step of providing an aqueous mixture containing a compound of formula (I) in the range of 30% to 70% (by weight) (w / w), more preferably 40% to 60% (by weight) (w / w), and even more preferably 45% to 55% (by weight) (w / w), (v-2) Adding ethanol until the water content of the mixture is in the range of 5% to 25% (by weight) (w / w), more preferably 7% to 20% (by weight) (w / w), (v-3)(v-2) 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%, and then dried by a second drying process, which involves adjusting the relative humidity until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%. This includes the isolation of the compound of formula (I) in crystalline form II.

[0107] In a more preferred embodiment, step (v) is as follows: (v-1) A step of providing an aqueous solution of the compound of formula (I) in the range of 30% to 70% (by weight) (w / w), more preferably 40% to 60% (by weight) (w / w), and even more preferably 45% to 55% (by weight) (w / w), (v-2) Adding ethanol until the water content of the mixture is in the range of 5% to 25% (by weight) (w / w), more preferably 7% to 20% (by weight) (w / w), (v-3)(v-2) 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%, and then dried by a second drying process, which involves adjusting the relative humidity until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%. This includes the isolation of the compound of formula (I) in crystalline form II.

[0108] In a more preferred embodiment, step (v) is as follows: (v-1) A step of providing an aqueous mixture containing a compound of formula (I) in the range of 30% to 70% (by weight) (w / w), more preferably 40% to 60% (by weight) (w / w), and even more preferably 45% to 55% (by weight) (w / w), (v-2) Adding ethanol until the water content of the mixture is in the range of 5% to 25% (by weight) (w / w), more preferably 7% to 20% (by weight) (w / w), (v-3)(v-2) 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 0.5 to 24 hours, and then dried by a second drying process in which the relative humidity is adjusted for 0.5 to 48 hours until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% is reached. This includes the isolation of the compound of formula (I) in crystalline form II.

[0109] Method for preparing crystalline form I of the compound of formula (I) The present invention provides a method for the selective preparation of the compound of formula (I) in crystalline form I. Details of the method according to steps (i) to (iv) above, as well as details of the process according to steps (v-1) to (v-3) above, for isolating the compound of formula (I) in crystalline form I, apply to the method described herein.

[0110] In a preferred embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent, (ii) The step of removing water from the mixture provided in (i), (iii) The step of adding a second organic solvent, (iv) The step of adding a third organic solvent, (v) A compound of formula (I) in crystalline form I, (v-1) The step of providing an aqueous mixture containing a compound of formula (I), (v-2) The step of adding ethanol, (v-3)(v-2) The solid obtained in (v-3)(v-2) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%. The process includes the steps of isolation and This includes methods.

[0111] In a preferred embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent, (ii) The step of removing water from the mixture provided in (i), (iii) The step of adding a second organic solvent, (iv) The step of adding a third organic solvent, (v) A compound of formula (I) in crystalline form I, (v-1) The step of providing an aqueous solution of the compound of formula (I), (v-2) The step of adding ethanol, (v-3)(v-2) The solid obtained in (v-3)(v-2) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%. The process includes the steps of isolation and This includes methods.

[0112] In a more preferred embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent, (ii) The step of removing water from the mixture provided in (i), (iii) The step of adding a second organic solvent, (iv) The step of adding a third organic solvent, (v) A compound of formula (I) in crystalline form I, (v-1) The step of providing an aqueous mixture containing a compound of formula (I), (v-2) The step of adding ethanol, (v-3)(v-2) The solid obtained in (v-3)(v-2) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%. The process includes the steps of isolation and This includes methods.

[0113] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent, (ii) The step of removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% (by weight) (w / w), (iii) A step of adding a second organic solvent, wherein the second organic solvent is an alcohol selected from the list consisting of ethanol, n-propanol and isopropanol, (iv) The step of adding a third organic solvent, wherein the third organic solvent is acetone, and the step of adding; (v) The compound of formula (I) in crystalline form I, (v-1) The step of providing an aqueous mixture containing the compound of formula (I); (v-2) The step of adding ethanol; (v-3) The step of drying the solid obtained in (v-2) at a relative humidity of 18% to 70%, preferably 30% to 65% and isolating by a process comprising relates to a method comprising.

[0114] In a further embodiment of the first aspect, the present invention is a method for the preparation of a compound of the above general formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method comprises: (i) The step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent; (ii) The step of removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% (by weight) (w / w); (iii) The step of adding a second organic solvent, wherein the second organic solvent is ethanol, and the step of adding; (iv) The step of adding a third organic solvent, wherein the third organic solvent is acetone, and the step of adding; (v) The compound of formula (I) in crystalline form I, (v-1) The step of providing an aqueous mixture containing the compound of formula (I); (v-2) The step of adding ethanol; (v-3) The step of drying the solid obtained in (v-2) at a relative humidity of 18% to 70%, preferably 30% to 65% and isolating by a process comprising relates to a method comprising.

[0115] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least one first organic solvent, wherein the at least one first organic solvent is DMSO. (ii) The step of removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% (by weight) (w / w), (iii) A step of adding a second organic solvent, wherein the second organic solvent is ethanol, (iv) A step of adding a third organic solvent, wherein the third organic solvent is acetone, (v) A compound of formula (I) in crystalline form I, (v-1) The step of providing an aqueous mixture containing a compound of formula (I), (v-2) The step of adding ethanol, (v-3)(v-2) The solid obtained in (v-3)(v-2) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%. The process includes the steps of isolation and This includes methods.

[0116] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least one first organic solvent, wherein the at least one first organic solvent is DMSO. (ii) The step of removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% (by weight) (w / w), (iii) A step of adding a second organic solvent, wherein the second organic solvent is ethanol, (iv) A step of adding a third organic solvent, wherein the third organic solvent is acetone, (v) A compound of formula (I) in crystalline form I, (v-1) The step of providing an aqueous mixture containing a compound of formula (I), (v-2) The step of adding ethanol, (v-3)(v-2) The solid obtained in (v-3)(v-2) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%. The process includes the steps of isolation and This includes methods.

[0117] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least one first organic solvent, wherein the at least one first organic solvent is DMSO. (ii) The step of removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% (by weight) (w / w), (iii) A step of adding a second organic solvent, wherein the second organic solvent is ethanol, (iv) A step of adding a third organic solvent, wherein the third organic solvent is acetone, (v) A compound of formula (I) in crystalline form I, (v-1) The step of providing an aqueous solution of the compound of formula (I), (v-2) The step of adding ethanol, (v-3)(v-2) The solid obtained in (v-3)(v-2) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%. by a process comprising the step of isolating and relates to a method comprising.

[0118] Method for the preparation of crystalline form II of a compound of formula (I) The present invention provides a method for the selective preparation of a compound of formula (I) in crystalline form II. The details of the method according to steps (i) to (iv) above are applied to the isolation of crystalline form II of the compound of formula (I) in the same manner as the details of the process according to steps (v-1) to (v-3) above.

[0119] Thus, in a more preferred embodiment of the first aspect, the present invention is a method for the preparation of a compound of the above general formula (I), or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein 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) adding a third organic solvent; (v) isolating the compound of formula (I) in crystalline form II by (v-1) providing an aqueous mixture comprising a compound of formula (I); (v-2) adding ethanol; (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 adjusting the relative humidity to reach a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70% for a second drying step by a process comprising the step of isolating and relates to a method comprising.

[0120] Therefore, in a more preferred embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or its stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent, (ii) The step of removing water from the mixture provided in (i), (iii) The step of adding a second organic solvent, (iv) The step of adding a third organic solvent, (v) Compound of formula (I) in crystal form II, (v-1) The step of providing an aqueous solution of the compound of formula (I), (v-2) The step of adding ethanol, (v-3)(v-2) 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%, and then the relative humidity is adjusted to a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%, in a second drying step. The process includes the steps of isolation and This includes methods.

[0121] Therefore, in a more preferred embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or its stereoisomer, tautomer, N-oxide, hydrate, solvate or salt, or mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent, (ii) The step of removing water from the mixture provided in (i), (iii) The step of adding a second organic solvent, (iv) The step of adding a third organic solvent, (v) Compound of formula (I) in crystal form II, (v-1) The step of providing an aqueous mixture containing a compound of formula (I), (v-2) The step of adding ethanol, (v-3)(v-2) The solid obtained in (v-3) is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then dried by a second drying process in which the relative humidity is adjusted until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%. The process includes the steps of isolation and This includes methods.

[0122] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent, (ii) The step of removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% (by weight) (w / w), (iii) A step of adding a second organic solvent, wherein the second organic solvent is an alcohol selected from the list consisting of ethanol, n-propanol and isopropanol, (iv) A step of adding a third organic solvent, wherein the third organic solvent is acetone, (v) Compound of formula (I) in crystal form II, (v-1) The step of providing an aqueous mixture containing a compound of formula (I), (v-2) The step of adding ethanol, (v-3)(v-2) The solid obtained in (v-3) is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then dried by a second drying process in which the relative humidity is adjusted until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%. The process includes the steps of isolation and This includes methods.

[0123] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent, (ii) The step of removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% (by weight) (w / w), (iii) A step of adding a second organic solvent, wherein the second organic solvent is ethanol, (iv) A step of adding a third organic solvent, wherein the third organic solvent is acetone, (v) Compound of formula (I) in crystal form II, (v-1) The step of providing an aqueous mixture containing a compound of formula (I), (v-2) The step of adding ethanol, (v-3)(v-2) The solid obtained in (v-3) is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then dried by a second drying process in which the relative humidity is adjusted until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%. The process includes the steps of isolation and This includes methods.

[0124] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least one first organic solvent, wherein the at least one first organic solvent is DMSO. (ii) The step of removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% (by weight) (w / w), (iii) A step of adding a second organic solvent, wherein the second organic solvent is ethanol, (iv) A step of adding a third organic solvent, wherein the third organic solvent is acetone, (v) Compound of formula (I) in crystal form II, (v-1) The step of providing an aqueous mixture containing a compound of formula (I), (v-2) The step of adding ethanol, (v-3)(v-2) The solid obtained in (v-3) is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then dried by a second drying process in which the relative humidity is adjusted until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%. The process includes the steps of isolation and This includes methods.

[0125] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least one first organic solvent, wherein the at least one first organic solvent is DMSO. (ii) The step of removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% (by weight) (w / w), (iii) A step of adding a second organic solvent, wherein the second organic solvent is ethanol, (iv) A step of adding a third organic solvent, wherein the third organic solvent is acetone, (v) Compound of formula (I) in crystal form II, (v-1) The step of providing an aqueous solution of the compound of formula (I), (v-2) The step of adding ethanol, (v-3)(v-2) The solid obtained in (v-3) is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then dried by a second drying process in which the relative humidity is adjusted until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%. The process includes the steps of isolation and This includes methods.

[0126] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent, (ii) The step of removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% (by weight) (w / w), (iii) A step of adding a second organic solvent, wherein the second organic solvent is an alcohol selected from the list consisting of ethanol, n-propanol and isopropanol, (iv) A step of adding a third organic solvent, wherein the third organic solvent is acetone, (v) Compound of formula (I) in crystal form II, (v-1) The step of providing an aqueous mixture containing a compound of formula (I), (v-2) The step of adding ethanol, (v-3)(v-2) The solid obtained in (v-3) is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, for 0.5 to 24 hours, followed by a second drying process in which the relative humidity is adjusted for 0.5 to 48 hours until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%, is reached. The process includes the steps of isolation and This includes methods.

[0127] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent, (ii) The step of removing water from the mixture provided in (i) until the water content of the mixture is between 10% and 20% (by weight) (w / w), (iii) A step of adding a second organic solvent, wherein the second organic solvent is ethanol, (iv) A step of adding a third organic solvent, wherein the third organic solvent is acetone, (v) Compound of formula (I) in crystal form II, (v-1) The step of providing an aqueous mixture containing a compound of formula (I), (v-2) The step of adding ethanol, (v-3)(v-2) The solid obtained in (v-3) is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, for 0.5 to 24 hours, followed by a second drying process in which the relative humidity is adjusted for 0.5 to 48 hours until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%, is reached. The process includes the steps of isolation and This includes methods.

[0128] In a further embodiment of the first aspect, the present invention relates to a method for preparing a compound of general formula (I) above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) (i) A step of providing a mixture comprising a compound of formula (I), water, and at least one first organic solvent, wherein the at least one first organic solvent is DMSO. (ii) The step of removing water from the mixture provided in (i) until the water content of the mixture is between 10 and 20% (by weight) (w / w), (iii) A step of adding a second organic solvent, wherein the second organic solvent is ethanol, (iv) A step of adding a third organic solvent, wherein the third organic solvent is acetone, (v) Compound of formula (I) in crystal form II, (v-1) The step of providing an aqueous mixture containing a compound of formula (I), (v-2) The step of adding ethanol, (v-3)(v-2) The solid obtained in (v-3) is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, for 0.5 to 24 hours, followed by a second drying process in which the relative humidity is adjusted for 0.5 to 48 hours until a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%, is reached. The process includes the steps of isolation and This includes methods.

[0129] Crystallization of Form I of the compound of formula (I) The present invention also provides a method for preparing crystalline form I, characterized in that the compound of formula I has a powder X-ray diffraction pattern that includes reflections at 2θ angles of (6.8±0.2)°, (9.1±0.2)°, (10.1±0.2)°, (11.4±0.2)° and (12.0±0.2)° when measured at room temperature using Cu-Kα1 radiation having a wavelength of 0.15419 nm.

[0130] Therefore, in one embodiment, the present invention is a method for preparing crystalline form I of a compound of formula (I), [ka] The method described above is (i) A step of providing an aqueous mixture containing a compound of formula (I), (ii) The step of adding an organic solvent, (iii)(ii) The solid obtained in (iii)(ii) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%, and This provides a method that includes [something].

[0131] In further embodiments, the present invention relates to a method for preparing crystalline form I of the compound of formula (I) described above, wherein the method is (i) A step of providing an aqueous mixture containing a compound of formula (I), (ii) Adding an organic solvent selected from the group consisting of ethanol, n-propanol, and isopropanol or mixtures thereof, (iii)(ii) The solid obtained in (iii)(ii) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%, and This provides a method that includes [something].

[0132] In further embodiments, the present invention relates to a method for preparing crystalline form I of the compound of formula (I) described above, wherein the method is (i) A step of providing an aqueous mixture containing a compound of formula (I), (ii) The step of adding ethanol, (iii)(ii) The solid obtained in (iii)(ii) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%, and This provides a method that includes [something].

[0133] In step (i), an aqueous mixture containing the compound of formula (I) is provided. Preferably, the sole 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. Therefore, 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. To achieve complete dissolution of the compound of formula (I) and / or to obtain an aqueous mixture or aqueous solution suitable for isolating the compound of formula (I) in crystalline form I or crystalline form II, processes such as filtration, diafiltration, ultrafiltration, nanofiltration, and 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% (on a weight basis) (w / w), more preferably 40% to 60% (on a weight basis) (w / w), and even more preferably 45% to 55% (on a weight basis) (w / w).

[0134] In step (ii), an organic solvent is added to the mixture provided in step (i). Preferably, the organic solvent is selected from the group consisting of ethanol, n-propanol, isopropanol, or mixtures 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 7% to 20% (by weight) (w / w).

