Microcrystalline forms of (R)-2-(n-[4-amino-5-(4-methoxybenzoyl) thiazol-2-yl]-4-fluoro-anilino) propanamide and processes for their preparation

Abstract

The present invention encompasses a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl) thiazol-2-yl]-4-fluoro-anilino) propanamide (I), and a process for the preparation thereof, as well as a pharmaceutical composition comprising the same. The present invention also encompasses a process for the preparation of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl) thiazol-2-yl]-4-fluoro-anilino) propanamide.

Description

[0001] The present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, methods for its preparation, and pharmaceutical compositions comprising the thereof. Technical Background

[0002] Among the characteristics of crystalline active pharmaceutical ingredients (APIs), polymorphism and particle size are the two most frequently mentioned features. The latter, according to the Noyes-Whitney equation (Noyes AA, Whitney WR. The rate of solution of solid substances in their own solutions. J Am Chem Soc. 1897; 19(12): 930–934), directly determines the dissolution rate (and thus the bioavailability in vivo). To improve the dissolution rate, APIs are often pulverized during their manufacturing process. A widely used method is jet milling (MJ). et al., Chemical Engineering Research and Design 2014, 92(3), 500-508; see http: / / dx.doi.org / 10.1016 / j.cherd.2013.09.011). Unfortunately, the mechanical stress caused by the collision between particles and the cavity wall may cause other fully crystalline input materials to become amorphous on the surface (M). S. Sheokand et al., Chemical Engineering Research and Design 2014, 92(3), 500-508; see http: / / dx.doi.org / 10.1016 / j.cherd.2013.09.011). The degree of amorphization generated during processing is often unpredictable and varies depending on the scale of the equipment. Therefore, even the smallest amount of amorphous material can alter the processing behavior and properties of APIs (S. Sheokand et al., Journal of Pharmaceutical Sciences 2014, 103, 2264-2276; see https: / / doi.org / 10.1002 / jps.24160), thus quantifying the degree of amorphization is crucial. Parameters affected by amorphization include: dissolution rate, apparent solubility, solid-state instability (recrystallization), and the resulting time-varying solubility properties (S. Sheokand et al., Journal of Pharmaceutical Sciences 2014, 103, 2264-2276; see https: / / doi.org / 10.1002 / jps.24160). Quantifying the degree of amorphization remains a significant analytical challenge (S. Sheokand et al., Journal of Pharmaceutical Sciences 2014, 103, 2264-2276; see https: / / doi.org / 10.1002 / jps.24160), and partial amorphization should generally be avoided.

[0003] The suitability of a given particle size distribution range for drug development of a given API depends on various parameters, including but not limited to, the intended route of administration and the solubility characteristics of the respective API (see BY Shekunov et al., Pharmaceutical Research 2007, 24(2), 203). (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide requires pulverized particles to provide good bioavailability via sufficient solubility and dissolution rate after oral administration, which is related to particle surface area and therefore particle size. Considering the specific circumstances of the project, a particle size distribution (PSD) of x10 / x50 / x90:>0.3 / 1-8 / <20 μm was chosen as the target PSD for micronized (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0004] In its research aimed at identifying pharmaceutically useful forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, starting with microcrystalline materials, it was found that the mechanical stress during jet milling micronization led to the formation of solid matter containing, in addition to crystalline particles, a large amount of amorphous material in varying proportions. Since partial amorphization poses a threat to the chemical and physical stability of pharmaceutical substances, potentially altering solubility, dissolution rate, and bioavailability, and because quantifying the degree of amorphization remains a significant analytical challenge (S. Sheokand et al., Journal of Pharmaceutical Sciences 2014, 103, 2264-2276; see https: / / doi.org / 10.1002 / jps.24160), efforts have been made to provide sufficiently small particles with full crystallinity. Despite significant efforts to optimize the jet milling process, it remains impossible to eliminate crystallinity loss when performing the jet milling process to achieve the desired particle size.

[0005] This invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, its preparation method, and pharmaceutical compositions comprising the present invention.

[0006] Existing technology

[0007] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide is a known compound for inhibiting the zeta isomer of diacylglycerol kinase (DGKzeta), which is disclosed as Example 62.2 in International Patent Application PCT / EP2021 / 060167 (published as WO 2021 / 214019).

[0008]

[0009] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazo-2-yl]-4-fluoro-aniline)propionamide

[0010] However, the prior art neither describes a method for crystallizing the compound (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide to obtain crystal particles of this size, which is advantageous for preparing solid pharmaceutical compositions that can then be used as pharmaceutical products, nor discloses the microcrystalline form of the compound or pharmaceutical compositions containing it.

[0011] It has now been discovered and forms the basis of the present invention that the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide of the present invention mentioned above, its preparation method, and pharmaceutical compositions comprising the thereof have surprising and beneficial properties.

[0012] The microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide of the present invention is characterized by the absence of amorphous material within the accurate range of the analytical method used, with a particle size distribution within the desired range, and exhibits significantly improved solubility properties compared with microcrystalline materials of the same compound.

[0013] Their preparation methods are robust and efficient, and provide materials with excellent chemical and enantiomeric purity. Furthermore, the methods eliminate the risk of racemization during the alkylation of the intermediate [4-amino-2-(4-fluoroaniline)-1,3-thiazolyl](4-methoxyphenyl) methyl ketone using (S)-2-bromopropionamide. Those skilled in the art know that these alkylations include the risk of racemization at the α-position of the carbonyl group, which serves as the alkylation site (see, for example, PSDragovich et al., J. Med. Chem. 2003, 46, 4572; L. Chen et al., Organic Process Research & Development 2006, 10(4), 838). As disclosed in WO 2021 / 214019, the synthesis of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide is achieved by synthesizing rac-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, followed by enantiomeric separation using preparative chiral HPLC. For drug development purposes, this enantiomeric separation is disadvantageous because it incurs costs and significantly prolongs processing time. Summary of the Invention

[0014] According to a first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide,

[0015]

[0016] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazo-2-yl]-4-fluoro-aniline)propionamide

[0017] in,

[0018] The amorphous form that exists is less than 15%.

[0019] The particle size distribution is as follows: x10 is <5μm, x50 is <10μm, and x90 is <35μm.

[0020] definition

[0021] Enantiomer excess is usually abbreviated as ee and is expressed as a percentage (%). It is derived from the proportion of (R)- and (S)-enantiomers in a given mixture of the two enantiomers and is calculated as ee = [(R)-(S) / (R)+(S)] x 100. This makes the racemic mixture 0% ee and the pure enantiomer 100% ee.

[0022] As used in this article, the term "leaving group" refers to an atom or group of atoms that is replaced by a stable species with bonding electrons in a chemical reaction. Specifically, the leaving group is selected from: halogen atoms, particularly fluorine, chlorine, bromine, or iodine atoms, which are replaced by halides, particularly fluorides, chlorides, bromides, or iodides; (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropylphenyl)sulfonyl]oxy, [(2,4,6-trimethylphenyl)sulfonyl]oxy, [(4-tert-butylphenyl)sulfonyl]oxy, and [(4-methoxyphenyl)sulfonyl]oxy.

[0023] As used herein, “microcrystal” refers to a fully crystalline solid form characterized by a particle size distribution in the range of x10 / x50 / x90: <5 / <10 / <35 μm, or <3 / 10-15 / <35 μm, or smaller, such as x10 / x50 / x90: <5 / <10 / <20 μm, particularly in the range of x10 / x50 / x90: 0.3-4 / 4-10 / 10-20 μm, 0.5-2.5 / 3-7 / 8-20 μm, 1-4 / 4-8 / 12-18 μm, 1-2 / 4-5.5 / 10-18 μm, or >0.3 / 1-8 / <20 μm.

[0024] As used herein, “microcrystals” refers to a fully crystalline solid form characterized by a particle size distribution ranging from x10 / x50 / x90: 3 / 10-15 / 35 μm or larger.

[0025] The term “C1-C3-alkyl” refers to a straight-chain or branched, saturated, monovalent hydrocarbon group having 1, 2, or 3 carbon atoms, such as methyl, ethyl, propyl, or isopropyl.

[0026] According to a second embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide.

[0027]

[0028] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazo-2-yl]-4-fluoro-aniline)propionamide

[0029] in

[0030] The number of amorphous forms present is less than 15%.

[0031] The particle size distributions are as follows: x10 is in the range of 0.3 to 4 μm, x50 is in the range of 4 to 10 μm, and x90 is in the range of 10 to 20 μm.

[0032] According to a third embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0033] The number of amorphous forms present is less than 15%.

[0034] The particle size distributions are as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

[0035] According to a fourth embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0036] The number of amorphous forms present is less than 15%.

[0037] The particle size distributions are as follows: x10 is in the range of 0.5 to 2.5 μm, x50 is in the range of 3 to 7 μm, and x90 is in the range of 8 to 20 μm.

[0038] According to a fifth embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide.

[0039] in

[0040] The number of amorphous forms that exist is less than 10%.

[0041] The particle size distributions are as follows: x10 is in the range of 0.5 to 2.5 μm, x50 is in the range of 3 to 7 μm, and x90 is in the range of 8 to 20 μm.

[0042] According to a sixth embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide,

[0043] in

[0044] The number of amorphous forms that exist is less than 10%.

[0045] The particle size distributions are as follows: x10 is in the range of 0.3 to 4 μm, x50 is in the range of 4 to 10 μm, and x90 is in the range of 10 to 20 μm.

[0046] According to a seventh embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide.

[0047] in

[0048] The number of amorphous forms that exist is less than 10%.

[0049] The particle size distributions are as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

[0050] According to an eighth embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0051] The enantiomeric excess is at least 95%.

[0052] The number of amorphous forms that exist is less than 10%.

[0053] The particle size distributions are as follows: x10 is in the range of 0.5 to 2.5 μm, x50 is in the range of 3 to 7 μm, and x90 is in the range of 8 to 20 μm.

[0054] According to a ninth embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0055] The enantiomeric excess is at least 95%.

[0056] The number of amorphous forms that exist is less than 10%.

[0057] The particle size distributions are as follows: x10 is in the range of 0.3 to 4 μm, x50 is in the range of 4 to 10 μm, and x90 is in the range of 10 to 20 μm.

[0058] According to a tenth embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0059] The enantiomeric excess is at least 95%.

[0060] The number of amorphous forms that exist is less than 10%.

[0061] The particle size distributions are as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

[0062] According to the eleventh embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0063] The number of amorphous forms present is less than 5%.

[0064] The particle size distributions are as follows: x10 is in the range of 0.5 to 2.5 μm, x50 is in the range of 3 to 7 μm, and x90 is in the range of 8 to 20 μm.

[0065] According to a twelfth embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0066] The number of amorphous forms present is less than 5%.

[0067] The particle size distributions are as follows: x10 is in the range of 0.3 to 4 μm, x50 is in the range of 4 to 10 μm, and x90 is in the range of 10 to 20 μm.

[0068] According to a thirteenth embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0069] The number of amorphous forms present is less than 5%.

[0070] The particle size distributions are as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

[0071] According to the fourteenth embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0072] The enantiomeric excess is at least 98%.

[0073] The number of amorphous forms present is less than 5%.

[0074] The particle size distributions are as follows: x10 is in the range of 0.5 to 2.5 μm, x50 is in the range of 3 to 7 μm, and x90 is in the range of 8 to 20 μm.

[0075] According to a fifteenth embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0076] The enantiomeric excess is at least 98%.

[0077] The number of amorphous forms present is less than 5%.

[0078] The particle size distributions are as follows: x10 is in the range of 0.3 to 4 μm, x50 is in the range of 4 to 10 μm, and x90 is in the range of 10 to 20 μm.

[0079] According to a sixteenth embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0080] The enantiomeric excess is at least 98%.

[0081] The number of amorphous forms present is less than 5%.

[0082] The particle size distributions are as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

[0083] According to the seventeenth embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0084] The enantiomeric excess is at least 99%.

[0085] The number of amorphous forms present is less than 5%.

[0086] The particle size distributions are as follows: x10 is in the range of 1 to 2 μm, x50 is in the range of 4 to 5.5 μm, and x90 is in the range of 10 to 18 μm.

[0087] According to the eighteenth embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0088] The enantiomeric excess is at least 99%.

[0089] The number of amorphous forms present is less than 5%.

[0090] The particle size distributions are as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

[0091] According to the nineteenth embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0092] The proportion of amorphous forms is less than 2.5%.

[0093] The particle size distributions are as follows: x10 is in the range of 0.5 to 2.5 μm, x50 is in the range of 3 to 7 μm, and x90 is in the range of 8 to 20 μm.

[0094] According to a twentieth embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0095] The proportion of amorphous forms is less than 2.5%.

[0096] The particle size distributions are as follows: x10 is in the range of 0.3 to 4 μm, x50 is in the range of 4 to 10 μm, and x90 is in the range of 10 to 20 μm.

[0097] According to a twenty-first embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0098] The proportion of amorphous forms is less than 2.5%.

[0099] The particle size distributions are as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

[0100] According to a twenty-second embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0101] The existing amorphous forms are below the detection limit of differential scanning calorimetry;

[0102] The particle size distributions are as follows: x10 is in the range of 1 to 2 μm, x50 is in the range of 4 to 5.5 μm, and x90 is in the range of 10 to 18 μm.

[0103] According to the twenty-third embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0104] The existing amorphous forms are below the detection limit of differential scanning calorimetry;

[0105] The particle size distributions are as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

[0106] According to the twenty-fourth embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0107] The existing amorphous forms are smaller than the detection limit of XRPD.

[0108] The particle size distributions are as follows: x10 is in the range of 1 to 2 μm, x50 is in the range of 4 to 5.5 μm, and x90 is in the range of 10 to 18 μm.

[0109] According to the twenty-fifth embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0110] The existing amorphous forms are smaller than the detection limit of XRPD.

[0111] The particle size distribution is as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

[0112] According to the twenty-sixth embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0113] According to the DSC1 method, the existing amorphous forms are smaller than the detection limit of differential scanning calorimetry;

[0114] Furthermore, the particle size distribution, as determined by the PSD2a method, is as follows: x10 is in the range of 1 to 2 μm, x50 is in the range of 4 to 5.5 μm, and x90 is in the range of 10 to 18 μm.

[0115] According to the twenty-seventh embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0116] According to the DSC1 method, the existing amorphous forms are smaller than the detection limit of differential scanning calorimetry;

[0117] Furthermore, according to the PSD4 method, its particle size distribution is as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

[0118] According to the twenty-eighth embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0119] According to the XRPD1 method, the existing amorphous forms are smaller than the detection limit of XRPD.

[0120] Furthermore, the particle size distribution, as determined by the PSD2a method, is as follows: x10 is in the range of 1 to 2 μm, x50 is in the range of 4 to 5.5 μm, and x90 is in the range of 10 to 18 μm.

[0121] According to the twenty-ninth embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0122] According to the XRPD1 method, the existing amorphous forms are smaller than the detection limit of XRPD.

[0123] Furthermore, according to the PSD4 method, its particle size distribution is as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

[0124] Further embodiments of the first aspect of the present invention

[0125] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0126] The enantiomeric excess is at least 95%.

[0127] The amorphous forms that exist account for less than 10%.

[0128] Furthermore, the particle size distribution, as determined by the PSD2a method, is as follows: x10 is in the range of 0.5 to 2.5 μm, x50 is in the range of 3 to 7 μm, and x90 is in the range of 8 to 20 μm.

[0129] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0130] The enantiomeric excess is at least 95%.

[0131] The number of amorphous forms that exist is less than 10%.

[0132] Furthermore, the particle size distribution, as determined by the PSD4 method, is as follows: x10 is in the range of 0.3 to 4 μm, x50 is in the range of 4 to 10 μm, and x90 is in the range of 10 to 20 μm.

[0133] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0134] The enantiomeric excess is at least 95%.

[0135] The number of amorphous forms that exist is less than 10%.

[0136] Furthermore, according to the PSD4 method, its particle size distribution is as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

[0137] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0138] The number of amorphous forms that exist is less than 5%.

[0139] Furthermore, the particle size distribution, as determined by the PSD2a method, is as follows: x10 is in the range of 0.5 to 2.5 μm, x50 is in the range of 3 to 7 μm, and x90 is in the range of 8 to 20 μm.

[0140] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0141] The number of amorphous forms that exist is less than 5%.

[0142] Furthermore, the particle size distribution, as determined by the PSD4 method, is as follows: x10 is in the range of 0.3 to 4 μm, x50 is in the range of 4 to 10 μm, and x90 is in the range of 10 to 20 μm.

[0143] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0144] The number of amorphous forms that exist is less than 5%.

[0145] Furthermore, according to the PSD4 method, its particle size distribution is as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

[0146] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0147] The enantiomeric excess is at least 98%.

[0148] The number of amorphous forms that exist is less than 5%.

[0149] Furthermore, the particle size distribution, as determined by the PSD2a method, is as follows: x10 is in the range of 0.5 to 2.5 μm, x50 is in the range of 3 to 7 μm, and x90 is in the range of 8 to 20 μm.

[0150] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0151] The enantiomeric excess is at least 98%.

[0152] The number of amorphous forms that exist is less than 5%.

[0153] Furthermore, the particle size distribution, as determined by the PSD4 method, is as follows: x10 is in the range of 0.3 to 4 μm, x50 is in the range of 4 to 10 μm, and x90 is in the range of 10 to 20 μm.

[0154] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0155] The enantiomeric excess is at least 98%.

[0156] The number of amorphous forms that exist is less than 5%.

[0157] Furthermore, according to the PSD4 method, its particle size distribution is as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

[0158] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0159] The enantiomeric excess is at least 99%.

[0160] The number of amorphous forms that exist is less than 5%.

[0161] Furthermore, the particle size distribution, as determined by the PSD2a method, is as follows: x10 is in the range of 1 to 2 μm, x50 is in the range of 4 to 5.5 μm, and x90 is in the range of 10 to 18 μm.

[0162] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0163] The enantiomeric excess is at least 99%.

[0164] The number of amorphous forms that exist is less than 5%.

[0165] Furthermore, according to the PSD4 method, its particle size distribution is as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

[0166] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0167] The proportion of amorphous forms is less than 2.5%.

[0168] Furthermore, the particle size distribution, as determined by the PSD2a method, is as follows: x10 is in the range of 0.5 to 2.5 μm, x50 is in the range of 3 to 7 μm, and x90 is in the range of 8 to 20 μm.

[0169] According to another embodiment of the first aspect, the present invention covers (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0170] The proportion of amorphous forms is less than 2.5%.

[0171] Furthermore, the particle size distribution, as determined by the PSD4 method, is as follows: x10 is in the range of 0.3 to 4 μm, x50 is in the range of 4 to 10 μm, and x90 is in the range of 10 to 20 μm.

[0172] According to another embodiment of the first aspect, the present invention covers (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0173] The proportion of amorphous forms is less than 2.5%.

[0174] Furthermore, according to the PSD4 method, its particle size distribution is as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

[0175] According to another embodiment of the first aspect, the present invention covers (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0176] The particle size distribution, as determined by the PSD2a method, is as follows: x10 is in the range of 1 to 2 μm.

[0177] According to another embodiment of the first aspect, the present invention covers (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0178] The particle size distribution, as determined by the PSD2a method, is as follows: x50 ranges from 4 to 5.5 μm.

[0179] According to another embodiment of the first aspect, the present invention covers (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0180] The particle size distribution, as determined by the PSD4 method, is as follows: x50 is in the range of 4 to 8 μm.

