Novel process for preparation of compounds and novel crystalline forms

Abstract

The present invention relates to a new process for the preparation of N-((5-(5-(difluoromethyl)-1, 3, 4-oxadiazol-2-yl) pyridin-2-yl) methyl)-N-phenylthiomorpholine-4-carboxamide 1, 1-dioxide, and a new synthetic route of the main intermediates used in the process, as well as a new crystalline form of the compound and a process thereof.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to a new method for preparing N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, a new method for preparing intermediates used in the synthesis of the compound, and a new crystalline form of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide. BACKGROUND

[0002] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by the following Chemical Formula 1 is a material having an effect of preventing or treating a disease associated with histone deacetylase 6 activity.

[0003] A method for preparing a compound represented by the following Chemical Formula 1 is disclosed in Korean Registered Patent No. 10-1799010: [Chemical Formula 1] .

[0004] In the conventional preparation method disclosed in the above patent, a compound of Chemical Formula 10, which is obtained by reacting aniline with a thiomorpholine derivative in the presence of triphosgene, is subjected to N-alkylation with a compound of Chemical Formula 8b to prepare a compound of Chemical Formula 5a, as shown in the following [Reaction Scheme 1]. A compound of Chemical Formula 6, which is obtained by reacting the synthesized compound of Chemical Formula 5a with hydrazine hydrate, is reacted with difluoroacetic anhydride to prepare a compound of Chemical Formula 9, and the compound represented by Chemical Formula 1 is prepared by using 1-methoxy-N-triethylammoniumsulfonyl-methane imidate (Burgess reagent).

[0005] [Reaction Scheme 1] However, the synthesis method through the path of Reaction Scheme 1 has many problems during the preparation process.

[0006] The trphosgene used in the preparation of the compound of Chemical Formula 10 has very high reactivity, and thus has low stability, easily decomposes when in contact with moisture, and releases toxic gas, which is problematic in terms of operational safety, thus causing a significant problem in terms of mass production. In addition, the long reaction time of 16 hours and the low reaction yield of 20% or less are problematic in terms of preparation efficiency and commercial potential. Furthermore, the base used in the preparation of the compound of Chemical Formula 5a from the compound of Chemical Formula 10 is sodium hydride, which is a flammable material, and the reaction yield is also low. In addition, according to the conventional method, when the compound represented by Chemical Formula 6 and the compound represented by Chemical Formula 1 are prepared, there are problems in that the reaction is performed at a high temperature of 100°C or more using a microwave, and the use of a generally undesirable and expensive reagent such as a Burgess reagent is required. In addition, column chromatography needs to be used for purification at all stages of the reaction, and thus it is not possible to perform industrial mass production.

[0007] In other words, according to the conventional method, the compound of Chemical Formula 1, which is a target material, is prepared with a total yield of only about 1.5% through a total of five steps, and the equipment and reagents used in the reaction are expensive and have a long reaction time, and the use of a flammable material or reagent having low safety is required, and thus it is almost impossible to perform industrial mass production with very low economic efficiency.

[0008] In the above-described patent, the compound represented by Chemical Formula 1 is prepared only in an oil state. However, the compound in an oil state is not suitable for development as a drug, and has disadvantages in that it is difficult to remove residual solvents and the compound is not easy to handle industrially.

[0009] Therefore, there is a need to develop a compound in a solid form, which is pharmaceutically suitable, easy to handle during preparation, and capable of stable production, and a method for preparing the same.

[0010] Prior art references Patent documents (Patent document 0001) Korean Registered Patent No. KR 1799010 B1 (Patent document 0002) International Patent Publication No. WO 2015 / 082616 A1 (Patent document 0003) International Patent Publication No. WO 2021 / 246781 A1 (Patent document 0004) International Patent Publication No. WO 2000 / 060044 A1 (Patent document 0005) International Patent Publication No. WO 2001 / 055115 A1 (Patent document 0006) International Patent Publication No. WO 2019 / 182938 A1 (Patent Document 0007) International Patent Publication No. WO 2002 / 000626 A1 (Patent Document 0008) Chinese Patent Publication No. CN 103265479 A. SUMMARY

[0011] TECHNICAL PROBLEM To solve the problems of the existing preparation method, the present disclosure can provide a new method for preparing N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (which is a compound represented by Chemical Formula 1) or a pharmaceutically acceptable salt thereof in an economic, efficient, and safe mass production method.

[0012] In addition, the present disclosure can provide a new method for preparing a compound represented by Chemical Formula 8a, a compound represented by Chemical Formula 3, a compound represented by Chemical Formula 5, and a compound represented by Chemical Formula 6, which are main intermediates used in the new method for preparing a compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof.

[0013] Compared to the existing known preparation method, the new preparation method of the present disclosure can relatively simplify the preparation process by reducing the number of synthesis steps, and can provide a compound represented by Chemical Formula 1 in a high yield and purity due to the efficiency of the work-up procedure and the purification method.

[0014] In addition, the reagents and reaction equipment used in the reaction are easily available, safe reagents and equipment are used, and the reaction conditions are relatively mild. In addition, processes such as column chromatography are not required and the process procedure is efficient, thereby enabling mass production, a safe production process, and economic production due to significantly reduced costs.

[0015] The present disclosure provides a new crystalline form of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide and a method for preparing the same.

[0016] TECHNICAL SOLUTION The present disclosure provides a new method for preparing a compound represented by Chemical Formula 1 and an intermediate for preparing a compound represented by Chemical Formula 1, which is a compound represented by Chemical Formula 8a, a compound represented by Chemical Formula 3, a compound represented by Chemical Formula 5, and a compound represented by Chemical Formula 6.

[0017] The present disclosure provides a method for preparing a compound represented by the following Chemical Formula 1, which comprises preparing in situ a compound represented by the following Chemical Formula 1 from a compound represented by the following Chemical Formula 6: [Chemical Formula 6] , [Chemical Formula 1] .

[0018] In the prior art, the compound represented by Chemical Formula 9 is prepared from the compound represented by Chemical Formula 6 through an N-acylation reaction, and then the compound is separated and purified to obtain the compound represented by Chemical Formula 9. Thereafter, the compound represented by Chemical Formula 1 is prepared from the compound represented by Chemical Formula 9 using an expensive 1-methoxy-N-triethylammoniumsulfonyl-methanimine (Burgess reagent) through a cyclization reaction: [Chemical Formula 9] .

[0019] However, unlike the above prior art in which the compound represented by Chemical Formula 1 is prepared by sequentially performing two reactions (N-acylation reaction / cyclization reaction) through in situ synthesis, the present disclosure does not use an expensive 1-methoxy-N-triethylammoniumsulfonyl-methanimine (Burgess reagent), and does not separately separate and purify the compound represented by Chemical Formula 9 from the compound represented by Chemical Formula 6.

[0020] In addition, the present disclosure can prepare the compound represented by Chemical Formula 1 using only general reaction apparatuses employed for preparing the compound represented by Chemical Formula 1, without special reaction apparatuses such as a microwave.

[0021] Further, the present disclosure can obtain the compound represented by Chemical Formula 1 without separation and purification processes such as column chromatography, and thus mass production of the compound represented by Chemical Formula 1 can be achieved on an industrial scale and can be economical due to a high yield. In addition, the compound represented by Chemical Formula 1 can be obtained in high purity without using column chromatography.

[0022] In other words, the present disclosure can mass produce the compound represented by Chemical Formula 1 in a high yield without a complicated process, and at the same time, can obtain the compound represented by Chemical Formula 1 in high purity.

[0023] In an exemplary embodiment of the present disclosure, the step of preparing the compound represented by Chemical Formula 1 from the compound represented by Chemical Formula 6 can be performed in the presence of a base. When the preparation is performed in the presence of a base, the reaction yield and purity can be excellent. For example, the base can be triethylamine, N,N-diisopropylethylamine (DIPEA), pyridine, imidazole, or a mixture thereof.

[0024] In an exemplary embodiment of the present disclosure, the base can be imidazole. When the base is imidazole, not only the reaction yield can be improved but also the reaction selectivity can be excellent, so that the occurrence of by-products is minimized, thereby not requiring a complicated purification process.

[0025] In exemplary embodiments of the present application, the compound represented by Chemical Formula 1 can be prepared by using at least one of a compound represented by the following [Chemical Formula A] and a compound represented by the following [Chemical Formula B], and a compound represented by Chemical Formula 6 as a reaction material: [Chemical Formula A] [Chemical Formula B] .

[0026] In the above Chemical Formula B, X1may be F, Cl, Br, or I.

[0027] In exemplary embodiments of the present application, the compound represented by Chemical Formula 6 can be directly reacted with the compound represented by Chemical Formula A or Chemical Formula B to prepare the compound represented by Chemical Formula 1. In this case, both the N-acylation reaction and the intramolecular cyclization reaction can be performed in situ to prepare the compound represented by Chemical Formula 1 from the compound represented by Chemical Formula 6 without a different separation and purification process for the compound represented by Chemical Formula 9 other than the prior art, thereby significantly simplifying the reaction process.

[0028] In exemplary embodiments of the present application, the method for preparing the compound represented by Chemical Formula 1 from the compound represented by Chemical Formula 6 can be performed in the presence of a base. In this case, the occurrence of by-products can be significantly reduced, and also the yield can be significantly improved, which can be advantageous for mass production.

[0029] In exemplary embodiments of the present application, the method for preparing the compound represented by Chemical Formula 1 from the compound represented by Chemical Formula 6 in the presence of a base can include: a) preparing a reaction part 1 including the compound represented by Chemical Formula A or Chemical Formula B and a base; and b) mixing the reaction part 1 with a reaction part 2 including the compound represented by Chemical Formula 6 to prepare the compound represented by Chemical Formula 1: [Chemical Formula A] [Chemical Formula B] .

[0030] In the above Chemical Formula B, X1may be F, Cl, Br, or I.

[0031] In an exemplary embodiment of the present application, in the preparation method, the reaction between the compound represented by Chemical Formula 6 and the compound represented by Chemical Formula A or the compound represented by Chemical Formula B (in particular, the compound represented by Chemical Formula A), such as difluoroacetic anhydride, can be performed in the presence of a base. When the reaction is performed in the presence of a base, the reaction yield and purity can be excellent. For example, the base can be triethylamine, N,N-diisopropylethylamine (DIPEA), pyridine, imidazole, or a mixture thereof.

[0032] In an exemplary embodiment of the present application, the base can be imidazole, in particular, when the compound represented by Chemical Formula 6 is reacted with the compound represented by Chemical Formula A, such as difluoroacetic anhydride. When the base is imidazole, not only the reaction yield can be further improved but also the reaction selectivity can be excellent so that the occurrence of by-products is minimized, and thus the complicated purification process can not be required.

[0033] In an exemplary embodiment of the present application, the amount of the compound represented by Chemical Formula A or Chemical Formula B, in particular, difluoroacetic anhydride and the base, used can be 2.0 to 4.0 equivalents, in particular, 2.5 to 3.5 equivalents, per 1 equivalent of the compound represented by Chemical Formula 6.

[0034] In an exemplary embodiment of the present application, the reaction molar ratio of the compound represented by Chemical Formula A or Chemical Formula B, in particular, difluoroacetic anhydride and the base, can be 2:1 to 1:2, in particular, 1.2:1 to 1:1.2, and more particularly, 1:1.

[0035] In an exemplary embodiment of the present application, in step a), the compound represented by Chemical Formula A or Chemical Formula B, in particular, difluoroacetic anhydride, can be reacted with imidazole to produce a carboimidazole derivative (the compound represented by Chemical Formula C): [Reaction Formula A] [Reaction Formula B] [Reaction Formula C] .

[0036] Even when the compound represented by Chemical Formula A or Chemical Formula B, specifically difluoroacetic anhydride, is directly reacted with the compound represented by Chemical Formula 6 as a reaction material without first reacting with a base in the process for preparing the compound represented by Chemical Formula 1, the in-situ reaction can also be carried out at a high yield. However, in this case, the reaction can be rapidly carried out, not only producing the compound represented by Chemical Formula 1, but also producing three or more by-products, but among them, the by-product having a difluoromethyl group (-CF2) removed from the compound represented by Chemical Formula 1 can be difficult to remove by a general purification method such as recrystallization used in mass production, which can be slightly disadvantageous for mass production.

[0037] When the compound represented by Chemical Formula A or Chemical Formula B, specifically difluoroacetic anhydride, is reacted with a base such as imidazole, a formyl imidazole derivative such as the compound represented by Chemical Formula C can be reacted with the compound represented by Chemical Formula 6. In this case, the appearance of by-products can be significantly inhibited and the compound represented by Chemical Formula 1 can be produced in-situ from the compound represented by Chemical Formula 6, which can be more advantageous for mass production.

[0038] According to an embodiment of the present application, in the step of preparing Reaction Part 1 of Step a) above, a mixture containing a solvent and a base (e.g., imidazole) can be mixed with the compound represented by Chemical Formula A or B, specifically difluoroacetic anhydride, wherein the temperature can be maintained at 30°C or less, particularly 0°C to 30°C, more particularly 10°C to 25°C, and even more particularly 10°C to 20°C.

[0039] According to an exemplary embodiment of the present application, Step a) can comprise: preparing a mixture comprising imidazole and a solvent; cooling the mixture to 0°C to 10°C; and adding the compound represented by Chemical Formula A or Chemical Formula B, specifically difluoroacetic anhydride, to the cooled mixture.

[0040] In an exemplary embodiment of the present application, a step of stirring after the compound represented by Chemical Formula A or Chemical Formula B is completely added can be further included, wherein the stirring step can be more advantageous for producing a formyl imidazole derivative such as the compound represented by Chemical Formula C, and the stirring can be carried out at room temperature for one hour or more.

[0041] In an exemplary embodiment of the present application, in the mixture comprising imidazole and a solvent, the solvent used can be dichloromethane, N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, toluene, xylene, or a mixture thereof. The solvent used can preferably be dichloromethane, acetonitrile, N,N-dimethylacetamide, toluene, tetrahydrofuran, or a mixture thereof, and particularly dichloromethane.

[0042] In exemplary embodiments of the present application, in step b), the compound of Formula 1 can be prepared by an N-acylation reaction of the formyl imidazole derivative, which is an intermediate prepared in step a), with the compound of Formula 6 and a subsequent intramolecular cyclization reaction. In other words, both the N-acylation reaction and the intramolecular cyclization reaction in step b) can be performed in situ to prepare the compound of Formula 1 from the compound of Formula 6 without a different separation and purification process for the compound of Formula 9 other than the prior art, thereby significantly simplifying the reaction process, significantly reducing the occurrence of by-products, and significantly improving the yield, which can be beneficial for mass production.

[0043] In exemplary embodiments of the present application, step b) can comprise: preparing a reaction part 2 comprising the compound of Formula 6 and a solvent; and reacting the reaction part 2 with the reaction part 1.

[0044] In exemplary embodiments of the present application, the step of reacting the reaction part 2 with the reaction part 1 can be performed by adding the reaction part 1 to the reaction part 2, or can be performed by adding the reaction part 2 to the reaction part 1, and particularly can be performed by adding the reaction part 1 to the reaction part 2.

[0045] According to exemplary embodiments of the present application, in step b), the reaction part 1 comprising a base (e.g., imidazole) and a formyl imidazole derivative (such as a compound of Formula A or Formula B, in particular a compound of Formula C produced by reaction with difluoroacetic anhydride) can be added to the reaction part 2 comprising a solvent and the compound of Formula 6.

[0046] In exemplary embodiments of the present application, during the step of adding the reaction part 1 to the reaction part 2, the temperature can be maintained at 5°C or less, particularly at -15°C to 5°C, and more particularly at -10°C to 5°C.

[0047] In exemplary embodiments of the present application, after adding the reaction part 1 to the reaction part 2, the mixture comprising the reaction part 1 and the reaction part 2 can be heated to 20°C or more, particularly 20°C to 45°C, and more particularly 30°C to 40°C.

[0048] In exemplary embodiments of the present application, the solvent used in the reaction part 2 can be dichloromethane, N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, toluene, xylene, or a mixture thereof. Preferably, the solvent used can be dichloromethane, acetonitrile, N,N-dimethylacetamide, toluene, tetrahydrofuran, or a mixture thereof, and particularly dichloromethane.

[0049] In an exemplary embodiment of the present application, the solvent included in the reaction part 1 and the solvent included in the reaction part 2 can be the same or different, particularly the same, and more particularly dichloromethane.

[0050] The present application provides a method for preparing a compound represented by the following Chemical Formula 6.

[0051] In the present disclosure, the method for preparing a compound represented by Chemical Formula 6 can include: In the presence of a solvent including a C1 to C6 linear or branched alcohol or a mixture of a C1 to C6 linear or branched alcohol and water, a compound represented by the following Chemical Formula 6 is prepared from hydrazine (N2H4) or a hydrate thereof and a compound represented by the following Chemical Formula 5: [Chemical Formula 5] [Chemical Formula 6] .

[0052] In the above Chemical Formula 5, R can be a C1-C6 linear or branched alkyl group or a benzyl group, specifically a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, or a benzyl group, more specifically a methyl group, an ethyl group, an isopropyl group, and even more specifically a methyl group.

[0053] In an exemplary embodiment of the present application, the reaction can be performed under mild conditions with a high yield without using microwaves.

[0054] In an exemplary embodiment of the present application, the preparation method can be a step of obtaining a compound of Chemical Formula 6, which is a hydrazide derivative, through a hydrazination reaction of a compound represented by Chemical Formula 5 with hydrazine or a hydrate thereof.

[0055] In an exemplary embodiment of the present application, when the solvent is a C1 to C6 linear or branched alcohol, the C1 to C6 linear or branched alcohol can be methanol, isopropanol, butanol, or a mixture thereof, and specifically methanol. In small-scale production of about 100 g or less, an alcohol such as methanol can be used alone as a solvent.

[0056] In an exemplary embodiment of the present application, the solvent can be a C1 to C6 linear or branched alcohol and water (e.g., distilled water), in which the C1 to C6 linear or branched alcohol can be a mixture of water and at least one selected from the group consisting of methanol, ethanol, isopropanol, and butanol, and specifically the solvent can be a mixture of methanol and water.

[0057] In an exemplary embodiment of the present application, using a mixture including an alcohol and water as a solvent can increase the stability of hydrazine or its hydrate and at the same time increase the reactivity. When only an alcohol is used as a single solvent in a production process requiring a Kg unit or more, the precipitation of the compound represented by Chemical Formula 6 during the reaction can occur, and then the compound represented by Chemical Formula 5, which is a starting material, can also be precipitated, so that the reaction can not be completed. Specifically, in a production process required in a Kg unit or more, the compound represented by Chemical Formula 6 is sufficiently dissolved in distilled water. Thus, when distilled water is mixed in the solvent, the precipitation of the compound represented by Chemical Formula 6 can not occur during the reaction, and the reaction can proceed, so that the reaction can be completed.

[0058] In an exemplary embodiment of the present application, when the solvent is a mixture of an alcohol and water (e.g., distilled water), the volume ratio of alcohol: water (e.g., distilled water) can be about 10: 1 to about 1: 1, and particularly about 2: 1.

[0059] In an exemplary embodiment of the present application, the amount of hydrazine or its hydrate used can be 3 to 10 equivalents, particularly 5 to 7 equivalents, per 1 equivalent of the compound represented by Chemical Formula 5.

[0060] In an exemplary embodiment of the present application, the reaction of the compound represented by Chemical Formula 5 with hydrazine or its hydrate can be carried out at 75°C or less, particularly at 40°C to 70°C, and more particularly at 58°C to 68°C.

[0061] In an exemplary embodiment of the present application, a step of purifying the compound represented by Chemical Formula 6 produced by the reaction of the compound represented by Chemical Formula 5 with hydrazine or its hydrate can be further included.

[0062] In an exemplary embodiment of the present application, in the purification step, a C1 to C6 linear or branched alcohol can be added as a solvent, particularly methanol, ethanol, isopropanol, butanol, or a mixture thereof can be added as a solvent, and more particularly ethanol can be added as a solvent.

[0063] In an exemplary embodiment of the present application, the solvent used in the reaction of the compound represented by Chemical Formula 5 with hydrazine or its hydrate can include a mixture of methanol and water (e.g., distilled water), and ethanol can be added as a solvent in the step of purifying the compound represented by Chemical Formula 6.

[0064] The present disclosure provides a method for preparing a compound represented by Chemical Formula 5.

[0065] In the present disclosure, the method for preparing the compound represented by Chemical Formula 5 can include a step of reacting a compound represented by Chemical Formula 3 with a compound represented by Chemical Formula 4 in the presence of a base to prepare the compound represented by Chemical Formula 5: [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] .

[0066] In chemical formulas 3 and 5 above, R is a C1-C6 straight-chain or branched alkyl group or benzyl. In chemical formula 4 above, X can be F, Cl, Br, or I. Specifically, in chemical formulas 3 and 5 above, R can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or benzyl. In chemical formula 4 above, X can be Cl, Br, or I. More specifically, in chemical formulas 3 and 5, R can be methyl or benzyl. In chemical formula 4 above, X can be Cl, and even more specifically, R can be methyl and X can be Cl.

[0067] In an exemplary embodiment of the present invention, the reaction of the compound represented by Formula 3 with the compound represented by Formula 4 can be carried out in the presence of a base, and the base used can be triethylamine, N,N-diisopropylethylamine, imidazole, pyridine, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or mixtures thereof, specifically triethylamine, N,N-diisopropylethylamine, imidazole, sodium bicarbonate or mixtures thereof, and more specifically N,N-diisopropylethylamine.

[0068] In an exemplary embodiment of the invention, the base may be used in an amount of 1.0 to 3.0 equivalents, and more specifically in an amount of 1.3 to 2.0 equivalents, based on the compound represented by chemical formula 3 in 1 equivalent.

[0069] In an exemplary embodiment of the present invention, the compound represented by formula 4 may be used in an amount of 1.0 to 3.0 equivalents, and more specifically in an amount of 1.1 to 1.5 equivalents, based on 1 equivalent of the compound represented by formula 3.

[0070] In an exemplary embodiment of the present invention, in the reaction of the compound represented by Formula 3 with the compound represented by Formula 4, the solvent used may be N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, toluene, benzene, xylene or a mixture thereof, specifically N,N-dimethylacetamide, tetrahydrofuran, toluene or a mixture thereof, and more specifically toluene.

[0071] In an exemplary embodiment of the present invention, the reaction temperature of the compound represented by chemical formula 3 above and the compound represented by chemical formula 4 above can be from 60°C to 110°C, particularly from 75°C to 100°C, and more specifically from 75°C to 90°C.

[0072] In an exemplary embodiment of the present invention, after the compound represented by chemical formula 3 reacts with the compound represented by chemical formula 4, a purification process can be performed to obtain the compound represented by chemical formula 5 with a high purity of 99% or higher.

[0073] In an exemplary embodiment of the present invention, the solvent used in the purification process may be methanol, ethanol, isopropanol, butanol, methyl tert-butyl ether (MTBE), diisopropyl ether, heptane, hexane, or a mixture thereof, and the compound represented by Formula 5 may be purified by slurrying or recrystallization in the solvent. Specifically, the solvent used in the purification process may be methanol, ethanol, isopropanol, methyl tert-butyl ether (MTBE), diisopropyl ether, or a mixture thereof, and more specifically, at least one selected from methanol and methyl tert-butyl ether (MTBE). For example, both methanol and methyl tert-butyl ether (MTBE) may be used.

[0074] In embodiments of the present invention, the purification process for the compound represented by chemical formula 5 can be carried out at 30°C to 70°C, and particularly at 30°C to 65°C.

[0075] This disclosure provides a method for preparing compounds represented by chemical formula 3: [Chemical Formula 3] .

[0076] In the above chemical formula 3, R can be a C1-C6 straight-chain or branched alkyl or benzyl, especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or benzyl, more specifically methyl, ethyl, isopropyl, and even more specifically methyl.

[0077] In the prior art, the compound represented by chemical formula 6 can be prepared from the compound represented by chemical formula 10, which is obtained by reacting aniline with a thiomorpholine derivative in the presence of triphosgene via a substitution reaction and a hydrazination reaction. However, this method has problems such as the use of unstable triphosgene and flammable sodium hydride, long reaction time, low yield, low efficiency, low economic benefits, and the use of microwaves in the hydrazination reaction. This method may not be suitable for mass production. [Chemical Formula 10] .

[0078] In the preparation method according to the present invention, the compound represented by chemical formula 3, which can be readily obtained in high yield and high purity, can be used as an intermediate.

[0079] In the preparation method according to the present invention, the compound represented by chemical formula 3 can be prepared using reaction reagents and preparation equipment that are generally readily available and have proven stability and safety. The target compound with high purity can be prepared based on shorter reaction time and higher preparation yield, which can be attributed to the efficient process procedure that enables commercial mass production, and can achieve safety and economic cost reduction.

[0080] In an exemplary embodiment of the present invention, the compound represented by chemical formula 3 can be prepared by the following two methods.

[0081] In this disclosure, method 1 for preparing the compound represented by the following chemical formula 3 may include: a) Prepare compounds of formula 8 from compounds of formula 7 by using a halogenating agent; and b) To prepare the compound represented by formula 3 by reacting the compound represented by formula 8 with aniline in the presence of a base: [Chemical Formula 7] [Chemical Formula 8] [Chemical Formula 3] .

[0082] In chemical formulas 3, 7, and 8 above, R can be a C1-C6 straight-chain or branched alkyl group or benzyl. In chemical formula 8, X can be F, Cl, Br, or I. Specifically, in chemical formulas 3, 7, and 8 above, R can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or benzyl. In chemical formula 8 above, X can be Cl, Br, or I. More specifically, in chemical formulas 3, 7, and 8 above, R can be methyl or benzyl. In chemical formula 8 above, X can be Cl, and even more specifically, R can be methyl and X can be Cl.

[0083] In an exemplary embodiment of the present invention, method 1 for preparing the compound represented by formula 3 is carried out in two steps. However, when preparing the compound represented by formula 3, the method may use a compound represented by formula 7, which is a low-cost starting material. In the process of preparing the compound represented by formula 8, different purification and separation processes may not be required, and hazardous reagents may not be used, which can facilitate large-scale production with excellent yield and safety. In other words, in the concentrated state of solvent concentration after preparing the compound represented by formula 8, the compound represented by formula 8 can be used as a reactant for preparing the compound represented by formula 3, which is itself in a concentrated state, without separating the compound into a solid state.

[0084] This disclosure provides a method for preparing the compound represented by the following chemical formula 8a from the compound represented by the following chemical formula 7 by using trichloroisocyanuric acid (TCCA) reagent alone: [Chemical Formula 7] [Chemical Formula 8a] .

[0085] In chemical formulas 7 and 8a above, R can be a C1-C6 straight-chain alkyl group or benzyl. Specifically, in chemical formulas 7 and 8a above, R can be methyl, ethyl, n-propyl, n-butyl, n-pentyl, or benzyl. More specifically, in chemical formulas 7 and 8a, R can be methyl or benzyl, and even more specifically, R can be methyl.

[0086] In an exemplary embodiment of the present invention, in the method for preparing the compound represented by the above chemical formula 3, the halogenating agent in step a) may be iodine, copper iodide, bromine, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), trichloroisocyanuric acid (TCCA) or a mixture thereof, specifically N-bromosuccinimide (NBS), trichloroisocyanuric acid (TCCA) or a mixture thereof, and more specifically trichloroisocyanuric acid (TCCA).

[0087] In an exemplary embodiment of the present invention, in the method for preparing the compound represented by chemical formula 3, X above can be Cl in step a). In this case, the halogenating agent can be trichloroisocyanuric acid (TCCA). In the present invention, the halogenation reaction (specifically the chlorination reaction) can be carried out in one step using trichloroisocyanuric acid (TCCA), thereby improving reaction efficiency and simplifying the reaction process, which is beneficial for mass production.

[0088] In an exemplary embodiment of the present invention, the halogenating agent used in the method for preparing the compound represented by ...

[0089] In an exemplary embodiment of the present invention, in step a) of the method for preparing a compound represented by chemical formula 3, and in the method for preparing a compound represented by chemical formula 8a from a compound represented by chemical formula 7, the step of preparing a compound represented by chemical formula 8 (specifically chemical formula 8a) from a compound represented by chemical formula 7 using a halogenating agent can be carried out without the use of a benzamide catalyst.