[0135] In step (ii), the organic solvent is added at a temperature of preferably 45°C to 75°C, more preferably 50°C to 70°C, and more preferably 55°C to 65°C. Addition of ethanol at the above temperatures is particularly preferred. After the addition of the organic solvent, the water content of the mixture is preferably in the range of 5% to 25% (by weight) (w / w), more preferably 7% to 20% (by weight) (w / w).

[0136] In step (ii), an organic solvent is added to obtain a solid, which is then dried in step (iii) at a relative humidity of 18% to 70%, preferably 30% to 65%, to obtain the compound of formula (I) in crystalline form I. Therefore, step (iii) includes drying the solid obtained from 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. Furthermore, step (iii) includes drying the solid obtained from step (ii) at a relative humidity of 18% to 70%, preferably 30% to 65%, to obtain a compound of formula (I) of crystalline form I, which includes reflections at 2θ angles of (6.8±0.2)°, (9.1±0.2)°, (10.1±0.2)°, (11.4±0.2)° and (12.0±0.2)° when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm. Preferably, the drying process is carried out at the above relative humidity for 1 to 48 hours.

[0137] In a preferred embodiment, the present invention is a method for preparing crystalline form I of the compound of formula (I) described above, wherein the method is (i) A step of providing an aqueous mixture containing a compound of formula (I), (ii) The step of adding ethanol, (iii)(ii) The solid obtained in (iii)(ii) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%, and This provides a method that includes [something].

[0138] In a preferred embodiment, the present invention is a method for preparing crystalline form I of the compound of formula (I) described above, wherein the method is (i) A step of providing an aqueous solution of the compound of formula (I), (ii) The step of adding ethanol, (iii)(ii) The solid obtained in (iii)(ii) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%, and This provides a method that includes [something].

[0139] In a more preferred embodiment, the present invention relates to a method for preparing crystalline form I of the compound of formula (I) described above, wherein the method is (i) Providing an aqueous mixture containing a compound of formula (I) in the range of 30% to 70% (by weight) (w / w), more preferably 40% to 60% (by weight) (w / w), and even more preferably 45% to 55% (by weight) (w / w), (ii) The step of adding ethanol, (iii)(ii) The solid obtained in (iii)(ii) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%, and This provides a method that includes [something].

[0140] In a more preferred embodiment, the present invention relates to a method for preparing crystalline form I of the compound of formula (I) described above, wherein the method is (i) Providing an aqueous mixture containing a compound of formula (I) in the range of 30% to 70% (by weight) (w / w), more preferably 40% to 60% (by weight) (w / w), and even more preferably 45% to 55% (by weight) (w / w), (ii) Adding ethanol until the water content of the mixture is in the range of 5% to 25% (by weight) (w / w), more preferably 7% to 20% (by weight) (w / w), (iii)(ii) The solid obtained in (iii)(ii) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%, and This provides a method that includes [something].

[0141] In a more preferred embodiment, the present invention relates to a method for preparing crystalline form I of the compound of formula (I) described above, wherein the method is (i) Providing an aqueous solution of the compound of formula (I) in the range of 30% to 70% (by weight) (w / w), more preferably 40% to 60% (by weight) (w / w), and even more preferably 45% to 55% (by weight) (w / w), (ii) Adding ethanol until the water content of the mixture is in the range of 5% to 25% (by weight) (w / w), more preferably 7% to 20% (by weight) (w / w), (iii)(ii) The solid obtained in (iii)(ii) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%, and This provides a method that includes [something].

[0142] In a more preferred embodiment, the present invention relates to a method for preparing crystalline form I of the compound of formula (I) described above, wherein the method is (i) Providing an aqueous mixture containing a compound of formula (I) in the range of 30% to 70% (by weight) (w / w), more preferably 40% to 60% (by weight) (w / w), and even more preferably 45% to 55% (by weight) (w / w), (ii) Adding ethanol until the water content of the mixture is in the range of 5% to 25% (by weight) (w / w), more preferably 7% to 20% (by weight) (w / w), (iii)(ii) The solid obtained in (iii)(ii) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%, for 1 to 48 hours. This provides a method that includes [something].

[0143] Crystallization of Form II of the compound of formula (I) The present invention also provides a method for preparing crystalline form II, characterized in that the compound of formula (I) has a powder X-ray diffraction pattern that includes reflections at 2θ angles of (7.3±0.2)°, (10.2±0.2)°, (10.8±0.2)°, (11.3±0.2)° and (13.3±0.2)° when measured at room temperature using Cu-Kα1 radiation having a wavelength of 0.15419 nm.

[0144] Therefore, in one embodiment, the present invention is a method for preparing crystalline form II of a compound of formula (I), [ka] The method described above is (i) A step of providing an aqueous mixture containing a compound of formula (I), (ii) The step of adding an organic solvent, (iii)(ii) The solid obtained in (iii)(ii) is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then dried by a second drying process in which the relative humidity is adjusted until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%. This provides a method that includes [something].

[0145] In further embodiments, the present invention relates to a method for preparing crystalline form II of the compound of formula (I) described above, wherein the method is (i) A step of providing an aqueous mixture containing a compound of formula (I), (ii) Adding an organic solvent selected from the group consisting of ethanol, n-propanol, and isopropanol or mixtures thereof, (iii)(ii) The solid obtained in (iii)(ii) is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then dried by a second drying process in which the relative humidity is adjusted until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%. This provides a method that includes [something].

[0146] In further embodiments, the present invention relates to a method for preparing crystalline form II of the compound of formula (I) described above, wherein the method is (i) A step of providing an aqueous mixture containing a compound of formula (I), (ii) The step of adding ethanol, (iii)(ii) The solid obtained in (iii)(ii) is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then dried by a second drying process in which the relative humidity is adjusted until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%. This provides a method that includes [something].

[0147] In further embodiments, the present invention relates to a method for preparing crystalline form II of the compound of formula (I) described above, wherein the method is (i) A step of providing an aqueous solution of the compound of formula (I), (ii) The step of adding ethanol, (iii)(ii) The solid obtained in (iii)(ii) is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then dried by a second drying process in which the relative humidity is adjusted until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%. This provides a method that includes [something].

[0148] In step (i), an aqueous mixture containing the compound of formula (I) is provided. Preferably, the sole 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. Therefore, 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. To achieve complete dissolution of the compound of formula (I) and / or to obtain an aqueous mixture or aqueous solution suitable for isolating the compound of formula (I) in crystalline form I or crystalline form II, processes such as filtration, diafiltration, ultrafiltration, nanofiltration, and 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% (on a weight basis) (w / w), more preferably 40% to 60% (on a weight basis) (w / w), and even more preferably 45% to 55% (on a weight basis) (w / w).

[0149] In step (ii), an organic solvent is added to the mixture provided in step (i). Preferably, the organic solvent is selected from the group consisting of ethanol, n-propanol, isopropanol, or mixtures 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 7% to 20% (by weight) (w / w).

[0150] In step (ii), the organic solvent is added at a temperature of preferably 45°C to 75°C, more preferably 50°C to 70°C, and more preferably 55°C to 65°C. Addition of ethanol at the above temperatures is particularly preferred. After the addition of the organic solvent, the water content of the mixture is preferably in the range of 5% to 25% (by weight) (w / w), more preferably 7% to 20% (by weight) (w / w).

[0151] In step (ii), an organic solvent is added to obtain a solid, which is then dried in step (iii) 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 it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%, thereby obtaining the compound of formula (I) in crystalline form II.

[0152] Therefore, step (iii) includes drying the solid obtained from step (ii) by a second drying process, which involves first drying it at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then adjusting the relative humidity until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%, to obtain a compound of formula (I) in crystalline form II.

[0153] Furthermore, or alternatively, step (iii) includes drying the solid obtained from step (ii) by a second drying process, which involves first drying it at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then adjusting the relative humidity until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%, to obtain a compound of formula (I) in crystalline form II, which includes reflections at 2θ angles of (7.3±0.2)°, (10.2±0.2)°, (10.8±0.2)°, (11.3±0.2)°, and (13.3±0.2)° when measured at room temperature using Cu-Kα1 radiation having a wavelength of 0.15419 nm.

[0154] Preferably, the first drying process is carried out at the above relative humidity for 0.5 to 24 hours, and the second drying process is carried out at the above relative humidity for 0.5 to 48 hours.

[0155] In a preferred embodiment, the present invention is a method for preparing crystalline form II of the compound of formula (I) described above, wherein the method is (i) A step of providing an aqueous mixture containing a compound of formula (I), (ii) The step of adding ethanol, (iii)(ii) The solid obtained in (iii)(ii) is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then dried by a second drying process in which the relative humidity is adjusted until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%. This provides a method that includes [something].

[0156] In a more preferred embodiment, the present invention relates to a method for preparing crystalline form II of the compound of formula (I) described above, wherein the method is (i) Providing an aqueous mixture containing a compound of formula (I) in the range of 30% to 70% (by weight) (w / w), more preferably 40% to 60% (by weight) (w / w), and even more preferably 45% to 55% (by weight) (w / w), (ii) The step of adding ethanol, (iii)(ii) The solid obtained in (iii)(ii) is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then dried by a second drying process in which the relative humidity is adjusted until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%. This provides a method that includes [something].

[0157] In a more preferred embodiment, the present invention relates to a method for preparing crystalline form II of the compound of formula (I) described above, wherein the method is (i) Providing an aqueous mixture containing a compound of formula (I) in the range of 30% to 70% (by weight) (w / w), more preferably 40% to 60% (by weight) (w / w), and even more preferably 45% to 55% (by weight) (w / w), (ii) Adding ethanol until the water content of the mixture is in the range of 5% to 25% (by weight) (w / w), more preferably 7% to 20% (by weight) (w / w), (iii)(ii) The solid obtained in (iii)(ii) is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then dried by a second drying process in which the relative humidity is adjusted until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%. This provides a method that includes [something].

[0158] In a more preferred embodiment, the present invention relates to a method for preparing crystalline form II of the compound of formula (I) described above, wherein the method is (i) Providing an aqueous solution of the compound of formula (I) in the range of 30% to 70% (by weight) (w / w), more preferably 40% to 60% (by weight) (w / w), and even more preferably 45% to 55% (by weight) (w / w); (ii) Adding ethanol until the water content of the mixture is in the range of 5% to 25% (by weight) (w / w), more preferably 7% to 20% (by weight) (w / w), (iii)(ii) The solid obtained in (iii)(ii) is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then dried by a second drying process in which the relative humidity is adjusted until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%. This provides a method that includes [something].

[0159] In a more preferred embodiment, the present invention relates to a method for preparing crystalline form II of the compound of formula (I) described above, wherein the method is (i) Providing an aqueous mixture containing a compound of formula (I) in the range of 30% to 70% (by weight) (w / w), more preferably 40% to 60% (by weight) (w / w), and most preferably 45% to 55% (by weight) (w / w), (ii) Adding ethanol until the water content of the mixture is in the range of 5% to 25% (by weight) (w / w), more preferably 7% to 20% (by weight) (w / w), (iii)(ii) The solid obtained in (iii)(ii) is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, for 0.5 to 24 hours, and then dried by a second drying process which involves adjusting the relative humidity for 0.5 to 48 hours until it reaches a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%. This provides a method that includes [something].

[0160] Preparation of compound (I) via compound (II) In further embodiments, the present invention relates to a method for preparing a compound of formula (I), (i-1) A step of providing a compound of formula (II) or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, [ka] (i-2) The step of reacting the compound of formula (II) with the compound of formula (III) or a salt thereof. [ka] This includes methods.

[0161] As described in the first embodiment, step (i) of a method for preparing the compound of general formula (I) above 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 embodiment, the provision in step (i) is (i-1) A step of providing a compound of formula (II) or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, [ka] (i-2) The step of reacting the compound of formula (II) with the compound of formula (III) or a salt thereof. [ka] Includes.

[0162] Therefore, further embodiments of the present invention are methods for preparing the compound of general formula (I) above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein the method is (i) A mixture comprising the compound of formula (I), water, and at least a first organic solvent, (i-1) A step of providing a compound of formula (II) or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, [ka] (i-2) The step of reacting the compound of formula (II) with the compound of formula (III) or a salt thereof. [ka] The process includes the steps provided, (ii) The step of removing water from the mixture provided in (i), (iii) The step of adding a second organic solvent, (iv) The step of adding a third organic solvent, (v) Steps to isolate the compound of formula (I) and This includes methods.

[0163] Step (i-1) provides a compound of formula (II) or its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof. 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., in crystalline form. More preferably, the compound of formula (II) is provided as a crystalline solid of crystalline form I. More preferably, the compound of formula (II) is provided as a crystalline solid of crystalline form I as described below herein. More preferably, the compound of formula (II) is provided as a crystalline solid of crystalline form I, characterized by having a powder X-ray diffraction pattern including reflections at 2θ angles of (8.0±0.2)°, (9.0±0.2)°, and (12.8±0.2)° when measured at room temperature using Cu-Kα1 radiation having a wavelength of 0.15419 nm.

[0164] Therefore, further embodiments of the present invention are methods for preparing the compound of general formula (I) above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein the method is (i) A mixture comprising the compound of formula (I), water, and at least a first organic solvent, (i-1) Providing a compound of formula (II) or its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof, as a solid, preferably as a crystalline solid; [ka] (i-2) The step of reacting the compound of formula (II) with the compound of formula (III) or a salt thereof. [ka] The process includes the steps provided, (ii) The step of removing water from the mixture provided in (i), (iii) The step of adding a second organic solvent, (iv) The step of adding a third organic solvent, (v) Steps to isolate the compound of formula (I) and This includes methods.

[0165] Therefore, further embodiments of the present invention are methods for preparing the compound of general formula (I) above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein the method is (i) A mixture comprising the compound of formula (I), water, and at least a first organic solvent, (i-1) Providing a compound of formula (II) or its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof, as a solid, preferably as a crystalline solid of crystal form I; [ka] (i-2) The step of reacting the compound of formula (II) with the compound of formula (III) or a salt thereof. [ka] The process includes the steps provided, (ii) The step of removing water from the mixture provided in (i), (iii) The step of adding a second organic solvent, (iv) The step of adding a third organic solvent, (v) Steps to isolate the compound of formula (I) and This includes methods.

[0166] In the context of the present invention, providing a compound of formula (II) and providing a mixture comprising the compound of formula (I), water, and at least a first organic solvent in step (i) by reacting the compound of formula (II) with the compound of formula (III) may be applied to any of the above or below embodiments of the present invention, including step (i).

[0167] In the context of the present invention, step (i) of the method of the present invention includes providing a compound of formula (II) and reacting the compound of formula (II) with a compound of formula (III) to provide a mixture comprising a compound of formula (I), water, and at least a first organic solvent.

[0168] The reaction between the compound of formula (II) and the compound of formula (III) is preferably carried out in water or 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 for the reaction between the compound of formula (II) and the compound of formula (III) is the same as at least the first organic solvent used in step (i) of the method of the present invention. Most preferably, the organic solvent for the reaction between the compound of formula (II) and the compound of formula (III) is dimethyl sulfoxide (DMSO).