[0181] According to another embodiment of the first aspect, the present invention covers (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0182] The particle size distribution, as determined by the PSD2a method, is as follows: x90 is in the range of 10 to 18 μm.

[0183] According to another embodiment of the first aspect, the present invention covers (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0184] The particle size distribution, as determined by the PSD4 method, is as follows: x90 is in the range of 12 to 18 μm.

[0185] According to another embodiment of the first aspect, the present invention covers (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0186] The particle size distribution, as determined by the PSD2a method, is as follows: x10 is in the range of 1 to 2 μm, x50 is in the range of 4 to 5.5 μm, and x90 is in the range of 10 to 18 μm.

[0187] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0188] The particle size distribution, as determined by the PSD4 method, is as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

[0189] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0190] The number of amorphous forms that exist is less than 15%.

[0191] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0192] The number of amorphous forms that exist is less than 10%.

[0193] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0194] The number of amorphous forms that exist is less than 5%.

[0195] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0196] The proportion of amorphous forms is less than 2.5%.

[0197] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0198] The existing amorphous forms are below the detection limit of differential scanning calorimetry.

[0199] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0200] The existing amorphous forms are smaller than the detection limit of XRPD.

[0201] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0202] According to the DSC1 method, the existing amorphous forms are below the detection limit of differential scanning calorimetry.

[0203] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0204] According to the XRPD1 method, the existing amorphous forms are smaller than the detection limit of XRPD.

[0205] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0206] The enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide is at least 99%.

[0207] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0208] The enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide is at least 98%.

[0209] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0210] The enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide is at least 9%.

[0211] According to another embodiment of the first aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[0212] The enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide is at least 90%.

[0213] In a further specific embodiment of the first aspect, the invention covers a combination of two or more embodiments referred to under the title “Further Embodiments of the First Aspect of the Invention”.

[0214] This invention covers any sub-combination within the scope of any embodiment or aspect of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide of the invention, its preparation method, and pharmaceutical compositions comprising it.

[0215] This invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, as described in the experimental section herein.

[0216] According to a second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-anilino)propionamide in microcrystalline form, said method comprising the following steps:

[0217] i. React the intermediate compound of formula (II) with the intermediate compound of formula (III), wherein LG is the leaving group as defined above.

[0218]

[0219] This provides (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide,

[0220]

[0221] ii. Dissolve the crude product obtained in step i in a solvent or a mixture of solvents.

[0222] iii. Mix the solution obtained in step ii with the antisolvent, and

[0223] iv. Separate and dry the resulting precipitate.

[0224] To provide (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form.

[0225] According to a second embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-anilino)propionamide in microcrystalline form, the method comprising the following steps:

[0226] i. React the intermediate compound of formula (II) with the intermediate compound of formula (III), wherein LG is the leaving group as defined above.

[0227]

[0228] This provides (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide,

[0229]

[0230] ii. Dissolve the crude product obtained in step i in acetone containing 0% to 30% (v / v) water.

[0231] iii. Mix the solution obtained in step ii with water, and

[0232] iv. Separate and dry the resulting precipitate.

[0233] To provide (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form.

[0234] According to a third embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-anilino)propionamide in microcrystalline form, said method comprising the following steps:

[0235] i. React the intermediate compound of formula (II) with the intermediate compound of formula (III), wherein LG is the leaving group as defined above.

[0236]

[0237] This provides (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide,

[0238]

[0239] ii. Dissolve the crude product obtained in step i in a dipole aprotic and / or protic solvent, followed optionally by filtration.

[0240] iii. Add the solution or filtrate obtained in step ii to the antisolvent, and

[0241] iv. Separate and dry the resulting precipitate.

[0242] To provide (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form.

[0243] According to a fourth embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, said method comprising the following steps:

[0244] iii. Add a solution (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in a dipolar aprotic solvent and / or a protic solvent (optionally filtered) to the antisolvent, and

[0245] iv. Separate and dry the resulting precipitate.

[0246] To provide (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form.

[0247] According to a fifth embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, said method comprising the following steps:

[0248] i. React the intermediate compound of formula (II) with the intermediate compound of formula (III), wherein LG is the leaving group as defined above.

[0249]

[0250] This provides (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide,

[0251]

[0252] The reaction is carried out in a solvent at a temperature of 20 to 80°C in the presence of at least 1 equivalent of a base for a reaction time of 30 minutes to 24 hours. The base is selected from alkali metal carbonates, alkali metal bicarbonates, and alkali metal phosphates. The solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidone, acetone, and isopropanol.

[0253] ii. Dissolve the crude product obtained in step i in a mixture of acetone and water, primarily acetone, at a ratio of 8:1 (v / v) to 12:1 (v / v), and then filter.

[0254] iii. Add the filtrate to water at a temperature of 0°C to 20°C for 20 minutes to 1.5 hours.

[0255] iv. Separate and dry the resulting precipitate.

[0256] To provide (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form.

[0257] According to a sixth embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-anilino)propionamide in microcrystalline form, said method comprising the following steps:

[0258] i. React the intermediate compound of formula (II) with the intermediate compound of formula (III), wherein LG is a bromine atom.

[0259]

[0260] This provides (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide,

[0261]

[0262] The reaction is carried out in acetonitrile in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature of 50 to 70 °C for 1 to 2 hours.

[0263] ii. Dissolve the crude product obtained in step i in a mixture of acetone and water, primarily acetone, at a ratio of 8:1 (v / v) to 12:1 (v / v), and then filter.

[0264] iii. Add the filtrate to water at a temperature of 4°C to 10°C for 30 minutes to 1 hour.

[0265] iv. Separate and dry the resulting precipitate.

[0266] To provide (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form.

[0267] According to a seventh embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-anilinoyl)propionamide in microcrystalline form, said method comprising the following steps:

[0268] i. React the intermediate compound of formula (II) with the intermediate compound of formula (III), wherein LG is a bromine atom.

[0269]

[0270] This provides (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide,

[0271]

[0272] The reaction is carried out in acetonitrile in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature of 50 to 70 °C for 1 to 2 hours, and then optionally the temperature is lowered to 20 °C for up to 1 hour.

[0273] ii. Dissolve the crude product obtained in step i in a mixture of acetone and water, primarily acetone, at a ratio of 8:1 (v / v) to 12:1 (v / v), and then filter.

[0274] iii. Add the filtrate to water at a temperature of 4°C to 10°C for 30 minutes to 1 hour.

[0275] iv. Separate and dry the resulting precipitate.

[0276] To provide (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form.

[0277] According to an eighth embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-anilinoyl)propionamide in microcrystalline form, said method comprising the following steps:

[0278] iii. At a temperature of 4°C to 10°C, a solution of filtered (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in a mixture of acetone and water in a ratio of 8:1 (v / v) to 12:1 (v / v) is added to water over a period of 30 minutes to 1 hour.

[0279] iv. Separate and dry the resulting precipitate.

[0280] To provide (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form.

[0281] Further embodiments of the second aspect of the present invention

[0282] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0283] Its particle size distribution is as follows: x10 is in the range of 1 to 2 μm.

[0284] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0285] Its particle size distribution is as follows: x50 is in the range of 4 to 5.5 μm.

[0286] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0287] Its particle size distribution is as follows: x50 is in the range of 4 to 8 μm.

[0288] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0289] Its particle size distribution is as follows: x90 is in the range of 10 to 18 μm.

[0290] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0291] The particle size distribution is as follows: x10 is in the range of 1 to 2 μm, x50 is in the range of 4 to 5.5 μm, and x90 is in the range of 10 to 18 μm.

[0292] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0293] The particle size distribution is as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

[0294] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0295] The particle size distribution, as determined by the PSD2a method, is as follows: x10 is in the range of 1 to 2 μm.

[0296] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0297] The particle size distribution, as determined by the PSD2a method, is as follows: x50 ranges from 4 to 5.5 μm.

[0298] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0299] The particle size distribution, as determined by the PSD4 method, is as follows: x50 is in the range of 4 to 8 μm.

[0300] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0301] The particle size distribution, as determined by the PSD2a method, is as follows: x90 is in the range of 10 to 18 μm.

[0302] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0303] The particle size distribution, as determined by the PSD4 method, is as follows: x90 is in the range of 12 to 18 μm.

[0304] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0305] The particle size distribution, as determined by the PSD2a method, is as follows: x10 is in the range of 1 to 2 μm, x50 is in the range of 4 to 5.5 μm, and x90 is in the range of 10 to 18 μm.

[0306] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0307] The particle size distribution, as determined by the PSD4 method, is as follows: x10 is in the range of 0.3 to 4 μm, x50 is in the range of 4 to 10 μm, and x90 is in the range of 10 to 20 μm.

[0308] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0309] The particle size distribution, as determined by the PSD4 method, is as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

[0310] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0311] The number of amorphous forms that exist is less than 15%.

[0312] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0313] The number of amorphous forms that exist is less than 10%.

[0314] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0315] The number of amorphous forms that exist is less than 5%.

[0316] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0317] The proportion of amorphous forms is less than 2.5%.

[0318] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0319] The existing amorphous forms are below the detection limit of differential scanning calorimetry.

[0320] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0321] The existing amorphous forms are smaller than the detection limit of XRPD.

[0322] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0323] According to the DSC1 method, the existing amorphous forms are below the detection limit of differential scanning calorimetry.

[0324] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0325] According to the XRPD1 method, the existing amorphous forms are smaller than the detection limit of XRPD.

[0326] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0327] The enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide is at least 99%.

[0328] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0329] The enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide is at least 98%.

[0330] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0331] The enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide is at least 95%.

[0332] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0333] The enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide is at least 90%.

[0334] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0335] In step i., the leaving group LG is a chlorine atom, a bromine atom, or an iodine atom, or a group selected from the following: (methylsulfonyl)oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, and [(4-methoxyphenyl)sulfonyl]oxy.

[0336] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0337] In step i., the leaving group LG is a chlorine atom, a bromine atom, or an iodine atom, or a group selected from the following: (methylsulfonyl)oxy, (phenylsulfonyl)oxy, and [(4-methylphenyl)sulfonyl]oxy.

[0338] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0339] In step i., the leaving group LG is a chlorine atom.

[0340] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0341] In step i., the leaving group LG is [(4-methylphenyl)sulfonyl]oxy.

[0342] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0343] In step i., the leaving group LG is a bromine atom or [(4-methylphenyl)sulfonyl]oxy.

[0344] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0345] In step i., the leaving group LG is a bromine atom.

[0346] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0347] Step i. is carried out in the presence of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates and N,N,N,N-tetratetra(C1-C3-alkyl)guanidine.

[0348] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0349] Step i. is carried out in the presence of a base selected from alkali metal carbonates, alkali metal bicarbonates, and alkali metal phosphates.

[0350] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0351] Step i. is carried out in the presence of at least 1 equivalent of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, and N,N,N,N-tetra(C1-C3-alkyl)guanidine.

[0352] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0353] Step i. is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, and N,N,N,N-tetratetra(C1-C3-alkyl)guanidine.

[0354] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0355] Step i. is carried out in the presence of 1.5 to 6 equivalents of an alkali, wherein the alkali is selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal phosphates.

[0356] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0357] Step i. is carried out in the presence of 1.5 to 6 equivalents of an alkali, wherein the alkali is selected from alkali metal carbonates, alkali metal bicarbonates and alkali metal phosphates, wherein the alkali metal carbonate is selected from sodium carbonate, potassium carbonate and cesium carbonate, wherein the alkali metal bicarbonate is selected from sodium bicarbonate, potassium bicarbonate and cesium bicarbonate, and wherein the alkali metal phosphate is selected from sodium phosphate, potassium phosphate and cesium phosphate.

[0358] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0359] Step i. is carried out in the presence of an alkali selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate, and potassium phosphate.

[0360] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0361] Step i. is carried out in the presence of 1.5 to 6 equivalents of a base, wherein the base is selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate and potassium phosphate.

[0362] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0363] Step i. is carried out in the presence of an alkali selected from potassium carbonate and potassium phosphate.

[0364] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0365] Step i. is carried out in the presence of 1.5 to 6 equivalents of an alkali selected from potassium carbonate and potassium phosphate.

[0366] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0367] Step i. is carried out in the presence of 1.5 to 3 equivalents of potassium phosphate.

[0368] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0369] Step i. is carried out in the presence of 2 to 6 equivalents of potassium carbonate.

[0370] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0371] Step i. Performed at a temperature between 0°C and 100°C.

[0372] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0373] Step i. Performed at a temperature between 20°C and 90°C.

[0374] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0375] Step i. is carried out at a temperature of 40°C to 80°C.

[0376] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0377] Step i. Performed at a temperature of 50°C to 70°C.

[0378] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0379] Step i. Perform at a temperature of 40°C to 80°C, and then optionally lower the temperature to 20°C for up to 1 hour.

[0380] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0381] Step i. Perform at a temperature of 50°C to 70°C, and then optionally lower the temperature to 20°C for up to 1 hour.

[0382] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0383] Step i. Perform at a temperature of 40°C to 80°C, and then allow the temperature to drop to 20°C over a period of no more than 1 hour.

[0384] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0385] Step i. Perform at a temperature of 50°C to 70°C, and then allow the temperature to drop to 20°C over a period of no more than 1 hour.

[0386] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0387] Step i. is carried out in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidone, acetone and isopropanol, or a mixture of acetone and isopropanol.

[0388] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0389] Step i. is carried out in a solvent selected from N,N-dimethylformamide, acetonitrile, N-methylpyrrolidone, acetone and isopropanol, or a mixture of acetone and isopropanol in a ratio of 5:1 (v / v) to 1:5 (v / v).

[0390] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0391] Step i. is carried out in a solvent selected from N,N-dimethylformamide and acetonitrile.

[0392] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0393] Step i. is carried out in N,N-dimethylformamide as a solvent.

[0394] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0395] Step i. is carried out in acetonitrile as a solvent.

[0396] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0397] Step i. is performed within 30 minutes to 24 hours.

[0398] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0399] Step i. is performed within 30 minutes to 6 hours.

[0400] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0401] Step i. Take place within 30 minutes to 2 hours.

[0402] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0403] Step i. is to be performed within 1 to 2 hours.

[0404] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0405] Step ii. is carried out in one or more dipole aprotic and / or polar solvents, optionally mixed with water.

[0406] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0407] Step ii. is carried out in one or more solvents selected from dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, optionally mixed with water.

[0408] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0409] Step ii. is carried out in one or more solvents selected from 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, optionally mixed with water.

[0410] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0411] Step ii. is carried out in one or more solvents selected from isopropanol, tetrahydrofuran, acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, optionally mixed with water.

[0412] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0413] Step ii. is carried out in one or more solvents selected from acetonitrile, diethyl ketone, methyl ethyl ketone, acetone and 1,4-dioxane, optionally mixed with water.

[0414] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0415] Step ii. is carried out in one or more solvents selected from acetonitrile, acetone and 1,4-dioxane, optionally mixed with water.

[0416] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0417] Step ii. is carried out in a mixture of acetone and water.

[0418] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0419] Step ii. is carried out in a mixture of acetone and water, with acetone as the main component, in a ratio of 5:1 (v / v) to 20:1 (v / v).

[0420] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0421] Step ii. is carried out in a mixture of acetone and water, with acetone as the main component, in a ratio of 6:1 (v / v) to 15:1 (v / v).

[0422] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0423] Step ii. is carried out in a mixture of acetone and water, with acetone as the main component, in a ratio of 6:1 (v / v) to 12:1 (v / v).

[0424] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0425] Step ii. is carried out in a mixture of acetone and water, with acetone as the main component, in a ratio of 8:1 (v / v) to 12:1 (v / v).

[0426] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0427] Step ii. is carried out in a mixture of acetone and water, with acetone as the main component, in a ratio of 8:1 (v / v) to 10:1 (v / v).

[0428] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0429] The ratio of the solvent used in step ii. to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide is in the range of 6:1 to 20:1 (w / w; solvent: compound).

[0430] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0431] The ratio of the solvent used in step ii. to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide is in the range of 8:1 to 15:1 (w / w; solvent: compound).

[0432] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0433] The ratio of the solvent to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide used in step ii. is in the range of 10:1 to 14:1 (w / w; solvent: compound), with the solvent being dominant.

[0434] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0435] The ratio of the solvent to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide used in step ii. is in the range of 11:1 to 12:1 (w / w; solvent: compound), with the solvent being dominant.

[0436] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0437] The mixture of acetone and water used in step ii. is in the range of 8:1 (w / w) to 15:1 (w / w) with the mixture of acetone and water as the main component.

[0438] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0439] The mixture of acetone and water used in step ii. is in the range of 10:1 (w / w) to 14:1 (w / w) with the mixture of acetone and water as the main component.

[0440] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0441] The mixture of acetone and water used in step ii. is in the range of 11:1 (w / w) to 12:1 (w / w) with the mixture of acetone and water as the main component.

[0442] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0443] The solvent in step iii. is a dipole aprotic and / or polar solvent, optionally mixed with water.

[0444] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0445] The solvent in step iii is one or more solvents selected from dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, optionally mixed with water.

[0446] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0447] The solvent in step iii is one or more solvents selected from 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, optionally mixed with water.

[0448] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0449] The solvent in step iii is one or more solvents selected from isopropanol, tetrahydrofuran, acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, 1,4-dioxane and 2-methyltetrahydrofuran, optionally mixed with water.

[0450] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0451] The solvent in step iii is one or more solvents selected from acetonitrile, diethyl ketone, methyl ethyl ketone, acetone and 1,4-dioxane, optionally mixed with water.

[0452] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0453] The solvent in step iii is one or more solvents selected from acetonitrile, acetone and 1,4-dioxane, optionally mixed with water.

[0454] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0455] The solvent in step iii is a mixture of acetone and water.

[0456] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0457] The solvent in step iii is a mixture of acetone and water, with acetone as the main component, in a ratio of 5:1 (v / v) to 20:1 (v / v).

[0458] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0459] The solvent in step iii is a mixture of acetone and water, with acetone as the main component, in a ratio of 6:1 (v / v) to 15:1 (v / v).

[0460] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0461] The solvent in step iii is a mixture of acetone and water, with acetone as the main component, in a ratio of 6:1 (v / v) to 12:1 (v / v).

[0462] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0463] The solvent in step iii is a mixture of acetone and water, with acetone as the main component, in a ratio of 8:1 (v / v) to 12:1 (v / v).

[0464] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0465] The solvent in step iii is a mixture of acetone and water, with acetone as the main component, in a ratio of 8:1 (v / v) to 10:1 (v / v).

[0466] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0467] In step iii, the ratio of solvent to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in the solution is in the range of 6:1 to 20:1 (w / w; solvent: compound).

[0468] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0469] In step iii, the ratio of solvent to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in the solution is in the range of 8:1 to 15:1 (w / w; solvent: compound).

[0470] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0471] In the solution used in step iii, the ratio of solvent to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide is in the range of 10:1 (w / w) to 14:1 (w / w), with the solvent being dominant.

[0472] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0473] In the solution used in step iii, the ratio of solvent to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide is in the range of 11:1 (w / w) to 12:1 (w / w), with the solvent being dominant.

[0474] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0475] In the solution used in step iii, the ratio of the acetone and water mixture to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide is in the range of 8:1 (w / w) to 15:1 (w / w), with the acetone and water mixture being the predominant component.

