Microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide and preparation thereof

Abstract

The present invention encompasses microcrystalline (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, (I), (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, methods for preparing the same, and pharmaceutical compositions containing the same. [Formula 1] TIFF2026511647000156.tif51155

Description

[Technical Field]

[0001] The present invention encompasses microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, a method for preparing the same, and pharmaceutical compositions containing the same. [Background technology]

[0002] Among the characteristics of crystalline active pharmaceutical ingredients (APIs), their polymorphisms and particle size are two of the most frequently mentioned. The latter directly determines the dissolution rate (and in vivo bioavailability) 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). To improve the dissolution rate, APIs are often pulverized during manufacturing. One widely applied method is jet milling (M. Djokic et al., Chemical Engineering Research and Design 2014,92(3),500-508; http: / / dx.doi.org / 10.1016 / j.cherd.2013.09.011 (See also). Unfortunately, due to mechanical stress induced by collisions between the microparticles and the chamber walls, the surface of the fully crystallized input material may become amorphous (M. Djokic et al., Chemical Engineering Research and Design 2014, 92(3), 500-508; http: / / dx.doi.org / 10.1016 / j.cherd.2013.09.011 (See also). The degree of amorphous formation that occurs during processing is often unpredictable and varies depending on the scale of the equipment used. Thus, even the smallest amount of amorphous material can alter the processing behavior and performance of the API (S. Sheokand et al., Journal of Pharmaceutical Sciences 2014, 103, 2264-2276; https: / / doi.org / 10.1002 / jps.24160(See also), it is important to quantify the degree of amorphization. Parameters affected by amorphization: dissolution rate, apparent solubility, solid state instability (recrystallization), and the resulting changes in dissolution properties over time (S. Sheokand et al., Journal of Pharmaceutical Sciences 2014, 103, 2264-2276; https: / / doi.org / 10.1002 / jps.24160 (See also). Quantifying the degree of amorphization remains an important analytical challenge (S. Sheokand et al., Journal of Pharmaceutical Sciences 2014, 103, 2264-2276; https: / / doi.org / 10.1002 / jps.24160 (See also), in general, partial amorphization should be avoided.

[0003] The suitability of a given particle size distribution range for the pharmaceutical development of a given API depends on various parameters, including but not limited to the intended administration route and the solubility characteristics of each API (see, for example, BYShekunov et al., Pharmaceutical Research 2007, 24(2), 203). (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, for example, requires particle grinding to provide good bioavailability after oral administration with sufficient solubility and dissolution rate, which correlates with particle surface and therefore particle size. Considering the project details, a particle size distribution (PSD) of x10 / x50 / x90:>0.3 / 1-8 / <20 μm was selected as the target particle size distribution for the micronized (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0004] In a study aimed at identifying pharmaceutically useful forms of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, starting from macrocrystalline material, it was found that mechanical stress during jet milling resulted in the formation of solid materials containing a considerable amount and varying proportions of amorphous material in addition to crystalline particles. Partial amorphization poses a threat to the chemical and physical stability of the active pharmaceutical ingredient and can cause variations in solubility, dissolution rate, and bioavailability. Therefore, quantifying the degree of amorphization remains an important analytical challenge (S. Sheokand et al., Journal of Pharmaceutical Sciences 2014, 103, 2264-2276; https: / / doi.org / 10.1002 / jps.24160 (See also) Attempts have been made to provide sufficiently small particles with perfect crystallinity. Despite considerable efforts to optimize the jet milling process, it has been impossible to eliminate the loss of crystallinity when performing the jet milling process to obtain the desired particle size.

[0005] The present invention encompasses microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, a method for preparing the same, and pharmaceutical compositions containing the same.

[0006] prior art

[0007] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is a compound known to inhibit the zeta isoform of diacylglycerol kinase (DGK zeta) and is disclosed as Example 62.2 in the international patent application PCT / EP2021 / 060167, published as WO2021 / 214019.

[0008] [ka] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2 -yl-4-fluoro-anilino)propanamide However, the latest technology does not describe a method for crystallizing the compound (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide to obtain crystalline particles of a preferred size for preparing a solid pharmaceutical composition that can be used as a drug, nor does it disclose the resulting microcrystals of the compound or a pharmaceutical composition containing them.

[0009] The above-described microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, a method for preparing the same, and pharmaceutical compositions containing the same have been found to possess remarkable and advantageous properties, which constitute the basis of the present invention.

[0010] The microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide of the present invention is free of amorphous material, features a particle size distribution within a desired range, and exhibits substantially improved solubility compared to the macrocrystalline form of the same compound, within the precision of the analytical method used.

[0011] The preparation method is robust, highly efficient, and produces substances with excellent chemical purity and enantiomeric purity. Furthermore, the method resolves the risk of racemization during the alkylation of the intermediate [4-amino-2-(4-fluoroanilino)-1,3-thiazol-5-yl](4-methoxyphenyl)methanone with (S)-2-bromopropanamide. The risk of racemization in such alkylations involving a stereocenter as the alkylation site at the alpha position relative to the carbonyl group is known to those skilled in the art (see, for example, P.S. Dragovich et al., J. Med. Chem. 2003, 46, 4572; L. Chen et al., Organic Process Research & Development 2006, 10(4), 838). The synthesis of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide disclosed in WO2021 / 214019 proceeds via the synthesis of rac-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide followed by enantiomeric separation by preparative chiral HPLC. For the purposes of drug development, such enantiomeric separation is costly and substantially lengthens the process time, and is thus undesirable.

Prior Art Documents

Patent Documents

[0012]

Patent Document 1

Non-Patent Documents

[0013]

Non-Patent Document 1

Non-Patent Document 2

[0014] According to a first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide,

[0015] [ka] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide Here, The presence of amorphous forms is less than 15%. The particle size distribution is as follows: x10 is <5 μm, x50 is <10 μm, and x90 is <35 μm.

[0016] definition The enantiomer excess is often omitted and expressed as a percentage (%), derived from the proportions of (R)- and (S)- enantiomers in a given mixture of two enantiomers, calculated as ee = [(R)-(S) / (R)+(S)] x 100, where a racemic mixture has 0% ee and pure enantiomers have 100% ee.

[0017] As used herein, the term “leaving group” means an atom or group of atoms that, in a chemical reaction, is substituted as a stable species in conjunction with the bonding electrons. In particular, such leaving groups are selected from the group including halogen atoms, especially fluorine atoms, chlorine atoms, bromine atoms or iodide atoms, and are substituted as halides, especially 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.

[0018] As used herein, "microcrystalline" refers to a perfectly crystalline solid form characterized by a particle size distribution within the range of x10 / x50 / x90:<5 / <10 / <35 μm, or <3 / 10-15 / <35 μm, or smaller, for example, within the range of x10 / x50 / x90:<5 / <10 / <20 μm, particularly within 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.

[0019] As used herein, "macrocrystalline" refers to a perfectly crystalline solid form characterized by a particle size distribution in the range of x10 / x50 / x90:3 / 10~15 / 35 μm or larger.

[0020] The term "C1-C3-alkyl" refers to a linear or branched saturated monovalent hydrocarbon group having one, two, or three carbon atoms, such as methyl, ethyl, propyl, or isopropyl groups.

[0021] According to a second embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide,

[0022] [ka] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide Here, The presence of amorphous forms is less than 15%. The particle size distribution 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.

[0023] According to a third embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The presence of amorphous forms is less than 15%. 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.

[0024] According to a fourth embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The presence of amorphous forms is less than 15%. The particle size distribution 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.

[0025] According to the fifth embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, Here, The presence of amorphous forms is less than 10%. The particle size distribution 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.

[0026] According to the sixth embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, Here, The presence of amorphous forms is less than 10%. The particle size distribution 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.

[0027] According to the seventh embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, Here, The presence of amorphous forms is less than 10%. 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.

[0028] According to the eighth embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The enantiomer excess rate is at least 95%, The presence of amorphous forms is less than 10%. The particle size distribution 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.

[0029] According to the ninth embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The enantiomer excess rate is at least 95%, The presence of amorphous forms is less than 10%. The particle size distribution 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.

[0030] According to the tenth embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The enantiomer excess rate is at least 95%, The presence of amorphous forms is less than 10%. 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.

[0031] According to the eleventh embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The presence of amorphous forms is less than 5%. The particle size distribution 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.

[0032] According to the twelfth embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The presence of amorphous forms is less than 5%. The particle size distribution 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.

[0033] According to the thirteenth embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The presence of amorphous forms is less than 5%. 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.

[0034] According to the fourteenth embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The enantiomer excess rate is at least 98%, The presence of amorphous forms is less than 5%. The particle size distribution 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.

[0035] According to the 15th embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The enantiomer excess rate is at least 98%, The presence of amorphous forms is less than 5%. The particle size distribution 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.

[0036] According to the sixteenth embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The enantiomer excess rate is at least 98%, The presence of amorphous forms is less than 5%. 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.

[0037] According to the 17th embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The enantiomer excess rate is at least 99%, The presence of amorphous forms is less than 5%. 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.

[0038] According to the 18th embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The enantiomer excess rate is at least 99%, The presence of amorphous forms is less than 5%. 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.

[0039] According to the 19th embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The presence of amorphous forms is less than 2.5%. The particle size distribution 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.

[0040] According to the 20th embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The presence of amorphous forms is less than 2.5%. The particle size distribution 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.

[0041] According to the 21st embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The presence of amorphous forms is less than 2.5%. 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.

[0042] According to the 22nd embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, The presence of amorphous morphology is below the detection limit of differential scanning calorimetry. 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.

[0043] According to the 23rd embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The presence of amorphous morphology is below the detection limit of differential scanning calorimetry. 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.

[0044] According to the 24th embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The presence of amorphous morphology is below the detection limit of XRPD. 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.

[0045] According to the 25th embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The presence of amorphous morphology is below the detection limit of XRPD. 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.

[0046] According to the 26th embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The presence of amorphous morphology is below the detection limit of differential scanning calorimetry by the DSC1 method. The particle size distribution determined according to 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.

[0047] According to the 27th embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The presence of amorphous morphology is below the detection limit of differential scanning calorimetry by the DSC1 method. The particle size distribution determined according to 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.

[0048] According to the 28th embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The presence of amorphous morphology is below the detection limit of XRPD by the XRPD1 method. The particle size distribution determined according to 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.

[0049] According to the 29th embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where, The presence of amorphous morphology is below the detection limit of XRPD by the XRPD1 method. The particle size distribution determined according to 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.

[0050] Further embodiments of the first aspect of the present invention: According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The enantiomer excess rate is at least 95%, The presence of amorphous forms is less than 10%. The particle size distribution determined according to 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.

[0051] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The enantiomer excess rate is at least 95%, The presence of amorphous forms is less than 10%. The particle size distribution determined according to 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.

[0052] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The enantiomer excess rate is at least 95%, The presence of amorphous forms is less than 10%. The particle size distribution determined according to 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.

[0053] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous forms is less than 5%. The particle size distribution determined according to 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.

[0054] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous forms is less than 5%. The particle size distribution determined according to 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.

[0055] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous forms is less than 5%. The particle size distribution determined according to 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.

[0056] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The enantiomer excess rate is at least 98%, The presence of amorphous forms is less than 5%. The particle size distribution determined according to 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.

[0057] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The enantiomer excess rate is at least 98%, The presence of amorphous forms is less than 5%. The particle size distribution determined according to 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.

[0058] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The enantiomer excess rate is at least 98%, The presence of amorphous forms is less than 5%. The particle size distribution determined according to 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.

[0059] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The enantiomer excess rate is at least 99%, The presence of amorphous forms is less than 5%. The particle size distribution determined according to 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.

[0060] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The enantiomer excess rate is at least 99%, The presence of amorphous forms is less than 5%. The particle size distribution determined according to 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.

[0061] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous forms is less than 2.5%. The particle size distribution determined according to 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.

[0062] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous forms is less than 2.5%. The particle size distribution measured according to 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.

[0063] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous forms is less than 2.5%. The particle size distribution determined according to 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.

[0064] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to the PSD2a method is as follows: x10 is in the range of 1 to 2 μm.

[0065] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to the PSD2a method is as follows: x50 is in the range of 4 to 5.5 μm.

[0066] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to the PSD4 method is as follows: x50 is in the range of 4 to 8 μm.

[0067] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to the PSD2a method is as follows: x90 is in the range of 10 to 18 μm.

[0068] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to the PSD4 method is as follows: x90 is in the range of 12-18 μm.

[0069] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to 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.

[0070] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to 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.

[0071] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous forms is less than 15%.

[0072] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous forms is less than 10%.

[0073] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous forms is less than 5%.

[0074] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous forms is less than 2.5%.

[0075] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous morphology is below the detection limit of differential scanning calorimetry.

[0076] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous morphology is below the detection limit of XRPD.

[0077] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous morphology is below the detection limit of differential scanning calorimetry by the DSC1 method.

[0078] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous morphology is below the detection limit of XRPD by the XRPD1 method.

[0079] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein,

[0080] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide has an enantiomer excess of at least 99%.

[0081] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein,

[0082] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide has an enantiomer excess of at least 98%.

[0083] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where

[0084] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide has an enantiomer excess of at least 95%.

[0085] According to a further embodiment of the first aspect, the present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein,

[0086] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide has an enantiomer excess of at least 90%.

[0087] In certain further embodiments of the first aspect, the present invention encompasses two or more combinations of the above embodiments, which are titled "Further Embodiments of the First Aspect of the Invention."

[0088] The present invention encompasses any subcombination within any embodiment or aspect of the present invention of microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, methods for preparing the same, and pharmaceutical compositions comprising the same.

[0089] The present invention comprises microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, as described in the experimental section of this specification.

[0090] According to a second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being i. Equation (II):

[0091] [ka] The intermediate compound is given by formula (III)

[0092] [ka] [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby

[0093] [ka] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is obtained, ii. Dissolve the crude product obtained from step i in a solvent or a solvent mixture. iii. Combine the solution obtained from step ii with a poor solvent, and iv. Isolate and dry the obtained precipitate.

[0094] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0095] According to a second embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being i. Equation (II):

[0096] [ka] The intermediate compound is given by formula (III):

[0097] [ka] [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby

[0098] [ka] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is obtained, ii. Dissolve the crude product obtained from step i in acetone containing water in the range of 0% to 30% (v / v). iii. Combine the solution obtained from step ii with water, and iv. Isolate and dry the obtained precipitate.

[0099] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0100] According to a third embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being i. Equation (II):

[0101] [ka] The intermediate compound is given by formula (III):

[0102] [ka] [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby

[0103] [ka] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is obtained, ii. The crude product obtained from step i is dissolved in a bipolar aprotic and / or protic solvent, and then optionally filtered. iii. Add the solution or filtrate obtained from step ii. to a poor solvent, and iv. Isolate and dry the obtained precipitate.

[0104] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0105] According to a fourth embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being iii. Add an optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in a bipolar aprotic and / or protic solvent to a poor solvent, and iv. Isolate and dry the obtained precipitate.

[0106] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0107] According to a fifth embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being i. In the presence of at least one equivalent of a base selected from alkaline carbonates, alkaline bicarbonates, and alkaline phosphates, at a temperature in the range of 20 to 80°C, in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidinone, acetone, and isopropanol, for a period of 30 minutes to 24 hours. Formula (II)

[0108] [ka] The intermediate compound is given by formula (III)

[0109] [ka] [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby

[0110] [ka] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is obtained, 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 being preferred, and then filtered. iii. Add the filtrate to water at a temperature within the range of 0°C to 20°C for a period of time within the range of 20 minutes to 1.5 hours, and iv. Isolate and dry the obtained precipitate.