[0169] The reaction between the compound of formula (II) and the compound of formula (III) is preferably carried out in the presence of a base. Such a base is preferably an organic base, and 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 excess. Preferably, the excess of the base is in the range of 4.2 to 8.0 equivalents relative to the amount of the compound of formula (III).

[0170] The reaction between the compound of formula (II) and the compound of formula (III) is preferably carried out at a temperature of 20°C to 60°C. To ensure a smooth conversion, the temperature is preferably in the range of 40°C to 60°C, more preferably 45°C to 55°C.

[0171] The reaction between the compound of formula (II) and the compound of formula (III) is preferably carried out using an excess amount of the compound of formula (II). Preferably, the excess amount of the compound of formula (II) is in the range of 4.0 to 6.0 equivalents, more preferably 4.0 to 4.6 equivalents.

[0172] After the reaction of the compound of formula (II) and the compound of formula (III), water is added to the reaction mixture before isolating the compound of formula (I). Preferably, water is added to the mixture obtained in step (i-2) from the reaction of the compound of formula (II) and the compound of formula (III), and the mixture is then treated with a base, preferably an inorganic base, such as sodium hydroxide, neutralized with a mineral acid such as hydrochloric acid, and optionally extracted with an organic solvent. A preferred organic solvent for any extraction is methyl tert-butyl ether (MTBE). Therefore, preferably, before step (ii), water is added to the mixture obtained in step (i-2) from the reaction of the compound of formula (II) and the compound of formula (III), and the mixture is then treated with a base, preferably an inorganic base such as sodium hydroxide, neutralized with a mineral acid such as hydrochloric acid, and optionally extracted with an organic solvent. If an extraction step is included, it is the aqueous phase subjected to step (ii) in the isolation of the compound of formula (I).

[0173] With respect to steps (ii), (iii), (iv), and (v), it will be understood that these may be carried out according to the method of the present invention for the preparation of the compound of formula (I), comprising steps (v-1), (v-2), and (v-3), as described throughout this specification.

[0174] Crystalline forms I, II, and III of the compound of formula (II) In step (i-1), the compound of formula (II) or its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof, are 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., in crystalline form.

[0175] Crystalline form I of the compound of formula (II) is characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (8.0±0.2)°, (9.0±0.2)°, and (12.8±0.2)° when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm. Preferably, crystalline form I of the compound of formula (II) is characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (8.0±0.2)°, (9.0±0.2)°, (11.7±0.2)°, (12.8±0.2)°, and (14.9±0.2)° when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm. Preferably, crystalline form I of the compound of formula (II) is characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (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)° when measured at room temperature using Cu-Kα1 radiation having a wavelength of 0.15419 nm. Preferably, crystalline form I of the compound of formula (II) is characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (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)° when measured at room temperature using Cu-Kα1 radiation having a wavelength of 0.15419 nm.

[0176] Alternatively, the crystalline form I of the compound of formula (II) is characterized in that, when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm, it has essentially the same powder X-ray diffraction pattern as that shown in Figure 18 of the present invention.

[0177] Alternatively, the crystalline form I of the compound of formula (II) is (1085 ± 2) cm³ when measured at room temperature using a diamond ATR cell. -1 , (1343±2)cm -1 and (1598±2)cm -1It is characterized by having a Fourier transform infrared spectrum that includes a band at a wavenumber. Preferably, the crystalline form I of the compound of formula (II) is (715±2) cm when measured at room temperature using a diamond ATR cell. -1 , (1085±2)cm -1 , (1343±2)cm -1 (1522±2)cm -1 and (1598±2)cm -1 It is characterized by having a Fourier transform infrared spectrum that includes a band at a wavenumber. Preferably, the crystalline form I of the compound of formula (II) is (715±2) cm when measured at room temperature using a diamond ATR cell. -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 It is characterized by having a Fourier transform infrared spectrum that includes a band at a wavenumber. Preferably, the crystalline form I of the compound of formula (II) is (715±2) cm when measured at room temperature using a diamond ATR cell. -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 It is characterized by having a Fourier transform infrared spectrum that includes a band at the wavenumber.

[0178] Alternatively, the crystalline form I of the compound of formula (II) is characterized in that, when measured at room temperature using a diamond ATR cell, it has essentially the same Fourier transform infrared spectrum as that shown in Figure 19 of the present invention.

[0179] Alternatively, the crystalline form I of the compound of formula (II) is (1111±2) cm² when measured at room temperature using a laser with a wavelength of 1064 nm. -1 , (1346±2)cm -1 and (1594±2)cm -1 It is characterized by having a Raman spectrum that includes a band at a wavenumber. Preferably, the crystalline form I of the compound of formula (II) is (1111±2)cm when measured at room temperature using a laser with a wavelength of 1064 nm. -1 , (1213±2)cm -1 , (1346±2)cm- 1 , (1594±2)cm -1 and (2884±2)cm -1 It is characterized by having a Raman spectrum that includes a band at a wavenumber. Preferably, the crystalline form I of the compound of formula (II) is (374±2)cm when measured at room temperature using a laser with a wavelength of 1064 nm. -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 It is characterized by having a Raman spectrum that includes a band at a wavenumber. Preferably, the crystalline form I of the compound of formula (II) is (374±2)cm when measured at room temperature using a laser with a wavelength of 1064 nm. -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 It is characterized by having a Raman spectrum that includes a band at a wavenumber.

[0180] Alternatively, the crystalline form I of the compound of formula (II) is characterized in that, when measured at room temperature using a laser with a wavelength of 1064 nm, it has essentially the same Raman spectrum as that shown in Figure 20 of the present invention.

[0181] Alternatively, the crystalline form I of the compound of formula (II) is characterized by having the differential scanning calorimetry curve shown in Figure 21 of the present invention.

[0182] Alternatively, the crystalline form I of the compound of formula (II) is characterized by having the TGA curve shown in Figure 22 of the present invention.

[0183] Crystalline form II of the compound of formula (II) is characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (6.6±0.2)°, (10.3±0.2)°, and (11.1±0.2)° when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm. Preferably, crystalline form II of the compound of formula (II) is characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (6.6±0.2)°, (10.3±0.2)°, (11.1±0.2)°, (11.5±0.2)°, and (11.7±0.2)° when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm. Preferably, crystalline form II of the compound of formula (II) is characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (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)° when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm. Preferably, crystalline form II of the compound of formula (II) is characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (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)° when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm.

[0184] Alternatively, the crystalline form II of the compound of formula (II) is characterized in that, when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm, it has essentially the same powder X-ray diffraction pattern as that shown in Figure 23 of the present invention.

[0185] Alternatively, the crystalline form II of the compound of formula (II) is (1085 ± 2) cm² when measured at room temperature using a diamond ATR cell. -1 , (1346±2)cm -1 and (1612±2)cm -1It is characterized by having a Fourier transform infrared spectrum that includes a band at a wavenumber. Preferably, the crystalline form II of the compound of formula (II) is (713±2) cm when measured at room temperature using a diamond ATR cell. -1- , (1085±2)cm -1 , (1321±2)cm -1 , (1346±2)cm -1 and (1612±2)cm -1 It is characterized by having a Fourier transform infrared spectrum that includes a band at a wavenumber. Preferably, the crystalline form II of the compound of formula (II) is (713±2) cm when measured at room temperature using a diamond ATR cell. -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 It is characterized by having a Fourier transform infrared spectrum that includes a peak at a wavenumber. Preferably, the crystalline form II of the compound of formula (II) is (713±2) cm when measured at room temperature using a diamond ATR cell. -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 It is characterized by having a Fourier transform infrared spectrum that includes a band at the wavenumber.

[0186] Alternatively, the crystalline form II of the compound of formula (II) is characterized in that, when measured at room temperature using a diamond ATR cell, it has essentially the same Fourier transform infrared spectrum as that shown in Figure 24 of the present invention.

[0187] Alternatively, the crystalline form II of the compound of formula (II) is (1335±2) cm² when measured at room temperature using a laser with a wavelength of 1064 nm. -1 , (1348±2)cm -1 and (1592±2)cm -1 It is characterized by having a Raman spectrum that includes a peak at a wavenumber. Preferably, the crystalline form II of the compound of formula (II) is (1111±2) cm when measured at room temperature using a laser with a wavelength of 1064 nm. -1 , (1335±2)cm -1 , (1348±2)cm -1 , (1592±2)cm -1 and (2935±2)cm -1 It is characterized by having a Raman spectrum that includes a peak at a wavenumber. Preferably, the crystalline form II of the compound of formula (II) is (864±2)cm when measured at room temperature using a laser with a wavelength of 1064 nm. -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 It is characterized by having a Raman spectrum that includes a band at a wavenumber. Preferably, the crystalline form II of the compound of formula (II) is (864±2)cm when measured at room temperature using a laser with a wavelength of 1064 nm. -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 It is characterized by having a Raman spectrum that includes a band at a wavenumber.

[0188] Alternatively, the crystalline form II of the compound of formula (II) is characterized in that, when measured at room temperature using a laser with a wavelength of 1064 nm, it has essentially the same Raman spectrum as that shown in Figure 25 of the present invention.

[0189] Alternatively, the crystalline form II of the compound of formula (II) is characterized by having the differential scanning calorimetry curve shown in Figure 26 of the present invention.

[0190] Alternatively, the crystalline form II of the compound of formula (II) is characterized by having the TGA curve shown in Figure 27 of the present invention.

[0191] Crystal form III of the compound of formula (II) is characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (5.8±0.2)°, (10.2±0.2)°, and (11.1±0.2)° when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm. Preferably, crystal form III of the compound of formula (II) is characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (5.8±0.2)°, (9.6±0.2)°, (10.2±0.2)°, (11.1±0.2)°, and (11.3±0.2)° when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm. Preferably, the crystalline form III of the compound of formula (II) is characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (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)° when measured at room temperature using Cu-Kα1 radiation having a wavelength of 0.15419 nm. Preferably, the crystalline form III of the compound of formula (II) is characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (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)° when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm.

[0192] Alternatively, the crystalline form III of the compound of formula (II) is characterized in that, when measured at room temperature using Cu-Kα1 radiation with a wavelength of 0.15419 nm, it has essentially the same powder X-ray diffraction pattern as that shown in Figure 28 of the present invention.

[0193] Alternatively, the crystalline form III of the compound of formula (II) is (1083±2) cm³ when measured at room temperature using a diamond ATR cell. -1 , (1329±2)cm -1 and (1607±2)cm -1It is characterized by having a Fourier transform infrared spectrum that includes a band at a wavenumber. Preferably, the crystalline form III of the compound of formula (II) is (1083±2) cm when measured at room temperature using a diamond ATR cell. -1 , (1291±2)cm -1 , (1329±2)cm -1 , (1521±2)cm -1 and (1607±2)cm -1 It is characterized by having a Fourier transform infrared spectrum that includes a band at a wavenumber. Preferably, the crystalline form III of the compound of formula (II) is (1083±2) cm when measured at room temperature using a diamond ATR cell. -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 It is characterized by having a Fourier transform infrared spectrum that includes a band at a wavenumber. Preferably, the crystalline form III of the compound of formula (II) is (709±2) cm when measured at room temperature using a diamond ATR cell. -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 It is characterized by having a Fourier transform infrared spectrum that includes a band at the wavenumber.

[0194] Alternatively, the crystalline form III of the compound of formula (II) is characterized in that, when measured at room temperature using a diamond ATR cell, it has essentially the same Fourier transform infrared spectrum as that shown in Figure 29 of the present invention.

[0195] Alternatively, the crystalline form III of the compound of formula (II) is (1113±2) cm² when measured at room temperature using a laser with a wavelength of 1064 nm. -1 , (1332±2)cm- -1 (1350±2)cm -1 It is characterized by having a Raman spectrum that includes a band at a wavenumber. Preferably, the crystalline form III of the compound of formula (II) is (1113±2) cm when measured at room temperature using a laser with a wavelength of 1064 nm. -1 , (1295±2)cm -1 (1332±2)cm -1 , (1350±2)cm -1 and (1592±2)cm -1 It is characterized by having a Raman spectrum that includes a band at a wavenumber. Preferably, the crystalline form III of the compound of formula (II) is (864±2)cm when measured at room temperature using a laser with a wavelength of 1064 nm. -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 It is characterized by having a Raman spectrum that includes a band at a wavenumber. Preferably, the crystalline form III of the compound of formula (II) is (864±2)cm when measured at room temperature using a laser with a wavelength of 1064 nm. -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 It is characterized by having a Raman spectrum that includes a band at a wavenumber.

[0196] Alternatively, the crystalline form III of the compound of formula (II) is characterized in that, when measured at room temperature using a laser with a wavelength of 1064 nm, it has essentially the same Raman spectrum as that shown in Figure 30 of the present invention.

[0197] Alternatively, the crystalline form III of the compound of formula (II) is characterized by having the differential scanning calorimetry curve shown in Figure 31 of the present invention.

[0198] Alternatively, the crystalline form III of the compound of formula (II) is characterized by having the TGA curve shown in Figure 32 of the present invention.

[0199] Method for preparing the compound of crystalline form (II) In a further embodiment, the present invention relates to a method for preparing a crystalline compound of formula (II), wherein the method is (a) A step of providing a compound of formula (IV), [ka] (b) The step of reacting the compound of formula (IV) with para-nitrophenol in the presence of a coupling agent, (c) A step of isolating the compound of formula (II) in crystalline form. This includes methods.

[0200] In a preferred embodiment, the compound of formula (II) is isolated in the crystalline form as described above herein. In a preferred embodiment, the compound of formula (II) is isolated in crystalline form I as described and characterized above.

[0201] In a preferred embodiment, the compound of formula (II) is isolated in a crystalline form characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (8.0±0.2)°, (9.0±0.2)°, (11.7±0.2)°, (12.8±0.2)° and (14.9±0.2)° when measured at room temperature using Cu-Kα1 radiation having a wavelength of 0.15419 nm.

[0202] In a preferred embodiment, the compound of formula (II) is isolated in a crystalline form characterized by having essentially the same powder X-ray diffraction pattern as that shown in Figure 18 of the present invention when measured at room temperature using Cu-Kα1 radiation having a wavelength of 0.15419 nm.

[0203] In a preferred embodiment, the compound of formula (II) yields (715±2) cm³ when measured at room temperature using a diamond ATR cell. -1 , (1085±2)cm -1 , (1343±2)cm -1 (1522±2)cm -1 and (1598±2)cm -1 It is isolated in a crystalline form characterized by having a Fourier transform infrared spectrum that includes a band at a wavenumber.

[0204] In a preferred embodiment, the compound of formula (II) is isolated in a crystalline form characterized by having essentially the same Fourier transform infrared spectrum as that shown in Figure 19 of the present invention.

[0205] In a preferred embodiment, the compound of formula (II) is (1111±2)cm -1 , (1213±2)cm -1 , (1346±2)cm -1 , (1594±2)cm -1 and (2884±2)cm -1 It is isolated in a crystalline form characterized by having a Raman spectrum that includes a band at a certain wavenumber.

[0206] In a preferred embodiment, the compound of formula (II) is isolated in a crystalline form characterized by having essentially the same Raman spectrum as that shown in Figure 20 of the present invention.

[0207] In a preferred embodiment, the compound of formula (II) is isolated in a crystalline form characterized by having a differential scanning calorimetry curve as shown in Figure 21 of the present invention.