[0476] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0477] In the solution used in step iii, the ratio of the acetone and water mixture to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide is in the range of 10:1 (w / w) to 14:1 (w / w), with the acetone and water mixture being the predominant component.

[0478] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0479] In the solution used in step iii, the ratio of the acetone and water mixture to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide is in the range of 11:1 (w / w) to 12:1 (w / w), with the acetone and water mixture being the predominant component.

[0480] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0481] In step iii, the antisolvent is water, or a mixture of water and one or more organic solvents selected from methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, acetone, 1,4-dioxane, or 2-methyltetrahydrofuran.

[0482] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0483] In step iii., the antisolvent is hexane, cyclohexane, n-heptane, ethyl acetate, or a mixture thereof with one or more solvents selected from the group consisting of ethyl acetate, isopropyl acetate, diethyl ether, diisopropyl ether, or methyl tert-butyl ether.

[0484] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0485] In step iii, the antisolvent is water, or a mixture of water and one or more organic solvents selected from methanol, ethanol, isopropanol, tetrahydrofuran, and acetonitrile.

[0486] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0487] In step iii, the antisolvent is hexane, cyclohexane, n-heptane, ethyl acetate, or a mixture thereof with one or more solvents selected from the group consisting of isopropyl acetate, diethyl ether, diisopropyl ether, or methyl tert-butyl ether.

[0488] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0489] In step iii, the antisolvent is water, or a mixture of water and one or more organic solvents selected from methanol, ethanol and isopropanol.

[0490] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0491] In step iii, the antisolvent is hexane, cyclohexane, n-heptane, or ethyl acetate.

[0492] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0493] In step iii, the antisolvent is water.

[0494] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0495] In step iii, the antisolvent is water, and there are no other antisolvents.

[0496] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0497] In step iii, the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide to antisolvent is in the range of 1:1 to 1:100 (w / w), with the antisolvent being the predominant solvent.

[0498] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0499] In step iii, the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide to antisolvent is in the range of 1:2 to 1:50 (w / w), with the antisolvent being the predominant solvent.

[0500] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0501] In step iii, the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide to antisolvent is in the range of 1:4 to 1:40 (w / w), with the antisolvent being the predominant solvent.

[0502] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0503] In step iii, the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide to antisolvent is in the range of 1:6 to 1:40 (w / w), with the antisolvent being the predominant solvent.

[0504] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0505] In step iii, the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide to antisolvent is in the range of 1:10 to 1:30 (w / w), with the antisolvent being the predominant solvent.

[0506] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0507] In step iii, the ratio between (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide and water, used as an antisolvent, is in the range of 1:4 to 1:40 (w / w), with water as the predominant solvent.

[0508] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0509] In step iii., the ratio between (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide and water, used as the antisolvent, is in the range of 1:6 to 1:40 (w / w), with water as the predominant solvent.

[0510] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0511] In step iii., the ratio between (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide and water, used as the antisolvent, is in the range of 1:10 to 1:30 (w / w), with water as the predominant solvent.

[0512] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0513] The ratio between the solvent used in step ii. and the antisolvent used in step iii. is in the range of 1:10 to 10:1 (v / v; solvent: antisolvent).

[0514] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0515] The ratio between the solvent used in step ii. and the antisolvent used in step iii. is in the range of 1:6 to 6:1 (v / v; solvent: antisolvent).

[0516] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0517] The ratio between the solvent used in step ii. and the antisolvent used in step iii. is in the range of 1:4 to 4:1 (v / v; solvent: antisolvent).

[0518] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0519] The ratio between the solvent used in step ii. and the antisolvent used in step iii. is in the range of 1:3 to 2:1 (v / v; solvent: antisolvent).

[0520] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0521] The ratio between the solvent used in step ii. and the antisolvent used in step iii. is in the range of 1:2 to 1:1 (v / v; solvent: antisolvent).

[0522] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0523] In step iii., the ratio between the solvent and the antisolvent used in the solution is in the range of 1:10 to 10:1 (v / v; solvent: antisolvent).

[0524] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0525] In step iii., the ratio between the solvent and the antisolvent used in the solution is in the range of 1:6 to 6:1 (v / v; solvent: antisolvent).

[0526] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0527] In step iii., the ratio between the solvent and the antisolvent used in the solution is in the range of 1:4 to 4:1 (v / v; solvent: antisolvent).

[0528] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0529] In step iii., the ratio between the solvent and the antisolvent used in the solution is in the range of 1:3 to 2:1 (v / v; solvent: antisolvent).

[0530] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0531] In step iii., the ratio between the solvent and the antisolvent used in the solution is in the range of 1:2 to 1:1 (v / v; solvent: antisolvent).

[0532] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0533] Step iii is performed at a temperature of 0°C to 20°C for a period of 20 minutes to 2 hours.

[0534] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0535] Step iii is performed at a temperature of 0°C to 20°C for a period of 20 minutes to 1.5 hours.

[0536] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0537] Step iii is performed at a temperature of 2°C to 15°C for 30 minutes to 1 hour.

[0538] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0539] Step iii is performed at a temperature of 4°C to 10°C for 30 minutes to 1 hour.

[0540] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0541] Step iii is performed at a temperature of 2°C to 15°C for 30 to 45 minutes.

[0542] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[0543] Step iii is performed at a temperature of 4°C to 10°C for 35 to 40 minutes.

[0544] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the addition of an optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in step iii. is carried out at a temperature of 0°C to 20°C for a period of 20 minutes to 2 hours.

[0545] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the addition of an optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in step iii. is carried out at a temperature of 0°C to 20°C for a period of 20 minutes to 1.5 hours.

[0546] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the addition of an optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in step iii. is carried out at a temperature of 2°C to 15°C for a period of 30 minutes to 1 hour.

[0547] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the addition of an optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in step iii. is carried out at a temperature of 2°C to 15°C for a period of 30 minutes to 1 hour.

[0548] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the addition of an optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in step iii. is carried out at a temperature of 4°C to 10°C for a period of 30 minutes to 1 hour.

[0549] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the addition of an optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in step iii. is carried out at a temperature of 4°C to 10°C for a period of 30 minutes to 1 hour.

[0550] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the addition of an optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in step iii. is carried out at a temperature of 2°C to 15°C for a time of 30 to 45 minutes.

[0551] According to another embodiment of the second aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the addition of an optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in step iii. is carried out at a temperature of 4°C to 10°C for a time of 35 to 40 minutes.

[0552] In another particular embodiment of the second aspect, the invention covers a combination of two or more of the above embodiments under the title “Other Embodiments of the Second Aspect of the Invention”.

[0553] The present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, its preparation method, and any sub-combination of pharmaceutical compositions comprising them, as described in any embodiment or aspect of the present invention.

[0554] This invention covers a method for preparing the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide of this invention, the method comprising the steps described in the experimental section herein.

[0555] According to a third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[0556] intermediate compound of formula (II)

[0557]

[0558] Reaction with intermediate compound of formula (III)

[0559]

[0560] Where LG is the leaving group as defined above.

[0561] Therefore, we obtain

[0562]

[0563] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide,

[0564] The resulting crude product is dissolved in a solvent or a mixture of solvents, and then...

[0565] Mix the resulting solution with the antisolvent, and then

[0566] Separate and dry the resulting precipitate.

[0567] To obtain the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0568] According to a second embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[0569] intermediate compound of formula (II)

[0570]

[0571] Reaction with intermediate compound of formula (III)

[0572]

[0573] Where LG is the leaving group as defined above.

[0574] Therefore, we obtain

[0575]

[0576] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide,

[0577] The resulting crude product was dissolved in acetone with a water content of 0% to 30% (v / v), and then...

[0578] Mix the resulting solution with water, and then

[0579] Separate and dry the resulting precipitate.

[0580] To obtain the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0581] According to a third embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[0582] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide was dissolved in a solvent or a mixture of solvents, and then...

[0583] Mix the resulting solution with the antisolvent, and then

[0584] Separate and dry the resulting precipitate.

[0585] To obtain the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0586] According to a fourth embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[0587] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide was dissolved in acetone containing 0% to 30% (v / v) water, and then...

[0588] Mix the resulting solution with water, and then

[0589] Separate and dry the resulting precipitate.

[0590] To obtain the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0591] According to a fifth embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[0592] 1) Make the intermediate compound of formula (II)

[0593]

[0594] Reaction with intermediate compound of formula (III)

[0595]

[0596] Where LG is the leaving group as defined above.

[0597] Therefore, we obtain

[0598]

[0599] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide,

[0600] 2) Dissolve the crude product obtained in step 1) in a solvent.

[0601] 3) Formation of a supersaturated solution,

[0602] 4) Add a nano-suspension containing additional (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, an antisolvent, at least one surfactant, and at least one polymer.

[0603] 5) Then proceed with one or more sub-steps selected from the following.

[0604] a. Cooling

[0605] b. Add antisolvent, and

[0606] c. Evaporate the solvent.

[0607] 6) Separate and dry the resulting precipitate.

[0608] To obtain the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0609] According to a sixth embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[0610] 2) Dissolve (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in a solvent.

[0611] 3) Formation of a supersaturated solution,

[0612] 4) Add a nano-suspension containing additional (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, an antisolvent, at least one surfactant, and at least one polymer.

[0613] 5) Then proceed with one or more sub-steps selected from the following.

[0614] a. Cooling

[0615] b. Add antisolvent, and

[0616] c. Evaporate the solvent.

[0617] 6) Separate and dry the resulting precipitate.

[0618] To obtain the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0619] According to a seventh embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[0620] 1) Make the intermediate compound of formula (II)

[0621]

[0622] Reaction with intermediate compound of formula (III)

[0623]

[0624] Where LG is the leaving group as defined above.

[0625] Therefore, we obtain

[0626]

[0627] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide,

[0628] 2) Dissolve the crude product obtained in step 1) in a dipolar aprotic solvent and / or a protic solvent, and optionally filter it.

[0629] 3) Forming a supersaturated solution through one or more sub-steps selected from the following:

[0630] a. Cooling

[0631] b. Add antisolvent, and

[0632] c. Evaporate the solvent.

[0633] 4) Add a nano-suspension containing additional (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, an antisolvent, at least one surfactant, and at least one polymer.

[0634] 5) Then proceed with one or more sub-steps selected from the following.

[0635] a. Cooling

[0636] b. Add antisolvent, and

[0637] c. Evaporate the solvent.

[0638] 6) Separate and dry the resulting precipitate.

[0639] To obtain the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0640] According to an eighth embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[0641] 2) Dissolve (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in a dipolar aprotic solvent and / or a protic solvent, and optionally filter.

[0642] 3) Forming a supersaturated solution through one or more sub-steps selected from the following:

[0643] a. Cooling

[0644] b. Add antisolvent, and

[0645] c. Evaporate the solvent.

[0646] 4) Add a nano-suspension containing additional (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, an antisolvent, at least one surfactant, and at least one polymer.

[0647] 5) Then proceed with one or more sub-steps selected from the following.

[0648] a. Cooling

[0649] b. Add antisolvent, and

[0650] c. Evaporate the solvent.

[0651] 6) Separate and dry the resulting precipitate.

[0652] To obtain the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0653] According to a ninth embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[0654] 1) Make the intermediate compound of formula (II)

[0655]

[0656] Reaction with intermediate compound of formula (III)

[0657]

[0658] Where LG is the leaving group as defined above.

[0659] Therefore, we obtain

[0660]

[0661] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide,

[0662] 2) Dissolve the crude product obtained in step 1) in a dipolar aprotic solvent and / or a protic solvent, and optionally filter it.

[0663] 3) A supersaturated solution is formed by cooling.

[0664] 4) Add a nano-suspension containing additional (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, an antisolvent, at least one surfactant, and at least one polymer.

[0665] 5) Subsequently

[0666] a. Cooling, then

[0667] b. Add an antisolvent

[0668] 6) Separate and dry the resulting precipitate.

[0669] To obtain the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0670] According to a tenth embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[0671] 2) Dissolve (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in a dipolar aprotic solvent and / or a protic solvent, and optionally filter.

[0672] 3) A supersaturated solution is formed by cooling.

[0673] 4) Add a nano-suspension containing additional (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, an antisolvent, at least one surfactant, and at least one polymer.

[0674] 5) Subsequently

[0675] a. Cooling, then

[0676] b. Add an antisolvent

[0677] 6) Separate and dry the resulting precipitate.

[0678] To obtain the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0679] According to the eleventh embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[0680] 1) Make the intermediate compound of formula (II)

[0681]

[0682] Reaction with intermediate compound of formula (III)

[0683]

[0685] Where LG is the leaving group as defined above.

[0686] The reaction takes place in the presence of at least one equivalent of a base selected from alkali metal carbonates, alkali metal bicarbonates, or alkali metal phosphates, at a temperature of 20°C to 80°C, in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidone, acetone, or isopropanol, for a time of 30 minutes to 24 hours.

[0687] Therefore, we obtain

[0688]

[0689] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide,

[0690] 2) Dissolve the crude product obtained in step 1) in acetone with a water content of 10% to 30% (v / v), and optionally filter.

[0691] 3) By cooling to form a supersaturated solution, the temperature is lowered by 5°C to 30°C.

[0692] 4) Add a nano-suspension containing additional (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, an antisolvent, at least one surfactant, and at least two polymers.

[0693] 5) Subsequently

[0694] a. Cooling, then

[0695] b. Add water.

[0696] 6) Separate and dry the resulting precipitate.

[0697] To obtain the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0698] According to a twelfth embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[0699] 2) Dissolve (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in acetone containing 10% to 30% (v / v) water, and optionally filter.

[0700] 3) By cooling to form a supersaturated solution, the temperature is lowered by 5°C to 30°C.

[0701] 4) Add a nano-suspension containing additional (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, an antisolvent, at least one surfactant, and at least two polymers.

[0702] 5) Subsequently

[0703] a. Cooling, then

[0704] b. Add water.

[0705] 6) Separate and dry the resulting precipitate.

[0706] To obtain the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0707] According to a thirteenth embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[0708] 1) Make the intermediate compound of formula (II)

[0709]

[0710] Reaction with intermediate compound of formula (III)

[0711]

[0712] Where LG is a bromine atom.

[0713] In the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature of 50°C to 70°C, in acetonitrile, for a reaction time of 1 to 2 hours,

[0714] Therefore, we obtain

[0715]

[0716] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide,

[0717] 2) Dissolve the crude product obtained in step 1) in acetone with a water content of 10% to 30% (v / v) at a temperature of 40°C to 70°C, and optionally filter.

[0718] 3) By cooling to form a supersaturated solution, the temperature is lowered by 15°C to 25°C.

[0719] 4) Add a nano-suspension comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide (5 to 20% w / w), water (60 to 90% w / w), at least one surfactant (0.05 to 1% w / w), and at least two polymers (0.5 to 15% w / w each), wherein the amount of the nano-suspension is 0.1 to 20% w / w of the supersaturated solution obtained in step 3).

[0720] 5) Subsequently

[0721] a. Cool down, reducing the temperature by 5°C to 25°C, then...

[0722] b. Add water.

[0723] 6) Separate and dry the resulting precipitate.

[0724] To obtain the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0725] According to the fourteenth embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[0726] 2) Dissolve (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in acetone containing 10% to 30% (v / v) water at a temperature of 40°C to 70°C, and optionally filter.

[0727] 3) By cooling to form a supersaturated solution, the temperature is lowered by 15°C to 25°C.

[0728] 4) Add a nano-suspension comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide (5 to 20% w / w), water (60 to 90% w / w), at least one surfactant (0.05 to 1% w / w), and at least two polymers (0.5 to 15% w / w each), wherein the amount of the nano-suspension is 0.1 to 20% w / w of the supersaturated solution obtained in step 3).

[0729] 5) Subsequently

[0730] a. Cool down, reducing the temperature by 5°C to 25°C, then...

[0731] b. Add water.

[0732] 6) Separate and dry the resulting precipitate.

[0733] To obtain the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0734] According to a fifteenth embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[0735] 1) Make the intermediate compound of formula (II)

[0736]

[0737] Reaction with intermediate compound of formula (III)

[0738]

[0739] Where LG is a bromine atom.

[0740] In the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature of 50°C to 70°C, in acetonitrile, for a reaction time of 1 to 2 hours, followed optionally by lowering the temperature to 20°C for up to one hour.

[0741] Therefore, we obtain

[0742]

[0743] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide,

[0744] 2) Dissolve the crude product obtained in step 1) in acetone with a water content of 10% to 30% (v / v) at a temperature of 40°C to 70°C, and optionally filter.

[0745] 3) By cooling to form a supersaturated solution, the temperature is lowered by 15°C to 25°C.

[0746] 4) Add a nano-suspension comprising additional (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide (5 to 20% w / w), water (60 to 90% w / w), at least one surfactant (0.05 to 1% w / w), and at least two polymers (each independently comprising 0.5 to 15% w / w), wherein the amount of the nano-suspension is 0.1 to 20% w / w of the supersaturated solution obtained in step 3), wherein

[0747] The at least one surfactant contains C8-C 20 Alkali metal salts of alkyl sulfuric acid

[0748] Furthermore, the at least two polymers comprise hydroxypropyl cellulose and polyvinylpyrrolidone.

[0749] Furthermore, the amount of the nano-suspension is 1 to 6% w / w of the supersaturated solution obtained in step 3).

[0750] 5) Subsequently

[0751] a. Cool down, reducing the temperature by 5°C to 25°C, then...

[0752] b. Add water.

[0753] 6) Separate and dry the resulting precipitate.

[0754] To obtain the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0755] According to a sixteenth embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[0756] 2) Dissolve (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in acetone containing 10% to 30% (v / v) water at a temperature of 40°C to 70°C, and optionally filter.

[0757] 3) By cooling to form a supersaturated solution, the temperature is lowered by 15°C to 25°C.

[0758] 4) Adding a nano-suspension comprising additional (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide (5 to 20% w / w), water (60 to 90% w / w), at least one surfactant (0.05 to 1% w / w), and at least two polymers (each independently comprising 0.5 to 15% w / w), wherein

[0759] The at least one surfactant contains C8-C 20 Alkali metal salts of alkyl sulfuric acid

[0760] Furthermore, the at least two polymers comprise hydroxypropyl cellulose and polyvinylpyrrolidone.

[0761] Furthermore, the amount of the nano-suspension is 1 to 6% w / w of the supersaturated solution obtained in step 3).

[0762] 5) Subsequently

[0763] a. Cool down, reducing the temperature by 5°C to 25°C, then...

[0764] b. Add water.

[0765] 6) Separate and dry the resulting precipitate.

[0766] To obtain the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0767] Other embodiments of the third aspect of the present invention:

[0768] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the particle size distribution is as follows: x10 is in the range of 1 to 2 μm.

[0769] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the particle size distribution is as follows: x50 is in the range of 4 to 5.5 μm.

[0770] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the particle size distribution is as follows: x50 is in the range of 4 to 8 μm.

[0771] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the particle size distribution is as follows: x90 is in the range of 10 to 18 μm.

[0772] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the particle size distribution is as follows: x10 is in the range of 1 to 2 μm, x50 is in the range of 4 to 5.5 μm, and x90 is in the range of 10 to 18 μm.

[0773] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the particle size distribution is as follows: x10 is in the range of 1 to 4 μm, x50 is in the range of 4 to 8 μm, and x90 is in the range of 12 to 18 μm.

[0774] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein its particle size distribution, as determined by method PSD2a, is as follows: x10 in the range of 1 to 2 μm.

