Novel methods for producing compounds and novel crystal forms

Abstract

The present invention relates to a novel method for producing N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, a novel synthetic route for the main intermediate used in the said method, a novel crystalline form of the said compound, and a method for producing the said compound.

Description

[Technical Field]

[0001] The present invention relates to a novel method for producing N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, a novel method for producing an intermediate used in the synthesis of the said compound, and a 1,3,4-oxadiazole derivative compound, which relates to the crystalline form of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide. [Background technology]

[0002] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by the following chemical formula 1, is a substance that has preventive or therapeutic effects on histone deacetylase 6 activity-related diseases.

[0003] A method for producing the compound represented by chemical formula 1 is disclosed in Korean Registered Patent No. 10-1799010.

[0004] [ka]

[0005] The conventional manufacturing method described in the aforementioned patent involves reacting aniline and a thiomorpholine derivative in the presence of triphosgene as shown in [Reaction Formula 1] below to produce compound 10 of chemical formula, which is then subjected to an N-alkylation reaction with compound 8b of chemical formula to produce compound 5a of chemical formula. The synthesized compound 5a of chemical formula is reacted with hydrazine hydrate to produce compound 6 of chemical formula, which is then reacted with difluoroacetic anhydride to produce compound 9 of chemical formula, and 1-methoxy-N-triethylammoniosulfonyl-methanemidate (Burgess reagent) is used to produce the compound represented by chemical formula 1.

[0006] [ka]

[0007] However, the synthesis method via the reaction route shown in reaction equation 1 presents numerous problems during the manufacturing process.

[0008] The triphosgene used in the production of compound 10 is highly reactive and unstable, easily decomposing upon contact with moisture and releasing toxic gases, making it vulnerable to safety concerns and potentially a major problem in mass production. Furthermore, the long reaction time of 16 hours and low reaction yield of less than 20% pose problems to production efficiency and commercial viability. Additionally, the base used in the production of compound 5a from compound 10 is sodium hydride, a flammable substance, and the reaction yield is also low. Moreover, conventional methods for producing compounds represented by chemical formula 6 and 1 require high-temperature conditions of over 100°C using microwaves, and necessitate the use of expensive and uncommon reagents such as Burgess reagent. Finally, the requirement to utilize column chromatography for purification at every step of the reaction makes industrial mass production impossible.

[0009] In other words, conventional methods involve a total of five steps to produce a target substance, a compound of chemical formula 1, with an overall yield of only about 1.5%. Furthermore, the equipment and reagents used in the reaction are expensive, the reaction time is long, and the use of flammable substances or reagents with low safety is required, making industrial mass production virtually impossible and resulting in very low economic efficiency.

[0010] Furthermore, the aforementioned patent only provides a compound represented by chemical formula 1 in an oil state and a method for producing the compound represented by chemical formula 1 in an oil state. However, the compound in an oil state is not suitable for development as a pharmaceutical, has the disadvantage of being difficult to remove residual solvents from, and is not easy to handle industrially.

[0011] Therefore, there is a need for a solid-state compound that can be manufactured safely and in large quantities, is economically produced with high yields, is pharmaceutically useful, is easy to handle during manufacturing, and allows for stable production. [Prior art documents] [Patent Documents]

[0012] [Patent Document 1] Korean Registered Patent Publication KR10-1799010 B1 [Patent Document 2] International Patent Application Publication WO2015 / 082616 A1 [Patent Document 3] International Patent Application Publication WO2021 / 246781 A1 [Patent Document 4] International Patent Application Publication WO2000 / 060044 A1 [Patent Document 5] International Patent Application Publication WO2001 / 055115 A1 [Patent Document 6] International Patent Application Publication WO2019 / 182938 A1 [Patent Document 7] International Patent Application Publication WO2002 / 000626 A1 [Patent Document 8] Chinese Patent Application Publication Gazette CN103265479 A

Summary of the Invention

Problems to be Solved by the Invention

[0013] The present invention solves the problems of existing manufacturing methods and provides a novel manufacturing method capable of economically, efficiently and safely mass-producing 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, and its pharmaceutically acceptable salts. The present invention also provides a novel manufacturing method for 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 novel manufacturing method of the compound of Chemical Formula 1 or its pharmaceutically acceptable salts.

[0014] The novel manufacturing method of the present invention can reduce the synthesis steps compared to the existing known manufacturing methods and relatively simplify the manufacturing process. Due to the efficiency of the post-treatment procedure and purification method, the compound represented by Chemical Formula 1 can be provided in a high yield and purity.

[0015] Furthermore, the reagents and reaction equipment used in the reaction can also be easily obtained. Safe reagents and equipment are used, and the reaction conditions are relatively mild. Also, processes such as column chromatography are not required, and the process procedure is efficient. It is not only possible to carry out large-scale production, but also the production process is safe and the required costs can be significantly reduced, making it economical.

[0016] The present invention provides a novel crystal 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 manufacturing the same.

Means for Solving the Problems

[0017] The present invention provides a novel method for producing a compound represented by chemical formula 1 and intermediates that can be used to produce the compound represented by chemical formula 1, namely 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.

[0018] The present invention provides a method for producing a compound represented by the following chemical formula 1, comprising the step of producing a compound represented by the following chemical formula 1 in situ from a compound represented by the following chemical formula 6:

[0019] [ka]

[0020] [ka]

[0021] In the prior art, a compound represented by chemical formula 9 is produced from a compound represented by chemical formula 6 through an N-acylation reaction, and then separated and purified to obtain the compound of chemical formula 9. Subsequently, the compound represented by chemical formula 1 is produced from the compound represented by chemical formula 9 through a cyclization reaction using the expensive 1-methoxy-N-triethylammoniosulfonyl methaneimidate (Burgess reagent):

[0022] [ka]

[0023] However, unlike the prior art described above, the present invention allows for the production of the compound represented by Chemical Formula 1 in a single manufacturing process by carrying out two reactions (N-acylation reaction / cyclization reaction) sequentially in situ, without the need for the expensive 1-methoxy-N-triethylammoniosulfonyl methaneimidate (Burgess reagent) and without the step of separately separating and purifying the compound represented by Chemical Formula 9 from the compound represented by Chemical Formula 6.

[0024] Furthermore, the present invention makes it possible to produce the compound represented by Chemical Formula 1 using only common reactors used for the production of compounds, without the need for special reactors such as microwaves.

[0025] Furthermore, the present invention allows for the acquisition of the compound represented by Chemical Formula 1 without separation and purification steps such as column chromatography, enabling large-scale industrial production of the compound represented by Chemical Formula 1, resulting in high production yields and economic efficiency. Moreover, the compound represented by Chemical Formula 1 can be obtained with high purity without the use of column chromatography.

[0026] In other words, the present invention makes it possible to mass-produce the compound represented by chemical formula 1 in high yield without complex processes, while simultaneously obtaining the compound represented by chemical formula 1 with high purity.

[0027] In one embodiment of the present invention, the step of producing a compound represented by chemical formula 1 in situ from a compound represented by chemical formula 6 is performed in the presence of a base. The reaction may also be carried out under a base, and when carried out under a base, the reaction yield and purity are excellent. For example, the base may be triethylamine, N,N-diisopropylethylamine (DIPEA), pyridine, imidazole, or a mixture thereof.

[0028] In one embodiment of the present invention, the base may be an imidazole. When the base is an imidazole, not only can the reaction yield be improved, but the reaction selectivity is excellent and the generation of by-products can be minimized, thereby eliminating the need for a complex purification process.

[0029] In one embodiment of the present invention, the compound represented by chemical formula 1 may be produced using at least one of the compounds represented by the following [chemical formula A] and the following [chemical formula B] as reactants and the compound represented by chemical formula 6.

[0030] [ka]

[0031] In the aforementioned chemical formula B, X1 may be F, Cl, Br, or I.

[0032] In one embodiment of the present invention, the compound represented by chemical formula 6 may react directly with the compound represented by chemical formula A or chemical formula B to produce the compound represented by chemical formula 1. In this case, the N-acylation reaction and the intramolecular cyclization reaction proceed entirely in situ, and unlike the prior art, the compound represented by chemical formula 1 can be produced from the compound represented by chemical formula 6 without any separate separation and purification steps for the compound represented by chemical formula 9, thereby significantly simplifying the reaction process.

[0033] In one embodiment of the present invention, the method for producing the compound represented by chemical formula 1 from the compound represented by chemical formula 6 may be carried out in the presence of a base. In this case, the generation of by-products can be significantly reduced, the yield can be significantly improved, and this is advantageous for mass production.

[0034] In one embodiment of the present invention, a method for producing a compound represented by chemical formula 1 from a compound represented by chemical formula 6 in the presence of a base is: a) A step of preparing a reaction unit 1 containing a compound represented by the following chemical formula A or B and a base; and b) The step may include mixing reaction unit 2 containing the compound represented by chemical formula 6 with reaction unit 1 to produce the compound represented by chemical formula 1:

[0035] [ka]

[0036] In the aforementioned chemical formula B, X1 may be F, Cl, Br, or I.

[0037] In one embodiment of the present invention, the reaction between the compound represented by chemical formula 6 and a compound represented by chemical formula A, such as difluoroacetic anhydride, or a compound represented by chemical formula B (specifically, the compound represented by chemical formula A) in the above production method may be carried out in the presence of a base. When the reaction is carried out in the presence of a base, the reaction yield and purity are excellent. For example, the base may be triethylamine, N,N-diisopropylethylamine (DIPEA), pyridine, imidazole, or a mixture thereof.

[0038] In one embodiment of the present invention, the base may be an imidazole. Specifically, in the reaction between a compound represented by chemical formula 6 and a compound represented by chemical formula A, such as difluoroacetic anhydride, the base may be an imidazole. When the base is an imidazole, not only can the reaction yield be further improved, but the reaction selectivity is excellent and the generation of by-products can be minimized, thereby eliminating the need for complex purification steps.

[0039] In one embodiment of the present invention, the amount of the compound represented by chemical formula A or chemical formula B, specifically difluoroacetic anhydride and the base used may be 2.0 to 4.0 equivalents per equivalent of the compound represented by chemical formula 6, and more specifically, 2.5 to 3.5 equivalents.

[0040] In one embodiment of the present invention, the reaction molar ratio of the compound represented by chemical formula A or B, specifically difluoroacetic anhydride, to the base may be 2:1 to 1:2, more specifically 1.2:1 to 1:1.2, and more specifically 1:1.

[0041] In one embodiment of the present invention, in step a), a compound represented by chemical formula A or B, specifically difluoroacetic anhydride, can react with imidazole to produce a carboimidazole derivative (a compound represented by chemical formula C).

[0042] [ka]

[0043] [ka]

[0044] [ka]

[0045] Even when the compound represented by chemical formula A or B, specifically difluoroacetic anhydride, used in the method for producing the compound represented by chemical formula 1, directly reacts with the compound represented by chemical formula 6, which is the reactant, without first reacting with the base, an in-situ reaction can be carried out in high yield. However, in this case, the reaction proceeds rapidly, and not only the compound represented by chemical formula 1 but also three or more by-products may be generated. Among these, the by-product from which the difluoromethyl group (-CF2) of the compound represented by chemical formula 1 has been removed may be difficult to remove by common purification methods used in mass production, such as recrystallization, which may be somewhat disadvantageous for mass production.

[0046] If a compound represented by chemical formula A or chemical formula B, specifically difluoroacetic anhydride, reacts with a base, such as imidazole, a carboimidazole derivative such as the compound represented by chemical formula C may react with the compound represented by chemical formula 6. In this case, not only is the generation of by-products significantly suppressed, but the compound represented by chemical formula 1 can be produced in situ from the compound represented by chemical formula 6, which may be advantageous for mass production.

[0047] According to embodiments of the present invention, in the step of producing the reaction unit 1 in step a), the mixture containing the solvent and a base, for example, imidazole, may be mixed with a compound represented by chemical formula A or chemical formula B, specifically difluoroacetic anhydride, and the temperature at this time can be maintained at 30°C or below, specifically at 0°C to 30°C, more specifically at 10°C to 25°C, and even more specifically at 10°C to 20°C.

[0048] According to an embodiment of the present invention, step a) is, A step of preparing a mixture containing imidazole and a solvent; The step of cooling the mixture to 0-10°C; and The step may include adding the compound represented by chemical formula A or chemical formula B, specifically difluoroacetic anhydride, to the cooled mixture.

[0049] In one embodiment of the present invention, the step of stirring after the addition of the compound represented by chemical formula A or chemical formula B may further be included, the stirring step being more advantageous for the formation of a carvoimidazole derivative such as the compound represented by chemical formula C, and the stirring may be carried out at room temperature for 1 hour or more.

[0050] In one embodiment of the present invention, the mixture contains the imidazole and a solvent, wherein the solvent may be dichloromethane, N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, toluene, xylene, or a mixture thereof. Preferably, it may be dichloromethane, acetonitrile, N,N-dimethylacetamide, toluene, tetrahydrofuran, or a mixture thereof, and more specifically, it may be dichloromethane.

[0051] In one embodiment of the present invention, in step b), the carboimidazole derivative, which is an intermediate produced in step a), undergoes an N-acylation reaction with the compound represented by chemical formula 6. The compound represented by chemical formula 1 can be produced through a series of intramolecular cyclization reactions. That is, in step b), the N-acylation reaction and the intramolecular cyclization reaction are carried out entirely in situ, and unlike the prior art, the compound represented by chemical formula 1 can be produced from the compound represented by chemical formula 6 without any separate separation and purification steps for the compound represented by chemical formula 9, the reaction process can be significantly simplified, the generation of by-products can be significantly reduced, the yield can also be significantly improved, and it may be advantageous for mass production.

[0052] In one embodiment of the present invention, step b) is, A step of preparing a reaction unit 2 containing the compound represented by the chemical formula 6 and a solvent; and The process may also include a step of reacting the reaction unit 2 with the reaction unit 1.

[0053] In one embodiment of the present invention, the step of reacting the reaction unit 2 and the reaction unit 1 may be carried out by adding the reaction unit 1 to the reaction unit 2, or by adding the reaction unit 2 to the reaction unit 1, and more specifically, by adding the reaction unit 1 to the reaction unit 2.

[0054] According to embodiments of the present invention, in step b), a reaction unit 2 containing a solvent and the compound represented by chemical formula 6 may be introduced into a reaction unit 1 containing a base (for example, imidazole) and a compound represented by chemical formula A or chemical formula B, specifically a carboimidazole derivative such as the compound represented by chemical formula C produced by the reaction of difluoroacetic anhydride.

[0055] In the embodiment of the present invention, the temperature can be maintained at 5°C or lower during the step of introducing the reaction unit 1 into the reaction unit 2, specifically at -15 to 5°C, and more specifically at -10 to 5°C.

[0056] In the embodiment of the present invention, after the reaction unit 1 is added to the reaction unit 2, the mixture containing the reaction unit 1 and the reaction unit 2 may be heated to 20°C or higher, more specifically to 20-45°C, and more specifically to 30-40°C.

[0057] In the embodiments of the present invention, the solvent in the reaction section 2 may be dichloromethane, N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, toluene, xylene, or a mixture thereof. Preferably, it may be dichloromethane, acetonitrile, N,N-dimethylacetamide, toluene, tetrahydrofuran, or a mixture thereof, and more specifically, it may be dichloromethane.

[0058] In the embodiments of the present invention, the solvent contained in reaction section 1 and the solvent contained in reaction section 2 may be the same or different, more specifically they may be the same, and more specifically dichloromethane.

[0059] The present invention provides a method for producing a compound represented by the following chemical formula 6.

[0060] In the present invention, the method for producing the compound represented by chemical formula 6 is: The step may include preparing a compound represented by the following chemical formula 6 from hydrazine (N2H4), or its hydrate, and a compound represented by the following chemical formula 5, in the presence of a solvent containing a C1-C6 linear or branched alcohol, or a mixture of a C1-C6 linear or branched alcohol and water:

[0061] [ka]

[0062] [ka]

[0063] In the above chemical formula 5, R may be a C1-C6 linear 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.

[0064] In the embodiments of the present invention, the reaction may be carried out under mild conditions with high yield without the use of microwaves.

[0065] In the embodiments of the present invention, the above-described manufacturing method may involve obtaining a compound of chemical formula 6, which is a hydrazide derivative, through a hydrazide reaction between the compound represented by chemical formula 5 and hydrazine or its hydrate.

[0066] In embodiments of the present invention, when the solvent is a C1-C6 linear or branched alcohol, the C1-C6 linear or branched alcohol may be methanol, isopropyl alcohol, butanol, or a mixture thereof, and specifically, it may be methanol. For small-scale production of about 100 g or less, an alcohol (e.g., methanol) may be used as the solvent alone.

[0067] In embodiments of the present invention, the solvent may be a mixture of a linear or branched C1-C6 alcohol and water (e.g., distilled water), in which case the linear or branched C1-C6 alcohol may be a mixture of water and at least one selected from methanol, ethanol, isopropyl alcohol, and butanol, and more specifically, the solvent may be a mixture of methanol and water.

[0068] In the embodiments of the present invention, the use of a mixture of alcohol and water as a solvent can increase the stability of hydrazine or its hydrate while simultaneously increasing its reactivity. When alcohol alone is used as the sole solvent in production processes requiring a scale of kilograms or more, a phenomenon may occur where the compound represented by chemical formula 6 precipitates during the reaction, followed by the precipitation of the starting material, the compound represented by chemical formula 5, and the reaction is not completed. Specifically, in production processes requiring a scale of kilograms or more, the compound represented by chemical formula 6 is well soluble in distilled water. Therefore, if distilled water is mixed with the solvent, the reaction will continue and be completed without the precipitation of the compound represented by chemical formula 6 during the reaction.

[0069] In embodiments of the present invention, when the solvent is a mixture of alcohol and water (e.g., distilled water), the volume ratio of alcohol to water (e.g., distilled water) may be about 10:1 to about 1:1, and specifically, the volume ratio may be about 2:1.

[0070] In the examples of the present invention, the amount of hydrazine or its hydrate used may be 3 to 10 equivalents per equivalent of the compound represented by chemical formula 5, and more specifically, it may be 5 to 7 equivalents.

[0071] In the embodiments of the present invention, the reaction between the compound represented by chemical formula 5 and hydrazine or its hydrate may be carried out at 75°C or lower, more specifically at 40 to 70°C, and more specifically at 58 to 68°C.

[0072] In the embodiments of the present invention, the step of purifying the compound represented by chemical formula 6, which is produced by the reaction of the compound represented by chemical formula 5 with hydrazine or its hydrate, may be further included.

[0073] In the embodiments of the present invention, a linear or branched C1-C6 alcohol may be added as a solvent in the purification step. Specifically, methanol, ethanol, isopropyl alcohol, butanol, or a mixture thereof may be added as a solvent, and more specifically, ethanol may be added as a solvent.

[0074] In the embodiments of the present invention, the solvent used in the reaction between the compound represented by chemical formula 5 and hydrazine or its hydrate may include a mixture of methanol and water (e.g., distilled water), and ethanol may be added as a solvent in the step of purifying the compound represented by chemical formula 6.

[0075] The present invention provides a method for producing a compound represented by the following chemical formula 5.

[0076] In the present invention, the method for producing the compound represented by chemical formula 5 may include the step of reacting the compound represented by chemical formula 3 with the compound represented by chemical formula 4 in the presence of a base to produce the compound represented by chemical formula 5:

[0077] [ka]

[0078] [ka]

[0079] [ka]

[0080] In chemical formulas 3 and 5, R is a C1-C6 linear or branched alkyl or benzyl, and in chemical formula 4, X may be F, Cl, Br, or I. Specifically, in chemical formulas 3 and 5, R may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or benzyl; in chemical formula 4, X may be Cl, Br, or I; more specifically, in chemical formulas 3 and 5, R may be methyl or benzyl; in chemical formula 4, X may be Cl; and even more specifically, R may be methyl and X may be Cl.