[0090] In the prior art, the step of treating compounds represented by Formula 7 with a halogenating agent to obtain benzyl halide derivatives can be synthesized by known methods (WO 2021 / 246781, WO 2000 / 060044, WO 2001 / 055115, WO 2019 / 182938, WO 2002 / 000626), but this method has the disadvantages of long reaction time and low yield. Specifically, the method for chlorinating compounds represented by Formula 7 has the disadvantage that chlorination is achieved through two steps via an oxidation step and a chlorination step. However, this disclosure solves this problem by using trichloroisocyanuric acid (TCCA) to successfully chlorinate in a short reaction time in only one step, and can efficiently and simply prepare compounds represented by Formula 8 (specifically Formula 8a) from compounds represented by Formula 7.

[0091] Furthermore, among the known methods in the prior art, there is also a method using trichloroisocyanuric acid (TCCA) (CN103265479), but the substituents introduced into the pyridine are limited to materials with tert-butyl groups, and a benzamide catalyst is required. If a pyridine derivative with tert-butyl groups is used as an intermediate by applying conventionally known methods, the subsequent hydrazination reaction of the compound to be prepared with the hydride or its hydrate may not proceed.

[0092] Unlike conventional methods, this disclosure provides an efficient chlorination reaction in compounds represented by Formula 8 when X is Cl, using only trichloroisocyanuric acid (TCCA) without the need for a benzamide catalyst, wherein the starting material is a material that can even promote the introduction of a substituent into a pyridine derivative (such as a methyl ester group).

[0093] In an exemplary embodiment of the present invention, the solvent used in step a) of the method for preparing the compound represented by chemical formula 3 and the method for preparing the compound represented by chemical formula 8 from the compound represented by chemical formula 7 by using a halogenating agent may be tetrahydrofuran, ethyl acetate, acetic acid, toluene, xylene, benzene, dichloromethane, dichloroethane, chloroform, diisopropyl ether, methyl tert-butyl ether, or a mixture thereof.

[0094] In an exemplary embodiment of the present invention, when the halogenating agent is N-bromosuccinimide (NBS), acetic acid can be used as a solvent, and when the halogenating agent is trichloroisocyanuric acid (TCCA), dichloromethane can be used as a solvent.

[0095] In an exemplary embodiment of the present invention, when the halogenating agent in step a) of the method for preparing the compound represented by chemical formula 3 and in the method for preparing the compound represented by chemical formula 8 from the compound represented by chemical formula 7 by using a halogenating agent is N-bromosuccinimide (NBS), the amount of halogenating agent used can be 2.0 to 4.0 equivalents, specifically 3.0 to 3.5 equivalents, based on 1 equivalent of the compound represented by chemical formula 7 as the starting material.

[0096] In an exemplary embodiment of the present invention, when the halogenating agent in step a) of the method for preparing the compound represented by chemical formula 3 and in the method for preparing the compound represented by chemical formula 8a from the compound represented by chemical formula 7 by using a halogenating agent is trichloroisocyanuric acid (TCCA), the amount of halogenating agent used may be 1.0 to 2.0 equivalents, specifically 1.1 to 1.5 equivalents, based on 1 equivalent of the compound represented by chemical formula 7 as the starting material.

[0097] In an exemplary embodiment of the present invention, when the halogenating agent in step a) of the method for preparing the compound represented by formula 3 is N-bromosuccinimide (NBS), the reaction temperature can be between 50°C and 80°C, and specifically between 55°C and 65°C.

[0098] In an exemplary embodiment of the present invention, when the halogenating agent in step a) of the method for preparing the compound represented by chemical formula 3 and in the method for preparing the compound represented by chemical formula 8a from the compound represented by chemical formula 7 by using a halogenating agent is trichloroisocyanuric acid (TCCA), the reaction temperature can be between 10°C and 30°C, and specifically between 15°C and 20°C.

[0099] In an exemplary embodiment of the present invention, the compound represented by Formula 8 may be subjected to N-alkylation with aniline in the presence of a base to obtain the compound represented by Formula 3.

[0100] This disclosure provides a method for preparing a compound represented by chemical formula 3 by reacting a compound represented by chemical formula 8 with aniline in the presence of a base: [Chemical Formula 3] [Chemical Formula 8] .

[0101] In Formulas 3 and 8 above, R can be a C1-C6 straight-chain or branched alkyl group or benzyl. In Formula 8, X can be F, Cl, Br, or I. Specifically, in Formulas 3 and 8 above, R can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or benzyl. In Formula 8 above, X can be Cl, Br, or I. More specifically, in Formulas 3 and 8, R can be methyl or benzyl. In Formula 8 above, X can be Cl, and even more specifically, R can be methyl and X can be Cl.

[0102] In the prior art (WO 2015 / 082616), N-alkylation is performed using aniline substituted with a protecting group, followed by a deprotection reaction to obtain the hydrochloride salt of the compound represented by Formula 3. However, in the preparation method disclosed herein, the reaction can be carried out directly without a protecting / deprotecting reaction, thereby shortening the process steps.

[0103] In an exemplary embodiment of the present invention, when X in the compound represented by Formula 8 is Cl, in order to increase the reaction rate, a halogen exchange reagent such as potassium bromide, potassium iodide, tetrabutylammonium bromide (TBAB) or a mixture thereof can be used, and specifically potassium iodide can be used, wherein the halogen exchange reagent can be used in an amount of 0.1 to 1.0 equivalents, and specifically 0.3 to 0.5 equivalents, per 1 equivalent of the compound represented by Formula 8.

[0104] In an exemplary embodiment of the present invention, the solvent used in the step of reacting the compound represented by Formula 8 with aniline may be N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, or a mixture thereof. Specifically, N,N-dimethylacetamide, N,N-dimethylformamide, or a mixture thereof may be used, and more specifically, N,N-dimethylacetamide may be used.

[0105] In an exemplary embodiment of the present invention, the base used in the step of reacting the compound represented by Formula 8 with aniline may be sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine or a mixture thereof, and specifically sodium bicarbonate or sodium carbonate.

[0106] In an exemplary embodiment of the invention, in the step of reacting the compound represented by Formula 8 with aniline, the base may be used in an amount of 1.0 to 3.0 equivalents, specifically 1.5 to 2.0 equivalents, per 1 equivalent of the compound represented by Formula 8.

[0107] In an exemplary embodiment of the invention, aniline may be used in amounts of 1.0 to 3.0 equivalents per 1 equivalent of the compound represented by Formula 8, and specifically in amounts of 2.0 to 2.5 equivalents.

[0108] In an exemplary embodiment of the present invention, preparation method 1 may further include a purification process for the compound represented by chemical formula 3. Through the purification process, the compound represented by chemical formula 3 can be obtained with a purity of 95% or higher.

[0109] In an exemplary embodiment of the present invention, during the purification process, the compound represented by Formula 3 can be purified by slurrying or recrystallization using methanol, ethanol, isopropanol, butanol, water (e.g., distilled water) or mixtures thereof as solvents. Specifically, the solvent used in the purification process can be a mixture of an alcohol selected from methanol, ethanol, and isopropanol with water (e.g., distilled water), and more specifically, a mixture of methanol and distilled water.

[0110] In an exemplary embodiment of the present invention, the purification process for the compound represented by chemical formula 3 can be carried out at 40°C to 60°C, and specifically at 45°C to 55°C.

[0111] In this disclosure, method 2 for preparing the compound represented by the above chemical formula 3 may include: Prepare compounds represented by chemical formula 3 from compounds represented by chemical formula 2 in the presence of aniline and a reducing agent: [Chemical Formula 2] [Chemical Formula 3] .

[0112] In the above chemical formula 2 or chemical formula 3, R can be a C1-C6 straight-chain or branched alkyl or benzyl, specifically methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or benzyl, more specifically methyl, ethyl, isopropyl, and even more specifically methyl.

[0113] In an exemplary embodiment of the present invention, preparation method 2 may involve a reductive amination reaction between the compound represented by chemical formula 2 and aniline to prepare the compound represented by chemical formula 3.

[0114] In an exemplary embodiment of the invention, aniline may be used in amounts of 0.95 to 1.3 equivalents per 1 equivalent of the compound represented by Formula 2, and specifically in amounts of 0.95 to 1.05 equivalents.

[0115] In an exemplary embodiment of the present invention, the reducing agent may include sodium borohydride (NaBH4), sodium cyanoborohydride (NaBH3CN), sodium triacetoxyborohydride (NaBH(OAc)3), or a mixture thereof, and specifically sodium triacetoxyborohydride (NaBH(OAc)3).

[0116] In an exemplary embodiment of the invention, the reducing agent may be used in an amount of 1.0 to 2.0 equivalents per 1 equivalent of the compound represented by Formula 2, and specifically in an amount of 1.3 to 1.7 equivalents.

[0117] In an exemplary embodiment of the present invention, the reaction for preparing the compound represented by formula 3 by reacting the compound represented by formula 2 with aniline can be carried out at a temperature of 10°C to 30°C, and specifically at a temperature of 15°C to 25°C.

[0118] In an exemplary embodiment of the present invention, the step of preparing the following compound represented by chemical formula 3 from the compound represented by chemical formula 2 may include: Preparation of a mixture comprising a compound of formula 2 and aniline; and The mixture is then reacted with a reducing agent.

[0119] In an exemplary embodiment of the present invention, the step of preparing the following compound represented by chemical formula 3 from the compound represented by chemical formula 2 may include: The reaction part 1 comprises a compound represented by chemical formula 2, aniline, and a solvent; and Reaction part 1 is made to react with reaction part 2, which contains a reducing agent and a solvent.

[0120] In an exemplary embodiment of the present invention, the step of reacting the reaction portion 2 with the reaction portion 1 may be the step of adding the reaction portion 1 to the reaction portion 2.

[0121] In an exemplary embodiment of the present invention, the solvents used in reaction part 1 and reaction part 2 may be the same or different, and the solvents used may be tetrahydrofuran, methanol, ethanol, isopropanol, acetonitrile, dichloromethane, toluene or mixtures thereof, specifically dichloromethane, and more specifically, the solvents used in reaction part 1 and reaction part 2 may all be dichloromethane.

[0122] In an exemplary embodiment of the present invention, the compound represented by chemical formula 2 can generate an imine intermediate by reacting with aniline, and after generating the imine intermediate, reaction part 1 containing the imine intermediate can be added to reaction part 2 containing a reducing agent to carry out the reaction.

[0123] In an exemplary embodiment of the invention, reaction portion 1 can be prepared by reacting a compound represented by formula 2 with aniline to synthesize an imine intermediate. In this case, the imine intermediate can be synthesized by stirring a mixture of the compound represented by formula 2 and reaction portion 1, including aniline, for one to two hours.

[0124] In an exemplary embodiment of the present invention, the imine intermediate may be a compound represented by the following chemical formula 11: [Chemical Formula 11] .

[0125] In the above chemical formula 11, R can be a C1-C6 straight-chain or branched alkyl or benzyl, specifically methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl or benzyl, more specifically methyl, ethyl, isopropyl, and even more specifically methyl.

[0126] In an exemplary embodiment of the present invention, in the step of adding reaction portion 1 to reaction portion 2, reaction portion 1 may be added to reaction portion 2 cooled to 5°C or lower, specifically 0°C to 5°C, while maintaining a temperature of 10°C or lower, specifically 0°C to 10°C.

[0127] In an exemplary embodiment of the present invention, after the addition is completed, the temperature of the mixture including reaction part 1 and reaction part 2 can be raised to 15°C to 30°C, and specifically to 15°C to 25°C.

[0128] In an exemplary embodiment of the invention, the step of preparing the compound represented by formula 3 from the compound represented by formula 2 can be carried out in the presence of an acid. Specifically, to accelerate the reaction rate of the formation of the imine intermediate, reaction section 1 may further include an acid additive such as acetic acid. Activation can be carried out sufficiently without the additive in reaction section 1, but when an acid additive is further included, the reduction reaction of the compound represented by formula 2 itself can be reduced, and thus the purity of the compound represented by formula 3 can be relatively improved.

[0129] This disclosure provides a method 1 for preparing a compound represented by the following chemical formula 1.

[0130] In this disclosure, method 1 for preparing the compound represented by chemical formula 1 may include: 1) Prepare compounds represented by chemical formula 8 from compounds represented by chemical formula 7 by using halogenating reagents; 2) The compound represented by chemical formula 3 is prepared by reacting the compound represented by chemical formula 8 with aniline in the presence of a base; 3) The compound represented by chemical formula 5 is obtained by reacting the compound represented by chemical formula 3 with the compound represented by chemical formula 4 in the presence of a base; 4) To obtain the compound represented by formula 6 by reacting hydrazine or its hydrate with the compound represented by formula 5; and 5) In-situ preparation of compounds represented by formula 1 from compounds represented by formula 6: [Chemical Formula 1] [Chemical Formula 3] (In the above chemical formula 3, R can be a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X can be F, Cl, Br or I) [Chemical Formula 5] (In the above chemical formula 5, R can be a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 6] [Chemical Formula 7] (In the above chemical formula 7, R can be a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 8] (In the above chemical formula 8, R can be a C1-C6 straight-chain or branched alkyl or benzyl, and X can be F, Cl, Br or I).

[0131] In an exemplary embodiment of the present invention, all the above-described methods for preparing compounds represented by chemical formula 8a, chemical formula 3, chemical formula 5, chemical formula 6, and chemical formula 1 can be applied to steps 1), 2), 3), 4), and 5) of method 1 for preparing compounds of chemical formula 1, which uses a compound represented by chemical formula 7 as a starting material and uses compounds represented by chemical formula 8, chemical formula 3, chemical formula 4, chemical formula 5, and chemical formula 6, unless these methods contradict each other. For example, reaction conditions, actions, and the like (such as solvents, reducing agents, halogenating agents, bases, temperatures, concentrations, etc.) can be applied to method 1 for preparing compounds of chemical formula 1.

[0132] This disclosure provides a method 2 for preparing compounds represented by the following chemical formula 1.

[0133] In this disclosure, method 2 for preparing the compound represented by the following chemical formula 1 may include: 1) Prepare the compound represented by the following chemical formula 3 from the compound represented by the following chemical formula 2 in the presence of aniline and a reducing agent; 2) The compound represented by chemical formula 5 is obtained by reacting the compound represented by chemical formula 3 with the compound represented by chemical formula 4 in the presence of a base; 3) To obtain the compound represented by chemical formula 6 by reacting hydrazine or its hydrate with the compound represented by chemical formula 5; and 4) Prepare compounds represented by formula 1 in situ from compounds represented by formula 6: [Chemical Formula 1] [Chemical Formula 2] (In the above chemical formula 2, R can be a C1-C6 alkyl or benzyl) [Chemical Formula 3] (In the above chemical formula 3, R can be a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X can be F, Cl, Br or I) [Chemical Formula 5] (In the above chemical formula 5, R can be a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 6] .

[0134] In an exemplary embodiment of the present invention, all the above-described methods for preparing compounds of formula 3, formula 5, formula 6, and formula 1 can be applied to steps 1), 2), 3), and 4) of method 2 for preparing compounds of formula 1, which uses compounds of formula 2 as starting materials and also uses compounds of formula 3, formula 4, formula 5, and formula 6, unless these methods contradict each other. For example, reaction conditions, actions, and the like (such as solvents, reducing agents, halogenating agents, bases, temperatures, concentrations, etc.) can be applied to method 2 for preparing compounds of formula 1.

[0135] If expressed by a reaction formula, then the preparation methods 1 and 2 for preparing compounds according to chemical formula 1 of this disclosure are similar to those used in the preparation of compounds according to chemical formula 1 of this disclosure. Figure 1The preparation method shown in [Reaction 2] is the same: [Reaction 2] .

[0136] In reaction formula 2 above, R can be a C1 to C6 straight-chain or branched alkyl or benzyl, X can be F, Cl, Br or I, and X1 can be F, Cl, Br or I.

[0137] This disclosure provides a method 3 for preparing compounds represented by the following chemical formula 1.

[0138] In this disclosure, method 3 for preparing the compound represented by the following chemical formula 1 may include: 1) To obtain the compound represented by chemical formula 6 by reacting hydrazine or its hydrate with the compound represented by chemical formula 5; and 2) Prepare compounds represented by formula 1 in situ from compounds represented by formula 6 below: [Chemical Formula 1] [Chemical Formula 5] (In the above chemical formula 5, R can be a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 6] .

[0139] In an exemplary embodiment of the present invention, in method 3 for preparing the compound represented by chemical formula 1, the method for preparing the compound represented by chemical formula 5 may include: To prepare the compound represented by chemical formula 5, react the compound represented by chemical formula 3 with the compound represented by chemical formula 4 in the presence of a base: [Chemical Formula 3] (In the above chemical formula 3, R can be a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X can be F, Cl, Br or I).

[0140] In an exemplary embodiment of the present invention, in method 3 for preparing the compound represented by chemical formula 1, the method for preparing the compound represented by chemical formula 5 may include: The compound represented by chemical formula 3 is prepared by reacting the compound represented by chemical formula 8 with aniline in the presence of a base; and To prepare the compound represented by chemical formula 5, react the compound represented by chemical formula 3 with the compound represented by chemical formula 4 in the presence of a base: [Chemical Formula 3] (In the above chemical formula 3, R can be a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X can be F, Cl, Br or I) [Chemical Formula 8] (In the above chemical formula 8, R can be a C1-C6 straight-chain or branched alkyl or benzyl, and X can be F, Cl, Br or I).

[0141] In an exemplary embodiment of the present invention, in method 3 for preparing the compound represented by chemical formula 1, the method for preparing the compound represented by chemical formula 5 may include: Compounds represented by chemical formula 8 are prepared from compounds represented by chemical formula 7 using halogenating reagents; The compound represented by chemical formula 3 is prepared by reacting the compound represented by chemical formula 8 with the following aniline in the presence of a base; and To prepare the compound represented by chemical formula 5, react the compound represented by chemical formula 3 with the compound represented by chemical formula 4 in the presence of a base: [Chemical Formula 3] (In the above chemical formula 3, R can be a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X can be F, Cl, Br or I) [Chemical Formula 7] (In the above chemical formula 7, R can be a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 8] (In the above chemical formula 8, R can be a C1-C6 straight-chain or branched alkyl or benzyl, and X can be F, Cl, Br or I).

[0142] In an exemplary embodiment of the present invention, in method 3 for preparing a compound represented by chemical formula 1 above, the method for preparing a compound represented by chemical formula 5 may include: Compounds of formula 3 are prepared from compounds of formula 2 in the presence of aniline and a reducing agent; and The compound represented by chemical formula 3 is reacted with the compound represented by chemical formula 4 in the presence of a base to prepare the compound represented by chemical formula 5: [Chemical Formula 2] (In the above chemical formula 2, R can be a C1-C6 alkyl or benzyl) [Chemical Formula 3] (In the above chemical formula 3, R can be a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X can be F, Cl, Br or I).

[0143] In an exemplary embodiment of the present invention, all of the above-described methods for preparing compounds of chemical formula 8a, method 1 for preparing compounds of chemical formula 3, method 2 for preparing compounds of chemical formula 3, method 5 for preparing compounds of chemical formula 5, method 6 for preparing compounds of chemical formula 6, and method 1 for preparing compounds of chemical formula 1 can be applied to method 3 for preparing compounds of chemical formula 1, unless these methods contradict each other. For example, reaction conditions, actions, and the like (such as solvents, reducing agents, halogenating agents, bases, temperatures, concentrations, etc.) can be applied to method 3 for preparing compounds of chemical formula 1.

[0144] This disclosure provides a method 1 for preparing a compound represented by the following chemical formula 5.

[0145] In this disclosure, method 1 for preparing the compound represented by formula 5 may include: 1) Prepare compounds represented by chemical formula 8 from compounds represented by chemical formula 7 by using halogenating reagents; 2) To prepare the compound represented by formula 3 by reacting the compound represented by formula 8 with aniline in the presence of a base; and 3) React the compound represented by chemical formula 3 with the compound represented by chemical formula 4 in the presence of a base to obtain the compound represented by chemical formula 5: [Chemical Formula 3] (In the above chemical formula 3, R can be a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X can be F, Cl, Br or I) [Chemical Formula 5] (In the above chemical formula 5, R can be a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 6] [Chemical Formula 7] (In the above chemical formula 7, R can be a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 8] (In the above chemical formula 8, R can be a C1-C6 straight-chain or branched alkyl or benzyl, and X can be F, Cl, Br or I).

[0146] In an exemplary embodiment of the present invention, all the above-described contents of method 1 for preparing a compound represented by chemical formula 3 and method 1 for preparing a compound represented by chemical formula 5 using a compound represented by chemical formula 3 as a starting material can be applied to all the above-described steps 1), 2), and 3) of method 1 for preparing a compound represented by chemical formula 5, which uses a compound represented by chemical formula 7 as a starting material and uses compounds represented by chemical formula 8, chemical formula 3, and chemical formula 4, unless these methods contradict each other. For example, reaction conditions, actions, and the like (such as solvents, reducing agents, halogenating agents, bases, temperatures, contents, etc.) can be applied to method 1 for preparing the above-described compound represented by chemical formula 5.

[0147] This disclosure provides a method 2 for preparing a compound represented by the following chemical formula 5.

[0148] In this disclosure, method 2 for preparing the compound represented by the following chemical formula 5 may include: 1) The compound represented by chemical formula 3 is prepared by reacting the compound represented by chemical formula 8 with aniline in the presence of a base; and 2) React the compound represented by chemical formula 3 with the compound represented by chemical formula 4 in the presence of a base to obtain the compound represented by chemical formula 5: [Chemical Formula 3] (In the above chemical formula 3, R can be a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X can be F, Cl, Br or I) [Chemical Formula 5] (In the above chemical formula 5, R can be a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 8] (In the above chemical formula 8, R can be a C1-C6 straight-chain or branched alkyl or benzyl, and X can be F, Cl, Br or I).

[0149] In an exemplary embodiment of the present invention, all the above-described methods for preparing compounds of formula 3 and for preparing compounds of formula 5 by using compounds of formula 3 as starting materials can be applied to steps 1) and 2) of method 2 for preparing compounds of formula 5, which uses compounds of formula 8 as starting materials and uses compounds of formula 3 and formula 4, unless these methods contradict each other. For example, reaction conditions, actions, and the like (such as solvents, reducing agents, halogenating agents, bases, temperatures, contents, etc.) can be applied to method 2 for preparing compounds of formula 5.

[0150] This disclosure provides a method 3 for preparing a compound represented by the following chemical formula 5.

[0151] In this disclosure, method 3 for preparing the compound represented by the following chemical formula 5 may include: 1) Prepare the compound represented by the following chemical formula 3 from the compound represented by the following chemical formula 2 in the presence of aniline and a reducing agent; and 2) React the compound represented by chemical formula 3 with the compound represented by chemical formula 4 in the presence of a base to obtain the compound represented by chemical formula 5: [Chemical Formula 2] (In the above chemical formula 2, R can be a C1-C6 alkyl or benzyl) [Chemical Formula 3] (In the above chemical formula 3, R can be a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X can be F, Cl, Br or I) [Chemical Formula 5] (In the above chemical formula 5, R can be a C1-C6 straight-chain or branched alkyl or benzyl).

[0152] In an exemplary embodiment of the present invention, all the above-described methods for preparing compounds of formula 3, formula 5, formula 6, and formula 1 can be applied to steps 1) and 2) of method 3 for preparing compounds of formula 5, which uses compounds of formula 2 as starting materials and compounds of formula 3 and formula 4, unless these methods contradict each other. For example, reaction conditions, actions, and the like (such as solvents, reducing agents, halogenating agents, bases, temperatures, concentrations, etc.) can be applied to method 3 for preparing compounds of formula 5.

[0153] This disclosure provides a novel crystalline form of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by the following chemical formula 1: [Chemical Formula 1] .

[0154] Specifically, this disclosure provides new crystalline forms I, II and III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide.

[0155] In Korean Patent No. 10-1799010, which discloses compounds of Formula 1, the compounds of Formula 1 are obtained only in an oil state. The compounds of Formula 1 in an oil state can be prepared in a solid form with a foam-like shape by additional drying, but they are not in a crystalline form.

[0156] Oily or foamy solids are unsuitable for drug development and have the disadvantages of being difficult to remove residual solvents and not easy to process industrially.

[0157] However, the crystalline forms I, II, and III of the compound represented by Formula 1 possess excellent properties associated with the solid form, such as handling and stability, and suitable solubility in formulations. Specifically, the crystalline forms I, II, and III of the compound represented by Formula 1 exhibit excellent long-term and accelerated stability, thermodynamic stability, light stability and crystal stability, low hygroscopicity, and advantageous properties for removing residual solvents, and therefore possess excellent safety and suitable solubility in formulations.

[0158] Furthermore, since the crystalline forms I, II, and III of the compounds represented by Chemical Formula 1 according to this disclosure have excellent storage stability, mechanical stability, and flowability, have uniform particles, are easy to process into pharmaceuticals, and the crystalline forms remain unchanged even after storage and formulation of the active pharmaceutical ingredient (API), the pharmaceuticals can ensure long shelf life and exhibit sufficient solubility for commercial production, and are therefore easy to formulate into pharmaceuticals and commercially reproducible.

[0159] In addition, the pharmacological properties, safety and pharmacokinetic properties are altered, and therefore, unexpected reactions may occur when multiple crystalline forms or mixtures of crystalline and amorphous forms are produced. This is because low crystal stability can easily lead to changes in crystalline form. However, the crystalline forms I, II and III of the compound represented by chemical formula 1 have excellent stability and can therefore maintain pure single crystal form for a long time.

[0160] Therefore, since the crystalline forms I, II and III of the compound represented by chemical formula 1 can be attributed to excellent thermodynamic stability, crystal stability and low hygroscopicity to maintain a constant content, the crystalline forms have a longer storage and distribution period, suitable solubility in formulations, and can achieve drug production without deviations in efficacy and safety.

[0161] The crystalline form I (Form I) of the compound represented by chemical formula 1. This disclosure provides crystalline form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by the following chemical formula 1: [Chemical Formula 1] .

[0162] According to an embodiment of the invention, the X-ray powder diffraction pattern of the crystalline form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide of the compound represented by Formula 1 may include diffraction peaks at three or more (e.g., three, four, five, six or seven) diffraction angles selected from the group consisting of: 7.85°, 14.54°, 17.14°, 18.09°, 19.62°, 21.41° and 23.58° (2θ±0.2°).

[0163] It should be understood that any 2θ diffraction angle specified herein means a specified value ±0.2°. For example, when the described embodiment or technical solution specifies 7.85° of 2θ, this should be understood to mean 7.85° ±0.2°, that is, a 2θ diffraction angle between 7.65° and 8.05°.

[0164] For example, in an X-ray powder diffraction pattern, a diffraction angle (2θ) of 7.85° is essentially the same as 7.85°±0.2°, a diffraction angle (2θ) of 14.54° is essentially the same as 14.54°±0.2°, a diffraction angle (2θ) of 17.14° is essentially the same as 17.14°±0.2°, a diffraction angle (2θ) of 18.09° is essentially the same as 18.09°±0.2°, a diffraction angle (2θ) of 19.62° is essentially the same as 19.62°±0.2°, a diffraction angle (2θ) of 21.41° is essentially the same as 21.41°±0.2°, and a diffraction angle (2θ) of 23.58° is essentially the same as 23.58°±0.2°.

[0165] For example, the X-ray powder diffraction pattern of crystalline form I of the compound represented by Formula 1 includes diffraction peaks at three or more (e.g., three, four, five, six, or seven) diffraction angles selected from the group consisting of 7.85°, 14.54°, 17.14°, 18.09°, 19.62°, 21.41°, and 23.58° (2θ ± 0.2°), and this X-ray powder diffraction pattern may be substantially identical to the X-ray powder diffraction pattern of crystalline form I represented by Formula 1: X-ray powder diffraction pattern including diffraction peaks at three or more (e.g., three, four, five, six or seven) diffraction angles selected from the following group: 7.90°, 14.59°, 17.20°, 18.15°, 19.68°, 21.49° and 23.65° (2θ±0.2°); X-ray powder diffraction patterns including diffraction peaks at three or more diffraction angles selected from the following group (e.g., three, four, five, six, or seven): 7.86°, 14.54°, 17.12°, 18.09°, 19.61°, 21.42°, and 23.59° (2θ ± 0.2°); or X-ray powder diffraction pattern including diffraction peaks at three or more (e.g., three, four, five, six or seven) diffraction angles selected from the following group: 7.83°, 14.52°, 17.11°, 18.08°, 19.59°, 21.41° and 23.56° (2θ±0.2°).

[0166] In an exemplary embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form I of the compound represented by Formula 1 may include diffraction peaks at the following diffraction angles (2θ ± 0.2°): 7.85°, 14.54°, 17.14°, 18.09°, 19.62°, 21.41°, and 23.58°.

[0167] It should be understood that any 2θ diffraction angle specified herein means a specified value ±0.2°.