[0775] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein its particle size distribution, as determined by method PSD2a, is as follows: x50 is in the range of 4 to 5.5 μm.

[0776] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein its particle size distribution, as determined by method PSD4, is as follows: x50 is in the range of 4 to 8 μm.

[0777] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein its particle size distribution, as determined by method PSD2a, is as follows: x90 in the range of 10 to 18 μm.

[0778] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein its particle size distribution, as determined by method PSD4, is as follows: x90 in the range of 12 to 18 μm.

[0779] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the particle size distribution determined according to method PSD2a is as follows: x10 in the range of 1 to 2 μm, x50 in the range of 4 to 5.5 μm, and x90 in the range of 10 to 18 μm.

[0780] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the particle size distribution determined according to method PSD4 is as follows: x10 in the range of 0.3 to 4 μm, x50 in the range of 4 to 10 μm, and x90 in the range of 10 to 20 μm.

[0781] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the particle size distribution determined according to method PSD4 is as follows: x10 in the range of 1 to 4 μm, x50 in the range of 4 to 8 μm, and x90 in the range of 12 to 18 μm.

[0782] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the presence of the amorphous form is less than 15%.

[0783] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the presence of the amorphous form is less than 10%.

[0784] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the presence of the amorphous form is less than 5%.

[0785] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the presence of the amorphous form is less than 2.5%.

[0786] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the presence of the amorphous form is below the detection limit of differential scanning calorimetry.

[0787] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the presence of the amorphous form is below the detection limit of XRPD.

[0788] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the presence of the amorphous form is below the detection limit of differential scanning calorimetry according to method DSC1.

[0789] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the presence of the amorphous form is below the detection limit of XRPD according to method XRPD1.

[0790] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoroaniline)propionamide has at least 99% enantiomeric excess.

[0791] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoroaniline)propionamide has an enantiomeric excess of at least 98%.

[0792] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoroaniline)propionamide has at least 95% enantiomeric excess.

[0793] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide has at least 90% enantiomeric excess.

[0794] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the leaving group LG in step 1) is a chlorine atom, a bromine atom, or an iodine atom, or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, or [(4-methoxyphenyl)sulfonyl]oxy.

[0795] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the leaving group LG in step 1) is a chlorine atom, a bromine atom, or an iodine atom, or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy, or [(4-methylphenyl)sulfonyl]oxy.

[0796] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the leaving group LG in step 1) is a chlorine atom.

[0797] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the leaving group LG in step 1) is a [(4-methylphenyl)sulfonyl]oxy group.

[0798] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the leaving group LG in step 1) is a bromine atom or a [(4-methylphenyl)sulfonyl]oxy group.

[0799] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the leaving group LG in step 1) is a bromine atom.

[0800] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out in the presence of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates or N,N,N,N-tetra(C1-C3-alkyl)guanidine.

[0801] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out in the presence of a base selected from alkali metal carbonates, alkali metal bicarbonates or alkali metal phosphates.

[0802] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out in the presence of at least 1 equivalent of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates or N,N,N,N-tetra(C1-C3-alkyl)guanidine.

[0803] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates or N,N,N,N-tetra(C1-C3-alkyl)guanidine.

[0804] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkali metal carbonates, alkali metal bicarbonates or alkali metal phosphates.

[0805] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out in the presence of 1.5 to 6 equivalents of a base selected from: an alkali metal carbonate selected from sodium carbonate, potassium carbonate or cesium carbonate; an alkali metal bicarbonate selected from sodium bicarbonate, potassium bicarbonate or cesium bicarbonate; or an alkali metal phosphate selected from sodium phosphate, potassium phosphate or cesium phosphate.

[0806] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out in the presence of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate or potassium phosphate.

[0807] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate or potassium phosphate.

[0808] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out in the presence of a base selected from potassium carbonate or potassium phosphate.

[0809] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate or potassium phosphate.

[0810] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out in the presence of 1.5 to 3 equivalents of potassium phosphate.

[0811] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out in the presence of 2 to 6 equivalents of potassium carbonate.

[0812] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out at a temperature of 0°C to 100°C.

[0813] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out at a temperature of 20°C to 90°C.

[0814] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out at a temperature of 40°C to 80°C.

[0815] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out at a temperature of 50°C to 70°C.

[0816] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out at a temperature of 40°C to 80°C, optionally followed by lowering the temperature to 20°C for up to one hour.

[0817] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out at a temperature of 50°C to 70°C, optionally followed by lowering the temperature to 20°C for up to one hour.

[0818] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out at a temperature of 40°C to 80°C, optionally followed by lowering the temperature to 20°C for up to one hour.

[0819] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out at a temperature of 50°C to 70°C, optionally followed by lowering the temperature to 20°C for up to one hour.

[0820] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidone, acetone, isopropanol, or a mixture of acetone and isopropanol.

[0821] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out in a solvent selected from N,N-dimethylformamide, acetonitrile, N-methylpyrrolidone, acetone, isopropanol, or a mixture of acetone and isopropanol in a ratio of 5:1 (v / v) to 1:5 (v / v).

[0822] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out in a solvent selected from N,N-dimethylformamide or acetonitrile.

[0823] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out in N,N-dimethylformamide as a solvent.

[0824] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is carried out in acetonitrile as a solvent.

[0825] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the time for performing step 1) is 30 minutes to 24 hours.

[0826] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the time for performing step 1) is 30 minutes to 6 hours.

[0827] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the time for performing step 1) is 30 minutes to 2 hours.

[0828] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 1) is performed for 1 to 2 hours.

[0829] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 2) is carried out in one or more dipolar aprotic solvents and / or polar solvents optionally mixed with water.

[0830] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 2) is carried out in a solvent optionally mixed with water, selected from dimethyl sulfoxide, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide, 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, 1,4-dioxane, or 2-methyltetrahydrofuran.

[0831] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 2) is carried out in one or more solvents selected from 1,2-dimethoxyethane, methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, 1,4-dioxane, or 2-methyltetrahydrofuran, optionally mixed with water.

[0832] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 2) is carried out in one or more solvents selected from isopropanol, tetrahydrofuran, acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, 1,4-dioxane or 2-methyltetrahydrofuran, optionally mixed with water.

[0833] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 2) is carried out in one or more solvents selected from acetonitrile, diethyl ketone, methyl ethyl ketone, acetone or 1,4-dioxane, optionally mixed with water.

[0834] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 2) is carried out in one or more solvents selected from acetonitrile, acetone or 1,4-dioxane, optionally mixed with water.

[0835] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 2) is carried out in a mixture of acetone and water.

[0836] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 2) is carried out in a mixture of acetone and water, the acetone containing water in the range of 0 to 50% v / v.

[0837] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 2) is carried out in a mixture of acetone and water, the acetone containing water in the range of 10 to 30% v / v.

[0838] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 2) is carried out at a temperature of 40°C to 70°C in a mixture of acetone and water, the acetone containing water in the range of 10% to 30% v / v.

[0839] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the ratio of the solvent used in step 2) to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide is 4:1 to 10:1 (w / w; solvent:compound).

[0840] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the ratio of the solvent used in step 2) to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide is 4:1 to 8:1 (w / w; solvent:compound).

[0841] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the solvent used in step 2) is in a ratio of 5:1 (w / w) to 7:1 (w / w) to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, which is advantageous for the solvent.

[0842] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the solvent used in step 2) is in a ratio of 5.5:1 (w / w) to 6:1 (w / w) to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, which is advantageous for the solvent.

[0843] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the ratio of the acetone and water mixture used in step 2) to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide is from 4:1 (w / w) to 8:1 (w / w), which is beneficial to the acetone and water mixture.

[0844] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the ratio of the acetone and water mixture used in step 2) to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide is from 5:1 (w / w) to 7:1 (w / w), which is beneficial to the acetone and water mixture.

[0845] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the ratio of the mixture of acetone and water used in step 2) to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide is from 5.5:1 (w / w) to 6:1 (w / w), which is beneficial to the acetone and water mixture.

[0846] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the formation of the supersaturated solution in step 3) is achieved by cooling.

[0847] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the formation of the supersaturated solution in step 3) is achieved by adding an antisolvent.

[0848] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the formation of the supersaturated solution in step 3) is achieved by evaporating the solvent.

[0849] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the formation of the supersaturated solution in step 3) is achieved by cooling and reducing the temperature by 5°C to 30°C.

[0850] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the formation of the supersaturated solution in step 3) is achieved by cooling and reducing the temperature by 15°C to 25°C.

[0851] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the formation of the supersaturated solution in step 3) is achieved by cooling and lowering the temperature by 5°C to 30°C, and wherein the solvent is acetone containing 10 to 30% v / v of water.

[0852] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the formation of the supersaturated solution in step 3) is achieved by cooling and lowering the temperature by 15°C to 25°C, and wherein the solvent is acetone containing 10 to 30% v / v of water.

[0853] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the formation of the supersaturated solution in step 3) is achieved by cooling and lowering the temperature by 15°C to 25°C, and wherein the solvent is acetone containing 10 to 30% v / v of water.

[0854] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the nano-suspension used in step 4) contains (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in the range of 5 to 20% w / w.

[0855] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the antisolvent in the nano-suspension used in step 4) is water.

[0856] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the nano-suspension used in step 4) contains water in the range of 60 to 90% w / w.

[0857] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the nano-suspension used in step 4) contains at least one surfactant in the range of 0.05 to 1% w / w.

[0858] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the nano-suspension used in step 4) contains a surfactant in the range of 0.05 to 1% w / w.

[0859] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the nano-suspension used in step 4) contains a surfactant in the range of 0.05 to 1% w / w, and wherein said surfactant is C8-C 20 Alkali metal salts of alkyl sulfuric acid.

[0860] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the nano-suspension used in step 4) contains a surfactant in the range of 0.05 to 1% w / w, and wherein said surfactant is C 10 -C 16 -Sodium or potassium salts of alkyl sulfates.

[0861] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the nano-suspension used in step 4) contains a surfactant in the range of 0.05 to 1% w / w, and wherein said surfactant is sodium dodecyl sulfate.

[0862] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the nano-suspension used in step 4) comprises at least two polymers, which are independently in the range of 0.5 to 15% w / w.

[0863] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the nano-suspension used in step 4) comprises at least two polymers, which are independently in the range of 0.5 to 15% w / w, wherein one polymer is hydroxypropyl cellulose and the other polymer is polyvinylpyrrolidone.

[0864] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the nano-suspension used in step 4) contains two polymers, which are independently in the range of 0.5 to 15% w / w, wherein one polymer is hydroxypropyl cellulose and the other polymer is polyvinylpyrrolidone.

[0865] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the amount of nano-suspension used in step 4) is 0.1 to 20% w / w of the supersaturated solution obtained in step 3).

[0866] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the amount of nano-suspension used in step 4) is 0.25 to 10% w / w of the supersaturated solution obtained in step 3).

[0867] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the amount of nano-suspension used in step 4) is 1 to 6% w / w of the supersaturated solution obtained in step 3).

[0868] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the amount of nano-suspension used in step 4) is 2 to 4% w / w of the supersaturated solution obtained in step 3).

[0869] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the amount of nano-suspension used in step 4) is 2.5 to 3.0% w / w of the supersaturated solution obtained in step 3).

[0870] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 5) is achieved by cooling followed by the addition of an antisolvent.

[0871] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 5) is achieved by cooling followed by the addition of water.

[0872] According to another embodiment of the third aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein step 5) is achieved by cooling, reducing the temperature by 5°C to 25°C, followed by the addition of water.

[0873] The present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, its preparation method, and any sub-combination of pharmaceutical compositions comprising them, as described in any embodiment or aspect of the present invention.

[0874] This invention covers a method for preparing the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide of the present invention, said method comprising the steps as described in the Experimental Section herein.

[0875] According to a fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroanilino)propionamide, said method comprising the following steps

[0876] intermediate compound of formula (II)

[0877]

[0878] Reaction with intermediate compound of formula (III)

[0879]

[0880] Where LG is the leaving group as defined above.

[0881] Therefore, we obtain

[0882]

[0883] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0884] According to a second embodiment of the fourth aspect, the present invention covers a method for preparing at least 80% enantiomeric excess (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, said method comprising the following steps

[0885] intermediate compound of formula (II)

[0886]

[0888] Reaction with intermediate compound of formula (III)

[0889]

[0890] Where LG is the leaving group as defined above.

[0891] Therefore, we obtain

[0892]

[0893] At least 80% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0894] According to a third embodiment of the fourth aspect, the present invention covers a method for preparing at least 90% enantiomeric excess (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, said method comprising the following steps

[0895] intermediate compound of formula (II)

[0896]

[0897] Reaction with intermediate compound of formula (III)

[0898]

[0899] Where LG is the leaving group as defined above.

[0900] Therefore, we obtain

[0901]

[0902] At least 90% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0903] According to a fourth embodiment of the fourth aspect, the present invention covers a method for preparing at least 90% enantiomeric excess (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, said method comprising the following steps

[0904] intermediate compound of formula (II)

[0905]

[0906] Reaction with intermediate compound of formula (III)

[0907]

[0908] Where LG is the leaving group as defined above.

[0909] The reaction takes place in the presence of at least one equivalent of a base selected from alkali metal carbonates, alkali metal bicarbonates, or alkali metal phosphates, at a temperature of 20°C to 80°C, in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidone, acetone, or isopropanol, for a time of 30 minutes to 24 hours.

[0910] Therefore, we obtain

[0911]

[0912] At least 90% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0913] According to a fifth embodiment of the fourth aspect, the present invention covers a method for preparing at least 90% enantiomeric excess (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, said method comprising the following steps

[0914] intermediate compound of formula (II)

[0915]

[0916] Reaction with intermediate compound of formula (III)

[0917]

[0918] Where LG is a bromine atom.

[0919] The reaction takes place in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate or sodium phosphate, at a temperature of 40°C to 80°C, in a solvent selected from N,N-dimethylformamide or acetonitrile, for a time of 30 minutes to 6 hours.

[0920] Therefore, we obtain

[0921]

[0922] At least 90% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0923] According to a sixth embodiment of the fourth aspect, the present invention covers a method for preparing at least 90% enantiomeric excess (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, said method comprising the following steps

[0924] intermediate compound of formula (II)

[0925]

[0926] Reaction with intermediate compound of formula (III)

[0927]

[0928] Where LG is a bromine atom.

[0929] The reaction is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate or potassium phosphate, at a temperature of 40°C to 80°C, in a solvent selected from N,N-dimethylformamide or acetonitrile, for a time of 30 minutes to 6 hours, optionally followed by a cooling to 20°C for up to one hour.

[0930] Therefore, we obtain

[0931]

[0932] At least 90% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0933] According to a seventh embodiment of the fourth aspect, the present invention covers a method for preparing at least 95% enantiomeric excess (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, said method comprising the following steps

[0934] intermediate compound of formula (II)

[0935]

[0936] Reaction with intermediate compound of formula (III)

[0937]

[0938] Where LG is a bromine atom.

[0939] In the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature of 50°C to 70°C, in acetonitrile, for a reaction time of 1 to 2 hours,

[0940] Therefore, we obtain

[0941]

[0942] At least 95% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0943] According to the eighth embodiment of the fourth aspect, the present invention covers a method for preparing at least 95% enantiomeric excess (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, said method comprising the following steps

[0944] intermediate compound of formula (II)

[0945]

[0946] Reaction with intermediate compound of formula (III)

[0947]

[0948] Where LG is a bromine atom.

[0949] In the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature of 50°C to 70°C, in acetonitrile, for a reaction time of 1 to 2 hours, optionally followed by a cooling to 20°C for up to one hour.

[0950] Therefore, we obtain

[0951]

[0952] At least 95% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide.

[0953] Other embodiments of the fourth aspect of the present invention:

[0954] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the leaving group LG in the included steps is a chlorine atom, a bromine atom, or an iodine atom, or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy, or [(4-methylphenyl)sulfonyl]oxy.

[0955] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the leaving group LG in the included steps is a chlorine atom.

[0956] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the leaving group LG in the included step is a [(4-methylphenyl)sulfonyl]oxy group.

[0957] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the leaving group LG in the included steps is a bromine atom or a [(4-methylphenyl)sulfonyl]oxy group.

[0958] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the leaving group LG in the included steps is a bromine atom.

[0959] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out in the presence of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates or N,N,N,N-tetra(C1-C3-alkyl)guanidine.

[0960] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out in the presence of a base selected from alkali metal carbonates, alkali metal bicarbonates or alkali metal phosphates.

[0961] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out in the presence of at least 1 equivalent of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates or N,N,N,N-tetra(C1-C3-alkyl)guanidine.

[0962] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out in the presence of 1.5 to 6 equivalents of a base selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates or N,N,N,N-tetra(C1-C3-alkyl)guanidine.

[0963] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps thereof are carried out in the presence of 1.5 to 6 equivalents of a base selected from alkali metal carbonates, alkali metal bicarbonates or alkali metal phosphates.

[0964] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps thereof are carried out in the presence of 1.5 to 6 equivalents of a base selected from: an alkali metal carbonate selected from sodium carbonate, potassium carbonate or cesium carbonate; an alkali metal bicarbonate selected from sodium bicarbonate, potassium bicarbonate or cesium bicarbonate; or an alkali metal phosphate selected from sodium phosphate, potassium phosphate or cesium phosphate.

[0965] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps thereof are carried out in the presence of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate or potassium phosphate.

[0966] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate or potassium phosphate.

[0967] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out in the presence of a base selected from potassium carbonate or potassium phosphate.

[0968] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate or potassium phosphate.

[0969] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out in the presence of 1.5 to 3 equivalents of potassium phosphate.

[0970] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out in the presence of 2 to 6 equivalents of potassium carbonate.

[0971] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out at a temperature of 0°C to 100°C.

[0972] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out at a temperature of 20°C to 90°C.

[0973] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out at a temperature of 40°C to 80°C.

[0974] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out at a temperature of 50°C to 70°C.

[0975] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out at a temperature of 40°C to 80°C, optionally followed by a reduction of the temperature to 20°C for up to one hour.

[0976] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out at a temperature of 50°C to 70°C, optionally followed by a reduction of the temperature to 20°C for up to one hour.

[0977] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out at a temperature of 40°C to 80°C, optionally followed by a reduction of the temperature to 20°C for up to one hour.

[0978] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out at a temperature of 50°C to 70°C, optionally followed by a reduction of the temperature to 20°C for up to one hour.

[0979] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidone, acetone, isopropanol, or a mixture of acetone and isopropanol.

[0980] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out in a solvent selected from N,N-dimethylformamide, acetonitrile, N-methylpyrrolidone, acetone, isopropanol, or a mixture of acetone and isopropanol in a ratio of 5:1 (v / v) to 1:5 (v / v).

[0981] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out in a solvent selected from N,N-dimethylformamide or acetonitrile.

[0982] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out in N,N-dimethylformamide as a solvent.

[0983] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the steps included therein are carried out in acetonitrile as a solvent.

[0984] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the time for carrying out the steps included therein is from 30 minutes to 24 hours.

[0985] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the time for carrying out the steps therein is from 30 minutes to 6 hours.

[0986] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the time for carrying out the steps included therein is from 30 minutes to 2 hours.

[0987] According to another embodiment of the fourth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide, wherein the time for carrying out the steps included therein is 1 to 2 hours.

[0988] According to a fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[0989] intermediate compound of formula (II)

[0990]

[0991] Reaction with intermediate compound of formula (III)

[0992]

[0993] Where LG is the leaving group as defined above.