[0208] In a preferred embodiment, the compound of formula (II) is isolated in a crystalline form characterized by having the TGA curve shown in Figure 22 of the present invention.

[0209] In preferred embodiments, the reaction of the compound of formula (IV) with para-nitrophenol in the presence of a coupling agent in step (b) is preferably carried out in an organic solvent or 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 para-nitrophenol in the presence of a coupling agent in step (b) is carried out in a mixture of acetonitrile and formamide or a mixture of tetrahydrofuran and formamide. More preferably, the solvent mixture for the reaction of the compound of formula (IV) with para-nitrophenol contains acetonitrile and formamide in a ratio of 2:1 to 5:1 by weight (w / w), preferably 2.3:1 to 4.0:1 by weight (w / w).

[0210] In a preferred embodiment, the reaction of the compound of formula (IV) with para-nitrophenol in step (d) is carried out in the presence of a coupling agent, preferably 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 para-nitrophenol in a suitable or preferred organic solvent or solvent mixture is stirred for 0.5 to 5 hours, more preferably 1 to 3 hours. Preferably, before adding the coupling agent, the mixture of the compound of formula (IV) and para-nitrophenol in a suitable or preferred organic solvent or solvent mixture is stirred at a temperature of -5°C to 5°C, more preferably -3°C to 3°C. 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 to 5 hours. Even more preferably, before adding the coupling agent, the mixture of the compound of formula (IV) and p-nitrophenol is stirred in a suitable or preferred organic solvent or solvent mixture at a temperature of -3°C to 3°C for 1 to 3 hours.

[0211] In a preferred embodiment, the reaction of the compound of formula (IV) with para-nitrophenol in the presence of the coupling agent in step (d) is preferably carried out at a temperature of 15°C to 40°C, more preferably 20°C to 26°C.

[0212] In a preferred embodiment, the reaction of the compound of formula (IV) with para-nitrophenol in the presence of the coupling agent in step (d) is preferably carried out for 6 to 72 hours, more preferably 10 to 43 hours, and most preferably 12 to 19 hours.

[0213] In a preferred embodiment, the reaction of the compound of formula (IV) with para-nitrophenol in the presence of the coupling agent in step (d) is carried out at a temperature of preferably 15°C to 40°C, more preferably 20°C to 26°C, for 6 to 72 hours, more preferably 10 to 43 hours, and most preferably 12 to 19 hours.

[0214] In a preferred embodiment, the isolation of the compound of formula (IV) in step (e) involves adding water and a mixture of an organic solvent selected from tetrahydrofuran and acetonitrile or a mixture thereof to the reaction mixture. Preferably, the organic solvent is acetonitrile.

[0215] Preferably, the amount of water in the mixture of water and organic solvent to be added is selected so that the final water content of the complete reaction mixture is in the range of 0% to 6% (by weight) (w / w), more preferably 2% to 5% (by weight) (w / w).

[0216] In a preferred embodiment, the present invention relates to a method for preparing a crystalline compound of formula (II), wherein the method is (a) A step of providing a compound of formula (IV), [ka] (b) A step of reacting the compound of formula (IV) with para-nitrophenol in the presence of a coupling agent, wherein the compound of formula (IV) and para-nitrophenol are stirred before the coupling agent is added to the reaction mixture. (c) A step of isolating the compound of formula (II) in crystalline form. This includes methods.

[0217] In a preferred embodiment, the present invention relates to a method for preparing a crystalline compound of formula (II), wherein the method is (a) A step of providing a compound of formula (IV), [ka] (b) A step of reacting a compound of formula (IV) with para-nitrophenol in the presence of a coupling agent N,N-diisopropylcarbodiimide, wherein the compound of formula (IV) and para-nitrophenol are stirred before the coupling agent is added to the reaction mixture. (c) A step of isolating the compound of formula (II) in crystalline form. This includes methods.

[0218] In a preferred embodiment, the present invention relates to a method for preparing a crystalline compound of formula (II), wherein the method is (a) A step of providing a compound of formula (IV), [ka] (b) A step of reacting the compound of formula (IV) with para-nitrophenol in the presence of a coupling agent, wherein the compound of formula (IV) and para-nitrophenol are stirred for 0.5 to 5 hours, preferably 1 to 3 hours, and then the coupling agent is added to the reaction mixture. (c) A step of isolating the compound of formula (II) in crystalline form. This includes methods.

[0219] In a preferred embodiment, the present invention relates to a method for preparing a crystalline compound of formula (II), wherein the method is (a) A step of providing a compound of formula (IV), [ka] (b) A step of reacting the compound of formula (IV) with para-nitrophenol in the presence of the coupling agent N,N-diisopropylcarbodiimide, wherein the compound of formula (IV) and para-nitrophenol are stirred for 0.5 to 5 hours, preferably 1 to 3 hours, and then the coupling agent is added to the reaction mixture. (c) A step of isolating the compound of formula (II) in crystalline form. This includes methods.

[0220] In a preferred embodiment, the present invention relates to a method for preparing a crystalline compound of formula (II), wherein the method is (a) A step of providing a compound of formula (IV), [ka] (b) A step of reacting the compound of formula (IV) with para-nitrophenol in the presence of a coupling agent, wherein the compound of formula (IV) and para-nitrophenol are stirred at a temperature of -3°C to 3°C for 0.5 to 5 hours, preferably 1 to 3 hours, and then the coupling agent is added to the reaction mixture. (c) A step of isolating the compound of formula (II) in crystalline form. This includes methods.

[0221] In a preferred embodiment, the present invention relates to a method for preparing a crystalline compound of formula (II), wherein the method is (a) A step of providing a compound of formula (IV), [ka] (b) A step of reacting the compound of formula (IV) with para-nitrophenol in the presence of a coupling agent, wherein the compound of formula (IV) and para-nitrophenol are stirred for 0.5 to 5 hours, preferably 1 to 3 hours, at a temperature of -3°C to 3°C, and then the coupling agent is added to the reaction mixture. (c) A step to isolate a compound of formula (II) in crystalline form, characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (8.0±0.2)°, (9.0±0.2)°, and (12.8±0.2)° when measured at room temperature using Cu-Kα1 radiation having a wavelength of 0.15419 nm. This includes methods.

[0222] In a preferred embodiment, the present invention relates to a method for preparing a crystalline compound of formula (II), wherein the method is (a) A step of providing a compound of formula (IV), [ka] (b) A step of reacting the compound of formula (IV) with para-nitrophenol in the presence of the coupling agent N,N-diisopropylcarbodiimide, wherein the compound of formula (IV) and para-nitrophenol are stirred at a temperature of -3°C to 3°C for 0.5 to 5 hours, preferably 1 to 3 hours, and then the coupling agent is added to the reaction mixture. (c) A step to isolate a compound of formula (II) in crystalline form, characterized by having a powder X-ray diffraction pattern that includes reflections at 2θ angles of (8.0±0.2)°, (9.0±0.2)°, and (12.8±0.2)° when measured at room temperature using Cu-Kα1 radiation having a wavelength of 0.15419 nm. This includes methods.

[0223] In a preferred embodiment, the present invention relates to a method for preparing a crystalline compound of formula (II), wherein the method is (a) A step of providing a compound of formula (IV), [ka] (b) A step of reacting the compound of formula (IV) with para-nitrophenol in the presence of a coupling agent, wherein the compound of formula (IV) and para-nitrophenol are stirred for 0.5 to 5 hours, preferably 1 to 3 hours, at a temperature of -3°C to 3°C, and then the coupling agent is added to the reaction mixture. (c) A step to isolate a crystalline compound of formula (II) characterized by having a powder X-ray diffraction pattern including reflections at 2θ angles of (8.0±0.2)°, (9.0±0.2)°, and (12.8±0.2)° when measured at room temperature using Cu-Kα1 radiation having a wavelength of 0.15419 nm, wherein the isolation step includes using water and an organic solvent, preferably a mixture of the organic solvent and acetonitrile, such that the final water content of the complete reaction mixture is in the range of 0% to 6% (by weight) (w / w), more preferably 2% to 5% (by weight) (w / w), and This includes methods.

[0224] It should also be understood that the present invention relates to any combination of the above embodiments.

[0225] Furthermore, the present invention encompasses the intermediate compounds disclosed in the Examples section of the following text.

[0226] general synthesis The compounds of formulas (III) and (IV) according to the method of the present invention can be prepared as described in the literature.

[0227] The compound of formula (III) can be prepared from pentaerythrityl tetrabromide according to W. Hayes et al., Tetrahedron 59 (2003), 7983-7996.

[0228] The compound of formula (IV) can be prepared starting from 10-tetraazacyclododecane, as described in German Patent Application Publication No. 19652386, Schering AG. [Brief explanation of the drawing]

[0229] [Figure 1] Relative humidity as a function of temperature and vapor pressure. [Figure 2] X-ray powder diffraction spectrum of the compound of formula (I) - amorphous material. [Figure 3]X-ray powder diffraction spectrum of compound (I) - Form I. [Figure 4] IR spectrum of compound (I) - Form I. [Figure 5] Raman spectrum of compound (I) - Form I. [Figure 6] DSC curve of compound (I) - Form I. [Figure 7] TGA curve of compound (I) - Form I. [Figure 8] X-ray powder diffraction spectrum of compound (I) - Form II. [Figure 9] IR spectrum of compound (I) - Form II. [Figure 10] Raman spectrum of compound (I) - Form II. [Figure 11] DSC curve of compound (I) - Form II. [Figure 12] TGA curve of compound (I) - Form II. [Figure 13] DVS isotherm plot of the transformation of the crystalline form (Form I to Form II) of the compound of formula (I) at 20°C from 50-0-90-50. [Figure 14] DVS isotherm plot of the 50-0-50 conversion of the crystalline form (Form I to Form II) of the compound of formula (I) at 20°C. [Figure 15] DVS isotherm plot of the crystalline form (Form I to Form II) conversion of the compound of formula (I) at 40°C (50-0-50). [Figure 16] The asymmetrical portion of the unit cell of diastereomer 1 of the compound of formula (I). [Figure 17] The asymmetrical portion of the unit cell of diastereomer 3 of the compound of formula (I). [Figure 18] X-ray powder diffraction spectrum of compound (II) - Form I. [Figure 19] IR spectrum of compound (II) - Form I. [Figure 20] Raman spectrum of compound (II) - Form I. [Figure 21] DSC curve of compound (II) - Form I. [Figure 22] TGA curve of compound (II) - Form I. [Figure 23] X-ray powder diffraction spectrum of compound (II) - Form II. [Figure 24] IR spectrum of compound (II) - Form II. [Figure 25] Raman spectrum of compound (II) - Form II. [Figure 26] DSC curve of compound (II) - Form II. [Figure 27] TGA curve of compound (II) - Form II. [Figure 28] X-ray powder diffraction spectrum of compound (II) - Form III. [Figure 29] IR spectrum of compound (II) - Form III. [Figure 30] Raman spectrum of compound (II) - Form III. [Figure 31] DSC curve of compound (II) - Form III. [Figure 32] TGA curve of compound (II) - Form III. [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 crystalline form II of the compound of formula (I). [Figure 34a] Sample solution 1 for assay of the compound of formula (II) by hydrolysis to 4-nitrophenol (HPLC-UV method b). [Figure 34b] Sample solution 2 (hydrolysis) for assay of the compound of formula (II) by hydrolysis to 4-nitrophenol (HPLC-UV method b). [Figure 35a] SST solution for assay of compound (II) by derivatization of compound (IV) to a benzylamide derivative (HPLC-UV method c). [Figure 35b]SST solution of compound (IV) in compound (II) (HPLC-UV method c-1). [Figure 36a] Crude SST solution 1 of the compound of formula (I) (HPLC-UV method d-1). [Figure 36b] Crude SST solution of compound (I) (HPLC-UV method d-1). [Figure 36c] SST solution of the compound of formula (I) (HPLC-UV method d-1). [Figure 37] HPLC chromatogram of the isolated substance, Example 2, crude compound of formula (I) (HPLC-UV method d-1). [Figure 38] Isolated substance, Example 4, HPLC chromatogram of the compound of formula (I) (HPLC-UV method d-1). [Figure 39] Isolated substance, Example 4.1, HPLC chromatogram of the compound of formula (I) (HPLC-UV method d-1). Example

[0230] Experimental Section Abbreviation

[0231] [Table 1A] [Table 1B]

[0232] Materials and instrumentation Unless otherwise specified, the chemicals used in the synthesis process were reagent-grade and used as obtained.

[0233] All reagents whose synthesis is not described in the Experimental Section are either commercially available, known compounds, or can be formed from known compounds by methods known to those skilled in the art.

[0234] Instrument setup for XRPD measurement (compound (I) is amorphous) X-ray powder diffraction (XRPD) data were recorded using a Panalytical X-Pert PRO diffractometer with a position-sensitive detector (CuKα radiation) at a generator setting of 40 kV and 40 mA. Samples were collected in transition mode and prepared as thin layers between two foils. The scanning range was between 2° and 38°²θ at 0.013° steps and 25 seconds / step.

[0235] Instrument settings for XRPD measurement (crystal forms I and II of compounds of formula (I), including transient crystal forms) X-ray powder diffraction (XRPD) data were recorded using a STOE STADI P diffractometer with monochromatic CuKα1 radiation as the position-sensitive detector, at a generator setting of 40 kV and 40 mA. Samples were collected in transition mode and prepared as thin layers between two foils. The scanning range was between 2° and 38°²θ at 0.2° steps and 15 seconds / step.

[0236] Instrument setup for XRPD measurement (crystal forms I, II, and III of the compound of formula (II)) X-ray powder diffraction (XRPD) data were recorded using a STOE STADI P diffractometer with monochromatic CuKα1 radiation as the position-sensitive detector, at a generator setting of 40 kV and 40 mA. Samples were collected in transition mode and prepared as thin layers between two foils. The scanning range was between 2° and 40°²θ at 0.5° steps and 15 seconds / step.

[0237] Instrument setup for SCD measurement (compound diastereomer 1 of formula (I)) Table 4 and Figure 16 show the crystallographic data of diastereomer 1 of compound (I), as well as the numbering of its thermal ellipsoid and structure. 100 mg of diastereomer 1 of compound (I) (see Example 5) was dissolved in 150 mg of water at 60°C, 700 mg of ethanol was slowly added, and finally, ethanol vapor was slowly diffused into the solution at 60°C to obtain colorless crystals.

[0238] Single-crystal X-ray diffraction data were collected using a Rigaku Oxford Diffraction XtaLAB Synergy-S diffractometer equipped with a dual-flex source (Cu at 0), a HyPix-6000HE detector, and an Oxford Cryosystems Cobra cooler. Data were collected using CuKα radiation. The structure was elucidated and refined using the Shelx package software program, and OLEX2 was used as the interface to display the structure and create drawings. Unless otherwise specified, hydrogen atoms bonded to carbon were geometrically positioned and purified using the riding isotropic displacement parameter. Hydrogen atoms bonded to heteroatoms were located in the difference Fourier synthesis map and could be freely purified using the isotropic displacement parameter. Asymmetric units were fully occupied Gd 3+ It was found that the compound diastereomer 1 of formula (I) contains 1 / 4 of the ions coordinated to the ligand. This also contains one fully occupied water molecule, one fully occupied EtOH molecule, and two partially occupied EtOH molecules refined to 75% and 80% occupancy, respectively (see Figure x). The molecule of compound (I) contains four Gd ligand units in which the central carbon atom (C21) is in a special position (rotationally inverted). The crystal structure belongs to conformal space group I-4, and rotationally inverted symmetry element-4 means that the sample of compound (I) investigated (Example 5) is actually an R,S,R,S (or S,R,S,R) diastereoisomer, and thus confirms the structure of compound diastereomer 1 of formula (I).