[0168] For example, the X-ray powder diffraction pattern of crystalline form I represented by chemical formula 1 includes diffraction peaks at diffraction angles selected from the group consisting of 7.85°, 14.54°, 17.14°, 18.09°, 19.62°, 21.41°, and 23.58° (2θ±0.2°), and this X-ray powder diffraction pattern may be substantially identical to the X-ray powder diffraction pattern of crystalline form I represented by chemical formula 1 as follows: X-ray powder diffraction patterns including diffraction peaks selected from the following groups of diffraction angles (2θ ± 0.2°): 7.90°, 14.59°, 17.20°, 18.15°, 19.68°, 21.49° and 23.65°. X-ray powder diffraction patterns including diffraction peaks selected from the following groups: diffraction angles (2θ ± 0.2°) of 7.86°, 14.54°, 17.12°, 18.09°, 19.61°, 21.42°, and 23.59°; or X-ray powder diffraction patterns including diffraction peaks at diffraction angles selected from the following group: 7.83°, 14.52°, 17.11°, 18.08°, 19.59°, 21.41° and 23.56° (2θ±0.2°).

[0169] In an exemplary embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form I of the compound represented by Formula 1 may further include diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six or seven) diffraction angles (2θ ± 0.2°) selected from 15.64°, 17.55°, 20.78°, 21.04°, 23.27°, 24.24° and 30.38°, and three or more (e.g., three, four, five, six or seven) diffraction angles (2θ ± 0.2°) selected from 7.85°, 14.54°, 17.14°, 18.09°, 19.62°, 21.41° and 23.58°.

[0170] It should be understood that any 2θ diffraction angle specified herein means a specified value ±0.2°.

[0171] For example, the X-ray powder diffraction pattern of crystalline form I of the compound represented by Formula 1 further includes diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six, or seven) diffraction angles (2θ ± 0.2°) selected from 15.64°, 17.55°, 20.78°, 21.04°, 23.27°, 24.24°, and 30.38°; and three or more (e.g., three, four, five, six, or seven) diffraction angles (2θ ± 0.2°) selected from 7.85°, 14.54°, 17.14°, 18.09°, 19.62°, 21.41°, and 23.58°. This X-ray powder diffraction pattern may be substantially identical to the X-ray powder diffraction pattern of crystalline form I represented by Formula 1. X-ray powder diffraction patterns including diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six or seven) diffraction angles (2θ±0.2°) selected from 15.70°, 17.61°, 20.84°, 21.10°, 23.34°, 24.30° and 30.44°, and three or more (e.g., three, four, five, six or seven) diffraction angles (2θ±0.2°) selected from 7.90°, 14.59°, 17.20°, 18.15°, 19.68°, 21.49° and 23.65°; X-ray powder diffraction patterns including diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six, or seven) diffraction angles (2θ ± 0.2°) selected from 15.66°, 17.55°, 20.77°, 21.04°, 23.27°, 24.23°, and 30.38°; and three or more (e.g., three, four, five, six, or seven) diffraction angles (2θ ± 0.2°) selected from 7.86°, 14.54°, 17.12°, 18.09°, 19.61°, 21.42°, and 23.59°; or X-ray powder diffraction patterns including diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six or seven) diffraction angles (2θ±0.2°) selected from 15.64°, 17.54°, 20.77°, 21.04°, 23.26°, 24.23° and 30.37°, and three or more (e.g., three, four, five, six or seven) diffraction angles (2θ±0.2°) selected from 7.83°, 14.52°, 17.11°, 18.08°, 19.59°, 21.41° and 23.56°.

[0172] In an exemplary embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form I of the compound represented by Formula 1 further includes diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six, or seven, etc.) selected from 9.40°, 11.62°, 11.77°, 13.49°, 14.92°, 15.64°, 17.55°, 18.82°, 20.78°, 21.04°, 22.6°. Diffraction angles of 9°, 23.27°, 24.24°, 26.35°, 27.58°, 28.91°, 30.38°, 33.57° and 36.74° (2θ±0.2°), and three or more (e.g. three, four, five, six or seven) selected from 7.85°, 14.54°, 17.14°, 18.09°, 19.62°, 21.41° and 23.58° (2θ±0.2°).

[0173] It should be understood that any 2θ diffraction angle specified herein means a specified value ±0.2°.

[0174] For example, the X-ray powder diffraction pattern of the crystalline form I of the compound represented by chemical formula 1 further includes diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six, or seven, etc.) selected from 9.40°, 11.62°, 11.77°, 13.49°, 14.92°, 15.64°, 17.55°, 18.82°, 20.78°, 21.04°, 22.69°, 23.27°, 24.24°, 26.35°, 27°, etc. The X-ray powder diffraction pattern can be substantially identical to the X-ray powder diffraction pattern of crystalline form I represented by the following chemical formula 1: 0.58°, 28.91°, 30.38°, 33.57° and 36.74° (2θ±0.2°), and three or more (e.g. three, four, five, six or seven) diffraction angles selected from 7.85°, 14.54°, 17.14°, 18.09°, 19.62°, 21.41° and 23.58° (2θ±0.2°). Further including the X-ray powder diffraction pattern of the crystalline form I of the compound represented by formula 1, with diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six, or seven, etc.) selected from 9.45°, 11.65°, 11.86°, 13.55°, 14.98°, 15.70°, 17.61°, 18.88°, 20.84°, 21.10°, 22.74°, 23.3°. Diffraction angles of 4°, 24.30°, 26.41°, 27.65°, 28.96°, 30.44°, 33.65° and 36.81° (2θ±0.2°), and three or more (e.g. three, four, five, six or seven) selected from 7.90°, 14.59°, 17.20°, 18.15°, 19.68°, 21.49° and 23.65° (2θ±0.2°); Further including the X-ray powder diffraction pattern of the crystalline form I of the compound represented by formula 1 with diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six, or seven, etc.) selected from 9.39°, 11.62°, 11.80°, 13.48°, 14.91°, 15.66°, 17.55°, 18.82°, 20.77°, 21.04°, 22.68°, 23.2°. Diffraction angles (2θ±0.2°) of 7°, 24.23°, 26.37°, 27.59°, 28.92°, 30.38°, 33.57°, and 36.74°, and three or more (e.g., three, four, five, six, or seven) selected from 7.86°, 14.54°, 17.12°, 18.09°, 19.61°, 21.42°, and 23.59°; or Further including the X-ray powder diffraction pattern of the crystalline form I of the compound represented by formula 1, with diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six, or seven, etc.) selected from 9.40°, 11.60°, 11.78°, 13.49°, 14.92°, 15.64°, 17.54°, 18.82°, 20.77°, 21.04°, 22.68°, 23.2°. Diffraction angles of 6°, 24.23°, 26.36°, 27.55°, 28.89°, 30.37°, 33.57° and 36.71° (2θ±0.2°), and three or more (e.g. three, four, five, six or seven) selected from 7.83°, 14.52°, 17.11°, 18.08°, 19.59°, 21.41° and 23.56° (2θ±0.2°).

[0175] In an exemplary embodiment of the present invention, the crystalline form I of the compound represented by chemical formula 1 may have the same characteristics as in the X-ray powder diffraction pattern. Figure 2 , Figure 4 , Figure 6 or Figure 14 The peak positions shown in the X-ray powder diffraction patterns are substantially the same as those in the standard X-ray powder diffraction patterns. In an exemplary embodiment of the invention, the crystalline form I of the compound represented by Formula 1 may have X-ray powder diffraction pattern peak positions that appear at substantially the same positions as the diffraction angles (2θ ± 0.2°) shown in Tables 1, 2, 3, or 6.

[0176] In an exemplary embodiment of the present invention, during differential scanning calorimetry (DSC) analysis, when the heating rate is 10 °C / min, the crystalline form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by Formula 1, has an endothermic peak at 132 °C (±0.5 °C) to 143 °C (±0.5 °C).

[0177] In an exemplary embodiment of the present invention, during differential scanning calorimetry (DSC) analysis, when the heating rate is 10 °C / min, the crystalline form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by Formula 1, has an endothermic peak at 134 °C (±0.5 °C) to 143 °C (±0.5 °C).

[0178] In an exemplary embodiment of the present invention, during differential scanning calorimetry (DSC) analysis, when the heating rate is 10 °C / min, the crystalline form I of the compound represented by Formula 1 may have an endothermic peak at 138 °C (±3 °C).

[0179] In an exemplary embodiment of the present invention, during differential scanning calorimetry (DSC) analysis, when the heating rate is 10 °C / min, the crystalline form I of the compound represented by Formula 1 may have an endothermic onset temperature of 134.1 °C (±0.5 °C) and an endothermic peak at a temperature of 138.0 °C (±0.5 °C); an endothermic onset temperature of 134.7 °C (±0.5 °C) and an endothermic peak at a temperature of 139.2 °C (±0.5 °C); or an endothermic onset temperature of 134.64 °C (±0.5 °C) and an endothermic peak at a temperature of 138.27 °C (±0.5 °C).

[0180] More specifically, the crystalline form I of the compound represented by chemical formula 1 may have the same... Figure 3 , Figure 5 or Figure 15 The endothermic peak shown is essentially the same as the endothermic peak of differential scanning calorimetry (DSC).

[0181] The crystalline form I of the compound represented by Formula 1 according to the present invention is suitable for the development of pharmaceuticals, has improved preparation efficiency, is suitable for mass production and easy to process industrially, and possesses excellent characteristics associated with pharmaceuticals in solid form, such as handling performance and stability. Specifically, the crystalline form I of the compound represented by Formula 1 has excellent long-term and accelerated stability, thermodynamic stability, light stability and crystal stability, low hygroscopicity and advantageous properties for removing residual solvents, and therefore has excellent safety and suitable solubility in formulations.

[0182] Furthermore, since the crystalline form I of the compound represented by chemical formula 1 according to the present invention has excellent storage stability, mechanical stability and flowability, has uniform particles, and is easy to process into pharmaceuticals, and the crystalline form can remain unchanged even after long-term storage of API and even under changes in the surrounding environment (such as temperature and humidity), the pharmaceuticals can ensure long shelf life and exhibit sufficient solubility for commercial production, and are therefore easy to formulate into pharmaceuticals and commercially reproducible.

[0183] In addition, since crystalline forms with weaker crystal stability can easily undergo changes in crystal form, multiple crystalline forms or mixtures of crystalline and amorphous forms are produced, resulting in changes in pharmacological properties, safety and pharmacokinetic properties, which can cause unexpected reactions. However, the crystalline form I of the compound represented by chemical formula 1 has excellent stability and can therefore maintain a pure single crystal form for a long time.

[0184] Specifically, since the crystalline form I of the compound represented by chemical formula 1 has excellent stability, it is possible to maintain an anhydride state that hardly absorbs water even in a humid environment, and even in a heating environment of 40°C or higher, the single crystalline form can maintain its crystalline form I for a long time without changing into another crystalline or amorphous form, so that harsh environments are not required during the preparation or storage process, and the crystalline form can be stably maintained.

[0185] Therefore, since the crystalline form I of the compound represented by chemical formula 1 can be attributed to its excellent thermodynamic and crystal stability and low hygroscopicity, which maintains a constant content, the crystalline form has a long storage and distribution period, suitable solubility in formulations, and can achieve drug production without deviations in efficacy and safety.

[0186] Crystallographic form II (Form II) of the compound represented by chemical formula 1. This disclosure provides crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by the following chemical formula 1: [Chemical Formula 1] .

[0187] According to embodiments of this disclosure, the X-ray powder diffraction pattern of crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide of the compound represented by Formula 1 may include diffraction peaks at three or more (e.g., three, four, five, six or seven) diffraction angles selected from the group consisting of: 7.83°, 12.22°, 19.02°, 19.67°, 21.40°, 22.35° and 26.44° (2θ ± 0.2°).

[0188] It should be understood that any 2θ diffraction angle specified herein means a specified value ±0.2°. For example, when the described embodiment or technical solution specifies 7.83° of 2θ, this should be understood to mean 7.83° ±0.2°, that is, a 2θ diffraction angle between 7.63° and 8.03°.

[0189] For example, in an X-ray powder diffraction pattern, a diffraction angle (2θ) of 7.83° is essentially the same as 7.83°±0.2°, a diffraction angle (2θ) of 12.22° is essentially the same as 12.22°±0.2°, a diffraction angle (2θ) of 19.02° is essentially the same as 19.02°±0.2°, a diffraction angle (2θ) of 19.67° is essentially the same as 19.67°±0.2°, a diffraction angle (2θ) of 21.40° is essentially the same as 21.40°±0.2°, a diffraction angle (2θ) of 22.35° is essentially the same as 22.35°±0.2°, and a diffraction angle (2θ) of 26.44° is essentially the same as 26.44°±0.2°.

[0190] For example, the X-ray powder diffraction pattern of crystalline form II of the compound represented by Formula 1, including three or more (e.g., three, four, five, six, or seven) diffraction peaks at diffraction angles selected from the group consisting of 7.83°, 12.22°, 19.02°, 19.67°, 21.40°, 22.35°, and 26.44° (2θ ± 0.2°), may be substantially identical to the X-ray powder diffraction pattern of crystalline form II of Formula 1 as follows: X-ray powder diffraction patterns including three or more (e.g., three, four, five, six or seven) diffraction peaks selected from the following group of diffraction angles (2θ ± 0.2°): 7.83°, 12.22°, 19.02°, 19.67°, 21.39°, 22.35° and 26.42°.

[0191] In one exemplary embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form II of the compound represented by Formula 1 may include diffraction peaks at diffraction angles (2θ ± 0.2°) of 7.83°, 12.22°, 19.02°, 19.67°, 21.40°, 22.35°, and 26.44°.

[0192] It should be understood that any 2θ diffraction angle specified herein means a specified value ±0.2°.

[0193] For example, the X-ray powder diffraction pattern of crystalline form II of the compound represented by Formula 1, including diffraction peaks at diffraction angles (2θ ± 0.2°) of 7.83°, 12.22°, 19.02°, 19.67°, 21.40°, 22.35°, and 26.44°, is substantially identical to the following X-ray powder diffraction pattern of crystalline form II represented by Formula 1: X-ray powder diffraction patterns of diffraction peaks at diffraction angles (2θ±0.2°) of 7.83°, 12.22°, 19.02°, 19.67°, 21.39°, 22.35° and 26.42°.

[0194] In an exemplary embodiment of the invention, the X-ray powder diffraction pattern of crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by Formula 1 may further include diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six, or seven, etc.) selected from 11.41°, 11.78°, 13.2°, etc. Diffraction angles (2θ±0.2°) of 8°, 15.70°, 16.64°, 17.48°, 18.28°, 19.37°, 20.71°, 24.58°, 27.35° and 33.73°, and three or more (e.g. three, four, five, six or seven) selected from 7.83°, 12.22°, 19.02°, 19.67°, 21.40°, 22.35° and 26.44°.

[0195] It should be understood that any 2θ diffraction angle specified herein means a specified value ±0.2°.

[0196] For example, the X-ray powder diffraction pattern of the crystalline form II of the compound represented by chemical formula 1 further includes diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six, or seven, etc.) selected from 11.41°, 11.78°, 13.28°, 15.70°, 16.64°, 17.48°, 18.28°, 19.37°, 20.71°, 24.58°, 27.3°. The X-ray powder diffraction pattern is substantially identical to that of crystalline form II represented by the following chemical formula 1, with diffraction angles of 5° and 33.73° (2θ ± 0.2°) and three or more (e.g., three, four, five, six or seven) selected from 7.83°, 12.22°, 19.02°, 19.67°, 21.40°, 22.35° and 26.44° (2θ ± 0.2°). X-ray powder diffraction pattern of crystalline form II of compound represented by chemical formula 1, including diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six or seven, etc.) diffraction angles selected from 11.39°, 11.77°, 13.26°, 15.72°, 16.60°, 17.48°, 18.27°, 19.35°, 20.67°, 24.56°, 27.34° and 33.72° (2θ±0.2°), and three or more (e.g., three, four, five, six or seven) diffraction angles selected from 7.83°, 12.22°, 19.02°, 19.67°, 21.39°, 22.35° and 26.42° (2θ±0.2°).

[0197] In an exemplary embodiment of the invention, the X-ray powder diffraction pattern of crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by Formula 1 may further include diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six or seven, etc.) selected from 10.72°, 10.92°, 11.41°, 11.78°, 13.28°, 15°. Diffraction angles of 70°, 16.64°, 16.97°, 17.48°, 18.28°, 19.37°, 20.71°, 24.58°, 27.35°, 30.49°, 32.19°, 33.73°, 35.44° and 35.91°, and three or more (e.g. three, four, five, six or seven) diffraction angles (2θ±0.2°) selected from 7.83°, 12.22°, 19.02°, 19.67°, 21.40°, 22.35° and 26.44°.

[0198] It should be understood that any 2θ diffraction angle specified herein means a specified value ±0.2°.

[0199] For example, the X-ray powder diffraction pattern of the crystalline form II of the compound represented by chemical formula 1 further includes diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six, or seven, etc.) selected from 10.72°, 10.92°, 11.41°, 11.78°, 13.28°, 15.70°, 16.64°, 16.97°, 17.48°, 18.28°, 19.37°, 20.71°, 24.58°, 27.35°, 30°, etc. The X-ray powder diffraction pattern is substantially identical to that of crystalline form II represented by the following chemical formula 1: 0.49°, 32.19°, 33.73°, 35.44° and 35.91° (2θ ± 0.2°), and three or more (e.g., three, four, five, six or seven, etc.) diffraction angles selected from 7.83°, 12.22°, 19.02°, 19.67°, 21.40°, 22.35° and 26.44° (2θ ± 0.2°). X-ray powder diffraction pattern of crystalline form II of compound represented by chemical formula I, including diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six, or seven, etc.) selected from 10.68°, 10.88°, 11.39°, 11.77°, 13.26°, 15.72°, 16.60°, 16.95°, 17.48°, 18.27°, 19.35°, 20.67°. Diffraction angles of 2θ ± 0.2°, 24.56°, 27.34°, 30.49°, 32.17°, 33.72°, 35.45°, and 35.94°, and three or more (e.g., three, four, five, six, or seven, etc.) selected from 7.83°, 12.22°, 19.02°, 19.67°, 21.39°, 22.35°, and 26.42°, selected from 2θ ± 0.2°.

[0200] In an exemplary embodiment of the present invention, the crystalline form II of the compound represented by chemical formula 1 may have the same characteristics as in the X-ray powder diffraction pattern. Figure 7 or Figure 16 The peak positions in the diffraction patterns shown are essentially the same.

[0201] In an exemplary embodiment of the invention, the crystalline form II of the compound represented by Formula 1 may have X-ray powder diffraction peak positions that appear at substantially the same positions as the diffraction angles (2θ ± 0.2°) shown in Table 4 or Table 7.

[0202] In an exemplary embodiment of the present invention, during differential scanning calorimetry (DSC) analysis, when the heating rate is 10 °C / min, the crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by Formula 1, has an endothermic peak at temperatures ranging from 124 °C (±0.5 °C) to 138 °C (±0.5 °C).

[0203] In an exemplary embodiment of the present invention, during differential scanning calorimetry (DSC) analysis, when the heating rate is 10 °C / min, the crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by Formula 1, has an endothermic peak at 125 °C (±0.5 °C) to 138 °C (±0.5 °C).

[0204] In an exemplary embodiment of the present invention, during differential scanning calorimetry (DSC) analysis, when the heating rate is 10 °C / min, the crystalline form II of the compound represented by Formula 1 may have an endothermic peak at 130 °C (±5 °C).

[0205] In one exemplary embodiment of the present invention, during differential scanning calorimetry (DSC) analysis, when the heating rate is 10 °C / min, the crystalline form II of the compound represented by Formula 1 may have an endothermic onset temperature of 125.7 °C (±0.5 °C) and an endothermic peak at a temperature of 132.2 °C (±0.5 °C); or an endothermic onset temperature of 125.61 °C (±0.5 °C) and an endothermic peak at a temperature of 130.43 °C.

[0206] More specifically, the crystalline form II of the compound represented by chemical formula 1 can have the same... Figure 8 or Figure 17 The endothermic peak shown is essentially the same as the endothermic peak of differential scanning calorimetry (DSC).

[0207] The crystalline form II of the compound represented by Formula 1 according to this disclosure is suitable for pharmaceutical development, exhibiting improved preparation efficiency, suitability for mass production and ease of industrial handling, and possessing excellent characteristics associated with the solid form, such as handling performance and stability. Specifically, the crystalline form II of the compound represented by Formula 1 exhibits excellent long-term and accelerated stability, thermodynamic stability, light stability and crystal stability, low hygroscopicity, and facilitates the removal of residual solvents, thus possessing excellent safety and suitable solubility in formulations.

[0208] Furthermore, since the crystalline form II of the compound represented by chemical formula 1 according to this disclosure has excellent storage stability, mechanical stability and flowability, has uniform particles, and is easy to process into a pharmaceutical, and the crystalline form remains unchanged even after long-term storage of the API and even under changes in the surrounding environment (such as temperature and humidity), the pharmaceutical can ensure a long shelf life and exhibit sufficient solubility for commercial production, and is therefore easy to formulate into a pharmaceutical and to prepare commercially reproducible products.

[0209] Due to the change in crystal form, various crystalline forms or mixtures of crystalline and amorphous forms are produced, resulting in changes in pharmacological properties, safety and pharmacokinetic properties. This can cause unexpected reactions. However, the crystalline form II of the compound represented by chemical formula 1 has excellent stability and can therefore maintain a pure single crystal form for a long time even when the surrounding environment (such as accelerated stability conditions) changes.

[0210] Specifically, since the crystalline form II of the compound represented by chemical formula 1 has excellent stability, it is possible to maintain an anhydride state that hardly absorbs water even in humid environments, and the single crystalline form can maintain its crystalline form II for a long time without changing into another crystalline or amorphous form, so that harsh environments are not required during the preparation or storage process, and the crystalline form can be stably maintained.

[0211] Therefore, since the crystalline form II of the compound represented by chemical formula 1 can be attributed to its excellent thermodynamic and crystal stability and low hygroscopicity, which maintains a constant content, the crystalline form has a long storage and distribution period, suitable solubility in formulations, and can achieve drug production without deviations in efficacy and safety.

[0212] Crystallographic form III (Form III) of the compound represented by chemical formula 1. This disclosure provides the crystalline form III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by the following chemical formula 1: [Chemical Formula 1] .

[0213] According to embodiments of the present invention, the X-ray powder diffraction pattern of the crystalline form III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide of the compound represented by Formula 1 may include diffraction peaks at three or more (e.g., three, four, five or six) diffraction angles selected from the group consisting of diffraction angles (2θ ± 0.2°) of 8.75°, 10.98°, 12.44°, 16.86°, 22.92° and 28.49°.

[0214] It should be understood that any 2θ diffraction angle specified herein means a specified value ±0.2°. For example, when the described embodiment or technical solution specifies 8.75° of 2θ, this should be understood to mean 8.75° ±0.2°, that is, a 2θ diffraction angle between 8.55° and 8.95°.

[0215] For example, in an X-ray powder diffraction pattern, a diffraction angle (2θ) of 8.75° is essentially the same as 8.75°±0.2°, a diffraction angle (2θ) of 10.98° is essentially the same as 10.98°±0.2°, a diffraction angle (2θ) of 12.44° is essentially the same as 12.44°±0.2°, a diffraction angle (2θ) of 16.86° is essentially the same as 16.86°±0.2°, a diffraction angle (2θ) of 22.92° is essentially the same as 22.92°±0.2°, and a diffraction angle (2θ) of 28.49° is essentially the same as 28.49°±0.2°.

[0216] For example, the X-ray powder diffraction pattern of crystalline form III of the compound represented by Formula 1 includes diffraction peaks at three or more (e.g., three, four, five, or six) diffraction angles selected from the group consisting of 8.75°, 10.98°, 12.44°, 16.86°, 22.92°, and 28.49° (2θ ± 0.2°), and this X-ray powder diffraction pattern may be substantially identical to the X-ray powder diffraction pattern of crystalline form I represented by Formula 1: X-ray powder diffraction pattern of the crystalline form III of the compound represented by chemical formula 1, which includes diffraction peaks at three or more (e.g., three, four, five or six) diffraction angles selected from the group consisting of diffraction angles of 8.73°, 10.95°, 12.40°, 16.84°, 22.90° and 28.47° (2θ ± 0.2°).

[0217] In an exemplary embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form III of the compound represented by Formula 1 may include diffraction peaks at diffraction angles (2θ ± 0.2°) of 8.75°, 10.98°, 12.44°, 16.86°, 22.92°, and 28.49°.

[0218] It should be understood that any 2θ diffraction angle specified herein means a specified value ±0.2°.

[0219] For example, the X-ray powder diffraction pattern of crystalline form III of the compound represented by Formula 1 includes diffraction peaks at diffraction angles (2θ ± 0.2°) of 8.75°, 10.98°, 12.44°, 16.86°, 22.92°, and 28.49°, and this X-ray powder diffraction pattern is substantially the same as the X-ray powder diffraction pattern of crystalline form III represented by Formula 1 below: X-ray powder diffraction pattern of the crystalline form III of the compound represented by chemical formula 1, which includes diffraction peaks at diffraction angles (2θ ± 0.2°) of 8.73°, 10.95°, 12.40°, 16.84°, 22.90° and 28.47°.

[0220] In an exemplary embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form III of the compound represented by Formula 1 may further include diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six or seven, etc.) diffraction angles (2θ±0.2°) selected from 17.48°, 19.95°, 20.49°, 20.79°, 21.55°, 21.87°, 22.07°, 24.04°, 24.72°, 24.99° and 26.30°; and three or more (e.g., three, four, five or six) diffraction angles (2θ±0.2°) selected from 8.75°, 10.98°, 12.44°, 16.86°, 22.92° and 28.49°.

[0221] It should be understood that any 2θ diffraction angle specified herein means a specified value ±0.2°.

[0222] For example, the X-ray powder diffraction pattern of crystalline form III of the compound represented by Formula 1 further includes diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six or seven, etc.) selected from 17.48°, 19.95°, 20.49°, 20.79°, 21.55°, 21.87°, 22.07°, 24.04°, 24.72°, 24.99° and 26.30° (2θ±0.2°), and three or more (e.g., three, four, five or six) selected from 8.75°, 10.98°, 12.44°, 16.86°, 22.92° and 28.49° (2θ±0.2°), which may be substantially identical to the X-ray powder diffraction pattern of crystalline form III represented by Formula 1: The X-ray powder diffraction pattern of the crystalline form III of the compound represented by chemical formula 1 further includes diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six or seven, etc.) diffraction angles (2θ±0.2°) selected from 17.47°, 19.93°, 20.45°, 20.77°, 21.53°, 21.84°, 22.05°, 24.02°, 24.70°, 24.96° and 26.27°; and three or more (e.g., three, four, five or six) diffraction angles (2θ±0.2°) selected from 8.73°, 10.95°, 12.40°, 16.84°, 22.90° and 28.47°.

[0223] In an exemplary embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form III of the compound represented by Formula 1 may further include diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six, or seven, etc.) selected from 14.28°, 15.45°, 17.48°, 18.49°, 18.77°, 19.95°, 20.49°, 20.79°, 21.55°, 21.87°. Diffraction angles of 22.07°, 24.04°, 24.72°, 24.99°, 26.30°, 29.22°, 30.20°, 31.40°, 34.10°, 37.13° and 38.86°, and three or more (e.g. three, four, five or six) diffraction angles (2θ±0.2°) selected from 8.75°, 10.98°, 12.44°, 16.86°, 22.92° and 28.49°.

[0224] It should be understood that any 2θ diffraction angle specified herein means a specified value ±0.2°.

[0225] For example, the X-ray powder diffraction pattern of the crystalline form III of the compound represented by chemical formula 1 further includes diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six, or seven, etc.) selected from 14.28°, 15.45°, 17.48°, 18.49°, 18.77°, 19.95°, 20.49°, 20.79°, 21.55°, 21.87°, 22.07°, 24.04°, 24.72°, 24.99°. The X-ray powder diffraction pattern can be substantially identical to the X-ray powder diffraction pattern of crystalline form I represented by the following chemical formula 1: 26.30°, 29.22°, 30.20°, 31.40°, 34.10°, 37.13°, and 38.86°, and three or more (e.g., three, four, five, or six) diffraction angles selected from 8.75°, 10.98°, 12.44°, 16.86°, 22.92°, and 28.49° (2θ ± 0.2°). The X-ray powder diffraction pattern of the crystalline form III of the compound represented by chemical formula 1, further comprising diffraction peaks at the following diffraction angles: one or more (e.g., one, two, three, four, five, six, or seven, etc.) selected from 14.20°, 15.45°, 17.47°, 18.44°, 18.75°, 19.93°, 20.45°, 20.77°, 21.53°, 21.84°, 22.05°. Diffraction angles of 24.02°, 24.70°, 24.96°, 26.27°, 29.20°, 30.18°, 31.39°, 34.09°, 37.09° and 38.82°, and three or more (e.g. three, four, five or six) diffraction angles (2θ±0.2°) selected from 8.73°, 10.95°, 12.40°, 16.84°, 22.90° and 28.47°.