[0994] Therefore, we obtain

[0995]

[0996] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form.

[0997] According to a second embodiment of the fifth aspect, the present invention covers a method for preparing at least 80% enantiomeric excess (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[0998] intermediate compound of formula (II)

[0999]

[1000] Reaction with intermediate compound of formula (III)

[1001]

[1002] Where LG is the leaving group as defined above.

[1003] Therefore, we obtain

[1004]

[1005] At least 80% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form.

[1006] According to a third embodiment of the fifth aspect, the present invention covers a method for preparing at least 90% enantiomeric excess (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[1007] intermediate compound of formula (II)

[1008]

[1009] Reaction with intermediate compound of formula (III)

[1010]

[1011] Where LG is the leaving group as defined above.

[1012] Therefore, we obtain

[1013]

[1014] At least 90% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form.

[1015] According to the fourth embodiment of the fifth aspect, the present invention covers a method for preparing at least 90% enantiomeric excess (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[1016] intermediate compound of formula (II)

[1017]

[1018] Reaction with intermediate compound of formula (III)

[1019]

[1020] Where LG is the leaving group as defined above.

[1021] The reaction takes place in the presence of at least one equivalent of a base selected from alkali metal carbonates, alkali metal bicarbonates, or alkali metal phosphates, at a temperature of 20 to 80°C, in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidone, acetone, or isopropanol, for a time of 30 minutes to 24 hours.

[1022] Therefore, we obtain

[1023]

[1024] At least 90% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form.

[1025] According to a fifth embodiment of the fifth aspect, the present invention covers a method for preparing microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide with at least 90% enantiomeric excess, said method comprising the following steps

[1026] intermediate compound of formula (II)

[1027]

[1028] Reaction with intermediate compound of formula (III)

[1029]

[1030] Where LG is a bromine atom.

[1031] The reaction takes place in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate or sodium phosphate, at a temperature of 40°C to 80°C, in a solvent selected from N,N-dimethylformamide or acetonitrile, for a time of 30 minutes to 6 hours.

[1032] Therefore, we obtain

[1033]

[1034] At least 90% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form.

[1035] According to a sixth embodiment of the fifth aspect, the present invention covers a method for preparing at least 90% enantiomeric excess (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[1036] intermediate compound of formula (II)

[1037]

[1038] Reaction with intermediate compound of formula (III)

[1039]

[1040] Where LG is a bromine atom.

[1041] The reaction is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate or potassium phosphate, at a temperature of 40°C to 80°C, in a solvent selected from N,N-dimethylformamide or acetonitrile, for a time of 30 minutes to 6 hours, optionally followed by a cooling to 20°C for up to one hour.

[1042] Therefore, we obtain

[1043]

[1044] At least 90% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form.

[1045] According to a seventh embodiment of the fifth aspect, the present invention covers a method for preparing at least 95% enantiomeric excess (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[1046] intermediate compound of formula (II)

[1047]

[1048] Reaction with intermediate compound of formula (III)

[1049]

[1050] Where LG is a bromine atom.

[1051] In the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature of 50°C to 70°C, in acetonitrile, for a reaction time of 1 to 2 hours,

[1052] Therefore, we obtain

[1053]

[1054] At least 95% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form.

[1055] According to the eighth embodiment of the fifth aspect, the present invention covers a method for preparing at least 95% enantiomeric excess (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[1056] intermediate compound of formula (II)

[1057]

[1058] Reaction with intermediate compound of formula (III)

[1059]

[1060] Where LG is a bromine atom.

[1061] In the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature of 50°C to 70°C, in acetonitrile, for a reaction time of 1 to 2 hours, optionally followed by a cooling to 20°C for up to one hour.

[1062] Therefore, we obtain

[1063]

[1064] At least 95% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form.

[1065] According to a ninth embodiment of the fifth aspect, the present invention covers a method for preparing a microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide with at least 98% enantiomeric excess, said method comprising the following steps

[1066] intermediate compound of formula (II)

[1067]

[1068] Reaction with intermediate compound of formula (III)

[1069]

[1070] Where LG is a bromine atom.

[1071] In the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature of 50°C to 70°C, in acetonitrile, for a reaction time of 1 to 2 hours,

[1072] Therefore, we obtain

[1073]

[1074] At least 98% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form.

[1075] According to a tenth embodiment of the fifth aspect, the present invention covers a method for preparing microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide with at least 98% enantiomeric excess, said method comprising the following steps

[1076] intermediate compound of formula (II)

[1077]

[1078] Reaction with intermediate compound of formula (III)

[1079]

[1080] Where LG is a bromine atom.

[1081] In the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature of 50°C to 70°C, in acetonitrile, for a reaction time of 1 to 2 hours,

[1082] Therefore, we obtain

[1083]

[1084] At least 98% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the presence of amorphous form is less than 5%, and its particle size distribution is as follows: x10 in the range of 0.5 to 2.5 μm, x50 in the range of 3 to 7 μm, and x90 in the range of 8 to 20 μm.

[1085] According to the eleventh embodiment of the fifth aspect, the present invention covers a method for preparing at least 98% enantiomeric excess (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[1086] intermediate compound of formula (II)

[1087]

[1088] Reaction with intermediate compound of formula (III)

[1089]

[1090] Where LG is a bromine atom.

[1091] In the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature of 50 to 70°C, in acetonitrile, for a reaction time of 1 to 2 hours,

[1092] Therefore, we obtain

[1093]

[1094] At least 98% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the presence of amorphous form is less than 5%, and its particle size distribution is as follows: x10 in the range of 1 to 4 μm, x50 in the range of 4 to 8 μm, and x90 in the range of 12 to 18 μm.

[1095] According to the twelfth embodiment of the fifth aspect, the present invention covers a method for preparing at least 99% enantiomeric excess (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[1096] intermediate compound of formula (II)

[1097]

[1098] Reaction with intermediate compound of formula (III)

[1099]

[1100] Where LG is a bromine atom.

[1101] In the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature of 50°C to 70°C, in acetonitrile, for a reaction time of 1 to 2 hours,

[1102] Therefore, we obtain

[1103]

[1104] At least 99% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the presence of amorphous form is below the detection limit of differential scanning calorimetry, and its particle size distribution is as follows: x10 in the range of 0.5 to 2.5 μm, x50 in the range of 3 to 7 μm, and x90 in the range of 8 to 20 μm.

[1105] According to a thirteenth embodiment of the fifth aspect, the present invention covers a method for preparing at least 99% enantiomeric excess (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[1106] intermediate compound of formula (II)

[1107]

[1109] Reaction with intermediate compound of formula (III)

[1110]

[1111] Where LG is a bromine atom.

[1112] In the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature of 50 to 70°C, in acetonitrile, for a reaction time of 1 to 2 hours,

[1113] Therefore, we obtain

[1114]

[1115] At least 99% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the presence of amorphous form is below the detection limit of differential scanning calorimetry, and its particle size distribution is as follows: x10 in the range of 1 to 4 μm, x50 in the range of 4 to 8 μm, and x90 in the range of 12 to 18 μm.

[1116] According to the fourteenth embodiment of the fifth aspect, the present invention covers a method for preparing at least 99% enantiomeric excess (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[1117] intermediate compound of formula (II)

[1118]

[1119] Reaction with intermediate compound of formula (III)

[1120]

[1121] Where LG is a bromine atom.

[1122] In the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature of 50°C to 70°C, in acetonitrile, for a reaction time of 1 to 2 hours,

[1123] Therefore, we obtain

[1124]

[1125] At least 99% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the presence of amorphous form is below the detection limit of XRPD, and its particle size distribution is as follows: x10 in the range of 0.5 to 2.5 μm, x50 in the range of 3 to 7 μm, and x90 in the range of 8 to 20 μm.

[1126] According to the fifteenth embodiment of the fifth aspect, the present invention covers a method for preparing at least 99% enantiomeric excess (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, said method comprising the following steps

[1127] intermediate compound of formula (II)

[1128]

[1129] Reaction with intermediate compound of formula (III)

[1130]

[1131] Where LG is a bromine atom.

[1132] In the presence of 1.5 to 5 equivalents of potassium phosphate, at a temperature of 50 to 70°C, in acetonitrile, for a reaction time of 1 to 2 hours,

[1133] Therefore, we obtain

[1134]

[1135] At least 99% enantiomeric excess of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the presence of amorphous form is below the detection limit of XRPD, and its particle size distribution is as follows: x10 in the range of 1 to 4 μm, x50 in the range of 4 to 8 μm, and x90 in the range of 12 to 18 μm.

[1136] Other embodiments of the fifth aspect of the present invention:

[1137] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the leaving group LG in the included steps is a chlorine atom, a bromine atom, or an iodine atom, or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy, or [(4-methylphenyl)sulfonyl]oxy.

[1138] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the leaving group LG in the included steps is a chlorine atom.

[1139] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide in microcrystalline form, wherein the leaving group LG in the included steps is a [(4-methylphenyl)sulfonyl]oxy group.

[1140] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1141] The leaving group LG in the steps it includes is a bromine atom or a [(4-methylphenyl)sulfonyl]oxy group.

[1142] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1143] The leaving group LG in the steps it includes is a bromine atom.

[1144] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1145] The steps involved are carried out in the presence of a base selected from the following: alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, and N,N,N,N-tetratetra(C1-C3-alkyl)guanidines.

[1146] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1147] The steps involved are carried out in the presence of a base selected from the following: alkali metal carbonates, alkali metal bicarbonates, and alkali metal phosphates.

[1148] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1149] The steps involved are carried out in the presence of at least one equivalent of a base selected from: alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, and N,N,N,N-tetratetra(C1-C3-alkyl)guanidine.

[1150] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, wherein

[1151] The steps involved are carried out in the presence of 1.5 to 6 equivalents of a base selected from the following: alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates, and N,N,N,N-tetratetra(C1-C3-alkyl)guanidine.

[1152] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1153] The steps involved are carried out in the presence of 1.5 to 6 equivalents of a base selected from the following: alkali metal carbonates, alkali metal bicarbonates, and alkali metal phosphates.

[1154] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1155] The steps involved are carried out in the presence of 1.5 to 6 equivalents of a base selected from: alkali metal carbonates selected from sodium carbonate, potassium carbonate and cesium carbonate; alkali metal bicarbonates selected from sodium bicarbonate, potassium bicarbonate and cesium bicarbonate; and alkali metal phosphates selected from sodium phosphate, potassium phosphate and cesium phosphate.

[1156] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1157] The steps involved are carried out in the presence of a base selected from the following: potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate, and potassium phosphate.

[1158] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1159] The steps involved are carried out in the presence of 1.5 to 6 equivalents of a base selected from the following: potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate, and potassium phosphate.

[1160] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1161] The steps involved are carried out in the presence of a base selected from potassium carbonate and potassium phosphate.

[1162] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1163] The steps involved are carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate.

[1164] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1165] The steps involved are carried out in the presence of 1.5 to 3 equivalents of potassium phosphate.

[1166] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1167] The steps involved are carried out in the presence of 2 to 6 equivalents of potassium carbonate.

[1168] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1169] The steps involved are carried out at temperatures between 0 and 100°C.

[1170] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1171] The steps involved are carried out at temperatures between 20 and 90°C.

[1172] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1173] The steps involved are carried out at temperatures between 40 and 80°C.

[1174] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1175] The steps involved are carried out at a temperature of 50 to 70°C.

[1176] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1177] The steps involved are carried out at a temperature of 40 to 80°C, and optionally the temperature is then reduced to 20°C for up to 1 hour.

[1178] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1179] The steps involved are performed at a temperature of 50 to 70°C, and optionally the temperature is then reduced to 20°C for up to one hour.

[1180] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1181] The steps involved are performed at temperatures between 40 and 80°C, followed by a reduction in temperature to 20°C over a period of up to one hour.

[1182] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1183] The steps involved are performed at a temperature of 50 to 70°C, and then the temperature is reduced to 20°C for up to one hour.

[1184] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1185] The steps involved are carried out in a solvent selected from the following: N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidone, acetone and isopropanol, or a mixture of acetone and isopropanol.

[1186] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1187] The steps involved are carried out in a solvent selected from the following: N,N-dimethylformamide, acetonitrile, N-methylpyrrolidone, acetone and isopropanol, or a mixture of acetone and isopropanol in a ratio of 5:1 (v / v) to 1:5 (v / v).

[1188] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1189] The steps involved are carried out in a solvent selected from N,N-dimethylformamide and acetonitrile.

[1190] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1191] The steps involved are carried out in the solvent N,N-dimethylformamide.

[1192] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1193] The steps involved are carried out in the solvent acetonitrile.

[1194] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1195] The steps involved are performed within 30 minutes to 24 hours.

[1196] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1197] The steps involved can take anywhere from 30 minutes to 6 hours.

[1198] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1199] The steps involved can take anywhere from 30 minutes to 2 hours.

[1200] According to another embodiment of the fifth aspect, the present invention covers a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, wherein

[1201] The steps involved take place over a period of 1 to 2 hours.

[1202] According to a sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients.

[1203] According to a second embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1204] The presence of amorphous forms is less than 15%.

[1205] Furthermore, its particle size distribution is as follows: x10<5μm, x50<10μm and x90<35μm.

[1206] According to a third embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1207] The presence of amorphous forms is less than 15%.

[1208] The particle size distribution is as follows: x10 ranges from 0.5 to 2.5 μm, x50 ranges from 3 to 7 μm, and x90 ranges from 8 to 20 μm.

[1209] According to the fourth embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1210] The presence of amorphous forms is less than 15%.

[1211] The particle size distribution is as follows: x10 ranges from 0.3 to 4 μm, x50 ranges from 4 to 10 μm, and x90 ranges from 10 to 20 μm.

[1212] According to a fifth embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1213] The presence of amorphous forms is less than 15%.

[1214] The particle size distribution is as follows: x10 ranges from 1 to 4 μm, x50 ranges from 4 to 8 μm, and x90 ranges from 12 to 18 μm.

[1215] According to a sixth embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1216] Enantiomer excess of at least 95%,

[1217] The presence of amorphous forms is less than 10%.

[1218] The particle size distribution is as follows: x10 ranges from 0.5 to 2.5 μm, x50 ranges from 3 to 7 μm, and x90 ranges from 8 to 20 μm.

[1219] According to a seventh embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1220] Enantiomer excess of at least 95%,

[1221] The presence of amorphous forms is less than 10%.

[1222] The particle size distribution is as follows: x10 ranges from 0.3 to 4 μm, x50 ranges from 4 to 10 μm, and x90 ranges from 10 to 20 μm.

[1223] According to an eighth embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1224] Enantiomer excess of at least 95%,

[1225] The presence of amorphous forms is less than 10%.

[1226] The particle size distribution is as follows: x10 ranges from 1 to 4 μm, x50 ranges from 4 to 8 μm, and x90 ranges from 12 to 18 μm.

[1227] According to a ninth embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1228] The presence of amorphous forms is less than 5%.

[1229] The particle size distribution is as follows: x10 ranges from 0.5 to 2.5 μm, x50 ranges from 3 to 7 μm, and x90 ranges from 8 to 20 μm.

[1230] According to a tenth embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1231] The presence of amorphous forms is less than 5%.

[1232] The particle size distribution is as follows: x10 ranges from 0.3 to 4 μm, x50 ranges from 4 to 10 μm, and x90 ranges from 10 to 20 μm.

[1233] According to the eleventh embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1234] The presence of amorphous forms is less than 5%.

[1235] The particle size distribution is as follows: x10 ranges from 1 to 4 μm, x50 ranges from 4 to 8 μm, and x90 ranges from 12 to 18 μm.

[1236] According to the twelfth embodiment of the sixth aspect, the present invention covers a pharmaceutical composition comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1237] Enantiomer excess of at least 98%,

[1238] The presence of amorphous forms is less than 5%.

[1239] The particle size distribution is as follows: x10 ranges from 0.5 to 2.5 μm, x50 ranges from 3 to 7 μm, and x90 ranges from 8 to 20 μm.

[1240] According to a thirteenth embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1241] Enantiomer excess of at least 98%,

[1242] The presence of amorphous forms is less than 5%.

[1243] The particle size distribution is as follows: x10 ranges from 0.3 to 4 μm, x50 ranges from 4 to 10 μm, and x90 ranges from 10 to 20 μm.

[1244] According to the fourteenth embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1245] Enantiomer excess of at least 98%,

[1246] The presence of amorphous forms is less than 5%.

[1247] The particle size distribution is as follows: x10 ranges from 1 to 4 μm, x50 ranges from 4 to 8 μm, and x90 ranges from 12 to 18 μm.

[1248] According to a fifteenth embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1249] Enantiomer excess of at least 99%,

[1250] The presence of amorphous forms is less than 5%.

[1251] The particle size distribution is as follows: x10 ranges from 1 to 2 μm, x50 ranges from 4 to 5.5 μm, and x90 ranges from 10 to 18 μm.

[1252] According to a sixteenth embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1253] Enantiomer excess of at least 99%,

[1254] The presence of amorphous forms is less than 5%.

[1255] The particle size distribution is as follows: x10 ranges from 1 to 4 μm, x50 ranges from 4 to 8 μm, and x90 ranges from 12 to 18 μm.

[1256] Other embodiments of the sixth aspect of the present invention:

[1257] According to another embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1258] Enantiomer excess of at least 95%,

[1259] The presence of amorphous forms is less than 10%.

[1260] The particle size distribution determined by method PSD2a is as follows: x10 ranges from 0.5 to 2.5 μm, x50 ranges from 3 to 7 μm and x90 ranges from 8 to 20 μm.

[1261] According to another embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1262] Enantiomer excess of at least 95%,

[1263] The presence of amorphous forms is less than 10%.

[1264] The particle size distribution determined by method PSD4 is as follows: x10 ranges from 0.3 to 4 μm, x50 ranges from 4 to 10 μm and x90 ranges from 10 to 20 μm.

[1265] According to another embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1266] Enantiomer excess of at least 95%,

[1267] The presence of amorphous forms is less than 10%.

[1268] The particle size distribution determined by method PSD4 is as follows: x10 ranges from 1 to 4 μm, x50 ranges from 4 to 8 μm and x90 ranges from 12 to 18 μm.

[1269] According to another embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1270] Enantiomer excess of at least 98%,

[1271] The presence of amorphous forms is less than 5%.

[1272] The particle size distribution determined by method PSD2a is as follows: x10 ranges from 0.5 to 2.5 μm, x50 ranges from 3 to 7 μm and x90 ranges from 8 to 20 μm.

[1273] According to another embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1274] Enantiomer excess of at least 98%,

[1275] The presence of amorphous forms is less than 5%.

[1276] The particle size distribution determined by method PSD4 is as follows: x10 ranges from 0.3 to 4 μm, x50 ranges from 4 to 10 μm and x90 ranges from 10 to 20 μm.

[1277] According to another embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1278] Enantiomer excess of at least 98%,

[1279] The presence of amorphous forms is less than 5%.

[1280] The particle size distribution determined by method PSD4 is as follows: x10 ranges from 1 to 4 μm, x50 ranges from 4 to 8 μm and x90 ranges from 12 to 18 μm.

[1281] According to another embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1282] Enantiomer excess of at least 99%,

[1283] The presence of amorphous forms is less than 5%.

[1284] The particle size distribution determined by method PSD2a is as follows: x10 ranges from 1 to 2 μm, x50 ranges from 4 to 5.5 μm and x90 ranges from 10 to 18 μm.