[0111] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0112] According to the sixth embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being i. In the presence of 1.5 to 5 equivalents of potassium phosphate, in acetonitrile at a temperature in the range of 50 to 70°C for a range of 1 to 2 hours, Formula (II)

[0113] [ka] The intermediate compound is given by formula (III)

[0114] [ka] [In the formula, LG represents a bromine atom.] It is reacted with an intermediate compound, thereby,

[0115] [ka] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is obtained, 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 being preferred, and then filtered. iii. Add the filtrate to water at a temperature within the range of 4-10°C for 1 hour and 30 minutes, and iv. Isolate and dry the obtained precipitate.

[0116] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0117] According to the seventh embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being i. In the presence of 1.5 to 5 equivalents of potassium phosphate, in acetonitrile at a temperature in the range of 50 to 70°C for a period of 1 to 2 hours, formula (II)

[0118] [ka] The intermediate compound is given by formula (III)

[0119] [ka] [In the formula, LG represents a bromine atom.] The intermediate compound is reacted with the intermediate compound, and then the temperature is lowered to 20°C over a period of time up to 1 hour, thereby,

[0120] [ka] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is obtained, 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 being preferred, and then filtered. iii. Add the filtrate to water at a temperature within the range of 4-10°C for 1 hour and 30 minutes, and iv. Isolate and dry the obtained precipitate.

[0121] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0122] According to the eighth embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being iii. Add a filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in a mixture of acetone and water in a ratio within the range of 8:1(v / v) to 12:1(v / v), with acetone preferred, to water at a temperature within the range of 4°C to 10°C for a period of 1 hour and 30 minutes, and iv. Isolate and dry the obtained precipitate.

[0123] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0124] Further embodiments of a second aspect of the present invention: According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution is as follows: x10 is in the range of 1 to 2 μm.

[0125] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution is as follows: x50 is in the range of 4 to 5.5 μm.

[0126] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution is as follows: x50 is in the range of 4 to 8 μm.

[0127] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution is as follows: x90 is in the range of 10 to 18 μm.

[0128] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, 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.

[0129] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, 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.

[0130] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to the PSD2a method is as follows: x10 is in the range of 1 to 2 μm.

[0131] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to the PSD2a method is as follows: x50 is in the range of 4 to 5.5 μm.

[0132] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to the PSD4 method is as follows: x50 is in the range of 4 to 8 μm.

[0133] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to the PSD2a method is as follows: x90 is in the range of 10 to 18 μm.

[0134] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to the PSD4 method is as follows: x90 is in the range of 12-18 μm.

[0135] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to 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.

[0136] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to 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.

[0137] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to 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.

[0138] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous forms is less than 15%.

[0139] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous forms is less than 10%.

[0140] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous forms is less than 5%.

[0141] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous forms is less than 2.5%.

[0142] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous morphology is below the detection limit of differential scanning calorimetry.

[0143] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous morphology is below the detection limit of XRPD.

[0144] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous morphology is below the detection limit of differential scanning calorimetry by the DSC1 method.

[0145] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous morphology is below the detection limit of XRPD by the XRPD1 method.

[0146] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein,

[0147] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide has an enantiomer excess of at least 99%.

[0148] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein,

[0149] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide has an enantiomer excess of at least 98%.

[0150] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein,

[0151] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide has an enantiomer excess of at least 95%.

[0152] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein,

[0153] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide has an enantiomer excess of at least 90%.

[0154] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The leaving group LG in step i 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, and [(4-methoxyphenyl)sulfonyl]oxy.

[0155] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The leaving group LG in step i is a chlorine atom, a bromine atom, or an iodine atom, or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy, and [(4-methylphenyl)sulfonyl]oxy.

[0156] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, In step i, the leaving group LG is a chlorine atom.

[0157] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The leaving group LG in step i is the [(4-methylphenyl)sulfonyl]oxy group.

[0158] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, In step i, the leaving group LG is either a bromine atom or a [(4-methylphenyl)sulfonyl]oxy group.

[0159] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, In step i, the leaving group LG is a bromine atom.

[0160] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step i is carried out in the presence of a base selected from alkali carbonates, alkali bicarbonates, alkali phosphates, and N,N,N,N-tetra(C1-C3-alkyl)guanidine.

[0161] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step i is carried out in the presence of a base selected from alkali carbonates, alkali bicarbonates, and alkali phosphates.

[0162] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step i is carried out in the presence of at least one equivalent of a base selected from alkali carbonates, alkali bicarbonates, alkali phosphates, and N,N,N,N-tetra(C1-C3-alkyl)guanidine.

[0163] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step i is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkali carbonates, alkali bicarbonates, alkali phosphates, and N,N,N,N-tetra(C1-C3-alkyl)guanidine.

[0164] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step i is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkali carbonates, alkali bicarbonates, and alkali phosphates.

[0165] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step i is carried out in the presence of 1.5 to 6 equivalents of a base selected from an alkaline carbonate selected from sodium carbonate, potassium carbonate, and cesium carbonate, an alkaline bicarbonate selected from sodium bicarbonate, potassium bicarbonate, and cesium bicarbonate, and an alkaline phosphate selected from sodium phosphate, potassium phosphate, and cesium phosphate.

[0166] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step i is carried out in the presence of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate, and potassium phosphate.

[0167] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step i 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, and potassium phosphate.

[0168] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step i is carried out in the presence of a base selected from potassium carbonate and potassium phosphate.

[0169] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step i is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate.

[0170] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step i is carried out in the presence of 1.5 to 3 equivalents of potassium phosphate.

[0171] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step i is carried out in the presence of 2 to 6 equivalents of potassium carbonate.

[0172] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step i is carried out at a temperature within the range of 0°C to 100°C.

[0173] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Process i is carried out at a temperature within the range of 20°C to 90°C.

[0174] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step i is carried out at a temperature within the range of 40°C to 80°C.

[0175] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step i is carried out at a temperature within the range of 50°C to 70°C.

[0176] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step i is carried out at a temperature in the range of 40°C to 80°C, and then optionally the temperature is lowered to 20°C over a period of up to 1 hour.

[0177] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step i is carried out at a temperature in the range of 50°C to 70°C, and then optionally the temperature is lowered to 20°C over a period of up to 1 hour.

[0178] According to a further embodiment of the second aspect, the present invention includes a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, wherein Step i. is carried out at a temperature within the range of 40 °C to 80 °C, and then the temperature is lowered to 20 °C over a time within the range of up to 1 hour.

[0179] According to a further embodiment of the second aspect, the present invention includes a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, wherein Step i. is carried out at a temperature within the range of 50 °C to 70 °C, and then the temperature is lowered to 20 °C over a time within the range of up to 1 hour.

[0180] According to a further embodiment of the second aspect, the present invention includes a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, wherein Step i. is carried out in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidinone, acetone, and isopropanol, or a mixture of acetone and isopropanol.

[0181] According to a further embodiment of the second aspect, the present invention includes a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, wherein Step i. is carried out in a solvent selected from N,N-dimethylformamide, acetonitrile, N-methylpyrrolidinone, acetone, and isopropanol, or a mixture of acetone and isopropanol within the range of 5:1 (v / v) to 1:5 (v / v).

[0182] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step i is carried out in a solvent selected from N,N-dimethylformamide and acetonitrile.

[0183] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step i is carried out in N,N-dimethylformamide as the solvent.

[0184] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step i is carried out in acetonitrile as the solvent.

[0185] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Process i is carried out over a period of time ranging from 30 minutes to 24 hours.

[0186] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Process i. is carried out over a period of time ranging from 30 minutes to 6 hours.

[0187] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Process i. is carried out over a period of time ranging from 30 minutes to 2 hours.

[0188] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Process i. is carried out over a period of time ranging from 1 to 2 hours.

[0189] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step ii is carried out in one or more dipolar aprotic and / or polar solvents, which are optionally mixed with water.

[0190] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, 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, which are optionally mixed with water.

[0191] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, 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, which may be mixed with water as desired.

[0192] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, 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, which are optionally mixed with water.

[0193] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step ii is carried out in one or more solvents selected from acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, and 1,4-dioxane, which are optionally mixed with water.

[0194] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step ii. is carried out in one or more solvents selected from acetonitrile, acetone and 1,4-dioxane, which are optionally mixed with water.

[0195] According to a further embodiment of the second aspect, the present invention includes a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, wherein Step ii. is carried out in a mixture of acetone and water.

[0196] According to a further embodiment of the second aspect, the present invention includes a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, wherein Step ii. is carried out in a mixture of acetone and water at a ratio within the range of 5:1 (v / v) to 20:1 (v / v) with a preference for acetone.

[0197] According to a further embodiment of the second aspect, the present invention includes a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, wherein Step ii. is carried out in a mixture of acetone and water at a ratio within the range of 6:1 (v / v) to 15:1 (v / v) with a preference for acetone.

[0198] According to a further embodiment of the second aspect, the present invention includes a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide, wherein Step ii. is carried out in a mixture of acetone and water at a ratio within the range of 6:1 (v / v) to 12:1 (v / v) with a preference for acetone.

[0199] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step ii is carried out in a mixture of acetone and water in a ratio within the range of 8:1 (v / v) to 12:1 (v / v), with acetone being preferred.

[0200] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step ii is carried out in a mixture of acetone and water in a ratio within the range of 8:1 (v / v) to 10:1 (v / v), with acetone being preferred.

[0201] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the solvent used in step ii. to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is in the range of 6:1 to 20:1 (w / w; solvent: compound).

[0202] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the solvent used in step ii. to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is in the range of 8:1 to 15:1 (w / w; solvent: compound).

[0203] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the solvent used in step ii. to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is within the range of 10:1 (w / w) to 14:1 (w / w), prioritizing the solvent.

[0204] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the solvent used in step ii. to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is within the range of 11:1 (w / w) to 12:1 (w / w), prioritizing the solvent.

[0205] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the acetone-water mixture to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide used in step ii. is in the range of 8:1 (w / w) to 15:1 (w / w), with preference given to the acetone-water mixture.

[0206] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the acetone-water mixture to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide used in step ii. is in the range of 10:1 (w / w) to 14:1 (w / w), with preference given to the acetone-water mixture.

[0207] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the acetone-water mixture to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide used in step ii. is in the range of 11:1 (w / w) to 12:1 (w / w), with preference given to the acetone-water mixture.

[0208] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The solvent in step iii is one or more bipolar aprotic and / or polar solvents, which are optionally mixed with water.

[0209] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, 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, which may be mixed with water.

[0210] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, 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, which may be mixed with water.

[0211] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, 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, which may be mixed with water.

[0212] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The solvent in step iii is one or more solvents selected from acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, and 1,4-dioxane, which may be mixed with water.

[0213] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The solvent in step iii is one or more solvents selected from acetonitrile, acetone, and 1,4-dioxane, which may be mixed with water.

[0214] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The solvent in step iii is a mixture of acetone and water.

[0215] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The solvent in step iii is a mixture of acetone and water in a ratio within the range of 5:1 (v / v) to 20:1 (v / v), with acetone being preferred.

[0216] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The solvent in step iii is a mixture of acetone and water in a ratio within the range of 6:1 (v / v) to 15:1 (v / v), with acetone being preferred.

[0217] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The solvent in step iii is a mixture of acetone and water in a ratio within the range of 6:1 (v / v) to 12:1 (v / v), with acetone being preferred.

[0218] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The solvent in step iii is a mixture of acetone and water in a ratio within the range of 8:1 (v / v) to 12:1 (v / v), with acetone being preferred.

[0219] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The solvent in step iii is a mixture of acetone and water in a ratio within the range of 8:1 (v / v) to 10:1 (v / v), with acetone being preferred.

[0220] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of solvent to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in the solution used in step iii. is within the range of 6:1 to 20:1 (w / w; solvent: compound).

[0221] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of solvent to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in the solution used in step iii. is within the range of 8:1 to 15:1 (w / w; solvent: compound).

[0222] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of solvent to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in the solution used in step iii. is within the range of 10:1 (w / w) to 14:1 (w / w), prioritizing the solvent.

[0223] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of solvent to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in the solution used in step iii. is within the range of 11:1 (w / w) to 12:1 (w / w), prioritizing the solvent.

[0224] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the acetone-water mixture to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in the solution used in step iii. is in the range of 8:1 (w / w) to 15:1 (w / w), with preference given to the acetone-water mixture.

[0225] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the acetone-water mixture to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in the solution used in step iii. is in the range of 10:1 (w / w) to 14:1 (w / w), with preference given to the acetone-water mixture.

[0226] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the acetone-water mixture to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in the solution used in step iii. is in the range of 11:1 (w / w) to 12:1 (w / w), with preference given to the acetone-water mixture.

[0227] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The poor solvent in step iii is water, or a mixture of water and one or more organic solvents selected from the group including methanol, ethanol, n-propanol, isopropanol, tetrahydrofuran, acetonitrile, acetone, 1,4-dioxane, or 2-methyltetrahydrofuran.

[0228] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The poor solvent in step iii is hexane, cyclohexane, n-heptane, ethyl acetate, or a mixture thereof with one or more solvents selected from the group including ethyl acetate, isopropyl acetate, diethyl ether, diisopropyl ether, or methyl tert-butyl ether.

[0229] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The poor solvent in step iii is water, or a mixture of water and one or more organic solvents selected from the group including methanol, ethanol, isopropanol, tetrahydrofuran, and acetonitrile.

[0230] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The poor solvent in step iii is hexane, cyclohexane, n-heptane, ethyl acetate, or a mixture thereof with one or more solvents selected from the group including isopropyl acetate, diethyl ether, diisopropyl ether, or methyl tert-butyl ether.

[0231] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The poor solvent in step iii is water, or a mixture of water and one or more organic solvents selected from the group including methanol, ethanol, and isopropanol.

[0232] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The poor solvent in step iii is hexane, cyclohexane, n-heptane, or ethyl acetate.

[0233] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The poor solvent in step iii is water.

[0234] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The poor solvent in step iii is water; there are no other poor solvents.

[0235] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, In step iii, the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide to the poor solvent is within the range of 1:1 to 1:100 (w / w), prioritizing the poor solvent.

[0236] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, In step iii, the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide to the poor solvent is within the range of 1:2 to 1:50 (w / w), prioritizing the poor solvent.

[0237] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, In step iii, the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide to the poor solvent is within the range of 1:4 to 1:40 (w / w), prioritizing the poor solvent.

[0238] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, In step iii, the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide to the poor solvent is within the range of 1:6 to 1:40 (w / w), prioritizing the poor solvent.

[0239] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, In step iii, the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide to the poor solvent is within the range of 1:10 to 1:30 (w / w), prioritizing the poor solvent.

[0240] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, In step iii, the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide to water used as the poor solvent is in the range of 1:4 to 1:40 (w / w), with water being preferred.

[0241] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, In step iii, the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide to water used as the poor solvent is in the range of 1:6 to 1:40 (w / w), with water being preferred.

[0242] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, In step iii, the ratio of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide to water, which is used as the poor solvent, is in the range of 1:10 to 1:30 (w / w), with water being preferred.

[0243] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the solvent used in step ii. to the poor solvent in step iii. is within the range of 1:10 to 10:1 (v / v; solvent:poor solvent).

[0244] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the solvent used in step ii. to the poor solvent in step iii. is within the range of 1:6 to 6:1 (v / v; solvent:poor solvent).

[0245] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the solvent used in step ii. to the poor solvent in step iii. is within the range of 1:4 to 4:1 (v / v; solvent:poor solvent).

[0246] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the solvent used in step ii. to the poor solvent in step iii. is within the range of 1:3 to 2:1 (v / v; solvent:poor solvent).

[0247] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the solvent used in step ii. to the poor solvent in step iii. is within the range of 1:2 to 1:1 (v / v; solvent:poor solvent).

[0248] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of solvent to poor solvent used in the solution in step iii is within the range of 1:10 to 10:1 (v / v; solvent:poor solvent).