[0081] In the embodiments of the present invention, the reaction between the compound represented by chemical formula 3 and the compound represented by flag chemical formula 4 may be carried out in the presence of a base, the base may be triethylamine, N,N-diisopropylethylamine, imidazole, pyridine, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, or a mixture thereof, more specifically triethylamine, N,N-diisopropylethylamine, imidazole, sodium bicarbonate, or a mixture thereof may be used, and more specifically, N,N-diisopropylethylamine may be used.

[0082] In the embodiments of the present invention, the base may be used in an amount of 1.0 to 3.0 equivalents per equivalent of the compound represented by chemical formula 3, and more specifically, in an amount of 1.3 to 2.0 equivalents.

[0083] In the embodiments of the present invention, the compound represented by chemical formula 4 may be used in an amount of 1.0 to 3.0 equivalents per equivalent of the compound represented by chemical formula 3, and more specifically, in an amount of 1.1 to 1.5 equivalents.

[0084] In the embodiments of the present invention, in the reaction between the compound represented by chemical formula 3 and the compound represented by chemical formula 4, the solvent may be N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, toluene, benzene, xylene, or a mixture thereof. More specifically, N,N-dimethylacetamide, tetrahydrofuran, toluene, or a mixture thereof may be used, and more specifically, toluene may be used.

[0085] In the embodiments of the present invention, the reaction temperature between the compound represented by chemical formula 3 and the compound represented by chemical formula 4 may be 60 to 110°C, more specifically 75 to 100°C, and more specifically 75 to 90°C.

[0086] In the embodiments of the present invention, a purification step may be performed after the reaction between the compound represented by chemical formula 3 and the compound represented by chemical formula 4, and a compound represented by chemical formula 5 with a high purity of 99% or more can be obtained through the purification step.

[0087] In the embodiments of the present invention, the solvent in the purification step is methanol, ethanol, isopodium Ropyr alcohol, butyl alcohol, methyl tert-butyl ether (MTBE), Diisopropyl ether, heptane, hexane, or mixtures thereof may be used, and the compound represented by chemical formula 5 may be purified by slurring or recrystallization in the solvent. Specifically, the solvent in the purification step may be methanol, ethanol, isopropyl alcohol, methyl tert-butyl ether (MTBE), diisopropyl ether A tert-butyl ether or a mixture thereof may be used, and more specifically, at least one selected from the group consisting of methanol and methyl tert-butyl ether (MTBE) It may also be used, for example, methanol and methyl tert-butyl ether (MTB E) may be used in its entirety.

[0088] In the embodiments of the present invention, the purification step for the compound represented by chemical formula 5 may be carried out at 30 to 70°C, and more specifically, at 30 to 65°C.

[0089] The present invention provides a method for producing the compound represented by the chemical formula 3.

[0090] [ka]

[0091] In the above chemical formula 3, R may be a C1-C6 linear 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.

[0092] In conventional technology, the compound represented by compound 6 is produced from a compound represented by the following chemical formula 10, obtained by reacting aniline and a thiomorpholine derivative in the presence of triphosgene, through a substitution reaction and a hydrazide reaction. However, problems arise with the use of triphosgene, which is fragile, and sodium hydride, which is a flammable substance, as well as the long reaction time, low production yield, production efficiency, and economics. Furthermore, the hydrazide reaction may be unsuitable for mass production because it is performed under microwave conditions.

[0093] [ka]

[0094] In the manufacturing method according to the present invention, a compound represented by chemical formula 3, which can be easily obtained in high purity and high yield, may be used as an intermediate.

[0095] In the manufacturing method according to the present invention, the compound represented by chemical formula 3 is used, and its stability and safety have been confirmed. It is produced using readily available reaction reagents and manufacturing equipment, with a short reaction time and high production yield. Based on this, high-purity target compounds can be manufactured, enabling commercial mass production through efficient process procedures, while achieving safety and economic cost reduction.

[0096] In the embodiments of the present invention, the compound represented by chemical formula 3 may be produced by the following two methods.

[0097] In the present invention, method 1 for producing the compound represented by the following chemical formula 3 is: a) A step of preparing a compound represented by chemical formula 8 using a halogenating agent from a compound represented by chemical formula 7 below; and b) The step of reacting a compound represented by the following chemical formula 8 with aniline in the presence of a base to produce the compound represented by the chemical formula 3 may also be included:

[0098] [ka]

[0099] [ka]

[0100] [ka]

[0101] In the aforementioned chemical formulas 3, 7, and 8, R may be a C1-C6 linear or branched alkyl or benzyl group, and in chemical formula 8, X may be F, Cl, Br, or I. More specifically, in the aforementioned chemical formulas 3, 7, and 8, R may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or benzyl; in chemical formula 8, X may be Cl, Br, or I; more specifically, in chemical formulas 3, 7, and 8, R may be methyl or benzyl; in chemical formula 8, X may be Cl; and even more specifically, R may be methyl and X may be Cl.

[0102] In the embodiments of the present invention, the method for producing the compound represented by chemical formula 3 is carried out in two steps, but when producing the compound represented by chemical formula 3, a low-cost starting material represented by chemical formula 7 may be used, and in the process of producing the compound represented by chemical formula 8, separate purification and fractionation may be performed. This method does not require a separation step, does not use hazardous reagents, is advantageous for mass production, offers excellent production yield, and is safe. In other words, after producing the compound represented by chemical formula 8, the solvent may be concentrated and the compound represented by chemical formula 8 may be used directly as a reactant in the production of the compound represented by chemical formula 3 without separating it into a solid state.

[0103] The present invention provides a method for producing a compound represented by the following chemical formula 8a using trichloroisocyanuric acid (TCCA) reagent alone with a compound represented by the following chemical formula 7:

[0104] [ka]

[0105] [ka]

[0106] In the aforementioned chemical formulas 7 and 8a, R may be a C1-C6 linear alkyl or benzyl, more specifically, in the aforementioned chemical formulas 7 and 8a, R may be methyl, ethyl, n-propyl, n-butyl, n-pentyl, or benzyl, more specifically, in the aforementioned chemical formulas 7 and 8a, R may be methyl or benzyl, and even more specifically, R may be methyl.

[0107] In the embodiments of the present invention, in the method for producing the compound represented by chemical formula 3, the halogenating reagent in step a) may be iodine, copper iodide, bromine, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), trichloroisocyanuric acid (TCCA), or a mixture thereof. More specifically, N-bromosuccinimide (NBS), trichloroisocyanuric acid (TCCA), or a mixture thereof may be used, and more specifically, trichloroisocyanuric acid (TCCA) may be used.

[0108] In the embodiments of the present invention, in the method for producing the compound represented by chemical formula 3, in step a), X may be Cl, and in this case, the halogenating reagent may be trichloroisocyanuric acid (TCCA). In the present invention, a halogenation reaction (specifically, a chloromination reaction) can be carried out in one step using trichloroisocyanuric acid (TCCA), which can increase reaction efficiency, simplify the process, and be advantageous for mass production.

[0109] In the embodiments of the present invention, trichloroisocyanuric acid (TCCA) may be used alone as the halogenating reagent used in the method for producing the compound represented by chemical formula 8a from the compound represented by chemical formula 7.

[0110] In the embodiment of the present invention, in the method for producing the compound represented by chemical formula 3, step In a method for producing a compound represented by chemical formula 8a from compound a) and the compound represented by chemical formula 7, the step of producing a compound represented by chemical formula 8, specifically the compound represented by chemical formula 8a, using a halogenating reagent on the compound represented by chemical formula 7 may be carried out without the use of a benzamide catalyst.

[0111] In the prior art, the step of treating a compound represented by chemical formula 7 with a halogenating reagent to obtain a benzyl halide derivative may be performed by methods already known (WO2021 / 246781, WO2000 / 060044, WO2001 / 055115, WO2019 / 182938, WO2002 / 000626), but these methods have the disadvantage of long reaction times and low yields. In particular, the chlorination method for the compound represented by chemical formula 7 has the disadvantage of requiring two steps: an oxidation step and a chlorination step. However, the present invention solves these problems by successfully performing chlorination in only one step with a short reaction time using trichloroisocyanuric acid (TCCA), enabling the production of the compound represented by chemical formula 8, specifically the compound represented by chemical formula 8a, from the compound represented by chemical formula 7 with high efficiency and a simple process.

[0112] Furthermore, among the existing publicly known methods, there is a method using trichloroisocyanuric acid (TCCA) (CN 103265479), but this is limited to substances in which the substituent introduced to pyridine is a tert-butyl ester group, and requires the use of a benzamide catalyst. If a pyridine derivative with a tert-butyl ester group introduced is used as an intermediate by applying a conventionally known method, the compound subsequently produced may not undergo the hydrazide reaction with hydrazine or its hydrate.

[0113] Unlike conventional methods, the present invention uses a starting material that incorporates a substituted pyridine derivative that can successfully proceed to the hydrazide reaction, such as a methyl ester group. When X is Cl in the compound represented by chemical formula 8, the present invention provides an efficient chlorination reaction that utilizes trichloroisocyanuric acid (TCCA) alone without using a benzamide catalyst.

[0114] In the embodiments of the present invention, in the method for producing the compound represented by chemical formula 3, the solvent in step a) and the method for producing the compound represented by chemical formula 8 using a halogenating reagent on the compound represented by chemical formula 7 may be tetrahydrofuran, ethyl acetate, acetic acid, toluene, xylene, benzene, dichloromethane, dichloroethane, chloroform, diisopropyl ether, methyl tert-butyl ether, or a mixture thereof. stomach.

[0115] In the embodiments of the present invention, when the halogenating reagent is N-bromosuccinimide (NBS), acetic acid can be used as the solvent, and when the halogenating reagent is trichloroisocyanuric acid (TCCA), dichloromethane can be used as the solvent.

[0116] In the embodiments of the present invention, in the method for producing the compound represented by chemical formula 3, in step a) and the method for producing the compound represented by chemical formula 8 using a halogenating reagent on the compound represented by chemical formula 7, if the halogenating reagent is N-bromosuccinimide (NBS), it may be used in an amount of 2.0 to 4.0 equivalents per equivalent of the starting material, the compound represented by chemical formula 7, and more specifically, in an amount of 3.0 to 3.5 equivalents.

[0117] In an embodiment of the present invention, in the method for producing the compound represented by chemical formula 3, in step a) and the method for producing the compound represented by chemical formula 8a using a halogenating reagent on the compound represented by chemical formula 7, if the halogenating reagent is trichloroisocyanuric acid (TCCA), then the amount of halogenating reagent per equivalent of the compound represented by chemical formula 7 is 1.0 It may be used in amounts of up to 2.0 equivalents, specifically, in amounts of 1.1 to 1.5 equivalents.

[0118] In the embodiments of the present invention, in the method for producing the compound represented by chemical formula 3, the reaction temperature in step a) may be 50 to 80°C, and more specifically, 55 to 65°C, when the halogenating reagent is N-bromosuccinimide (NBS).

[0119] In the embodiments of the present invention, in the method for producing the compound represented by chemical formula 3, the reaction temperature in step a) and the method for producing the compound represented by chemical formula 8a using a halogenating reagent on the compound represented by chemical formula 7 may be 10 to 30°C, and more specifically, 15 to 20°C, when the halogenating reagent is trichloroisocyanuric acid (TCCA).

[0120] In the embodiments of the present invention, the compound represented by chemical formula 8 can be subjected to an N-alkylation reaction in the presence of aniline and a base to obtain the compound represented by chemical formula 3.

[0121] This invention provides a method for producing a compound represented by the following chemical formula 3 by reacting a compound represented by the following chemical formula 8 with aniline in the presence of a base:

[0122] [ka]

[0123] [ka]

[0124] In chemical formulas 3 and 8, R may be a C1-C6 linear or branched alkyl or benzyl, and in chemical formula 8, X may be F, Cl, Br, or I. Specifically, in chemical formulas 3 and 8, R may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, or benzyl, and in chemical formula 8, X may be Cl, Br, or I. More specifically, in chemical formulas 3 and 8, R may be methyl or benzyl, and in chemical formula 8, X may be Cl. Even more specifically, R may be methyl and X may be Cl.

[0125] In the prior art (WO2015 / 082616), N-alkylation is performed using aniline substituted with a protecting group, and then a deprotection reaction is carried out to obtain the hydrochloride salt of the compound represented by chemical formula 3. However, in the production method of the present invention, protection / deprotection reactions are not performed directly Because contact reactions can be performed, the process steps can be shortened.

[0126] In the embodiments of the present invention, when X is Cl in the compound represented by chemical formula 8, halogen exchange reagents such as potassium brominated, potassium iodide, tetrabutylammonium bromide (TBAB), or mixtures thereof may be used to increase the reaction rate. Specifically, potassium iodide may be used, in which case 0.1 to 1.0 equivalents of halogen exchange reagent may be used per equivalent of the compound represented by chemical formula 8, and specifically, 0.3 to 0.5 equivalents may be used.

[0127] In the embodiments of the present invention, in the step of reacting the compound represented by chemical formula 8 with aniline, the solvent may be N,N-dimethylacetamide, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, acetonitrile, or a mixture thereof. More specifically, N,N-dimethylacetamide, N,N-dimethylformamide, or a mixture thereof may be used, and more specifically, N,N-dimethylacetamide may be used.

[0128] In the embodiments of the present invention, in the step of reacting the compound represented by chemical formula 8 with aniline, the base may be sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine, or a mixture thereof, and specifically, sodium bicarbonate or sodium carbonate may be used.

[0129] In the embodiments of the present invention, in the step of reacting the compound represented by chemical formula 8 with aniline, the amount of base used may be 1.0 to 3.0 equivalents per equivalent of the compound represented by chemical formula 8, and more specifically, 1.5 to 2.0 equivalents may be used.

[0130] In the embodiments of the present invention, when aniline is used, 1.0 to 3.0 equivalents of aniline may be used per equivalent of the compound represented by chemical formula 8, and more specifically, 2.0 to 2.5 equivalents may be used. In the embodiments of the present invention, the production method 1 may further include a purification step for the compound represented by chemical formula 3. Through the purification step, the compound represented by chemical formula 3 can be obtained with a purity of 95% or more.

[0131] In embodiments of the present invention, the solvent used in the purification step may be methanol, ethanol, isopropyl alcohol, butanol, water (e.g., distilled water), or a mixture thereof, to purify the compound represented by chemical formula 3 through slurrying or recrystallization. Specifically, the solvent used in the purification step may be a mixture of one alcohol selected from methanol, ethanol, and isopropyl alcohol and water (e.g., distilled water), and more specifically, a mixture of methanol and distilled water may be used.

[0132] In the embodiments of the present invention, the purification step for the compound represented by chemical formula 3 may be carried out at 40 to 60°C, and more specifically, at 45 to 55°C.

[0133] In the present invention, the method for producing the compound represented by chemical formula 3, 2 is: The step may include preparing a compound represented by the following chemical formula 3 from a compound represented by the following chemical formula 2 in the presence of aniline and a reducing agent:

[0134] [ka]

[0135] [ka]

[0136] In the above chemical formula 2 or 3, R may be a C1-C6 linear 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.

[0137] In the embodiment of the present invention, the production method 2 can produce the compound represented by chemical formula 3 by performing a reductive amination reaction between the compound represented by chemical formula 2 and aniline.

[0138] In the embodiments of the present invention, the amount of aniline used may be 0.95 to 1.3 equivalents per equivalent of the compound represented by chemical formula 2, and more specifically, 0.95 to 1.05 equivalents may be used.

[0139] In the embodiments of the present invention, the reducing agent may be sodium borohydride (NaBH4), sodium cyanoborohydride (NaBH3CN), sodium triacetoxyborohydride (NaBH(OAc)3), or a mixture thereof. Specifically, sodium triacetoxyborohydride (NaBH(OAc)3) may be used.

[0140] In the embodiments of the present invention, the reducing agent may be used in an amount of 1.0 to 2.0 equivalents per equivalent of the compound represented by chemical formula 2, and more specifically, 1.3 to 1.7 equivalents may be used.

[0141] In the embodiments of the present invention, the reaction in which the compound represented by chemical formula 2 reacts with aniline to produce the compound represented by chemical formula 3 may be carried out at a temperature of 10 to 30°C, and more specifically, at a temperature of 15 to 25°C.

[0142] In the embodiments of the present invention, the step of producing a compound represented by the following chemical formula 3 from the compound represented by the chemical formula 2 is: A step of producing a mixture containing the compound of chemical formula 2 and aniline; and The process may also include a step of reacting the mixture with a reducing agent.

[0143] In the embodiments of the present invention, the step of producing a compound represented by the following chemical formula 3 from the compound represented by the chemical formula 2 is: A step of preparing a reaction unit 1 containing a compound represented by chemical formula 2, aniline, and a solvent; and The process may include a step of reacting reaction section 2, which contains a reducing agent and a solvent, with reaction section 1.

[0144] In the embodiment of the present invention, the step of reacting the reaction unit 2 with the reaction unit 1 may be the step of adding the reaction unit 1 to the reaction unit 2.

[0145] In the embodiments of the present invention, the solvents used in reaction section 1 and reaction section 2 may be the same or different, and the solvent may be tetrahydrofuran, methanol, ethanol, isopropyl alcohol, acetonitrile, dichloromethane, toluene, or a mixture thereof, and more specifically, it may be dichloromethane, and more specifically, the solvent used in both reaction section 1 and reaction section 2 may be dichloromethane.

[0146] In embodiments of the present invention, the compound represented by chemical formula 2 can produce an imine intermediate through a reaction with aniline, and after the imine intermediate is produced, the reaction unit 1 containing the imine intermediate can be added to the reaction unit 2 containing a reducing agent to carry out the reaction.

[0147] In the embodiments of the present invention, the production of the reaction unit 1 may be carried out by synthesizing an imine intermediate through the reaction of the compound represented by chemical formula 2 with aniline, in which case the imine intermediate may be synthesized by stirring the mixture of the compound represented by chemical formula 2 and the reaction unit 1 containing aniline, and the stirring may be carried out for 1 to 2 hours.

[0148] In the embodiments of the present invention, the imine intermediate may be a compound represented by the following chemical formula 11.

[0149] [ka]

[0150] In the above chemical formula 11, R may be a C1-C6 linear 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.

[0151] In the embodiment of the present invention, the step of adding the reaction unit 1 to the reaction unit 2 may be performed by adding the reaction unit 1 to the reaction unit 2, which has been cooled to 5°C or lower, specifically to 0°C to 5°C, while maintaining a temperature of 10°C or lower, specifically to 0°C to 10°C.

[0152] In the embodiment of the present invention, after the addition is complete, the temperature of the mixing section including reaction section 1 and reaction section 2 may rise to 15 to 30°C, specifically, to 15 to 25°C.

[0153] In embodiments of the present invention, the step of producing the compound represented by chemical formula 3 from the compound represented by chemical formula 2 may be carried out in the presence of an acid. Specifically, the reaction unit 1 may further contain an acid additive such as acetic acid to accelerate the reaction rate of the formation of the imine intermediate. Activation may be sufficiently performed even without the additive in the reaction unit 1, but if an acid additive is further included, the reaction in which the compound represented by chemical formula 2 is spontaneously reduced can be reduced, thereby relatively improving the purity of the compound represented by chemical formula 3.

[0154] The present invention provides a method 1 for producing a compound represented by the following chemical formula 1.

[0155] In the present invention, the method for producing the compound represented by chemical formula 1 is: 1) A step of preparing a compound represented by the chemical formula 8 using a halogenating agent from a compound represented by the chemical formula 7 below; 2) A step of reacting the compound represented by chemical formula 8 with aniline in the presence of a base to produce the compound represented by chemical formula 3; 3) A step of reacting the compound represented by 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) The step of reacting hydrazine or its hydrate with the compound represented by the chemical formula 5 to obtain the compound represented by the following chemical formula 6; and 5) The step may include producing the compound represented by chemical formula 1 in situ from the compound represented by chemical formula 6:

[0156] [ka]

[0157] [ka]

[0158] (In the above chemical formula 3, R may be a C1-C6 linear or branched alkyl or benzyl.)

[0159] [ka]

[0160] (In the above chemical formula 4, X may be F, Cl, Br, or I.)