[1285] According to another embodiment of the sixth aspect, the present invention covers pharmaceutical compositions comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form and one or more pharmaceutically acceptable excipients, wherein

[1286] Enantiomer excess of at least 99%,

[1287] The presence of amorphous forms is less than 5%.

[1288] The particle size distribution determined by method PSD4 is as follows: x10 ranges from 1 to 4 μm, x50 ranges from 4 to 8 μm and x90 ranges from 12 to 18 μm.

[1289] The microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide of the present invention can be used to inhibit, block, reduce or decrease DGKζ activity, thereby modulating dysregulated immune responses, such as blocking immunosuppression and increasing immune cell activation and infiltration in the context of cancer and cancer immunotherapy, ultimately leading to a reduction in tumor growth.

[1290] The method involves administering a specific amount of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form to a mammal (including a human) in need; which effectively treats the condition.

[1291] The present invention also provides methods for treating a variety of other conditions, wherein DGKζ relates to, for example but not limited to, conditions of immune dysregulation, inflammation, vaccination against infection and cancer, viral infection, lymphoproliferative disorders, asthma, eye diseases and type 2 diabetes / insulin resistance.

[1292] These conditions are well characterized in humans, but also exist in other mammals with similar etiologies, and can be treated by administering the pharmaceutical compositions of the present invention.

[1293] According to another aspect, the present invention covers the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide as described above, for the treatment or prevention of diseases, particularly cancers or conditions with dysregulation of immune response or other conditions associated with abnormal DGKζ signaling.

[1294] The pharmaceutical activity of the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-aniline)propionamide of the present invention can be explained by the activity of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-aniline)propionamide, the base compound for DGKζ inhibitors.

[1295] According to another aspect, the present invention covers the use of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form as described above for the treatment or prevention of diseases, particularly cancers or conditions with immune dysregulation or other conditions associated with abnormal DGKζ signaling, especially liquid and solid tumors.

[1296] According to another aspect, the present invention covers the use of the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide as described above for the treatment or prevention of diseases, particularly cancers or conditions with immune dysregulation or other conditions associated with abnormal DGKζ signaling, especially liquid and solid tumors.

[1297] According to another aspect, the present invention covers the use of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form as described above in methods for treating or preventing diseases, particularly cancers or conditions with dysregulation of immune response or other conditions associated with abnormal DGKζ signaling, especially liquid and solid tumors.

[1298] According to another aspect, the present invention covers the use of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form as described above in methods for treating or preventing diseases, particularly cancers or conditions with dysregulation of immune response or other conditions associated with abnormal DGKζ signaling, especially liquid and solid tumors.

[1299] According to another aspect, the present invention covers the use of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form as described above for the preparation of pharmaceutical compositions, preferably pharmaceutical agents, for the treatment or prevention of diseases, particularly cancers or conditions with immune dysregulation or other conditions associated with abnormal DGKζ signaling, especially liquid and solid tumors.

[1300] According to another aspect, the present invention covers methods for treating or preventing diseases, particularly cancers or conditions with immune dysregulation or other conditions associated with abnormal DGKζ signaling, especially liquid and solid tumors, using effective amounts of the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide as described above.

[1301] According to another aspect, the present invention covers pharmaceutical compositions, particularly formulations, comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form as described above and one or more excipients, particularly one or more pharmaceutically acceptable excipients. Such pharmaceutical compositions can be prepared in suitable dosage forms using conventional method steps.

[1302] Furthermore, the present invention also covers pharmaceutical compositions, particularly pharmaceutical preparations, comprising at least one of the microcrystalline forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide of the present invention, conventionally together with one or more pharmaceutically suitable excipients, and their use for the above-mentioned purposes.

[1303] The microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide of the present invention can have systemic and / or local activity. Therefore, they can be administered in suitable manner, for example, by oral, parenteral, pulmonary, nasal, sublingual, tongue, buccal, rectal, vaginal, dermal, transdermal, conjunctival, ear canal, or as implants or scaffolds.

[1304] For these routes of administration, the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide of the present invention can be administered in a suitable manner.

[1305] For oral administration, the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-aniline)propionamide of the present invention can be formulated in microcrystalline form into dosage forms known in the art for rapid and / or modified delivery of the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-aniline)propionamide of the present invention, such as tablets (uncoated or coated tablets, such as delayed-dissolving or insoluble enteric or controlled-release coated tablets), orally disintegrating tablets, films / sheets, films / lyophilized products, capsules (e.g., hard gelatin capsules or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, or aerosols.

[1306] Parenteral administration can be performed while avoiding absorption steps (e.g., intravenous, intra-arterial, intracardiac, intraspinal, or lumbar) or involving absorption (e.g., intramuscular, subcutaneous, intradermal, percutaneous, or intraperitoneal). Suitable parenteral administration forms are particularly those for injection and infusion in the form of suspensions, emulsions, lyophilized products, or sterile powders.

[1307] Examples of other routes of administration include: inhaled drug forms [especially powder inhalers, nebulizers], nasal drops, nasal sprays; tablets / films / sheets / capsules for administration via the tongue, sublingual or oral cavity; suppositories; eye drops, eye ointments, eye washes, ophthalmic inserts, ear drops, ear sprays, ear powders, ear washes, earplugs; vaginal capsules, aqueous suspensions (washes, shaken mixtures), lipophilic suspensions, emulsions, ointments, creams, transdermal therapy systems (such as patches), lotions, pastes, foams, powders, implants or stents.

[1308] The (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide of the present invention can be introduced in the described administration formulation. This can be achieved, in a manner known per se, by mixing with a pharmaceutically suitable excipient. Pharmaceutically suitable excipients particularly include:

[1309] • Fillers and carriers (e.g., cellulose, microcrystalline cellulose) ), lactose, mannitol, starch, calcium phosphate (e.g.) )),

[1310] • Ointment base (such as petrolatum, paraffin, triglycerides, wax, lanolin, lanolin alcohol, hydrophilic ointments, polyethylene glycol),

[1311] • Suppository base (e.g., polyethylene glycol, cocoa butter, solid fat),

[1312] Solvents (e.g., water, ethanol, isopropanol, glycerol, propylene glycol, medium-chain triglyceride fatty oils, liquid polyethylene glycol, paraffin),

[1313] Surfactants, emulsifiers, dispersants or wetting agents (e.g., sodium lauryl sulfate), lecithin, phospholipids, fatty alcohols (e.g.) ), dehydrated sorbitol fatty acid esters (such as ), polyoxyethylene dehydrated sorbitol fatty acid esters (such as ), polyoxyethylene fatty acid glycerides (such as ), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamer (such as ),

[1314] • Buffers, acids and bases (e.g., phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, tromethamine, triethanolamine),

[1315] • Isotonic agents (e.g., glucose, sodium chloride),

[1316] • Adsorbent (e.g., highly dispersed silica),

[1317] • Tackifiers, gelling agents, thickeners and / or adhesives (e.g., polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, starch, carbomer, polyacrylic acid (e.g.) (); alginate, gelatin),

[1318] • Disintegrants (e.g., modified starch, sodium carboxymethyl cellulose, sodium starch glycolate (e.g., ), cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose (e.g., )),

[1319] • Flow conditioners, lubricants, flow aids, and release agents (e.g., magnesium stearate, stearic acid, talc, highly dispersed silica (e.g., )),

[1320] • Coating materials (e.g., sugar, shellac) and film-forming agents that dissolve rapidly or in a modified manner in the form of films or diffusion films (e.g., polyvinylpyrrolidone). Polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate, cellulose phthalate, polyacrylate, polymethacrylate (e.g.) )),

[1321] • Capsule materials (e.g., gelatin, hydroxypropyl methylcellulose),

[1322] • Synthetic polymers (e.g., polylactic acid, polyglycolic acid, polyacrylate, polymethacrylate) ), polyvinylpyrrolidone (e.g.) Polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, polyethylene glycol and their copolymers and block copolymers),

[1323] Plasticizers (e.g., polyethylene glycol, propylene glycol, glycerin, triacetyl citrate, dibutyl phthalate),

[1324] • Penetration enhancer

[1325] • Stabilizers (e.g., antioxidants such as ascorbic acid, ascorbate palmitate, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate),

[1326] • Preservatives (such as parabens, sorbic acid, thimerosal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

[1327] • Colorants (e.g., inorganic pigments, such as iron oxide, titanium dioxide),

[1328] • Flavoring agents, sweeteners, flavor and / or odor masking agents.

[1329] The present invention also relates to pharmaceutical compositions comprising at least one of the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamides of the present invention in microcrystalline form, conventionally together with one or more pharmaceutically suitable excipients, and their use according to the present invention.

[1330] Based on known standard laboratory techniques, the effective dose of the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl]-4-fluoroaniline)propionamide for treating cancers or conditions with dysregulated immune responses or other conditions associated with abnormal DGKζ signaling can be readily determined for each desired indication by standard toxicity tests and standard pharmacological tests used to determine treatment for the aforementioned identified conditions in mammals, and by comparing these results with those of known active ingredients or agents used to treat these conditions. The amount of active ingredient administered in the treatment of one of these conditions may vary widely depending on the following considerations: the specific microcrystalline form and dosage unit of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide used, the route of administration, the duration of treatment, the age and sex of the patient being treated, and the nature and extent of the condition being treated.

[1331] The total amount of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form generally ranges from about 0.001 mg / kg to about 200 mg / kg body weight / day, preferably from about 0.01 mg / kg to about 20 mg / kg body weight / day. Clinically useful dosing regimens are from once to three times daily to once every four weeks. In addition, a "withdrawal period"—in which the patient is not given the drug for a period of time—may be beneficial for the overall balance between pharmacological efficacy and tolerability. Unit doses may contain from about 0.5 mg to about 1500 mg of active ingredient and may be administered once or more daily, or less than once daily. The average daily dose administered by injection—including intravenous, intramuscular, subcutaneous, and parenteral injection—and by infusion techniques is preferably from 0.01 to 200 mg / kg body weight. The average daily rectal dosing regimen is preferably from 0.01 to 200 mg / kg body weight. The preferred average daily vaginal dosage regimen is 0.01 to 200 mg / kg of total body weight. The preferred average daily topical dosage regimen is 0.1 to 200 mg administered once to four times daily. The preferred transdermal concentration is the concentration required to maintain a daily dose of 0.01 to 200 mg / kg. The preferred average daily inhalation dosage regimen is 0.01 to 100 mg / kg of total body weight.

[1332] Of course, the specific initial and continuous dosage regimens for each patient will vary depending on the following factors: the nature and severity of the condition as determined by the attending physician, the activity of the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide used, the patient's age and overall condition, timing of administration, route of administration, drug excretion rate, drug combination, etc. The desired mode of treatment and dosage of the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide of the present invention, or its pharmaceutically acceptable salts or esters, or combinations thereof, can be determined by those skilled in the art using conventional therapeutic trials. Attached Figure Description

[1333] Figure 1 XRPD (Method XRPD1) of the material obtained in Example 2

[1334] Figure 2 DSC (Method DSC1) of the material obtained in Example 2

[1335] Figure 3 XRPD of the material obtained in Example 3 (the figure below shows peak extraction).

[1336] Table 1: Corresponding to Figure 3Peak extraction from the image below:

[1337]

[1338]

[1339] Figure 4 DSC (Method DSC1) of the material obtained in Example 3

[1340] Figure 5 Dissolution profiles were compared in 0.1% SDS phosphate buffer (pH 6.8); the thermodynamic solubility of the crystalline material was approximately 20%; 100% dissolution equals 201.5 μg / mL. The materials presented are (i) the material of Reference Example 1 after jet milling (- - - - - -), (ii) the material of Example 3 (- · - · - ·), and (iii) the material of Reference Example 2 (- - - - - -). The Y-axis relates to the amount dissolved (%), and the X-axis relates to time in minutes.

[1341] Figure 6 : Enlarged display as Figure 5 The dissolution curves shown are compared after the first hour, with the y-axis clipped to 30%.

[1342] Figure 7 XRPD (Method XRPD2) of the material obtained from Reference Example 1 before jet milling.

[1343] Figure 8 DSC (Method DSC2) of the material obtained from Reference Example 1 before jet milling.

[1344] Figure 9 DSC (Method DSC2) of the material obtained from Reference Example 1 after jet milling.

[1345] Figure 10 XRPD comparison of the material in Example 1 before (top diffraction pattern) and after (bottom diffraction pattern) jet milling (Method XRPD2)

[1346] Figure 11 XRPD (Method XRPD 3) of the material obtained from Reference Example 2

[1347] Figure 12 DSC (Method DSC 3) of the material obtained from Reference Example 2

[1348] Figure 13 Particle size distribution of the material obtained from Example 4 (Method PSD 4)

[1349] Figure 14DSC (Method DSC1) of the material obtained from Example 4

[1350] Figure 15 XRPD (Method XRPD 1) of the material obtained from Example 4

[1351] Figure 16 Dissolution profiles of tablets containing equal amounts of microcrystalline (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide obtained according to Examples 3 (-▲-) and 4 (-◆-) were compared. The Y-axis represents the amount dissolved (%), and the X-axis represents time in minutes.

[1352] Experimental Section

[1353] Table 2: Abbreviations

[1354] The following table lists the abbreviations used in this article.

[1355] XRPD X-ray powder diffraction

[1356] DSC Differential Scanning Calorimetry

[1357] PSD particle size distribution

[1358] HPLC (High Performance Liquid Chromatography)

[1359] UPLC (Ultra-High Performance Liquid Chromatography)

[1360] ee or ee enantiomer excess

[1361] w / w weight ratio

[1362] v / v volume ratio

[1363] ELSD Evaporative Light Scattering Detector

[1364] MS mass spectrometry

[1365] NMR (Nuclear Magnetic Resonance)

[1366] RT,rt room temperature

[1367] t R Retention time

[1368] SDS Sodium lauryl sulfate

[1369] PMMA (Polymethyl Methacrylate)

[1370] The following examples illustrate various aspects of the invention described in this application, and these examples are not intended to limit the invention in any way.

[1371] The exemplary test experiments described herein are for illustrative purposes only, and the invention is not limited to the given embodiments.

[1372] Experimental Section - Materials and Methods

[1373] HPLC and LC / MS methods:

[1374] Method HPLC1: Preparative HPLC :

[1375] Instruments: Pump: Labomatic HD-5000 or HD-3000, head HDK 280, low-pressure gradient module ND-B1000; Manual injection valve: Rheodyne 3725i038; Detector: Knauer Azura UVD 2.15; Collector: LabomaticLabocol Vario-4000; Column: Chromatorex RP C-18 10μm, 125x30mm; Eluent: Solvent A: Water + 0.2 vol% ammonia (32%), Solvent B: Acetonitrile; Gradient: 0.00-0.50 min 15% B (150 ml / min), 0.50-6.00 min 15-55% B (150 ml / min), 6.00-6.10 min 55-100% B (150 ml / min), 6.10-8.00 min 100% B (150ml / min); UV: 361nm

[1376] Method 2: HPLC; Analytical UPLC / MS:

[1377] Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.750x2.1mm; Eluent: Solvent A: Water + 0.2% (v / v) ammonia (32%), Eluent Solvent B: Acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate: 0.8 mL / min; Temperature: 60℃; Injection volume: 2 μL; DAD scan: 210-400 nm; ELSD

[1378] Method HPLC3: Analytical chiral HPLC:

[1379] Instruments: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SB 3μ, 100x4.6; Eluent solvent A: hexane + 0.1 v / v diethylamine; Eluent solvent B: 2-propanol; Isocratic ratio: 60% A + 40% B; Flow rate: 1.4 ml / min; Temperature: 25 °C; UV: 254 nm

[1380] Method HPLC4: Chemical purity, Examples 3 and 4 and Reference Example 2:

[1381] Equipment: High-performance liquid chromatograph (pressure range up to 600 bar, hysteresis volume approximately 850 μL), with a temperature-controlled column oven, UV detector, and data evaluation system (e.g., Agilent 1260).

[1382] Column:Waters Acquity BEH Shield C18

[1383] Length: 50mm, Inner Diameter: 2.1mm, Particle Size: 1.7μm

[1385] Maximum pressure: 600 bar

[1386] Standard starting pressure: 500 bar

[1387] Eluent: A: 1580 mg ammonium bicarbonate + 80 μL formic acid (98+%) / 1 L Milli-Q water (compressibility: solvent type used)

[1388] B: Acetonitrile (Compressibility: Solvent type used)

[1390] gradient:

[1391] The percentage of mobile phase A is the difference between B (%) and 100%.

[1392] Equilibrium time: 1 min (under initial conditions)

[1393] Flow rate: 0.7 mL / min

[1394] Inhalation rate: 200 μL / min

[1395] Injection volume: 2.5 μL (RT)

[1396] Needle cleaning: Flushing hole time (7 seconds)

[1397] Solvent: methanol

[1398] Column temperature: 40℃

[1399] Data sampling rate: 20Hz (>0.013min (0.25s response time))

[1400] Detection wavelength: 270nm, bandwidth: 4nm

[1401] Compensation for negative absorption: 100mAU

[1403] Detector cell path: 10mm

[1404] Slit: 4nm

[1405] Sample solvent: acetonitrile

[1406] Sample / calibration solution: Dissolve the sample with a concentration of approximately 0.25 mg / mL (e.g., accurately weigh 25 mg and dissolve it in 100 mL) in the sample solvent and fill it into the calibration mark.

[1407] Method HPLC 5: Enantiomer excess, Examples 3 and 4 and Reference Example 2:

[1408] Equipment: Ultra-high performance liquid chromatograph with a temperature-controlled column oven, UV detector, and data evaluation system; hysteresis volume approximately 200 μL (e.g., Agilent 1290).

[1409] Column: Daicel Chiralpak IB N-3

[1410] Length: 150mm, Inner Diameter: 4.6mm, Particle Size: 3.0μm

[1411] Maximum pressure: 300 bar

[1412] Standard starting pressure: 210 bar

[1413] Column temperature: 25℃

[1414] Mobile phase: A: n-Heptane / ethanol + 0.1% TFA (50% + 50%; V: V) (Compressibility: Solvent type used)

[1415] Flow rate 1.50 mL / min

[1416] Isotropic: A (%): 100

[1417] Runtime: 8.0 min

[1418] Detector cell path: 10mm

[1419] Detection wavelength: 265nm, bandwidth: 4nm

[1420] Data sampling rate: 2.5Hz (>0.1 min (2 s response time))

[1421] Compensation for negative absorption: 100mAU

[1422] Slit: 4nm

[1423] Injection volume: 3.0 μL (RT)

[1424] Inhalation rate: 200 μL / min

[1425] Needle cleaning: Flushing hole time (7 seconds)

[1426] Solvent: Ethanol

[1427] Sample solvent: Ethanol. Sample solution: Dissolve the sample with a concentration of approximately 1.0 mg / mL (e.g., accurately weigh 25 mg and dissolve it in 25 mL) in the sample solvent and fill to the calibration mark.

[1428] Method HPLC6: Preparative chiral HPLC:

[1429] Instruments: Labomatic HD3000, Knauer Pump 100, Labcol Vario 4000Plus, Knauer DAD 2600; Column: amylose SB 5μm 250x50mm Nr.34; Eluent A: Hexane + 0.1 v / v diethylamine (99%); Eluent B: 2-propanol; Isocratic Osmosis: 60% A + 40% B; Flow Rate: 150.0 ml / min, decreasing to 180 ml / min after 16 min; UV @ 254 nm

[1430] Particle size distribution (PSD)

[1431] Method PSD1: Particle size distribution (PSD) was measured by laser diffraction using a Malvern Panalytical Mastersizer 3000. 0.1% Span 85 in heptane was used as the dispersion medium. The sample was sonicated at 40% intensity for 45 seconds.