[0249] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of solvent to poor solvent used in the solution in step iii is within the range of 1:6 to 6:1 (v / v; solvent:poor solvent).

[0250] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein The ratio of solvent to poor solvent used in the solution in step iii is within the range of 1:4 to 4:1 (v / v; solvent:poor solvent).

[0251] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of solvent to poor solvent used in the solution in step iii is within the range of 1:3 to 2:1 (v / v; solvent:poor solvent).

[0252] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of solvent to poor solvent used in the solution in step iii is within the range of 1:2 to 1:1 (v / v; solvent:poor solvent).

[0253] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step iii is carried out at a temperature within the range of 0°C to 20°C for a duration of 20 minutes to 2 hours.

[0254] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step iii is carried out at a temperature within the range of 0°C to 20°C for a duration of 20 minutes to 1.5 hours.

[0255] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step iii is carried out at a temperature within the range of 2°C to 15°C for a duration of 30 minutes to 1 hour.

[0256] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step iii is carried out at a temperature within the range of 4°C to 10°C for a duration of 30 minutes to 1 hour.

[0257] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step iii is carried out at a temperature within the range of 2°C to 15°C for a time within the range of 30 to 45 minutes.

[0258] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step iii is carried out at a temperature within the range of 4°C to 10°C for a time within the range of 35 to 40 minutes.

[0259] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The addition of an optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in step iii. is carried out at a temperature in the range of 0°C to 20°C for a period of time in the range of 20 minutes to 2 hours.

[0260] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The addition of an optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in step iii. is carried out at a temperature in the range of 0°C to 20°C for a period of time in the range of 20 minutes to 1.5 hours.

[0261] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The addition of an optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in step iii is carried out at a temperature in the range of 2°C to 15°C for a period of time in the range of 30 minutes to 1 hour.

[0262] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, In step iii, the filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is added over a period of 30 minutes to 1 hour at a temperature in the range of 2°C to 15°C.

[0263] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The addition of an optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in step iii. is carried out at a temperature in the range of 4°C to 10°C for a period of time in the range of 30 minutes to 1 hour.

[0264] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The addition of the filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in step iii. is carried out at a temperature in the range of 4°C to 10°C for a period of time in the range of 30 minutes to 1 hour.

[0265] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The addition of the filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in step iii is carried out at a temperature in the range of 2°C to 15°C over a period of 30 to 45 minutes.

[0266] According to a further embodiment of the second aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The addition of the filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in step iii. is carried out at a temperature in the range of 4°C to 10°C over a period of 35 to 40 minutes.

[0267] In certain further embodiments of the second aspect, the present invention encompasses two or more combinations of the above embodiments, which are titled "Further Embodiments of the Second Aspect of the Invention."

[0268] The present invention encompasses any subcombination within any embodiment or aspect of the present invention of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide microcrystals, a method for preparing the same, and pharmaceutical compositions containing the same.

[0269] The present invention encompasses a method for preparing microcrystals of the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide of the present invention, the method comprising the steps described in the Experiments section herein.

[0270] According to a third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being Formula (II)

[0271] [ka] The intermediate compound is given by formula (III)

[0272] [ka] [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby

[0273] [ka] (R)N-(2-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is obtained, The crude product obtained is dissolved in a solvent or solvent mixture, and then, The resulting solution is combined with a poor solvent, and then, The resulting precipitate was isolated and dried.

[0274] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0275] According to a second embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being Formula (II)

[0276] [ka] The intermediate compound is given by formula (III)

[0277] [ka] [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby,

[0278] [ka] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is obtained, The obtained crude product is dissolved in acetone containing water in the range of 0% to 30% (v / v), and then The resulting solution is then mixed with water, The obtained precipitate is isolated and dried,

[0279] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0280] According to a third embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being

[0281] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is dissolved in a solvent or a mixture of solvents, then The resulting solution is then combined with a poor solvent, The resulting precipitate was isolated and dried.

[0282] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0283] According to a fourth embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being

[0284] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is dissolved in acetone containing water in the range of 0% to 30% (v / v), and then The resulting solution is then mixed with water, The resulting precipitate was isolated and dried.

[0285] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0286] According to a fifth embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being 1) Formula (II)

[0287] [ka] The intermediate compound is given by formula (III)

[0288] [ka] [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby

[0289] [ka] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is obtained, 2) Dissolve the crude product obtained from step 1) in a solvent. 3) Create supersaturation, 4) Add a nanosuspension further comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, a poor solvent, at least one surfactant and at least one polymer, 5) a. Cooling b. Addition of poor solvents, and c. Evaporation of the solvent One or more sub-processes selected from these are followed by 6) The obtained precipitate is isolated and dried,

[0290] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0291] According to the sixth embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being 2) Dissolve (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in a solvent, 3) Create supersaturation, 4) Add a nanosuspension further comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, a poor solvent, at least one surfactant and at least one polymer, 5) a. Cooling b. Addition of poor solvents, and c. Evaporation of the solvent One or more sub-processes selected from these are followed by 6) The obtained precipitate is isolated and dried,

[0292] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0293] According to the seventh embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being 1) Formula (II)

[0294] [ka] The intermediate compound is given by formula (III)

[0295] [ka] [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby

[0296] [ka] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is obtained, 2) The crude product obtained from step 1) is dissolved in a bipolar aprotic and / or protic solvent and optionally filtered. 3) a. Cooling b. Addition of poor solvents, and c. Evaporation of the solvent Supersaturation is created through one or more sub-steps selected from, 4) Add a nanosuspension further comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, a poor solvent, at least one surfactant and at least one polymer, 5) a. Cooling b. Addition of poor solvents, and c. Evaporation of the solvent One or more sub-processes selected from these are followed by 6) The obtained precipitate is isolated and dried,

[0297] The method includes a step of obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0298] According to the eighth embodiment of the third aspect, the present invention relates to a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the method is as follows: 2) (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is dissolved in a bipolar aprotic and / or protic solvent, and optionally filtered, 3) a. Cooling b. Addition of poor solvents, and c. Evaporation of the solvent Supersaturation is created through one or more sub-steps selected from, 4) Add a nanosuspension further comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, a poor solvent, at least one surfactant and at least one polymer, 5) a. Cooling b. Addition of poor solvents, and c. Evaporation of the solvent One or more sub-processes selected from these are followed by 6) The obtained precipitate is isolated and dried,

[0299] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0300] According to the ninth embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being 1) Formula (II)

[0301] [ka] The intermediate compound is given by formula (III)

[0302] [ka] [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby

[0303] [ka] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is obtained, 2) The crude product obtained from step 1) is dissolved in a bipolar aprotic and / or protic solvent and optionally filtered. 3) Create supersaturation by cooling, 4) Add a nanosuspension further comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, a poor solvent, at least one surfactant and at least one polymer, 5) Next, a. Cool, then, b. Add a poor solvent, 6) The obtained precipitate is isolated and dried,

[0304] The method includes a step of obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0305] According to the tenth embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being 2) (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is dissolved in a bipolar aprotic and / or protic solvent, and optionally filtered, 3) Create supersaturation by cooling, 4) Add a nanosuspension further comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, a poor solvent, at least one surfactant and at least one polymer, 5) Next, a. Cool, then b. Add a poor solvent, 6) The obtained precipitate is isolated and dried,

[0306] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0307] According to the eleventh embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being 1) In the presence of at least one equivalent of a base selected from alkali carbonates, alkali bicarbonates, and alkali phosphates, in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidinone, acetone, and isopropanol, at a temperature in the range of 20 to 80°C for a period of 30 minutes to 24 hours, formula (II)

[0308] [ka] The intermediate compound is given by formula (III)

[0309] [ka] [In the formula, LG is the leaving group as defined above.] By reacting with the intermediate compound, thereby,

[0310] [ka] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is obtained, 2) Dissolve the crude product obtained from step 1) in acetone containing water in the range of 10-30% v / v, and optionally filter it. 3) Supersaturation is created by cooling, and the temperature decrease is within the range of 5°C to 30°C. 4) Add a nanosuspension further comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, water, at least one surfactant and at least two polymers, 5) Next, a. Cool, then, b. Add water, 6) The obtained precipitate is isolated and dried,

[0311] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0312] According to the twelfth embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being 2) Dissolve (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in acetone containing water in the range of 10-30% v / v, and optionally filter it. 3) Supersaturation is created by cooling, and the temperature decrease is within the range of 5°C to 30°C. 4) Add a nanosuspension further comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, water, at least one surfactant and at least two polymers, 5) Next, a. Cool, then, b. Add water, 6) The obtained precipitate is isolated and dried,

[0313] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0314] According to the thirteenth embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being 1) In the presence of 1.5 to 5 equivalents of potassium phosphate, in acetonitrile at a temperature in the range of 50 to 70°C for a period of 1 to 2 hours, formula (II)

[0315] [ka] The intermediate compound is given by formula (III)

[0316] [ka] [In the formula, LG represents a bromine atom.] It is reacted with an intermediate compound, thereby,

[0317] [ka] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is obtained, 2) Dissolve the crude product obtained from step 1) in acetone containing 10-30% v / v water at a temperature in the range of 40°C to 70°C, and optionally filter it. 3) Supersaturation is created by cooling, and the temperature decrease is within the range of 15°C to 25°C. 4) Add a nanosuspension further comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (5-20% w / w), water (60-90% w / w), at least one surfactant (0.05-1% w / w), and at least two polymers (each 0.5-15% w / w), wherein the amount of the nanosuspension is within the range of 0.1-20% w / w of the supersaturated solution obtained from step 3. 5) Next, a. Cool the temperature, and the temperature drop should be within the range of 5°C to 25°C. b. Add water, 6) The obtained precipitate is isolated and dried,

[0318] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0319] According to the fourteenth embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being 2) Dissolve (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in acetone containing 10-30% v / v water at a temperature of 40°C-70°C, and optionally filter it. 3) Supersaturation is created by cooling, and the temperature decrease is within the range of 15°C to 25°C. 4) Add a nanosuspension further comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (5-20% w / w), water (60-90% w / w), at least one surfactant (0.05-1% w / w), and at least two polymers (each 0.5-15% w / w), wherein the amount of the nanosuspension is within the range of 0.1-20% w / w of the supersaturated solution obtained from step 3. 5) Next, a. Cool the temperature, and the temperature drop should be within the range of 5°C to 25°C, then, b. Add water, 6) The obtained precipitate is isolated and dried,

[0320] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0321] According to the fifteenth embodiment of the third aspect of the present invention, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being 1) In the presence of 1.5 to 5 equivalents of potassium phosphate, in acetonitrile, at a temperature in the range of 50 to 70°C for a period of 1 to 2 hours, formula (II)

[0322] [ka] The intermediate compound is given by formula (III)

[0323] [ka] [In the formula, LG represents a bromine atom.] The intermediate compound is reacted with the intermediate compound, and then the temperature is lowered to 20°C over a period of time up to 1 hour, thereby,

[0324] [ka] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is obtained, 2) Dissolve the crude product obtained from step 1) in acetone containing 10-30% v / v water at a temperature in the range of 40°C to 70°C, and optionally filter it. 3) Supersaturation is created by cooling, and the temperature decrease is within the range of 15°C to 25°C. 4) Add a nanosuspension further comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (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 at 0.5-15% w / w), where, At least one surfactant is C8-C 20 -Contains alkali salts of alkyl sulfates, and at least two polymers include hydroxypropylcellulose and polyvinylpyrrolidone, And here, the amount of the nanosuspension is in the range of 1-6% w / w of the supersaturated solution obtained from step 3), 5) Next, a. Cool the temperature, and the temperature drop will be within the range of 5°C to 25°C. b. Add water, 6) The obtained precipitate is isolated and dried,

[0325] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0326] According to the sixteenth embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being 2) Dissolve (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in acetone containing 10-30% v / v water at a temperature of 40°C-70°C, and optionally filter it. 3) Supersaturation is created by cooling, and the temperature decrease is within the range of 15°C to 25°C. 4) Add a nanosuspension further comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (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 at 0.5-15% w / w), where, At least one surfactant is C8-C 20 -Contains alkali salts of alkyl sulfates, and at least two polymers include hydroxypropylcellulose and polyvinylpyrrolidone, And here, the amount of the nanosuspension is in the range of 1-6% w / w of the supersaturated solution obtained from step 3), 5) Next, a. Cool the temperature, and the temperature drop will be within the range of 5°C to 25°C. b. Add water, 6) The obtained precipitate is isolated and dried,

[0327] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0328] Further embodiments of a third aspect of the present invention: According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution is as follows: x10 is in the range of 1 to 2 μm.

[0329] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution is as follows: x50 is in the range of 4 to 5.5 μm.

[0330] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution is as follows: x50 is in the range of 4 to 8 μm.

[0331] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution is as follows: x90 is in the range of 10 to 18 μm.

[0332] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, 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.

[0333] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, 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.

[0334] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to the PSD2a method is as follows: x10 is in the range of 1 to 2 μm.

[0335] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to the PSD2a method is as follows: x50 is in the range of 4 to 5.5 μm.

[0336] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to the PSD4 method is as follows: x50 is in the range of 4 to 8 μm.

[0337] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to the PSD2a method is as follows: x90 is in the range of 10 to 18 μm.

[0338] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to the PSD4 method is as follows: x90 is in the range of 12-18 μm.

[0339] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to 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.

[0340] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to 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.

[0341] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The particle size distribution determined according to 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.

[0342] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous forms is less than 15%.

[0343] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous forms is less than 10%.

[0344] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous forms is less than 5%.

[0345] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous forms is less than 2.5%.

[0346] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous morphology is below the detection limit of differential scanning calorimetry.

[0347] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous morphology is below the detection limit of XRPD.

[0348] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous morphology is below the detection limit of differential scanning calorimetry by the DSC1 method.

[0349] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The presence of amorphous morphology is below the detection limit of XRPD by the XRPD1 method.

[0350] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein,

[0351] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide has an enantiomer excess of at least 99%.

[0352] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein,

[0353] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide has an enantiomer excess of at least 98%.

[0354] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein,

[0355] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide has an enantiomer excess of at least 95%.

[0356] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide,

[0357] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide has an enantiomer excess of at least 90%.

[0358] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, 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, and [(4-methoxyphenyl)sulfonyl]oxy.

[0359] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, In step 1), the leaving group LG is a chlorine atom, a bromine atom, or an iodine atom, or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy, and [(4-methylphenyl)sulfonyl]oxy.

[0360] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, In step 1), the leaving group LG is a chlorine atom.

[0361] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The leaving group LG in step 1) is a [(4-methylphenyl)sulfonyl]oxy group.

[0362] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, In step 1), the leaving group LG is a bromine atom or a [(4-methylphenyl)sulfonyl]oxy group.

[0363] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, In step 1), the leaving group LG is a bromine atom.

[0364] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out in the presence of a base selected from alkali carbonates, alkali bicarbonates, alkali phosphates, and N,N,N,N-tetra(C1-C3-alkyl)guanidine.

[0365] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out in the presence of a base selected from alkali carbonates, alkali bicarbonates, and alkali phosphates.

[0366] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out in the presence of at least one equivalent of a base selected from alkali carbonates, alkali bicarbonates, alkali phosphates, and N,N,N,N-tetra(C1-C3-alkyl)guanidine.

[0367] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkali carbonates, alkali bicarbonates, alkali phosphates, and N,N,N,N-tetra(C1-C3-alkyl)guanidine.

[0368] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkali carbonates, alkali bicarbonates, and alkali phosphates.

[0369] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out in the presence of 1.5 to 6 equivalents of a base selected from an alkaline carbonate selected from sodium carbonate, potassium carbonate, and cesium carbonate, an alkaline bicarbonate selected from sodium bicarbonate, potassium bicarbonate, and cesium bicarbonate, and an alkaline phosphate selected from sodium phosphate, potassium phosphate, and cesium phosphate.