[0226] In an exemplary embodiment of the present invention, the crystalline form III of the compound represented by chemical formula 1 may have the same characteristics as in the X-ray powder diffraction pattern. Figure 9 or Figure 18 The peak positions in the diffraction patterns shown are essentially the same.

[0227] In an exemplary embodiment of the invention, the crystalline form III of the compound represented by Formula 1 may have X-ray powder diffraction peak positions that appear at substantially the same positions as the diffraction angles (2θ ± 0.2°) shown in Table 5 or Table 8.

[0228] In an exemplary embodiment of the present invention, during differential scanning calorimetry (DSC) analysis, at a heating rate of 10 °C / min, the crystalline form III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, representing the compound of formula 1, exhibits an endothermic peak at 120 °C (±0.5 °C) to 130 °C (±0.5 °C).

[0229] In an exemplary embodiment of the present invention, during differential scanning calorimetry (DSC) analysis, when the heating rate is 10 °C / min, the crystalline form III of the compound represented by Formula 1 may have an endothermic peak at 125 °C (±5 °C).

[0230] In an exemplary embodiment of the present invention, during differential scanning calorimetry (DSC) analysis, when the heating rate is 10 °C / min, the crystalline form III of the compound represented by Formula 1 may have an endothermic onset temperature of 120.5 °C (±0.5 °C) and an endothermic peak at a temperature of 124.7 °C (±0.5 °C); or an endothermic onset temperature of 120.4 °C (±0.5 °C) and an endothermic peak at a temperature of 124.8 °C (±0.5 °C).

[0231] The crystalline form III of the compound represented by Formula 1 according to this disclosure is suitable for pharmaceutical development, exhibiting improved preparation efficiency, suitability for mass production and ease of industrial handling, and possessing excellent characteristics associated with the solid form, such as handling performance and stability. Specifically, the crystalline form III of the compound represented by Formula 1 possesses excellent long-term and accelerated stability, thermodynamic stability, light stability and crystal stability, low hygroscopicity, and advantageous properties for removing residual solvents, and therefore exhibits excellent safety and suitable solubility in formulations.

[0232] Furthermore, since the crystalline form III of the compound represented by chemical formula 1 of this disclosure has excellent storage stability, mechanical stability and flowability, has uniform particles, and is easy to process into pharmaceuticals, and the crystalline form remains unchanged even after long-term storage of APIs and even under changes in the surrounding environment (such as temperature and humidity), the pharmaceuticals can ensure long shelf life and exhibit sufficient solubility for commercial production, and are therefore easy to formulate into pharmaceuticals and commercially reproducible.

[0233] In addition, since the crystalline form with weak crystal stability can easily undergo changes in crystal form, a variety of crystalline forms or mixtures of crystalline and amorphous forms are produced, resulting in changes in pharmacological properties, safety and pharmacokinetic properties, which can cause unexpected reactions. Furthermore, the crystalline form III of the compound represented by chemical formula 1 has excellent stability and can therefore maintain a pure single crystal form for a long time.

[0234] Specifically, since the crystalline form III of the compound represented by chemical formula 1 has excellent stability, it is possible to maintain an anhydride state that hardly absorbs water even in humid environments, and the single crystalline form can maintain its crystalline form III for a long time without changing into another crystalline or amorphous form, so that harsh environments are not required during the preparation or storage process, and the crystalline form can be stably maintained.

[0235] Therefore, since the crystalline form III of the compound represented by chemical formula 1 can be attributed to its excellent thermodynamic and crystal stability and low hygroscopicity, which maintains a constant content, the crystalline form has a long storage and distribution period, suitable solubility in formulations, and can achieve drug production without deviations in efficacy and safety.

[0236] Pharmaceutical compositions comprising crystalline forms I, II, or III This disclosure provides a pharmaceutical composition comprising a novel crystalline form of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by the following chemical formula 1: [Chemical Formula 1] .

[0237] In an exemplary embodiment of the present invention, the pharmaceutical composition can prevent or treat diseases associated with histone deacetylase 6 activity.

[0238] In exemplary embodiments of the present invention, diseases associated with histone deacetylase 6 activity include infectious diseases such as prion diseases; tumors such as benign tumors (e.g., myelodysplastic syndrome) or malignant tumors (e.g., multiple myeloma, lymphoma, leukemia, lung cancer, colorectal cancer, colon cancer, prostate cancer, urothelial carcinoma, breast cancer, melanoma, skin cancer, liver cancer, brain cancer, stomach cancer, ovarian cancer, pancreatic cancer, head and neck cancer, oral cancer, or glioma); endocrine, nutritional, and metabolic diseases such as Wilson's disease, amyloidosis, or diabetes; mental and behavioral disorders such as depression or Rett's syndrome; and neurological diseases such as central nervous system atrophy (e.g., Huntington's disease, spinal muscular atrophy (SMA), spinocerebellar ataxia (SCA)), neurodegenerative diseases (e.g., Alzheimer's disease), and movement disorders (e.g., Parkinson's disease). Diseases, neuropathy (e.g., hereditary neuropathy (Charcot-Marie-Tooth disease, incidental neuropathy, inflammatory neuropathy, and drug-induced neuropathy), motor neuron diseases (e.g., amyotrophic lateral sclerosis (ALS)), or central nervous system demyelinating diseases (e.g., multiple sclerosis (MS)); eye and adnexal diseases, such as uveitis; circulatory system diseases, such as stroke; respiratory system diseases, such as asthma; digestive system diseases, such as alcoholic liver disease, inflammatory bowel disease, Crohn's disease, or ulcerative colitis; skin and subcutaneous tissue diseases, such as psoriasis; musculoskeletal and connective tissue diseases, such as rheumatoid arthritis, osteoarthritis, or systemic lupus erythematosus (SLE); and congenital malformations, deformities, and chromosomal abnormalities, such as autosomal dominant polycystic kidney disease, and may also include other symptoms or diseases associated with abnormal function of histone deacetylase 6.

[0239] In an exemplary embodiment of the present invention, the X-ray powder diffraction pattern of the crystalline form I, crystalline form II or crystalline form III of the compound represented by chemical formula 1 contained in the pharmaceutical composition, and the endothermic peak of differential scanning calorimetry (DSC) analysis are as described above.

[0240] In an exemplary embodiment of the present invention, the crystalline forms I, II, and III of the compound represented by Formula 1 contained in the pharmaceutical composition exhibit excellent physicochemical properties. Therefore, the pharmaceutical composition containing the crystalline forms I, II, or III of the compound represented by Formula 1 exhibits excellent crystal stability, which facilitates commercial mass production, enables reproducible preparation, and maintains the physicochemical properties for a long period of time as in the initial preparation, ensuring a long distribution period and eliminating the need for separate harsh storage conditions.

[0241] The pharmaceutical compositions of the present invention may further comprise one or more pharmaceutically acceptable additives, and the additives may be those commonly used in this art.

[0242] Where necessary, the pharmaceutical compositions of the present invention can be formulated in appropriate forms, such as patches, liquids, pills, capsules, granules, tablets, suppositories, and similar forms. These formulations can be formulated by typical methods used in the art or by the methods disclosed in Remington's Pharmaceutical Sciences (latest version), Mack Publishing Company, Easton PA, and can be formulated into various formulations according to diseases or according to the components.

[0243] Preparation methods of crystalline forms I, II, and III of the compound represented by chemical formula 1 This disclosure provides a method for preparing new crystalline forms I, II, and III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is represented by the following chemical formula 1: [Chemical Formula 1] .

[0244] According to the preparation method of the present invention, it is possible to prepare the crystalline form of the compound represented by Formula 1 with high purity and high yield, while minimizing the generation of impurities without special equipment and complex processes, thus facilitating the large-scale production of the crystalline form. Specifically, according to the method for preparing crystalline form I, crystalline form II, or crystalline form III of the compound represented by Formula 1 according to the present invention, it is possible to prepare crystalline form I, crystalline form II, or crystalline form III with a high yield of 85% or higher, specifically 90% or higher, and with a purity of 99% or higher as determined by HPLC, so that crystalline form I, crystalline form II, or crystalline form III can be prepared with sufficient purity for use as a pharmaceutical. In addition, since the solvents used for the preparation of the crystalline form are inexpensive, an economical preparation process for large-scale production can be established, making it suitable for industrial production.

[0245] In this disclosure, a method for preparing crystalline form I of the compound represented by chemical formula 1 may include the following steps: (a) Dissolving N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide in a solvent selected from the group consisting of: ethyl acetate, ethanol, methanol, isopropanol, butanol, methyl tert-butyl ether (MTBE), diisopropyl ether, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone, dichloromethane, dimethylformamide, N-methyl-2-pyrrolidone, toluene, tetrahydrofuran, heptane, hexane, acetonitrile, and mixtures thereof; and (b) A solid is produced from the solution.

[0246] In an exemplary embodiment of the present invention, in the preparation of the crystalline form I of the compound represented by Formula 1, the solvent in step (a) may be one or more alcohols selected from ethanol, methanol, isopropanol and butanol; ethyl acetate; or a mixture of said alcohol and ethyl acetate.

[0247] In an exemplary embodiment of the present invention, in the preparation of the crystalline form I of the compound represented by chemical formula 1, the solvent in step (a) may be a mixture of one or more alcohols selected from ethanol, methanol, isopropanol and butanol and ethyl acetate.

[0248] In an exemplary embodiment of the present invention, in the preparation of the crystalline form I of the compound represented by chemical formula 1, obtaining the solution (a) may include: (a1) Adding the compound represented by chemical formula 1 to a solvent to obtain a mixture; and (a2) Heat the mixture to a temperature exceeding 40°C.

[0249] In an exemplary embodiment of the present invention, the heating in (a2) can be carried out at a temperature above 40°C, 45°C or higher, specifically in the range of 45°C to 70°C, more specifically in the range of 45°C to 65°C, and even more specifically in the range of 50°C to 65°C.

[0250] In an exemplary embodiment of the present invention, in the method for preparing the crystalline form I of the compound represented by Formula 1, the generation of the solid in step (b) may include: (b1) A mixture is prepared by adding one or more alcohols selected from ethanol, methanol, isopropanol, and butanol to the solution obtained in step (a); and (b2) Stir the mixture after adding the alcohol from step (b1).

[0251] In an exemplary embodiment of the present invention, steps (b1) and (b2) may be performed at a temperature above 40°C, specifically at a temperature above 40°C and 60°C or lower.

[0252] In an exemplary embodiment of the invention, solids may be generated during the stirring process in step (b2).

[0253] In an exemplary embodiment of the invention, a cooling process may be further performed, and the cooling may be performed at a temperature of 10°C or lower, specifically from 0°C to 10°C, and more specifically from 0°C to 7°C.

[0254] In an exemplary embodiment of the present invention, the physical state of the compound represented by Formula 1 of the starting material for step (a) of the method for preparing crystalline form I is not limited and can be any physical state, as long as it is a compound represented by Formula 1. Specifically, the compound can be liquid or solid, such as a solution or suspension, and the solid state can also be in foam form, amorphous form or similar form, and more specifically, the compound can be in oil or foam form, or amorphous solid form, and more specifically, an amorphous form having an oil or foam-like shape, but is not limited thereto.

[0255] In an exemplary embodiment of the present invention, the compound represented by chemical formula 1 can be prepared by preparation methods known in the art, and for example, the compound represented by chemical formula 1 can be prepared by the preparation method disclosed in Korean Patent Registration No. 10-1799010.

[0256] In an exemplary embodiment of the present invention, the method for preparing the crystalline form I of the compound represented by chemical formula 1 may further include, prior to step (a): The compound represented by Formula 1 is dissolved in dichloromethane, followed by primary concentration, thereby producing a concentrated residue; and Ethyl acetate was added to the concentrated residue and then subjected to secondary concentration.

[0257] In this disclosure, a method for preparing the crystalline form II of a compound represented by chemical formula 1 may include the following steps: (a) Adding N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, a compound of formula 1, to a solvent selected from the group consisting of methanol, ethanol, isopropanol, butanol, diisopropyl ether, tetrahydrofuran, heptane, hexane, and mixtures thereof; (b) Heating the mixture to a temperature of 30°C to 40°C to obtain a solution; and (c) A solid is produced from the solution at a temperature of 40°C or lower.

[0258] In an exemplary embodiment of the present invention, in the preparation of the crystalline form II of the compound represented by Formula 1, the solvent in step (a) may be ethanol, isopropanol, or a mixture thereof.

[0259] In an exemplary embodiment of the present invention, in the preparation of the crystalline form II of the compound represented by chemical formula 1, the solvent in step (a) may be ethanol.

[0260] In an exemplary embodiment of the present invention, in the preparation of the crystalline form II of the compound represented by chemical formula 1, the heating in step (b) may be carried out at 40°C or lower, specifically in the temperature range of 30°C to 40°C.

[0261] In an exemplary embodiment of the present invention, in the preparation of the crystalline form II of the compound represented by Formula 1, the step (c) of generating a solid from the solution at a temperature of 40°C or lower may include stirring the solution at a temperature of 40°C or lower.

[0262] In an exemplary embodiment of the present invention, in the preparation of the crystalline form II of the compound represented by Formula 1, step (c) may be carried out at a temperature range of 40°C or lower, more specifically 20°C to 40°C, and more specifically 30°C to 40°C.

[0263] In an exemplary embodiment of the present invention, the physical state of the compound represented by Formula 1 of the starting material for step (a) of the method for preparing crystalline form II is not limited and can be any physical state, as long as it is a compound represented by Formula 1. In particular, the compound can be liquid or solid, such as a solution or suspension, and the solid state can also be in foam form, amorphous form or similar form, and more specifically, the compound can be in oil or foam form, or amorphous solid form, and more specifically, an amorphous form having an oil or foam-like shape, but is not limited thereto.

[0264] In an exemplary embodiment of the present invention, the compound represented by Formula 1 can be prepared by preparation methods known in the art, and for example, the compound represented by Formula 1 can be prepared by the preparation method disclosed in Korean Patent No. 10-1799010.

[0265] In an exemplary embodiment of the present invention, forming a solid in step (c) may include stirring the solution.

[0266] In an exemplary embodiment of the invention, solids may be generated during the stirring process.

[0267] In an exemplary embodiment of the present invention, the method for preparing the crystalline form II of the compound represented by Formula 1 may further include, prior to step (a): The compound represented by Formula 1 is dissolved in dichloromethane, followed by primary concentration, thereby producing a concentrated residue; and Ethanol was added to the concentrated residue and then subjected to secondary concentration.

[0268] In this disclosure, a method for preparing the crystalline form III of the compound represented by Formula 1 may include the following steps: (a) Adding an amorphous N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by Formula 1, to a solvent selected from the group consisting of: methyl tert-butyl ether (MTBE), heptane, octane, hexane, pentane, and mixtures thereof; and (b) Obtaining solids from the slurry.

[0269] In an exemplary embodiment of the present invention, in the preparation of the crystalline form III of the compound represented by Formula 1, the solvent in step (a) may be methyl tert-butyl ether (MTBE), heptane, or a mixture thereof.

[0270] In an exemplary embodiment of the present invention, in the preparation of the crystalline form III of the compound represented by Formula 1, the production of the slurry of (a) can take place for 12 hours to 20 days, specifically 12 hours to 7 days, and more specifically 12 hours to 3 days. For example, the production of the slurry of (a) can take place for 12 hours to 36 hours, specifically 15 hours to 30 hours, and more specifically 20 hours to 27 hours.

[0271] In an exemplary embodiment of the present invention, in a method for preparing the crystalline form III of the compound represented by chemical formula 1, obtaining the solid of (b) may include filtering the slurry obtained in step (a).

[0272] In an exemplary embodiment of the present invention, the generation of the slurry in (a) and the acquisition of the solid in (b) can be carried out at 30°C or lower, specifically 20°C to 30°C, and more specifically 20°C to 25°C.

[0273] In an exemplary embodiment of the present invention, crystalline forms I to III of the compound represented by chemical formula 1 can be prepared using the compound represented by chemical formula 1 prepared according to the method of the present disclosure as a starting material.

[0274] In an exemplary embodiment of the present invention, when the starting material is a compound of chemical formula 1 prepared by the method according to the present disclosure, the method for preparing crystalline form I of the compound of chemical formula 1 may include the following steps: (a) Dissolving N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide in a solvent selected from the group consisting of: ethyl acetate, ethanol, methanol, isopropanol, butanol, methyl tert-butyl ether (MTBE), diisopropyl ether, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone, dichloromethane, dimethylformamide, N-methyl-2-pyrrolidone, toluene, tetrahydrofuran, heptane, hexane, acetonitrile, and mixtures thereof; and (b) A solid is produced from the solution.

[0275] In an exemplary embodiment of the present invention, in the preparation of the crystalline form I of the compound represented by Formula 1, the solvent in step (a) may be one or more alcohols selected from ethanol, methanol, isopropanol and butanol; ethyl acetate; or a mixture of said alcohol and ethyl acetate.

[0276] In an exemplary embodiment of the present invention, in the preparation of the crystalline form I of the compound represented by chemical formula 1, the solvent in step (a) may be a mixture of one or more alcohols selected from ethanol, methanol, isopropanol and butanol and ethyl acetate.

[0277] In an exemplary embodiment of the present invention, in the preparation of the crystalline form I of the compound represented by Formula 1, obtaining the solution (a) may include: (a1) Adding the compound represented by chemical formula 1 to a solvent to obtain a mixture; and (a2) Heat the mixture to a temperature exceeding 40°C.

[0278] In an exemplary embodiment of the present invention, the heating in (a2) can be carried out at a temperature above 40°C, 45°C or higher, specifically in the range of 45°C to 70°C, more specifically in the range of 45°C to 65°C, and even more specifically in the range of 50°C to 65°C.

[0279] In an exemplary embodiment of the present invention, in the method for preparing the crystalline form I of the compound represented by Formula 1, the generation of the solid in step (b) may include: (b1) A mixture is prepared by adding one or more alcohols selected from ethanol, methanol, isopropanol, and butanol to the solution obtained in step (a); and (b2) Stir the mixture after adding the alcohol from step (b1).

[0280] In an exemplary embodiment of the present invention, steps (b1) and (b2) may be performed at a temperature above 40°C, specifically at a temperature above 40°C and 60°C or lower.

[0281] In an exemplary embodiment of the invention, solids may be generated during the stirring process in step (b2).

[0282] In an exemplary embodiment of the invention, a cooling process may be further performed, and the cooling may be performed at a temperature of 10°C or lower, specifically from 0°C to 10°C, and more specifically from 0°C to 7°C.

[0283] In an exemplary embodiment of the present invention, the physical state of the compound represented by Formula 1 of the starting material for step (a) of the method for preparing crystalline form I is not limited and can be any physical state, as long as it is a compound represented by Formula 1. In particular, the compound can be liquid or solid, such as a solution or suspension, and the solid state can also be in foam form, amorphous form or similar form, and more specifically, the compound can be in oil or foam form, or amorphous solid form, and more specifically, an amorphous form having an oil or foam-like shape, but is not limited thereto.

[0284] In an exemplary embodiment of the present invention, in a method for preparing crystalline form I of a compound represented by chemical formula 1, the compound represented by chemical formula 1 as a starting material may be prepared according to, but is not limited to, the method for preparing the compound represented by chemical formula 1 described in detail above. For example, in a method for preparing crystalline form I, the starting material may be a compound represented by chemical formula 1 prepared by the novel method described herein, or it may be prepared according to conventionally known methods.

[0285] In an exemplary embodiment of the present invention, the method for preparing crystalline form I of the compound represented by Formula 1 may further include the following steps: prior to step (a), adding ethyl acetate to the compound represented by Formula 1 and concentrating the resulting mixture. In this case, the compound represented by Formula 1 may be a compound represented by Formula 1 obtained by the novel preparation method described herein, wherein the compound represented by Formula 1 may be in an oil state, but is not limited thereto.

[0286] In an exemplary embodiment of the present invention, in a method for preparing crystalline form I of a compound represented by chemical formula 1, the compound represented by chemical formula 1, as a starting material, can be prepared by the method described herein. Specifically, the compound represented by chemical formula 1 can be prepared in situ from a compound represented by chemical formula 6. In this case, the reactants and reaction conditions can be the same as previously described herein.

[0287] More specifically, the crystalline form I of the compound represented by chemical formula 1 can be prepared by methods including the following (1) to (3): (1) Prepare compounds represented by chemical formula 1 in situ from compounds represented by chemical formula 6: [Chemical Formula 6] [Chemical Formula 1] ; (2) Dissolve the compound of formula 1 obtained in step (1) in a solvent selected from the group consisting of: ethyl acetate, ethanol, methanol, isopropanol, butanol, methyl tert-butyl ether (MTBE), diisopropyl ether, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone, dichloromethane, dimethylformamide, N-methyl-2-pyrrolidone, toluene, tetrahydrofuran, heptane, hexane, acetonitrile, and mixtures thereof; and (3) A solid is produced from the solution.

[0288] In the method for preparing crystalline form I of the compound represented by Formula 1, step (1) may be substantially the same as the method for preparing the compound represented by Formula 1 from the compound represented by Formula 6 previously described herein. For example, the reactants, reaction conditions, and specific reaction details are substantially the same as those previously described herein. In the method for preparing crystalline form I of the compound represented by Formula 1, steps (2) and (3) may be substantially the same as steps (a) and (b) of the method for preparing crystalline form I of the compound represented by Formula 1, which uses the compound represented by Formula 1 as a starting material that can be prepared according to the present disclosure previously described. For example, the reactants, reaction conditions, and specific reaction details are substantially the same as those previously described herein.

[0289] In an exemplary embodiment of the present invention, the method for preparing crystalline form I of the compound represented by Formula 1 may further include adding ethyl acetate to the compound represented by Formula 1 and concentrating it prior to step (2). In this case, the compound represented by Formula 1 can be prepared by the novel method described herein, wherein the compound represented by Formula 1 may be in an oil state, but is not limited thereto.

[0290] In an exemplary embodiment of the invention, the X-ray powder diffraction pattern and differential scanning calorimetry (DSC) analysis at a heating rate of 10 °C / min are identical to those previously described herein with respect to crystalline form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, representing the compound of formula 1.

[0291] In an exemplary embodiment of the present invention, when the starting material is a compound of formula 1 prepared by the method according to the present disclosure, the method for preparing crystalline form II of the compound of formula 1 may include the following steps: (a) Adding the compound N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by chemical formula 1, to a solvent selected from the group consisting of methanol, ethanol, isopropanol, butanol, diisopropyl ether, tetrahydrofuran, heptane, hexane, and mixtures thereof; (b) Heating the mixture to a temperature of 30°C to 40°C to obtain a solution; and (c) A solid is produced from the solution at a temperature of 40°C or lower.

[0292] In an exemplary embodiment of the present invention, in the preparation of the crystalline form II of the compound represented by Formula 1, the solvent in step (a) may be ethanol, isopropanol, or a mixture thereof.

[0293] In an exemplary embodiment of the present invention, in the preparation of the crystalline form II of the compound represented by chemical formula 1, the solvent in step (a) may be ethanol.

[0294] In an exemplary embodiment of the present invention, in the preparation of the crystalline form II of the compound represented by chemical formula 1, the heating in step (b) may be carried out at 40°C or lower, specifically in the temperature range of 30°C to 40°C.

[0295] In an exemplary embodiment of the present invention, in the preparation of the crystalline form II of the compound represented by Formula 1, the step (c) of generating a solid from the solution at a temperature of 40°C or lower may include stirring the solution at a temperature of 40°C or lower.

[0296] In an embodiment of the present invention, in the preparation of the crystalline form II of the compound represented by the above chemical formula 1, step (c) may be carried out at a temperature range of 40°C or lower, more specifically 20°C to 40°C, and more specifically 30°C to 40°C.

[0297] In an exemplary embodiment of the present invention, the physical state of the compound represented by Formula 1 of the starting material for step (a) of the method for preparing crystalline form II is not limited and can be any physical state, as long as it is a compound represented by Formula 1. Specifically, the compound can be liquid or solid, such as a solution or suspension, and the solid state can also be in foam form, amorphous form or similar form, and more specifically, the compound can be in oil or foam form, or amorphous solid form, and more specifically, an amorphous form having an oil or foam-like shape, but is not limited thereto.

[0298] In an exemplary embodiment of the present invention, in a method for preparing crystalline form II of a compound represented by chemical formula 1, the compound represented by chemical formula 1 as a starting material may be prepared according to a novel method for preparing the compound represented by chemical formula 1 as described in detail above, but is not limited thereto. For example, in a method for preparing crystalline form II, the starting material may be a compound represented by chemical formula 1 prepared by the novel method described herein.

[0299] In an exemplary embodiment of the present invention, forming a solid in step (c) may include stirring the solution.

[0300] In an exemplary embodiment of the invention, solids may be generated during the stirring process.

[0301] In an exemplary embodiment of the present invention, the method for preparing crystalline form II of the compound represented by Formula 1 may further include the following steps: adding ethanol to the compound represented by Formula 1 and concentrating the resulting mixture prior to step (a). In this case, the compound represented by Formula 1 may be a compound represented by Formula 1 obtained by the novel preparation method described in this specification, wherein the compound represented by Formula 1 may be in an oil state, but is not limited thereto.

[0302] In an exemplary embodiment of the invention, the compound represented by Formula 1 can be prepared by the methods previously described herein. Specifically, the compound represented by Formula 1 can be prepared in situ from the compound represented by Formula 6. In this case, the reactants and reaction conditions can be the same as previously described herein.

[0303] More specifically, the crystalline form II of the compound represented by chemical formula 1 can be prepared by methods comprising the following (1) to (4): (1) Prepare compounds represented by chemical formula 1 in situ from compounds represented by chemical formula 6: [Chemical Formula 6] [Chemical Formula 1] ; (2) Adding N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is a compound represented by chemical formula 1, to a solvent selected from the group consisting of methanol, ethanol, isopropanol, butanol, diisopropyl ether, tetrahydrofuran, heptane, hexane, and mixtures thereof; (3) The mixture is heated to a temperature of 30°C to 40°C to obtain a solution; and (4) A solid is produced from the solution at a temperature of 40°C or lower.

[0304] In the method for preparing the crystalline form II of the compound represented by Formula 1, step (1) may be substantially the same as the method for preparing the compound represented by Formula 1 from the compound represented by Formula 6 previously described herein. For example, the reactants, reaction conditions and specific reaction details are substantially the same as those previously described herein.

[0305] In the method for preparing the crystalline form II of the compound represented by Formula 1, steps (2), (3), and (4) are substantially the same as steps (a), (b), and (c) of the method for preparing the crystalline form II of the compound represented by Formula 1, which uses the compound represented by Formula 1 as a starting material that can be prepared according to the previously described present disclosure. For example, the reactants, reaction conditions, and specific reaction details are substantially the same as previously described herein.

[0306] In an exemplary embodiment of the invention, the method for preparing crystalline form II of the compound represented by Formula 1 may further include adding ethanol to the compound represented by Formula 1 and concentrating it prior to step (2). In this case, the compound represented by Formula 1 can be prepared by the novel method described herein, wherein the compound represented by Formula 1 may be in an oil state, but is not limited thereto.

[0307] In an exemplary embodiment of the invention, the X-ray powder diffraction pattern and differential scanning calorimetry (DSC) analysis at a heating rate of 10 °C / min are identical to those previously described herein with respect to the crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide of formula 1.

[0308] In this disclosure, a method for preparing the crystalline form III of the compound represented by Formula 1 may include the following steps: (a) Adding an amorphous N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by Formula 1, to a solvent selected from the group consisting of: methyl tert-butyl ether (MTBE), heptane, octane, hexane, pentane, and mixtures thereof; and (b) Obtaining solids from the slurry.

[0309] In an exemplary embodiment of the present invention, in the preparation of the crystalline form III of the compound represented by Formula 1, the solvent in step (a) may be methyl tert-butyl ether (MTBE), heptane, or a mixture thereof.