[1432] Method PSD2a: Particle size distribution (PSD) was measured by laser diffraction using a Sympatec Helos instrument. Water containing a small amount of surfactant was used as the dispersion medium. The sample was sonicated for 240 seconds.

[1433] Method PSD2b: Particle size distribution (PSD) was measured by laser diffraction using a Sympatec Helo instrument. Kerosene (Paraffin) was used as the dispersion medium. The sample was sonicated for 240 seconds.

[1434] Method PSD3: Particle size analysis was performed by laser diffraction using Sympatatec (HELOS) with Baysilone (Element 14PDMS10-A) as the dispersion medium. The sample was sonicated at 80% intensity for 90 seconds (with a 60-second interruption) and stirred with a magnetic stirrer at 800 rpm. Measurements were performed three times (with a 30-second interruption), and the arithmetic mean was calculated.

[1435] Method PSD4: Particle size analysis was performed using a Malvern Panalytical Mastersizer 3000 via laser diffraction. A water medium containing one drop of Tween 80 was used as the dispersion medium. The sample was sonicated for 180 seconds.

[1436] Differential scanning calorimetry (DSC)

[1437] Method DSC1:

[1438] Differential scanning calorimetry (DSC) was performed using a Mettler Toledo TGA / DSC 3+ instrument. The instrument was purged with nitrogen at a flow rate of 20 ml / min. -1 Place approximately 1-15 mg of each sample into an aluminum crucible and start at 25°C, incubating at 20°C for 1 minute. -1 Heating is performed at a specific heating rate. No sample preparation is required.

[1439] Method DSC2:

[1440] Differential scanning calorimetry (DSC) was performed using a Mettler Toledo TGA / DSC 3+ instrument. The instrument was purged with nitrogen at a flow rate of 30 ml / min. -1 Place approximately 1-15 mg of each sample into an aluminum crucible and, starting at 25°C, incubate at 10 or 20°C per minute. -1 Heating is performed at a specific heating rate. No sample preparation is required.

[1441] Method DSC 3:

[1442] Differential scanning calorimetry (DSC) was performed using a Mettler Toledo DSC3. The calorimeter was purged with nitrogen at a flow rate of 50 ml / min. -1 Place approximately 3-5 mg of sample into an aluminum crucible; no sample preparation is required. The temperature range is -10 to 230 °C, and the heating rate is 20 °C / min. -1 .

[1443] X-ray powder diffraction (XRPD)

[1444] Method XRPD1:

[1445] X-ray powder diffraction (XRPD) data were obtained using Cu Kα1 radiation. Data were recorded on a Bruker D2 PHASER diffractometer with a LYNXEYE-2 detector. All samples were prepared and measured at ambient temperature on low-background silicon single-crystal sample holders (open or with PMMA domes). Data were recorded in 0.3-second steps between 3 and 40° (2θ) or 4 and 40° (2θ). -1The X-ray tube was collected in a Bragg-Brentano (θ / 2θ) horizontal geometry with a step size of 0.02°. The X-ray tube was operated at 30 kV and 10 mA.

[1446] Method XRPD2:

[1447] X-ray powder diffraction (XRPD) data were recorded on a PANalytical X'Pert PRO diffractometer using monochromatic Cu-Kα1 radiation at a generator setting of 40 kV and 40 mA. Samples were collected in transmission mode and prepared as thin layers between two foils. The scanning range was between 2° and 40°2θ, with a step size of 0.013° at 25 sec / step.

[1448] Method XRPD3:

[1449] X-ray powder diffraction (XRPD) data were recorded on a STOESTADI P diffractometer using monochromatic Cu-Kα1 radiation and a position-sensitive detector at a generator setting of 40 kV and 40 mA. Samples were collected in transmission mode and prepared as a thin layer between two foils. The scanning range was between 2° and 40°2θ, with a step size of 0.5° at 15 seconds per step.

[1450] Solubility comparison

[1451] The solubility properties of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, from the material of Example 3, compared with the materials of Reference Examples 1 and 2.

[1452] method

[1453] sample

[1454] The following batches were provided for the comparative experiments:

[1455] The product obtained from Example 3, namely, (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide microcrystals prepared according to the method of the present invention.

[1456] The product obtained from Reference Example 1, namely, a batch of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, was prepared by jet milling of a crystallization batch and contained a portion of amorphous material.

[1457] The crude batch of the product obtained from Reference Example 2, namely, (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide

[1458] set up

[1459] Phosphate buffer with pH 6.8 and 0.1% SDS was used as the dissolution medium. The 100% level was set at 201.5 μg / ml. Based on previous solubility data for (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, the thermodynamic solubility of this compound from the crystallized batch should result in approximately 20% release. Possible supersaturation in the studied batch was detected using a higher weighing energy.

[1460] calibration

[1461] Calibration and measurements were performed using the μDissolver from PION, a compact dissolution device with an in-situ UV probe that enables high temporal resolution. Five-point calibration was recorded from 0 to 207 μg / ml in phosphate buffer at pH 6.8 containing 2% SDS. Detection wavelengths were set to 255–268 nm (method range, second derivative).

[1462] Measurement

[1463] 2.015 mg (±0.1 mg) of the corresponding active pharmaceutical ingredient (API) was transferred to a μDiss container, and 10 ml of phosphate buffer (pH 6.8) containing 0.1% SDS was added. Dissolution profiles were recorded over approximately five and a half hours. Measurements were repeated for each sample (n=2). For the batch in Reference Example 2, the in-situ UV probe in one container became clogged with particles during the measurement; therefore, this batch was studied from only a single container (n=1).

[1464] Experimental Section - Examples

[1465] Example 1: Preparation of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide (screening of method variants)

[1466] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazo-2-yl]-4-fluoro-aniline)propionamide

[1467]

[1468] Example 1a

[1469] [4-amino-2-(4-fluoroaniline)-1,3-thiazolyl-5-yl](4-methoxyphenyl) methyl ketone (100 mg, 0.29 mmol, CAS 697232-63-6, WO2021 / 214019, see also Reference Example 1 below, step 1) was dissolved in N,N-dimethylformamide (2.1 mL), followed by the addition of potassium carbonate (K2CO3, 201 mg, 1.46 mmol) and (2S)-2-bromopropionamide (53.1 mg, 0.35 mmol, CAS 41137-34-2, purchased from Enamine). The reaction mixture was stirred at room temperature for 24 hours, filtered, and purified by preparative HPLC (method HPLC 1) to give 73.8 mg (0.18 mmol, 61% yield) of the title compound with 88% ee.

[1470] Example 1b

[1471] [4-amino-2-(4-fluoroaniline)-1,3-thiazolyl-5-yl](4-methoxyphenyl) methyl ketone (50 mg, 0.145 mmol) was dissolved in isopropanol / acetone 3 / 1 (1.2 mL), followed by the addition of N,N,N,N-tetramethylguanidine (25 mg, 0.22 mmol) and (2S)-2-bromopropionamide (26.6 mg, 0.17 mmol). The reaction mixture was stirred at room temperature for 48 hours and then at 50 °C for 2 hours. The mixture was filtered and purified by preparative HPLC (method HPLC 1) to give 22.7 mg (0.05 mmol, 38% yield) of the title compound with 61% ee.

[1472] Example 1c

[1473] [4-amino-2-(4-fluoroaniline)-1,3-thiazolyl-5-yl](4-methoxyphenyl) methyl ketone (50 mg, 0.145 mmol) was dissolved in 1-methyl-2-pyrrolidone (1.3 mL), followed by the addition of potassium carbonate (100 mg, 0.73 mmol) and (2S)-2-bromopropionamide (26.6 mg, 0.17 mmol). The reaction mixture was stirred at room temperature for 48 hours, filtered, and purified by preparative HPLC (method HPLC 1) to give 27 mg (0.06 mmol, 44% yield) of the title compound with 76% ee.

[1474] Example 1d

[1475] [4-amino-2-(4-fluoroaniline)-1,3-thiazolyl-5-yl](4-methoxyphenyl) methyl ketone (50 mg, 0.145 mmol) was dissolved in N,N-dimethylformamide (1.2 mL), followed by the addition of potassium bicarbonate (KHCO3, 73 mg, 0.73 mmol) and (2S)-2-bromopropionamide (26.6 mg, 0.17 mmol). The reaction mixture was stirred at room temperature for 48 hours and then at 50 °C for 2 hours. The mixture was filtered and purified by preparative HPLC (method HPLC 1) to give 27 mg (0.06 mmol, 44% yield) of the title compound with 63% ee.

[1476] Example 1e

[1477] [4-amino-2-(4-fluoroaniline)-1,3-thiazolyl-5-yl](4-methoxyphenyl) methyl ketone (100 mg, 0.29 mmol) was dissolved in N,N-dimethylformamide (2.1 mL), followed by the addition of potassium carbonate (201 mg, 1.46 mmol) and (2S)-2-bromopropionamide (53.1 mg, 0.35 mmol). The reaction mixture was stirred at room temperature for 5 hours, filtered, and purified by preparative HPLC (method HPLC 1) to give 73.8 mg (0.18 mmol, 61% yield) of the title compound with 91% ee.

[1478] Example 1f

[1479] [4-Amino-2-(4-fluoroaniline)-1,3-thiazolyl-5-yl](4-methoxyphenyl) ketone (50 mg, 0.145 mmol) was dissolved in N,N-dimethylformamide (1.2 mL), followed by the addition of N,N,N,N-tetramethylguanidine (25 mg, 0.22 mmol) and (2S)-2-bromopropionamide (26.6 mg, 0.17 mmol). The reaction mixture was stirred at room temperature for 24 h, filtered, and purified by preparative HPLC (method HPLC 1) to give 26 mg (0.06 mmol, 43.6% yield) of the title compound with 86% ee.

[1480] Example 1g

[1481] [4-Amino-2-(4-fluoroaniline)-1,3-thiazolyl-5-yl](4-methoxyphenyl) methyl ketone (65 mg, 0.19 mmol) was dissolved in N,N-dimethylformamide (1.4 mL), followed by the addition of potassium carbonate (133 mg, 0.96 mmol) and (S)-1-amino-1-oxopropyl-2-yl 4-methylbenzenesulfonate (56 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 24 hours and then at 60 °C for 2 hours. The mixture was filtered and purified by preparative HPLC (method HPLC 1) to give 46 mg (0.11 mmol, 58% yield) of the title compound with 88% ee.

[1482] Example 1h

[1483] [4-Amino-2-(4-fluoroaniline)-1,3-thiazolyl-5-yl](4-methoxyphenyl) methyl ketone (71.5 mg, 0.21 mmol) was dissolved in N,N-dimethylformamide (1.4 mL), followed by the addition of potassium carbonate (144 mg, 1.04 mmol) and (S)-1-amino-1-oxopropyl-2-yl 4-methylbenzenesulfonate (61 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for 4 hours and then at 60 °C for 1 hour. The mixture was filtered and purified by preparative HPLC (method HPLC 1) to give 24 mg (0.06 mmol, 28% yield) of the title compound with 94% ee.

[1484] Example 1i

[1485] [4-amino-2-(4-fluoroaniline)-1,3-thiazolyl-5-yl](4-methoxyphenyl) methyl ketone (71.5 mg, 0.21 mmol) was dissolved in N,N-dimethylformamide (1.4 mL), followed by the addition of N,N,N,N-tetramethylguanidine (36 mg, 0.31 mmol) and (S)-1-amino-1-oxopropyl-2-yl 4-methylbenzenesulfonate (61 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for 2 hours and then at 60 °C for 1 hour. The mixture was filtered and purified by preparative HPLC (method HPLC 1) to give 24 mg (0.06 mmol, 28% yield) of the title compound with 95% ee.

[1486] Data analysis of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide obtained from Examples 1a-1i:

[1487] LC / MS (Method HPLC2):t R =1.06min / MS(ESIpos):m / z=415.5[M+H]+

[1488] Analytical chiral HPLC (Method HPLC3):t R = 5.92 min (t of Example 1a; Example 1b-1i) R The time was 5.9 to 6.2 minutes; (S)-enantiomers were found at t R (Washed off in 3.49 to 3.55 minutes)

[1489] 1 H-NMR (400MHz, DMSO-d6): δppm=1.16(d,3H),3.75(s,3H),5.06(q,1H),6.93(d,2H),7.2 2-7.27(m,1H),7.34(dd,2H),7.48(d,2H),7.57(s,1H),7.64(dd,2H),7.79-8.38(m,2H).

[1490] Example 2: Crystallization of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide yielded the microcrystalline form of the present invention.

[1491] 2.5 g of solid (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide was weighed and added to a 100 mL crystallization container. 26.74 g of acetone and 2.98 g of water were added. The suspension was stirred at 20 °C for 10 minutes to obtain an API solution. In a second 100 mL crystallization container, 59.42 g of water was pre-cooled to 5 °C and stirred. The API solution was metered onto the pre-cooled water over 30 minutes while maintaining the temperature at 5 °C. The resulting suspension was separated by filtration, and the filter cake was washed with a replacement wash solution of 70 wt% (5.0 g) of acetone / H₂O, followed by a wash solution of H₂O (5.0 g). The wet filter cake was vacuum dried at 60 °C, yield: 89.9%.

[1492] Compared to WO 2021 / 214019 (see within) Figure 9 Table 16), the XRPD analysis (method XRPD 1) of the (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide obtained therefrom showed no evidence of amorphous material or crystal form difference. Figure 1 DSC (method DSC1) indicates complete crystallinity and shows no evidence of the presence of amorphous material. Figure 2 The PSD, measured by method PSD1, is 1.8 / 4.3 / 12.6 μm for x10 / x50 / x90.

[1493] Example 3: Preparation of microcrystalline (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide

[1494] A suspension of [4-amino-2-(4-fluoroanilino)thiazolyl-5-yl]-(4-methoxyphenyl)methyl ketone (120 g, 349 mmol), (2S)-2-bromopropionamide (63.7 g, 419 mmol, 1.2 equivalents, 95% enantiomeric excess) and potassium phosphate (K3PO4, 148 g, 699 mmol, 2.0 equiv) in acetonitrile (1200 mL) was heated to 60 °C and stirred at that temperature for 1 hour. The temperature was then lowered to 20 °C over 40 minutes, while water (1200 mL) was added over 20 minutes simultaneously. The resulting three-phase mixture was stirred at 20°C for 3 hours, filtered, and the filter cake was washed with water (3 x 240 mL) to obtain a pale yellow solid (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide (124 g wet, purity 99.14%, 99.2% enantiomeric excess). The water content of the wet filter cake was determined to be 16%, equivalent to 20 mL of residual water in the wet filter cake. This amount was taken into account in the subsequent microcrystallization step.

[1495] At ambient temperature, the wet filter cake was dissolved in a mixture of acetone (1350 mL) and water (130 mL) to obtain a solution with a small amount of residual solids. The mixture was filtered and the filtrate was added to water (2000 mL) at 4–10 °C over 38 minutes. The resulting dispersed, grayish-white suspension was filtered, the filter cake was washed with water (2 x 150 mL), and dried under vacuum at 50 °C to obtain a grayish-white, blocky powder of (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide (90.3 g, 216 mmol, 62% yield, 99.12% purity, 99.3% enantiomeric excess). The PSD determined by method PSD2a was (x10 / x50 / x90): 1.2 / 4.6 / 16.1 μm.

[1496] According to HPLC methods 4 and 5 above, determine the chemical purity and enantiomeric excess as specified above.

[1497] Chemical purity (HPLC method 4): t R =5.4min.

[1498] Enantiomer excess (HPLC method 5):

[1499] t R=2.9min((2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide)

[1500] t R =2.3min((2S)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide)

[1501] Compared with WO 2021 / 214019 ( Figure 3 XRPD analysis (method XRPD 1) of (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide obtained therefrom showed no evidence of amorphous material or crystal form difference. Figure 1 DSC (method DSC1) indicates complete crystallinity and shows no evidence of the presence of amorphous material. Figure 4 The dissolution rate of the material is only slightly slower than that obtained from jet milling of coarse-grained material (see Reference Example 1), but slower than that of the coarse-grained comparative material disclosed in Reference Example 2. Figure 5 , 6 The material dissolves much faster.

[1502] Preparation of starting materials for Example 3:

[1503] Preparation of [4-amino-2-(4-fluoroanilino)thiazolyl-5-yl]-(4-methoxyphenyl)methyl ketone:

[1504] A mixture of 1-fluoro-4-isothiocyanobenzene (300 g, 1.96 mol) and triethylamine (297 g, 2.94 mol, 1.5 equivalents) in acetonitrile (0.90 L) was heated to 60 °C. Over one hour, a solution of cyanamide (90.6 g, 2.15 mol, 1.1 equivalents) in acetonitrile (1.35 L) was added to the mixture. After another hour, a solution of 2-bromo-1-(4-methoxyphenyl)ethyl ketone (449 g, 1.96 mol, 1.0 equivalents) in acetonitrile (2.25 L) was added over 75 minutes at 60 °C. After another 15 minutes, the suspension was cooled to 20 °C over 0.5 hours and stirred at this temperature for another 0.5 hours. The mixture was filtered, the precipitate was washed with H2O and dried under vacuum at 50 °C to give a yellow or orange solid [4-amino-2-(4-fluoroanilino)thiazolyl-5-yl]-(4-methoxyphenyl)methyl ketone (606 g, 1.75 mol, 89% yield, 99.0% purity).

[1505] Preparation of (2S)-2-bromopropionamide:

[1506] A mixture of (2S)-2-bromopropionic acid (200 g, 1.31 mol, 88% ee, purchased from ABCR) and thionyl chloride (218 g, 1.83 mol, 1.4 equivalents) was heated to 50 °C. After 18 hours, the resulting crude acyl chloride was diluted with 2-methyltetrahydrofuran (1.85 L) and added to a 30% aqueous ammonia solution (381 g, 3.27 mol, 2.5 equivalents) over 75 minutes at -15 to 7 °C. After the addition was complete, the temperature was raised to 20 °C and water (200 mL) was added. The layers were separated and the aqueous layer was extracted with 2-methyltetrahydrofuran. The combined organic layers were washed with a saturated aqueous sodium chloride solution and some solvent was removed under vacuum at 40 °C. Heptane was added, and the resulting suspension was cooled to 0–5 °C and maintained at this temperature for 1 hour. The suspension was filtered and the precipitate was washed with heptane. The filter cake was vacuum dried at 35 °C to obtain a colorless solid (2S)-2-bromopropionamide (147 g, 967 mmol, 74% yield, 99.65% purity, 95% enantiomeric excess).

[1507] Example 4: Preparation of microcrystalline (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide

[1508] 180 g of (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide powder (substantially anhydrous, prepared according to the method described in Example 3) was added to a mixture of acetone (877 g) and water (175.5 g) and heated to a maximum of 55°C to obtain a solution containing a small amount of residual solids. The mixture was filtered through a K300 20 μm filter cloth, and the filtrate was cooled to 35°C over 1 hour. A 35 g nanoparticle suspension containing 79.8 wt% water, 10 wt% (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, 8 wt% PVP K12, 2 wt% HPCKlucel ELF, and 0.2 wt% SDS (prepared by the method described in European Patent Application No. 22196150.1, published as EP4154872A1, Example 1.1) was added as seed material. The suspension was then cooled to 20°C over 1 hour. To increase the yield, 1165.5 g of water was continuously added over 1 hour, followed by stirring for 1 hour. The resulting dispersed white suspension was filtered through a pressure filter and a PP 2703 filter cloth. The filter cake was washed with water (2 x 800 mL) and dried under vacuum at 50 °C to obtain a white, lumpy powder of (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide (164.55 g, 91.4% yield, 99.59% purity, 99.74% enantiomeric excess). The PSD was determined by method PSD4 to be (x10 / x50 / x90): 3.22 / 6.87 / 13.2 μm (…). Figure 13 ).