[0239] Equipment setup for SCD measurement (compound diastereomer 3 of formula (I)) Table 5 and Figure 17 show the crystallographic data of diastereomer 3 of compound (I), as well as a diagram illustrating the numbering of the thermal ellipsoid and structure. 50 mg of diastereomer 3 of compound (I) (see Example 7) was dissolved in 36 mg of water at 60°C, 100 mg of ethanol was slowly added, and finally, isopropanol vapor was slowly diffused into the solution at 60°C to obtain colorless crystals.

[0240] Single-crystal X-ray diffraction data were collected using a Rigaku Oxford Diffraction XtaLAB Synergy-S diffractometer equipped with a dual-flex source (Cu at 0), a HyPix-6000HE detector, and an Oxford Cryosystems Cobra cooler. Data were collected using CuKα. The structure was elucidated and refined using the Shelx package software program, and OLEX2 was used as an interface to display the structure and create drawings. Unless otherwise specified, hydrogen atoms bonded to carbon were geometrically arranged and purified using the riding isotropic displacement parameter. Hydrogen atoms bonded to heteroatoms were located in the difference Fourier synthesis map and could be freely purified using the isotropic displacement parameter. The asymmetric unit was found to contain one molecule of compound diastereomer 3 of formula (I) (see Figure 17). In the crystal structure, there is a considerable amount of diffusive electron density corresponding to large, disordered, and partially occupied solvent molecules located in the large voids between adjacent molecules of compound diastereomer 3 of formula (I). This diffusive electron density was removed during structural refinement using the Olex2 implementation of the Platon Squeeze routine. This technique significantly improved the final model and enabled convergence by least squares. Due to the highly diffusive nature of the electron density, all hydrogen atoms located on heteroatoms were refined at calculated positions (AFIX 47) as if they were on their parent atoms. In this structure, one disordered carboxylate group was modeled across two sites and refined in a ratio of 0.60:0.40. In this structure, 50% of the compound molecule of formula (I) has all stereocenters (C15, C36, C45, C76) in the R configuration, and the other 50% has another in the S configuration (centrosymmetric space group P21 / n). This means that the crystal structure of a sample of the compound of formula (I) (Example 7) contains an equimolar mixture of (R,R,R,R) and (S,S,S,S) diastereomers, confirming the structure of compound diastereomer 3 of formula (I).

[0241] Setting up equipment for IR measurement IR measurements were performed using a Bruker α spectrometer with attenuated total internal reflection (ATR) geometry. No sample preparation was performed, and each measurement consisted of 32 scans.

[0242] Setting up equipment for Raman measurements Raman measurements were performed using a Bruker MultiRAM spectrometer. No sample preparation was performed, and each measurement consisted of 64 scans using a 300mW laser output.

[0243] Instrument setup for TGA measurement (crystal forms I and I of the compound of formula (I)) Thermogravimetric analysis (TGA) was performed using a Mettler Toledo TGA / DSC 3+. The instrument was set to 50 ml / min. -1 The samples were purged with nitrogen gas at a flow rate of [specified flow rate]. Approximately 3-10 mg of each sample was placed in an aluminum crucible and kept at 10°C for 1 minute. -1 The temperature was heated from 25°C to 350°C at the following heating rate.

[0244] Instrument setup for TGA measurement (crystal forms I, II, and III of the compound of formula (II)) Thermogravimetric analysis (TGA) was performed using a Mettler Toledo TGA / DSC 3+. The instrument was run at 10 or 20 ml / min intervals. -1 The samples were purged with nitrogen gas at a flow rate of [percentage]. Approximately 1-15 mg of each sample was placed in an aluminum or aluminum oxide crucible and kept at 25°C to 10°C for 10 minutes. -1 It was heated at the following heating rate.

[0245] Equipment setup for DSC measurement Differential scanning calorimetry (DSC) was performed using a Mettler Toledo DSC3+. The calorimeter was used at 50 ml / min. -1 The samples were purged with nitrogen gas at a flow rate of [specified flow rate]. Each sample (3-10 mg) was placed in an aluminum crucible and incubated at 20°C for a minimum of 10 minutes. -1 It was heated from -10°C to 250°C at a certain rate.

[0246] Instrument setup for DVS measurement (crystal forms I and II of the compound of formula (I)) Water sorption isotherms were determined using a Surface Measurement Systems Ltd DVS1 gravimetric sorption analyzer. 10–20 mg samples were equilibrated at 50% relative humidity, and their weights were recorded. Isotherms were then recorded by varying the humidity in 10% steps. The equilibrium criterion was set to a relative mass change of dm / dt = 0.002% / min.

[0247] Analysis method HPLC chromatography HPLC-UV method a: Equipment: Agilent Series 1260, Pump: G1312B, Autosampler: G1329B, Degasser: G4225A, Column Oven: G1316C, Detector: G1314F; Detection Wavelength: 198nm, Bandwidth: 8nm; Data Rate: 40Hz; Column Temperature: 40℃, Column: YMC Triart Phenyl C18 100mm×3mm, 3μm, Eluent A: 0.1 wt% formic acid in water; Eluent B: Acetonitrile, Flow Rate: 1.20mL / min; Gradient (A): 0 min: 98%; 1 min: 98%; 9 min: 20%; 11 min: 20%; Equilibrium Time: 3 min, Injection Volume: 10μL.

[0248] HPLC-UV method b: (Assassination of the compound of formula (II)) Evaluation by hydrolysis to 4-nitrophenol, sample preparation protocol: Sample Solution 1: Dissolve approximately 0.2 mg / mL of the sample in a mixture of 85% acetonitrile and 15% water (v / v). The sample must be dissolved only immediately before analysis (maximum time between sample dissolution and injection: 15 minutes).

[0249] 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 hours. After cooling, fill to the required volume (if stored at room temperature, use the sample solution within 24 hours).

[0250] The assay for the compound of formula (II) is determined indirectly via the 4-nitrophenol content after hydrolysis of the sample (direct determination is impossible due to the inherent instability of the compound of formula (II) in aqueous media / HPLC conditions). The analysis is evaluated by external standard calibration against a 4-nitrophenol standard. The 4-nitrophenol content is determined for sample solution 1 (before hydrolysis) and sample solution 2 (after hydrolysis). Subsequently, the 4-nitrophenol content determined from sample solution 1 is subtracted from the 4-nitrophenol content determined for sample solution 2. The difference is used for the assay calculation of the compound of formula (II). The assay for the compound of formula (II) is then calculated inversely based on a coefficient that takes into account the molecular weight fraction of the compound of formula (II) relative to 4-nitrophenol.

[0251] HPLC-UV parameters: Instrument: e.g., Agilent Series 1290, detection wavelength: 316nm, bandwidth: 6nm; data rate: 10Hz; column temperature: 40℃, column: Acquity BEH Phenyl 100mm×3mm, 1.7μm, eluent A: 10 mmol / L ammonium phosphate buffer, pH 2.4~1 L; eluent B: acetonitrile, flow rate: 1.0mL / 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; equilibrium time: included in the gradient, injection volume: 1μL.

[0252] HPLC-UV method b-2 (Determination of formamide in the compound of formula (II)) 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 supplement with volumetric solution. Evaluate by multilevel calibration over appropriate linear regression using a formamide reference standard.

[0253] HPLC-UV parameters Instrument: e.g., Agilent Series 1290; Detection wavelength: 195 nm; Bandwidth: 4 nm; Data rate: 10 Hz; Column temperature: 40 °C; Column: Nucleodur HILIC, 125 mm × 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; Operating time: 5 minutes; Injection volume: 20 μL

[0254] HPLC-UV method c (assay of compound (II) via benzylamide derivative of compound (IV)): Evaluation of the compound of formula (II) by derivatization of the compound of formula (IV) to a benzylamide derivative, sample preparation protocol:

[0255] Derivatization reagent: Benzylamine in DMSO (e.g., 1.75 μL / 1 mL)

[0256] Preparation of the blank reaction solution: Pipette 2 mL of the derivatization reagent from the small reaction vessel and stir on a temperature-controlled magnetic block at 40°C for 30 minutes.

[0257] Preparation of blank solution: Dilute 90 μL of blank reaction solution with 1410 μL of water.

[0258] Preparation of reaction solution for sample: Prepare a sample solution of approximately 10 mg / mL using the derivatizing reagent as the solvent (for example, weigh 20 mg of the substance in a small reaction vessel and add 2 mL of the derivatizing reagent), and stir on a temperature-controlled magnetic block at 40°C for 30 minutes for complete reaction.

[0259] Sample solution preparation: Dilute 90 μL of sample reaction solution with 1410 μL of water (sample concentration of approximately 0.6 mg / mL).

[0260] The analysis is evaluated by external standard calibration of the compound of formula (IV) against a benzylamide derivative standard. The assay for the compound of formula (II) is calculated based on a coefficient that takes into account the molecular weight fraction of the benzylamide derivative of the compound of formula (IV) relative to the compound of formula (II).

[0261] HPLC-UV parameters: Instrument: e.g., Agilent series 1260; detection wavelength: 200nm; bandwidth: 4nm; data rate: 5Hz; column temperature: 25℃; column: Waters Atlantis Premier BEH C18AX, 100mm × 4.6mm, 2.5μm; eluent A: 0.1% formic acid + 0.5% acetonitrile in water; eluent B: 0.1% formic acid in water with 30% acetonitrile; flow rate: 1.0mL / 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; equilibrium time: 5 min at 0% B; injection volume: 5μL.

[0262] HPLC-UV method c-1 (i.e., compound of formula (IV) in compound of formula (II): Evaluation of derivatized solutions using HPLC-UV method c, sample preparation protocol:

[0263] Preparation of the blank reaction solution: Same as in "HPLC method c (novel, assay)".

[0264] Preparation of blank solution: Dilute the blank reaction solution with water in a 1:1 ratio.

[0265] Preparation of reaction solution for sample: Same as in "HPLC method c (novel, assay)".

[0266] Preparation of sample solution: Dilute the sample reaction solution 1:1 with water (using a sample concentration of approximately 5 mg / mL).

[0267] HPLC-UV parameters: Same as HPLC method c

[0268] HPLC method d-1: Instrument: e.g., Agilent Series 1290, detection wavelength: 198nm, bandwidth: 4nm; data rate: 5Hz; column temperature: 35℃, column: Acquity BEH Phenyl 100mm×3mm, 1.7μm, eluent A: 30mL acetonitrile packed with 10 mmol / L ammonium phosphate buffer, pH 2.4~1 L; eluent B: 600mL acetonitrile + 400mL aqueous solution of ammonium phosphate buffer, pH 2.4, flow rate: 0.4mL / 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; equilibrium time: 5 min, injection volume: 5μL.

[0269] HPLC method d-2 (alternative method to d-1): 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 × 3 mm, 3 μm, Potassium phosphate buffer solution: 1 L from 640 μL of phosphoric acid (85%) composed of 1.36 g potassium hydrogen phosphate + water; Eluent A: 99% potassium phosphate buffer solution + 1% acetonitrile v / v; Eluent B: 35% potassium phosphate buffer solution + 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%; Equilibrium time: at least 10 min, Injection volume: 10 μL.

[0270] HPLC method: Instrument: Agilent Series 1260, Pump: G1312B, Autosampler: G1329B, Degasser: G4225A, Column Oven: G1316C, Detector: G1314F; Detection Wavelength: 200nm, Bandwidth: 6nm; Data Rate: 10Hz; Column Temperature: 20℃, Column: YMC Triart C18 150mm×3mm, 3μm, 1L from 640μL of 85% phosphoric acid composed of 1.36g potassium hydrogen phosphate + water; Eluent A: 99% potassium phosphate buffer aqueous solution + 1% acetonitrile v / v; Eluent B: 95% potassium phosphate buffer aqueous solution + 5% acetonitrile v / v; Flow Rate: 0.4mL / min; Gradient: 0min: 100% A, 27.0min: 95% A, 37.0min: 50% A, 50min: 0% A; 60 minutes: 0%; Equilibrium time: at least 10 minutes, injection volume: 10 μL.

[0271] Determination of residual solvent Formamide content (Method a; GC): Instrument: Agilent GC HP 7890A or GC HP 7890B; Autosampler: Agilent GC Headspace Sampler 7693; Injection temperature: 220℃; Injection volume: 0.5μL; Detection temperature: 300℃; Data rate: 10Hz; Column: Rxi-624 Sil MS 22m × 0.18mm × 1μm; Column flow rate: 0.7mL / min; Split flow rate: 3.5mL / min; Split ratio: 5; Liner: SLG Focus Liner No. 092219; Analysis method: 50℃, Initial time 2.0min, Temperature increase 10℃ / min to 150℃, Temperature increase 70℃ / min to 250℃, Retention time 2.57min; Carrier gas: Hydrogen.

[0272] Residual solvent content (i.e., ethanol) determined by GC headspace (Method a) Instrument: Agilent GC HP 7890A or similar instrument; Autosampler: Perkin-Elmer HS 40 XL sampler or Agilent GC headspace sampler 7697 A; Injection temperature: 160°C; Injection volume: 80 μL; Detection temperature: 300°C; Data rate: 20 Hz; Column: Rxi-624 Sil MS 20 m × 0.18 mm × 1 μm; Column flow rate: 1.2 mL / min; Split flow rate: 21.6 mL / min; Split ratio: 18; Liner: Transfer liner Agilent part number 18740-80200; Analytical method: 40°C, initial time 4.5 min, heating 14°C / min to 70°C, heating 90°C / min to 220°C, retention time 1.69 min; Carrier gas: Hydrogen.

[0273] Ethanol content (Method b) USP <467> Headspace gas chromatography based on this method.

[0274] Determination of water content Moisture content (method a): Instrument: 870 KF-Titrino Plus, Metrohm AG, Herisau, Switzerland; Solvent: Hydranal® solvent for volumetric measurement of water content by Karl Fischer; Titrator: Hydranal® titrant 5.

[0275] Moisture content (method b): According to Pharm.Eur.2.5.32 (Karl Fischer method; coulometric analysis)

[0276] Example 1 - Synthesis of the compound of formula (II) 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

[0277] Reaction scheme [ka] 4-nitrophenol (0.994 kg, CAS: 100-02-7, purchased from Amarjyot Chemical Corporation, India) was added to a 36 L reactor, and acetonitrile (11.0 kg) was added. The mixture was stirred at 25°C (jacket temperature) for 15 minutes to obtain a clear solution, and gadolinium 10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (2.25 kg, CAS: 208252-78-2, German Patent Application Publication No. 19652386, refer to Schering AG, supplied as a dihydrate, with 5.6 wt% water) was added as a solid. The supply container and addition funnel were rinsed with acetonitrile (1.29 kg). The mixture was stirred at 25°C (jacket temperature) for a further 15 minutes, and then cooled to 0°C (internal temperature). Formamide (4.21 kg) was added, the tube was rinsed with acetonitrile (0.890 kg), and the mixture was stirred at this temperature for 3 hours. Then, a solution of N,N-diisopropylcarbodiimide (0.676 kg, CAS: 693-13-0, purchased from Kemilabs, Hungary) in acetonitrile (0.670 kg) was added within 8 minutes. The supply container and tube were rinsed with acetonitrile (0.630 kg). The mixture was heated to 23°C (internal temperature) and then stirred for 19 hours. A solution of acetonitrile (4.56 kg) and water (0.810 kg) was added, and the mixture was stirred for 3 hours. The mixture was filtered, and the product was washed with acetonitrile (3 times, 3.51 kg, 3.99 kg, 3.51 kg). The solid was dried under reduced pressure and high temperature to obtain the title compound (2.33 kg, 87%) as a colorless to slightly yellow crystalline solid.