[0161] [ka]

[0162] (In the above chemical formula 5, R may be a C1-C6 linear or branched alkyl or benzyl.)

[0163] [ka]

[0164] [ka]

[0165] (In the above chemical formula 7, R may be a C1-C6 linear or branched alkyl or benzyl.)

[0166] [ka]

[0167] (In the above chemical formula 8, R is a C1-C6 linear or branched alkyl or benzyl, and X may be F, Cl, Br, or I).

[0168] In one embodiment of the present invention, in a production method 1 for producing a compound of chemical formula 1 using a compound represented by chemical formula 7 as a starting material and a compound represented by chemical formula 8, a compound represented by chemical formula 3, a compound represented by chemical formula 4, a compound represented by chemical formula 5, and a compound represented by chemical formula 6, steps 1), 2), 3), 4), and 5) are all applicable to the methods for producing the compound represented by chemical formula 8a, the method for producing the compound represented by chemical formula 3, the method for producing the compound represented by chemical formula 5, the method for producing the compound represented by chemical formula 6, and the method for producing the compound represented by chemical formula 1, provided that the details described in detail do not contradict each other. For example, reaction conditions and effects such as solvent, reducing agent, halogenating agent, base, temperature, and content are all applicable to the production method 1 for producing the compound of chemical formula 1.

[0169] The present invention provides a method 2 for producing a compound represented by the following chemical formula 1.

[0170] In the present invention, the method for producing the compound represented by the following chemical formula 1 is: 1) A step of preparing a compound represented by the following chemical formula 3 from a compound represented by the following chemical formula 2 in the presence of aniline and a reducing agent; 2) A step of reacting a compound represented by chemical formula 3 and a compound represented by chemical formula 4 in the presence of a base to obtain a compound represented by chemical formula 5; 3) The step of reacting hydrazine or its hydrate with a compound represented by the following chemical formula 5 to obtain a compound represented by the following chemical formula 6; and 4) The step may include preparing a compound represented by the following chemical formula 1 in situ from a compound represented by the following chemical formula 6:

[0171] [ka]

[0172] [ka]

[0173] (In the above chemical formula 2, R may be a C1-C6 alkyl or benzyl.)

[0174] [ka]

[0175] (In the above chemical formula 3, R may be a C1-C6 linear or branched alkyl or benzyl.)

[0176] [ka]

[0177] (In the above chemical formula 4, X may be F, Cl, Br, or I.)

[0178] [ka]

[0179] (In the above chemical formula 5, R may be a C1-C6 linear or branched alkyl or benzyl.)

[0180] [ka]

[0181] In one embodiment of the present invention, in a production method 2 for producing a compound of chemical formula 1 using a compound represented by chemical formula 2 as a starting material and a compound represented by chemical formula 3, a compound represented by chemical formula 4, a compound represented by chemical formula 5, and a compound represented by chemical formula 6, steps 1), 2), 3), and 4) are all applicable to the production method 2 for producing the compound represented by chemical formula 3, the method for producing the compound represented by chemical formula 5, the method for producing the compound represented by chemical formula 6, and the method for producing the compound represented by chemical formula 1, provided that the details described are not contradictory. For example, reaction conditions and effects such as solvent, reducing agent, halogenating agent, base, temperature, and content are all applicable to the production method 2 for producing the compound of chemical formula 1.

[0182] The production methods 1 and 2 for producing the compound of chemical formula 1 according to the present invention are shown in the reaction equation below, as shown in Figure 1 [Reaction Equation 2].

[0183] [ka]

[0184] In the above reaction formula 2, R may be a linear or branched alkyl group of C1 to C6, or benzyl, X may be F, Cl, Br, or I, and X1 may be F, Cl, Br, or I.

[0185] The present invention provides a method 3 for producing a compound represented by the following chemical formula 1.

[0186] In the present invention, the method for producing the compound represented by the following chemical formula 1 is: 1) The step of reacting hydrazine or its hydrate with a compound represented by the following chemical formula 5 to obtain a compound represented by the following chemical formula 6; and 2) The step may include preparing a compound represented by the following chemical formula 1 in situ from a compound represented by the following chemical formula 6:

[0187] [ka]

[0188] [ka]

[0189] (In the above chemical formula 5, R may be a C1-C6 linear or branched alkyl or benzyl.)

[0190] [ka]

[0191] In an embodiment of the present invention, in a manufacturing method 3 for producing the compound represented by chemical formula 1, The method for producing the compound represented by the chemical formula 5 is as follows: The step of reacting a compound represented by the following chemical formula 3 with a compound represented by the following chemical formula 4 in the presence of a base to produce the compound represented by the chemical formula 5 may also be included:

[0192] [ka]

[0193] (In the above chemical formula 3, R may be a C1-C6 linear or branched alkyl or benzyl.)

[0194] [ka]

[0195] (In the above chemical formula 4, X may be F, Cl, Br, or I.)

[0196] In an embodiment of the present invention, in a manufacturing method 3 for producing the compound represented by chemical formula 1, The method for producing the compound represented by the chemical formula 5 is as follows: The steps of reacting a compound represented by chemical formula 8 with aniline in the presence of a base to produce a compound represented by chemical formula 3; and The step of reacting a compound represented by the following chemical formula 3 with a compound represented by the following chemical formula 4 in the presence of a base to produce the compound represented by the chemical formula 5 may also be included:

[0197] [ka]

[0198] (In the above chemical formula 3, R may be a C1-C6 linear or branched alkyl or benzyl.)

[0199] [ka]

[0200] (In the above chemical formula 4, X may be F, Cl, Br, or I.)

[0201] [ka]

[0202] (In the above chemical formula 8, R is a C1-C6 linear or branched alkyl or benzyl, and X may be F, Cl, Br, or I.)

[0203] In an embodiment of the present invention, in a manufacturing method 3 for producing the compound represented by chemical formula 1, The method for producing the compound represented by the following Chemical Formula 5 may include: a step of producing a compound represented by the following Chemical Formula 8 from a compound represented by the following Chemical Formula 7 using a halogenating reagent; a step of reacting a compound represented by the following Chemical Formula 8 with aniline in the presence of a base to produce a compound represented by Chemical Formula 3; and a step of reacting a compound represented by the following Chemical Formula 3 with a compound represented by the following Chemical Formula 4 in the presence of a base to produce a compound represented by Chemical Formula 5:

[0204]

Chem.

[0205] (In the above Chemical Formula 3, R may be a C1-C6 straight-chain or branched-chain alkyl or benzyl.)

[0206]

Chem.

[0207] (In the above Chemical Formula 4, X may be F, Cl, Br, or I.)

[0208]

Chem.

[0209] (In the above Chemical Formula 7, R may be a C1-C6 straight-chain or branched-chain alkyl or benzyl.)

[0210]

Chem.

[0211] (In the above Chemical Formula 8, R is a C1-C6 straight-chain or branched-chain alkyl or benzyl, and X may be F, Cl, Br, or I.)

[0212] In an embodiment of the present invention, in Production Method 3 for producing the compound represented by Chemical Formula 1, the production method of the compound represented by Chemical Formula 5 is a step of producing a compound represented by the following Chemical Formula 3 from a compound represented by the following Chemical Formula 2 in the presence of aniline and a reducing agent; and it may include a step of reacting a compound represented by the following Chemical Formula 3 and a compound represented by the following Chemical Formula 4 in the presence of a base to produce a compound represented by the following Chemical Formula 5:

[0213]

Chemical formula

[0214] (In the above Chemical Formula 2, R may be C1-C6 alkyl or benzyl)

[0215]

Chemical formula

[0216] (In the above Chemical Formula 3, R may be C1-C6 linear or branched alkyl or benzyl)

[0217]

Chemical formula

[0218] (In the above Chemical Formula 4, X may be F, Cl, Br, or I)

[0219] In one embodiment of the present invention, the manufacturing method 3 for producing the compound of chemical formula 1 is applicable to the manufacturing method for producing the compound represented by chemical formula 8a, the manufacturing method 1 for producing the compound represented by chemical formula 3, the manufacturing method 2 for producing the compound represented by chemical formula 3, the manufacturing method for producing the compound represented by chemical formula 5, the manufacturing method for producing the compound represented by chemical formula 6, and the manufacturing method for producing the compound represented by chemical formula 1, as long as the details described are not contradictory. For example, reaction conditions and effects such as solvent, reducing agent, halogenating agent, base, temperature, and content are all applicable to the manufacturing method 3 for producing the compound of chemical formula 1.

[0220] The present invention provides a method 1 for producing a compound represented by the following chemical formula 5.

[0221] In the present invention, the method for producing the compound represented by chemical formula 5 is as follows: 1) A step of preparing a compound represented by the chemical formula 8 using a halogenating agent from a compound represented by the chemical formula 7 below; 2) The step of reacting a compound represented by chemical formula 8 with aniline in the presence of a base to produce a compound represented by chemical formula 3; and 3) The step may include reacting a compound represented by chemical formula 3 with a compound represented by chemical formula 4 in the presence of a base to obtain a compound represented by chemical formula 5:

[0222] [ka]

[0223] (In the above chemical formula 3, R may be a C1-C6 linear or branched alkyl or benzyl.)

[0224] [ka]

[0225] (In the above chemical formula 4, X may be F, Cl, Br, or I.)

[0226] [ka]

[0227] (In the above chemical formula 5, R may be a C1-C6 linear or branched alkyl or benzyl.)

[0228] [ka]

[0229] [ka]

[0230] (In the above chemical formula 7, R may be a C1-C6 linear or branched alkyl or benzyl.)

[0231] [ka]

[0232] (In the above chemical formula 8, R is a C1-C6 linear or branched alkyl or benzyl, and X may be F, Cl, Br, or I.)

[0233] In one embodiment of the present invention, in a production method 1 for producing a compound of chemical formula 5 using a compound represented by chemical formula 7 as a starting material and a compound represented by chemical formula 8, a compound represented by chemical formula 3, and a compound represented by chemical formula 4, steps 1), 2), and 3) are all applicable to the production method 1 for producing the compound represented by chemical formula 3 and the method for producing a compound represented by chemical formula 5 using a compound represented by chemical formula 3 as a starting material, provided that the details described are not contradictory. For example, reaction conditions and effects such as solvent, reducing agent, halogenating agent, base, temperature, and content are all applicable to the production method 1 for producing the compound of chemical formula 5.

[0234] The present invention provides a method 2 for producing a compound represented by the following chemical formula 5.

[0235] In the present invention, the method for producing the compound represented by the following chemical formula 5 is: 1) The step of reacting a compound represented by chemical formula 8 with aniline in the presence of a base to produce a compound represented by chemical formula 3; and 2) The step may include reacting a compound represented by the following chemical formula 3 with a compound represented by the following chemical formula 4 in the presence of a base to obtain a compound represented by the following chemical formula 5:

[0236] [ka]

[0237] (In the above chemical formula 3, R may be a C1-C6 linear or branched alkyl or benzyl.)

[0238] [ka]

[0239] (In the above chemical formula 4, X may be F, Cl, Br, or I.)

[0240] [ka]

[0241] (In the above chemical formula 5, R may be a C1-C6 linear or branched alkyl or benzyl.)

[0242] [ka]

[0243] (In the above chemical formula 8, R is a C1-C6 linear or branched alkyl or benzyl, and X may be F, Cl, Br, or I.)

[0244] In one embodiment of the present invention, in a production method 2 for producing a compound of chemical formula 5 using a compound represented by chemical formula 8 as a starting material and a compound represented by chemical formula 3 and a compound represented by chemical formula 4, steps 1) and 2) are all applicable to the production method 1 for producing the compound represented by chemical formula 3 and the method for producing the compound represented by chemical formula 5 using a compound represented by chemical formula 3 as a starting material, provided that the details described in detail do not contradict each other. For example, reaction conditions and effects such as solvent, reducing agent, halogenating agent, base, temperature, and content are all applicable to the production method 2 for producing the compound of chemical formula 5.

[0245] The present invention provides a method 3 for producing a compound represented by the following chemical formula 5.

[0246] In the present invention, method 3 for producing the compound represented by the following chemical formula 5 is: 1) The step of producing a compound represented by the following chemical formula 3 from a compound represented by the following chemical formula 2 in the presence of aniline and a reducing agent; and 2) The step may include reacting a compound represented by the following chemical formula 3 with a compound represented by the following chemical formula 4 in the presence of a base to obtain a compound represented by the following chemical formula 5:

[0247] [ka]

[0248] (In the above chemical formula 2, R may be a C1-C6 alkyl or benzyl.)

[0249] [ka]

[0250] (In the above chemical formula 3, R may be a C1-C6 linear or branched alkyl or benzyl.)

[0251] [ka]

[0252] (In the above chemical formula 4, X may be F, Cl, Br, or I.)

[0253] [ka]

[0254] (In the above chemical formula 5, R may be a C1-C6 linear or branched alkyl or benzyl.)

[0255] In one embodiment of the present invention, in a production method 3 for producing a compound of chemical formula 5 using a compound represented by chemical formula 2 as a starting material and a compound represented by chemical formula 3 and a compound represented by chemical formula 4, steps 1) and 2) are all applicable to the production method 2 for producing the compound represented by chemical formula 3, the production method for producing the compound represented by chemical formula 5, the production method for producing the compound represented by chemical formula 6, and the production method for producing the compound represented by chemical formula 1, provided that the details described are not inconsistent. For example, reaction conditions and effects such as solvent, reducing agent, halogenating agent, base, temperature, and content are all applicable to the production method 3 for producing the compound of chemical formula 5.

[0256] The present invention relates to N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthio, represented by the following chemical formula 1. This provides a novel crystalline form of morpholine-4-carboxamide 1,1-dioxide.

[0257] [ka]

[0258] Specifically, the present invention provides novel crystalline forms I, II, and III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide.

[0259] In Korean Registered Patent No. 10-1799010, which discloses the compound of chemical formula 1, the compound represented by chemical formula 1 is obtained exclusively in an oil state, and the compound represented by chemical formula 1 in an oil state may be produced in a solid form having a foam form through further drying, but this is also not in a crystalline form.

[0260] In the case of solids in the form of oil or foam, they are not suitable for development as pharmaceuticals, have the disadvantages of being difficult to remove residual solvents from, and are not easy to handle industrially.

[0261] However, crystalline forms I, II, and III of the compound represented by chemical formula 1 exhibit excellent properties related to the solid form, such as handling and stability, and have suitable solubility for formulation. Specifically, crystalline forms I, II, and III of the compound represented by chemical formula 1 exhibit excellent long-term and accelerated stability, thermodynamic stability, photostability, and crystalline stability, have low hygroscopicity, possess properties advantageous for the removal of residual solvents, are highly safe, and have suitable solubility for formulation.

[0262] Furthermore, the crystalline forms I, II, and III of the compound represented by chemical formula 1 according to the present invention have excellent storage stability, mechanical stability, and fluidity, the particles are uniform and the crystalline form is easy to process as a pharmaceutical, the crystalline form can be maintained without change even after storage of the raw material and after dosage form formation, the pharmaceutical can be guaranteed to have a long shelf life, and it can exhibit solubility sufficient for commercialization, so it can be easily formed into a pharmaceutical and can be manufactured commercially with reproducibility.

[0263] Furthermore, if crystal stability is low, the crystal form can easily change, resulting in the formation of multiple crystal forms or mixtures of crystal forms and amorphous materials. This can lead to changes in pharmacological properties, safety, and pharmacokinetic properties, as well as unexpected reactions. However, crystal forms I, II, and III of the compound represented by chemical formula 1 exhibit excellent stability and can maintain a pure single crystal form for a long period of time.

[0264] Therefore, the crystalline forms I, II, and III of the compound represented by chemical formula 1 exhibit excellent thermodynamic stability and crystalline stability, and have low hygroscopicity, allowing them to maintain a constant content. This enables the manufacture of pharmaceuticals with long storage and distribution periods, suitable solubility for dosage form formulation, and consistent efficacy and safety.

[0265] Crystalline form I of a compound represented by chemical formula 1

[0266] The present invention provides crystalline form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by the following chemical formula 1.

[0267] [ka]

[0268] According to embodiments of the present invention, the X-ray powder diffraction pattern of crystalline form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is the compound represented by chemical formula 1, may include diffraction peaks at three or more diffraction angles (e.g., three, four, five, six, or seven) selected from the group consisting of diffraction angles (2θ±0.2°) of 7.85°, 14.54°, 17.14°, 18.09°, 19.62°, 21.41°, and 23.58°.

[0269] Any 2θ diffraction angle specified herein should be understood to mean a specific value ± 0.2°. For example, when specifying a 2θ of 7.85° in the X-ray powder diffraction pattern of the described examples or claims, this may be understood to mean a 2θ angle of 7.85° ± 0.2°, i.e., 7.65° to 8.05°.

[0270] For example, in an X-ray powder diffraction pattern, a diffraction angle (2θ) of 7.85° may be substantially the same as a diffraction angle within the range of 7.85° ± 0.2°, a diffraction angle (2θ) of 14.54° may be substantially the same as a diffraction angle within the range of 14.54° ± 0.2°, a diffraction angle (2θ) of 17.14° may be substantially the same as a diffraction angle within the range of 17.14° ± 0.2°, and a diffraction angle (2θ) of 18.09° may be... The diffraction angle (2θ) may be substantially the same as the diffraction angle within the range of 18.09°±0.2°, 19.62° may be substantially the same as the diffraction angle within the range of 19.62°±0.2°, 21.41° may be substantially the same as the diffraction angle within the range of 21.41°±0.2°, and 23.58° may be substantially the same as the diffraction angle within the range of 23.58°±0.2°.

[0271] For example, the X-ray powder diffraction pattern of crystalline form I of the compound represented by chemical formula 1, which includes diffraction peaks at three or more diffraction angles (e.g., three, four, five, six, or seven) selected from the group consisting of diffraction angles (2θ±0.2°) of 7.85°, 14.54°, 17.14°, 18.09°, 19.62°, 21.41°, and 23.58°, may be substantially identical to the following X-ray powder diffraction pattern of crystalline form I of the compound represented by chemical formula 1: An X-ray powder diffraction pattern containing diffraction peaks at three or more diffraction angles (e.g., three, four, five, six, or seven) selected from the group consisting of diffraction angles (2θ±0.2°) of 7.90°, 14.59°, 17.20°, 18.15°, 19.68°, 21.49°, and 23.65°; An X-ray powder diffraction pattern containing diffraction peaks at three or more diffraction angles (e.g., three, four, five, six, or seven) selected from the group consisting of diffraction angles (2θ±0.2°) of 7.86°, 14.54°, 17.12°, 18.09°, 19.61°, 21.42°, and 23.59°; or An X-ray powder diffraction pattern containing diffraction peaks at three or more diffraction angles (e.g., three, four, five, six, or seven) selected from the group consisting of diffraction angles (2θ±0.2°) of 7.83°, 14.52°, 17.11°, 18.08°, 19.59°, 21.41°, and 23.56°.

[0272] In one embodiment of the present invention, the X-ray powder diffraction pattern of crystalline form I of the compound represented by chemical formula 1 may include diffraction peaks at diffraction angles (2θ±0.2°) of 7.85°, 14.54°, 17.14°, 18.09°, 19.62°, 21.41°, and 23.58°.

[0273] Any 2θ diffraction angle specified herein should be understood to mean a specific value ±0.2°.

[0274] For example, the X-ray powder diffraction pattern of crystalline form I of the compound represented by chemical formula 1, which includes diffraction peaks at diffraction angles (2θ±0.2°) of 7.85°, 14.54°, 17.14°, 18.09°, 19.62°, 21.41°, and 23.58°, may be substantially identical to the following X-ray powder diffraction pattern of crystalline form I of the compound represented by chemical formula 1: X-ray powder diffraction pattern including diffraction peaks at diffraction angles (2θ±0.2°) of 7.90°, 14.59°, 17.20°, 18.15°, 19.68°, 21.49°, and 23.65°; X-ray powder diffraction pattern including diffraction peaks at diffraction angles (2θ±0.2°) of 7.86°, 14.54°, 17.12°, 18.09°, 19.61°, 21.42°, and 23.59°; or An X-ray powder diffraction pattern containing diffraction peaks at substantially the same diffraction angles as a diffraction pattern containing diffraction peaks at diffraction angles (2θ±0.2°) of 7.83°, 14.52°, 17.11°, 18.08°, 19.59°, 21.41°, and 23.56°.