[0310] In an exemplary embodiment of the present invention, in the preparation of the crystalline form III of the compound represented by Formula 1, the production of the slurry of (a) can take place for 12 hours to 20 days, specifically 12 hours to 7 days, and more specifically 12 hours to 3 days. For example, the production of the slurry of (a) can take place for 12 hours to 36 hours, specifically 15 hours to 30 hours, and even more specifically 20 hours to 27 hours.

[0311] In an exemplary embodiment of the present invention, in a method for preparing the crystalline form III of the compound represented by chemical formula 1, obtaining the solid of (b) may include filtering the slurry obtained in step (a).

[0312] In an exemplary embodiment of the present invention, the generation of the slurry in (a) and the acquisition of the solid in (b) can be carried out at 30°C or lower, specifically 20°C to 30°C, and more specifically 20°C to 25°C.

[0313] In an exemplary embodiment of the present invention, in the method for preparing the crystalline form III of the compound represented by Chemical Formula 1, the compound represented by Chemical Formula 1 as the starting material can be prepared according to a novel method for preparing the compound represented by Chemical Formula 1 described in detail herein, but is not limited thereto. For example, in the method for preparing the crystalline form III, the amorphous form of the compound represented by Chemical Formula 1 as the starting material can be prepared from the compound represented by Chemical Formula 1 prepared by the novel method described herein, or can be prepared according to conventionally known methods.

[0314] More specifically, the crystalline form III of the compound represented by chemical formula 1 can be prepared by methods comprising the following (1) to (4): (1) Prepare compounds represented by chemical formula 1 in situ from compounds represented by chemical formula 6: [Chemical Formula 6] [Chemical Formula 1] ; (2) The compound represented by chemical formula 1 obtained in (1) is vacuum dried to prepare the amorphous form of the compound represented by chemical formula 1; (3) Adding the amorphous form of the compound represented by Formula 1 to a solvent selected from the group consisting of: methyl tert-butyl ether (MTBE), heptane, octane, hexane, pentane, and mixtures thereof; and (4) Obtain solids from the slurry.

[0315] In the method for preparing the crystalline form III of the compound represented by Formula 1, step (1) may be substantially the same as the method for preparing the compound represented by Formula 1 from the compound represented by Formula 6 previously described herein. For example, the reactants, reaction conditions and specific reaction details are substantially the same as those previously described herein.

[0316] In the method for preparing the crystalline form III of the compound represented by Formula 1, steps (3) and (4) may be substantially the same as steps (a) and (b) of the method for preparing the crystalline form III of the compound represented by Formula 1. For example, the reactants, reaction conditions and specific reaction details are substantially the same as those previously described herein.

[0317] In an exemplary embodiment of the invention, the X-ray powder diffraction pattern and differential scanning calorimetry (DSC) analysis at a heating rate of 10 °C / min are identical to those previously described herein with respect to the crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide of formula 1.

[0318] Beneficial effects Compared with conventional preparation methods, the new preparation method of this invention simplifies the synthesis steps, uses readily available reagents and reaction equipment, mild reaction conditions, and efficient process procedures, and does not require column chromatography, enabling mass production. It also has the significantly better stability and economic benefits necessary for mass production.

[0319] Therefore, the new preparation method is extremely efficient because the overall yield of compounds represented by Formula 1 is approximately 60%, which is about 40 times higher than the 1.5% yield of conventional methods. Furthermore, due to the simple post-processing procedure and efficient purification method, compounds of Formula 1 with HPLC purity of 99% or higher can be obtained without column chromatography.

[0320] The crystalline form of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide disclosed herein exhibits excellent long-term and accelerated stability, thermodynamic stability, light stability, and crystallinity stability, and possesses suitable solubility for formulation. Furthermore, due to its low hygroscopicity, the crystalline form maintains a constant concentration even during long-term storage without denaturation due to environmental factors, and it also possesses advantageous characteristics for removing residual solvents.

[0321] Furthermore, the crystalline form of the present invention has excellent storage stability, mechanical stability and flowability, and because of the uniform particles, it does not require a complex process for formulation, and the crystalline form can be easily obtained with high purity and high yield through a simple method.

[0322] Furthermore, the method for preparing the crystalline form according to this disclosure is readily applicable to production (scale-up) and can stably prepare crystals, and is suitable for industrial production, because of the economical preparation process established by the use of inexpensive solvents for production (scale-up). Attached Figure Description

[0323] Figure 1 A view showing reaction formula 2 for preparing the compound of chemical formula 1 according to an embodiment of the present invention.

[0324] Figure 2 , Figure 4 and Figure 6 The results of X-ray powder diffraction (XRPD) analysis of the crystalline form I of the compound represented by chemical formula 1 according to one embodiment of the present invention are shown.

[0325] Figure 3 and Figure 5 The results of differential scanning calorimetry (DSC) thermal analysis of the crystalline form I of the compound represented by chemical formula 1 according to one embodiment of the present invention are shown.

[0326] Figure 7 The results of X-ray powder diffraction (XRPD) analysis of the crystalline form II of the compound represented by chemical formula 1 according to one embodiment of the present invention are shown.

[0327] Figure 8 The results of differential scanning calorimetry (DSC) thermal analysis of the crystalline form II of the compound represented by chemical formula 1 according to one embodiment of the present invention are shown.

[0328] Figure 9 The results of X-ray powder diffraction (XRPD) analysis of the crystalline form III of the compound represented by chemical formula 1 according to one embodiment of the present invention are shown.

[0329] Figure 10 The results of differential scanning calorimetry (DSC) thermal analysis for crystalline form III of the compound represented by chemical formula 1 according to one embodiment of the present invention are shown.

[0330] Figure 11 and Figure 12 The results of X-ray powder diffraction (XRPD) analysis of the amorphous form of the compound represented by chemical formula 1 are shown.

[0331] Figure 13 This displays the results of differential scanning calorimetry (DSC) thermal analysis (thermal analysis graph) of the amorphous form of the compound represented by chemical formula 1 according to one preparation embodiment of the present invention.

[0332] Figure 14 The X-ray powder diffraction (XRPD) analysis results of the crystalline form I of the compound represented by chemical formula 1 according to one embodiment of the present invention are shown (start: 3.0° - end: 39.999° / step: 0.020° - step time: 46.5 s / operation: Strip kAlpha2 0.5000 / background 1.000, 1.000).

[0333] Figure 15 This displays the results of differential scanning calorimetry (DSC) thermal analysis (thermal analysis graph) of crystalline form I of the compound represented by chemical formula 1 according to an embodiment of the present invention.

[0334] Figure 16 The X-ray powder diffraction (XRPD) analysis results of the crystalline form II of the compound represented by chemical formula 1 according to one embodiment of the present invention are shown (start: 3.0° - end: 39.999° / step: 0.020° - step time: 46.5 s / operation: Strip kAlpha2 0.5000 / background 1.000, 1.000).

[0335] Figure 17 This displays the results of differential scanning calorimetry (DSC) thermal analysis (thermal analysis graph) of crystalline form II of the compound represented by chemical formula 1 according to an embodiment of the present invention.

[0336] Figure 18 The X-ray powder diffraction (XRPD) analysis results of the crystalline form III of the compound represented by chemical formula 1 according to one embodiment of the present invention are shown (start: 3.0° - end: 39.999° / step: 0.020° - step time: 46.5 s / operation: Strip kAlpha2 0.5000 / background 1.000, 1.000).

[0337] Figure 19 This displays the results of differential scanning calorimetry (DSC) thermal analysis (thermal analysis graph) of crystalline form III of the compound represented by chemical formula 1 according to an embodiment of the present invention.

[0338] Figure 20 The results of dynamic gas-phase adsorption (DVS) of the crystalline form I of the compound represented by chemical formula 1 according to an embodiment of the present invention are shown.

[0339] Figure 21The results of dynamic gas-phase adsorption (DVS) of the crystalline form II of the compound represented by chemical formula 1 according to an embodiment of the present invention are shown.

[0340] Figure 22 The results of dynamic gas-phase adsorption (DVS) of the crystalline form III of the compound represented by chemical formula 1 according to one embodiment of the present invention are shown.

[0341] Figure 23 The results of dynamic gas-phase adsorption (DVS) of the amorphous form of the compound represented by Formula 1 according to one preparation embodiment of the present invention are shown.

[0342] Figure 24 The compound shown as N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide is represented by chemical formula 1. 1 H NMR results.

[0343] Figure 25 The compound shown as N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide is represented by chemical formula 1. 13 C NMR results. Detailed Implementation

[0344] Implementation Plan Implementation Scheme 1. A method for preparing a compound represented by the following chemical formula 1, the method comprising: Prepare compounds represented by formula 1 from compounds represented by formula 6 in situ: [Chemical Formula 1] [Chemical Formula 6] .

[0345] Implementation Scheme 2. The method according to Implementation Scheme 1, wherein the preparation of the compound represented by chemical formula 1 from the compound represented by chemical formula 6 is carried out in the presence of a base.

[0346] Implementation Scheme 3. The method according to Implementation Scheme 1 or 2, wherein the base comprises imidazole.

[0347] Implementation Scheme 4. The method according to any one of Implementation Schemes 1 to 3, wherein the compound represented by Chemical Formula 1 is prepared by using at least one of the compounds represented by [Chemical Formula A] and [Chemical Formula B] and the compound represented by Chemical Formula 6 as reactants: [Chemical Formula A] [Chemical Formula B] In the above chemical formula B, X1 is F, Cl, Br or I.

[0348] Implementation Scheme 5. The method according to any one of Implementation Schemes 1 to 4, wherein the preparation of the compound represented by Chemical Formula 1 from the compound represented by Chemical Formula 6 comprises: a) Preparation of reaction part 1, which comprises a compound represented by chemical formula A or chemical formula B and a base; and b) Mix reaction portion 1 with reaction portion 2, which contains the compound represented by chemical formula 6, to prepare the compound represented by chemical formula 1: [Chemical Formula A] [Chemical Formula B] In the above chemical formula B, X1 is F, Cl, Br or I.

[0349] Implementation Scheme 6. The method according to any one of Implementation Schemes 1 to 5, wherein step a) is carried out by mixing a mixture containing a base and a solvent with a compound represented by chemical formula A or chemical formula B.

[0350] Implementation Scheme 7. The method according to any one of Implementation Schemes 1 to 6, wherein step a) includes: Preparation of a mixture containing an alkali and a solvent; and A compound represented by chemical formula A or chemical formula B is added to the mixture.

[0351] Implementation Scheme 8. The method according to any one of Implementation Schemes 1 to 7, the method further comprising: cooling the mixture to 0-10°C after preparing the mixture comprising an alkali and a solvent.

[0352] Implementation Scheme 9. The method according to any one of Implementation Schemes 1 to 8 further includes: stirring after adding the compound represented by chemical formula A or chemical formula B to the mixture.

[0353] Implementation Scheme 10. The method according to any one of Implementation Schemes 1 to 9, wherein the reaction portion 2 in step b) comprises a compound represented by chemical formula 6 and a solvent.

[0354] Implementation Scheme 11. The method according to any one of Implementation Schemes 1 to 10, wherein mixing reaction part 2 with reaction part 1 in step b) is performed by adding reaction part 1 to reaction part 2.

[0355] Implementation Scheme 12. The method according to any one of Implementation Schemes 1 to 11, wherein the addition of reaction part 1 to reaction part 2 is carried out at -15°C to 5°C.

[0356] Implementation Scheme 13. The method according to any one of Implementation Schemes 1 to 12 further comprises: heating to a temperature of 20°C to 45°C after complete mixing in step b).

[0357] Implementation Scheme 14. A method for preparing a compound represented by the following chemical formula 6, the method comprising: In the presence of a solvent containing a mixture of C1 to C6 straight-chain or branched alcohols or C1 to C6 straight-chain or branched alcohols and water, the following compounds are prepared from hydrazine (N2H4) or its hydrate and compounds represented by the following chemical formula 5: [Chemical Formula 5] [Chemical Formula 6] In the above chemical formula 5, R is a C1-C6 straight-chain or branched alkyl or benzyl group.

[0358] Implementation Scheme 15. The method according to Implementation Scheme 14, wherein the solvent is methanol or a mixture of methanol and water.

[0359] Implementation Scheme 16. The method according to Implementation Scheme 14 or 15, wherein the volume ratio of alcohol to water is 10:1 to 1:1.

[0360] Implementation Scheme 17. The method according to any one of Implementation Schemes 14 to 16, wherein R is methyl.

[0361] Implementation Scheme 18. A method for preparing a compound represented by chemical formula 5, the method comprising: To prepare the compound represented by chemical formula 5, react the compound represented by chemical formula 3 with the compound represented by chemical formula 4 in the presence of a base: [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] In chemical formulas 3 and 5 above, R is a C1-C6 straight-chain or branched alkyl or benzyl, and in chemical formula 4 above, X is F, Cl, Br or I.

[0362] Implementation Scheme 19. The method according to Implementation Scheme 18, wherein R is methyl and X is Cl.

[0363] Implementation Scheme 20. The method according to Implementation Scheme 18 or 19, wherein the base is triethylamine, N,N-diisopropylethylamine, imidazole, pyridine, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, or a mixture thereof.

[0364] Implementation Scheme 21. The method according to any one of Implementation Schemes 18 to 20, the method further comprising: purifying the compound represented by Chemical Formula 5.

[0365] Implementation Scheme 22. The method according to any one of Implementation Schemes 18 to 21, wherein purification is carried out in a solvent selected from the group consisting of methanol, ethanol, isopropanol, butanol, methyl tert-butyl ether (MTBE), diisopropyl ether, heptane, hexane, and mixtures thereof.

[0366] Implementation Scheme 23. A method for preparing a compound represented by the following chemical formula 3, the method comprising: Compounds represented by chemical formula 8 are prepared from compounds represented by chemical formula 7 using a halogenating agent; and The compound represented by the following chemical formula 8 is reacted with aniline in the presence of a base to prepare the compound represented by the following chemical formula 3: [Chemical Formula 7] [Chemical Formula 8] [Chemical Formula 3] In formulas 3, 7 and 8 above, R is a C1-C6 straight-chain or branched alkyl or benzyl, and in formula 8, X is F, Cl, Br or I.

[0367] Implementation Scheme 24. The method according to Implementation Scheme 23, wherein R is methyl and X is Cl.

[0368] Implementation Scheme 25. The method according to Implementation Scheme 23 or 24, wherein the halogenating agent is iodine, copper iodide, bromine, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), trichloroisocyanuric acid (TCCA), or a mixture thereof.

[0369] Implementation Scheme 26. The method according to Implementation Scheme 24, wherein X in the compound represented by the above chemical formula 8 is Cl, and the halogenating agent is N-chlorosuccinimide (NCS), trichloroisocyanuric acid (TCCA), or a mixture thereof.

[0370] Implementation Scheme 27. The method according to any one of Implementation Schemes 24 to 26, wherein the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine and mixtures thereof.

[0371] Implementation Scheme 28. The method according to any one of Implementation Schemes 24 to 27, wherein the reaction of the compound represented by Formula 8 with aniline is carried out in the presence of potassium bromide, potassium iodide, tetrabutylammonium bromide (TBAB), or a mixture thereof.

[0372] Implementation Scheme 29. A method for preparing a compound represented by the following chemical formula 8a, the method comprising: The following compound, represented by chemical formula 8a, is prepared by using only trichloroisocyanuric acid (TCCA) as the reagent in the compound represented by chemical formula 7: [Chemical Formula 7] [Chemical Formula 8a] In chemical formulas 7 and 8a above, R is a C1-C6 straight-chain alkyl group or benzyl group.

[0373] Implementation Scheme 30. A method for preparing a compound represented by chemical formula 3, the method comprising: The compound represented by the following chemical formula 8 is reacted with aniline in the presence of a base to prepare the compound represented by the following chemical formula 3: [Chemical Formula 3] [Chemical Formula 8] In chemical formulas 3 and 8 above, R is a C1-C6 straight-chain or branched alkyl or benzyl, and in chemical formula 8 above, X is F, Cl, Br or I.

[0374] Implementation Scheme 31. The method according to Implementation Scheme 30, wherein the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine and mixtures thereof.

[0375] Implementation Scheme 32. The method according to Implementation Scheme 30 or 31, wherein the reaction of the compound represented by Formula 8 with aniline is carried out in the presence of potassium bromide, potassium iodide, tetrabutylammonium bromide (TBAB) or a mixture thereof.

[0376] Implementation Scheme 33. A method for preparing a compound represented by chemical formula 3, the method comprising: Prepare compounds represented by chemical formula 3 from compounds represented by chemical formula 2 in the presence of aniline and a reducing agent: [Chemical Formula 2] [Chemical Formula 3] In chemical formula 2 or chemical formula 3 above, R is a C1-C6 straight-chain or branched alkyl or benzyl.

[0377] Implementation Scheme 34. The method according to Implementation Scheme 33, wherein the preparation of the compound represented by chemical formula 3 from the compound represented by chemical formula 2 comprises: Preparation of a mixture comprising the compound represented by chemical formula 2 and aniline; and The mixture is then reacted with a reducing agent.

[0378] Implementation Scheme 35. The method according to Implementation Scheme 33 or 34, wherein the preparation of the compound represented by Chemical Formula 3 from the compound represented by Chemical Formula 2 comprises: Preparation reaction part 1, comprising a compound represented by chemical formula 2, aniline, and a solvent; and Mix reaction part 1 with reaction part 2, which contains reducing agent and solvent.

[0379] Implementation Scheme 36. The method according to any one of Implementation Schemes 33 to 35, wherein the reducing agent comprises one or more of the following: sodium borohydride (NaBH4), sodium cyanoborohydride (NaBH3CN) and sodium triacetoxyborohydride (NaBH(OAc)3).

[0380] Implementation Scheme 37. The method according to any one of Implementation Schemes 33 to 36, wherein the preparation of the compound represented by Chemical Formula 3 from the compound represented by Chemical Formula 2 is carried out in the presence of an acid.

[0381] Implementation Scheme 38. A method for preparing a compound represented by the following chemical formula 1, the method comprising: 1) Prepare compounds represented by chemical formula 8 from compounds represented by chemical formula 7 using a halogenating agent; 2) React the compound represented by the following chemical formula 8 with aniline in the presence of a base to prepare the compound represented by chemical formula 3; 3) React the compound represented by the following chemical formula 3 with the compound represented by the following chemical formula 4 in the presence of a base to obtain the compound represented by the following chemical formula 5; 4) Reacting hydrazine or its hydrate with a compound represented by chemical formula 5 to obtain a compound represented by chemical formula 6; and 5) Prepare compounds represented by formula 1 in situ from compounds represented by formula 6 below: [Chemical Formula 1] [Chemical Formula 3] (In the above chemical formula 3, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X is F, Cl, Br or I) [Chemical Formula 5] (In the above chemical formula 5, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 6] [Chemical Formula 7] (In the above chemical formula 7, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 8] (In the above chemical formula 8, R is a C1-C6 straight-chain or branched alkyl or benzyl, and X is F, Cl, Br or I).

[0382] Implementation Scheme 39. A method for preparing a compound represented by the following chemical formula 1, the method comprising: 1) Prepare the compound represented by the following chemical formula 3 from the compound represented by the following chemical formula 2 in the presence of aniline and a reducing agent; 2) React the compound represented by the following chemical formula 3 with the compound represented by the following chemical formula 4 in the presence of a base to obtain the compound represented by the following chemical formula 5; 3) Reacting hydrazine or its hydrate with a compound represented by chemical formula 5 to obtain a compound represented by chemical formula 6; and 4) Prepare compounds represented by formula 1 in situ from compounds represented by formula 6: [Chemical Formula 1] [Chemical Formula 2] (In chemical formula 2 above, R is a C1-C6 alkyl or benzyl) [Chemical Formula 3] (Whereinafter, in chemical formula 3 above, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X can be F, Cl, Br or I) [Chemical Formula 5] (Wherein, in the above chemical formula 5, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 6] .

[0383] Implementation Scheme 40. A method for preparing a compound represented by the following chemical formula 1, the method comprising: 1) Reaction of hydrazine or its hydrate with a compound represented by chemical formula 5 to obtain a compound represented by chemical formula 6; and 2) Prepare compounds represented by formula 1 in situ from compounds represented by formula 6 below: [Chemical Formula 1] [Chemical Formula 5] (In the above chemical formula 5, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 6] .

[0384] Implementation Scheme 41. The method according to Implementation Scheme 40, wherein the method for preparing the compound represented by the above chemical formula 5 comprises: To prepare the compound represented by chemical formula 5, react the compound represented by chemical formula 3 with the compound represented by chemical formula 4 in the presence of a base: [Chemical Formula 3] (In the above chemical formula 3, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X is F, Cl, Br or I).

[0385] Implementation Scheme 42. The method according to Implementation Scheme 40 or 41, wherein the method for preparing the compound represented by Formula 5 comprises: The compound represented by chemical formula 8 is reacted with aniline in the presence of a base to prepare the compound represented by chemical formula 3; and To prepare the compound represented by chemical formula 5, react the compound represented by chemical formula 3 with the compound represented by chemical formula 4 in the presence of a base: [Chemical Formula 3] (In the above chemical formula 3, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X is F, Cl, Br or I) [Chemical Formula 8] (In the above chemical formula 8, R is a C1-C6 straight-chain or branched alkyl or benzyl, and X is F, Cl, Br or I).

[0386] Implementation Scheme 43. The method according to any one of Implementation Schemes 40 to 42, wherein the method for preparing the compound represented by Formula 5 comprises: The following compounds, represented by chemical formula 8, are prepared from compounds represented by chemical formula 7 using halogenating reagents; The compound represented by chemical formula 8 is reacted with aniline in the presence of a base to prepare the compound represented by chemical formula 3. To prepare the compound represented by chemical formula 5, react the compound represented by chemical formula 3 with the compound represented by chemical formula 4 in the presence of a base: [Chemical Formula 3] (In the above chemical formula 3, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X is F, Cl, Br or I) [Chemical Formula 7] (In the above chemical formula 7, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 8] (In the above chemical formula 8, R is a C1-C6 straight-chain or branched alkyl or benzyl, and X is F, Cl, Br or I).

[0387] Implementation Scheme 44. The method according to any one of Implementation Schemes 40 to 43, wherein the method for preparing the compound represented by Formula 5 comprises: Compounds of formula 3 are prepared from compounds of formula 2 in the presence of aniline and a reducing agent; and The compound represented by chemical formula 3 is reacted with the compound represented by chemical formula 4 in the presence of a base to prepare the compound represented by chemical formula 5: [Chemical Formula 2] (In chemical formula 2 above, R is a C1-C6 alkyl or benzyl) [Chemical Formula 3] (In the above chemical formula 3, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X is F, Cl, Br or I).

[0388] Implementation Scheme 45. A crystalline form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by the following chemical formula 1, wherein the X-ray powder diffraction pattern includes diffraction peaks at three or more diffraction angles (2θ ± 0.2°) selected from 7.85°, 14.54°, 17.14°, 18.09°, 19.62°, 21.41°, and 23.58°: [Chemical Formula 1] .

[0389] Implementation Scheme 46. Crystallization form I according to Implementation Scheme 45, wherein the X-ray powder diffraction pattern further includes diffraction peaks at one or more diffraction angles selected from the group consisting of: 15.64°, 17.55°, 20.78°, 21.04°, 23.27°, 24.24° and 30.38° (2θ ± 0.2°).

[0390] Implementation Scheme 47. Crystalline form I according to Implementation Scheme 45 or 46, wherein the X-ray powder diffraction pattern further includes one or more diffraction peaks selected from the group consisting of diffraction angles (2θ ± 0.2°) of 9.40°, 11.62°, 11.77°, 13.49°, 14.92°, 15.64°, 17.55°, 18.82°, 20.78°, 21.04°, 22.69°, 23.27°, 24.24°, 26.35°, 27.58°, 28.91°, 30.38°, 33.57°, and 36.74°.

[0391] Implementation Scheme 48. Crystallization form I according to any one of Implementation Schemes 45 to 47, wherein during differential scanning calorimetry (DSC) analysis, when the heating rate is 10 °C / min, crystallization form I has an endothermic peak between 132 °C (±0.5 °C) and 143 °C (±0.5 °C).

[0392] Implementation Scheme 49. Crystallization form I according to any one of Implementation Schemes 45 to 48, wherein during differential scanning calorimetry (DSC) analysis, crystallization form I has an endothermic peak at 138 °C (±3 °C) when the heating rate is 10 °C / min.

[0393] Implementation Scheme 50. A crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by the following chemical formula 1, wherein the X-ray powder diffraction pattern includes three or more diffraction peaks at diffraction angles (2θ ± 0.2°) selected from 7.83°, 12.22°, 19.02°, 19.67°, 21.40°, 22.35°, and 26.44°: [Chemical Formula 1] .

[0394] Implementation Scheme 51. According to the crystalline form II of Implementation Scheme 50, wherein the X-ray powder diffraction pattern further includes diffraction peaks at one or more diffraction angles selected from the group consisting of: 11.41°, 11.78°, 13.28°, 15.70°, 16.64°, 17.48°, 18.28°, 19.37°, 20.71°, 24.58°, 27.35° and 33.73° (2θ ± 0.2°).

[0395] Implementation Scheme 52. Crystallization form II according to Implementation Scheme 50 or 51, wherein the X-ray powder diffraction pattern further includes diffraction peaks at one or more diffraction angles selected from the group consisting of: 10.72°, 10.92°, 11.41°, 11.78°, 13.28°, 15.70°, 16.64°, 16.97°, 17.48°, 18.28°, 19.37°, 20.71°, 24.58°, 27.35°, 30.49°, 32.19°, 33.73°, 35.44° and 35.91° (2θ ± 0.2°).

[0396] Implementation Scheme 53. Crystallization form II according to any one of Implementation Schemes 50 to 52, wherein during differential scanning calorimetry (DSC) analysis, when the heating rate is 10 °C / min, crystallization form II has an endothermic peak in the range of 124 °C (±0.5 °C) to 138 °C (±0.5 °C).

[0397] Implementation Scheme 54. Crystallization form II according to any one of Implementation Schemes 50 to 53, wherein during differential scanning calorimetry (DSC) analysis, crystallization form II has an endothermic peak at 130 °C (±5 °C) when the heating rate is 10 °C / min.

[0398] Implementation Scheme 55. A crystalline form III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by the following chemical formula 1, wherein the X-ray powder diffraction pattern includes diffraction peaks at three or more diffraction angles (2θ ± 0.2°) selected from 8.75°, 10.98°, 12.44°, 16.86°, 22.92° and 28.49°: [Chemical Formula 1] .

[0399] Implementation Scheme 56. Crystallization form III according to Implementation Scheme 55, wherein the X-ray powder diffraction pattern further includes diffraction peaks at one or more diffraction angles selected from the group consisting of: 17.48°, 19.95°, 20.49°, 20.79°, 21.55°, 21.87°, 22.07°, 24.04°, 24.72°, 24.99° and 26.30° (2θ ± 0.2°).

[0400] Implementation Scheme 57. Crystallization form III according to Implementation Scheme 55 or 56, wherein the X-ray powder diffraction pattern further includes diffraction peaks at one or more diffraction angles selected from the group consisting of: 14.28°, 15.45°, 17.48°, 18.49°, 18.77°, 19.95°, 20.49°, 20.79°, 21.55°, 21.87°, 22.07°, 24.04°, 24.72°, 24.99°, 26.30°, 29.22°, 30.20°, 31.40°, 34.10°, 37.13°, and 38.86° (2θ ± 0.2°).

[0401] Implementation Scheme 58. Crystallization form III according to any one of Implementation Schemes 55 to 57, wherein during differential scanning calorimetry (DSC) analysis, crystallization form III has an endothermic peak at 120 °C (±0.5 °C) to 130 °C (±0.5 °C) at a heating rate of 10 °C / min.

[0402] Implementation Scheme 59. Crystallization form III according to any one of Implementation Schemes 55 to 57, wherein during differential scanning calorimetry (DSC) analysis, crystallization form III has an endothermic peak at 125 °C (±5 °C) when the heating rate is 10 °C / min.

[0403] Implementation Scheme 60. A method for preparing crystalline form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, of the compound represented by the following chemical formula 1, the method comprising: (a) Dissolving N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by Formula 1, in a solvent selected from the group consisting of: ethyl acetate, ethanol, methanol, isopropanol, butanol, methyl tert-butyl ether (MTBE), diisopropyl ether, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone, dichloromethane, dimethylformamide, N-methyl-2-pyrrolidone, toluene, tetrahydrofuran, heptane, hexane, acetonitrile, and mixtures thereof; and (b) The formation of a solid from the solution: [Chemical Formula 1] .