[0278] analysis HPLC (method a), R t :4.23 minutes HPLC (method b), R t :4.52 minutes Assay (Method b): 78.3% by weight

[0279] [Table 2]

[0280] Formamide (Method b): 11.9% by weight Water (method b): 2.2% by weight Solid State Form: Form I

[0281] The following examples were carried out in the same manner as described above.

[0282] [Table 3]

[0283] **Different addition order:** 4-nitrophenol and gadolinium-10-[4-carboxy-1-methyl-2-oxo-3-azabutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid were added to the reactor. Acetonitrile was then added to obtain a suspension, which was then carried out as described above. ***When formamide was added, 1 wt% 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 (Form I) was added as a seed crystal to the reaction product. Instead of adding a solution of acetonitrile and water, the two components were added sequentially. Water was added within 45-60 minutes. § The actual yield is higher. Due to production line delays, it was not possible to isolate all the substances. $ Water content of the mixture after adding all reagents, solvents, and water: 3.2% by weight

[0284] Example 2 - Crude synthesis of compound (I) [4,10-bis(carboxylatomethyl)-7-{3,6,12,15-tetraoxo-16-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-9,9-bis({[({2-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoyl}aminoacetyl]-amino}methyl)-4,7,11,14-tetraazaheptadecan-2-yl}-1,4,7,10-tetraazacyclododecane-1-yl]acetate

[0285] Reaction scheme: [ka] Dimethyl sulfoxide (7.26 kg) was added to 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) was added and the mixture was stirred for 15 minutes. 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 (2.20 kg | 77 wt%) was added and the mixture was stirred for 30 minutes. Then, N,N-diisopropylethylamine (0.303 kg) was added. The mixture was heated to 50°C (internal temperature) and stirred for 4 hours. The reaction mixture was cooled to 23°C, and water (6.6 kg) was slowly added while maintaining 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 hour. The pH was adjusted to 6.5-7.5 by slowly adding aqueous hydrochloric acid solution (10 wt%, 2.1 kg). The mixture was successively washed with methyl tert-butyl ether (2 × 4.88 kg), and the organic layer from each wash was discarded. The aqueous layer was filtered and then concentrated under reduced pressure (50 mbar) until the internal temperature reached approximately 58°C. The water content was determined to be approximately 16 wt% by volumetric analysis Karl Fischer titration. The mixture was cooled to room temperature, and ethanol (containing approximately 1% methyl ethyl ketone, 5.5 kg) was added. Subsequently, acetone (11 kg) was added within 2 hours. The resulting suspension was stirred for 30 minutes and filtered. The resulting solid was washed with acetone (twice, 2.75 kg each time) and subsequently dried under reduced pressure and high temperature. The title compound was obtained as a colorless solid (2.13 kg, 155% assay correction based on 2,2-bis(aminomethyl)propane-1,3-diamine tetrahydrochloride used, 94% assay correction).

[0286] Typically, such substances have an assay of 50–80%. Apart from the main impurities, the compound of formula (IV) derived from the compound of formula (II) and other organic impurities, the substance also contains inorganic salts such as sodium chloride, residual solvents such as dimethyl sulfoxide, formamide, and water.

[0287] The synthesis of the compound of formula (I) based on the presented synthetic route yields a mixture of three isomer types: (RRRR / SSSS), (RRRS / SSSR), and (RRSS) (their selective isolation is described in Examples 5, 6, and 7). Given the reaction mechanism, the statistical distribution of isomers is expected to yield a ratio of approximately 1:5:4 with respect to (RRRR / SSSS):(RRRS / SSSR):(RRSS), which is nearly observed in the reaction mixture as outlined for this batch.

[0288] analysis: Purity (area %, method d-1): 89.2% Assay HPLC (Method d-1): 60.6% Diastereomer distribution: Diastereomer 1(R t :20.3 minutes):40.5% Diastereomer 2(R) t :20.9 minutes):50.2% Diastereomer 3(R) t :22.4 minutes):9.3% Water (KF-Fischer, volumetric, method a): 4% by weight

[0289] The following examples were carried out in the same manner as described above. The ratio of compound (IV) to compound (III) is outlined below.

[0290] [Table 4]

[0291] *The manufacturing process differed in that the solid, the compound of formula (III), and the compound of formula (II) were added to the reactor before the addition of dimethyl sulfoxide. **The reaction was carried out in the same manner as described above, but without treatment with sodium hydroxide aqueous solution or hydrochloric acid aqueous solution.** ***The reaction was carried out in the same manner as above, but the basic treatment when adding the sodium hydroxide aqueous solution was performed at 50°C and pH=8.5. $ The reaction was carried out in the same manner as described above, but the basic treatment during the addition of the sodium hydroxide aqueous solution was performed at 50°C and pH=9.5. $$ The reaction was carried out in the same manner as described above, but triethylamine was used instead of diisopropylethylamine. $$$ The reaction was carried out in the same manner as described above, but tributylamine was used instead of diisopropylethylamine. $$$$ The reaction was carried out in the same manner as described above, but washing with tert-butyl methyl ether was not performed. $$$$$ The reaction was carried out in the same manner as described above, but a sodium hydroxide aqueous solution was added and a basic treatment was performed at 50°C and pH=9. Washing with tert-butyl methyl ether was not performed. § Distillation was carried out at 75 mbar until the internal temperature reached 66°C. The water content was determined to be 16.9% by weight.

[0292] Example 3: Synthesis of the compound of formula (I) | Aqueous solution: [4,10-bis(carboxylatomethyl)-7-{3,6,12,15-tetraoxo-16-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-9,9-bis({[({2-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoyl}aminoacetyl]-amino}methyl)-4,7,11,14-tetraazaheptadecan-2-yl}-1,4,7,10-tetraazacyclododecane-1-yl]acetate | Synthesis of aqueous solution

[0293] Reaction scheme: [ka] Crude compound of formula (I) (32.5 kg, approximately 51 wt% assay, 16.5 kg of compound of formula (I)) was dissolved in water (190 kg) in a total of four parts. Each part was filtered and stored in a container. The reactor and tubing were washed with water (14 kg) as a whole. The mixture was transferred to a second reactor via filter and container, and the tubing was rinsed with water (21 kg). A 2 kDa membrane (12 m) was then prepared. 2 The solution was dialyzed using a surface (Hydrosart®, purchased from Satorius AG, Germany), and the volume of concentrated water was changed a total of seven times to maintain a constant mass in the concentrated water container. After completion, the concentrated water mass was concentrated by ultrafiltration, the mixture was stored in a container, and the system was rinsed with water. In total, 127.9 kg of solution was obtained in the assay of the compound of formula (I) at a concentration of approximately 12.2 wt% (yield approximately 95%).

[0294] analysis: Purity (area %, method d-1): 92.5% Diastereomer content (area %, method d-1): Diastereomer 1(R) t :20.7 min):36.5 area% Diastereomer 2(R) t :21.4min):46.0area% Diastereomer 3(R) t :23.1min):9.0area%

[0295] The following examples were carried out in the same manner as described above, except that the film size was scaled to the required size.

[0296] [Table 5]

[0297] **Due to the high purity of the crude compound of formula (I), only four cycles of diafiltration were performed before concentrating the aqueous solution.** ***UF / DF was conducted at 40℃. $ Because the crude product of the compound of formula (I) had high purity, only 5 cycles of diafiltration were performed before concentrating the aqueous solution. $$ UF / DF was performed at 35°C. $$$ Diafiltration was performed for only 3 cycles. § The aqueous solution was collected in a container equipped with a fill level sensor but without a balance. The solution was further processed. Furthermore, residue remains in the tube and container. Therefore, the yield is >95%.

[0298] Synthesis of the compound of formula (I) in Example 4 [4,10-bis(carboxylatomethyl)-7-{3,6,12,15-tetraoxo-16-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-9,9-bis({[({2-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoyl}aminoacetyl]-amino}methyl)-4,7,11,14-tetraazaheptadecan-2-yl}-1,4,7,10-tetraazacyclododecane-1-yl]acetate

[0299] Reaction scheme: [ka] The solution of compound (I) in water (128 kg, assay: approximately 12.3 wt%, approximately 15.7 kg of compound (I)) in a container was transferred to a 250 L reactor, and the container and tubing were rinsed with water (10.0 kg in total). The resulting solution was concentrated under reduced pressure (50-70 mbar) at a high temperature (jacket temperature: 75°C) to obtain an aqueous solution of compound (I) at approximately 20 wt%. The solution was transferred to a second reactor and a feed source reactor, and the tubing was rinsed with water (5.2 kg). Activated carbon (0.830 kg, type Norit A Supra DAB) was added, and the mixture was heated to 60°C and stirred for 1 hour. The mixture was cooled to 20°C, then filtered, and transferred to a third reactor. The feed source reactor and tubing were washed with water (12.4 kg). The resulting aqueous solution was concentrated under reduced pressure (50 to 70 mbar) and high temperature (jacket temperature: 75°C) to obtain an aqueous solution of the compound of formula (I) in water at a concentration of approximately 50% by weight. The mixture was heated to 60°C and ethanol (containing approximately 1% methyl ethyl ketone, 78.5 kg) was added within 2 hours. The water content of the mixture was determined to be approximately 13.5% by weight by volumetric Karl Fischer titration. The resulting suspension was stirred at this temperature for a further 2 hours and then cooled to 20°C within 90 minutes. The mixture was stirred for 15 minutes, filtered, and washed with ethanol (containing approximately 1% methyl ethyl ketone, twice, 29.9 kg and 16.1 kg). The resulting solid was dried in a stirred Nutsch dryer at high temperature and under reduced pressure. Such a substance was transferred to an oven containing two trays filled with water. When the substance was equilibrated under reduced pressure (30 mbar) and slightly higher temperature (equivalent to 36°C and approximately 50% relative humidity) for 20 hours, the title compound (14.7 kg, 94%, 83% assay corrected) was obtained as a colorless crystalline solid.

[0300] analysis: HPLC purity (method d-1, area %): 99.8% HPLC (method d-1): Diastereomer distribution: Diastereomer 1(R t :20.1min):46.4% Diastereomer 2(R) t :20.7 minutes):52.6% Diastereomer 3(R)t :22.3 minutes):1.0% Assay: 86.9% by weight.

[0301] Mass spectrometry [LC-MS, modified method d-1 using formic acid instead of phosphate buffer]: The detected mass follows the sum of the diastereomers of the compound in formula (I).

[0302] [Table 6]

[0303] Water (method b): 12.5% ​​by weight Ethanol (Method b): <0.050% by weight Solid state: Mixture; Form II and Form I

[0304] Example 4.1: Selective manufacturing of Form II The aqueous solution of the compound of formula (I) in the container (8.6 kg, approximately 15.7 wt%, approximately 1.35 kg of the compound of formula (I)) was transferred to a 26 L reactor, and the tubes were rinsed with the aqueous solution of the compound of formula (I) (1.05 kg, approximately 2.6 wt%, approximately 0.027 kg of the compound of formula (I)). Activated carbon (0.059 kg, Norit SX Plus 20 type) was suspended in the aqueous solution of the compound of formula (I) (1.5 kg, approximately 2.6 wt%, approximately 0.039 kg of the compound of formula (I) in the water) and added to the mixture. The mixture was heated to 60°C and stirred for 1 hour. The mixture was cooled to 22°C and then filtered. The feed reactor and filter were washed with water (1.35 kg). The obtained solution (11.9 kg) was transferred to a 50 L reactor and subsequently concentrated under reduced pressure (75 mbar) and high temperature (jacket temperature: 80°C) to obtain an aqueous solution of the compound of formula (I) in water at approximately 50% by weight (recovered distillate: 9.68 kg). The mixture was heated to 60°C and ethanol (containing approximately 1% methyl ethyl ketone, 6.8 kg) was added within 2 hours. The water content of the mixture was determined to be approximately 8-9% by weight by volumetric Karl Fischer titration. The obtained suspension was stirred at this temperature for a further 2 hours and then cooled to 25°C within 45 minutes. The mixture was stirred for 30 minutes, filtered, and washed twice with ethanol (containing approximately 1% methyl ethyl ketone, 1.35 kg each time). The obtained solid was dried in a stirred Nutsch dryer at high temperature (initial jacket temperature: 80°C) and reduced pressure (pump pressure: 20 mbar). Once the pressure reached 27 mbar (internal pressure inside the dryer) and the product temperature reached 47.5°C, steam was applied. § The substance was dried for 3 hours at approximately 25–29 mbar (pressure inside the dryer) and a product temperature of 64–68°C (equal to approximately 9–12% rH). Drying in the presence of water vapor was continued at 25–29 mbar (pressure inside the dryer). 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 approximately 66% rH) within 4.5 hours to obtain the title compound (1.2 kg, 89%, 78% assay corrected) as a colorless crystalline solid.

[0305] §Steam was generated in a pressure reactor at a jacket temperature of 130°C and a pressure of 1200-1500 mbar (abs). The high-temperature steam was passed through a Nutsch dryer using heated hoses. The flow rate was controlled by valves.

[0306] analysis: HPLC purity (method d-1, area %): 99.9% HPLC (method d-1): Diastereomer distribution: Diastereomer 1(R t :20.1min):46.7% Diastereomer 2(R) t :20.7 minutes):52.3% Diastereomer 3(R) t :22.3 minutes):1.1% Assay: 87.2% by weight. Water (method b): 13.2% by weight Ethanol (Method b): Not detected Solid state: Form II

[0307] Example 4.2: Selective Manufacturing of Form I The aqueous solution of the compound of formula (I) in the container (15.2 kg, approximately 16.0 wt%, approximately 2.43 kg of the compound of formula (I)) was transferred to a 26 L reactor, and the tubes were rinsed with the aqueous solution of the compound of formula (I) (3.05 kg, approximately 4.4 wt%, approximately 0.134 kg of the compound of formula (I)). Activated carbon (0.106 kg, type Norit A Supra DAB) was suspended in the aqueous solution of the compound of formula (I) (1.6 kg, approximately 4.4 wt%, approximately 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 hour. The mixture was cooled to 22°C and subsequently filtered. The feed reactor and filter were washed with water (1.2 kg). The obtained solution (20.8 kg) was transferred to a 50 L reactor and subsequently concentrated under reduced pressure (75 mbar) and high temperature (jacket temperature: 80°C) to obtain an aqueous solution of the compound of formula (I) in water at approximately 50% by weight (recovered distillate: approximately 16 kg). The mixture was heated to 60°C and ethanol (containing approximately 1% methyl ethyl ketone, 12 kg) was added within 2 hours. The water content of the mixture was determined to be approximately 15% by weight by volumetric Karl Fischer titration. The obtained suspension was stirred at this temperature for a further 2 hours and then cooled to 25°C within 45 minutes. The mixture was stirred for 30 minutes, filtered, and washed with ethanol (containing approximately 1% methyl ethyl ketone, twice, 2.4 kg each time). The wet material was dried in a stirred Nutsch dryer using steam. § In the presence of [substance name], the product was dried for 24 hours at a product temperature of 31-38°C (equal to approximately 44-69% rH) at a pressure of 29-32 mbar (inside the dryer) and the title compound (2.28 kg, 87%, 71% assay corrected) was obtained at a final product temperature of 31°C and 29 mbar (inside the dryer, equivalent to approximately 65% ​​rH). §§ It was obtained as a colorless crystalline solid.