[0275] In one embodiment of the present invention, the X-ray powder diffraction pattern of crystalline form I of the compound represented by chemical formula 1 may further include diffraction peaks at three or more diffraction angles (e.g., 3, 4, 5, 6, or 7) selected from the group consisting of 7.85°, 14.54°, 17.14°, 18.09°, 19.62°, 21.41°, and 23.58° (2θ±0.2°), in addition to one or more diffraction angles (e.g., 1, 2, 3, 4, 5, 6, or 7) selected from the group consisting of 15.64°, 17.55°, 20.78°, 21.04°, 23.27°, 24.24°, and 30.38° (2θ±0.2°).

[0276] Any 2θ diffraction angle specified herein should be understood to mean a specific value ±0.2°.

[0277] For example, the X-ray powder diffraction pattern of crystalline form I of the compound represented by chemical formula 1 may further include diffraction peaks at three or more diffraction angles (2θ±0.2°) selected from the group consisting of 7.85°, 14.54°, 17.14°, 18.09°, 19.62°, 21.41°, and 23.58° (e.g., 3, 4, 5, 6, or 7), as well as one or more diffraction angles (2θ±0.2°) selected from the group consisting of 15.64°, 17.55°, 20.78°, 21.04°, 23.27°, 24.24°, and 30.38° (e.g., 1, 2, 3, 4, 5, 6, or 7). The following X-ray powder diffraction pattern of the material's crystalline form I may be substantially identical: An X-ray powder diffraction pattern that may further include diffraction peaks at three or more diffraction angles (2θ±0.2°) selected from the group consisting of 7.90°, 14.59°, 17.20°, 18.15°, 19.68°, 21.49°, and 23.65° (e.g., 3, 4, 5, 6, or 7), in addition to one or more diffraction angles (2θ±0.2°) selected from the group consisting of 15.70°, 17.61°, 20.84°, 21.10°, 23.34°, 24.30°, and 30.44° (e.g., 1, 2, 3, 4, 5, 6, or 7); An X-ray powder diffraction pattern that may further include diffraction peaks at three or more diffraction angles (2θ±0.2°) selected from the group consisting of 7.86°, 14.54°, 17.12°, 18.09°, 19.61°, 21.42°, and 23.59° (e.g., 3, 4, 5, 6, or 7), in addition to one or more diffraction angles (2θ±0.2°) selected from the group consisting of 15.66°, 17.55°, 20.77°, 21.04°, 23.27°, 24.23°, and 30.38° (e.g., 1, 2, 3, 4, 5, 6, or 7); or An X-ray powder diffraction pattern that may further include diffraction peaks at three or more diffraction angles (2θ±0.2°) selected from the group consisting of 7.83°, 14.52°, 17.11°, 18.08°, 19.59°, 21.41°, and 23.56° (e.g., 3, 4, 5, 6, or 7), in addition to one or more diffraction angles (2θ±0.2°) selected from the group consisting of 15.64°, 17.54°, 20.77°, 21.04°, 23.26°, 24.23°, and 30.37° (e.g., 1, 2, 3, 4, 5, 6, or 7).

[0278] In one embodiment of the present invention, in addition to three or more (e.g., three, four, five, six, or seven) diffraction angles (2θ±0.2°) selected from the group consisting of 7.85°, 14.54°, 17.14°, 18.09°, 19.62°, 21.41°, and 23.58° for the crystalline form I of the compound represented by chemical formula 1, 9.40°, 11.62°, 11.77°, 13.49°, 14.92° are also included. The diffraction peaks may further include one or more (e.g., one, two, three, four, five, six, or seven, etc.) selected from the group consisting of diffraction angles (2θ±0.2°) of 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°.

[0279] Any 2θ diffraction angle specified herein should be understood to mean a specific value ±0.2°.

[0280] For example, in addition to three or more diffraction angles (2θ±0.2°) selected from the group consisting of 7.85°, 14.54°, 17.14°, 18.09°, 19.62°, 21.41°, and 23.58° (e.g., 3, 4, 5, 6, or 7), 9.40°, 11.62°, 11.77°, 13.49°, 14.92°, 15.64°, 17.55°, 18.82°, 20.78°, 21.04°, 22.69°, 23.27°, and 24. The X-ray powder diffraction pattern of crystalline form I of the compound represented by chemical formula 1, which may further include one or more diffraction peaks (e.g., one, two, three, four, five, six, or seven, etc.) selected from the group consisting of diffraction angles (2θ ± 0.2°) of 24°, 26.35°, 27.58°, 28.91°, 30.38°, 33.57°, and 36.74°, may be substantially identical to the following X-ray powder diffraction pattern of crystalline form I of the compound represented by chemical formula 1: Three or more diffraction angles (2θ±0.2°) selected from the group consisting of diffraction angles (2θ±0.2°) 7.90°, 14.59°, 17.20°, 18.15°, 19.68°, 21.49°, and 23.65°, plus 9.45°, 11.65°, 11.86°, 13.55°, 14.98°, and 15.70°. A diffraction pattern that may further include one or more diffraction peaks selected from the group consisting of diffraction angles (2θ±0.2°) of 2θ, 17.61°, 18.88°, 20.84°, 21.10°, 22.74°, 23.34°, 24.30°, 26.41°, 27.65°, 28.96°, 30.44°, 33.65°, and 36.81°; In addition to three or more diffraction angles (2θ±0.2°) selected from the group consisting of 7.86°, 14.54°, 17.12°, 18.09°, 19.61°, 21.42°, and 23.59° (e.g., 3, 4, 5, 6, or 7), the following are also included: 9.39°, 11.62°, 11.80°, 13.48°, 14.91°, 15.66°, 17.55°, 18.82°, A diffraction pattern that may further include one or more diffraction peaks (e.g., one, two, three, four, five, six, or seven, etc.) selected from the group consisting of diffraction angles (2θ±0.2°) of 20.77°, 21.04°, 22.68°, 23.27°, 24.23°, 26.37°, 27.59°, 28.92°, 30.38°, 33.57°, and 36.74°; or In addition to three or more diffraction angles (2θ±0.2°) selected from the group consisting of 7.83°, 14.52°, 17.11°, 18.08°, 19.59°, 21.41°, and 23.56°, the following angles are also considered: 9.40°, 11.60°, 11.78°, 13.49°, 14.92°, 15.64°, 17.54°, and 18.8°. A diffraction pattern that may include one or more diffraction peaks (e.g., one, two, three, four, five, six, or seven, etc.) selected from the group consisting of diffraction angles (2θ±0.2°) of 2°, 20.77°, 21.04°, 22.68°, 23.26°, 24.23°, 26.36°, 27.55°, 28.89°, 30.37°, 33.57°, and 36.71°.

[0281] In one embodiment of the present invention, the crystalline form I of the compound represented by chemical formula 1 may have a peak position in the X-ray powder diffraction pattern that is substantially the same as the peak position in the X-ray powder diffraction pattern shown in Figure 2, Figure 4, Figure 6, or Figure 14.

[0282] In one embodiment of the present invention, the crystalline form I of the compound represented by chemical formula 1 may be shown at substantially the same position as the diffraction angle (2θ±0.2°) of the X-ray powder diffraction pattern described in Table 1, Table 2, Table 3, or Table 6.

[0283] In one embodiment of the present invention, the crystalline form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is the compound represented by chemical formula 1, may have an endothermic peak at 132°C (±0.5°C) to 143°C (±0.5°C) when analyzed by differential scanning calorimetry (DSC) at a heating rate of 10°C / min.

[0284] In one embodiment of the present invention, the crystalline form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is the compound represented by chemical formula 1, may have an endothermic peak at 134°C (±0.5°C) to 143°C (±0.5°C) when analyzed by differential scanning calorimetry (DSC) at a heating rate of 10°C / min.

[0285] In one embodiment of the present invention, the crystalline form I of the compound represented by chemical formula 1 may have an endothermic peak at 138°C (±3°C) when analyzed by differential scanning calorimetry (DSC) at a heating rate of 10°C / min.

[0286] In one embodiment of the present invention, the crystalline form I of the compound represented by chemical formula 1, when the heating rate is 10°C / min, exhibits endothermic peaks at an endothermic onset temperature of 134.1°C (±0.5°C) and 138.0°C (±0.5°C) during differential scanning calorimetry (DSC) analysis. It may have; or it may have an endothermic onset temperature of 134.7°C (±0.5°C) and an endothermic peak at 139.2°C (±0.5°C); or it may have an endothermic onset temperature of 134.64°C (±0.5°C) and an endothermic peak at 138.27°C (±0.5°C).

[0287] More specifically, the crystalline form I of the compound represented by chemical formula 1 may have a differential scanning calorimetry (DSC) endothermic peak that is substantially identical to the endothermic peak shown in Figure 3, Figure 5, or Figure 15 when the heating rate is 10°C / min.

[0288] Crystalline form I of the compound represented by chemical formula 1 according to the present invention is suitable for development as a pharmaceutical, offers improved manufacturing efficiency, is suitable for mass production, is easy to handle industrially, and has excellent pharmaceutically relevant properties in solid form such as handling and stability. Specifically, crystalline form I of the compound represented by chemical formula 1 has excellent long-term and accelerated stability, thermodynamic stability, photostability, and crystal stability, has low hygroscopicity, has properties advantageous for the removal of residual solvents, is highly safe, and has solubility suitable for formulation.

[0289] Furthermore, the crystalline form I of the compound represented by chemical formula 1 according to the present invention has excellent storage stability, mechanical stability, and fluidity, the particles are uniform and the crystalline form is easy to process as a pharmaceutical, the crystalline form can be maintained without change even with long-term storage of the raw material and changes in the surrounding environment such as temperature and humidity, the pharmaceutical can be guaranteed to have a long shelf life, and it can exhibit solubility sufficient for commercialization, so it can be easily formulated into a dosage form as a pharmaceutical and can be manufactured commercially with reproducibility.

[0290] Furthermore, crystalline forms that are fragile in terms of crystal stability can easily undergo changes in crystal form, generating multiple crystalline forms or mixtures of crystalline forms and amorphous materials. This can lead to changes in the pharmacological, safety, and pharmacokinetic properties of the formulation, as well as unexpected reactions. However, crystalline form I of the compound represented by chemical formula 1 exhibits excellent stability and can maintain a pure single crystalline form for a long period of time.

[0291] In particular, crystalline form I of the compound represented by chemical formula 1 exhibits excellent stability and can maintain an anhydrous state that absorbs almost no moisture even in humid environments. Furthermore, even under heating environments of 40°C or higher, the single crystalline form maintains its crystalline form I form without changing to other crystalline forms or amorphous states for extended periods. Thus, strict environmental conditions are not required during the manufacturing or storage process, and the crystalline form can be stably maintained.

[0292] Therefore, crystalline form I of the compound represented by chemical formula 1 exhibits excellent thermodynamic stability and crystalline stability, and has low hygroscopicity, allowing it to maintain a constant content. This enables long storage and distribution periods, suitable solubility for dosage form formulation, and the manufacture of pharmaceuticals without deviations in efficacy and safety.

[0293] Crystalline form II of the compound represented by chemical formula 1

[0294] The present invention provides crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by the following chemical formula 1.

[0295] [ka]

[0296] According to embodiments of the present invention, the crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is the compound represented by chemical formula 1, may contain diffraction peaks at three or more diffraction angles (e.g., three, four, five, six, or seven) selected from the group consisting of diffraction angles of 7.83°, 12.22°, 19.02°, 19.67°, 21.40°, 22.35°, and 26.44° (2θ±0.2°).

[0297] Any 2θ diffraction angle specified herein should be understood to mean a specific value ± 0.2°. For example, when specifying a 2θ of 7.83° in the X-ray powder diffraction pattern of the described examples or claims, this may be understood to mean a 2θ angle of 7.83° ± 0.2°, i.e., 7.63° to 8.03°.

[0298] For example, in an X-ray powder diffraction pattern, the diffraction angle (2θ) of 7.83° may be substantially the same as a diffraction angle within the range of 7.83°±0.2°, the diffraction angle (2θ) of 12.22° may be substantially the same as a diffraction angle within the range of 12.22°±0.2°, the diffraction angle (2θ) of 19.02° may be substantially the same as a diffraction angle within the range of 19.02°±0.2°, the diffraction angle (2θ) of 19.67° may be substantially the same as a diffraction angle within the range of 19.67°±0.2°, the diffraction angle (2θ) of 21.40° may be substantially the same as a diffraction angle within the range of 21.40°±0.2°, the diffraction angle (2θ) of 22.35° may be substantially the same as a diffraction angle within the range of 22.35°±0.2°, and the diffraction angle (2θ) of 26.44 ° may be substantially the same as the diffraction angle within the range of 26.44 °±0.2°.

[0299] For example, the X-ray powder diffraction pattern of crystalline form II of the compound represented by chemical formula 1, which may contain diffraction peaks at three or more diffraction angles (e.g., three, four, five, six, or seven) selected from the group consisting of diffraction angles (2θ±0.2°) of 7.83°, 12.22°, 19.02°, 19.67°, 21.40°, 22.35°, and 26.44°, may be substantially identical to the following X-ray powder diffraction pattern of crystalline form II of the compound represented by chemical formula 1: A diffraction pattern containing diffraction peaks at three or more diffraction angles (e.g., three, four, five, six, or seven) selected from the group consisting of diffraction angles (2θ±0.2°) of 7.83°, 12.22°, 19.02°, 19.67°, 21.39°, 22.35°, and 26.42°.

[0300] According to embodiments of the present invention, the X-ray powder diffraction pattern of crystalline form II of the compound represented by chemical 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°.

[0301] Any 2θ diffraction angle specified herein is understood to mean a specific value ±0.2°. It must be done.

[0302] For example, the X-ray powder diffraction pattern of crystalline form II of the compound represented by chemical formula 1, which includes diffraction peaks at diffraction angles (2θ±0.2°) of 7.83°, 12.22°, 19.02°, 19.67°, 21.40°, 22.35°, and 26.44°, may be substantially identical to the following X-ray powder diffraction pattern of crystalline form II of the compound represented by chemical formula 1: X-ray powder diffraction pattern including diffraction peaks at diffraction angles (2θ±0.2°) of 7.83°, 12.22°, 19.02°, 19.67°, 21.39°, 22.35°, and 26.42°.

[0303] In one embodiment of the present invention, the X-ray powder diffraction pattern of crystalline form II of the compound N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by chemical formula 1, is selected from the group consisting of diffraction angles (2θ±0.2°) of 7.83°, 12.22°, 19.02°, 19.67°, 21.40°, 22.35°, and 26.44°. In addition to the three or more diffraction angles (e.g., three, four, five, six, or seven) that have been determined, diffraction peaks may further be included at one or more diffraction angles (e.g., one, two, three, four, five, six, or seven, etc.) selected from the group consisting of diffraction angles 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°).

[0304] Any 2θ diffraction angle specified herein should be understood to mean a specific value ±0.2°.

[0305] For example, in addition to three or more diffraction angles (e.g., three, four, five, six, or seven) selected from the group consisting of diffraction angles (2θ±0.2°) 7.83°, 12.22°, 19.02°, 19.67°, 21.40°, 22.35°, and 26.44°, 11.41°, 11.78°, 13.28°, 15.70°, 16.64°, 17.48°, 18.28°, 19.37°, 20.71°, The X-ray powder diffraction pattern of crystalline form II of the compound represented by chemical formula 1, which may further include diffraction peaks at one or more diffraction angles (e.g., one, two, three, four, five, six, or seven, etc.) selected from the group consisting of diffraction angles of 24.58°, 27.35°, and 33.73° (2θ ± 0.2°), may be substantially identical to the following X-ray powder diffraction pattern of crystalline form II of the compound represented by chemical formula 1: An X-ray powder diffraction pattern that may further include diffraction peaks at three or more diffraction angles (e.g., 3, 4, 5, 6, or 7) selected from the group consisting of diffraction angles (2θ±0.2°) of 7.83°, 12.22°, 19.02°, 19.67°, 21.39°, 22.35°, and 26.42°, in addition to one or more diffraction angles (e.g., 1, 2, 3, 4, 5, 6, or 7) selected from the group consisting of diffraction angles (2θ±0.2°) of 11.39°, 11.77°, 13.26°, 15.72°, 16.60°, 17.48°, 18.27°, 19.35°, 20.67°, 24.56°, 27.34°, and 33.7.

[0306] In one embodiment of the present invention, the X-ray powder diffraction pattern of crystalline form II of the compound N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by chemical formula 1, is in addition to three or more diffraction angles (e.g., three, four, five, six, or seven) selected from the group consisting of diffraction angles (2θ±0.2°) of 7.83°, 12.22°, 19.02°, 19.67°, 21.40°, 22.35°, and 26.44°, as well as 10.72°, 10.92°, 11.41°, 11.78°, and 13.28°. The X-ray powder diffraction peaks may further include one or more diffraction angles (e.g., one, two, three, four, five, six, or seven, etc.) selected from the group consisting of diffraction angles (2θ±0.2°) of 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°.

[0307] Any 2θ diffraction angle specified herein should be understood to mean a specific value ±0.2°.

[0308] For example, in addition to three or more diffraction angles (e.g., 3, 4, 5, 6, or 7) selected from the group consisting of diffraction angles (2θ±0.2°) 7.83°, 12.22°, 19.02°, 19.67°, 21.40°, 22.35°, and 26.44°, the following are also included: 10.72°, 10.92°, 11.41°, 11.78°, 13.28°, 15.70°, 16.64°, 16.97°, 17.48°, 18.28°, 19.37°, 20.71°, and 24. The X-ray powder diffraction pattern of crystalline form II of the compound represented by chemical formula 1, which may further include diffraction peaks at one or more diffraction angles (e.g., one, two, three, four, five, six, or seven, etc.) selected from the group consisting of diffraction angles (2θ±0.2°) of 58°, 27.35°, 30.49°, 32.19°, 33.73°, 35.44°, and 35.91°, may be substantially identical to the following X-ray powder diffraction pattern of crystalline form I of the compound represented by chemical formula 1: In addition to three or more diffraction angles (e.g., three, four, five, six, or seven) selected from the group consisting of diffraction angles (2θ±0.2°) of 7.83°, 12.22°, 19.02°, 19.67°, 21.39°, 22.35°, and 26.42°, the following are also included: 10.68°, 10.88°, 11.39°, 11.77°, 13.26°, 15.72°, 16.60°, 16.95°, An X-ray powder diffraction pattern that may further include diffraction peaks at one or more diffraction angles (e.g., one, two, three, four, five, six, or seven, etc.) selected from the group consisting of diffraction angles (2θ±0.2°) of 17.48°, 18.27°, 19.35°, 20.67°, 24.56°, 27.34°, 30.49°, 32.17°, 33.72°, 35.45°, and 35.94°.

[0309] In one embodiment of the present invention, the crystalline form II of the compound represented by chemical formula 1 may have a peak position in the X-ray powder diffraction pattern that is substantially the same as the peak position in the diffraction pattern shown in Figure 7 or Figure 16.

[0310] In one embodiment of the present invention, the crystalline form II of the compound represented by chemical formula 1 may be shown at substantially the same position as the diffraction angle (2θ ± 0.2°) of the X-ray powder diffraction pattern described in Table 4 or Table 7.

[0311] In one embodiment of the present invention, the crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is the compound represented by chemical formula 1, may have an endothermic peak between 124°C (±0.5°C) and 138°C (±0.5°C) when analyzed by differential scanning calorimetry (DSC) at a heating rate of 10°C / min.

[0312] In one embodiment of the present invention, the crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is the compound represented by chemical formula 1, may have an endothermic peak between 125°C (±0.5°C) and 138°C (±0.5°C) when analyzed by differential scanning calorimetry (DSC) at a heating rate of 10°C / min.