[0370] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out in the presence of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate, and potassium phosphate.

[0371] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, 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, and potassium phosphate.

[0372] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out in the presence of a base selected from potassium carbonate and potassium phosphate.

[0373] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate.

[0374] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out in the presence of 1.5 to 3 equivalents of potassium phosphate.

[0375] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out in the presence of 2 to 6 equivalents of potassium carbonate.

[0376] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out at a temperature within the range of 0°C to 100°C.

[0377] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out at a temperature within the range of 20°C to 90°C.

[0378] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out at a temperature within the range of 40°C to 80°C.

[0379] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out at a temperature within the range of 50°C to 70°C.

[0380] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out at a temperature in the range of 40°C to 80°C, and optionally followed by a decrease in temperature to 20°C over a period of up to 1 hour.

[0381] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out at a temperature in the range of 50°C to 70°C, and optionally followed by lowering the temperature to 20°C over a period of up to 1 hour.

[0382] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out at a temperature in the range of 40°C to 80°C, followed by a decrease in temperature to 20°C over a period of up to 1 hour.

[0383] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out at a temperature in the range of 50°C to 70°C, followed by a decrease in temperature to 20°C over a period of up to 1 hour.

[0384] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidinone, acetone, and isopropanol, or a mixture of acetone and isopropanol.

[0385] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out in a solvent selected from N,N-dimethylformamide, acetonitrile, N-methylpyrrolidinone, acetone, and isopropanol, or in a mixture of acetone and isopropanol in the range of 5:1 (v / v) to 1:5 (v / v).

[0386] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out in a solvent selected from N,N-dimethylformamide and acetonitrile.

[0387] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out in N,N-dimethylformamide as the solvent.

[0388] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out in acetonitrile as the solvent.

[0389] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out over a period of time ranging from 30 minutes to 24 hours.

[0390] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out over a period of time ranging from 30 minutes to 6 hours.

[0391] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out over a period of time ranging from 30 minutes to 2 hours.

[0392] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 1) is carried out over a period of time ranging from 1 to 2 hours.

[0393] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 2) is carried out in one or more dipolar aprotic and / or polar solvents, which are optionally mixed with water.

[0394] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 2) 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, which may be mixed with water as desired.

[0395] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, 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, and 2-methyltetrahydrofuran, which may be mixed with water as desired.

[0396] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, 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, and 2-methyltetrahydrofuran, which are optionally mixed with water.

[0397] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 2) is carried out in one or more solvents selected from acetonitrile, diethyl ketone, methyl ethyl ketone, acetone, and 1,4-dioxane, which are optionally mixed with water.

[0398] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 2) is carried out in one or more solvents selected from acetonitrile, acetone, and 1,4-dioxane, which are optionally mixed with water.

[0399] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 2) is carried out in a mixture of acetone and water.

[0400] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 2) is carried out in a mixture of acetone and water, where the acetone contains water in the range of 0-50% v / v.

[0401] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 2) is carried out in a mixture of acetone and water, where the acetone contains water in the range of 10-30% v / v.

[0402] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, Step 2) is carried out in a mixture of acetone and water at a temperature in the range of 40°C to 70°C, where the acetone contains water in the range of 10 to 30% v / v.

[0403] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the solvent used in step 2) to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is in the range of 4:1 to 10:1 (w / w; solvent: compound).

[0404] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the solvent used in step 2) to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is in the range of 4:1 to 8:1 (w / w; solvent: compound).

[0405] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the solvent used in step 2) to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is within the range of 5:1 (w / w) to 7:1 (w / w), prioritizing the solvent.

[0406] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the solvent used in step 2) to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is within the range of 5.5:1 (w / w) to 6:1 (w / w), prioritizing the solvent.

[0407] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the acetone-water mixture to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide used in step 2) is in the range of 4:1(w / w) to 8:1(w / w), with preference given to the acetone-water mixture.

[0408] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the acetone-water mixture to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide used in step 2) is in the range of 5:1(w / w) to 7:1(w / w), with preference given to the acetone-water mixture.

[0409] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The ratio of the acetone-water mixture to (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide used in step 2) is in the range of 5.5:1(w / w) to 6:1(w / w), with preference given to the acetone-water mixture.

[0410] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where the creation of supersaturation in step 3) is achieved by cooling.

[0411] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where the creation of supersaturation in step 3) is achieved by adding a poor solvent.

[0412] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where the creation of supersaturation in step 3) is achieved by evaporating the solvent.

[0413] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the creation of supersaturation in step 3) is achieved by cooling, and the temperature reduction is in the range of 5°C to 30°C.

[0414] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the creation of supersaturation in step 3) is achieved by cooling, and the temperature reduction is in the range of 15°C to 25°C.

[0415] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the creation of supersaturation in step 3) is achieved by cooling, the temperature reduction is in the range of 5°C to 30°C, and the solvent is acetone containing water in the range of 10 to 30% v / v.

[0416] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the creation of supersaturation in step 3) is achieved by cooling, the temperature reduction is in the range of 15°C to 25°C, and the solvent is acetone containing water in the range of 10 to 30% v / v.

[0417] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the creation of supersaturation in step 3) is achieved by cooling, the temperature reduction is in the range of 15°C to 25°C, and the solvent is acetone containing water in the range of 10 to 30% v / v.

[0418] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the nanosuspension used in step 4) contains (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in an amount of 5-20% w / w.

[0419] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the poor solvent in the nanosuspension used in step 4) is water.

[0420] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the nanosuspension used in step 4) contains water in the range of 60-90% w / w.

[0421] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the nanosuspension used in step 4) comprises at least one surfactant in the range of 0.05 to 1% w / w.

[0422] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the nanosuspension used in step 4) contains one surfactant in the range of 0.05 to 1% w / w.

[0423] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the nanosuspension used in step 4) contains one surfactant in the range of 0.05 to 1% w / w, and wherein the surfactant is C8-C 20 -It is an alkali salt of alkyl sulfate.

[0424] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the nanosuspension used in step 4) contains one surfactant in the range of 0.05 to 1% w / w, and wherein the surfactant is C 10 -C 16 -It is a sodium or potassium salt of alkyl sulfate.

[0425] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the nanosuspension used in step 4) contains one surfactant in the range of 0.05 to 1% w / w, and wherein the surfactant is sodium dodecyl sulfate.

[0426] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the nanosuspension used in step 4) comprises at least two polymers independently of each other in the range of 0.5 to 15% w / w.

[0427] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the nanosuspension used in step 4) comprises at least two polymers independently of each other in the range of 0.5 to 15% w / w, where one polymer is hydroxypropyl cellulose and the other polymer is polyvinylpyrrolidone.

[0428] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the nanosuspension used in step 4) contains two polymers independently of each other in the range of 0.5 to 15% w / w, where one polymer is hydroxypropyl cellulose and the other polymer is polyvinylpyrrolidone.

[0429] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the amount of nanosuspension used in step 4) is in the range of 0.1 to 20% w / w of the supersaturated solution obtained from step 3).

[0430] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the amount of nanosuspension used in step 4) is in the range of 0.25 to 10% w / w of the supersaturated solution obtained from step 3).

[0431] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the amount of nanosuspension used in step 4) is in the range of 1-6% w / w of the supersaturated solution obtained from step 3).

[0432] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the amount of nanosuspension used in step 4) is in the range of 2-4% w / w of the supersaturated solution obtained from step 3).

[0433] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein the amount of nanosuspension used in step 4) is in the range of 2.5-3.0% w / w of the supersaturated solution obtained from step 3).

[0434] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where step 5) is achieved by cooling, followed by the addition of a poor solvent.

[0435] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where step 5) is achieved by cooling, followed by the addition of water.

[0436] According to a further embodiment of the third aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, where step 5) is achieved by cooling, with the temperature decrease being in the range of 5°C to 25°C, followed by the addition of water.

[0437] The present invention encompasses any subcombination within any embodiment or aspect of the present invention of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide microcrystals, methods for preparing them, and pharmaceutical compositions containing them.

[0438] The present invention encompasses a method for preparing microcrystals of the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide of the present invention, the method comprising the steps described in the Experiments section herein.

[0439] According to a fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method comprising formula (II)

[0440] [ka] The intermediate compound is given by formula (III)

[0441] [ka] [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby,

[0442] [ka] The process includes the step of obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoroanilino)propanamide.

[0443] According to the second embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 80%, wherein the method is based on formula (II)

[0444] [ka] The intermediate compound is given by formula (III)

[0445] [ka] [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby,

[0446] [ka] The method comprises the step of obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 80%.

[0447] According to the third embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 90%, wherein the method is based on formula (II)

[0448] [ka] The intermediate compound is given by formula (III)

[0449] [ka] [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby,

[0450] [ka] The process includes obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 90%.

[0451] According to the fourth embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 90%, the method comprising: in the presence of at least one equivalent of a base selected from alkaline carbonates, alkaline bicarbonates and alkaline phosphates, at a temperature in the range of 20 to 80°C, in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidinone, acetone and isopropanol, for a period of 30 minutes to 24 hours, formula (II)

[0452] [ka] The intermediate compound is given by formula (III)

[0453] [ka] [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby,

[0454] [ka] The process includes obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 90%.

[0455] According to the fifth embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 90%, the method comprising: in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate, at a temperature in the range of 40 to 80°C, in a solvent selected from N,N-dimethylformamide and acetonitrile, for a period of 30 minutes to 6 hours, formula (II)

[0456] [ka] The intermediate compound is given by formula (III)

[0457] [ka] [In the formula, LG represents a bromine atom.] It is reacted with an intermediate compound, thereby,

[0458] [ka] The process includes obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 90%.

[0459] According to the sixth embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 90%, the method comprising: preparing the propanamide in a solvent selected from N,N-dimethylformamide and acetonitrile for a period of 30 minutes to 6 hours at a temperature in the range of 40 to 80°C in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate; Formula (II)

[0460] [ka] The intermediate compound is given by formula (III)

[0461] [ka] [In the formula, LG represents a bromine atom.] The intermediate compound is reacted with the intermediate compound, and optionally subsequently the temperature is lowered to 20°C over a period of up to 1 hour, thereby,

[0462] [ka] The process includes obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 90%.

[0463] According to the seventh embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 95%, the method comprising: dissolving in acetonitrile at a temperature in the range of 50-70°C for a period of 1-2 hours in the presence of 1.5-5 equivalents of potassium phosphate, formula (II)

[0464] [ka] The intermediate compound is given by formula (III)

[0465] [ka] [In the formula, LG represents a bromine atom.] It is reacted with an intermediate compound, thereby,

[0466] [ka] The process includes obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 95%.

[0467] According to the eighth embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 95%, the method comprising: in the presence of 1.5 to 5 equivalents of potassium phosphate, in acetonitrile, at a temperature in the range of 50 to 70°C for a period of 1 to 2 hours, formula (II)

[0468] [ka] The intermediate compound is given by formula (III)

[0469] [ka] [In the formula, LG represents a bromine atom.] The intermediate compound is reacted with the intermediate compound, and optionally subsequently the temperature is lowered to 20°C over a period of up to 1 hour, thereby,

[0470] [ka] The process includes obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 95%.

[0471] Further embodiments of a fourth aspect of the present invention: According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The leaving group LG in the process included therein is either a chlorine atom, a bromine atom, or an iodine atom, or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy, and [(4-methylphenyl)sulfonyl]oxy.

[0472] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The leaving group LG in the process involved is a chlorine atom.

[0473] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The leaving group LG in the process involved is the [(4-methylphenyl)sulfonyl]oxy group.

[0474] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The leaving group LG in the process involved is either a bromine atom or a [(4-methylphenyl)sulfonyl]oxy group.

[0475] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The leaving group LG in the process involved is a bromine atom.

[0476] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process included therein is carried out in the presence of a base selected from alkaline carbonates, alkaline bicarbonates, alkaline phosphates, and N,N,N,N-tetra(C1-C3-alkyl)guanidine.

[0477] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes included therein are carried out in the presence of a base selected from alkaline carbonates, alkaline bicarbonates, and alkaline phosphates.

[0478] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process included therein is carried out in the presence of at least one equivalent of a base selected from alkali carbonates, alkali bicarbonates, alkali phosphates, and N,N,N,N-tetra(C1-C3-alkyl)guanidine.

[0479] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkaline carbonates, alkaline bicarbonates, alkaline phosphates, and N,N,N,N-tetra(C1-C3-alkyl)guanidine.

[0480] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process included therein is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkaline carbonates, alkaline bicarbonates, and alkaline phosphates.

[0481] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkaline carbonates selected from sodium carbonate, potassium carbonate, and cesium carbonate, alkaline bicarbonates selected from sodium bicarbonate, potassium bicarbonate, and cesium bicarbonate, and alkaline phosphates selected from sodium phosphate, potassium phosphate, and cesium phosphate.

[0482] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process included therein is carried out in the presence of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate, and potassium phosphate.

[0483] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process 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, and potassium phosphate.

[0484] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process involved is carried out in the presence of a base selected from potassium carbonate and potassium phosphate.

[0485] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process included therein is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate.

[0486] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes involved are carried out in the presence of 1.5 to 3 equivalents of potassium phosphate.

[0487] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes involved are carried out in the presence of 2 to 6 equivalents of potassium carbonate.

[0488] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes included in this are carried out at temperatures within the range of 0°C to 100°C.

[0489] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes included in this are carried out at temperatures within the range of 20°C to 90°C.

[0490] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes included in this are carried out at temperatures within the range of 40°C to 80°C.

[0491] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes included in this are carried out at temperatures within the range of 50°C to 70°C.

[0492] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process included in this is carried out at a temperature in the range of 40°C to 80°C, followed optionally by lowering the temperature to 20°C over a period of up to 1 hour.

[0493] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process included in this is carried out at a temperature in the range of 50°C to 70°C, followed optionally by lowering the temperature to 20°C over a period of up to 1 hour.

[0494] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process involves carrying out steps at temperatures ranging from 40°C to 80°C, followed by a reduction in temperature to 20°C over a period of up to one hour.

[0495] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process involves carrying out steps at a temperature in the range of 50°C to 70°C, followed by a reduction in temperature to 20°C over a period of up to one hour.

[0496] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process included therein is carried out in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidinone, acetone, and isopropanol, or in a mixture of acetone and isopropanol.

[0497] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes included therein are carried out in a solvent selected from N,N-dimethylformamide, acetonitrile, N-methylpyrrolidinone, acetone, and isopropanol, or in a mixture of acetone and isopropanol in a ratio of 5:1 to 1:5.

[0498] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The steps included therein are carried out in a solvent selected from N,N-dimethylformamide and acetonitrile.

[0499] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The steps included in this process are carried out in N,N-dimethylformamide as the solvent.

[0500] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The steps included in this process are carried out in acetonitrile, which is used as the solvent.

[0501] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes included in this will be carried out over a period of time ranging from 30 minutes to 24 hours.

[0502] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes included in this will be carried out over a period of time ranging from 30 minutes to 6 hours.

[0503] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes included in this will be carried out over a period of time ranging from 30 minutes to 2 hours.

[0504] According to a further embodiment of the fourth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes included in this will be carried out over a period of time ranging from one to two hours.

[0505] According to a fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the method being Formula (II)

[0506] [ka] The intermediate compound is given by formula (III)

[0507] [ka] [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby,

[0508] [ka] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

[0509] According to a second embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 80%, the method being Formula (II)

[0510] [ka] The intermediate compound is given by formula (III)

[0511] [ka] [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby,

[0512] [ka] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 80%.

[0513] According to the third embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 90%, the method being Formula (II)

[0514] [ka] The intermediate compound is given by formula (III)

[0515] [ka] [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby,

[0516] [ka] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 90%.