[0404] Implementation Scheme 61. The method according to Implementation Scheme 60, wherein in step (a), the solvent is one or more alcohols selected from ethanol, methanol, isopropanol and butanol; ethyl acetate; or a mixture of said alcohol and ethyl acetate.

[0405] Implementation Scheme 62. The method according to Implementation Scheme 60 or 61, wherein obtaining the solution (a) comprises: (a1) Adding the compound represented by chemical formula 1 to a solvent to obtain a mixture; and (a2) Heat the mixture to a temperature exceeding 40°C.

[0406] Implementation Scheme 63. The method according to any one of Implementation Schemes 60 to 62, wherein the generation of the solid in step (b) further comprises: (b1) Additionally, one or more alcohols selected from ethanol, methanol, isopropanol, and butanol are added to the solution of step (a); and (b2) Stir the mixture after adding the alcohol from step (b1).

[0407] Implementation Scheme 64. The method according to any one of Implementation Schemes 60 to 63, wherein steps (b1) and (b2) are performed at a temperature exceeding 40°C.

[0408] Implementation Scheme 65. The method according to any one of Implementation Schemes 60 to 64 further includes, prior to performing step (a), The compound represented by Formula 1 is dissolved in dichloromethane, and then subjected to primary concentration, thereby producing a concentrated residue; and Ethyl acetate was added to the concentrated residue and then subjected to secondary concentration.

[0409] Implementation Scheme 66. According to the method of Implementation Scheme 60, the compound represented by Formula 1 is prepared in situ from the compound represented by Formula 6: [Chemical Formula 6] .

[0410] Implementation Scheme 67. A method for preparing the crystalline form II of compound N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by the following chemical formula 1, the method comprising: (a) Adding N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by the following chemical formula 1, to a solvent selected from the group consisting of methanol, ethanol, isopropanol, butanol, diisopropyl ether, tetrahydrofuran, heptane, hexane, and mixtures thereof; (b) Heating the mixture to 40°C or lower to obtain a solution; and (c) A solid is produced from the solution at a temperature of 40°C or lower: [Chemical Formula 1] .

[0411] Implementation Scheme 68. The method according to Implementation Scheme 67, wherein in step (a), the solvent is ethanol, isopropanol, or a mixture thereof.

[0412] Implementation Scheme 69. The method according to Implementation Scheme 67 or 68 further includes, prior to performing step (a), The compound represented by chemical formula 1 is dissolved in dichloromethane and then subjected to primary concentration, thereby producing a concentrated residue; Ethanol was added to the concentrated residue and secondary concentration was performed.

[0413] Implementation Scheme 70. According to the method of any one of Implementation Schemes 67 to 69, the compound represented by Formula 1 is prepared in situ from the compound represented by Formula 6: [Chemical Formula 1] [Chemical Formula 6] .

[0414] Implementation Scheme 71. A method for preparing the crystalline form III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is a compound represented by the following chemical formula 1, the method comprising: (a) Adding an amorphous N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by Formula 1, to a solvent selected from the group consisting of: methyl tert-butyl ether (MTBE), heptane, octane, hexane, pentane, and mixtures thereof; and (b) Obtaining solids from the slurry: [Chemical Formula 1] .

[0415] Implementation Scheme 72. The method according to Implementation Scheme 71, wherein the solvent in step (a) is methyl tert-butyl ether (MTBE), heptane, or a mixture thereof.

[0416] Implementation Scheme 73. The method according to Implementation Scheme 71 or 72, wherein (a) the slurry is produced for 12 hours to 20 days.

[0417] Implementation Scheme 74. The method according to any one of Implementation Schemes 71 to 73, wherein (b) obtaining the solids further comprises filtering the slurry.

[0418] Implementation Scheme 75. The method according to Implementation Schemes 71 to 74, wherein (a) the generation of slurry and (b) the acquisition of solids are carried out at a temperature of 30°C or lower.

[0419] Implementation Scheme 76. The method according to Implementation Schemes 71 to 75, wherein the preparation of the amorphous form of the compound represented by Formula 1 comprises: In-situ preparation of compounds represented by formula 1 from compounds represented by formula 6; and The compound represented by chemical formula 1 was subjected to vacuum drying: [Chemical Formula 1] [Chemical Formula 6] .

[0420] Implementation Scheme A1. A method for preparing a compound represented by the following chemical formula 1, the method comprising: Prepare compounds represented by formula 1 from compounds represented by formula 6 in situ: [Chemical Formula 1] [Chemical Formula 6] .

[0421] Implementation Scheme A2. The method according to Implementation Scheme A1, wherein the preparation of the compound represented by chemical formula 1 from the compound represented by chemical formula 6 is carried out in the presence of a base.

[0422] Implementation scheme A3. The method according to implementation scheme A2, wherein the base contains imidazole.

[0423] Implementation Scheme A4. The method according to any one of Implementation Schemes A1 to A3, wherein the compound represented by Chemical Formula 1 is prepared by using at least one of the compounds represented by [Chemical Formula A] and [Chemical Formula B] and the compound represented by Chemical Formula 6 as reactants: [Chemical Formula A] [Chemical Formula B] In the above chemical formula B, X1 is F, Cl, Br or I.

[0424] Implementation Scheme A5. The method according to any one of Implementation Schemes A1 to A3, wherein the preparation of the compound represented by Chemical Formula 1 from the compound represented by Chemical Formula 6 comprises: a) Preparation of reaction part 1, which comprises a compound represented by chemical formula A or chemical formula B and a base; and b) Mix reaction portion 1 with reaction portion 2, which contains the compound represented by chemical formula 6, to prepare the compound represented by chemical formula 1: [Chemical Formula A] [Chemical Formula B] In the above chemical formula B, X1 is F, Cl, Br or I.

[0425] Implementation Scheme A6. The method according to Implementation Scheme A5, wherein step a) is carried out by mixing a mixture containing a base and a solvent with a compound represented by chemical formula A or chemical formula B.

[0426] Implementation Plan A7. According to the method of Implementation Plan A5 or A6, step a) includes: Prepare a mixture containing an alkali and a solvent; Cool the mixture to 0°C to 10°C; and A compound represented by chemical formula A or chemical formula B is added to a cooled mixture.

[0427] Implementation Scheme A8. The method according to any one of Implementation Schemes A5 to A7 further comprises: stirring after adding the compound represented by chemical formula A or chemical formula B to the mixture.

[0428] Implementation Plan A9. The method according to any one of Implementation Plans A5 to A8, wherein step b) includes: Preparation reaction part 2, which comprises a compound represented by chemical formula 6 and a solvent; and This causes reaction part 2 to react with reaction part 1.

[0429] Implementation scheme A10. The method according to any one of implementation schemes A5 to A9, wherein the reaction between reaction part 2 and reaction part 1 in step b) is carried out by adding reaction part 1 to reaction part 2.

[0430] Implementation Scheme A11. The method according to Implementation Scheme A10, wherein the addition of reaction part 1 to reaction part 2 is carried out at -15°C to 5°C.

[0431] Implementation scheme A12. The method according to implementation scheme A10 or A11 further includes: heating to a temperature of 20°C to 45°C after complete addition in step b).

[0432] Implementation Scheme A13. A method for preparing a compound represented by the following chemical formula 6, the method comprising: In the presence of a solvent comprising a mixture of C1 to C6 straight-chain or branched alcohols or C1 to C6 straight-chain or branched alcohols and water, the following compounds represented by chemical formula 5 are prepared from hydrazine or its hydrates and the compounds represented by chemical formula 5: [Chemical Formula 5] [Chemical Formula 6] In the above chemical formula 5, R is a C1-C6 straight-chain or branched alkyl or benzyl group.

[0433] Implementation Scheme A14. The method according to Implementation Scheme A13, wherein the solvent is methanol or a mixture of methanol and water.

[0434] Implementation Scheme A15. The method according to Implementation Scheme A13 or 14, wherein the volume ratio of alcohol to water is 10:1 to 1:1.

[0435] Implementation Scheme A16. A method for preparing a compound represented by chemical formula 5, the method comprising: To prepare the compound represented by chemical formula 5, react the compound represented by chemical formula 3 with the compound represented by chemical formula 4 in the presence of a base: [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] In chemical formulas 3 and 5 above, R is a C1-C6 straight-chain or branched alkyl or benzyl, and in chemical formula 4 above, X is F, Cl, Br or I.

[0436] Implementation scheme A17. The method according to implementation scheme A16, wherein R is methyl and X is Cl.

[0437] Implementation Scheme A18. The method according to Implementation Scheme A16 or A17, wherein the base is triethylamine, N,N-diisopropylethylamine, imidazole, pyridine, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, or a mixture thereof.

[0438] Implementation Scheme A19. The method according to any one of Implementation Schemes A16 to A18, the method further comprising: purifying the compound represented by Chemical Formula 5.

[0439] Implementation Scheme A20. The method according to Implementation Scheme A19, wherein purification is carried out in a solvent selected from the group consisting of: methanol, ethanol, isopropanol, butanol, methyl tert-butyl ether (MTBE), diisopropyl ether, heptane, hexane, and mixtures thereof.

[0440] Implementation Scheme A21. A method for preparing a compound represented by the following chemical formula 3, the method comprising: Compounds represented by chemical formula 8 are prepared from compounds represented by chemical formula 7 using a halogenating agent; and The compound represented by the following chemical formula 8 is reacted with aniline in the presence of a base to prepare the compound represented by the following chemical formula 3: [Chemical Formula 7] [Chemical Formula 8] [Chemical Formula 3] In formulas 3, 7 and 8 above, R is a C1-C6 straight-chain or branched alkyl or benzyl, and in formula 8, X is F, Cl, Br or I.

[0441] Implementation Scheme A22. The method according to Implementation Scheme A21, wherein the halogenating agent is iodine, copper iodide, bromine, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), trichloroisocyanuric acid (TCCA), or a mixture thereof.

[0442] Implementation Scheme A23. The method according to Implementation Scheme A21 or A22, wherein X in the compound represented by the above chemical formula 8 is Cl, and the halogenating agent is N-chlorosuccinimide (NCS), trichloroisocyanuric acid (TCCA), or a mixture thereof.

[0443] Implementation Scheme A24. The method according to any one of Implementation Schemes A21 to A23, wherein the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and mixtures thereof.

[0444] Implementation Scheme A25. The method according to any one of Implementation Schemes A21 to A24, wherein the reaction of the compound represented by Formula 8 with aniline is carried out in the presence of potassium bromide, potassium iodide, tetrabutylammonium bromide (TBAB), or a mixture thereof.

[0445] Implementation Scheme A26. A method for preparing a compound represented by the following chemical formula 8a, the method comprising: The following compound represented by chemical formula 8a was prepared by using only trichloroisocyanuric acid (TCCA) as a reagent in the compound represented by chemical formula 7: [Chemical Formula 7] [Chemical Formula 8a] In the above chemical formulas 7 and 8a, R is a C1-C6 straight-chain alkyl group or benzyl group.

[0446] Implementation Scheme A27. A method for preparing a compound represented by chemical formula 3, the method comprising: The compound represented by the following chemical formula 8 is reacted with aniline in the presence of a base to prepare the compound represented by the following chemical formula 3: [Chemical Formula 3] [Chemical Formula 8] In the above chemical formulas 3 and 8, R is a C1-C6 straight-chain or branched alkyl or benzyl group.

[0447] Implementation Scheme A28. The method according to Implementation Scheme A27, wherein the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine and mixtures thereof.

[0448] Implementation Scheme A29. The method according to Implementation Scheme A27 or A28, wherein the reaction of the compound represented by Formula 8 with aniline is carried out in the presence of potassium bromide, potassium iodide, tetrabutylammonium bromide (TBAB) or a mixture thereof.

[0449] Implementation Scheme A30. A method for preparing a compound represented by chemical formula 3, the method comprising: Prepare compounds represented by chemical formula 3 from compounds represented by chemical formula 2 in the presence of aniline and a reducing agent: [Chemical Formula 2] [Chemical Formula 3] In the above chemical formula 2 or chemical formula 3, R is a C1-C6 straight-chain or branched alkyl or benzyl.

[0450] Implementation Scheme A31. The method according to Implementation Scheme A30, wherein the preparation of the compound represented by chemical formula 3 from the compound represented by chemical formula 2 comprises: Preparation of a mixture comprising a compound of formula 2 and aniline; and The mixture is then reacted with a reducing agent.

[0451] Implementation Scheme A32. The method according to Implementation Scheme A30 or A31, wherein the preparation of the compound represented by Chemical Formula 3 from the compound represented by Chemical Formula 2 comprises: Preparation reaction part 1, comprising a compound represented by chemical formula 2, aniline, and a solvent; and Reaction part 1 is made to react with reaction part 2, which contains a reducing agent and a solvent.

[0452] Implementation Scheme A33. The method according to any one of Implementation Schemes A30 to A32, wherein the reducing agent comprises one or more of the following: sodium borohydride (NaBH4), sodium cyanoborohydride (NaBH3CN) and sodium triacetoxyborohydride (NaBH(OAc)3).

[0453] Implementation Scheme A34. The method according to any one of Implementation Schemes A30 to A33, wherein the preparation of the compound represented by chemical formula 3 from the compound represented by chemical formula 2 is carried out in the presence of an acid.

[0454] Implementation Scheme A35. A method for preparing a compound represented by the following chemical formula 1, the method comprising: 1) Prepare compounds represented by chemical formula 8 from compounds represented by chemical formula 7 by using halogenating reagents; 2) React the compound represented by the following chemical formula 8 with aniline in the presence of a base to prepare the compound represented by chemical formula 3; 3) React the compound represented by the following chemical formula 3 with the compound represented by the following chemical formula 4 in the presence of a base to obtain the compound represented by the following chemical formula 5; 4) Reacting hydrazine or its hydrate with a compound represented by chemical formula 5 to obtain a compound represented by chemical formula 6; and 5) Prepare compounds represented by formula 1 in situ from compounds represented by formula 6 below: [Chemical Formula 1] [Chemical Formula 3] (Whereinafter, in chemical formula 3 above, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X is F, Cl, Br or I) [Chemical Formula 5] (Wherein, in the above chemical formula 5, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 6] [Chemical Formula 7] (Wherein, in the above chemical formula 7, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 8] (In the above chemical formula 8, R is a C1-C6 straight-chain or branched alkyl or benzyl, and X is F, Cl, Br or I) Implementation Scheme A36. A method for preparing a compound represented by the following chemical formula 1, the method comprising: 1) Prepare the compound represented by the following chemical formula 3 from the compound represented by the following chemical formula 2 in the presence of aniline and a reducing agent; 2) React the compound represented by the following chemical formula 3 with the compound represented by the following chemical formula 4 in the presence of a base to obtain the compound represented by the following chemical formula 5; 3) Reacting hydrazine or its hydrate with a compound represented by chemical formula 5 to obtain a compound represented by chemical formula 6; and 4) Prepare compounds represented by formula 1 in situ from compounds represented by formula 6: [Chemical Formula 1] [Chemical Formula 2] (Wherein, in chemical formula 2 above, R is a C1-C6 alkyl or benzyl) [Chemical Formula 3] (Whereinafter, in chemical formula 3 above, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X can be F, Cl, Br or I) [Chemical Formula 5] (Wherein, in the above chemical formula 5, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 6] .

[0455] Implementation Scheme A37. A method for preparing a compound represented by the following chemical formula 1, the method comprising: 1) Reaction of hydrazine or its hydrate with a compound represented by chemical formula 5 to obtain a compound represented by chemical formula 6; and 2) Prepare compounds represented by formula 1 in situ from compounds represented by formula 6 below: [Chemical Formula 1] [Chemical Formula 5] (Wherein, in the above chemical formula 5, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 6] .

[0456] Implementation Scheme A38. The method according to Implementation Scheme 37, wherein the method for preparing the compound represented by the above chemical formula 5 comprises: To prepare the compound represented by chemical formula 5, react the compound represented by chemical formula 3 with the compound represented by chemical formula 4 in the presence of a base: [Chemical Formula 3] (Whereinafter, in chemical formula 3 above, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X is F, Cl, Br or I).

[0457] Implementation Scheme A39. The method according to Implementation Scheme A37, wherein the method for preparing the compound represented by Chemical Formula 5 comprises: The compound represented by chemical formula 8 is reacted with aniline in the presence of a base to prepare the compound represented by chemical formula 3; and To prepare the compound represented by chemical formula 5, react the compound represented by chemical formula 3 with the compound represented by chemical formula 4 in the presence of a base: [Chemical Formula 3] (Whereinafter, in chemical formula 3 above, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X is F, Cl, Br or I) [Chemical Formula 8] (In the above chemical formula 8, R is a C1-C6 straight-chain or branched alkyl or benzyl, and X is F, Cl, Br or I).

[0458] Implementation Scheme A40. The method according to Implementation Scheme A37, wherein the method for preparing the compound represented by chemical formula 5 comprises: Compounds represented by chemical formula 8 are prepared from compounds represented by chemical formula 7 using halogenating reagents; The compound represented by chemical formula 8 is reacted with aniline in the presence of a base to prepare the compound represented by chemical formula 3. To prepare the compound represented by chemical formula 5, react the compound represented by chemical formula 3 with the compound represented by chemical formula 4 in the presence of a base: [Chemical Formula 3] (Whereinafter, in chemical formula 3 above, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X is F, Cl, Br or I) [Chemical Formula 7] (Wherein, in the above chemical formula 7, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 8] (In the above chemical formula 8, R is a C1-C6 straight-chain or branched alkyl or benzyl, and X is F, Cl, Br or I).

[0459] Implementation Scheme A41. The method according to Implementation Scheme A37, wherein the method for preparing the compound represented by chemical formula 5 comprises: Compounds of formula 3 are prepared from compounds of formula 2 in the presence of aniline and a reducing agent; and The compound represented by chemical formula 3 is reacted with the compound represented by chemical formula 4 in the presence of a base to prepare the compound represented by chemical formula 5: [Chemical Formula 2] (Wherein, in chemical formula 2 above, R is a C1-C6 alkyl or benzyl) [Chemical Formula 3] (Whereinafter, in chemical formula 3 above, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X is F, Cl, Br or I).

[0460] Implementation Scheme B1. A crystalline form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by the following chemical formula 1, wherein the X-ray powder diffraction pattern includes diffraction peaks at three or more diffraction angles (2θ ± 0.2°) selected from 7.83°, 14.52°, 17.11°, 18.08°, 19.59°, 21.41°, and 23.56°: [Chemical Formula 1] .

[0461] Implementation Scheme B2. Crystallization form I according to Implementation Scheme B1, wherein the X-ray powder diffraction pattern further includes diffraction peaks at one or more diffraction angles selected from the group consisting of: 15.64°, 17.54°, 20.77°, 21.04°, 23.26°, 24.23° and 30.37° (2θ ± 0.2°).

[0462] Implementation Scheme B3. According to the crystalline form I of Implementation Scheme B1, wherein the X-ray powder diffraction pattern further includes one or more diffraction peaks selected from the group consisting of diffraction angles (2θ ± 0.2°) of 9.40°, 11.60°, 11.78°, 13.49°, 14.92°, 15.64°, 17.54°, 18.82°, 20.77°, 21.04°, 22.68°, 23.26°, 24.23°, 26.36°, 27.55°, 28.89°, 30.37°, 33.57° and 36.71°.

[0463] Implementation Scheme B4. Crystallization form I according to any one of Implementation Schemes B1 to B3, wherein during differential scanning calorimetry (DSC) analysis, when the heating rate is 10 °C / min, crystallization form I has an endothermic peak between 134 °C (±0.5 °C) and 142 °C (±0.5 °C).

[0464] Implementation scheme B5. Crystallization form I according to any one of implementation schemes B1 to B4, wherein during differential scanning calorimetry (DSC) analysis, crystallization form I has an endothermic peak at 138 °C (±3 °C) when the heating rate is 10 °C / min.

[0465] Implementation Scheme B6. Crystallization form I according to any one of Implementation Schemes B1 to B5, wherein during differential scanning calorimetry (DSC) analysis, when the heating rate is 10 °C / min, crystallization form I has an endothermic peak at an initial temperature of 134.64 °C (±0.5 °C) and a temperature of 138.27 °C (±0.5 °C).

[0466] Implementation Scheme B7. A crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by the following chemical formula 1, wherein the X-ray powder diffraction pattern includes three or more diffraction peaks at diffraction angles (2θ ± 0.2°) selected from 7.83°, 12.22°, 19.02°, 19.67°, 21.39°, 22.35°, and 26.42°: [Chemical Formula 1] .

[0467] Implementation Scheme B8. Crystallization form II according to Implementation Scheme B7, wherein the X-ray powder diffraction pattern further includes diffraction peaks at one or more diffraction angles selected from the group consisting of: 11.39°, 11.77°, 13.26°, 15.72°, 16.60°, 18.27°, 19.35°, 20.67°, 24.56°, 27.34° and 33.72° (2θ ± 0.2°).

[0468] Implementation Scheme B9. Crystallization form II according to Implementation Scheme B7, wherein the X-ray powder diffraction pattern further includes diffraction peaks at one or more diffraction angles selected from the group consisting of: 10.68°, 10.88°, 11.39°, 11.77°, 13.26°, 15.72°, 16.60°, 16.95°, 17.48°, 18.27°, 19.35°, 20.67°, 21.59°, 24.56°, 27.34°, 30.49°, 32.17°, 33.72°, 35.45° and 35.94° (2θ ± 0.2°).

[0469] Implementation Scheme B10. Crystallization form II according to any one of Implementation Schemes B7 to B9, wherein during differential scanning calorimetry (DSC) analysis, crystallization form II has an endothermic peak at 125 °C (±0.5 °C) to 135 °C (±0.5 °C) at a heating rate of 10 °C / min.

[0470] Implementation scheme B11. Crystallization form II according to any one of implementation schemes B7 to B10, wherein during differential scanning calorimetry (DSC) analysis, crystallization form II has an endothermic peak at 130 °C (±5 °C) when the heating rate is 10 °C / min.

[0471] Implementation Scheme B12. Crystallization form II according to any one of Implementation Schemes B7 to B11, wherein during differential scanning calorimetry (DSC) analysis, at a heating rate of 10 °C / min, crystallization form II has an endothermic peak at an initial temperature of 125.61 °C (±0.5 °C) and a temperature of 130.43 °C (±0.5 °C).

[0472] Implementation Scheme B13. A method for preparing crystalline form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, of the compound represented by the following chemical formula 1, the method comprising: (a) A solution is obtained by dissolving N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by Formula 1, in a solvent selected from the group consisting of: ethyl acetate, ethanol, methanol, isopropanol, butanol, methyl tert-butyl ether (MTBE), diisopropyl ether, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone, dichloromethane, dimethylformamide, N-methyl-2-pyrrolidone, toluene, tetrahydrofuran, heptane, hexane, acetonitrile, and mixtures thereof; and (b) The formation of a solid from the solution: [Chemical Formula 1] .

[0473] Implementation Scheme B14. The method according to Implementation Scheme B13, wherein in step (a), the solvent is one or more alcohols selected from ethanol, methanol, isopropanol and butanol; ethyl acetate; or a mixture of said alcohol and ethyl acetate.

[0474] Implementation Scheme B15. According to the method of Implementation Scheme B14 or 15, the obtaining of said solution (a) comprises: (a1) Obtaining a mixture by adding a compound represented by chemical formula 1 to a solvent; and (a2) Heat the mixture to a temperature exceeding 40°C.

[0475] Implementation Scheme B16. The method according to any one of Implementation Schemes B13 to B15, wherein the solid generation in step (b) further comprises: (b1) Additionally, one or more alcohols selected from ethanol, methanol, isopropanol, and butanol are added to the solution of step (a); and (b2) Stir the mixture after adding the alcohol from step (b1).

[0476] Implementation Scheme B17. The method according to Implementation Scheme B16, wherein steps (b1) and (b2) are performed at a temperature exceeding 40°C.

[0477] Implementation Scheme B18. The method according to Implementation Schemes B13 to B17 further includes, prior to performing step (a), The compound represented by Formula 1 is dissolved in dichloromethane, followed by primary concentration, thereby producing a concentrated residue; and Ethyl acetate was added to the concentrated residue and a second concentration was performed.

[0478] Implementation Scheme B19. A method for preparing crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, of the following chemical formula 1, the method comprising: (a) A mixture is prepared by adding N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by the following chemical formula 1, to a solvent selected from the group consisting of methanol, ethanol, isopropanol, butanol, diisopropyl ether, tetrahydrofuran, heptane, hexane, and mixtures thereof; (b) Obtaining a solution by heating the mixture to 40°C or lower; and (c) A solid is produced from the solution at a temperature of 40°C or lower: [Chemical Formula 1] .

[0479] Implementation Scheme B20. The method according to Implementation Scheme B19, wherein in step (a), the solvent is ethanol, isopropanol, or a mixture thereof.

[0480] Implementation Scheme B21. The method according to Implementation Scheme B19 or B20 further includes, prior to performing step (a), The compound represented by chemical formula 1 is dissolved in dichloromethane and then subjected to primary concentration, thereby producing a concentrated residue. Ethanol was added to the concentrated residue and a second concentration was performed.

[0481] Implementation Scheme B22. A method for preparing the crystalline form III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is a compound represented by the following chemical formula 1, the method comprising: (a) A slurry is produced by adding an amorphous N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by Formula 1, to a solvent selected from the group consisting of: methyl tert-butyl ether (MTBE), heptane, octane, hexane, pentane, and mixtures thereof; and (b) Obtaining solids from the slurry: [Chemical Formula 1] .

[0482] Implementation Scheme B23. The method according to Implementation Scheme B22, wherein the solvent in step (a) is methyl tert-butyl ether (MTBE), heptane, or a mixture thereof.

[0483] Implementation scheme B24. According to the method of implementation scheme B22 or B23, wherein (a) the slurry is produced for 3 to 20 days.

[0484] Implementation scheme B25. The method according to any one of implementation schemes B22 to B24, wherein (b) obtaining the solids further includes filtering the slurry.

[0485] Implementation scheme B26. The method according to any one of implementation schemes B28 to B31, wherein (a) the generation of slurry and (b) the acquisition of solids are carried out at a temperature of 30°C or lower.

[0486] Detailed description of exemplary implementation schemes The present invention will be described in detail below with reference to embodiments to aid in understanding the invention. However, the following embodiments are merely illustrative and the scope of the invention is not limited to these embodiments. Embodiments of the invention are provided to provide a more complete description of the invention to those skilled in the art.

[0487] <Example 1> Preparation of methyl 6-(chloromethyl)nicotinic acid (8a) 6-Methylnicotinate (380 g, 7a) and dichloromethane (5.7 L) were added to the reaction mixture, and trichloroisocyanuric acid (701 g) was added in fractions at 15-22°C for one hour. The mixture was stirred at 17-22°C for 2-4 hours, cooled to 5°C or lower, and filtered. The solid obtained through filtration was washed with dichloromethane (760 mL) to remove insoluble solids. At 25°C or lower, a 20% sodium sulfite aqueous solution (1.9 L) was slowly added dropwise to the filtrate obtained through filtration, and the mixture was stirred at 20-25°C for one hour. The stirred mixture was filtered through diatomaceous earth and washed with dichloromethane (760 mL) to separate the organic layer. The separated organic layer was washed successively with distilled water (1.9 L) and a 10% sodium chloride aqueous solution (1.9 L), and water was removed using sodium sulfate (380 g). The reaction product was concentrated to remove the solvent to obtain the title compound (466.6 g, 100% yield) with HPLC purity of 93.08%.

[0488] TLC (EA / Hx = 1 / 4) : Rf 0.3 1 H NMR (400 MHz, CDCl3) δ 9.15 (d, J=2.0Hz, 1H), 8.32 (dd, J=8.1,2.1Hz, 1H), 7.58 (d, J=8.1Hz, 1H), 4.71 (s. 2H), 3.95 (s, 3H).

[0489] <Example 2> Preparation of methyl 6-((aniline)methyl)nicotinic acid (3a) The methyl 6-(chloromethyl)nicotinate (466.6 g, 8a) prepared in Example 1, sodium bicarbonate (422.3 g), potassium iodide (125.19 g), dimethylacetamide (1.4 L), and aniline (468.21 g) were added to the reaction mixture, and the mixture was stirred at 25-30°C for three hours to allow the reaction to proceed. After the reaction, the temperature was cooled to room temperature, and ethyl acetate (3.7 L) and a 10% aqueous solution of ammonium chloride (2.3 L) were added, followed by stirring for 0.5 hours. The organic layer was separated and washed successively with a 15% aqueous solution of ammonium chloride (2.3 L) and a 9% aqueous solution of sodium bicarbonate (2.3 L), and the solvent was concentrated to remove it.