[0313] In one embodiment of the present invention, the crystalline form II of the compound represented by chemical formula 1 may have an endothermic peak at 130°C (±5°C) when analyzed by differential scanning calorimetry (DSC) at a heating rate of 10°C / min.

[0314] In one embodiment of the present invention, when the heating rate is 10°C / min, the crystalline form II of the compound represented by chemical formula 1 may have an endothermic onset temperature of 125.7°C (±0.5°C) and an endothermic peak at 132.2°C (±0.5°C) during differential scanning calorimetry (DSC) analysis, or it may have an endothermic onset temperature of 125.61°C (±0.5°C) and an endothermic peak at 130.43°C (±0.5°C).

[0315] More specifically, the crystalline form II of the compound represented by chemical formula 1 may have a differential scanning calorimetry (DSC) endothermic peak that is substantially identical to the endothermic peak shown in Figure 8 or Figure 17 when the heating rate is 10°C / min.

[0316] Crystalline form II of the compound represented by chemical formula 1 according to the present invention is suitable for development as a pharmaceutical, offers improved manufacturing efficiency, is suitable for mass production, is easy to handle industrially, and has excellent properties related to the solid form, such as handling and stability. Specifically, crystalline form II of the compound represented by chemical formula 1 has excellent long-term and accelerated stability, thermodynamic stability, photostability, and crystal stability, low hygroscopicity, is advantageous for the removal of residual solvents, is highly safe, and has solubility suitable for formulation.

[0317] Furthermore, the crystalline form II of the compound represented by chemical formula 1 according to the present invention has excellent storage stability, mechanical stability, and fluidity, the particles are uniform and the crystalline form is easy to process as a pharmaceutical, the crystalline form can be maintained without change even under the storage conditions of the raw materials and the surrounding environment such as temperature and humidity, the pharmaceutical can be guaranteed to have a long shelf life, and it can exhibit solubility sufficient for commercialization, so it can be easily formulated into a dosage form as a pharmaceutical and can be manufactured commercially with reproducibility.

[0318] Crystalline form changes can occur, generating multiple crystalline forms or mixtures of crystalline and amorphous materials, which can alter the pharmacological, safety, and pharmacokinetic properties of the formulation and induce unexpected reactions. However, crystalline form II of the compound represented by chemical formula 1 exhibits excellent stability and can maintain a pure single crystalline form for extended periods even under changes in the surrounding environment, such as accelerated stability conditions.

[0319] In particular, the crystalline form II of the compound represented by chemical formula 1 exhibits excellent stability and can maintain an anhydrous state that absorbs almost no moisture even in humid environments. The single crystalline form maintains the crystalline form II form without changing to other crystalline forms or amorphous states for a long period of time, and the crystalline form can be stably maintained without requiring strict environmental conditions during the manufacturing or storage process.

[0320] Therefore, the crystalline form II of the compound represented by chemical formula 1 exhibits excellent thermodynamic stability and crystalline stability, and has low hygroscopicity, allowing it to maintain a constant content. This enables long storage and distribution periods, provides suitable solubility for dosage form formulation, and facilitates the manufacture of pharmaceuticals without deviations in efficacy and safety.

[0321] Crystal form III of the compound represented by chemical formula 1

[0322] The present invention provides crystalline form III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by the following chemical formula 1.

[0323] [ka]

[0324] According to embodiments of the present invention, the crystalline form III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is the compound represented by chemical formula 1, may have an X-ray powder diffraction pattern that includes diffraction peaks at three or more diffraction angles (e.g., three, four, five, or six) selected from the group consisting of diffraction angles of 8.75°, 10.98°, 12.44°, 16.86°, 22.92°, and 28.49° (2θ±0.2°).

[0325] Any 2θ diffraction angle specified herein should be understood to mean a specific value ± 0.2°. For example, when specifying a 2θ of 8.75° in the X-ray powder diffraction pattern of the described examples or claims, this may be understood to mean a 2θ angle of 8.75° ± 0.2°, i.e., between 8.55° and 8.95°.

[0326] For example, in an X-ray powder diffraction pattern, the diffraction angle (2θ) of 8.75° may be substantially the same as a diffraction angle within the range of 8.75° ± 0.2°, the diffraction angle (2θ) of 10.98° may be substantially the same as a diffraction angle within the range of 10.98° ± 0.2°, the diffraction angle (2θ) of 12.44° may be substantially the same as a diffraction angle within the range of 12.44° ± 0.2°, the diffraction angle (2θ) of 16.86° may be substantially the same as a diffraction angle within the range of 16.86° ± 0.2°, the diffraction angle (2θ) of 22.92° may be substantially the same as a diffraction angle within the range of 22.92° ± 0.2°, and the diffraction angle (2θ) of 28.49° may be substantially the same as a diffraction angle within the range of 28.49° ± 0.2°.

[0327] For example, the X-ray powder diffraction pattern of crystalline form III of the compound represented by chemical formula 1, which may contain diffraction peaks at three or more diffraction angles (e.g., three, four, five, or six) 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°, may be substantially identical to the following X-ray powder diffraction pattern of crystalline form III of the compound represented by chemical formula 1: An X-ray powder diffraction pattern that may contain diffraction peaks at three or more diffraction angles (e.g., three, four, five, or six) selected from the group consisting of diffraction angles (2θ±0.2°) of 8.73°, 10.95°, 12.40°, 16.84°, 22.90°, and 28.47°.

[0328] In one embodiment of the present invention, crystalline form III of the compound represented by chemical formula 1 may include diffraction peaks in its X-ray powder diffraction pattern at diffraction angles (2θ±0.2°) of 8.75°, 10.98°, 12.44°, 16.86°, 22.92°, and 28.49°.

[0329] Any 2θ diffraction angle specified herein should be understood to mean a specific value ±0.2°.

[0330] For example, 8.75°, 10.98°, 12.44°, 16.86°, 22.92°, The X-ray powder diffraction pattern of crystalline form III of the compound represented by chemical formula 1, which may contain diffraction peaks at diffraction angles of 28.49° (2θ±0.2°), may be substantially identical to the following X-ray powder diffraction pattern of crystalline form III of the compound represented by chemical formula 1: X-ray powder diffraction patterns that may contain diffraction peaks at diffraction angles (2θ±0.2°) of 8.73°, 10.95°, 12.40°, 16.84°, 22.90°, and 28.47°.

[0331] In one embodiment of the present invention, the X-ray powder diffraction pattern of crystalline form III of the compound represented by chemical formula 1 may further include diffraction peaks at three or more diffraction angles (e.g., 3, 4, 5, or 6) 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°, and one or more diffraction angles (e.g., 1, 2, 3, 4, 5, 6, or 7) selected from the group consisting of diffraction angles (2θ±0.2°) of 17.48°, 19.95°, 20.49°, 20.79°, 21.55°, 21.87°, 22.07°, 24.04°, 24.72°, 24.99°, and 26.30°.

[0332] Any 2θ diffraction angle specified herein should be understood to mean a specific value ±0.2°.

[0333] For example, three or more diffraction angles (e.g., 3, 4, 5, or 6) selected from the group consisting of diffraction angles (2θ±0.2°) 8.75°, 10.98°, 12.44°, 16.86°, 22.92°, and 28.49°, along with 17.48°, 19.95°, 20.49°, 20.79°, 21.55°, 21.87°, 22.07°, 24.04°, 24.72°, and 24.9°. The X-ray powder diffraction pattern of crystalline form III of the compound represented by chemical formula 1, which may further include diffraction peaks at one or more diffraction angles selected from the group consisting of 9° and 26.30° (2θ±0.2°) (e.g., 1, 2, 3, 4, 5, 6, or 7), may be substantially identical to the following X-ray powder diffraction pattern of crystalline form III of the compound represented by chemical formula 1: An X-ray powder diffraction pattern that may further include diffraction peaks at three or more diffraction angles (e.g., 3, 4, 5, or 6) selected from the group consisting of diffraction angles (2θ±0.2°) of 8.73°, 10.95°, 12.40°, 16.84°, 22.90°, and 28.47°, in addition to one or more diffraction angles (e.g., 1, 2, 3, 4, 5, 6, or 7) selected from the group consisting of diffraction angles (2θ±0.2°) of 17.47°, 19.93°, 20.45°, 20.77°, 21.53°, 21.84°, 22.05°, 24.02°, 24.70°, 24.96°, and 26.27°.

[0334] In one embodiment of the present invention, the crystalline form III of the compound represented by chemical formula 1 is an X-ray powder diffraction pattern consisting of three or more diffraction angles (e.g., three, four, five, or six) selected from the group consisting of diffraction angles of 8.75°, 10.98°, 12.44°, 16.86°, 22.92°, and 28.49° (2θ±0.2°), in addition to 14.28°, 15.45°, 17.48°, 18.49°, 18.77°, 19.95°, The diffraction peaks may further include one or more diffraction angles (e.g., one, two, three, four, five, six, or seven, etc.) selected from the group consisting of diffraction angles (2θ±0.2°) of 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°.

[0335] Any 2θ diffraction angle specified herein should be understood to mean a specific value ±0.2°.

[0336] For example, 8.75°, 10.98°, 12.44°, 16.86°, 22.92°, In addition to three or more diffraction angles (e.g., 3, 4, 5, or 6) selected from the group consisting of diffraction angles of 28.49° and 2θ±0.2°, the following diffraction angles are also selected: 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 The X-ray powder diffraction pattern of crystalline form III of the compound represented by chemical formula 1, which may further include diffraction peaks at one or more diffraction angles (e.g., one, two, three, four, five, six, or seven, etc.) selected from the group consisting of diffraction angles 0.40°, 34.10°, 37.13°, and 38.86° (2θ±0.2°), may be substantially identical to the following X-ray powder diffraction pattern of crystalline form III of the compound represented by chemical formula 1: In addition to three or more diffraction angles (e.g., three, four, five, or six) selected from the group consisting of diffraction angles (2θ±0.2°) of 8.73°, 10.95°, 12.40°, 16.84°, 22.90°, and 28.47°, the following are also included: 14.20°, 15.45°, 17.47°, 18.44°, 18.75°, 19.93°, 20.45°, 20.77°, 21.53°, and 21.84°. An X-ray powder diffraction pattern that may further include diffraction peaks at one or more diffraction angles (e.g., one, two, three, four, five, six, or seven, etc.) selected from the group consisting of diffraction angles (2θ±0.2°) of 2θ, 22.05°, 24.02°, 24.70°, 24.96°, 26.27°, 29.20°, 30.18°, 31.39°, 34.09°, 37.09°, and 38.82°.

[0337] In one embodiment of the present invention, the crystalline form III of the compound represented by chemical formula 1 may have a peak position in the X-ray powder diffraction pattern that is substantially the same as the peak position in the diffraction pattern shown in Figure 9 or Figure 18.

[0338] In one embodiment of the present invention, the crystalline form III of the compound represented by chemical formula 1 may be shown at substantially the same position as the diffraction angle (2θ±0.2°) of the X-ray powder diffraction pattern described in Table 5 or Table 8.

[0339] In one embodiment of the present invention, the crystalline form III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is the compound represented by chemical formula 1, may have an endothermic peak at 120°C (±0.5°C) to 130°C (±0.5°C) when analyzed by differential scanning calorimetry (DSC) at a heating rate of 10°C / min.

[0340] In one embodiment of the present invention, the crystalline form III of the compound represented by chemical formula 1 may have an endothermic peak at 125°C (±5°C) when analyzed by differential scanning calorimetry (DSC) at a heating rate of 10°C / min.

[0341] In one embodiment of the present invention, when the heating rate is 10°C / min, the crystalline form III of the compound represented by chemical formula 1 may have an endothermic onset temperature of 120.5°C (±0.5°C) and an endothermic peak at 124.7°C (±0.5°C) during differential scanning calorimetry (DSC) analysis, or it may have an endothermic onset temperature of 120.4°C (±0.5°C) and an endothermic peak at 124.8°C (±0.5°C).

[0342] Crystalline form III of the compound represented by chemical formula 1 according to the present invention is suitable for development as a pharmaceutical, offers improved manufacturing efficiency, is suitable for mass production, is easy to handle industrially, and has excellent properties related to the solid form, such as handling and stability. Specifically, crystalline form III of the compound represented by chemical formula 1 has excellent long-term and accelerated stability, thermodynamic stability, photostability, and crystal stability, has low hygroscopicity, and possesses properties advantageous for the removal of residual solvents. It offers excellent safety and possesses suitable solubility for formulation.

[0343] Furthermore, the crystalline form III of the compound represented by chemical formula 1 according to the present invention has excellent storage stability, mechanical stability, and fluidity, the particles are uniform and the crystalline form is easy to process as a pharmaceutical, the crystalline form can be maintained without change even with long-term storage of the raw material and changes in the surrounding environment such as temperature and humidity, the pharmaceutical can be guaranteed to have a long shelf life, and it can exhibit solubility sufficient for commercialization, so it can be easily formulated into a dosage form as a pharmaceutical and can be manufactured commercially with reproducibility.

[0344] Furthermore, crystalline forms that are fragile in terms of crystal stability can easily undergo changes in crystal form, generating multiple crystalline forms or mixtures of crystalline forms and amorphous materials. This can lead to changes in the pharmacological, safety, and pharmacokinetic properties of the formulation, as well as unexpected reactions. However, crystalline form III of the compound represented by chemical formula 1 exhibits excellent stability and can maintain a pure single crystalline form for a long period of time.

[0345] In particular, the crystalline form III of the compound represented by chemical formula 1 exhibits excellent stability and can maintain an anhydrous state that absorbs almost no moisture even in humid environments. The single crystalline form maintains its crystalline form III form without changing to other crystalline forms or amorphous states for a long period of time, and the crystalline form can be stably maintained without requiring difficult conditions during the manufacturing or storage process.

[0346] Therefore, crystalline form III of the compound represented by chemical formula 1 exhibits excellent thermodynamic stability and crystalline stability, and has low hygroscopicity, allowing it to maintain a constant content. This enables long storage and distribution periods, provides suitable solubility for dosage form formulation, and facilitates the manufacture of pharmaceuticals without deviations in efficacy and safety.

[0347] Pharmaceutical composition containing crystalline form I, II, or III

[0348] The present invention provides a pharmaceutical composition comprising a novel crystalline form of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by the following chemical formula 1:

[0349] [ka]

[0350] In one embodiment of the present invention, the pharmaceutical composition can prevent or treat diseases related to histone deacetylase 6 activity. In one embodiment of the present invention, diseases associated with histone deacetylase 6 activity include infectious diseases such as prion diseases; benign tumors (e.g., myelodysplastic syndromes); or malignant tumors (e.g., multiple myeloma, lymphoma, leukemia, lung cancer, colorectal cancer, colon cancer, prostate cancer, urothelial cell carcinoma, breast cancer, melanoma, skin cancer). Neoplasms such as liver cancer, brain tumors, stomach cancer, ovarian cancer, pancreatic cancer, head and neck cancer, oral cancer, or glioma; endocrine, nutritional, and metabolic disorders such as Wilson's disease, amyloidosis, or diabetes; mental and behavioral disorders such as depression or Rett syndrome; systemic atrophy of the central nervous system (e.g., Huntington's disease, spinal muscular atrophy (SMA), spinocerebellar ataxia (SCA)), neurodegenerative diseases (e.g., Alzheimer's disease), motor disorders (e.g., Parkinson's disease), neuropathy (e.g., hereditary neuropathy (Charcot-Marie-Tooth disease), sporadic neuropathy, inflammatory neuropathy, drug-induced neuropathy), motor neuron disorders (e.g., muscular atrophy) This includes neurological disorders such as degenerative lateral sclerosis (ALS) or demyelinating diseases of the central nervous system (e.g., multiple sclerosis (MS)); eye and adnexal disorders such as uveitis; cardiovascular disorders such as stroke; respiratory disorders such as asthma; gastrointestinal disorders such as alcoholic liver disease, inflammatory bowel disease, Crohn's disease, or ulcerative bowel disease; skin and subcutaneous tissue disorders such as psoriasis; musculoskeletal and connective tissue disorders 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 conditions or disorders associated with abnormal function of histone deacetylase 6.

[0351] In one embodiment of the present invention, the X-ray powder diffraction patterns and endothermic peaks 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 are as described above.

[0352] In one embodiment of the present invention, crystalline forms I, II, and III of the compound represented by chemical formula 1 contained in the pharmaceutical composition can exhibit excellent physicochemical properties. As a result, the pharmaceutical composition containing crystalline form I, II, or III of the compound represented by chemical formula 1 exhibits excellent crystal stability, is easily mass-produced commercially, can be manufactured reproducibly, maintains its physicochemical properties for a long period of time as in the initial production, ensures a long distribution period, and does not require separate, strict storage conditions.

[0353] The pharmaceutical composition of the present invention may further contain one or more pharmaceutically acceptable additives, which may be commonly used in the industry.

[0354] The pharmaceutical compositions of the present invention may be formulated in appropriate dosage forms as needed, such as patches, liquids, pills, capsules, granules, tablets, suppositories, etc. These formulations may be manufactured by conventional methods used in formulation in the art or by methods disclosed in Remington's Pharmaceutical Science (most recent edition), Mack Publishing Company, Easton PA, and can be formulated into various formulations depending on the disease or component.

[0355] Methods for producing crystalline forms I, II, and III of the compound represented by chemical formula 1

[0356] The present invention provides a novel method for producing crystalline forms I, II, and III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is represented by the following chemical formula 1.

[0357] [ka]

[0358] According to the manufacturing method of the present invention, it is possible to produce a crystalline form of the compound represented by chemical formula 1 with high purity and high yield, minimizing the generation of impurities, without the need for special equipment or complex processes, and it is easy to mass-produce the crystalline form. Specifically, according to the manufacturing method of crystalline form I, crystalline form II, or crystalline form III of the compound represented by chemical formula 1 according to the present invention, it is possible to produce crystalline form I, crystalline form II, or crystalline form III with a high yield of 85% or more, specifically, a high yield of 90% or more, and it is possible to produce crystalline form I, crystalline form II, or crystalline form III with a purity of 99% or more as measured by HPLC, which is sufficient for use as a pharmaceutical product. Furthermore, the solvent used in the production of the crystalline form is inexpensive, and it is possible to establish an economical manufacturing process for mass production, making it suitable for industrial production.

[0359] In the present invention, the method for producing crystalline form I of the compound represented by chemical formula 1 may include the following steps: (a) N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is the compound represented by the chemical formula 1, is mixed with ethyl acetate, ethanol, methanol, isopropyl alcohol, butyl alcohol, methyl tert-butyl alcohol. The steps of obtaining a solution by dissolving in a solvent selected from the group consisting of methyl 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 step of producing a solid from the solution.

[0360] In one embodiment of the present invention, in the production of crystalline form I of the compound represented by chemical formula 1, the solvent in step (a) may be one or more alcohols selected from the group consisting of ethanol, methanol, isopropyl alcohol, and butyl alcohol, ethyl acetate, or a mixture of the alcohols and ethyl acetate.

[0361] In one embodiment of the present invention, in the production of 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 the group consisting of ethanol, methanol, isopropyl alcohol, and butyl alcohol, and ethyl acetate. In one embodiment of the present invention, in the production of crystalline form I of the compound represented by chemical formula 1, the step of obtaining the (a) solution is: (a1) The step of adding a compound represented by chemical formula 1 to the solvent to obtain a mixture; and (a2) The step may include heating the mixture to a temperature exceeding 40°C.

[0362] In one embodiment of the present invention, the heating in (a2) is greater than 40°C, 45°C or higher, specifically 45°C to 70°C, more specifically 45°C to 65°C, and even more specifically 50°C. This may be done in a temperature range of ~65°C.

[0363] In one embodiment of the present invention, in a method for producing crystalline form I of the compound represented by chemical formula 1, the step of producing the solid in step (b) is: (b1) A step of preparing a mixture by further adding one or more alcohols selected from the group consisting of ethanol, methanol, isopropyl alcohol, and butyl alcohol to the solution obtained in step (a); and (b2) The step may include stirring the mixture after adding the alcohol in step (b1).