[0517] According to the fourth embodiment of the fifth aspect of the present invention, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 90%, the method comprising: in the presence of at least one equivalent of a base selected from alkaline carbonates, alkaline bicarbonates and alkaline phosphates, at a temperature in the range of 20 to 80°C, in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidinone, acetone and isopropanol, for a period of 30 minutes to 24 hours; Formula (II)

[0518] [ka] The intermediate compound is given by formula (III)

[0519] [ka] [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby,

[0520] [ka] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 90%.

[0521] According to the fifth embodiment of the fifth aspect of the present invention, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 90%, the method comprising: in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate, at a temperature in the range of 40 to 80°C, in a solvent selected from N,N-dimethylformamide and acetonitrile, for a period of 30 minutes to 6 hours; Formula (II)

[0522] [ka] The intermediate compound is given by formula (III)

[0523] [ka] [In the formula, LG represents a bromine atom.] It is reacted with an intermediate compound, thereby,

[0524] [ka] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 90%.

[0525] According to the sixth embodiment of the fifth aspect of the present invention, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 90%, the method comprising: in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate, at a temperature in the range of 40 to 80°C, in a solvent selected from N,N-dimethylformamide and acetonitrile, for a period of 30 minutes to 6 hours; Formula (II)

[0526] [ka] The intermediate compound is given by formula (III)

[0527] [ka] [In the formula, LG represents a bromine atom.] The intermediate compound is reacted with the intermediate compound, and optionally subsequently the temperature is lowered to 20°C over a period of up to 1 hour, thereby,

[0528] [ka] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 90%.

[0529] According to the seventh embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 95%, the method comprising: preparing the microcrystals in acetonitrile in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70°C for a period of 1 to 2 hours; Formula (II)

[0530] [ka] The intermediate compound is given by formula (III)

[0531] [ka] [In the formula, LG represents a bromine atom.] It is reacted with an intermediate compound, thereby,

[0532] [ka] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 95%.

[0533] According to the eighth embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 95%, the method comprising: preparing the crystals in acetonitrile in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70°C for a period of 1 to 2 hours; Formula (II)

[0534] [ka] The intermediate compound is given by formula (III)

[0535] [ka] [In the formula, LG represents a bromine atom.] The intermediate compound is reacted with the intermediate compound, and optionally subsequently the temperature is lowered to 20°C over a period of up to 1 hour, thereby,

[0536] [ka] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 95%.

[0537] According to the ninth embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 98%, the method comprising: preparing the microcrystals in acetonitrile in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70°C for a period of 1 to 2 hours; Formula (II)

[0538] [ka] The intermediate compound is given by formula (III)

[0539] [ka] [In the formula, LG represents a bromine atom.] It is reacted with an intermediate compound, thereby,

[0540] [ka] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 98%.

[0541] According to the tenth embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 98%, the method comprising: preparing the microcrystals in acetonitrile in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70°C for a period of 1 to 2 hours; Formula (II)

[0542] [ka] The intermediate compound is given by formula (III)

[0543] [ka] [In the formula, LG represents a bromine atom.] It is reacted with an intermediate compound, thereby,

[0544] [ka] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 98%, wherein, The presence of amorphous forms is less than 5%. The particle size distribution 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.

[0545] According to the eleventh embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 98%, the method comprising: preparing the microcrystals in acetonitrile in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70°C for a period of 1 to 2 hours; Formula (II)

[0546] [ka] The intermediate compound is given by formula (III)

[0547] [ka] [In the formula, LG represents a bromine atom.] It is reacted with an intermediate compound, thereby,

[0548] [ka] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 98%, wherein, The presence of amorphous forms is less than 5%. 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.

[0549] According to the twelfth embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 99%, the method comprising: preparing the crystals in acetonitrile in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70°C for a period of 1 to 2 hours; Formula (II)

[0550] [ka] The intermediate compound is given by formula (III)

[0551] [ka] [In the formula, LG represents a bromine atom.] It is reacted with an intermediate compound, thereby,

[0552] [ka] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 99%, wherein, The presence of amorphous morphology is below the detection limit of differential scanning calorimetry. The particle size distribution 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.

[0553] According to the thirteenth embodiment of the fifth aspect of the present invention, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 99%, the method comprising: preparing the crystals in acetonitrile in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70°C for a period of 1 to 2 hours; Formula (II)

[0554] [ka] The intermediate compound is given by formula (III)

[0555] [ka] [In the formula, LG represents a bromine atom.] It is reacted with an intermediate compound, thereby,

[0556] [ka] The method includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 99%, wherein, The presence of amorphous morphology is below the detection limit of differential scanning calorimetry. 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.

[0557] According to the 14th embodiment of the fifth aspect of the present invention, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazol-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 99%, the method comprising: preparing the microcrystals in acetonitrile in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70°C for a period of 1 to 2 hours; Formula (II)

[0558] [ka] The intermediate compound is given by formula (III)

[0559] [ka] [In the formula, LG represents a bromine atom.] It is reacted with an intermediate compound, thereby,

[0560] [ka] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 99%, wherein, The presence of amorphous morphology is below the detection limit of XRPD. The particle size distribution 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.

[0561] According to the fifteenth embodiment of the fifth aspect of the present invention, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 99%, the method comprising: preparing the microcrystals in acetonitrile in the presence of 1.5 to 5 equivalents of potassium phosphate at a temperature in the range of 50 to 70°C for a period of 1 to 2 hours; Formula (II)

[0562] [ka] The intermediate compound is given by formula (III)

[0563] [ka] In the formula, LG is a bromine atom. It is reacted with an intermediate compound, thereby,

[0564] [ka] The process includes obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 99%, wherein, The presence of amorphous morphology is below the detection limit of XRPD. 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.

[0565] Further embodiments of a fifth aspect of the present invention: According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The leaving group LG in the process included therein is either a chlorine atom, a bromine atom, or an iodide atom, or a group selected from (methylsulfonyl)oxy, (phenylsulfonyl)oxy, and [(4-methylphenyl)sulfonyl]oxy.

[0566] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The leaving group LG in the process involved is a chlorine atom.

[0567] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The leaving group LG in the process involved is the [(4-methylphenyl)sulfonyl]oxy group.

[0568] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The leaving group LG in the process involved is either a bromine atom or a [(4-methylphenyl)sulfonyl]oxy group.

[0569] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The leaving group LG in the process involved is a bromine atom.

[0570] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process included therein is carried out in the presence of a base selected from alkaline carbonates, alkaline bicarbonates, alkaline phosphates, and N,N,N,N-tetra(C1-C3-alkyl)guanidine.

[0571] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes included therein are carried out in the presence of a base selected from alkaline carbonates, alkaline bicarbonates, and alkaline phosphates.

[0572] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process included therein is carried out in the presence of at least one equivalent of a base selected from alkali carbonates, alkali bicarbonates, alkali phosphates, and N,N,N,N-tetra(C1-C3-alkyl)guanidine.

[0573] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkaline carbonates, alkaline bicarbonates, alkaline phosphates, and N,N,N,N-tetra(C1-C3-alkyl)guanidine.

[0574] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process included therein is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkaline carbonates, alkaline bicarbonates, and alkaline phosphates.

[0575] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process is carried out in the presence of 1.5 to 6 equivalents of a base selected from alkaline carbonates selected from sodium carbonate, potassium carbonate, and cesium carbonate, alkaline bicarbonates selected from sodium bicarbonate, potassium bicarbonate, and cesium bicarbonate, and alkaline phosphates selected from sodium phosphate, potassium phosphate, and cesium phosphate.

[0576] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process included therein is carried out in the presence of a base selected from potassium carbonate, cesium carbonate, potassium bicarbonate, cesium bicarbonate, and potassium phosphate.

[0577] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process 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, and potassium phosphate.

[0578] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process involved is carried out in the presence of a base selected from potassium carbonate and potassium phosphate.

[0579] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process included therein is carried out in the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate.

[0580] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes involved are carried out in the presence of 1.5 to 3 equivalents of potassium phosphate.

[0581] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes involved are carried out in the presence of 2 to 6 equivalents of potassium carbonate.

[0582] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes included in this are carried out at temperatures within the range of 0°C to 100°C.

[0583] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes included in this are carried out at temperatures within the range of 20°C to 90°C.

[0584] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes included in this are carried out at temperatures within the range of 40°C to 80°C.

[0585] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes included in this are carried out at temperatures within the range of 50°C to 70°C.

[0586] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process included in this is carried out at a temperature in the range of 40°C to 80°C, followed optionally by lowering the temperature to 20°C over a period of up to 1 hour.

[0587] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process included in this is carried out at a temperature in the range of 50°C to 70°C, followed optionally by lowering the temperature to 20°C over a period of up to 1 hour.

[0588] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process involves carrying out steps at a temperature in the range of 40°C to 80°C, followed by a reduction in temperature to 20°C over a period of up to one hour.

[0589] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process involves carrying out steps at a temperature in the range of 50°C to 70°C, followed by a reduction in temperature to 20°C over a period of up to one hour.

[0590] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The process included therein is carried out in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidinone, acetone, and isopropanol, or in a mixture of acetone and isopropanol.

[0591] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The steps included therein are carried out in a solvent selected from N,N-dimethylformamide, acetonitrile, N-methylpyrrolidinone, acetone, and isopropanol, or in a mixture of acetone and isopropanol in a ratio of 5:1 (v / v) to 1:5 (v / v).

[0592] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The steps included therein are carried out in a solvent selected from N,N-dimethylformamide and acetonitrile.

[0593] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The steps included in this process are carried out in N,N-dimethylformamide as the solvent.

[0594] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The steps included in this process are carried out in acetonitrile, which is used as the solvent.

[0595] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes included in this will be carried out over a period of time ranging from 30 minutes to 24 hours.

[0596] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes included in this will be carried out over a period of time ranging from 30 minutes to 6 hours.

[0597] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes included in this will be carried out over a period of time ranging from 30 minutes to 2 hours.

[0598] According to a further embodiment of the fifth aspect, the present invention comprises a method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, wherein, The processes included in this will be carried out over a period of time ranging from one to two hours.

[0599] According to a sixth aspect, the present invention encompasses pharmaceutical compositions comprising microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide and one or more pharmaceutically acceptable excipients.

[0600] According to the second embodiment of the sixth aspect of the present invention, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The presence of amorphous forms is less than 15%. The particle size distribution is as follows: x10 is <5 μm, x50 is <10 μm, and x90 is <35 μm. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0601] According to the third embodiment of the sixth aspect of the present invention, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The presence of amorphous forms is less than 15%. The particle size distribution 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. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0602] According to the fourth embodiment of the sixth aspect of the present invention, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The presence of amorphous forms is less than 15%. The particle size distribution 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. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0603] According to the fifth embodiment of the sixth aspect of the present invention, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The presence of amorphous forms is less than 15%. 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. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0604] According to the sixth embodiment of the sixth aspect of the present invention, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The enantiomer excess rate is at least 95%, The presence of amorphous forms is less than 10%. The particle size distribution 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. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0605] According to the seventh embodiment of the sixth aspect, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The enantiomer excess rate is at least 95%, The presence of amorphous forms is less than 10%. The particle size distribution 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. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0606] According to the eighth embodiment of the sixth aspect, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The enantiomer excess rate is at least 95%, The presence of amorphous forms is less than 10%. 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. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0607] According to the ninth embodiment of the sixth aspect, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The presence of amorphous forms is less than 5%. The particle size distribution 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. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0608] According to the tenth embodiment of the sixth aspect of the present invention, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The presence of amorphous forms is less than 5%. The particle size distribution 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. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0609] According to the eleventh embodiment of the sixth aspect of the present invention, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The presence of amorphous forms is less than 5%. 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. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0610] According to the twelfth embodiment of the sixth aspect, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The enantiomer excess rate is at least 98%, The presence of amorphous forms is less than 5%. The particle size distribution 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. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0611] According to the 13th embodiment of the 6th aspect, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The enantiomer excess rate is at least 98%, The presence of amorphous forms is less than 5%. The particle size distribution 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. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0612] According to the 14th embodiment of the 6th aspect, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The enantiomer excess rate is at least 98%, The presence of amorphous forms is less than 5%. 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. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0613] According to the 15th embodiment of the 6th aspect, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The enantiomer excess rate is at least 99%, The presence of amorphous forms is less than 5%. The particle size distribution is as follows: x10 is in the range of 1-2 μm, x50 is in the range of 4-5.5 μm, and x90 is in the range of 10-18 μm. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0614] According to the sixteenth embodiment of the sixth aspect of the present invention, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The enantiomer excess rate is at least 99%, The presence of amorphous forms is less than 5%. 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. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0615] Further embodiments of the sixth aspect of the present invention: According to a further embodiment of the sixth aspect, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The enantiomer excess rate is at least 95%, The presence of amorphous forms is less than 10%. The particle size distribution determined according to 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. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0616] According to a further embodiment of the sixth aspect, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The enantiomer excess rate is at least 95%, The presence of amorphous forms is less than 10%. The particle size distribution determined according to 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. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0617] According to a further embodiment of the sixth aspect, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The enantiomer excess rate is at least 95%, The presence of amorphous forms is less than 10%. The particle size distribution determined according to the PSD4 method is as follows: x10 is in the range of 1-4 μm, x50 is in the range of 4-8 μm, and x90 is in the range of 12-18 μm. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0618] According to a further embodiment of the sixth aspect, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The enantiomer excess rate is at least 98%, The presence of amorphous forms is less than 5%. The particle size distribution determined according to 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. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0619] According to a further embodiment of the sixth aspect, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The enantiomer excess rate is at least 98%, The presence of amorphous forms is less than 5%. The particle size distribution determined according to 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. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0620] According to a further embodiment of the sixth aspect, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The enantiomer excess rate is at least 98%, The presence of amorphous forms is less than 5%. The particle size distribution determined according to the PSD4 method is as follows: x10 is in the range of 1-4 μm, x50 is in the range of 4-8 μm, and x90 is in the range of 12-18 μm. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0621] According to a further embodiment of the sixth aspect, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The enantiomer excess rate is at least 99%, The presence of amorphous forms is less than 5%. The particle size distribution determined according to the PSD2a method is as follows: x10 is in the range of 1-2 μm, x50 is in the range of 4-5.5 μm, and x90 is in the range of 10-18 μm. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0622] According to a further embodiment of the sixth aspect, the present invention provides microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (where, The enantiomer excess rate is at least 99%, The presence of amorphous forms is less than 5%. The particle size distribution determined according to the PSD4 method is as follows: x10 is in the range of 1-4 μm, x50 is in the range of 4-8 μm, and x90 is in the range of 12-18 μm. and one or more pharmaceutically acceptable excipients It includes pharmaceutical compositions containing the following:

[0623] The microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide of the present invention can be used to inhibit, block, reduce or decrease DGKζ activity, for example, in connection with cancer and cancer immunotherapy, which ultimately leads to a reduction in tumor growth, blocking immunosuppression and increasing immune cell activation and infiltration, thereby modulating dysregulated immune responses.

[0624] This method involves administering a microcrystalline amount of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide effective in treating a disease to a mammal in need, including humans.

[0625] The present invention also provides methods for treating various other diseases involving DGKζ, including, but not limited to, disorders with dysregulation of the immune response, inflammation, infection and cancer, viral infections, lymphoproliferative disorders, asthma, eye diseases, and type 2 diabetes / insulin resistance.

[0626] Although these diseases are well-characterized in humans, they also exist in other mammals with similar etiologies and can be treated by administering the pharmaceutical compositions of the present invention.

[0627] In a further embodiment, the present invention comprises microcrystals of the above-mentioned (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide for use in the treatment or prevention of diseases, in particular cancer or conditions involving dysregulation of the immune response, or other diseases associated with abnormal DGKζ signaling.

[0628] The pharmaceutically active properties of the microcrystalline form of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide according to the present invention can be explained by the activity of the basic compound (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide as a DGKζ inhibitor.