[0490] Methanol (2.3 L) was added to the concentrated residue, which was then dissolved at 45–50 °C, cooled to room temperature, and stirred for two hours. Distilled water (2.3 L) was slowly added dropwise to the reactants at room temperature and stirred for two hours. After stirring, the temperature was cooled to 0–5 °C, stirred for 1–2 hours, and filtered. The solid obtained through filtration was washed with distilled water (930 mL) and dried under vacuum for 12 hours to obtain the title compound (501.2 g, yield: 82.4%) with HPLC purity of 95.54%.

[0491] TLC (EA / Hx = 1 / 2) : Rf 0.3 1 H NMR (400 MHz, CDCl3) δ 9.18 (dd, J=2.2, 0.8Hz, 1H), 8.23 ​​(dd, J=8.1, 2.1Hz, 1H), 7.42(dd, J=8.2, 0.7Hz, 1H), 7.19-7.15 (m. 2H), 6.75-6.71 (m.1H), 6.65-6.62 (m. 2H), 4.52 (s, 2H), 3.94 (s, 3H).

[0492] <Example 3> Preparation of methyl 6-((1,1-dioxo-N-phenylthiomorpholine-4-carboxamido)methyl)nicotinic acid (5a) The methyl 6-((anilino)methyl)nicotinate (500 g, 3a), thiomorpholine-4-carboxyl chloride 1,1-dioxide (469 g, 4a), N,N-diisopropylethylamine (DIPEA, 346.8 g) and toluene (1.5 L) prepared in Example 2 were added to the reaction mixture, heated to 75-85°C, and then stirred for 2-3 hours.

[0493] After cooling to 20-30°C, dichloromethane (3.5 L) was added dropwise and stirred at room temperature for 0.5-1 hour. The organic layer was separated, and a 10% ammonium chloride aqueous solution (2.5 L) was added, and the mixture was stirred at 20-30°C for 0.5 hours. After stirring, the organic layer was separated and washed sequentially with a 10% ammonium chloride aqueous solution (2.5 L) and distilled water (2.5 L).

[0494] The reactants were concentrated to remove the solvent, and methanol (2.5 L) was subsequently added, followed by stirring at 55-65 °C for 2-3 hours. After cooling to 45-55 °C, methyl tert-butyl ether (4 L) was slowly added, and the mixture was stirred at 35-45 °C for 1-2 hours. The mixture was then cooled to 0-5 °C, stirred for 1-2 hours, and subsequently filtered. The solid obtained through filtration was washed with methyl tert-butyl ether (1 L) and dried under vacuum for six hours to obtain the title compound (731.7 g, yield: 87.9%) with HPLC purity of 99.65%.

[0495] TLC (EA / Hx = 1 / 2) : Rf 0.1 1 H NMR (400 MHz, CDCl3) δ 9.12 (dd, J=2.1, 0.8Hz, 1H), 8.26 (dd, J=8.1, 2.2Hz, 1H), 7.39 (dd, J=8.1, 0.7Hz, 1H), 7.33-7.31 (m. 2H), 7.16-7.13 (m. 3H), 5.06 (s, 2H), 3.94 (s, 3H), 3.72-3.69 (m, 4H), 2.96-2.94 (m, 4H).

[0496] <Example 4> Preparation of N-((5-(hydrazine carbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (6) The methyl 6-((1,1-dioxo-N-phenylthiomorpholine-4-carboxamido)methyl)nicotinic acid ester (700 g, 5a), hydrazine monohydrate (434.3 g), methanol (2.8 L) and distilled water (1.4 L) prepared in Example 3 were added to the reaction mixture, heated to 58-68°C, and then stirred for 3-5 hours.

[0497] The temperature was cooled to 20-30°C, and the mixture was stirred for one hour, after which anhydrous ethanol (2.8 L) was slowly added dropwise to the reactants. The temperature was then cooled to 0-5°C, and the mixture was stirred for one hour, followed by filtration. The solid obtained by filtration was washed with a mixture of anhydrous ethanol and distilled water (5:1 (v:v), 1.4 L) and dried under vacuum at 50-55°C for 12 hours to obtain a preliminarily purified title compound.

[0498] The preliminarily purified title compound and dichloromethane (4.9 L) were added to the reaction mixture, which was stirred at 25–35 °C for two hours and then cooled to 0–5 °C. The cooled mixture was stirred for one hour and then filtered. The solid obtained by filtration was washed with dichloromethane (1.4 L) and dried under vacuum at 50–55 °C for 12 hours to obtain the title compound (631.5 g, yield: 90.2%) with HPLC purity of 99.63%.

[0499] TLC (MC / MeOH = 10 / 1): Rf 0.2 1 H NMR (400 MHz, DMSO) δ 9.90 (s, 1H), 8.85 (dd, J=2.2, 0.7Hz, 1H), 8.11 (dd, J=8.2, 2.2Hz, 1H), 7.49-7.48 (m,1H), 7.36-7.32 (m. 2H), 7.26-7.24(m. 2H), 7.12 (t, J=7.3Hz, 1H), 4.98 (s, 2H), 4.38 (s, 2H), 3.56 (s, 4H), 3.00-2.98 (m, 4H).

[0500] <Example 5> Preparation of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (1) and its crystalline form I Imidazole (303.73 g) and dichloromethane (0.9 L) were added to reaction part 1 and the temperature was cooled to 0-10°C. Difluoroacetic anhydride (776.5 g) was slowly added to the cooled mixture while maintaining the temperature at 25°C or lower, and the mixture was then stirred at room temperature for 1-2 hours.

[0501] The N-((5-(hydrazine carbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (600 g, 6) prepared in Example 4 and dichloromethane (2.7 L) were added to another reaction part 2, and the temperature was cooled to 0°C or lower.

[0502] The mixture of reaction fraction 1 was slowly added to the mixture of reaction fraction 2, which was cooled to 0°C or lower, while maintaining the temperature at -10⁻⁵°C. After the addition was complete, the temperature was raised to 35-40°C, and then stirred for 3-4 hours. After stirring, the reactants were cooled to room temperature, and 10% ammonium chloride aqueous solution (3 L) was added and stirred for 0.5 hours. The organic layer was separated, and then 9% sodium bicarbonate aqueous solution (3 L) was added and stirred for 0.5 hours. The organic layer was then separated and washed with distilled water (3 L). Sodium sulfate (600 g) was added to the organic layer and water was removed from it, while stirring for 0.5 hours. The reactants were then filtered and the solvent was concentrated to obtain the title compound (689 g) represented by Formula 1 with HPLC purity of 99.60%.

[0503] Ethyl acetate (600 mL) was injected into the compound of Formula 1 obtained as described above for further concentration. Ethyl acetate (900 mL) and anhydrous ethanol (1.2 L) were added to the concentrated residue, and the residue was dissolved by raising the temperature to 55-65 °C. Anhydrous ethanol (2.4 L) was added and the mixture was stirred at 40-50 °C for three hours to precipitate a solid. Further addition of anhydrous ethanol (2.4 L) was made, and the mixture was stirred at 40-50 °C for 2-4 hours, cooled to 5 °C or lower, stirred for one hour, and then filtered. The solid obtained by filtration was washed with anhydrous ethanol (1.2 L) and dried under vacuum at 35-40 °C for six hours to obtain crystalline form I (632.3 g, yield: 91.7%) of the compound of Formula 1 with HPLC purity of 99.84%.

[0504] The NMR analysis results of the compound represented by chemical formula 1 obtained in Example 5 are as follows: TLC (EA / Hx = 1 / 2) : Rf 0.6 1 H NMR (400 MHz, CDCl3) δ 9.22 (dd, J=2.2, 0.8Hz, 1H), 8.37 (dd, J=8.2, 2.2Hz, 1H), 7.53 (dd, J=8.2, 0.8Hz, 1H), 7.37-7.33 (m, 2H), 7.20-7.16(m, 3H), 6.93 (t. J=51.6Hz, 1H), 5.09 (s, 2H), 3.72-3.70 (m, 4H), 2.94-2.91(m, 4H).

[0505] In addition, the X-ray powder diffraction (XRPD) diagram of crystalline form I obtained in Example 5 above is shown in... Figure 2And in Table 1, the results of differential scanning calorimetry (DSC) analysis are shown. Figure 3 middle.

[0506] [Table 1] <Example 6> Preparation of methyl 6-((aniline)methyl)nicotinic acid (3a) Methyl 6-formylnicotinic acid (180 g, 2a) and dichloromethane (900 mL) were added to reaction part 1, followed by the slow addition of aniline (101.5 g) while maintaining a temperature of 10-30°C, and then stirring at 20-30°C for 1-2 hours.

[0507] Sodium triacetoxyborohydride (346.5 g) and dichloromethane (1.62 L) were added to another reaction part 2 and cooled to 5°C or lower.

[0508] The mixture from reaction fraction 1 was slowly added to the mixture from reaction fraction 2, which was cooled to 5°C or lower, while maintaining a temperature of 10°C or lower. After the addition, a small amount of the remaining mixture from reaction fraction 1 was washed with dichloromethane (180 mL) and added to reaction fraction 2. After the addition was complete, the temperature was raised to 15–25°C and then stirred for 2–3 hours. After stirring, 1 N hydrochloric acid aqueous solution (1.8 L) and 9% sodium bicarbonate aqueous solution (360 mL) were slowly added sequentially, and the mixture was stirred at 20–30°C for 0.5 hours. The organic layer was separated, and then 9% sodium bicarbonate aqueous solution (1.44 L) was added and stirred for 0.5 hours. The organic layer was then separated and washed with sodium chloride aqueous solution (1.8 L). Water was removed from the organic layer by using sodium sulfate (180 g), and the resulting product was filtered and the solvent concentrated to obtain the title compound (264.07 g, 100% yield) with HPLC purity of 99.01%.

[0509] TLC (EA / Hx = 1 / 2) : Rf 0.3 1 H NMR (400 MHz, CDCl3) δ 9.18 (dd, J=2.2, 0.8Hz, 1H), 8.23 ​​(dd, J=8.1, 2.1Hz, 1H), 7.42(dd, J=8.2, 0.7Hz, 1H), 7.19-7.15 (m. 2H), 6.75-6.71 (m.1H), 6.65-6.62 (m. 2H), 4.52 (s, 2H), 3.94 (s, 3H).

[0510] <Example 7> Preparation of methyl 6-((1,1-dioxo-N-phenylthiomorpholine-4-carboxamido)methyl)nicotinic acid (5a) The methyl 6-((anilino)methyl)nicotinic acid (264.07 g, 3a), thiomorpholine-4-carboxyl chloride (280 g, 4a), N,N-diisopropylethylamine (DIPEA, 281.7 g) and toluene (3.43 L) prepared in Example 6 were added to the reaction mixture, heated to 90-100°C, and then stirred for 2-3 hours.

[0511] After cooling to 65-70°C, distilled water (792 mL) was added dropwise while stirring at 65-70°C for one hour. 2-Butanol (792 mL) was added to the reaction mixture at 65-70°C, and the temperature was cooled to 35-40°C. Then, dichloromethane (528 mL) was added dropwise while stirring at 35-40°C for 0.5 hours. The organic layer was separated, filtered through diatomaceous earth, and washed with 2-butanol (528 mL). Distilled water (1.85 L) was added and the mixture was stirred at 25-30°C for 0.5 hours. The organic layer was then separated and washed successively with 10% ammonium chloride aqueous solution (2.6 L) and distilled water (1.3 L).

[0512] The reactants were concentrated to remove the solvent, and methanol (1.3 L) was then added and stirred at 55–65 °C for two hours. After cooling to 50–55 °C, methyl tert-butyl ether (2.1 L) was slowly added and stirred at 35–45 °C for one hour. The temperature was then cooled to 0–5 °C, stirred for 1–2 hours, and then filtered. The solid obtained by filtration was washed with methyl tert-butyl ether (528 mL) and dried under vacuum for six hours to obtain the title compound (372 g, yield: 84.6%) with HPLC purity of 99.72%.

[0513] TLC (EA / Hx = 1 / 2) : Rf 0.1 1 H NMR (400 MHz, CDCl3) δ 9.12 (dd, J=2.1, 0.8Hz, 1H), 8.26 (dd, J=8.1, 2.2Hz, 1H), 7.39 (dd, J=8.1, 0.7Hz, 1H), 7.33-7.31 (m. 2H), 7.16-7.13 (m. 3H), 5.06 (s, 2H), 3.94 (s, 3H), 3.72-3.69 (m, 4H), 2.96-2.94 (m, 4H).

[0514] <Example 8> Preparation of N-((5-(hydrazine carbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (6) The methyl 6-((1,1-dioxo-N-phenylthiomorpholine-4-carboxamido)methyl)nicotinic acid ester (370 g, 5a), hydrazine monohydrate (229.5 g), methanol (1.48 L), and distilled water (740 mL) prepared in Example 7 were added to the reaction mixture, heated to 58-68°C, and then stirred for 3-5 hours.

[0515] The temperature was cooled to 20–30 °C, and the mixture was stirred for one hour while anhydrous ethanol (2.22 L) was slowly added dropwise to the reactants. The temperature was then cooled to 0–5 °C, and the mixture was stirred for one hour, followed by filtration. The solid obtained by filtration was washed with a mixture of anhydrous ethanol and distilled water (5:1 (v:v), 740 mL) and dried under vacuum at 50–55 °C for 12 hours to obtain a preliminarily purified title compound.

[0516] The preliminarily purified title compound and dichloromethane (1.85 L) were added to the reaction mixture, and the mixture was stirred at 25–35 °C for two hours, followed by cooling to 0–5 °C. The cooled mixture was stirred for one hour and then filtered. The solid obtained by filtration was washed with dichloromethane (740 mL) and dried under vacuum at 50–55 °C for 12 hours to obtain the title compound (333 g, yield: 90%) with HPLC purity of 99.56%.

[0517] TLC (MC / MeOH = 10 / 1): Rf 0.2 1 H NMR (400 MHz, DMSO) δ 9.90 (s, 1H), 8.85 (dd, J=2.2, 0.7Hz, 1H), 8.11 (dd, J=8.2, 2.2Hz, 1H), 7.49-7.48 (m,1H), 7.36-7.32 (m. 2H), 7.26-7.24(m. 2H), 7.12 (t, J=7.3Hz, 1H), 4.98 (s, 2H), 4.38 (s, 2H), 3.56 (s, 4H),3.00-2.98 (m, 4H) <Example 9> Preparation of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (1) and its crystalline form I Imidazole (164.83 g) and dichloromethane (1.3 L) were added to reaction part 1 and the temperature was cooled to 0-10°C. Difluoroacetic anhydride (421.4 g) was slowly added to the cooled mixture while maintaining the temperature at 20°C or lower, and the mixture was then stirred at room temperature for 1-2 hours.

[0518] The N-((5-(hydrazine carbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (325.6 g, 6) prepared in Example 8 and dichloromethane (1.63 L) were added to another reaction part 2, and the temperature was cooled to 0°C or lower.

[0519] The mixture of reaction fraction 1 was slowly added to the mixture of reaction fraction 2, which was cooled to 0°C or lower, while maintaining the temperature at -10 to 0°C. After the addition was complete, the temperature was raised to 35–40°C, and then stirred for 3–4 hours. After stirring, the reactants were cooled to room temperature, and a 10% aqueous solution of ammonium chloride (3.26 L) was added and stirred for 0.5 hours. The organic layer was separated, and then a 9% aqueous solution of sodium bicarbonate (3.26 L) was added and stirred for 0.5 hours. The organic layer was then separated and washed with distilled water (1.63 L). Sodium sulfate (326 g) was added to the organic layer and water was removed from it, while stirring for 0.5 hours. The reactants were then filtered and the solvent was concentrated to obtain the title compound (374 g) represented by Formula 1 with HPLC purity of 99.69%.

[0520] Ethyl acetate (326 mL) was injected into the compound represented by Formula 1 obtained as described above for further concentration. Ethyl acetate (326 mL) and anhydrous ethanol (1.3 L) were added to the concentrated residue, which was then dissolved by raising the temperature to 50–60 °C. Anhydrous ethanol (1.95 L) was further added, and the mixture was stirred at 45–50 °C for three hours, cooled to 5 °C or lower, and then filtered. The solid obtained by filtration was washed with anhydrous ethanol (652 mL) and dried under vacuum at 35–40 °C for six hours to obtain the title compound (343.2 g, 91.8% yield) with HPLC purity of 99.83%.

[0521] The NMR analysis results of the compound represented by chemical formula 1 obtained in Example 9 are as follows: TLC (EA / Hx = 1 / 2) : Rf 0.6 1H NMR (400 MHz, CDCl3) δ 9.22 (dd, J=2.2, 0.8Hz, 1H), 8.37 (dd, J=8.2, 2.2Hz, 1H), 7.53 (dd, J=8.2, 0.8Hz, 1H), 7.37-7.33 (m, 2H), 7.20-7.16(m, 3H), 6.93 (t. J=51.6Hz, 1H), 5.09 (s, 2H), 3.72-3.70 (m, 4H), 2.94-2.91(m, 4H).

[0522] The X-ray powder diffraction (XRPD) diagram of crystalline form I obtained in Example 9 above is shown in Figure 9. Figure 4 And in Table 2, the results of differential scanning calorimetry (DSC) analysis are shown. Figure 5 middle.

[0523] [Table 2] <Example 10> Preparation of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (compound represented by chemical formula 1) and its crystalline form I Imidazole (1.61 kg) and dichloromethane (15.9 L) were added to reaction part 1 and the temperature was cooled to 5-10°C. Difluoroacetic anhydride (4.12 kg) was slowly added to the cooled mixture while maintaining the temperature at 30°C or lower, and the mixture was then stirred at room temperature for one hour.

[0524] N-((5-(hydrazine carbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (3.18 kg) and dichloromethane (15.9 L) were added to another reaction part 2, and the temperature was cooled to 0°C or lower.

[0525] The mixture of reaction fraction 1 was slowly added to the mixture of reaction fraction 2, which was cooled to 0°C or lower, while maintaining the temperature at 5°C or lower. After the addition was complete, the temperature was raised to 35°C to 40°C and maintained for one hour, followed by stirring for two hours. After confirming the completion of the reaction by HPLC, the reactants were cooled to room temperature, and a 10% aqueous solution of ammonium chloride (31.8 L) was added and stirred for 0.5 hours. The organic layer was separated, and a 9% aqueous solution of sodium bicarbonate (31.8 L) was added and stirred for 0.5 hours. Subsequently, the organic layer was separated and washed with distilled water (15.9 L). Sodium sulfate (3.18 kg) was added to the organic layer and water was removed from it, while stirring for 0.5 hours. The reactants were then filtered and the solvent was concentrated to obtain the title compound represented by Formula 1 (3.65 kg) with HPLC purity of 99.69%.

[0526] Ethyl acetate (3.18 L) was injected into 3.65 kg of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, the compound of formula 1 obtained as described above, and further concentrated. Ethyl acetate (3.18 L) and ethanol (12.72 L) were added to the concentrated residue, and it was then dissolved by raising the temperature to 50-55 °C. Ethanol (19.08 L) was further added, and the mixture was stirred at 50-55 °C for 1.5 h, cooled to 5 °C or lower, and then filtered. The solid obtained by filtration was washed with ethanol (6.36 L) and dried under vacuum for 14 hours to obtain the title compound (N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide crystalline form I) with HPLC purity of 99.90% (3.38 kg, 92.3% yield).

[0527] The X-ray powder diffraction (XRPD) diagram of crystalline form I obtained in Example 10 is shown in Figure 10. Figure 6 And in Table 3.

[0528] [Table 3] <Example 11> Preparation of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (compound represented by chemical formula 1) and its crystalline form II Imidazole (405.4 g) and dichloromethane (4.45 L) were added to reaction part 1 and the temperature was cooled to 0°C to 5°C. Difluoroacetic anhydride (1.04 kg) was slowly added to the cooled mixture while maintaining the temperature at 0-10°C, and the mixture was then stirred at room temperature for one hour.

[0529] N-((5-(hydrazine carbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (890 g) and dichloromethane (8.9 L) were added to another reaction part 2, and the temperature was cooled to 0-5 °C.

[0530] The mixture of reaction fraction 1 was slowly added to the cooled mixture of reaction fraction 2 while maintaining the temperature at 0–5 °C. After the addition was complete, the temperature was raised to 35–40 °C and maintained for one hour, followed by stirring for four hours. After confirming the completion of the reaction by HPLC, the reactants were cooled to room temperature, and 8.9 L of a 10% ammonium chloride aqueous solution was added and stirred for 0.5 hours. The organic layer was separated, and 8.9 L of a 9% sodium bicarbonate aqueous solution was added and stirred for 0.5 hours. Subsequently, the organic layer was separated and washed with distilled water (4.45 L). Sodium sulfate (890 g) was added to the organic layer and water was removed from it while stirring for 0.5 hours. The reactants were then filtered and the solvent was concentrated to obtain the title compound represented by formula 1.

[0531] Ethanol (2 L) was injected into N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (1022.4 g) as the compound of formula 1 obtained as described above and concentrated. Ethanol (7.15 L) was added to the concentrated residue, the temperature was raised to 35°C to 40°C, and the mixture was stirred for 13 hours. The precipitated mixture was filtered while stirring. The solid obtained by filtration was washed with ethanol (2 L) and dried for 14 hours to obtain the title compound (N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide crystalline form II) (985.8 g, 96.4% yield) with HPLC purity of 99.6%.

[0532] The X-ray powder diffraction (XRPD) diagram of crystalline form II obtained in Example 11 is shown in [image / image]. Figure 7 And in Table 4, the results of differential scanning calorimetry (DSC) analysis are shown. Figure 8 middle.

[0533] [Table 4] <Example 12> Preparation of amorphous N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (compound represented by chemical formula 1) and its crystalline form III Imidazole (15.2 g) and dichloromethane (150 mL) were added to reaction part 1 and the temperature was cooled to 0°C to 5°C. Difluoroacetic anhydride (38.8 g) was slowly added to the cooled mixture while maintaining the temperature at 20°C or lower, and the mixture was then stirred at room temperature for one hour.

[0534] N-((5-(hydrazine carbonyl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (30 g) and dichloromethane (150 mL) were added to another reaction part 2, and the temperature was cooled to 0-5℃.

[0535] The mixture of reaction fraction 1 was slowly added to the cooled mixture of reaction fraction 2 while maintaining the temperature at 0–5 °C. After the addition was complete, the temperature was raised to 35–40 °C and maintained for one hour, followed by stirring for three hours. After confirming the completion of the reaction by HPLC, the reactants were cooled to room temperature, and 300 mL of a 10% ammonium chloride aqueous solution was added and stirred for 0.5 hours. The organic layer was separated, and 300 mL of a 9% sodium bicarbonate aqueous solution was added and stirred for 0.5 hours. Subsequently, the organic layer was separated and washed with distilled water (150 mL). Sodium sulfate (30 g) was added to the organic layer and water was removed from it while stirring for 0.5 hours. Subsequently, the compound represented by formula 1 obtained by filtration and solvent concentration was vacuum dried at room temperature for 14 hours to obtain an amorphous solid (34.46 g) of the compound represented by formula 1.

[0536] Methyl tert-butyl ether (MTBE, 400 mL) was added to 20 g of the compound represented by Formula 1 as an amorphous solid, and the reaction mixture was slurried at 20-25 °C for 24 h, followed by filtration. The solid obtained by filtration was washed with methyl tert-butyl ether (MTBE, 40 mL) and dried under vacuum for 14 h to obtain the title compound (N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide crystalline form III) with HPLC purity of 99.86% (18.6 g, 93% yield).

[0537] The X-ray powder diffraction (XRPD) diagram of crystalline form III obtained in Example 12 is shown in [image / image]. Figure 9 And in Table 5, the results of differential scanning calorimetry (DSC) analysis are shown. Figure 10 middle.

[0538] [Table 5] Meanwhile, the X-ray powder diffraction (XRPD) diagram of the amorphous compound represented by chemical formula 1 used in the preparation process of crystalline form III is shown in... Figure 11 middle.

[0539] <Preparation Examples> Preparation Example 1. Preparation of the amorphous form of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide 20 g of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (the compound represented by Formula 1) was dissolved in 400 mL of dichloromethane, and the resulting solution was subsequently concentrated. The concentrated solution was dried under vacuum at 20°C to 30°C for 14 hours to obtain 20 g of the title compound (N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide) in amorphous form (melting point: 129.5°C) with HPLC purity of 99.77%. Its X-ray powder diffraction (XRPD) pattern is shown in Figure 1. Figure 12 The results of differential scanning calorimetry (DSC) analysis are shown in... Figure 13 middle.

[0540] Example 13. Preparation of Crystalline Form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide 34.5 g of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (represented by Formula 1) was completely dissolved by injecting dichloromethane (600 mL), and the resulting solution was subsequently concentrated. After injecting ethyl acetate (30 mL) into the concentrated residue and concentrating the resulting mixture, ethyl acetate (30 mL) and ethanol (120 mL) were added, and the mixture was dissolved by heating to 50°C to 55°C. 180 mL of ethanol was then added, and the mixture was stirred at 50°C to 55°C for 3 hours to precipitate a solid. The precipitated solid was then cooled to 5°C or lower and filtered. The solid obtained by filtration was washed with ethanol (60 mL) and dried under vacuum for 14 hours to obtain the title compound (Crystal form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide) with HPLC purity of 99.91% (32.5 g, 94.3% yield, melting point: 138.3 °C). X-ray powder diffraction (XRPD) of crystalline form I is shown in the figure. Figure 14 And in Table 6, the results of differential scanning calorimetry (DSC) analysis are shown in... Figure 15 middle.

[0541] [Table 6] Example 14. Preparation of crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide 23 g of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (the compound represented by Formula 1) was completely dissolved in dichloromethane (400 mL), and the resulting solution was subsequently concentrated. After adding ethanol (40 mL) to the concentrated residue and concentrating the resulting mixture, ethanol (140 mL) was added to it, and the mixture was dissolved by heating to 35°C to 40°C to prepare a solution, which was then stirred for 1 to 2 hours. The solids precipitated during stirring were filtered off. The solid obtained by filtration was dried for 14 hours to obtain the title compound (N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide crystalline form II) (20.9 g, 91% yield, melting point: 130.4 °C) with HPLC purity of 99.6%. X-ray powder diffraction (XRPD) of crystalline form II is illustrated in [image / image / image / image]. Figure 16 And in Table 7, the results of differential scanning calorimetry (DSC) analysis are shown in... Figure 17 middle.

[0542] [Table 7] Example 15. Preparation of crystalline form III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide Methyl tert-butyl ether (MTBE, 400 mL) was added to 20 g of the amorphous solid N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (the compound represented by Formula 1) obtained in Preparation Example 1, and the resulting mixture was slurried at 20°C to 25°C for 24 hours, followed by filtration. The solid obtained by filtration was washed with methyl tert-butyl ether (MTBE, 40 mL) and dried under vacuum for 14 hours to obtain the title compound (Crystal form III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide) with HPLC purity of 99.8% (18.5 g, 92.5% yield, melting point: 125.0°C). The X-ray powder diffraction (XRPD) diagram of crystal form III is shown in Figure 18 And in Table 8, the results of differential scanning calorimetry (DSC) analysis are shown in... Figure 19 middle.

[0543] [Table 8] <Experimental Examples> Experimental Example 1. Stability and accelerated stability tests of amorphous and crystalline forms I, II and III. The crystalline form of a compound can change to another crystalline form depending on the surrounding environment, and such crystalline forms with weak crystal stability are prone to change in crystalline form, and therefore can exist in multiple crystalline forms.

[0544] In this case, the change in the pharmacokinetic properties of the final drug may induce unexpected pharmacokinetic reactions. Therefore, the crystal stability and accelerated stability tests (accelerated conditions: 40℃ ± 2℃, 75% RH ± 5%) of amorphous N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, crystalline form 1, crystalline form II, and crystalline form III were performed. After 6 months, the purity and X-ray powder diffraction (XPRD) patterns were checked again, and the analytical results are shown in Table 9.

[0545] [Table 9]

[0546] As shown in Table 9, due to the excellent crystal stability of crystal forms I, II and III, the crystals remained stable for 6 months without any change in purity or crystal form, thus proving that they are easy to store.

[0547] However, in the case of the amorphous form, although the purity remained unchanged under accelerated conditions, it was confirmed that the amorphous form readily transformed into crystalline form I within 3 months. Furthermore, the purity of the amorphous form was observed to decrease to 94.6% within 6 months. Based on these observations, the relative instability of the amorphous form is confirmed.