[0364] In one embodiment of the present invention, steps (b1) and (b2) may be carried out at a temperature exceeding 40°C, and more specifically, at a temperature between 40°C and 60°C.

[0365] In one embodiment of the present invention, a solid may be formed during the stirring step (b2).

[0366] In one embodiment of the present invention, a cooling step may be further performed, and the cooling may be performed to a temperature of 10°C or lower, specifically 0°C to 10°C, and more specifically 0°C to 7°C.

[0367] In one embodiment of the present invention, the compound represented by chemical formula 1, which is the starting material in step (a) of the method for producing crystalline form I, is not limited to any physical state and can be any physical state as long as it is a compound represented by chemical formula 1. Specifically, it can be a liquid such as a solution or suspension, or a solid state, and the solid state can be in any form, such as foam or amorphous. More specifically, it may be in the form of an oil or foam, or an amorphous solid, and even more specifically, it may be amorphous having the form of an oil or foam, but is not limited thereto.

[0368] In one embodiment of the present invention, the compound represented by chemical formula 1 may be produced by a conventionally known production method, for example, by the method described in Korean Registered Patent No. 10-1799010.

[0369] In one embodiment of the present invention, the method for producing crystalline form I of the compound represented by chemical formula 1 is to perform the following steps before step (a): dissolving the compound represented by chemical formula 1 in dichloromethane, then primary concentrating it to produce a concentrated residue; and The process may further include the step of adding ethyl acetate to the concentrated residue and performing a secondary concentration.

[0370] In the present invention, the method for producing crystalline form II of the compound represented by chemical formula 1 may include the following steps: (a) A step of preparing a mixture by adding N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is the compound represented by chemical formula 1, to a solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, butyl alcohol, diisopropyl ether, tetrahydrofuran, heptane, hexane, and mixtures thereof; (b) A step of heating the mixture to a temperature of 30-40°C to obtain a solution; and (c) A step of producing a solid from the solution at a temperature of 40°C or lower.

[0371] In one embodiment of the present invention, in the production of crystalline form II of the compound represented by chemical formula 1, the solvent in step (a) is ethanol, isopropyl alcohol, or A mixture of these may also be used.

[0372] In one embodiment of the present invention, in the production of crystalline form II of the compound represented by chemical formula 1, the solvent in step (a) may be ethanol.

[0373] In one embodiment of the present invention, in the production of crystalline form II of the compound represented by chemical formula 1, the heating in step (b) may be carried out at a temperature of 40°C or lower, specifically in the range of 30°C to 40°C.

[0374] In one embodiment of the present invention, in the production of crystalline form II of the compound represented by chemical formula 1, the step of producing a solid from the solution at a temperature of 40°C or lower in step (c) may include the step of stirring the solution at a temperature of 40°C or lower.

[0375] In one embodiment of the present invention, in the production of crystalline form II of the compound represented by chemical formula 1, step (c) may be carried out at a temperature of 40°C or lower, more specifically, in a temperature range of 20°C to 40°C, and more specifically, in a temperature range of 30°C to 40°C.

[0376] In one embodiment of the present invention, the compound represented by chemical formula 1, which is the starting material in step (a) of the method for producing crystalline form II, is not limited in its physical state, and can be any physical state as long as it is the compound represented by chemical formula 1. Specifically, it can be a liquid such as a solution or suspension, or a solid state, and the solid state can be in any form, such as foam or amorphous, more specifically, it may be in the form of an oil or foam, or an amorphous solid, and even more specifically, it may be amorphous having the form of an oil or foam, but is not limited thereto.

[0377] In one embodiment of the present invention, the compound represented by chemical formula 1 may be produced by a conventionally known production method, for example, by the method described in Korean Registered Patent No. 10-1799010.

[0378] In one embodiment of the present invention, the step of producing the solid in step (c) may include the step of stirring the solution.

[0379] In one embodiment of the present invention, a solid may be generated during the stirring process.

[0380] In one embodiment of the present invention, the method for producing crystalline form II of the compound represented by chemical formula 1 is as follows: Before performing step (a), The steps include: dissolving the compound represented by chemical formula 1 in dichloromethane, then performing primary concentration to produce a concentrated residue; and The process may further include the step of adding ethanol to the concentrated residue and performing a secondary concentration.

[0381] In the present invention, the method for producing crystalline form III of the compound represented by chemical formula 1 may include the following steps: (a) The amorphous N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by chemical formula 1 is converted to methyl tert-butyl ether. The steps of adding (Methyl Tertiary Butyl Ether, MTBE), heptane, octane, hexane, pentane, and mixtures thereof to a solvent selected from the group and forming a slurry; and (b) A step of obtaining a solid from the slurry. In one embodiment of the present invention, the production of crystalline form III of the compound represented by chemical formula 1 The solvent in step (a) is methyl tert-butyl ether (MTBE), Heptane, or a mixture thereof, may be used.

[0382] In one embodiment of the present invention, in the production of crystalline form III of the compound represented by chemical formula 1, the slurrying step (a) may be carried out for 12 hours to 20 days, specifically 12 hours to 7 days, more specifically 12 hours to 3 days, for example, 12 hours to 36 hours, specifically 15 hours to 30 hours, more specifically 20 hours to 27 hours.

[0383] In one embodiment of the present invention, in the production of crystalline form III of the compound represented by chemical formula 1, the step of obtaining the solid of (b) is: The step may include filtering the slurry obtained in step (a).

[0384] In one embodiment of the present invention, the steps of (a) slurring and (b) obtaining a solid may be carried out at a temperature of 30°C or lower, specifically 20°C to 30°C, and more specifically 20°C to 25°C.

[0385] In one embodiment of the present invention, crystalline forms I to III of the compound represented by chemical formula 1 may be produced using the compound represented by chemical formula 1 produced by the method of the present invention as a starting material.

[0386] In embodiments of the present invention, when a compound represented by chemical formula 1 produced by the method of the present invention is used as a starting material, the method for producing crystalline form I of the compound represented by chemical formula 1 may include the following steps: (a) N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is the compound represented by the chemical formula 1, is mixed with ethyl acetate, ethanol, methanol, isopropyl alcohol, butyl alcohol, methyl tert-butyl alcohol. The steps of obtaining a solution by dissolving in a solvent selected from the group consisting of methyl 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 step of producing a solid from the solution.

[0387] In one embodiment of the present invention, in the production of crystalline form I of the compound represented by chemical formula 1, the solvent in step (a) may be one or more alcohols selected from the group consisting of ethanol, methanol, isopropyl alcohol, and butyl alcohol, ethyl acetate, or a mixture of the alcohols and ethyl acetate.

[0388] In the embodiments of the present invention, in the production of 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 the group consisting of ethanol, methanol, isopropyl alcohol, and butyl alcohol, and ethyl acetate.

[0389] In one embodiment of the present invention, in the production of crystalline form I of the compound represented by chemical formula 1, the step of obtaining the (a) solution is: (a1) The step of adding a compound represented by chemical formula 1 to the solvent to obtain a mixture; and (a2) The step may include heating the mixture to a temperature exceeding 40°C.

[0390] In one embodiment of the present invention, the heating in (a2) may be carried out in the range of more than 40°C, 45°C or higher, specifically 45°C to 70°C, more specifically 45°C to 65°C, and even more specifically 50°C to 65°C.

[0391] In an embodiment of the present invention, in the method for producing crystalline form I of the compound represented by chemical formula 1, the step of producing the solid in step (b) is: (b1) A step of preparing a mixture by further adding one or more alcohols selected from the group consisting of ethanol, methanol, isopropyl alcohol, and butyl alcohol to the solution obtained in step (a); and (b2) The step may include stirring the mixture after adding the alcohol in step (b1).

[0392] In embodiments of the present invention, steps (b1) and (b2) may be carried out at a temperature exceeding 40°C, specifically at a temperature between 40°C and 60°C.

[0393] In the embodiments of the present invention, a solid may be formed during the stirring step (b2).

[0394] In embodiments of the present invention, a cooling step may be further performed, and the cooling may be performed to a temperature of 10°C or lower, specifically 0°C to 10°C, and more specifically 0°C to 7°C.

[0395] In the embodiments of the present invention, the compound represented by chemical formula 1, which is the starting material in step (a) of the method for producing crystalline form I, is not limited to any physical state and can be any physical state as long as it is a compound represented by chemical formula 1. Specifically, it can be a liquid such as a solution or suspension, or a solid state, and the solid state can be in any form, such as foam or amorphous. More specifically, it may be in the form of an oil or foam, or an amorphous solid, and even more specifically, it may be amorphous having the form of an oil or foam, but is not limited thereto.

[0396] In the embodiments of the present invention, in the method for producing crystalline form I of the compound represented by chemical formula 1, the starting material, which is the compound represented by chemical formula 1, may be produced by the method for producing the compound represented by chemical formula 1 described in detail above, but is not limited thereto. For example, in the method for producing crystalline form I, the starting material may be the compound represented by chemical formula 1 produced by the novel method described herein.

[0397] In embodiments of the present invention, the method for producing crystalline form I of the compound represented by chemical formula 1 may further include a step of adding ethyl acetate to the compound represented by chemical formula 1 and concentrating it before performing step (a). In this case, the compound represented by chemical formula 1 may be a compound represented by chemical formula 1 obtained by the novel production method described herein, and the compound represented by chemical formula 1 may be in an oil state, but is not limited thereto.

[0398] In the embodiments of the present invention, in the method for producing crystalline form I of the compound represented by chemical formula 1, the starting material, the compound represented by chemical formula 1, may be produced by the method described herein as described above. Specifically, the compound represented by chemical formula 1 may be produced in situ from the compound represented by chemical formula 6, in which case the reactants and reaction conditions are as described above.

[0399] More specifically, the crystalline form I of the compound represented by the chemical formula 1 of the present invention is determined by the following steps It may be manufactured by a method including (1) to (3): (1) A step of producing a compound represented by the chemical formula 1 in situ from a compound represented by the chemical formula 6 below;

[0400] [ka]

[0401] [ka]

[0402] (2) The compound represented by chemical formula 1 produced in step 1 is used with ethyl acetate, ethanol, methanol, isopropyl alcohol, butyl alcohol, methyl tert- The steps of obtaining a solution by dissolving in a solvent selected from the group consisting of methyl 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 step of producing a solid from the solution.

[0403] In a method for producing crystalline form I of the compound represented by chemical formula 1, step (1) is substantially the same as that described in the method for producing the compound represented by chemical formula 1 from the compound represented by chemical formula 6, and for example, the reactants, reaction conditions, and specific detailed reactions may be substantially the same as those described above. In a method for producing crystalline form I of the compound represented by chemical formula 1, steps (2) and (3) are substantially the same as steps (a) and (b), respectively, of a method for producing crystalline form I of the compound represented by chemical formula 1 using the compound represented by chemical formula 1 produced by the method of the present invention as a starting material, and for example, the reactants, reaction conditions, and specific detailed reactions may be substantially the same as those described above.

[0404] In embodiments of the present invention, the method for producing crystalline form I of the compound represented by chemical formula 1 may further include a step of adding ethyl acetate to the compound represented by chemical formula 1 and concentrating it before performing step (2). In this case, the compound represented by chemical formula 1 may be a compound represented by chemical formula 1 obtained by the novel production method described herein. At this time, the compound represented by chemical formula 1 may be in an oil state, but is not limited thereto. I can't.

[0405] In the embodiments of the present invention, when the X-ray powder diffraction pattern and heating rate of crystal form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is represented by the chemical formula 1, are 10°C / min, the differential scanning calorimetry (DSC) analysis is as described above for crystal form I.

[0406] In embodiments of the present invention, when a compound represented by chemical formula 1 produced by the method of the present invention is used as a starting material, the method for producing crystalline form II of the compound represented by chemical formula 1 may include the following steps: (a) A step of preparing a mixture by adding N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is the compound represented by chemical formula 1, to a solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, butyl alcohol, diisopropyl ether, tetrahydrofuran, heptane, hexane, and mixtures thereof; (b) A step of heating the mixture to a temperature of 30-40°C to obtain a solution; and (c) A step of producing a solid from the solution at a temperature of 40°C or lower.

[0407] In one embodiment of the present invention, in the production of crystalline form II of the compound represented by chemical formula 1, the solvent in step (a) may be ethanol, isopropyl alcohol, or a mixture thereof.

[0408] In one embodiment of the present invention, in the production of crystalline form II of the compound represented by chemical formula 1, the solvent in step (a) may be ethanol.

[0409] In one embodiment of the present invention, in the production of crystalline form II of the compound represented by chemical formula 1, the heating in step (b) may be carried out at a temperature of 40°C or lower, specifically in the range of 30°C to 40°C.

[0410] In one embodiment of the present invention, in the production of crystalline form II of the compound represented by chemical formula 1, the step of producing a solid from the solution at a temperature of 40°C or lower in step (c) may include the step of stirring the solution at a temperature of 40°C or lower.

[0411] In one embodiment of the present invention, in the production of crystalline form II of the compound represented by chemical formula 1, step (c) may be carried out at a temperature of 40°C or lower, more specifically, in a temperature range of 20°C to 40°C, and more specifically, in a temperature range of 30°C to 40°C.

[0412] In one embodiment of the present invention, the compound represented by chemical formula 1, which is the starting material in step (a) of the method for producing crystalline form II, is not limited in its physical state, and can be any physical state as long as it is the compound represented by chemical formula 1. Specifically, it can be a liquid such as a solution or suspension, or a solid state, and the solid state can be in any form, such as foam or amorphous, more specifically, it may be in the form of an oil or foam, or an amorphous solid, and even more specifically, it may be amorphous having the form of an oil or foam, but is not limited thereto.

[0413] In the embodiments of the present invention, in the method for producing crystalline form II of the compound represented by chemical formula 1, the starting material, the compound represented by chemical formula 1, may be produced by a novel method for producing the compound represented by chemical formula 1 as described in detail herein. However, it is not limited thereto. For example, in the method for producing crystalline form II, the starting material may be a compound represented by chemical formula 1 produced by the novel method described herein.

[0414] In one embodiment of the present invention, the step of producing the solid in step (c) may include the step of stirring the solution.

[0415] In one embodiment of the present invention, a solid may be generated during the stirring process.

[0416] In one embodiment of the present invention, the method for producing crystalline form II of the compound represented by chemical formula 1 is as follows: Before performing step (a), The process may further include a step of adding ethanol to the compound represented by chemical formula 1 and concentrating it. In this case, the compound represented by chemical formula 1 may be a compound represented by chemical formula 1 obtained by the novel manufacturing method described herein, and the compound represented by chemical formula 1 may be in oil form, but is not limited thereto.

[0417] In the embodiments of the present invention, the compound represented by chemical formula 1 may be produced by the method described herein as described above. Specifically, the compound represented by chemical formula 1 may be produced in situ from the compound represented by chemical formula 6, in which case the reactants and reaction conditions are as described above.

[0418] More specifically, the crystalline form II of the compound represented by chemical formula 1 of the present invention may be produced by a method comprising the following steps (1) to (4): (1) A step of producing a compound represented by the chemical formula 1 in situ from a compound represented by the chemical formula 6 below;

[0419] [ka]

[0420] [ka]

[0421] (2) The compound represented by the chemical formula 1 is N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-F A step of preparing a mixture by adding nylthiomorpholine-4-carboxamide 1,1-dioxide to a solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, butyl alcohol, diisopropyl ether, tetrahydrofuran, heptane, hexane, and mixtures thereof; (3) A step of heating the mixture to a temperature of 30-40°C to obtain a solution; and (4) A step of producing a solid from the solution at a temperature of 40°C or lower.

[0422] In the method for producing crystalline form II of the compound represented by chemical formula 1, step (1) is substantially the same as that described in the method for producing the compound represented by chemical formula 1 from the compound represented by chemical formula 6, and for example, the reactants, reaction conditions, and specific detailed reactions may be substantially the same as those described above.

[0423] In the method for producing crystalline form II of the compound represented by chemical formula 1, steps (2), (3), and (4) are substantially the same as steps (a), (b), and (c) of the method for producing crystalline form II of the compound represented by chemical formula 1 using the compound represented by chemical formula 1 produced by the method of the present invention described above as a starting material. For example, the reactants, reaction conditions, and specific detailed reactions may be substantially the same as described above.

[0424] In embodiments of the present invention, the method for producing crystalline form II of the compound represented by chemical formula 1 may further include a step of adding ethanol to the compound represented by chemical formula 1 and concentrating it before performing step (2). In this case, the compound represented by chemical formula 1 may be a compound represented by chemical formula 1 obtained by the novel production method described herein, and the compound represented by chemical formula 1 may be in an oil state, but is not limited thereto.

[0425] In the embodiments of the present invention, when the X-ray powder diffraction pattern and heating rate of crystal form II of the compound represented by chemical formula 1, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, are 10°C / min, the differential scanning calorimetry (DSC) analysis is as described above for crystal form I.

[0426] In the present invention, the method for producing crystalline form III of the compound represented by chemical formula 1 may include the following steps: (a) The amorphous N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by the chemical formula 1 is methyl tert-butylated. The steps of adding to a solvent selected from the group consisting of methyl tertiary butyl ether (MTBE), heptane, octane, hexane, pentane, and mixtures thereof to form a slurry; and (b) A step of obtaining a solid from the slurry.

[0427] In one embodiment of the present invention, in the production of crystalline form III of the compound represented by chemical formula 1, the solvent in step (a) is methyl tert-butyl ether (MTBE). It may be heptane, or a mixture thereof.

[0428] In one embodiment of the present invention, in the production of crystalline form III of the compound represented by chemical formula 1, the slurrying step (a) may be carried out for 12 hours to 20 days, specifically 12 hours to 7 days, more specifically 12 hours to 3 days, for example 12 hours to 36 hours, more specifically 15 hours to 30 hours, and even more specifically 20 hours to 27 hours. It may be done in between.

[0429] In one embodiment of the present invention, in the production of crystalline form III of the compound represented by chemical formula 1, the step of obtaining the solid of (b) is: The step may include filtering the slurry obtained in step (a).

[0430] In one embodiment of the present invention, the steps of (a) slurring and (b) obtaining a solid may be carried out at a temperature of 30°C or lower, specifically 20°C to 30°C, and more specifically 20°C to 25°C.

[0431] In the embodiments of the present invention, in the method for producing crystalline form III of the compound represented by chemical formula 1, the starting material, the compound represented by chemical formula 1, may be produced by the novel method for producing the compound represented by chemical formula 1 described in detail in this specification, but is not limited thereto. For example, in the method for producing crystalline form III, the amorphous form of the compound represented by chemical formula 1, which is the starting material, may be produced from the compound represented by chemical formula 1 produced by the novel method described in this specification, or from the compound represented by chemical formula 1 produced by a conventionally known method.

[0432] More specifically, the crystalline form III of the compound represented by chemical formula 1 of the present invention may be produced by a method comprising the following steps (1) to (4): (1) A step of producing a compound represented by the chemical formula 1 in situ from a compound represented by the chemical formula 6 below;

[0433] [ka]

[0434] [ka]

[0435] (2) A step of producing an amorphous compound represented by chemical formula 1 by vacuum drying the compound represented by chemical formula 1 from step 1 for 6 to 20 hours; (3) The amorphous compound represented by chemical formula 1 is methyl tert-butyl ether (M Add to a solvent selected from the group consisting of ethyl tertiary butyl ether (MTBE), heptane, octane, hexane, pentane, and mixtures thereof. The step of turning it into a slurry; and (4) A step of obtaining a solid from the slurry.

[0436] In the method for producing crystalline form III of the compound represented by chemical formula 1, step (1) is substantially the same as that described in the method for producing the compound represented by chemical formula 1 from the compound represented by chemical formula 6 that was investigated, and for example, the reactants, reaction conditions, and specific detailed reactions may be substantially the same as those described above.

[0437] In the method for producing crystalline form III of the compound represented by chemical formula 1, steps (3) and (4) are substantially the same as steps (a) and (b) of the method for producing crystalline form III of the compound represented by chemical formula 1, and for example, the reactants, reaction conditions, and specific detailed reactions may be substantially the same as those described above.