[0629] In a further embodiment, the present invention encompasses the use of microcrystals of the above-mentioned (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide for the treatment or prevention of diseases, particularly cancer or conditions involving dysregulation of the immune response, or other diseases associated with abnormal DGKζ signaling, in particular humoral and solid tumors.

[0630] In a further embodiment, the present invention comprises microcrystals of the above-mentioned (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide for use in the treatment or prevention of diseases, particularly cancer or conditions involving dysregulation of the immune response, or other disorders associated with abnormal DGKζ signaling, in particular humoral and solid tumors.

[0631] In a further embodiment, the present invention encompasses the use of microcrystals of the above-mentioned (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in methods for treating or preventing diseases, particularly cancer or conditions involving dysregulation of the immune response, or other diseases associated with abnormal DGKζ signaling, in particular humoral and solid tumors.

[0632] In a further embodiment, the present invention encompasses the use of microcrystals of the above-mentioned (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in methods for treating or preventing diseases, particularly cancer or conditions involving dysregulation of the immune response, or other diseases associated with abnormal DGKζ signaling, in particular humoral and solid tumors.

[0633] In a further embodiment, the present invention encompasses the use of microcrystalline (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide as described above for the prevention or treatment of diseases, particularly cancer or conditions involving dysregulation of the immune response, or other diseases associated with abnormal DGKζ signaling, in particular liquid and solid tumors, preferably for the preparation of pharmaceuticals.

[0634] In a further embodiment, the present invention encompasses methods for treating or preventing diseases, particularly cancer or conditions involving dysregulation of the immune response, or other diseases associated with abnormal DGKζ signaling, particularly humoral and solid tumors, using an effective amount of microcrystalline (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide as described above.

[0635] In a further embodiment, the present invention encompasses pharmaceutical compositions, particularly pharmaceuticals, comprising microcrystals of the above-mentioned (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide and one or more excipients, in particular one or more pharmaceutically acceptable excipients. Conventional procedures can be utilized to prepare such pharmaceutical compositions in a suitable dosage form.

[0636] The present invention further encompasses pharmaceutical compositions, particularly pharmaceuticals, comprising at least one microcrystal of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide according to the present invention, usually together with one or more pharmaceutically appropriate excipients, and their use for the above purposes.

[0637] Microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide according to the present invention may have systemic and / or local activity. For this purpose, they can be administered in a preferred manner, for example, orally, parenterally, pulmonaryly, nasally, sublingually, lingually, buccally, rectally, vaginally, skin, percutaneously, conjunctivally, or via the ear route, or as implants or stents.

[0638] For these administration routes, the microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide according to the present invention can be administered in a suitable dosage form.

[0639] For oral administration, microcrystals of the (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide of the present invention can be formulated into dosage forms known in the art, such as tablets (uncoated or coated tablets, e.g., those with enteric or controlled-release coatings that dissolve with a delay or are insoluble), orally disintegrating tablets, films / wafers, films / lyophilized products, capsules (e.g., rigid or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, or aerosols.

[0640] Parenteral administration can be carried out by avoiding the absorption process (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar), or by including absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal). Preferred forms of administration for parenteral administration are, in particular, injection and infusion preparations in the form of suspensions, emulsions, lyophilized products, or sterile powders.

[0641] Examples of other suitable routes of administration include pharmaceutical forms for inhalation [especially powder inhalers, nebulizers], nasal drops, nasal sprays; tablets / films / wafers / capsules for tongue, sublingual or oral administration; suppositories; eye drops, eye ointments, eye baths, ophthalmic inserts, ear drops, ear sprays, ear powders, ear washes, ear tampons; vaginal capsules, aqueous suspensions (lotions, Mixcherae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal treatment systems (e.g., patches), milk, pastes, foams, powders, implants, or stents.

[0642] Microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide according to the present invention can be incorporated into the described dosage forms. This can be done by mixing with pharmaceutically suitable excipients in a manner known by itself. Pharmaceutically suitable excipients include, among others: • Fillers and carriers (e.g., cellulose, microcrystalline cellulose (e.g., Avicel®), lactose, mannitol, starch, calcium phosphate (e.g., Di-Cafos®)), • Ointment base (e.g., petrolatum, paraffin, triglycerides, waxes, wool wax, wool wax alcohol, lanolin, hydrophilic ointment, polyethylene glycol), • Suppository base (e.g., polyethylene glycol, cocoa butter, hard fat), • Solvents (e.g., water, ethanol, isopropanol, glycerol, propylene glycol, medium-chain triglyceride fatty oil, liquid polyethylene glycol, paraffin), • Surfactants, emulsifiers, dispersants or wetting agents (e.g., sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (e.g., Lanette®), sorbitan fatty acid esters (e.g., Span®), polyoxyethylene sorbitan fatty acid esters (e.g., Tween®), polyoxyethylene fatty acid glycerides (e.g., Cremophor®), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (e.g., Pluronic®), • Buffers, acids and bases (e.g., phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), • Isotonic agents (e.g., glucose, sodium chloride), • Adsorbent (e.g., highly dispersed silica), • Thickeners, gel-forming agents, thickeners and / or binders (e.g., polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomer, polyacrylic acid (e.g., Carbopol®); alginates, gelatin), • Disintegrants (e.g., modified starch, carboxymethylcellulose-sodium, starch glycolate-sodium (e.g., Explotab®), cross-linked polyvinylpyrrolidone, croscarmellose-sodium (e.g., AcDiSol®)), • Flow regulators, lubricants, flow promoters and release agents (e.g., magnesium stearate, stearic acid, talc, highly dispersible silica (e.g., Aerosil®)), • Coating materials (e.g., sugars, shellac) and film-forming agents for films or diffusion films that dissolve rapidly or in a modified form (e.g., polyvinylpyrrolidone (e.g., Kollidon®), polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethylcellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylate, polymethacrylate, e.g., Eudragit®)), • Capsule material (e.g., gelatin, hydroxypropyl methylcellulose), • Synthetic polymers (e.g., polylactide, polyglycolide, polyacrylate, polymethacrylate (e.g., Eudragit®), polyvinylpyrrolidone (e.g., Kollidon®), polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, polyethylene glycol and their copolymers and block copolymers), • Plasticizers (e.g., polyethylene glycol, propylene glycol, glycerol, triacetin, triacetyl citrate, dibutyl phthalate), • Penetration enhancer, • Stabilizers (e.g., antioxidants such as ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate, etc.) • Preservatives (e.g., parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), • Colorants (e.g., inorganic pigments such as iron oxide and titanium dioxide), • Flavorings, sweeteners, flavorings, and / or odor-masking agents.

[0643] The present invention further relates to pharmaceutical compositions comprising at least one microcrystal of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide according to the present invention, usually together with one or more pharmaceutically appropriate excipients, and to the use thereof according to the present invention.

[0644] To evaluate the microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide useful for the treatment of cancer or conditions with abnormal immune responses or other diseases associated with abnormal DGKζ signaling, based on known standard laboratory techniques, by standard toxicity tests and standard pharmacological assays for determining the treatment of the above-identified conditions in mammals, and by comparing these results with the results of known active ingredients or agents used to treat these conditions, the effective dose of the microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide of the present invention can be easily determined for the treatment of each desired indication by evaluating the microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide of the present invention useful for the treatment of cancer or conditions with abnormal immune responses or other diseases associated with abnormal DGKζ signaling. The amount of the active ingredient administered in the treatment of one of these conditions can vary widely depending on considerations such as the specific microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the dosage units used, the mode of administration, the duration of treatment, the age and sex of the patient being treated, and the nature and severity of the condition being treated.

[0645] The total amount of microcrystalline (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide administered is generally in the range of about 0.001 mg / kg to about 200 mg / kg body weight / day, preferably about 0.01 mg / kg to about 20 mg / kg body weight / day. Clinically useful dosing schedules range from 1 to 3 doses per day to 1 dose every 4 weeks. Furthermore, "drug-free days" during which the patient does not receive the drug for a certain period can be beneficial to the overall balance between pharmacological effect and tolerability. A unit dose can contain about 0.5 mg to about 1500 mg of the active ingredient and can be administered once or multiple times per day or less than once per day. The average daily dose for administration by injection, including intravenous, intramuscular, subcutaneous, and parenteral injection, and for use of infusion techniques, will preferably be 0.01 to 200 mg / kg total body weight. The average daily rectal dosing regimen is preferably 0.01 to 200 mg / kg of total body weight. The average daily vaginal dosing regimen will preferably be 0.01 to 200 mg / kg of total body weight. The average daily topical dosing regimen will preferably be 0.1 to 200 mg administered 1 to 4 times a day. The transdermal concentration will preferably be the concentration necessary to maintain a daily dose of 0.01 to 200 mg / kg. The average daily inhalation dosing regimen will preferably be 0.01 to 100 mg / kg of total body weight.

[0646] Of course, the specific initial and continuing medication regimens for each patient will vary according to the nature and severity of the condition as determined by the attending physician, the activity of the microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide used, the patient's age and general condition, administration time, route of administration, drug excretion rate, drug combination, etc. The desired mode of treatment and dosage of the microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide of the present invention or its pharmaceutically acceptable salts or esters or compositions thereof can be confirmed by those skilled in the art using conventional therapeutic tests. [Brief explanation of the drawing]

[0647] [Figure 1] XRPD of the substance obtained in Example 2 (XRPD1 method) [Figure 2] DSC (DSC1 method) of the substance obtained in Example 2 [Figure 3] XRPD (XRPD1 method) of the substance obtained in Example 3 (graph below with peak picking) Table 1: Peak list corresponding to Figure 3, graph below:

[0648] [Table 1]

[0649] [Figure 4] DSC (DSC1 method) of the substance obtained in Example 3 [Figure 5] Comparison of dissolution profiles in phosphate buffer (pH 6.8) + 0.1% SDS; the thermodynamic solubility of crystalline substances is approximately 20%; 100% dissolution is equal to 201.5 μg / mL. The profiled substances were:

[0650] (i) Substance from Reference Example 1 after jet milling ( (TIFF2026511647000117.tif9113), (ii) Substance from Example 3 ( (TIFF2026511647000118.tif10110), and (iii) Substance from Reference Example 2 ( This is TIFF2026511647000119.tif12113). The Y-axis represents the amount of dissolution (%), and the X-axis represents the time in minutes. [Figure 6] Figure 5 is a magnified view showing the first hour of the comparison of dissolution profiles, with the y-axis cropped to 30%. [Figure 7] XRPD (XRPD2 method) of the substance obtained from Reference Example 1 before jet milling. [Figure 8] DSC (DSC2 method) of the substance obtained from Reference Example 1 before jet milling. [Figure 9] DSC (DSC2 method) of the substance obtained from Reference Example 1 after jet milling. [Figure 10] Comparison of substances from Reference Example 1 before (upper diffractogram) and after (lower diffractogram) jet milling using XRPD (XRPD2 method). [Figure 11] XRPD (XRPD3 method) of the substance obtained from Reference Example 2 [Figure 12] DSC (DSC3 method) of the substance obtained from Reference Example 2 [Figure 13] Particle size distribution of the substance obtained from Example 4 (PSD4 method) [Figure 14] DSC (DSC1 method) of the substance obtained from Example 4 [Figure 15] XRPD (XRPD1 method) of the substance obtained from Example 4 [Figure 16] Comparison of dissolution profiles of tablets containing an equal amount of microcrystals of (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, obtained as described in Example 3 (-▲-) and Example 4 (-◆-). The Y-axis represents the amount dissolved (%), and the X-axis represents the time in minutes. [Examples]

[0651] Experiment Department Table 2: Abbreviations The following table lists the abbreviations used in this specification.

[0652] [Table 2]

[0653] Various aspects of the present invention described in this application are illustrated by the following embodiments, which are not intended to limit the present invention in any sense.

[0654] The test and experimental examples described herein are helpful in illustrating the present invention, and the present invention is not limited to the given examples.

[0655] Experimental section - Materials and methods HPLC and LC / MS methods: HPLC1 method: Preparative HPLC: Equipment: 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: Labomatic Labocol 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);361nm

[0656] HPLC2 method: Analytical UPLC / MS: Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7 50×2.1mm; Eluent: Solvent A: Water + 0.2 vol% aqueous 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: 2 μL; DAD scan: 210~400 nm; ELSD

[0657] HPLC Method 3: Analytical Chiral HPLC: Instrument: Thermo Fisher UltiMate 3000; Column: YMC Cellulose SB 3μ, 100x4.6; Eluent solvent A: Hexane + 0.1 vol% diethylamine; Eluent solvent B: 2-propanol; Isocratic: 60% A + 40% B; Flow rate: 1.4 ml / min; Temperature: 25℃; UV: 254 nm

[0658] HPLC Method 4: Chemical Purity, Examples 3 and 4, and Reference Example 2: [Table 3]

[0659] [Table 4]

[0660] HPLC method 5: Enantiomer excess, Examples 3 and 4, and Reference Example 2: [Table 5]

[0661] HPLC 6 Methods: Preparative Chiral HPLC: Equipment: Labomatic HD3000, Knauer Pump 100, Labcol Vario 4000 Plus, Knauer DAD 2600; Column: Amylose SB 5μ 250x50mm Nr.34; Eluent A: Hexane + 0.1 vol% diethylamine (99%); Eluent B: 2-propanol; Isocratic: 60%A + 40%B; Flow rate: 150.0 ml / min, 16 min to 180 ml / min; UV @ 254nm Particle size distribution (PSD) PSD1 method: 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.

[0662] PSD2a method: Particle size distribution (PSD) was measured by laser diffraction using a Sympatec Helos device. Water containing a small amount of surfactant was used as the dispersion medium. The sample was sonicated for 240 seconds.

[0663] PSD2b method: The particle size distribution (PSD) was measured by laser diffraction using a Sympatec Helos device. Paraffin was used as the dispersion medium. The sample was sonicated for 240 seconds.

[0664] PSD3 method: Particle size analysis was performed by laser diffraction using Sympatec (HELOS) with Baysilone (Element 14 PDMS 10 - A) as the dispersion medium. The sample was sonicated at 80% intensity for 90 seconds (with a 60 - second pause), and then stirred at 800 rpm using a magnetic stirrer. The measurement was taken three times (with a 30 - second pause), and the arithmetic mean value was calculated.

[0665] PSD4 method: Particle size analysis was measured by laser diffraction using a Malvern Panalytical Mastersizer 3000. Water containing one drop of Tween80 was used as the dispersion medium. The sample was sonicated for 180 seconds.

[0666] Differential scanning calorimetry (DSC) DSC1 method: Differential scanning calorimetry (DSC) was performed using a Mettler Toledo TGA / DSC 3+. The instrument was purged with nitrogen gas at a flow rate of 20 ml / min. Each sample of approximately 1 - 15 mg was placed in an aluminum crucible and heated starting from 25°C at a heating rate of 20°C / min. No sample preparation was carried out. -1 of the flow rate, nitrogen gas was used to purge. Approximately 1 - 15 mg of each sample was placed in an aluminum crucible and heated starting from 25°C at a heating rate of 20°C / min. No sample preparation was carried out. -1 of the heating rate and heated. No sample preparation was carried out.

[0667] DSC2 method: Differential scanning calorimetry (DSC) was performed using a Mettler Toledo TGA / DSC 3+. The instrument was purged with nitrogen gas at a flow rate of 30 ml / min. Each sample of about 1 - 15 mg was placed in an aluminum crucible and heated starting from 25°C at a heating rate of 10 - 20°C / min. No sample preparation was carried out. -1 of the flow rate, nitrogen gas was used to purge. Each sample of about 1 - 15 mg was placed in an aluminum crucible and heated starting from 25°C at a heating rate of 10 - 20°C / min. No sample preparation was carried out. -1 of the heating rate and heated. No sample preparation was carried out.