[0308] § Steam was generated in a pressure reactor at a jacket temperature of 130°C and a pressure of 1200-1500 mbar (abs). The high-temperature steam was passed through a Nutsch dryer using heated hoses. The flow rate was controlled by valves.

[0309] §§The actual yield was higher, but it was not possible to completely empty the agitated Nutsch dryer. The remaining material was dissolved in water.

[0310] analysis: HPLC purity (method d-1, area %): >99% HPLC (method d-1): Diastereomer distribution: Diastereomer 1(R t :20.1min):48.7% Diastereomer 2(R) t :20.7 minutes):50.4% Diastereomer 3(R) t :22.3 minutes):0.9% Assay: 82.4% by weight Water (KF-Fischer, method b): 17.2% by weight Ethanol (Method b): 0.222% by weight Solid state: Form I

[0311] The following examples were carried out in the same manner as the above examples. The drying / equilibrium conditions differed in part from those described above.

[0312] [Table 7]

[0313] *The crystallization and isolation procedures were slightly different: After concentration under vacuum, the mixture was cooled to room temperature. Ethanol was then added, and the mixture was heated to 60°C to crystallize the product. The product was isolated, washed with ethanol, and dried under reduced pressure. Since the ethanol level exceeded the specification limit (approximately 2% by weight was detected), the product was exposed to air for several hours to absorb water. The product was dried again under reduced pressure (but not in the presence of water) to obtain the final compound. **Normalized yield. The completely wet product was not equilibrated.** ***The wet product was directly equilibrated in a rotary glass dryer in the presence of water, with a jacket temperature of 30°C, a product temperature of approximately 30°C, and a pump pressure of 20 mbar (equal to approximately 48% rH). Due to the technical configuration, the pressure inside the dryer was not measured. Direct drying was performed in a glass rotary dryer in the presence of water. First, at a jacket temperature of 70°C | product temperature of approximately 62°C | pump pressure of 20 mbar (equal to approximately 9% rH) for 1.75 hours, followed by a jacket temperature of 30°C | pump pressure of 20 mbar for 2.25 hours (cooling) + 1.25 hours (holding time), with a final product temperature of 29°C (equal to approximately 50% rH). Due to the technical configuration, the pressure inside the dryer was not measured. § Once the required parameters were met, direct drying was performed in a stirred Nutsch dryer in the presence of water. First, the product was dried for 4.5 hours at a jacket temperature of 80°C, a product temperature of 68 to 73°C, a pump pressure of 20 mbar, and a pressure of approximately 32 mbar in the dryer (equal to approximately 9-11% rH), followed by 5 hours at a jacket temperature of 31-40°C, a pump pressure of 20 mbar, and a pressure of approximately 30 mbar in the dryer, bringing the final product temperature to 31°C (equal to approximately 67% rH). §§ Once the required parameters were met, direct drying was performed in a stirred Nutsch dryer in the presence of water. First, the product was dried for 3 hours in the dryer at a jacket temperature of 72°C, a product temperature of 61–65°C, a pump pressure of 20 mbar, and a pressure of 22–24 mbar (equal to 9–11% rH), followed by 4.5 hours in the dryer at a jacket temperature of 30°C, a pump pressure of 20 mbar, and a pressure of approximately 21 mbar, with a final product temperature of 31°C (equal to approximately 48% rH). §§§Once the required parameters were met, direct drying was performed in a stirred Nutsch dryer in the presence of water. First, the mixture was dried in the dryer for 3 hours at a jacket temperature of 63°C | 55–57°C, product temperature of 20 mbar, and pump pressure of 30–31 mbar (equal to 18–19% rH), followed by 1.5 hours in the dryer at a jacket temperature of 30°C | 20 mbar, and pump pressure of approximately 28 mbar, with a final product temperature of 38°C (equal to approximately 43% rH) to obtain the mixture (Form I and Form II). Drying was continued in the presence of water, first in a dryer at a jacket temperature of 72°C, a product temperature of 60-63°C, a pump pressure of 20 mbar, and a pressure of 27-31 mbar (equal to 12-15% rH) for 2 hours, then in a dryer at a jacket temperature of 30°C, a pump pressure of 20 mbar, and a pressure of approximately 27 mbar for 2.5 hours, and finally at a product temperature of 33°C (equal to approximately 54% rH) to obtain Form II. §§§§ Once the required parameters were met, direct drying was performed in a stirred Nutsch dryer in the presence of water. First, the mixture was dried in the dryer for 3 hours at a jacket temperature of 93–95°C | product temperature of 78–82°C | pump pressure of 21–24 mmbars | pressure of 29–33 mmbars (equal to 6–7% rH), followed by 4 hours in the dryer at a jacket temperature of 30°C | pump pressure of 20 mmbars | pressure of approximately 27 mmbars, and finally at a temperature of 32°C (equal to approximately 56% rH) to obtain the mixture (Form I and Form II). Drying was continued in the presence of water, first in a dryer at a jacket temperature of 80°C, a product temperature of 58-71°C, a pump pressure of 20 mbar, and a pressure of 30-31 mbar (equal to 9-17% rH) for 3 hours, followed by drying in the dryer at a jacket temperature of 30°C, a pump pressure of 20 mbar, and a pressure of approximately 28 mbar for 2.5 hours, and finally drying at a product temperature of 33°C (equal to approximately 55% rH) to obtain Form II. $Equilibrium was performed in a stirred Nutsch dryer. Steam was generated in a pressure reactor at a jacket temperature of 125-130°C and 1200-1500 mbar, ABS. The high-temperature steam was passed through the Nutsch dryer using heated hoses. The flow rate was controlled by valves. $$ The actual yield was higher, but it was not possible to completely empty the agitated Nutsch dryer. The remaining material was dissolved in water. $$$ Once the required parameters were met, direct drying was performed in a rotary glass dryer in the presence of water. First, the mixture was dried in the dryer at a jacket temperature of 65–68°C | 54–63°C for 2 hours | pump pressure of 20 mbar (equal to approximately 9–13% rH), followed by a jacket temperature of approximately 30°C | pump pressure of 20 mbar for 3 hours (cooling) + 2 hours (holding time), and the mixture was obtained at a final product temperature of 29°C (equal to approximately 50% rH) (Form I and Form II). Due to the technical configuration, the pressure inside the dryer was not measured. $$$$ The reaction was carried out in the same manner as described above, but crystallization was achieved by slowly adding a mixture of ethanol and isopropanol (w / w=4:1) within 2 hours. Therefore, the isolated wet product was washed with a mixture of ethanol and isopropanol (w / w=4:1). Drying in the presence of water vapor was not performed. In addition to ethanol, 0.16 wt% isopropanol was detected. The solid state was not determined. $$$$$ The reaction was carried out in the same manner as described above, but crystallization was achieved by slowly adding a mixture of ethanol and isopropanol (w / w=3:2) within 2 hours. Therefore, the isolated wet product was washed with a mixture of ethanol and isopropanol (w / w=3:2). Drying in the presence of water vapor was not performed. In addition to ethanol, 0.73 wt% isopropanol was detected. The solid state was not determined. #After completely adding ethanol for crystallization, the water content was determined to be approximately 14% by weight by volumetric Karl Fischer titration. Once the required parameters (product temperature in the dryer 45°C | pressure < 40 mbar) were reached, drying was carried out in the presence of steam (approximately 15 kg / h) in a stirred Nutsch dryer at a jacket temperature of 35 mbar until the product temperature reached 64°C (equal to approximately 15% rH), with the entire mixture exposed to steam for approximately 12 hours. The jacket temperature was then reduced to 38°C, and drying continued in the presence of steam for approximately 7 hours until the product temperature reached 45°C at 35 mbar (equal to approximately 35% rH). Throughout this process, steam was applied in a pressure range of approximately 30–45 mbar. At normal frequencies (approximately 20–40 minutes), the steam was turned off to clean the steam filter and reduce the relative humidity over approximately 8 minutes. The actual yield was higher, but it was not possible to completely empty the stirred Nutsch dryer. The remaining material was dissolved in water. ## After completely adding ethanol for crystallization, the water content was determined to be 23 wt% by volumetric Karl Fischer titration. Once the required parameters (product temperature of 45°C | pressure in the dryer < 40 mbar) were reached, drying was carried out in a stirred Nutsch dryer at jacket temperature in the presence of steam (approximately 15 kg / h) for approximately 500 minutes, while being fully exposed to steam, until the product temperature reached 65°C at 45 mbar (equal to approximately 18% rH). The jacket temperature was then lowered to 43°C, and drying continued in the presence of steam for approximately 330 minutes or less until the product temperature reached 50°C at 45 mbar (equal to approximately 37% rH), with steam applied throughout the entire process in a pressure range of approximately 35–55 mbar. At normal frequencies (approximately 20–40 minutes), the steam was turned off to clean the steam filter and reduce the relative humidity over approximately 8 minutes. The actual yield was higher, but it was not possible to completely empty the stirred Nutsch dryer. The remaining substance was dissolved in water. ###Once the required parameters (product temperature of 50°C | pressure in the dryer < 50 mbar) were reached, drying was carried out in a stirred Nutsch dryer at jacket temperature in the presence of steam (approximately 15 kg / h) for approximately 430 minutes, while being fully exposed to steam, until the product temperature reached 65°C at 45 mbar (equal to approximately 18% rH). The jacket temperature was then reduced to 43°C, and drying continued in the presence of steam for approximately 300 minutes or less until the product temperature reached 50°C at 45 mbar (equal to approximately 37% rH), with steam applied throughout the entire process in a pressure range of approximately 40–55 mbar. At normal frequencies (approximately 20–40 minutes), the steam was turned off to clean the steam filter and reduce the relative humidity over approximately 8 minutes. The actual yield was higher, but it was not possible to completely empty the stirred Nutsch dryer. The remaining material was dissolved in water.

[0314] The isomers of the compound of formula (I) can be separated as outlined below to obtain substances for characterization purposes.

[0315] Example 5: Isolation of compound diastereomer 1 (RRSS) of formula (I) Examples 5.1, 5.2, and 5.3 describe the concentration of a substance relative to compound diastereomer 1 of formula (I):

[0316] Example 5.1: The compound of formula (I) (38 g, obtained by crystallization as described above, HPLC purity > 99%, diastereomer 1 = approximately 50%, diastereomer 2 = approximately 48.5%, diastereomer 3 = 1%) was dissolved in water (38 mL). Ethanol (containing approximately 1% methyl ethyl ketone, 38 mL) was added, and the mixture was heated under reflux. Further ethanol (containing approximately 1% methyl ethyl ketone, 342 mL) was added in three portions, and the mixture was refluxed for 4 hours, cooled to room temperature, and stirred for 18 hours. The resulting precipitate was filtered off and washed with ethanol (containing approximately 1% methyl ethyl ketone, 10 mL) to obtain a wet product (50 g). The resulting wet product was dissolved in water (50 mL). Ethanol (containing approximately 1% methyl ethyl ketone, 500 mL) was added, and the mixture was heated under reflux for 2 hours. The resulting suspension was cooled to room temperature, the precipitate was filtered off, and the mixture was washed with ethanol (containing approximately 1% methyl ethyl ketone) to obtain the wet product (47 g).

[0317] The resulting wet product was dissolved in water (50 mL). Ethanol (containing approximately 1% methyl ethyl ketone, 500 mL) was added, and the mixture was heated under reflux for 2 hours. The resulting suspension was cooled to room temperature and stirred for 18 hours. The precipitate was filtered off and washed with ethanol (containing approximately 1% methyl ethyl ketone) to obtain the wet product (42 g).

[0318] HPLC purity (method e, area %): >99% Diastereomer 1 = approximately 54% Diastereomer 2 = approximately 46% Diastereomer 3 = Not detected.

[0319] The resulting wet product was dissolved in water (126 mL). Ethanol (containing approximately 1% methyl ethyl ketone, 230 mL) was added, and the mixture was heated under reflux for 2 hours. Since no crystallization was observed, additional ethanol (containing approximately 1% methyl ethyl ketone, 230 mL) was added, and the mixture was heated under reflux for 2 hours. The resulting suspension was cooled to room temperature and stirred for 18 hours. The precipitate was filtered off and washed with ethanol (containing approximately 1% methyl ethyl ketone) to obtain the wet product (27 g).

[0320] HPLC purity (method e, area %): >99% Diastereomer 1 = approximately 69% Diastereomer 2 = approximately 31% Diastereomer 3 = Not detected.

[0321] The resulting wet product was dissolved in water (126 mL). Ethanol (containing approximately 1% methyl ethyl ketone, 230 mL) was added, and the mixture was heated under reflux for 2 hours. Since no crystallization was observed, additional ethanol (containing approximately 1% methyl ethyl ketone, 230 mL) was added, and the mixture was heated under reflux for 2 hours. The resulting suspension was cooled to room temperature and stirred for 18 hours. The precipitate was filtered off and washed with ethanol (containing approximately 1% methyl ethyl ketone) to obtain a wet product, which was dried under reduced pressure and high temperature to obtain the compound of formula (I) (27 g, HODA 6004-2-9) as a colorless solid.

[0322] HPLC purity (method e, area %): >99% Diastereomer 1 = approximately 82% Diastereomer 2 = approximately 18% Diastereomer 3 = Not detected.

[0323] In Example 5.2, similar to the method described in Example 5.1, the compound of formula (I) (21.3 g obtained by the crystallization described above, HPLC purity > 98%, diastereomer 1 = approximately 49%, diastereomer 2 = approximately 48%, diastereomer 3 = approximately 1%) was repeatedly recrystallized from a mixture of ethanol (containing approximately 1% methyl ethyl ketone) and water to obtain a colorless solid (7.1 g). HPLC purity (method e, area %): >98% Diastereomer 1 = approximately 87% Diastereomer 2 = approximately 11% Diastereomer 3 = Not detected

[0324] In Example 5.3, similar to the method described in Example 5.1, the compound of formula (I) (26 g of the wet product obtained by crystallization as described above, HPLC purity > 99%, diastereomer 1 = approximately 59%, diastereomer 2 = approximately 40%, diastereomer 3 = approximately 1%) was repeatedly recrystallized from a mixture of ethanol (containing approximately 1% methyl ethyl ketone) and water to obtain a colorless solid (18.8 g). HPLC purity (method e, area %): >98% Diastereomer 1 = approximately 77% Diastereomer 2 = approximately 23% Diastereomer 3 = Not detected

[0325] Preparation of the title compound: The three batches described above were combined and dissolved in water (100 mL). Ethanol (containing approximately 1% methyl ethyl ketone, 500 mL) was added, and the mixture was heated under reflux for 4 hours. The mixture was cooled to room temperature and stirred for 1 hour. The suspension was filtered, and the solid was washed with ethanol (containing approximately 1% methyl ethyl ketone, 50 mL). The residue was dried under reduced pressure and high temperature to obtain a mixture of diastereomers of the compound of formula (I) as a colorless solid (41.6 g).