[0438] According to an example of the present invention, when the X-ray powder diffraction pattern and heating rate of crystal form III of the compound represented by chemical formula 1, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, are 10°C / min, the differential scanning calorimetry (DSC) analysis is as described above for crystal form III. [Effects of the Invention]

[0439] The novel manufacturing method of the present invention simplifies the synthesis steps compared to conventional manufacturing methods, the reagents and reaction equipment used in the reaction are also generally readily available, and it does not require mild reaction conditions, efficient process procedures, or the use of column chromatography, thus enabling mass production, and also exhibits outstanding stability and economic efficiency, which are essential for mass production.

[0440] Therefore, the novel manufacturing method is extremely efficient, as it achieves an overall yield of approximately 60% for obtaining the compound represented by chemical formula 1, which is about 40 times higher than the 1.5% yield of conventional manufacturing methods. Furthermore, high-purity chemical formula 1 compounds with HPLC purity of 99% or more can be obtained without using column chromatography through simple post-processing procedures and effective purification methods.

[0441] The N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide crystalline form of the present invention exhibits excellent long-term and accelerated stability, thermodynamic stability, photostability, and crystal stability, and has a solubility suitable for formulation. Furthermore, due to its low hygroscopicity, it does not degrade due to the surrounding environment during long-term storage, maintaining a constant content and possessing properties advantageous for the removal of residual solvents. Furthermore, the crystalline form of the present invention exhibits excellent storage stability, mechanical stability, and fluidity, and the particles are uniform, eliminating the need for complex formulation processes. The crystalline form can be easily obtained in high purity and high yield using a simple method.

[0442] Furthermore, the method for producing crystalline forms according to the present invention is easily applicable to production (scale-up), can stably produce crystals, and allows for the establishment of an economical production process using inexpensive solvents, making it suitable for industrial production. [Brief explanation of the drawing]

[0443] [Figure 1] The reaction formula 2 shown is for producing the compound of chemical formula 1 according to the examples of the present invention. [Figure 2] This is the result of X-ray powder diffraction (XRPD) analysis of crystalline form I of the compound represented by chemical formula 1 according to one embodiment of the present invention. [Figure 3]This is the result of differential scanning calorimetry (DSC) thermal analysis (thermogram) of crystalline form I of the compound represented by chemical formula 1 according to one embodiment of the present invention. [Figure 4] This is the result of X-ray powder diffraction (XRPD) analysis of crystalline form I of the compound represented by chemical formula 1 according to one embodiment of the present invention. [Figure 5] This is the result of differential scanning calorimetry (DSC) thermal analysis (thermogram) of crystalline form I of the compound represented by chemical formula 1 according to one embodiment of the present invention. [Figure 6] This is the result of X-ray powder diffraction (XRPD) analysis of crystalline form I of the compound represented by chemical formula 1 according to one embodiment of the present invention. [Figure 7] This is the result of X-ray powder diffraction (XRPD) analysis of crystalline form II of the compound represented by chemical formula 1 according to one embodiment of the present invention. [Figure 8] This is the result of differential scanning calorimetry (DSC) thermal analysis (thermogram) of crystalline form II of the compound represented by chemical formula 1 according to one embodiment of the present invention. [Figure 9] This is the result of X-ray powder diffraction (XRPD) analysis of crystalline form III of the compound represented by chemical formula 1 according to one embodiment of the present invention. [Figure 10] This is the result of differential scanning calorimetry (DSC) thermal analysis (thermogram) of crystalline form III of the compound represented by chemical formula 1 according to one embodiment of the present invention. [Figure 11] This is the result of X-ray powder diffraction (XRPD) analysis of the amorphous form of the compound represented by chemical formula 1. [Figure 12] This is the result of X-ray powder diffraction (XRPD) analysis of the amorphous form of the compound represented by chemical formula 1. [Figure 13]This is the result of differential scanning calorimetry (DSC) thermal analysis (thermogram) of an amorphous compound represented by chemical formula 1 according to one example of the present invention. [Figure 14] This is the result of X-ray powder diffraction (XRPD) analysis of crystalline form I of the compound represented by chemical formula 1 according to one embodiment of the present invention (Start: 3.0° - End: 39.999° / Step: 0.020° - step time: 46.5 s / Operation: Strip kAlpha2 0.5000 / Background 1.000, 1.000). [Figure 15] This is the result of differential scanning calorimetry (DSC) thermal analysis (thermogram) of crystalline form I of the compound represented by chemical formula 1 according to one embodiment of the present invention. [Figure 16] This is the result of X-ray powder diffraction (XRPD) analysis of crystalline form II of the compound represented by chemical formula 1 according to one embodiment of the present invention (Start: 3.0° - End: 39.999° / Step: 0.020° - step time: 46.5 s / Operation: Strip kAlpha2 0.5000 / Background 1.000, 1.000). [Figure 17] This is the result of differential scanning calorimetry (DSC) thermal analysis (thermogram) of crystalline form II of the compound represented by chemical formula 1 according to one embodiment of the present invention. [Figure 18] This is the result of X-ray powder diffraction (XRPD) analysis of crystalline form III of the compound represented by chemical formula 1 according to one embodiment of the present invention (Start: 3.0° - End: 39.999° / Step: 0.020° - step time: 46.5 s / Operation: Strip kAlpha2 0.5000 / Background 1.000, 1.000). [Figure 19]This is the result of differential scanning calorimetry (DSC) thermal analysis (thermogram) of crystalline form III of the compound represented by chemical formula 1 according to one embodiment of the present invention. [Figure 20] This is the result of a water adsorption analysis (dynamic vapor sorption, DVS) of crystalline form I of the compound represented by chemical formula 1 according to one embodiment of the present invention. [Figure 21] This is the result of a water adsorption analysis (dynamic vapor sorption, DVS) of crystalline form II of the compound represented by chemical formula 1 according to one embodiment of the present invention. [Figure 22] This is the result of a water adsorption analysis (dynamic vapor sorption, DVS) of crystalline form III of the compound represented by chemical formula 1 according to one embodiment of the present invention. [Figure 23] This is the result of a water adsorption analysis (dynamic vapor sorption, DVS) of an amorphous compound represented by chemical formula 1 according to one example of the present invention. [Figure 24] This is the 1H NMR result for N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, a compound represented by chemical formula 1. [Figure 25] This is the 13C NMR result for N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, a compound represented by chemical formula 1. [Modes for carrying out the invention]

[0444] Examples of implementation

[0445] Implementation Example 1. A method for producing a compound represented by the following chemical formula 1, comprising the step of producing a compound represented by the following chemical formula 6 in situ:

[0446] [ka]

[0447] [ka]

[0448] Implementation Example 2. A manufacturing method in which, in Implementation Example 1, the step of producing the compound represented by chemical formula 1 from the compound represented by chemical formula 6 is carried out in the presence of a base.

[0449] Implementation Example 3. A method for manufacturing in which, in Implementation Example 1 or 2, the base contains an imidazole.

[0450] Implementation Example 4. In any one of Implementation Examples 1 to 3, the compound represented by Chemical Formula 1 is produced using at least one compound selected from the compounds represented by [Chemical Formula A] and [Chemical Formula B] below and the compound represented by Chemical Formula 6 as reactants. Production Method:

[0451] [ka]

[0452] In the aforementioned chemical formula B, X1 is F, Cl, Br, or I.

[0453] Implementation Example 5. In any one of Implementation Examples 1 to 4, the step of producing the compound represented by chemical formula 1 from the compound represented by chemical formula 6 is: a) A step of preparing a reaction unit 1 containing a compound represented by the following chemical formula A or B and a base; and b) A manufacturing method comprising the step of mixing the reaction unit 1 and the reaction unit 2 containing the compound represented by chemical formula 6 to produce the compound represented by chemical formula 1:

[0454] [ka]

[0455] In the aforementioned chemical formula B, X1 is F, Cl, Br, or I.

[0456] Implementation Example 6. A manufacturing method in which, in any one of Implementation Examples 1 to 5, step a) is to mix a mixture containing a base and a solvent with a compound represented by chemical formula A or chemical formula B.

[0457] Implementation Example 7. In any one of Implementation Examples 1 to 6, step a) is: A step of preparing a mixture containing a base and a solvent; and A method for producing a compound represented by chemical formula A or chemical formula B, comprising the step of adding the compound represented by chemical formula A or chemical formula B to the mixture.

[0458] Implementation Example 8. A manufacturing method comprising the step of preparing a mixture containing the base and a solvent, and then cooling the mixture to 0 to 10°C, in any one of Implementation Examples 1 to 7.

[0459] Implementation Example 9. A manufacturing method comprising the step of adding the compound represented by chemical formula A or chemical formula B to the mixture, and then stirring, in any one of Implementation Examples 1 to 8.

[0460] Implementation Example 10. A manufacturing method in which, in any one of Implementation Examples 1 to 9, in step b), the reaction unit 2 contains the compound represented by the chemical formula 6 and a solvent.

[0461] Implementation Example 11. A manufacturing method in which, in any one of Implementation Examples 1 to 10, the step of mixing the reaction unit 2 and the reaction unit 1 in step b) is the step of adding the reaction unit 1 to the reaction unit 2.

[0462] Implementation Example 12. A manufacturing method in which, in any one of Implementation Examples 1 to 11, the addition of the reaction unit 1 to the reaction unit 2 is carried out at a temperature of -15°C to 5°C.

[0463] Implementation Example 13. A manufacturing method comprising, in any one of Implementation Examples 1 to 12, further comprising the step of raising the temperature to 20 to 45°C after mixing in step b).

[0464] Implementation Example 14. A method for producing a compound represented by the following chemical formula 6, comprising the step of producing a compound represented by the following chemical formula 6 from hydrazine (N2H4), or its hydrate, and a compound represented by the following chemical formula 5, in the presence of a solvent containing a linear or branched C1-C6 alcohol, or a mixture of a linear or branched C1-C6 alcohol and water:

[0465] [ka]

[0466] [ka]

[0467] In the above chemical formula 5, R is a C1-C6 linear or branched alkyl or benzyl group.

[0468] Implementation Example 15. A method for production in which, in Implementation Example 14, the solvent is methanol or a mixture of methanol and water.

[0469] Implementation Example 16. A manufacturing method in which, in Implementation Example 14 or 15, the volume ratio of alcohol to water is 10:1 to 1:1.

[0470] Implementation Example 17. A manufacturing method in which, in any one of Implementation Examples 14 to 16, R is methyl.

[0471] Implementation Example 18. A step in which a compound represented by chemical formula 5 is produced by reacting a compound represented by chemical formula 3 and a compound represented by chemical formula 4 in the presence of a base, the compound represented by chemical formula 5. Method for producing the compound:

[0472] [ka]

[0473] [ka]

[0474] [ka]

[0475] In chemical formulas 3 and 5, R is a C1-C6 linear or branched alkyl or benzyl, and in chemical formula 4, X is F, Cl, Br, or I.

[0476] Implementation Example 19. A manufacturing method in which, in Implementation Example 18, R is methyl and X is Cl.

[0477] Implementation Example 20. A method for production in which, in Implementation Example 18 or 19, the base is triethylamine, N,N-diisopropylethylamine, imidazole, pyridine, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, or a mixture thereof.

[0478] Implementation Example 21. A manufacturing method in which, in any one of Implementation Examples 18 to 20, the manufacturing method further includes a step of purifying a compound represented by chemical formula 5.

[0479] Implementation Example 22. In any one of Implementation Examples 18 to 21, the purification step involves methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl tert- A method for producing a product, carried out under a solvent selected from the group consisting of butyl ether (MTBE), diisopropyl ether, heptane, hexane, and mixtures thereof.

[0480] Implementation Example 23. The step of preparing a compound represented by the following chemical formula 8 using a halogenating agent from a compound represented by the following chemical formula 7; and The process includes the step of reacting a compound represented by the following chemical formula 8 with aniline in the presence of a base to produce a compound represented by the following chemical formula 3. Method for producing the compound represented by the following chemical formula 3:

[0481] [ka]

[0482] [ka]

[0483] [ka]

[0484] In chemical formulas 3, 7, and 8, R is a C1-C6 linear or branched alkyl or benzyl, and in chemical formula 8, X is F, Cl, Br, or I.

[0485] Implementation Example 24. A manufacturing method in which, in Implementation Example 23, R is methyl and X is Cl.

[0486] Implementation Example 25. A method for producing the halogenating reagent in Implementation Example 23 or 24, wherein the halogenating reagent is iodine, copper iodide, bromine, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), trichloroisocyanuric acid (TCCA), or a mixture thereof.

[0487] Implementation Example 26. A method for producing the compound represented by chemical formula 8 in Implementation Example 24, wherein X is Cl, and the halogenating reagent is N-chlorosuccinimide (NCS), trichloroisocyanuric acid (TCCA), or a mixture thereof.

[0488] Implementation Example 27. A method for producing a base in any one of Implementation Examples 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.

[0489] Implementation Example 28. A method for production in which, in any one of Implementation Examples 24 to 27, the step of reacting the compound represented by chemical formula 8 with aniline is carried out in the presence of potassium brominated, potassium iodide, tetrabutylammonium bromide (TBAB), or a mixture thereof.

[0490] Example 29. A method for producing the compound represented by the chemical formula 8a below, comprising the step of using only trichloroisocyanuric acid (TCCA) reagent alone with the compound represented by the chemical formula 7 below to produce the compound represented by the chemical formula 8a below:

[0491] [ka]

[0492] [ka]

[0493] In the chemical formulas 7 and 8a, R is a C1-C6 linear alkyl or benzyl group.

[0494] Implementation Example 30. A method for producing a compound represented by chemical formula 3, comprising the step of reacting a compound represented by the following chemical formula 8 with aniline in the presence of a base to produce a compound represented by the following chemical formula 3:

[0495] [ka]

[0496] [ka]

[0497] In chemical formulas 3 and 8, R is a C1-C6 linear or branched alkyl or benzyl, and in chemical formula 8, X is F, Cl, Br, or I.

[0498] Implementation Example 31. A method for producing the base in Implementation Example 30, wherein the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and mixtures thereof.

[0499] Implementation Example 32. A method for production in which, in Implementation Example 30 or 31, the step of reacting the compound represented by chemical formula 8 with aniline is carried out in the presence of potassium brominated, potassium iodide, tetrabutylammonium bromide (TBAB), or a mixture thereof.

[0500] Example 33. A method for producing a compound represented by chemical formula 3, comprising the step of producing a compound represented by chemical formula 3 from a compound represented by chemical formula 2 in the presence of aniline and a reducing agent:

[0501] [ka]

[0502] [ka]

[0503] In the aforementioned chemical formulas 2 or 3, R is a C1-C6 linear or branched alkyl or benzyl group.

[0504] Implementation Example 34. In Implementation Example 33, the step of producing the compound represented by chemical formula 3 from the compound represented by chemical formula 2 is: A step of producing a mixture containing the compound represented by the chemical formula 2 and aniline; and A method for producing the mixture, comprising the step of reacting the mixture with a reducing agent.

[0505] Implementation Example 35. In Implementation Example 33 or 34, the step of producing the compound represented by chemical formula 3 from the compound represented by chemical formula 2 is: A step of preparing a reaction unit 1 containing a compound represented by chemical formula 2, aniline, and a solvent; and A manufacturing method comprising the step of mixing a reaction section 2 containing a reducing agent and a solvent with the reaction section 1.

[0506] Implementation Example 36. A method for manufacturing in which, in any one of Implementation Examples 33 to 35, the reducing agent is at least one selected from the group consisting of sodium borohydride (NaBH4), sodium cyanoborohydride (NaBH3CN), and sodium triacetoxyborohydride (NaBH(OAc)3).

[0507] Implementation Example 37. A manufacturing method in which, in any one of Implementation Examples 33 to 36, the step of producing the compound represented by chemical formula 3 from the compound represented by chemical formula 2 is carried out in the presence of an acid.

[0508] Example 38. A method for producing a compound represented by the following chemical formula 1, 1) A step of preparing a compound represented by the chemical formula 8 using a halogenating agent from a compound represented by the chemical formula 7 below; 2) A step of reacting the compound represented by chemical formula 8 with aniline in the presence of a base to produce the compound represented by chemical formula 3; 3) A step of reacting the compound represented by 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) The step of reacting hydrazine or its hydrate with the compound represented by the chemical formula 5 to obtain the compound represented by the following chemical formula 6; and 5) A step of producing the compound represented by chemical formula 1 in situ from the compound represented by chemical formula 6, A method for producing a compound represented by chemical formula 1, which contains the following:

[0509] [ka]

[0510] [ka]

[0511] (In the above chemical formula 3, R is a C1-C6 linear or branched alkyl or benzyl (It is)

[0512] [ka]

[0513] (In the above chemical formula 4, X is F, Cl, Br, or I.)

[0514] [ka]

[0515] (In the above chemical formula 5, R is a C1-C6 linear or branched alkyl or benzyl.)

[0516] [ka]

[0517] [ka]

[0518] (In the above chemical formula 7, R is a C1-C6 linear or branched alkyl or benzyl group.)

[0519] [ka]

[0520] (In the above chemical formula 8, R is a C1-C6 linear or branched alkyl or benzyl, and X is F, Cl, Br, or I).

[0521] Example 39. A method for producing a compound represented by the following chemical formula 1, 1) A step of preparing a compound represented by the following chemical formula 3 from a compound represented by the following chemical formula 2 in the presence of aniline and a reducing agent; 2) A step of reacting the compound represented by 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) The step of reacting hydrazine or its hydrate with the compound represented by chemical formula 5 to obtain the compound represented by the following chemical formula 6; and 4) A step of producing the compound represented by chemical formula 1 in situ from the compound represented by chemical formula 6, A method for producing a compound represented by chemical formula 1, which contains the following:

[0522] [ka]

[0523] [ka]

[0524] (In the above chemical formula 2, R is a C1-C6 alkyl or benzyl.)

[0525] [ka]

[0526] (In the above chemical formula 3, R is a C1-C6 linear or branched alkyl or benzyl group.)

[0527] [ka]

[0528] (In the above chemical formula 4, X is F, Cl, Br, or I.)

[0529] [ka]

[0530] (In the above chemical formula 5, R is a C1-C6 linear or branched alkyl or benzyl.)

[0531] [ka]

[0532] Example 40. A method for producing a compound represented by the following chemical formula 1, 1) The step of reacting hydrazine or its hydrate with a compound represented by the following chemical formula 5 to obtain a compound represented by the following chemical formula 6; and 2) A step of producing the compound represented by chemical formula 1 in situ from the compound represented by chemical formula 6 below, A method for producing a compound represented by chemical formula 1, which contains the following:

[0533] [ka]

[0534] [ka]

[0535] (In the above chemical formula 5, R is a C1-C6 linear or branched alkyl or benzyl.)

[0536] [ka]

[0537] Implementation Example 41. In Implementation Example 40, the method for producing the compound represented by chemical formula 5 is: A method for producing the compound represented by chemical formula 1, comprising the step of reacting a compound represented by the following chemical formula 3 with a compound represented by the following chemical formula 4 in the presence of a base to produce the compound represented by chemical formula 5:

[0538] [ka]

[0539] (In the above chemical formula 3, R is a C1-C6 linear or branched alkyl or benzyl group.)

[0540] [ka]

[0541] (In the above chemical formula 4, X is F, Cl, Br, or I).

[0542] Implementation Example 42. In Implementation Example 40 or 41, the method for producing the compound represented by chemical formula 5 is: The steps of: reacting the compound represented by chemical formula 8 with aniline in the presence of a base to produce the compound represented by chemical formula 3; and The method includes the step of reacting a compound represented by the following chemical formula 3 with a compound represented by the following chemical formula 4 in the presence of a base to produce the compound represented by the chemical formula 5. A method for producing the compound represented by the above chemical formula 1:

[0543] [ka]

[0544] (In the above chemical formula 3, R is a C1-C6 linear or branched alkyl or benzyl group.)

[0545] [ka]

[0546] (In the above chemical formula 4, X is F, Cl, Br, or I.)

[0547] [ka]

[0548] (In the above chemical formula 8, R is a C1-C6 linear or branched alkyl or benzyl, and X is F, Cl, Br, or I).