[0668] DSC3 method: Differential scanning calorimetry (DSC) was performed using a Mettler Toledo DSC3. A 50 ml portion of the calorimeter was used. -1 The area was purged with nitrogen gas at a flow rate of [percentage]. Approximately 3-5 mg of the sample was placed in an aluminum crucible without any sample preparation. The temperature range was [temperature range], with a heating rate of 20°C min / second. -1 The temperature range was -10 to 230°C.

[0669] X-ray powder diffraction (XRPD) XRPD1 method: X-ray powder diffraction (XRPD) data was recorded using a Bruker D2 PHASER diffractometer equipped with a LYNXEYE-2 detector and Cu Kα1 radiation (1.54060 Å). All samples were prepared and measured at ambient temperature, either open or with a PMMA dome, on a Si-single crystal low-background sample holder. The measurements were performed in a Bragg-Brentano (θ / 2θ) horizontal plane, between 3°~40°(2θ) or 4°~40°(2θ), in 0.3-second steps. -1 Data was acquired in 0.02° steps. The X-ray tube was operated at 30 kV and 10 mA.

[0670] XRPD2 method: X-ray powder diffraction (XRPD) data was recorded using a PANalytical X'Pert PRO diffractometer with monochromatic Cu-Kα1 radiation at generator settings of 40 kV and 40 mA. The sample was collected in transmission mode and prepared as a thin layer between two foils. The scanning range was 2° to 40°²θ at 0.013° steps with a scanning interval of 25 seconds / step.

[0671] XRPD3 method: X-ray powder diffraction (XRPD) data was recorded using a STOE STADI P diffractometer with monochromatic Cu-Kα1 radiation and a position detection element, with generator settings of 40 kV and 40 mA. The sample was collected in transmission mode and prepared as a thin layer between two foils. The scanning range was 2° to 40°²θ in 0.5° steps at 15 seconds / step.

[0672] Comparison of dissolution Elution properties of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, a substance from Example 3, compared with substances from Reference Examples 1 and 2.

[0673] methodology sample The following batches were supplied for comparative experiments: The product obtained from Example 3, i.e., microcrystalline (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide produced using the method according to the present invention. The product obtained from Reference Example 1, namely a batch of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, produced by jet milling of a crystalline batch, and containing partially amorphous material. A macrocrystalline batch of the product obtained from Reference Example 2, namely (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide

[0674] setting A phosphate buffer containing 0.1% SDS at pH 6.8 was used as the dissolution medium. The 100% level was set to 201.5 μg / ml. Based on previous solubility data for (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, the thermodynamic solubility of the compound from a crystalline batch should result in a release of approximately 20%. Higher weights were used to allow detection of possible supersaturation in the batches investigated.

[0675] proofreading Calibration and measurement were performed using PION's μDissolver (a small dissolution device equipped with an in-situ UV probe), which enables high temporal resolution. Five-point calibration was recorded at concentrations of 0–207 μg / ml in phosphate buffer containing 2% SDS at pH 6.8. The detection wavelength was set to 255–268 nm (method range, second derivative).

[0676] measurement 2.015 mg (±0.1 mg) of each active pharmaceutical ingredient batch 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 5.5 hours. Each sample was measured as a replica (n=2). For the batch from Reference Example 2, the in-situ UV probe in one container was blocked by particles during measurement; therefore, this batch was investigated from only one container (n=1).

[0677] Experimental Section - Examples Example 1: Preparation of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (screening of process variants)

[0678] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide

[0679] [ka] Example 1a

[0680] [4-amino-2-(4-fluoroanilino)-1,3-thiazole-5-yl](4-methoxyphenyl)methanone (100 mg, 0.29 mmol, CAS 697232-63-6, WO2021 / 214019, see Reference Example 1, Step 1, below) was dissolved in N,N-dimethylformamide (2.1 mL), followed by potassium carbonate (K2CO3, 201 mg, 1.46 mmol) and (2S)-2-bromopropanamide (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 (HPLC I) to obtain 73.8 mg (0.18 mmol, yield 61%) of the title compound in 88% ee.

[0681] Example 1b

[0682] [4-amino-2-(4-fluoroanilino)-1,3-thiazole-5-yl](4-methoxyphenyl)methanone (50 mg, 0.145 mmol) was dissolved in isopropanol / acetone 3 / 1 (1.2 mL), and then N,N,N,N-tetramethylguanidine (25 mg, 0.22 mmol) and (2S)-2-bromopropanamide (26.6 mg, 0.17 mmol) were added. The reaction mixture was stirred at room temperature for 48 hours and then at 50°C for 2 hours, filtered, and purified by preparative HPLC (HPLC I) to obtain 22.7 mg (0.05 mmol, yield 38%) of the title compound with a 61% ee.

[0683] Example 1c [4-amino-2-(4-fluoroanilino)-1,3-thiazole-5-yl](4-methoxyphenyl)methanone (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-bromopropanamide (26.6 mg, 0.17 mmol). The reaction mixture was stirred at room temperature for 48 hours, filtered, and purified by preparative HPLC (HPLC I) to obtain 27 mg (0.06 mmol, yield 44%) of the title compound at 76% ee.

[0684] Example 1d [4-amino-2-(4-fluoroanilino)-1,3-thiazole-5-yl](4-methoxyphenyl)methanone (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-bromopropanamide (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 (HPLC I) to obtain 27 mg (0.06 mmol, 44% yield) of the title compound at 63% ee.

[0685] Example 1e [4-amino-2-(4-fluoroanilino)-1,3-thiazole-5-yl](4-methoxyphenyl)methanone (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-bromopropanamide (53.1 mg, 0.35 mmol). The reaction mixture was stirred at room temperature for 5 hours, filtered, and purified by preparative HPLC (HPLC I) to obtain 73.8 mg (0.18 mmol, yield 61%) of the title compound with 91% ee.

[0686] Example 1f [4-amino-2-(4-fluoroanilino)-1,3-thiazole-5-yl](4-methoxyphenyl)methanone (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-bromopropanamide (26.6 mg, 0.17 mmol). The reaction mixture was stirred at room temperature for 24 hours, filtered, and purified by preparative HPLC (HPLC I) to obtain 26 mg (0.06 mmol, yield 43.6%) of the title compound with an 86% ee.

[0687] Example 1g [4-amino-2-(4-fluoroanilino)-1,3-thiazole-5-yl](4-methoxyphenyl)methanone (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-oxopropan-2-yl 4-methylbenzenesulfonate (56 mg, 0.23 mmol). The reaction mixture was stirred at room temperature for 24 hours and at 60°C for 2 hours, filtered, and purified by preparative HPLC (HPLC I) to obtain 46 mg (0.11 mmol, yield 58%) of the title compound with an 88% ee.

[0688] Example 1h [4-amino-2-(4-fluoroanilino)-1,3-thiazole-5-yl](4-methoxyphenyl)methanone (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-oxopropan-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 (HPLC I) to obtain 24 mg (0.06 mmol, yield 28%) of the title compound with 94% ee.

[0689] Example 1i [4-amine-2-(4-fluoroanilino)-1,3-thiazole-5-yl](4-methoxyphenyl)methanone (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-amine-1-oxopropan-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 (HPLC I) to obtain 24 mg (0.06 mmol, yield 28%) of the title compound at 95% ee.

[0690] Analytical data of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide obtained in Examples 1a-1i: LC / MS (HPLC2 method): t R =1.06min / MS(ESIpos):m / z=415.5[M+H] + Analytical chiral HPLC (HPLC-3 method): R = 5.92 minutes (Example 1a; Examples 1b~1i) R The range is 5.9 to 6.2 minutes; (S)-enantiomers are t R (It was found that it elutes in 3.49 to 3.55 minutes.) 1 H-NMR (400 MHz, DMSO-d6): δ ppm = 1.16 (d, 3 H), 3.75 (s, 3 H), 5.06 (q, 1 H), 6.93 (d, 2 H), 7.22 - 7.27 (m, 1 H), 7.34 (dd, 2 H), 7.48 (d, 2 H), 7.57 (s, 1 H), 7.64 (dd, 2 H), 7.79 - 8.38 (m, 2 H).

[0691] Example 2: Obtaining microcrystals of the present invention by crystallization of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide. 2.5 g of solid (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide was weighed into a 100 mL crystallization vessel. 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 the API solution. In a second 100 mL crystallization vessel, 59.42 g of water was pre-cooled to 5°C and stirred. The API solution was added to pre-cooled water over 30 minutes while maintaining the temperature at 5°C. The resulting suspension was isolated by filtration, and the filter cake was rinsed with a substitution washing solution of acetone / H2O 70 wt% (5.0 g), followed by a substitution washing solution of H2O (5.0 g). The moistened filter cake was vacuum-dried at 60°C. Yield: 89.9%.

[0692] XRPD analysis (XRPD1 method) of the thus obtained (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide showed no evidence of amorphous material or differences in crystalline morphology (Figure 1) compared to WO2021 / 214019 (see Figure 9, Table 16). DSC (DSC1 method) showed perfect crystallinity and no evidence of amorphous material (Figure 2). The PSD determined by PSD1 method was found to be 1.8 / 4.3 / 12.6 μm for x10 / x50 / x90.

[0693] Example 3: Preparation of microcrystalline (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide A suspension of [4-amino-2-(4-fluoroanilino)thiazole-5-yl]-(4-methoxyphenyl)methanone (120 g, 349 mmol), (2S)-2-bromopropanamide (63.7 g, 419 mmol, 1.2 equivalents, 95% enantiomer excess), and potassium phosphate (K3PO4, 148 g, 699 mmol, 2.0 equivalents) in acetonitrile (1200 mL) was heated to 60°C and stirred at that temperature for 1 hour. Then, the temperature was lowered to 20°C within 40 minutes, and water (1200 mL) was added simultaneously within 20 minutes. The resulting three-phase mixture was stirred at 20°C for 3 hours, filtered, and the filter cake was washed with water (3 × 240 mL) to obtain (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide as a pale yellow solid (124 g wet, purity 99.14%, enantiomer excess 99.2%). The water content of the wet filter cake was measured and found to be 16%, which corresponds to 20 mL of residual water in the wet filter cake. This amount was taken into consideration in the subsequent microcrystallization step.

[0694] A wet filter cake was dissolved in a mixture of acetone (1350 mL) and water (130 mL) at ambient temperature to obtain a solution with a small amount of residual solid. The mixture was filtered, and the filtrate was added to water (2000 mL) at 4-10°C within 38 minutes. The resulting dispersed off-white suspension was filtered, the filter cake was washed with water (2 × 150 mL), and vacuum-dried at 50°C to obtain (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (90.3 g, 216 mmol, yield 62%, purity 99.12%, enantiomer excess 99.3%) as an off-white bulk powder. The PSD determined by the PSD2a method was found to be (x10 / x50 / x90): 1.2 / 4.6 / 16.1 μm.

[0695] The chemical purity and enantiomer excess were determined according to HPLC methods 4 and 5 described above, as specified above. Chemical purity (HPLC method 4):t R =5.4 minutes. Enantiomer excess (HPLC method 5): t R =2.9 min ((2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide) t R =2.3 min ((2S)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide) XRPD analysis (XRPD1 method) of the thus obtained (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide showed no evidence of amorphous material or difference in crystalline form compared to WO2021 / 214019 (Figure 3). DSC (DSC1 method) showed perfect crystallinity and no evidence of amorphous material (Figure 4). The dissolution of the material was only slightly slower compared to the dissolution of materials obtained from jet milling of macrocrystalline materials (see Reference Example 1), but substantially faster compared to the macrocrystalline comparative material disclosed in Reference Example 2 (Figures 5, 6).

[0696] Preparation of the starting materials for Example 3: Preparation of [4-amino-2-(4-fluoroanilino)thiazole-5-yl]-(4-methoxyphenyl)methanone: A mixture of 1-fluoro-4-isothiocyanatobenzene (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. To this mixture, a solution of cyanamide (90.6 g, 2.15 mol, 1.1 equivalents) in acetonitrile (1.35 L) was added within 1 hour. After another 1 hour, a solution of 2-bromo-1-(4-methoxyphenyl)ethanone (449 g, 1.96 mol, 1.0 equivalent) in acetonitrile (2.25 L) was added within 75 minutes at 60°C. After another 15 minutes, the suspension was cooled to 20°C within 0.5 hours and stirred at that temperature for a further 0.5 hours. This mixture was filtered, the precipitate was washed with H2O, and dried under reduced pressure at 50°C to obtain [4-amino-2-(4-fluoroanilino)thiazole-5-yl]-(4-methoxyphenyl)methanone (606 g, 1.75 mol, yield 89%, purity 99.0%) as a yellow to orange solid.

[0697] Preparation of (2S)-2-bromopropanamide: A mixture of (2S)-2-bromopropanoic 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 30% aqueous ammonia solution (381 g, 3.27 mol, 2.5 equivalents) within 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 saturated aqueous sodium chloride solution, part of the solvent was removed by vacuum at 40°C, n-heptane was added, the resulting suspension was cooled to 0 to 5°C, held at that temperature for 1 hour, filtered, and the precipitate was washed with n-heptane. By drying the filter cake in a vacuum at 35°C, (2S)-2-bromopropanamide (147 g, 967 mmol, yield 74%, purity 99.65%, enantiomer excess 95%) was obtained as a colorless solid.

[0698] Example 4: Preparation of microcrystalline (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide powder (essentially anhydrous, prepared according to the protocol described in Example 3) (180 g) was added to a mixture of acetone (877 g) and water (175.5 g), and heated to 55°C to obtain a solution with a small amount of residual solid. The mixture was filtered through a K300 20 μm filter cloth, and the filtrate was cooled to 35°C for 1 hour. A 35 g nanosuspension (prepared by the method described in European Patent Application No. 22196150.1, published as Example 1.1, EP4154872A1) containing 79.8 wt% water, 10 wt% (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, 8 wt% PVP K12, 2 wt% HPC Klucel ELF, and 0.2 wt% SDS was added as a seeding 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 a 1 hour stirring time. The resulting dispersed white suspension was filtered through a pressure filter and PP 2703 filter cloth. The filter cake was washed with water (2 × 800 mL) and vacuum-dried at 50°C to obtain (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (164.55 g, yield 91.4%, purity 99.59%, enantiomer excess 99.74%) as a white, lumpy powder. The PSD determined by the PSD4 method was found to be (x10 / x50 / x90): 3.22 / 6.87 / 13.2 μm (Figure 13).

[0699] XRPD analysis (XRPD1 method) of the (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide obtained in this manner showed no evidence of the presence of amorphous material or differences in crystalline form compared to the disclosure in WO2021 / 214019 (Figure 15), and similarly, DSC analysis (DSC1 method) showed no evidence of the presence of amorphous material (Figure 14).

[0700] The dissolution of the substance was slightly faster or equal to that of the substance obtained from Example 3. Specifically, the dissolution of tablets containing equal volumes of microcrystalline (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, obtained as described in Example 3 (-▲-) and Example 4 (-◆-), was measured according to PH.Eur.2.9.3. using a pH 4.5 acetate buffer containing 2% SDS (sodium dodecyl sulfate) as the dissolution medium (Figure 16). A paddle apparatus as defined in the United States Pharmacopeia (USP Apparatus 2 (paddle)) was used with a stirring speed of 50 rpm and a total medium volume of 900 mL.

[0701] Experimental Section - Reference Examples for Comparison with Examples According to the Present Invention Reference Example 1: Partial Amorphization of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide as a result of jet milling Jet milling protocol An LSM Zero air jet mill was used to pulverize the compound.

[0702] The compound (4.00 g) prepared as shown below was sieved through a 1 mm manual sieve, and a small fraction was added to an air jet mill. Micronization was performed at room temperature (23°C, 40% relative humidity) for approximately 1 hour with an injector pressure of 8 bar, a grinding pressure of 6 bar, and nitrogen as the air jet medium.