[0548] Therefore, the crystalline forms I, II and III of the present invention exhibit sufficiently excellent stability for use in pharmaceuticals and can be stored for a long time without any changes in pharmacological effects, safety and pharmacokinetic properties, because the crystalline forms are stably maintained when manufactured into pharmaceuticals. Thus, the crystalline forms can maintain excellent therapeutic effects for a long time and also have significant and excellent economic feasibility.

[0549] Experimental Example 2. Hygroscopicity Test Hygroscopic compounds are unsuitable for formulations because they readily absorb moisture, are difficult to handle, and do not flow smoothly. Furthermore, their weak stability limits their long-term storage, and the inconsistent concentrations make it difficult to obtain reproducible results.

[0550] Therefore, the hygroscopicity of the crystalline form of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide was evaluated. The hygroscopicity of the crystalline form of this application was confirmed by water adsorption analysis (dynamic gas phase adsorption, DVS) and compared with the measurement results of the amorphous compound, as shown in Table 10 and Figures 20 to 23 middle.

[0551] <Water Adsorption Analysis (Dynamic Gas Phase Adsorption, DVS)> Under the condition of Δmass / Δtime (dm / dt), the mass change of crystalline and amorphous forms was measured using a water adsorption analyzer (Dynamic Gas Phase Adsorption, DVS) (Surface Measurement Systems' DVS Intrinsic model) at 25°C by gradually changing the relative humidity in 10% increments from an initial 0% to 95%. The mass change based on the humidity variation is plotted on... Figure 20 (Crystal form I) Figure 21 (Crystal Form II) Figure 22 (Crystal form III) and Figure 23 In (amorphous) form, the hygroscopicity confirmed by mass change at 25°C / 80% RH is shown in Table 10 below.

[0552] [Table 10]

[0553] according to Figures 20 to 23 It is confirmed that, according to the present invention, crystalline forms I, II, and III stably maintain an anhydrous state unaffected by changes in ambient relative humidity. However, compared to the crystalline forms, the amorphous forms show a tendency to absorb 1% to 2.5% water depending on the relative humidity (70 to 90% RH).

[0554] Furthermore, as can be seen from Table 10, it can be found that even at a relative humidity of 80%, the water weight percentage of crystalline forms I, II and III according to the present invention remains substantially unchanged, while the increased water weight percentage confirms that the amorphous forms absorb water.

[0555] Therefore, the crystalline forms I, II, and III of the present invention are stable crystalline forms with low hygroscopicity, which can be maintained stably for a long time without being affected by ambient humidity and therefore do not require separate storage conditions during storage. They are also beneficial for formulations because they can stably maintain their physicochemical properties without being affected by ambient moisture, resulting in formulations with excellent content uniformity and excellent therapeutic effects that can be maintained stably for a long time. This makes the crystalline forms highly reproducible and economically feasible.

[0556] Experimental Example 3. Residual Solvent Removal Tests for Amorphous Forms, Crystalline Forms I, II, and III All residual solvents offer no therapeutic benefit and therefore need to be removed to levels suitable for product specifications, Good Pharmaceutical Manufacturing Practices (GMP) or other quality standards, and these residual solvents should not exceed levels permitted by the safety data in the formulation. Furthermore, residual levels need to be adjusted according to ICH guidelines to protect patients from potential adverse reactions due to the toxicity of residual solvents. Therefore, residual solvent management is as important as impurity management in the final API, and the efficiency of residual solvent removal can vary greatly depending on the type of crystalline form. Therefore, the extent of residual solvent removal in both amorphous and crystalline forms in this application needs to be evaluated.

[0557] Table 11 below shows the degree of residual solvent removal in the amorphous and crystalline forms I, II, and III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide obtained by common drying methods (vacuum drying and humidification drying), and the results are shown in Table 11 below.

[0558] In the residual solvent removal experiment, vacuum drying was performed at a temperature of 20°C to 30°C, followed by humidification drying at a temperature of 20°C to 30°C and a relative humidity of 80% to 90%. In the amorphous form, the drying was performed under vacuum and then under humidification drying, as described in Preparation Example 1.

[0559] [Table 11]

[0560] As shown in Table 11, the crystalline forms I, II, and III of this invention are confirmed to be suitable for use as pharmaceutical substances. This is because, even with conventional vacuum drying alone, residual solvents are removed to below ICH guideline standards, whereas even with additional humidification drying after vacuum drying, it is difficult to remove residual solvents from the amorphous form to below the ICH specified values. In other words, it is confirmed that residual solvents can be effectively removed from the crystalline forms I, II, and III of this invention compared to the amorphous form.

[0561] Therefore, the crystalline forms I, II, and III of the present invention are safe from toxicity due to residual solvents, meet excellent standards as pharmaceutical substances, and do not require complex processes to remove residual solvents, making the crystalline forms easy to use as pharmaceuticals and thus suitable for mass production, achieving excellent therapeutic effects and safety.

[0562] Experimental Example 4. NMR Analysis and Testing NMR analysis was performed on N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide prepared by Preparation Example 1. The NMR spectra were analyzed using a 700 MHz NMR spectrometer manufactured by Brukerr, and the results are shown in [Figure / Table / Insert Table ... Figure 24 ( 1 H NMR) and Figure 25 ( 13 In C NMR).

[0563] The conditions for X-ray powder diffraction analysis, thermal analysis, and high-performance liquid chromatography (HPLC) in this invention are as follows.

[0564] 1. X-ray powder diffraction analysis X-ray powder diffraction patterns were measured using an X-ray diffractometer (manufacturer: Bruker (Germany), model name: D8 ADVANCE) as the detector, and were measured at various angles (2θ) after the test sample was applied to the XPRD sample holder. The supply source was CuKα, λ = 1.5406. Generator: 40 kV - 40 mA; Detector: PSD, Lynx Eye; DongShinFinetek DS-20.

[0565] Unless otherwise stated herein, X-ray powder diffraction analysis is performed using CuKα radiation as described above. For example, the X-ray powder diffraction (XRPD) patterns in Tables 1 through 8 are measured using CuKα radiation.

[0566] 2. Thermal Analysis Examples 1 to 12 Differential scanning calorimetry (DSC) analysis was performed using a thermal analysis apparatus (manufacturer: Netzsch, model name: DSC204 F1 Phoenix).

[0567] Weigh approximately 1 to 10 mg of sample and place it in a covered aluminum dish. Evaluate the sample using a linear heating lamp operating at 10 °C / min in the range of 25 °C to 400 °C.

[0568] Examples 13 to 15 Differential scanning calorimetry (DSC) was performed using a thermal analysis apparatus (manufacturer: METTLER TOLEDO, model name: DSC823e (crystal form I, crystal form II) / manufacturer: Netzsch, model name: DSC204 F1 Phoenix (amorphous, crystal form III)).

[0569] Weigh approximately 1 to 10 mg of sample and place it in a covered aluminum dish. Evaluate the sample using a linear heating lamp operating at 10 °C / min in the range of 25 °C to 400 °C.

[0570] 3. High-performance liquid chromatography (HPLC) - Detector: UV absorbance luminometer (detection wavelength 245 nm) - String: Waters Cortecs C18+ (3.0 × 100 mm, 2.7 μm) - Column temperature: 35℃ - Flow rate: 0.7 mL / min Injection volume: 2.0 μl -Mobile phase A: Water containing 0.1% acetic acid -Mobile phase B: Acetonitrile containing 0.1% acetic acid - Diluent: Mobile Phase A: Mobile Phase B = 50:50 (v / v) - Sample concentration: 0.5 mg / mL -Transitional phase gradient condition:

[0571] 4. Hygroscopicity Analysis Water adsorption analysis (Dynamic gas phase adsorption, DVS) Water adsorption was analyzed at 25°C using a water adsorption analyzer (Dynamic Gas Phase Adsorption, DVS, DVS Intrinsic model of Surface Measurement Systems) from 0% RH to 95% RH. Under the condition of Δmass / Δtime (dm / dt), the mass change in crystalline or amorphous forms was measured by gradually changing the relative humidity by 10% from the initial 0% to 95%.

Claims

1. A method for preparing a compound represented by the following chemical formula 1, the method comprising: Prepare compounds represented by chemical formula 1 in situ from compounds represented by chemical formula 6. [Chemical Formula 1] [Chemical Formula 6] 。 2. The method according to claim 1, wherein the preparation of the compound represented by the compound represented by the chemical formula 6 is carried out in the presence of a base.

3. The method of claim 2, wherein the base comprises imidazole.

4. The method according to claim 1, wherein the compound represented by chemical formula 1 is prepared by using at least one selected from compounds represented by [chemical formula A] and [chemical formula B], and the compound represented by chemical formula 6 as reactants: [Chemical Formula A] [Chemical Formula B] in, In the above chemical formula B, X1 is F, Cl, Br or I.

5. The method of claim 1, wherein preparing the compound represented by chemical formula 1 from the compound represented by chemical formula 6 comprises: a) Prepare reaction part 1, which includes a compound represented by chemical formula A or chemical formula B and a base; and b) Mixing reaction portion 1 with reaction portion 2 containing the compound represented by chemical formula 6 to prepare the compound represented by chemical formula 1: [Chemical Formula A] [Chemical Formula B] In the above chemical formula B, X1 is F, Cl, Br or I.

6. The method of claim 5, wherein step a) is carried out by mixing a mixture comprising a base and a solvent with a compound represented by said chemical formula A or chemical formula B.

7. The method of claim 5, wherein step a) comprises: Prepare a mixture comprising the alkali and the solvent; and The compound represented by chemical formula A or chemical formula B is added to the mixture.

8. The method of claim 7, further comprising: After preparing the mixture comprising the alkali and the solvent, the mixture is cooled to 0-10°C.

9. The method of claim 5, further comprising: The mixture is stirred after the compound represented by chemical formula A or chemical formula B is added to it.

10. The method of claim 5, wherein the reaction portion 2 in step b) comprises the compound represented by chemical formula 6 and the solvent.

11. The method of claim 5, wherein mixing the reaction portion 2 with the reaction portion 1 in step b) is performed by adding the reaction portion 1 to the reaction portion 2.

12. The method of claim 11, wherein the addition of reaction portion 1 to reaction portion 2 is carried out at -15°C to 5°C.

13. The method of claim 12, further comprising: After complete mixing in step b), heat to a temperature of 20°C to 45°C.

14. A method for preparing a compound represented by the following chemical formula 6, the method comprising: Compounds represented by the following chemical formula 6 are prepared from hydrazine (N2H4) or its hydrate and compounds represented by the following chemical formula 5 in the presence of a solvent comprising C1 to C6 straight-chain or branched alcohols, or a mixture of C1 to C6 straight-chain or branched alcohols and water: [Chemical Formula 5] [Chemical Formula 6] In the above chemical formula 5, R is a C1-C6 straight-chain or branched alkyl or benzyl group.

15. The method of claim 14, wherein the solvent is methanol, or a mixture of methanol and water.

16. The method of claim 14, wherein the volume ratio of the alcohol to water is from 10:1 to 1:

1.

17. The method of claim 14, wherein R is methyl.

18. A method for preparing a compound represented by chemical formula 5, the method comprising: The compound represented by chemical formula 3 is reacted with the compound represented by chemical formula 4 in the presence of a base to prepare the compound represented by chemical formula 5. [Chemical Formula 3] [Chemical Formula 4] [Chemical Formula 5] In chemical formulas 3 and 5 above, R is a C1-C6 straight-chain or branched alkyl or benzyl, and in chemical formula 4 above, X is F, Cl, Br or I.

19. The method of claim 18, wherein R is methyl and X is Cl.

20. The method of claim 18, wherein the base is triethylamine, N,N-diisopropylethylamine, imidazole, pyridine, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, or a mixture thereof.

21. The method of claim 18, further comprising: Purify the compound represented by chemical formula 5.

22. The method of claim 21, wherein the purification is carried out in a solvent selected from the group consisting of methanol, ethanol, isopropanol, butanol, methyl tert-butyl ether (MTBE), diisopropyl ether, heptane, hexane, and mixtures thereof.

23. A method for preparing a compound represented by the following chemical formula 3, the method comprising: The compound represented by the following chemical formula 8 is prepared from the compound represented by the following chemical formula 7 using a halogenating agent; and The compound represented by the following chemical formula 8 is reacted with aniline in the presence of a base to prepare the compound represented by the following chemical formula 3: [Chemical Formula 7] [Chemical Formula 8] [Chemical Formula 3] In formulas 3, 7 and 8 above, R is a C1-C6 straight-chain or branched alkyl or benzyl, and in formula 8, X is F, Cl, Br or I.

24. The method of claim 23, wherein R is methyl and X is Cl.

25. The method according to claim 24, wherein the halogenating agent is iodine, copper iodide, bromine, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), trichloroisocyanuric acid (TCCA), or a mixture thereof.

26. The method of claim 24, wherein X in the compound represented by the above chemical formula 8 is Cl, and the halogenating agent is N-chlorosuccinimide (NCS), trichloroisocyanuric acid (TCCA), or a mixture thereof.

27. The method of claim 24, wherein the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and mixtures thereof.

28. The method of claim 24, wherein the reaction of the compound represented by formula 8 with aniline is carried out in the presence of potassium bromide, potassium iodide, tetrabutylammonium bromide (TBAB), or a mixture thereof.

29. A method for preparing a compound represented by the following chemical formula 8a, the method comprising: The compound represented by chemical formula 8a was prepared by using only trichloroisocyanuric acid (TCCA) reagent in the compound represented by chemical formula 7. [Chemical Formula 7] [Chemical Formula 8a] In chemical formulas 7 and 8a above, R is a C1-C6 straight-chain alkyl group or benzyl group.

30. A method for preparing a compound represented by chemical formula 3, the method comprising: The compound represented by chemical formula 3 is prepared by reacting the compound represented by chemical formula 8 with aniline in the presence of a base. [Chemical Formula 3] [Chemical Formula 8] In chemical formulas 3 and 8 above, R is a C1-C6 straight-chain or branched alkyl or benzyl, and in chemical formula 8 above, X is F, Cl, Br or I.

31. The method of claim 30, wherein the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and mixtures thereof.

32. The method of claim 30, wherein the reaction of the compound represented by formula 8 with aniline is carried out in the presence of potassium bromide, potassium iodide, tetrabutylammonium bromide (TBAB), or a mixture thereof.

33. A method for preparing a compound represented by chemical formula 3, the method comprising: Compounds represented by chemical formula 3 can be prepared from compounds represented by chemical formula 2 in the presence of aniline and a reducing agent. [Chemical Formula 2] [Chemical Formula 3] In the above chemical formula 2 or chemical formula 3, R is a C1-C6 straight-chain or branched alkyl or benzyl.

34. The method of claim 33, wherein preparing the compound represented by chemical formula 3 from the compound represented by chemical formula 2 comprises: Prepare a mixture comprising the compound represented by chemical formula 2 and aniline; and The mixture is then reacted with the reducing agent.

35. The method of claim 33, wherein preparing the compound represented by chemical formula 3 from the compound represented by chemical formula 2 comprises: The reaction part 1 is prepared by comprising the compound represented by chemical formula 2, aniline, and a solvent; and The reaction portion 1 is mixed with the reaction portion 2, which contains the reducing agent and the solvent.

36. The method of claim 33, wherein the reducing agent comprises one or more of the group consisting of sodium borohydride (NaBH4), sodium cyanoborohydride (NaBH3CN), and sodium triacetoxyborohydride (NaBH(OAc)3).

37. The method of claim 33, wherein the preparation of the compound represented by the compound represented by the chemical formula 2 is carried out in the presence of an acid.

38. A method for preparing a compound represented by the following chemical formula 1, the method comprising: 1) Prepare compounds represented by chemical formula 8 from compounds represented by chemical formula 7 using a halogenating agent; 2) React the compound represented by the following chemical formula 8 with aniline in the presence of a base to prepare the compound represented by chemical formula 3; 3) React the compound represented by the following chemical formula 3 with the compound represented by the following chemical formula 4 in the presence of a base to obtain the compound represented by the following chemical formula 5; 4) Reacting hydrazine or its hydrate with a compound represented by chemical formula 5 to obtain a compound represented by chemical formula 6; and 5) Prepare compounds represented by formula 1 in situ from compounds represented by formula 6 below: [Chemical Formula 1] ， [Chemical Formula 3] (In the above chemical formula 3, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X is F, Cl, Br, or I). [Chemical Formula 5] (In chemical formula 5 above, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 6] ， [Chemical Formula 7] (In the above chemical formula 7, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 8] (In the above chemical formula 8, R is a C1-C6 straight-chain or branched alkyl or benzyl, and X is F, Cl, Br or I).

39. A method for preparing a compound represented by the following chemical formula 1, the method comprising: 1) Prepare compounds represented by chemical formula 3 from compounds represented by chemical formula 2 in the presence of aniline and a reducing agent; 2) React the compound represented by the following chemical formula 3 with the compound represented by the following chemical formula 4 in the presence of a base to obtain the compound represented by the following chemical formula 5; 3) Reacting hydrazine or its hydrate with a compound represented by chemical formula 5 to obtain a compound represented by chemical formula 6; and 4) Prepare compounds represented by formula 1 in situ from compounds represented by formula 6: [Chemical Formula 1] ， [Chemical Formula 2] (Whereinafter, in chemical formula 2 above, R is a C1-C6 alkyl or benzyl), [Chemical Formula 3] (In the above chemical formula 3, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X can be F, Cl, Br, or I). [Chemical Formula 5] (In chemical formula 5 above, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 6] 。 40. A method for preparing a compound represented by the following chemical formula 1, the method comprising: 1) React hydrazine or its hydrate with the compound represented by the following chemical formula 5 to obtain the compound represented by the following chemical formula 6; and 2) Prepare compounds represented by formula 1 in situ from compounds represented by formula 6 below: [Chemical Formula 1] ， [Chemical Formula 5] (Whereinafter, in chemical formula 5 above, R is a C1-C6 straight-chain or branched alkyl or benzyl group), [Chemical Formula 6] 。 41. The method of claim 40, wherein the method for preparing the compound represented by the above chemical formula 5 comprises: The compound represented by chemical formula 3 is reacted with the compound represented by chemical formula 4 in the presence of a base to prepare the compound represented by chemical formula 5. [Chemical Formula 3] (In the above chemical formula 3, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X is F, Cl, Br or I).

42. The method of claim 40, wherein the method for preparing the compound represented by chemical formula 5 comprises: The compound represented by chemical formula 8 is reacted with aniline in the presence of a base to prepare the compound represented by chemical formula 3; and The compound represented by chemical formula 3 is reacted with the compound represented by chemical formula 4 in the presence of a base to prepare the compound represented by chemical formula 5: [Chemical Formula 3] (In the above chemical formula 3, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X is F, Cl, Br, or I). [Chemical Formula 8] (In the above chemical formula 8, R is a C1-C6 straight-chain or branched alkyl or benzyl, and X is F, Cl, Br or I).

43. The method of claim 40, wherein the method for preparing the compound represented by chemical formula 5 comprises: The following compounds, represented by chemical formula 8, are prepared from compounds represented by chemical formula 7 using halogenating reagents; The compound represented by chemical formula 8 is reacted with aniline in the presence of a base to prepare the compound represented by chemical formula 3. The compound represented by chemical formula 3 is reacted with the compound represented by chemical formula 4 in the presence of a base to prepare the compound represented by chemical formula 5: [Chemical Formula 3] (In the above chemical formula 3, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X is F, Cl, Br, or I). [Chemical Formula 7] (In the above chemical formula 7, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 8] (In the above chemical formula 8, R is a C1-C6 straight-chain or branched alkyl or benzyl, and X is F, Cl, Br or I).

44. The method of claim 40, wherein the method for preparing the compound represented by chemical formula 5 comprises: Compounds represented by chemical formula 3 are prepared from compounds represented by chemical formula 2 in the presence of aniline and a reducing agent; and The compound represented by chemical formula 3 is reacted with the compound represented by chemical formula 4 in the presence of a base to prepare the compound represented by chemical formula 5: [Chemical Formula 2] (In chemical formula 2 above, R is a C1-C6 alkyl or benzyl). [Chemical Formula 3] (In the above chemical formula 3, R is a C1-C6 straight-chain or branched alkyl or benzyl) [Chemical Formula 4] (In the above chemical formula 4, X is F, Cl, Br or I).

45. A crystalline form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by the following chemical formula 1, wherein the X-ray powder diffraction pattern includes diffraction peaks at three or more diffraction angles selected from the group consisting of: 7.85°, 14.54°, 17.14°, 18.09°, 19.62°, 21.41°, and 23.58° (2θ ± 0.2°). [Chemical Formula 1] 。 46. ​​The crystalline form I according to claim 45, wherein the X-ray powder diffraction pattern further includes diffraction peaks at one or more diffraction angles selected from the group consisting of diffraction angles of 15.64°, 17.55°, 20.78°, 21.04°, 23.27°, 24.24° and 30.38° (2θ ± 0.2°).

47. The crystalline form I according to claim 45, wherein the X-ray powder diffraction pattern further comprises one or more diffraction peaks selected from the following diffraction angles (2θ ± 0.2°): 9.40°, 11.62°, 11.77°, 13.49°, 14.92°, 15.64°, 17.55°, 18.82°, 20.78°, 21.04°, 22.69°, 23.27°, 24.24°, 26.35°, 27.58°, 28.91°, 30.38°, 33.57°, and 36.74°.

48. Crystalline form I according to claim 45, wherein during differential scanning calorimetry (DSC) analysis, crystalline form I has an endothermic peak from 132°C (±0.5°C) to 143°C (±0.5°C) at a heating rate of 10°C / min.

49. Crystalline form I according to claim 45, wherein during differential scanning calorimetry (DSC) analysis, crystalline form I has an endothermic peak at 138 °C (±3 °C) when the heating rate is 10 °C / min.

50. A crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by the following chemical formula 1, wherein the X-ray powder diffraction pattern includes three or more diffraction peaks selected from the following diffraction angles (2θ ± 0.2°): 7.83°, 12.22°, 19.02°, 19.67°, 21.40°, 22.35°, and 26.44°. [Chemical Formula 1] 。 51. The crystalline form II of claim 50, wherein the X-ray powder diffraction pattern further comprises diffraction peaks at one or more diffraction angles selected from the group consisting of: 11.41°, 11.78°, 13.28°, 15.70°, 16.64°, 17.48°, 18.28°, 19.37°, 20.71°, 24.58°, 27.35° and 33.73° (2θ ± 0.2°).

52. The crystalline form II of claim 50, wherein the X-ray powder diffraction pattern further comprises diffraction peaks at one or more diffraction angles selected from the group consisting of: 10.72°, 10.92°, 11.41°, 11.78°, 13.28°, 15.70°, 16.64°, 16.97°, 17.48°, 18.28°, 19.37°, 20.71°, 24.58°, 27.35°, 30.49°, 32.19°, 33.73°, 35.44°, and 35.91° (2θ ± 0.2°).

53. Crystalline form II according to claim 50, wherein during differential scanning calorimetry (DSC) analysis, crystalline form II has an endothermic peak from 124 °C (±0.5 °C) to 138 °C (±0.5 °C) at a heating rate of 10 °C / min.

54. Crystalline form II according to claim 50, wherein during differential scanning calorimetry (DSC) analysis, crystalline form II has an endothermic peak at 130 °C (±5 °C) when the heating rate is 10 °C / min.

55. A crystalline form III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by the following chemical formula 1, wherein the X-ray powder diffraction pattern includes diffraction peaks at three or more diffraction angles selected from the group consisting of: 8.75°, 10.98°, 12.44°, 16.86°, 22.92° and 28.49° (2θ ± 0.2°): [Chemical Formula 1] 。 56. The crystalline form III of claim 55, wherein the X-ray powder diffraction pattern further comprises diffraction peaks at one or more diffraction angles selected from the group consisting of: 17.48°, 19.95°, 20.49°, 20.79°, 21.55°, 21.87°, 22.07°, 24.04°, 24.72°, 24.99° and 26.30° (2θ ± 0.2°).

57. The crystalline form III of claim 55, wherein the X-ray powder diffraction pattern further comprises diffraction peaks at one or more diffraction angles selected from the group consisting of: 14.28°, 15.45°, 17.48°, 18.49°, 18.77°, 19.95°, 20.49°, 20.79°, 21.55°, 21.87°, 22.07°, 24.04°, 24.72°, 24.99°, 26.30°, 29.22°, 30.20°, 31.40°, 34.10°, 37.13°, and 38.86° (2θ ± 0.2°).

58. Crystalline form III according to claim 55, wherein during differential scanning calorimetry (DSC) analysis, crystalline form III has an endothermic peak at 120°C (±0.5°C) to 130°C (±0.5°C) at a heating rate of 10°C / min.

59. Crystalline form III according to claim 55, wherein during differential scanning calorimetry (DSC) analysis, crystalline form III has an endothermic peak at 125 °C (±5 °C) when the heating rate is 10 °C / min.

60. A method for preparing the crystalline form I of compound N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by the following chemical formula 1, said method comprising: (a) Dissolving N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by Formula 1, in a solvent selected from the group consisting of: ethyl acetate, ethanol, methanol, isopropanol, butanol, methyl tert-butyl ether (MTBE), diisopropyl ether, acetone, methyl isobutyl ketone (MIBK), methyl ethyl ketone, dichloromethane, dimethylformamide, N-methyl-2-pyrrolidone, toluene, tetrahydrofuran, heptane, hexane, acetonitrile, and mixtures thereof; and (b) The solid is produced from the solution: [Chemical Formula 1] 。 61. The method of claim 60, wherein in step (a), the solvent is one or more alcohols selected from ethanol, methanol, isopropanol and butanol; ethyl acetate; or a mixture of the alcohol and ethyl acetate.

62. The method of claim 60, wherein obtaining the solution (a) comprises: (a1) A mixture is obtained by adding the compound represented by chemical formula 1 to the solvent; and (a2) Heat the mixture to a temperature exceeding 40°C.

63. The method of claim 60, wherein the generation of the solid in step (b) further comprises: (b1) In addition, one or more alcohols selected from ethanol, methanol, isopropanol and butanol are added to the solution of step (a); and (b2) Stir the mixture after adding the alcohol from step (b1).

64. The method of claim 63, wherein steps (b1) and (b2) are performed at a temperature exceeding 40°C.

65. The method of claim 60, further comprising, prior to performing step (a), The compound represented by Formula 1 is dissolved in dichloromethane and subsequently subjected to primary concentration, thereby producing a concentrated residue; and Ethyl acetate was added to the concentrated residue and a second concentration was performed.

66. The method of claim 60, wherein the compound represented by chemical formula 1 is prepared in situ from the compound represented by chemical formula 6: [Chemical Formula 6] 。 67. A method for preparing the crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by the following chemical formula 1, said method comprising: (a) Adding N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by the following chemical formula 1, to a solvent selected from the group consisting of methanol, ethanol, isopropanol, butanol, diisopropyl ether, tetrahydrofuran, heptane, hexane, and mixtures thereof; (b) Obtaining a solution by heating the mixture to 40°C or lower; and (c) A solid is produced from the solution at a temperature of 40°C or lower: [Chemical Formula 1] 。 68. The method of claim 67, wherein in step (a), the solvent is ethanol, isopropanol, or a mixture thereof.

69. The method of claim 67, further comprising, prior to performing step (a), The compound represented by Formula 1 is dissolved in dichloromethane and then subjected to primary concentration, thereby producing a concentrated residue. Ethanol was added to the concentrated residue and a second concentration was performed.

70. The method of claim 67, wherein the compound represented by chemical formula 1 is prepared in situ from the compound represented by chemical formula 6: [Chemical Formula 1] [Chemical Formula 6] 。 71. A method for preparing the crystalline form III of compound N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by formula 1, said method comprising: (a) Adding an amorphous N-((5-(5-(difluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by Formula 1, to a solvent selected from the group consisting of: methyl tert-butyl ether (MTBE), heptane, octane, hexane, pentane, and mixtures thereof; and (b) Obtaining solids from the slurry: [Chemical Formula 1] 。 72. The method of claim 71, wherein the solvent in step (a) is methyl tert-butyl ether (MTBE), heptane, or a mixture thereof.

73. The method of claim 71, wherein the production of the slurry in (a) takes 12 hours to 20 days.

74. The method of claim 71, wherein obtaining the solid in (b) further comprises filtering the slurry.

75. The method of claim 71, wherein (a) the generation of the slurry and (b) the acquisition of the solid are carried out at a temperature of 30°C or lower.

76. The method of claim 71, wherein preparing the amorphous form of the compound represented by formula 1 comprises: The compound represented by chemical formula 1 is prepared in situ from the compound represented by chemical formula 6; and The compound represented by chemical formula 1 was subjected to vacuum drying: [Chemical Formula 1] [Chemical Formula 6] 。

Images