[1509] Compared with the published content of WO 2021 / 214019 ( Figure 15 XRPD analysis (method XRPD 1) of the resulting (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide showed no evidence of amorphous material or crystal form difference; similarly, DSC analysis (method DSC 1) showed no evidence of amorphous material. Figure 14 ).

[1510] The dissolution of this material was slightly faster or comparable to that of the material obtained from Example 3. Specifically, according to PH.Eur.2.9.3, the solubility of tablets containing equal amounts of microcrystalline (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoroaniline)propionamide as described in Examples 3 (-▲-) and 4 (-◆-) was determined using a pH 4.5 acetate buffer containing 2% SDS (sodium dodecyl sulfate) as the dissolution medium. Figure 16 Using the paddle device (USP device 2 (paddle)) specified in the United States Pharmacopeia, the stirrer speed was 50 rpm and the total media volume was 900 mL.

[1511] Experimental Section - Reference Examples for Comparison with Embodiments of the Invention

[1512] Reference Example 1: Partial amorphization of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide caused by jet milling

[1513] Jet milling solution

[1514] Micronization of compounds using the LSM Zero air jet mill

[1515] The compound (4.00 g) prepared as described below was sieved through a 1 mm manual sieve and a small portion was added to an air jet mill. At room temperature (23°C, 40% relative humidity), the jet pressure was 8 bar, the grinding pressure was 6 bar, and nitrogen was used as the air jet medium. The micronization lasted for about 1 hour.

[1516] After micronization, the particle size analysis (Method PSD3), DSC (Method DSC2), and XRPD analysis (Method XRPD2) of the compound were performed, and the yield was determined (3.78 g, 94.5%). The PSD of the obtained material, determined by Method PSD3, was (x10 / x50 / x90): 2.55 / 11.08 / 25.95 μm.

[1517] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, obtained by the chemical synthesis described below and used for jet milling, is a crystalline solid and was characterized by diffraction patterns, as shown below. Figure 7 As shown (obtained using method XRPD2), using method DSC2 ( Figure 8 The thermal properties were characterized, with a single endothermic event (melting) occurring at 195°C (start).

[1518] Partial amorphization occurring during jet milling can be clearly detected by differential scanning calorimetry (DSC, method DSC2), where recrystallization of some amorphous material can be observed during exothermic events between 100 and 140 °C. Figure 9 Direct comparison of XRPD data (obtained using method XRPD2) before and after jet milling also showed a decrease in crystallinity level in the jet-milled material. Figure 10 (The latter received) Figure 10 (See the image below).

[1519] The material used for jet milling is prepared in the following manner:

[1520] Step 1: [4-amino-2-(4-fluoroaniline)-1,3-thiazolyl-5-yl](4-methoxyphenyl) methyl ketone

[1521]

[1522] 1-Fluoro-4-isothiocyanobenzene (51.175 g, 98%, 327.4 mmol, CAS 1544-68-9, Aldrich) was dissolved in acetonitrile (1930 mL, Honeywell). Cyanoamine (16.52 g, 393 mmol, CAS 420-04-2, Aldrich) was added at room temperature, followed by DBU (48.9 mL, 327.4 mmol, Sigma-Aldrich). The reaction mixture was stirred for 45 minutes, and then another 24.4 mL (163.7 mmol) of DBU was added at room temperature, followed by a solution of 2-bromo-1-(4-methoxyphenyl)ethyl-1-one (75 g, 327.4 mmol, CAS 2632-13-5, Fluka and Aldrich) in acetonitrile (570 mL). After suspension formation, the reaction mixture was stirred at room temperature for 48 hours. Add a large amount of water, filter out the precipitate, wash with water, suspend in water, freeze dry to obtain 122.57g (quantitative yield, purity 91%) of solid, which can be used directly in the next step without further purification.

[1523] 1 H NMR (400MHz, DMSO-d6) δppm=3.81 (s, 3H) 7.01 (d, 2H) 7.21 (dd, 2H) 7.59-7.65 (m, 2H) 7.66 (d, 2H) 8.12 (br s, 2H) 10.76 (br s, 1H).

[1524] LC / MS (Method HPLC2):t R =1.07min; MS(ESIpos)m / z=344.2[M+H]+ .

[1525] Step 2: rac-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide

[1526]

[1527] [4-Amino-2-(4-fluoroaniline)-1,3-thiazolyl-5-yl](4-methoxyphenyl) methyl ketone (87.36 g, 254.4 mmol) was dissolved in N,N-dimethylformamide (1863 mL, Aldrich), followed by the addition of potassium carbonate (175.8 g, 1272 mmol, Riedel-de-Haen) and rac-2-bromopropionamide (46.4 g, 305.3 mmol, CAS 5875-25-2, Aldrich). The reaction mixture was stirred at room temperature for 3 days. Water was added and the precipitate was filtered off. The precipitate was washed with water, suspended in water, and lyophilized to give 82.6 g (199.29 mmol, 78% yield) of the title compound.

[1528] 1 H-NMR (400MHz, DMSO-d6): δppm=1.16(d,3H),3.75(s,3H),5.06(q,1H),6.93(d,2H),7.2 2-7.27(m,1H),7.34(dd,2H),7.48(d,2H),7.57(s,1H),7.64(dd,2H),7.79-8.38(m,2H).

[1529] LC / MS (Method HPLC2):t R =1.06min / MS(ESIpos):m / z=415.5[M+H] +

[1530] Step 3: (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide

[1531]

[1532] Rac-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-aniline)propionamide (82.60 g, 199.3 mmol) was separated by chiral HPLC to yield 33.0 g (79.62 mmol, 39.95%) S-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-aniline)propionamide, enantiomer 1, and 38.8 g (93.61 mmol, 46.97%) R-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-aniline)propionamide, enantiomer 2, with minor impurities. R-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide was suspended in methyl tert-butyl ether (500 mL, Aldrich) and stirred for 16 days. The suspension was filtered and the solid was washed with methyl tert-butyl ether. Water was added and the precipitate was filtered off, washed with water, suspended in water, and freeze-dried to give 35.7 g (84.44 mmol, 42.4% yield) of the title compound as the crystalline material, which was characterized as described below and as above. Figure 7 and 8 As discussed in the article.

[1533] Preparative chiral HPLC (Method HPLC6)

[1534] Enantiomer 1t R =10.2-12.1min

[1535] Enantiomer 2t R =14.6-21.4min

[1536] Analytical chiral HPLC (Method HPLC3): Enantiomer 2,(R),t R =5.99min

[1537] 1 H-NMR (400MHz, DMSO-d6): δppm=1.16(d,3H),3.75(s,3H),5.06(q,1H),6.93(d,2H),7.2 2-7.27(m,1H),7.34(dd,2H),7.48(d,2H),7.57(s,1H),7.64(dd,2H),7.79-8.38(m,2H).

[1538] [α] D 20 = +150.65° (chloroform)

[1539] Reference Example 2: Crude (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide

[1540] Crude (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl]-4-fluoroaniline)propionamide was prepared by thoroughly mixing three equal-mass sub-batches of (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl]-4-fluoroaniline)propionamide solids until homogeneous, each sub-batch being produced according to the following steps:

[1541] A suspension of [4-amino-2-(4-fluoroanilino)thiazolyl-5-yl]-(4-methoxyphenyl)methyl ketone (120 g, 349 mmol), (2S)-2-bromopropionamide (63.7 g, 419 mmol, 1.2 equivalents, 90% enantiomeric excess) and potassium phosphate (K3PO4, 148 g, 699 mmol, 2.0 equiv) in acetonitrile (1200 mL) was heated to 60 °C and stirred at that temperature for 1 hour. The temperature was then lowered to 20 °C over 40 minutes, followed by the simultaneous addition of water (1200 mL) over 20 minutes. The resulting three-phase mixture was stirred at 20 °C for 3 hours and filtered. The filter cake was washed with water (3 x 240 mL) and dried under vacuum at 50 °C to give a pale yellow solid (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide (105 g, 252 mmol, 72% yield, 99.74% purity, 99.0% enantiomeric excess). The PSD determined by method PSD2b was (x10 / x50 / x90): 5.6 / 34 / 131 μm.

[1542] Compared with WO 2021 / 214019 ( Figure 11 XRPD analysis (method XRPD3) of the coarse-grained (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide obtained therefrom showed no evidence of amorphous material or crystal form difference. Figure 1 DSC (method DSC3) indicates complete crystallinity and shows no evidence of the presence of amorphous material. Figure 12 ).

Claims

1. Microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in The presence of amorphous forms is less than 15%. The particle size distribution is as follows: x10 < 5 μm, x50 < 10 μm and x90 < 35 μm.

2. The microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide according to claim 1, in The particle size distribution is as follows: x10 ranges from 0.5 to 2.5 μm, x50 ranges from 3 to 7 μm and x90 ranges from 8 to 20 μm.

3. The microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide according to claim 1, in The particle size distribution is as follows: x10 ranges from 0.3 to 4 μm, x50 ranges from 4 to 10 μm, and x90 ranges from 10 to 20 μm.

4. The microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide according to claim 1, 2 or 3, in Enantiomer excess of at least 95%.

5. The microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide according to claim 1, 2, 3 or 4, in The presence of amorphous forms is less than 5%.

6. The microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide according to claim 1, 2, 3, 4 or 5, in The particle size distribution is as follows: x10 ranges from 1 to 2 μm, x50 ranges from 4 to 5.5 μm and x90 ranges from 10 to 18 μm.

7. The microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide according to claim 1, 3, 4 or 5, in The particle size distribution is as follows: x10 ranges from 1 to 4 μm, x50 ranges from 4 to 8 μm, and x90 ranges from 12 to 18 μm.

8. The microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide according to claim 1, 2, 4 or 5, in Enantiomer excess of at least 98%, The presence of amorphous forms is less than 5%. The particle size distribution is as follows: x10 ranges from 0.5 to 2.5 μm, x50 ranges from 3 to 7 μm, and x90 ranges from 8 to 20 μm.

9. The microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide according to claim 1, 3, 4 or 5, in Enantiomer excess of at least 98%, The presence of amorphous forms is less than 5%. The particle size distribution is as follows: x10 ranges from 0.3 to 4 μm, x50 ranges from 4 to 10 μm, and x90 ranges from 10 to 20 μm.

10. The microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide according to claim 1, 2, 3, 4, 5, 6 or 8, in Enantiomer excess of at least 99%, The presence of amorphous forms is less than 5%. The particle size distribution is as follows: x10 ranges from 1 to 2 μm, x50 ranges from 4 to 5.5 μm, and x90 ranges from 10 to 18 μm.

11. The microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide according to claims 1, 3, 4, 5, 7 or 9, in Enantiomer excess of at least 99%, The presence of amorphous forms is less than 5%. The particle size distribution is as follows: x10 ranges from 1 to 4 μm, x50 ranges from 4 to 8 μm, and x90 ranges from 12 to 18 μm.

12. A method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in microcrystalline form, the method comprising the steps of: Dissolve (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in a solvent or a mixture of solvents, then The resulting solution was mixed with the antisolvent, and then The precipitate obtained by separation and drying The microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide was obtained.

13. The method according to claim 12, wherein the method comprises the following steps: A solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, optionally filtered, in a dipolar aprotic and / or protic solvent is added to the antisolvent, and The precipitate obtained by separation and drying Microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide was obtained.

14. The method according to claim 12 or 13, wherein the method comprises the following steps: At a temperature of 4°C to 10°C, over a period of 30 minutes to 1 hour, a filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide was added to a mixture of acetone and water in a ratio of 8:1 (v / v) to 12:1 (v / v). The precipitate obtained by separation and drying Microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide was obtained.

15. The method of claim 12, wherein the method comprises the following steps: 2) Dissolve (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in a solvent. 3) A supersaturated solution is produced. 4) Add a nano-suspension, said nano-suspension comprising additional (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, an antisolvent, at least one surfactant, and at least one polymer. 5) Then perform one or more sub-steps selected from the following: a. Cooling b. Add the antisolvent, and c. Evaporate the solvent. 6) Separate and dry the resulting precipitate. Microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide was obtained.

16. The method according to claim 12 or 15, wherein the method comprises the following steps: 2) Dissolve (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in acetone containing 10 to 30% v / v water, and optionally filter. 3) By cooling to produce a supersaturated solution, the temperature is lowered by 5°C to 30°C. 4) Add a nano-suspension, said nano-suspension comprising additional (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, water, at least one surfactant, and at least two polymers. 5) Then a. Cool, then b. Add water. 6) Separate and dry the resulting precipitate. Microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide was obtained.

17. The method according to claim 12 or 13, wherein the method comprises the following steps: i. The intermediate compound of formula (II) Reaction with intermediate compound of formula (III) Where LG is the leaving group as defined above. Therefore, we obtain (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, ii. Dissolve the crude product obtained in step i in a dipole aprotic and / or protic solvent, and then optionally filter. iii. Add the solution or filtrate obtained in step ii to the antisolvent, and iv. Separate and dry the resulting precipitate. Microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide was obtained.

18. The method according to claim 12, 13 or 17, wherein the method comprises the following steps: i. At a temperature of 20 to 80 °C, the intermediate compound of formula (II) is... The intermediate compound of formula (III) is reacted with the intermediate compound in a solvent in the presence of at least one equivalent of a base for 30 minutes to 24 hours, wherein the base is selected from alkali metal carbonates, alkali metal bicarbonates, and alkali metal phosphates, and the solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidone, acetone, and isopropanol. Where LG is the leaving group as defined above. Therefore, we obtain (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, ii- The crude product obtained from step (i) is dissolved in a mixture of acetone and water in a ratio of 8:1 (v / v) to 12:1 (v / v), with acetone as the main component, and then filtered. iii. At a temperature of 0 to 20°C, add the filtrate to water over a period of 20 minutes to 1.5 hours, and iv. Separate and dry the resulting precipitate. Microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide was obtained.

19. The method according to claim 12, 13, 14, 17 or 18, wherein the method comprises the following steps: i. At a temperature of 50 to 70°C, the intermediate compound of formula (II) is... The intermediate compound of formula (III) was reacted with acetonitrile in the presence of 1.5 to 5 equivalents of potassium phosphate for 1 to 2 hours, and then the temperature was lowered to 20°C for up to 1 hour. Where LG represents bromine atoms. Therefore, we obtain (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, ii. The crude product obtained from step (i) is dissolved in a mixture of acetone and water in a ratio of 8:1 (v / v) to 12:1 (v / v), with acetone as the main component, and then filtered. iii. At a temperature of 4 to 10°C, add the filtrate to water over a period of 30 minutes to 1 hour, and iv. Separate and dry the resulting precipitate. Microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide was obtained.

20. The method according to claim 12 or 15, wherein the method comprises the following steps: 1) The intermediate compound of formula (II) Reaction with intermediate compound of formula (III) Where LG is the leaving group as defined above. Thus obtained (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, 2) Dissolve the crude product obtained in step 1) in a solvent. 3) A supersaturated solution is produced. 4) Add a nano-suspension, said nano-suspension comprising additional (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, an antisolvent, at least one surfactant, and at least one polymer. 5) Then perform one or more sub-steps selected from the following: a. Cooling b. Add the antisolvent, and c. Evaporate the solvent. 6) Separate and dry the resulting precipitate. Microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide was obtained.

21. The method according to claim 12, 15, 16 or 20, wherein the method comprises the following steps: 1) At a temperature of 20 to 80°C, the intermediate compound of formula (II) is... The intermediate compound of formula (III) is reacted with the intermediate compound in a solvent in the presence of at least one equivalent of a base for 30 minutes to 24 hours, wherein the base is selected from alkali metal carbonates, alkali metal bicarbonates, and alkali metal phosphates, and the solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidone, acetone, and isopropanol. Where LG is the leaving group as defined above. Thus obtained (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, 2) Dissolve the crude product obtained in step 1) in acetone containing 10 to 30% v / v water, and optionally filter. 3) By cooling to produce a supersaturated solution, the temperature is lowered by 5°C to 30°C. 4) Add a nano-suspension, said nano-suspension comprising additional (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, water, at least one surfactant, and at least two polymers. 5) Then a. Cool, then b. Add water. 6) Separate and dry the resulting precipitate. Microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide was obtained.

22. The method according to claim 12, 15, 16, 20 or 21, wherein the method comprises the following steps: 1) At a temperature of 50 to 70°C, the intermediate compound of formula (II) is... The intermediate compound of formula (iii) was reacted with acetonitrile in the presence of 1.5 to 5 equivalents of potassium phosphate for 1 to 2 hours, and then the temperature was lowered to 20°C for up to 1 hour. Where LG represents bromine atoms. Thus obtained (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, 2) The crude product obtained in step 1) is dissolved in acetone containing 10 to 30% v / v water at a temperature of 40°C to 70°C, and optionally filtered. 3) By cooling to produce a supersaturated solution, the temperature is lowered by 15°C to 25°C. 4) Add a nano-suspension comprising additional (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide (5-20% w / w), water (60-90% w / w), at least one surfactant (0.05-1% w / w), and at least two polymers (each independently 0.5-15% w / w), wherein The at least one surfactant contains C8-C 20 Alkali metal salts of alkyl sulfuric acid Furthermore, the at least two polymers comprise hydroxypropyl cellulose and polyvinylpyrrolidone. Furthermore, the amount of the nano-suspension is 1 to 6% w / w of the supersaturated solution obtained in step 3). 5) Then a. Cool, reducing the temperature by 5°C to 25°C, then b. Add water. 6) Separate and dry the resulting precipitate. Microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide was obtained.

23. A pharmaceutical composition comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide in the microcrystalline form according to any one of claims 1 to 11 and one or more pharmaceutically acceptable excipients.

24. A method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide, the method comprising the following steps: The intermediate compound of formula (II) Reaction with intermediate compound of formula (III) Where LG is the leaving group as defined above. Thus obtained (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide.

25. The method of claim 24, wherein the method comprises the following steps: At a temperature of 40 to 80°C, the intermediate compound of formula (II) is... The intermediate compound of formula (iii) is reacted with the intermediate compound in a solvent in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate in a solvent selected from N,N-dimethylformamide and acetonitrile. Where LG represents bromine atoms. Thus obtained An enantiomeric excess of at least 90% of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl-4-fluoro-aniline)propionamide.

26. The method according to claim 24 or 25, wherein the method comprises the following steps: At a temperature of 50 to 70°C, the intermediate compound of formula (II) is... The intermediate compound of formula (iii) was reacted with acetonitrile in the presence of 1.5 to 5 equivalents of potassium phosphate for 1 to 2 hours, and then the temperature was lowered to 20°C for up to 1 hour. Where LG represents bromine atoms. Thus obtained An enantiomeric excess of at least 95% of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazolyl-2-yl]-4-fluoro-aniline)propionamide.

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