[0703] Particle size analysis (PSD3 method), DSC (DSC2 method), and XRPD analysis (XRPD2 method) of the compound were performed after the micronization process to determine the yield (3.78 g, 94.5%). The PSD of the material obtained in this way was determined by the PSD3 method and found to be (x10 / x50 / x90): 2.55 / 11.08 / 25.95 μm.

[0704] (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, obtained by the following chemical synthesis and used for jet milling, is a crystalline solid characterized by its diffraction pattern shown in Figure 7 (obtained by the XRPD2 method) and its thermal behavior characterized by the DSC2 method (Figure 8), in which a single endothermic event (melting) occurs at 195°C (start).

[0705] Partial amorphous formation during jet milling can be clearly detected by differential scanning calorimetry (DSC, DSC2), where recrystallization of partially amorphous material is observed in exothermic events between 100 and 140°C (Figure 9). Direct comparison of XRPD data (obtained by XRPD2) of the material before and after jet milling also shows a decrease in the level of crystallinity present in the jet-milled material (Figure 10) (the latter resulting in the graph at the bottom of Figure 10).

[0706] The material used for jet milling was prepared as follows: Step 1: [4-amino-2-(4-fluoroanilino)-1,3-thiazole-5-yl](4-methoxyphenyl)methanone

[0707] [ka] 1-Fluoro-4-isothiocyanatobenzene (51.175 g, 98%, 327.4 mmol, CAS 1544-68-9, Aldrich) was dissolved in acetonitrile (1930 mL, Honeywell). Cyanamide (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, then an additional DBU (24.4 mL, 163.7 mmol) was added, followed by 2-bromo-1-(4-methoxyphenyl)ethane-1-one (75 g, 327.4 mmol, CAS 2632-13-5, Fluka and Aldrich) as a solution in acetonitrile (570 mL) at room temperature. The reaction mixture was stirred at room temperature for 48 hours until a suspension formed. A large amount of water was added, the precipitate was filtered off, washed with water, suspended in water, and dried by freeze-drying to obtain 122.57 g of solid (quantitative yield, purity 91%), which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ ppm= 3.81 (s, 3 H) 7.01 (d, 2 H) 7.21 (dd, 2 H) 7.59 - 7.65 (m, 2 H) 7.66 (d, 2 H) 8.12 (br s, 2 H) 10.76 (br s, 1 H). LC / MS (HPLC2 method): t R = 1.07 min; MS(ESIpos) m / z = 344.2 [M+H] + .

[0708] Step 2: rac-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide

[0709] [ka] [4-amino-2-(4-fluoroanilino)-1,3-thiazole-5-yl](4-methoxyphenyl)methanone (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-bromopropanamide (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, the precipitate was filtered off, washed with water, suspended in water, and freeze-dried to obtain 82.6 g (199.29 mmol, yield 78%) of the title compound. 1 H-NMR (400 MHz, DMSO-d6): δ ppm = 1.16 (d, 3 H), 3.75 (s, 3 H), 5.06 (q, 1 H), 6.93 (d, 2 H), 7.22 - 7.27 (m, 1 H), 7.34 (dd, 2 H), 7.48 (d, 2 H), 7.57 (s, 1 H), 7.64 (dd, 2 H), 7.79 - 8.38 (m, 2 H). LC / MS (HPLC2 method): t R = 1.06 min / MS (ESIpos): m / z = 415.5 [M+H] +

[0710] Step 3: (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide

[0711] [ka] rac-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (82.60 g, 199.3 mmol) was separated by chiral HPLC to obtain enantiomer 1, which is S-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, in an amount of 33.0 g (79.62 mmol, 39.95%), and enantiomer 2, which is R-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, containing a small amount of impurities, in an amount of 38.8 g (93.61 mmol, 46.97%). R-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide 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, the precipitate was filtered off, washed with water, suspended in water, and dried by freeze-drying to obtain 35.7 g (84.44 mmol, yield 42.4%) of the title compound as a crystalline substance, as shown below and as discussed above in relation to Figures 7 and 8.

[0712] Preparative chiral HPLC (HPLC-6 method) enantiomer 1t R =10.2-12.1 minutes enantiomer 2T R =14.6-21.4 minutes Analytical chiral HPLC (HPLC method 3): Enantiomer 2, (R), t R =5.99 minutes 1 H-NMR (400 MHz, DMSO-d6): δ ppm = 1.16 (d, 3 H), 3.75 (s, 3 H), 5.06 (q, 1 H), 6.93 (d, 2 H), 7.22 - 7.27 (m, 1 H), 7.34 (dd, 2 H), 7.48 (d, 2 H), 7.57 (s, 1 H), 7.64 (dd, 2 H), 7.79 - 8.38 (m, 2 H). [α]D 20 = +150.65° (chloroform)

[0713] Reference Example 2: Macrocrystalline (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide Macrocrystalline (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide was prepared by thoroughly mixing and homogenizing three qualitatively equivalent sub-batches of (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide solids, each prepared according to the following procedure: A suspension of [4-amino-2-(4-fluoroanilino)thiazole-5-yl]-(4-methoxyphenyl)methanone (120 g, 349 mmol), (2S)-2-bromopropanamide (63.7 g, 419 mmol, 1.2 equivalents, enantiomer excess 90%), and potassium phosphate (K3PO4, 148 g, 699 mmol, 2.0 equivalents) in acetonitrile (1200 mL) was heated to 60°C and stirred at that temperature for 1 hour. Then, within 40 minutes, the temperature was lowered to 20°C, and simultaneously, within 20 minutes, water (1200 mL) was added. The resulting three-phase mixture was stirred at 20°C for 3 hours and filtered. The filter cake was washed with water (3 × 240 mL) and vacuum-dried at 50°C to obtain (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide as a pale yellow solid (105 g, 252 mmol, yield 72%, purity 99.74%, enantiomer excess 99.0%). The PSD determined by the PSD2b method was found to be (x10 / x50 / x90): 5.6 / 34 / 131 μm.

[0714] XRPD analysis (XRPD3 method) of the resulting macrocrystalline (2R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide showed no evidence of amorphous material or differences in crystal morphology compared to WO2021 / 214019 (Figure 11). DSC (DSC3 method) showed perfect crystallinity and no evidence of amorphous material (Figure 12).

Claims

1. (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide microcrystals, 【Chemistry 1】 (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide Here, The presence of amorphous forms is less than 15%. Furthermore, the particle size distribution is as follows: x10 is <5 μm, x50 is <10 μm, and x90 is <35 μm.

2. A microcrystal of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide according to claim 1, Here, The particle size distribution 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.

3. A microcrystal of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide according to claim 1, Here, The particle size distribution 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.

4. Microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide according to claim 1, 2, or 3, Here, The enantiomer excess rate is at least 95%.

5. Microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide according to claim 1, 2, 3, or 4, Here, The presence of amorphous morphology is less than 5%.

6. Microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide according to claim 1, 2, 3, 4, or 5, Here, 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.

7. Microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide according to claim 1, 3, 4, or 5, Here, 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.

8. Microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide according to claim 1, 2, 4, or 5, Here, The enantiomer excess rate is at least 98%, The presence of amorphous forms is less than 5%. And the particle size distribution 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.

9. Microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide according to claim 1, 3, 4, or 5, Here, The enantiomer excess rate is at least 98%, The presence of amorphous forms is less than 5%. And the particle size distribution 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.

10. Microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide according to claim 1, 2, 3, 4, 5, 6, or 8, Here, The enantiomer excess rate is at least 99%, The presence of amorphous forms is less than 5%. And 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.

11. Microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide according to claim 1, 3, 4, 5, 7, or 9, Here, The enantiomer excess rate is at least 99%, The presence of amorphous forms is less than 5%. And 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.

12. A method for preparing microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoroanilino)propanamide, (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is dissolved in a solvent or solvent mixture, and then, The resulting solution is combined with a poor solvent, and then, The resulting precipitate was isolated and dried. The method comprising the step of obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

13. A method according to claim 12, A optionally filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoroanilino)propanamide in a bipolar aprotic and / or protic solvent is added to a poor solvent, and The resulting precipitate was isolated and dried. The method comprising the step of obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

14. A method according to claim 12 or 13, A filtered solution of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide in a mixture of acetone and water in a ratio of 8:1 (v / v) to 12:1 (v / v) with acetone preferred is added to water at a temperature in the range of 4°C to 10°C for a time in the range of 30 minutes to 1 hour, and The resulting precipitate was isolated and dried. The method comprising the step of obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

15. A method according to claim 12, 2) Dissolve (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoroanilino)propanamide in a solvent, 3) Create supersaturation, 4) Add a nanosuspension further comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoroanilino)propanamide, a poor solvent, at least one surfactant and at least one polymer, ５） a. cooling b. Addition of poor solvents, and c. Evaporation of the solvent One or more substeps selected from the following will follow: 6) Isolate and dry the obtained precipitate. The method comprising the step of obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

16. A method according to claim 12 or 15, 2) Dissolve (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoroanilino)propanamide in acetone containing 10-30% v / v water, and optionally filter it. 3) Supersaturation is created by cooling, and the temperature decrease is within the range of 5°C to 30°C. 4) Add a nanosuspension further comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, water, at least one surfactant and at least two polymers, 5) Next, a. Cool, then b. Add water, 6) Isolate and dry the obtained precipitate. The method comprising the step of obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

17. A method according to claim 12 or 13, i. Equation (II) 【Chemistry 2】 The intermediate compound is given by formula (III) 【Transformation 3】 [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby, 【Chemistry 4】 (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is obtained, ii. The crude product obtained from step i is dissolved in a bipolar aprotic and / or protic solvent, and then optionally filtered. iii. Add the solution or filtrate obtained from step ii. to a poor solvent, and iv. Isolate and dry the obtained precipitate. The method comprising the step of obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

18. A method according to claim 12, 13, or 17, i. In the presence of at least one equivalent of a base selected from alkali carbonates, alkali bicarbonates, and alkali phosphates, at a temperature in the range of 20 to 80°C, in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidinone, acetone, and isopropanol, for a period of 30 minutes to 24 hours, formula (II) 【Transformation 5】 The intermediate compound is given by formula (III) 【Transformation 6】 [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby, 【Transformation 7】 (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is obtained, 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 being preferred, and then filtered. iii. Add the filtrate to water at a temperature in the range of 0°C to 20°C for a period of time in the range of 20 minutes to 1.5 hours, and iv. Isolate and dry the obtained precipitate. The method comprising the step of obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

19. The method according to claim 12, 13, 14, 17, or 18, i. In the presence of 1.5 to 5 equivalents of potassium phosphate, in acetonitrile at a temperature in the range of 50 to 70°C for a period of 1 to 2 hours, formula (II) 【Transformation 8】 The intermediate compound is given by formula (III) 【Chemistry 9】 [In the formula, LG represents a bromine atom.] The intermediate compound is reacted with the intermediate compound, and then the temperature is lowered to 20°C over a period of up to 1 hour, thereby 【Chemistry 10】 (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is obtained, 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 being preferred, and then filtered. iii. Add the filtrate to water at a temperature in the range of 4 to 10°C for a period of 30 minutes to 1 hour, and iv. Isolate and dry the obtained precipitate. The method comprising the step of obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

20. A method according to claim 12 or 15, 1) Formula (II) 【Chemistry 11】 The intermediate compound is given by formula (III) 【Chemistry 12】 [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby, 【Chemistry 13】 (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is obtained, 2) Dissolve the crude product obtained from step 1) in a solvent. 3) Create supersaturation, 4) Add a nanosuspension further comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoroanilino)propanamide, a poor solvent, at least one surfactant and at least one polymer, ５） a. cooling b. Addition of poor solvents, and c. Evaporation of the solvent One or more substeps selected from the following will follow: 6) Isolate and dry the obtained precipitate. The method comprising the step of obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

21. The method according to claim 12, 15, 16, or 20, 1) In the presence of at least one equivalent of a base selected from alkali carbonates, alkali bicarbonates, and alkali phosphates, at a temperature in the range of 20 to 80°C, in a solvent selected from N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, propionitrile, N-methylpyrrolidinone, acetone, and isopropanol, for a period of 30 minutes to 24 hours, formula (II) 【Chemistry 14】 The intermediate compound is given by formula (III) 【Chemistry 15】 [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby, 【Chemistry 16】 (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is obtained, 2) Dissolve the crude product obtained from step 1) in acetone containing 10-30% v / v water, and optionally filter it. 3) Supersaturation is created by cooling, and the temperature decrease is within the range of 5°C to 30°C. 4) Add a nanosuspension further comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide, water, at least one surfactant and at least two polymers, 5) Next, a. Cool, then, b. Add water, 6) Isolate and dry the obtained precipitate. The method comprising the step of obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

22. A method according to claim 12, 15, 16, 20, or 21, 1) In the presence of 1.5 to 5 equivalents of potassium phosphate, in acetonitrile, at a temperature in the range of 50 to 70°C, for a period of 1 to 2 hours, formula (II) 【Chemistry 17】 The intermediate compound is given by formula (III) [Chemistry 18] [In the formula, LG represents a bromine atom.] The intermediate compound is reacted with the intermediate compound, and then optionally the temperature is lowered to 20°C for a period of up to 1 hour, thereby, 【Chemistry 19】 (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide is obtained, 2) Dissolve the crude product obtained from step 1) in acetone containing 10-30% v / v water at a temperature in the range of 40°C to 70°C, and optionally filter it. 3) Supersaturation is created by cooling, and the temperature decrease is within the range of 15°C to 25°C. 4) A nanosuspension further comprising (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide (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 at 0.5-15% w / w), wherein, At least one surfactant is C ８ -C ２０ - Contains alkali salts of alkyl sulfates, and at least two polymers comprising hydroxypropylcellulose and polyvinylpyrrolidone, And here, the amount of the nanosuspension is added such that it is within the range of 1 to 6% w / w of the supersaturated solution obtained from step 3). 5) Next, a. Cooling is performed, and the temperature decrease is within the range of 5°C to 25°C, followed by, b. Add water, 6) Isolate and dry the obtained precipitate. The method comprising the step of obtaining microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide.

23. A pharmaceutical composition comprising microcrystals of (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide as described in 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)thiazole-2-yl]-4-fluoroanilino)propanamide, Formula (II) 【Chemistry 20】 The intermediate compound is given by formula (III) 【Chemistry 21】 [In the formula, LG is the leaving group as defined above.] It is reacted with an intermediate compound, thereby, 【Chemistry 22】 The method comprising the step of obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoroanilino)propanamide.

25. The method according to claim 24, In the presence of 1.5 to 6 equivalents of a base selected from potassium carbonate and potassium phosphate, at a temperature in the range of 40 to 80°C, in a solvent selected from N,N-dimethylformamide and acetonitrile, for a period of 30 minutes to 6 hours, formula (II) 【Chemistry 23】 The intermediate compound is given by formula (III) 【Chemistry 24】 [In the formula, LG represents a bromine atom.] It is reacted with an intermediate compound, thereby, 【Chemistry 25】 The method comprising the step of obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 90%.

26. The method according to claim 24 or 25, wherein, in the presence of 1.5 to 5 equivalents of potassium phosphate, in acetonitrile, at a temperature in the range of 50 to 70°C, for a period of 1 to 2 hours, formula (II) 【Chemistry 26】 The intermediate compound is given by formula (III) 【Chemistry 27】 [In the formula, LG represents a bromine atom.] The intermediate compound is reacted with the intermediate compound, and then the temperature is lowered to 20°C over a period of up to 1 hour, thereby, 【Chemistry 28】 The method comprising the step of obtaining (R)-2-(N-[4-amino-5-(4-methoxybenzoyl)thiazole-2-yl]-4-fluoro-anilino)propanamide with an enantiomer excess of at least 95%.

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