[0326] HPLC purity (method e, area %): >99% Diastereomer 1 = approximately 81% Diastereomer 2 = approximately 19% Diastereomer 3 = Not detected.

[0327] Such a substance (41.5 g) was dissolved in water (120 mL). Ethanol (containing approximately 1% methyl ethyl ketone, 420 mL) was added, and the mixture was heated under reflux for 4 hours. The mixture was cooled to room temperature and stirred for 1 hour. The suspension was filtered, and the solid was washed with ethanol (containing approximately 1% methyl ethyl ketone, 50 mL). The residue was dried under reduced pressure and high temperature to obtain a mixture of compounds of diastereomer formula (I) (36.5 g) as a colorless solid.

[0328] HPLC purity (method e, area %): >99% Diastereomer 1 = approximately 88% Diastereomer 2 = approximately 12% Diastereomer 3 = Not detected.

[0329] 36.5 g of this substance was dissolved in 90 mL of water and filtered. The filter was washed with 18 mL of water. Ethanol (containing approximately 1% methyl ethyl ketone, 360 mL) was added, and the mixture was heated under reflux for 4 hours. The mixture was cooled to room temperature and stirred for 1 hour. The suspension was filtered, and the solid was washed with ethanol (containing approximately 1% methyl ethyl ketone, 50 mL). The residue was dried under reduced pressure and high temperature to obtain the title compound (32.6 g).

[0330] analysis: Prior to analytical characterization, the substance was equilibrated by storing it in a desiccator on a saturated solution of potassium carbonate for at least 48 hours.

[0331] HPLC purity (method d-2, area %): >99.9% HPLC (method d-2): Diastereomer distribution Diastereomer D1: 94.1% Diastereomer D2: 5.9% Diastereomer D3: Not detected Moisture content (method b): 11.2% by weight Residual ethanol: (Method b) Not detected Relaxation R1 [in water]: 10.3 [L / (mmol*sec)] Relaxation R2 [in water]: 11.7 [L / (mmol*sec)] Solubility in water data: ≥593 mg / mL Solid state: Form II

[0332] The stereochemical configuration and molecular structure were further investigated by single-crystal X-ray diffraction. For details, please refer to the Instruments and Methods section and Table 4 / Figure 16.

[0333] Example 6: Isolation of compound diastereomer 2 (RRRS and SSSR) of formula (I) Since diastereomers 2 and 3 of the compound of formula (I) are better soluble in the crystallization medium water and ethanol than diastereomer 1 of the compound of formula (I), several mother liquors from the crystallization experiment performed in the same manner as above in Example 5 were combined and concentrated to dryness under reduced pressure and high temperature to concentrate diastereomer 1 of the compound of formula (I).

[0334] A mixture of isomers of the compound of formula (I) (69.4 g) was dissolved in water (150 mL). Ethanol (containing approximately 1% methyl ethyl ketone, 250 mL) was added, and the mixture was heated under reflux. Further ethanol (containing approximately 1% methyl ethyl ketone, 250 mL) was added. Then, 100 mL of solvent was removed by distillation, and the mixture was stirred under reflux for 2 hours. The mixture was cooled to room temperature and stirred for 1 hour. The suspension was filtered, and the solid was washed with ethanol (containing approximately 1% methyl ethyl ketone, 70 mL). The residue was dried under reduced pressure and high temperature to obtain the compound of formula (I), a mixture of isomers (32.5 g), as a colorless solid.

[0335] HPLC purity (method e, area %): >99% Diastereomer 1 = approximately 25% Diastereomer 2 = approximately 75% Diastereomer 3 = Not detected.

[0336] The mother liquor was concentrated to obtain the residue (36.7 g). HPLC purity (method e, area %): >99% Diastereomer 1 = Not detected Diastereomer 2 = approximately 92% Diastereomer 3 = approximately 8%.

[0337] To this substance (36.7 g), ethanol (containing approximately 1% methyl ethyl ketone, 50 mL) was added, and the mixture was stirred at 60°C for 2 hours to form a white suspension. The mixture was cooled to room temperature and stirred for 1 hour. The suspension was filtered, and the solid was dried under reduced pressure and high temperature to obtain a mixture of isomers of the compound of formula (I) (25.4 g) as a colorless solid.

[0338] HPLC purity (method d-2, area %): 98.7% Diastereomer 1 = 1.9% Diastereomer 2 = 95.3% Diastereomer 3 = 1.6%.

[0339] To reduce the high ethanol content (approximately 5% by weight) of such a substance, it was stored in ambient atmosphere for 24 hours, followed by drying under reduced pressure and high temperature to obtain the title compound (23.8 g).

[0340] analysis: Prior to analytical characterization, the substance was equilibrated by storing it in a desiccator on a saturated solution of potassium carbonate for at least 48 hours.

[0341] HPLC purity (method d-2, area %): 99.4% HPLC (method d-2): Diastereomer distribution Diastereomer D1: 1.9% Diastereomer D2: 96.0% Diastereomer D3: 1.6%. Moisture content (method b): 15.1% by weight Residual ethanol: (Method b) Not detected Relaxation R1 [in water]: 10.3 [L / (mmol*sec)] Relaxation R2 [in water]: 11.9 [L / (mmol*sec)] Solubility in water ≥ 548 mg / mL Solid state: Form II with amorphous content

[0342] Example 6.1 This example was carried out in the same manner as described above, and by repeating the recrystallization and combination of the mother liquor, compound diastereomer 2 of formula (I) was obtained. HPLC purity (method d-1, area %): 99.8% HPLC (method d-1): Diastereomer distribution Diastereomer D1: 4.6% Diastereomer D2: 95.2% Diastereomer D3: 0.05%. Moisture content (method a): 9.3% by weight Residual ethanol: (Method a) 0.2% by weight

[0343] Example 7: Isolation of compound diastereomer 3 (RRRR and SSSS) of formula (I) The mother liquor and washing solution from the crystallization process (conducted on a 2.5 kg scale) were concentrated under reduced pressure to a high-viscosity residue (approximately 2-3 L). The residue was divided into two parts, and ethanol (containing approximately 500 mL of 1% methyl ethyl ketone) was added to each part. The mixture was concentrated under reduced pressure at 60°C to obtain a syrup. Further ethanol (containing approximately 1 L of 1% methyl ethyl ketone) was added, and the mixture was concentrated under reduced pressure to obtain a mixture of crystalline material and amorphous aggregates. The crystalline material from both trials was manually separated (approximately 600 g) and not advanced.

[0344] Some of the remaining amorphous aggregates described above were dissolved in water (25 mL). Ethanol (containing approximately 1% methyl ethyl ketone, 1 L) was added, and the mixture was heated under reflux. Since no crystallization was observed, seed crystal material was added (5 g, wet product, purity (method e) = approximately 99%, diastereomer 1 = approximately 26%, diastereomer 2 = approximately 70%, diastereomer 3 = approximately 3%), and the mixture was heated under reflux for 5 hours, and a total of 250 mL of solvent was removed by distillation. The mixture was slowly cooled to room temperature and stirred for 72 hours. The precipitate was filtered off and washed with ethanol (containing approximately 1% methyl ethyl ketone, 25 mL). The filtrate was concentrated under reduced pressure and high temperature. Acetone (1 L) was added to the obtained residue, and the resulting suspension was stirred at room temperature for 1 hour. The precipitate was filtered off, washed with acetone, and subsequently dried under reduced pressure and high temperature to obtain a colorless solid (207 g).

[0345] HPLC purity (method d-2, area %): 64.4% Diastereomer 1 = 2.1% Diastereomer 2 = 14.8% Diastereomer 3 = 47.5%.

[0346] Such a substance was dissolved in water (500 mL), and an ion exchange resin (211 g, type MB 6113, purchased from Merck KGaA, Germany) was added. The supply container was rinsed with water (250 mL), and the mixture was stirred at room temperature for 3 hours. The resin was filtered off and washed with water. The filtrate was concentrated under reduced pressure. Ethanol (containing approximately 1% methyl ethyl ketone, 250 mL) 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 hour to form a suspension. The mixture was cooled to room temperature. The precipitate was filtered off, washed with acetone, and dried under reduced pressure and high temperature to obtain a solid (71.5 g).

[0347] HPLC purity (method d-2, area %): 76.5% Diastereomer 1 = 2.6%, Diastereomer 2 = 19.4% Diastereomer 3 = 54.5%.

[0348] These substances were further purified by preparative HPLC.

[0349] Instrument: Agilent Series 1260 Infinity, Pump: G1361A, Autosampler: G2260A, Fraction Collector: G1364C, Detector: G1315D; Column: YMC Triart Actus C18, Column Size: 250×30mm, 5μm, Bandwidth: 12nm, Detection: DAD, Wavelength: 210nm; Flow Rate: 36mL / min; Eluent A: 0.1% Formic Acid in Water; Eluent B: 0.1% Formic Acid in Water:Acetonitrile = 9:1; Gradient: Isocratic, 65% A, 35% B.

[0350] 0.2 g of the substance was added to 2 mL of water, and the experiment was performed a total of 140 times.

[0351] The combined product-containing fraction from chromatography was concentrated under reduced pressure and high temperature (bath temperature: 60°C) to obtain a residue, which was then dissolved in water (50 mL) and showed a slightly acidic pH due to formic acid produced from chromatography. Ion exchange resin (16 g, type IRA 67, purchased from Merck KGaA, Germany) was added, and the mixture was stirred for 1 hour to adjust the pH to approximately 7. The resin was filtered off and washed with water. The filtrate was concentrated under reduced pressure and high temperature to obtain a colorless foamy solid (13.1 g).

[0352] analysis: Prior to analytical characterization, the substance was equilibrated by storing it in a desiccator on a saturated solution of potassium carbonate for at least 48 hours.

[0353] HPLC purity (method d-2, area %): 96.2% HPLC (method d-2): Diastereomer distribution: Diastereomer D1: <0.03% Diastereomer D2: 0.4% Diastereomer D3: 99.6%. Moisture content (method b): 17.8% by weight Residual ethanol: (Method b) Not detected Relaxation R1 [in water]: 10.3 [L / (mmol*sec)] Relaxation R2 [in water]: 11.8 [L / (mmol*sec)] Solubility in water ≥ 565 mg / mL Solid state: Amorphous

[0354] The retention time of diastereomer 3 of the compound of formula (I) is consistent with that of one of the samples prepared by selective chemical synthesis as described in European Patent No. 3303307, Examples 3-1 and 3-2.

[0355] The stereochemical configuration and molecular structure were further investigated by single-crystal X-ray diffraction. For details, please refer to the Instruments and Methods section and Table 5 / Figure 17.

[0356] Crystal form Crystalline form of the compound of formula (I)

[0357] [Table 8]

[0358] [Table 9]

[0359] [Table 10A] [Table 10B]

[0360] Crystal form of the diastereomer of the compound of formula (I) As described above, the compounds of formula (I) can exist in different configurations, namely (R,R,R,R) and (S,S,S,S,) (diastereomer 3); (R,S,S,S) and (S,R,R,R) (diastereomer 2); and (S,S,R,R) (meso-form, diastereomer 1), either in their pure form or as mixtures of two or more of these diastereomer configurations.

[0361] The absolute configurations of diastereomers 1 and 3 of the compound of formula (I) were determined by single-crystal diffraction (SCD). For diastereomer 1, the asymmetric region of the unit cell is shown in Figure 16. Crystal data and structural refinement are shown in Table 4. For diastereomer 3, the asymmetric region of the unit cell is shown in Figure 17. Crystal data and structural refinement are shown in Table 5.

[0362] [Table 11]

[0363] [Table 12]

[0364] Crystalline form of the compound of formula (II)

[0365] [Table 13]

[0366] [Table 14]

[0367] [Table 15]

Claims

1. Compounds of general formula (I), 【Chemistry 1】 or a method for isolating a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof, wherein the method is (i) A step of providing a mixture comprising a compound of formula (I), water, and at least a first organic solvent, (ii) The step of removing water from the mixture provided in (i), (iii) The step of adding a second organic solvent, (iv) Depending on the case, the step of adding a third organic solvent, (v) The step of isolating the compound of formula (I) above Methods that include...

2. The method according to claim 1, wherein the second organic solvent in step (iii) is an alcohol selected from the list consisting of ethanol, n-propanol and isopropanol, and 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) is to remove 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 isolation of the compound of formula (I) in step (v) is performed in the following steps: (v-1) The step of providing an aqueous mixture containing the compound of formula (I), (v-2) The step of adding an organic solvent, (v-3) The step of drying the solid obtained in (v-2) and The method according to any one of claims 1 to 5, including the method described in any one of claims 1 to 5.

7. The method according to claim 6, wherein the organic solvent in (v-2) is ethanol, and in (v-3), the solid obtained in (v-2) is dried at a relative humidity of 18% to 70%, preferably 30% to 65%.

8. The method according to claim 6 or 7, wherein in (v-2) the organic solvent is ethanol, and in (v-3) a second drying process is carried out by 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 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 by having a powder X-ray diffraction pattern that, when measured at room temperature using Cu-Kα1 radiation having a wavelength of 0.15419 nm, includes reflections at 2θ angles of (6.8±0.2)°, (9.1±0.2)°, and (11.4±0.2)°, preferably including reflections at 2θ angles of (6.8±0.2)°, (9.1±0.2)°, (10.1±0.2)°, (11.4±0.2)°, and (12.0±0.2)°, and more preferably including reflections at 2θ angles of (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 by having a powder X-ray diffraction pattern that, when measured at room temperature using Cu-Kα1 radiation having a wavelength of 0.15419 nm, includes reflections at 2θ angles of (10.2±0.2)°, (10.8±0.2)°, and (11.3±0.2)°, preferably including reflections at 2θ angles of (7.3±0.2)°, (10.2±0.2)°, (10.8±0.2)°, (11.3±0.2)°, and (13.3±0.2)°, and more preferably including reflections at 2θ angles of (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) described in claim 9, 【Chemistry 2】 The method described above is (i) Providing an aqueous mixture containing the compound of formula (I), (ii) The step of adding an organic solvent, (iii) The step of drying the solid obtained in (ii) above at a relative humidity of 18% to 70%, preferably 30% to 65%. Methods that include...

12. A method for preparing the crystalline form II of the compound of formula (I) described in claim 10, 【Transformation 3】 The method described above is (i) Providing an aqueous mixture containing the compound of formula (I), (ii) The step of adding an organic solvent, (iii) A step of drying the solid obtained in (ii) by a second drying process, in which the solid is first dried at a relative humidity of 0% to 25%, preferably 2% to 18%, more preferably 5% to 16%, and then the relative humidity is adjusted to a final value of 18% to 70%, preferably 25% to 70%, more preferably 30% to 70%. Methods that include...

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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