[0549] Implementation Example 43. In any one of Implementation Examples 40 to 42, the method for producing the compound represented by chemical formula 5 is: A step of preparing a compound represented by chemical formula 8 using a halogenating reagent from a compound represented by chemical formula 7 below; A step of reacting the compound represented by chemical formula 8 with aniline in the presence of a base to produce the compound represented by the following chemical formula 3; The method includes the step of reacting the compound represented by chemical formula 3 with the compound represented by chemical formula 4 in the presence of a base to produce the compound represented by chemical formula 5. A method for producing the compound represented by the above chemical formula 1:

[0550] [ka]

[0551] (In the above chemical formula 3, R is a C1-C6 linear or branched alkyl or benzyl group.)

[0552] [ka]

[0553] (In the above chemical formula 4, X is F, Cl, Br, or I.)

[0554] [ka]

[0555] (In the above chemical formula 7, R is a C1-C6 linear or branched alkyl or benzyl group.)

[0556] [ka]

[0557] (In the above chemical formula 8, R is a C1-C6 linear or branched alkyl or benzyl, and X is F, Cl, Br, or I).

[0558] Implementation Example 44. In any one of Implementation Examples 40 to 43, the method for producing the compound represented by chemical formula 5 is: The steps of producing a compound represented by the following chemical formula 3 from a compound represented by the following chemical formula 2 in the presence of aniline and a reducing agent; and The method includes the step of reacting the compound represented by chemical formula 3 with the compound represented by the following chemical formula 4 in the presence of a base to produce the compound represented by the following chemical formula 5. A method for producing the compound represented by the above chemical formula 1:

[0559] [ka]

[0560] (In the above chemical formula 2, R is a C1-C6 alkyl or benzyl.)

[0561] [ka]

[0562] (In the above chemical formula 3, R is a C1-C6 linear or branched alkyl or benzyl group.)

[0563] [ka]

[0564] (In the above chemical formula 4, X is F, Cl, Br, or I).

[0565] Realization Example 45. The X-ray powder diffraction pattern contains diffraction peaks at three or more diffraction angles selected from the group consisting of diffraction angles (2θ±0.2°) of 7.85°, 14.54°, 17.14°, 18.09°, 19.62°, 21.41°, and 23.58°, and is the crystalline form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by the following chemical formula 1:

[0566] [ka]

[0567] Realization Example 46. In Realization Example 45, the X-ray powder diffraction pattern further includes diffraction peaks at one or more diffraction angles selected from the group consisting of diffraction angles (2θ±0.2°) of 15.64°, 17.55°, 20.78°, 21.04°, 23.27°, 24.24°, and 30.38°, crystal form I.

[0568] Realization Example 47. Crystal form I, in Realization Example 45 or 46, further comprising 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° in the X-ray powder diffraction pattern.

[0569] Implementation Example 48. In any one of Implementation Examples 45 to 47, when the heating rate is 10°C / min, crystal form I exhibits an endothermic peak between 132°C (±0.5°C) and 143°C (±0.5°C) during differential scanning calorimetry (DSC) analysis.

[0570] Implementation Example 49. In any one of Implementation Examples 45-48, when the heating rate is 10°C / min, the crystal form I exhibits an endothermic peak at 138°C (±3°C) during differential scanning calorimetry (DSC) analysis.

[0571] Realization Example 50. The X-ray powder diffraction pattern contains three or more diffraction peaks selected from the group consisting of diffraction angles (2θ±0.2°) of 7.83°, 12.22°, 19.02°, 19.67°, 21.40°, 22.35°, and 26.44°, and is the crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by the following chemical formula 1:

[0572] [ka]

[0573] Realization Example 51. Crystal form II, 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 (2θ±0.2°) 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°.

[0574] Realization Example 52. Crystal form II, wherein the X-ray powder diffraction pattern in Realization Example 50 or 51 further includes diffraction peaks at one or more diffraction angles selected from the group consisting of diffraction angles (2θ±0.2°) 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°.

[0575] Implementation Example 53. In any one of Implementation Examples 50 to 52, when the heating rate is 10°C / min, the crystal form II exhibits an endothermic peak between 124°C (±0.5°C) and 138°C (±0.5°C) during differential scanning calorimetry (DSC) analysis.

[0576] Implementation Example 54. In any one of Implementation Examples 50-53, when the heating rate is 10°C / min, the crystal form II exhibits an endothermic peak at 130°C (±5°C) during differential scanning calorimetry (DSC) analysis.

[0577] Realization Example 55. The X-ray powder diffraction pattern contains diffraction peaks at three or more 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°, and is the crystalline form III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by the following chemical formula 1:

[0578] [ka]

[0579] Implementation Example 56. In Implementation Example 55, the X-ray powder diffraction patterns were 17.48° and 19.95°. Crystal form III further includes diffraction peaks at one or more diffraction angles selected from the group consisting of diffraction angles (2θ±0.2°) of 20.49°, 20.79°, 21.55°, 21.87°, 22.07°, 24.04°, 24.72°, 24.99°, and 26.30°.

[0580] Implementation Example 57. Crystal form III, wherein the X-ray powder diffraction pattern in Implementation Example 55 or 56 further includes diffraction peaks at one or more diffraction angles selected from the group consisting of diffraction angles (2θ±0.2°) 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°.

[0581] Implementation Example 58. In any one of Implementation Examples 55 to 57, when the heating rate is 10°C / min, the crystal form III exhibits an endothermic peak between 120°C (±0.5°C) and 130°C (±0.5°C) during differential scanning calorimetry (DSC) analysis.

[0582] Implementation Example 59. In any one of Implementation Examples 55-57, when the heating rate is 10°C / min, the crystal form III exhibits an endothermic peak at 125°C (±5°C) during differential scanning calorimetry (DSC) analysis.

[0583] Example 60. (a) N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by the following chemical formula 1 is converted to ethyl acetate, ethanol, methanol, isopropyl alcohol, butyl alcohol, methyl tert-butyl alcohol The steps of obtaining a solution by dissolving in a solvent selected from the group consisting of methyl 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 step of producing a solid from the solution, A method for producing the compound represented by the above chemical formula 1, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide crystalline form I:

[0584] [ka]

[0585] Implementation Example 61. In Implementation Example 60, in step (a), the solvent is A method for producing a substance, comprising one or more alcohols selected from the group consisting of ethanol, methanol, isopropyl alcohol, and butyl alcohol, ethyl acetate, or a mixture of the alcohols and ethyl acetate.

[0586] Implementation Example 62. In Implementation Example 60 or 61, (a) the step of obtaining the solution is: (a1) The step of adding a compound represented by chemical formula 1 to the solvent to obtain a mixture; and (a2) A method for producing the mixture, comprising the step of heating the mixture to a temperature exceeding 40°C.

[0587] Implementation Example 63. In any one of Implementation Examples 60 to 62, the step of generating the solid in step (b) is: (b1) Adding one or more alcohols selected from the group consisting of ethanol, methanol, isopropyl alcohol, and butyl alcohol to the solution of step (a); and (b2) The step further includes stirring after adding alcohol in step (b1), Manufacturing method.

[0588] Implementation Example 64. In any one of Implementation Examples 60 to 63, steps (b1) and (b2) are performed at a temperature exceeding 40°C. Manufacturing method.

[0589] Implementation Example 65. In any one of Implementation Examples 60-64, before performing step (a), The steps include: dissolving the compound represented by chemical formula 1 in dichloromethane, then performing primary concentration to produce a concentrated residue; and The method further includes the step of adding ethyl acetate to the concentrated residue and performing a secondary concentration. Manufacturing method.

[0590] Implementation Example 66. In Implementation Example 60, the compound represented by chemical formula 1 is The following method involves producing a compound represented by chemical formula 1 in situ from a compound represented by chemical formula 6:

[0591] [ka]

[0592] Implementation Example 67. (a) A step of preparing a mixture by adding N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-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, isopropyl alcohol, butyl alcohol, diisopropyl ether, tetrahydrofuran, heptane, hexane, and mixtures thereof; (b) A step of heating the mixture to a temperature of 40°C or lower to obtain a solution; and (c) The method includes the step of producing a solid from the solution at a temperature of 40°C or lower. The compound represented by the aforementioned chemical formula 1 is N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylmethyl Method for producing crystalline form II of omorpholine-4-carboxamide 1,1-dioxide:

[0593] [ka]

[0594] Implementation Example 68. A method for production in which, in step (a) of Implementation Example 67, the solvent is ethanol, isopropanol, or a mixture thereof.

[0595] Implementation Example 69. In Implementation Example 67 or 68, before performing step (a), The compound represented by the chemical formula 1 is dissolved in dichloromethane, and then the mixture is concentrated to produce a concentrated residue; The method further includes the step of adding ethanol to the concentrated residue and performing a secondary concentration. Manufacturing method.

[0596] Implementation Example 70. In any one of Implementation Examples 67 to 69, the compound represented by chemical formula 1 is: The following method involves producing a compound represented by chemical formula 1 in situ from a compound represented by chemical formula 6:

[0597] [ka]

[0598] [ka]

[0599] Implementation Example 71. (a) The amorphous N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by the following chemical formula 1 is converted to methyl tert-butyl ether (MTBE), heptane, octane, hexane, pentane, and this The step of adding to a solvent selected from the group consisting of these mixtures to form a slurry; and (b) The step of obtaining a solid from the slurry, A method for producing crystalline form III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is represented by the chemical formula 1:

[0600] [ka]

[0601] Implementation Example 72. In Implementation Example 71, the solvent in step (a) is methyl tert- It is thyryl ether (MTBE), heptane, or a mixture thereof. Manufacturing method.

[0602] Implementation Example 73. A manufacturing method in which, in Implementation Example 71 or 72, the step of (a) forming a slurry is carried out for 12 hours to 20 days.

[0603] Implementation Example 74. A manufacturing method in which, in any one of Implementation Examples 71 to 73, (b) the step of obtaining a solid includes the step of filtering the slurry.

[0604] Implementation Example 75. A manufacturing method in which, in any one of Implementation Examples 71 to 74, the steps of (a) forming a slurry and (b) obtaining a solid are carried out at a temperature of 30°C or lower.

[0605] Implementation Example 76. In any one of Implementation Examples 71 to 75, the step of producing the amorphous form of the compound represented by chemical formula 1 is: A step of producing the compound represented by chemical formula 1 in situ from the compound represented by chemical formula 6 below; and A method for producing a compound represented by the aforementioned chemical formula 1, comprising the step of vacuum drying:

[0606] [ka]

[0607] [ka]

[0608] Implementation Example A1. A method for producing a compound represented by chemical formula 1, comprising the step of producing a compound represented by chemical formula 1 in situ from a compound represented by chemical formula 6:

[0609] [ka]

[0610] [ka]

[0611] Implementation Example A2. A manufacturing method in which, in Implementation Example A1, the step of producing the compound represented by chemical formula 1 from the compound represented by chemical formula 6 is carried out in the presence of a base.

[0612] Implementation Example A3. A method for manufacturing in which the base in Implementation Example A2 contains imidazole.

[0613] Implementation Example A4. In any one of Implementation Examples A1 to A3, the compound represented by Chemical Formula 1 is produced using at least one compound selected from the compounds represented by [Chemical Formula A] and [Chemical Formula B] below, and the compound represented by Chemical Formula 6, as reactants. Production Method:

[0614] [ka]

[0615] In the aforementioned chemical formula B, X1 is F, Cl, Br, or I.

[0616] Implementation Example A5. In any one of Implementation Examples A1 to A3, the step of producing the compound represented by chemical formula 1 from the compound represented by chemical formula 6 is: a) A step of preparing a reaction unit 1 containing a compound represented by the following chemical formula A or B and a base; and b) A manufacturing method comprising the step of mixing the reaction unit 1 and the reaction unit 2 containing the compound represented by chemical formula 6 to produce the compound represented by chemical formula 1:

[0617] [ka]

[0618] In the aforementioned chemical formula B, X1 is F, Cl, Br, or I.

[0619] Implementation Example A6. A manufacturing method in which, in Implementation Example A5, step a) is to mix a mixture containing a base and a solvent with a compound represented by chemical formula A or chemical formula B.

[0620] Implementation Example A7. In Implementation Example A5 or A6, step a) is: A step of preparing a mixture containing a base and a solvent; The step of cooling the mixture to 0-10°C; and A method for producing a compound represented by chemical formula A or chemical formula B, comprising the step of adding the compound represented by chemical formula A or chemical formula B to the cooled mixture.

[0621] Implementation Example A8. A manufacturing method further comprising the step of adding a compound represented by chemical formula A or chemical formula B to the mixture, in any one of Implementation Examples A5 to A7, and then stirring.

[0622] Implementation Example A9. In any one of Implementation Examples A5 to A8, step b) is: A step of preparing a reaction unit 2 containing the compound represented by the chemical formula 6 and a solvent; and A manufacturing method comprising the step of reacting the reaction unit 2 with the reaction unit 1.

[0623] Implementation Example A10. A manufacturing method in which, in any one of Implementation Examples A5 to A9, the step of reacting the reaction unit 2 and the reaction unit 1 in step b) is the step of adding the reaction unit 1 to the reaction unit 2.

[0624] Implementation Example A11. A manufacturing method in which, in Implementation Example A10, the addition of the reaction unit 1 to the reaction unit 2 is carried out at a temperature of -15°C to 5°C.

[0625] Implementation Example A12. A manufacturing method that, in Implementation Example A10 or A11, further includes a step of raising the temperature to 20-45°C after the completion of step b).

[0626] Implementation Example A13. A method for producing the compound represented by the chemical formula 6, comprising the step of producing the compound represented by the chemical formula 6 from hydrazine or its hydrate and the compound represented by the chemical formula 5 in the presence of a solvent containing a linear or branched C1-C6 alcohol, or a mixture of a linear or branched C1-C6 alcohol and water:

[0627] [ka]

[0628] [ka]

[0629] In the above chemical formula 5, R is a C1-C6 linear or branched alkyl or benzyl group.

[0630] Implementation Example A14. A method for producing the compound represented by chemical formula 6, wherein, in Implementation Example A13, the solvent is methanol or a mixture of methanol and water.

[0631] Implementation Example A15. A manufacturing method in which, in Implementation Example A13 or A14, the volume ratio of alcohol to water is 10:1 to 1:1.

[0632] Implementation Example A16. A method for producing the compound represented by chemical formula 5, comprising the step of reacting the compound represented by chemical formula 3 with the compound represented by chemical formula 4 in the presence of a base to produce the compound represented by chemical formula 5:

[0633] [ka]

[0634] [ka]

[0635] [ka]

[0636] In chemical formulas 3 and 5, R is a C1-C6 linear or branched alkyl or benzyl, and in chemical formula 4, X is F, Cl, Br, or I.

[0637] Implementation Example A17. A manufacturing method in which, in Implementation Example A16, R is methyl and X is Cl.

[0638] Implementation Example A18. A method for manufacturing in which, in Implementation Example A16 or A17, the base is triethylamine, N,N-diisopropylethylamine, imidazole, pyridine, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, or a mixture thereof.

[0639] Implementation Example A19. A manufacturing method in which, in any one of Implementation Examples A16 to A18, the manufacturing method further includes a step of purifying a compound represented by chemical formula 5.

[0640] Implementation Example A20. In Implementation Example A19, the purification step involves methanol, ethanol, isopropyl alcohol, butyl alcohol, and methyl tert-butyl ether (MT A method for production, which is carried out under a solvent selected from the group consisting of BE, diisopropyl ether, heptane, hexane, and mixtures thereof.

[0641] Implementation Example A21. The step of preparing a compound represented by the following chemical formula 8 using a halogenating reagent with a compound represented by the following chemical formula 7; and A method for producing the compound represented by chemical formula 3, comprising the step of reacting a compound represented by the following chemical formula 8 with aniline in the presence of a base to produce the compound represented by the following chemical formula 3:

[0642] [ka]

[0643] [ka]

[0644] [ka]

[0645] In chemical formulas 3, 7, and 8, R is a C1-C6 linear or branched alkyl or benzyl, and in chemical formula 8, X is F, Cl, Br, or I.

[0646] Implementation Example A22. A method for manufacturing the halogenating reagent in Implementation Example A21, wherein the halogenating reagent is iodine, copper iodide, bromine, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), trichloroisocyanuric acid (TCCA), or a mixture thereof.

[0647] Implementation Example A23. A method for producing the compound represented by chemical formula 8 in Implementation Example A21 or A22, wherein X is Cl, and the halogenating reagent is N-chlorosuccinimide (NCS), trichloroisocyanuric acid (TCCA), or a mixture thereof.

[0648] Implementation Example A24. A method for production in which, in any one of Implementation Examples A21 to A23, the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and mixtures thereof.

[0649] Implementation Example A25. A method for production in which, in any one of Implementation Examples A21 to A24, the step of reacting the compound represented by chemical formula 8 with aniline is carried out in the presence of potassium brominated, potassium iodide, tetrabutylammonium bromide (TBAB), or a mixture thereof.

[0650] Implementation Example A26. A method for producing the compound represented by the following chemical formula 8a, comprising the step of using only trichloroisocyanuric acid (TCCA) reagent alone with the compound represented by the following chemical formula 7 to produce the compound represented by the following chemical formula 8a:

[0651] [ka]

[0652] [ka]

[0653] In the chemical formulas 7 and 8a, R is a C1-C6 linear alkyl or benzyl group. That is the case.

[0654] Implementation Example A27. A method for producing a compound represented by chemical formula 3, comprising the step of reacting a compound represented by the following chemical formula 8 with aniline in the presence of a base to produce a compound represented by the following chemical formula 3:

[0655] [ka]

[0656] [ka]

[0657] In chemical formulas 3 and 8, R is a C1-C6 linear or branched alkyl or benzyl group.

[0658] Implementation Example A28. A method for producing the base in Implementation Example A27, wherein the base is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, triethylamine, diisopropylethylamine, and mixtures thereof.

[0659] Implementation Example A29. A method for production in which, in Implementation Example A27 or A28, the step of reacting the compound represented by chemical formula 8 with aniline is carried out in the presence of potassium brominated, potassium iodide, tetrabutylammonium bromide (TBAB), or a mixture thereof.

[0660] Example A30. A method for producing a compound represented by chemical formula 3, comprising the step of producing a compound represented by chemical formula 3 from a compound represented by chemical formula 2 in the presence of aniline and a reducing agent:

[0661] [ka]

[0662] [ka]

[0663] In the aforementioned chemical formulas 2 or 3, R is a C1-C6 linear or branched alkyl or benzyl group.

[0664] Implementation Example A31. In Implementation Example A30, the step of producing the compound represented by chemical formula 3 from the compound represented by chemical formula 2 is: A step of producing a mixture containing the compound of chemical formula 2 and aniline; and A method for producing the mixture, comprising the step of reacting the mixture with a reducing agent.

[0665] Implementation Example A32. In Implementation Example A30 or A31, the step of producing the compound represented by chemical formula 3 from the compound represented by chemical formula 2 is: A step of preparing a reaction unit 1 containing a compound represented by chemical formula 2, aniline, and a solvent; and A manufacturing method comprising the step of reacting a reaction section 2 containing a reducing agent and a solvent with the reaction section 1.

[0666] Implementation Example A33. A method for manufacturing in which, in any one of Implementation Examples A30 to A32, the reducing agent is at least one selected from the group consisting of sodium borohydride (NaBH4), sodium cyanoborohydride (NaBH3CN), and sodium triacetoxyborohydride (NaBH(OAc)3).

[0667] Implementation Example A34. A manufacturing method in which, in any one of Implementation Examples A30 to A33, the step of producing the compound represented by chemical formula 3 from the compound represented by chemical formula 2 is carried out in the presence of an acid.

[0668] Example A35. A method for producing a compound represented by the following chemical formula 1, 1) A step of preparing a compound represented by the chemical formula 8 using a halogenating agent from a compound represented by the chemical formula 7 below; 2) A step of reacting the compound represented by chemical formula 8 with aniline in the presence of a base to produce the compound represented by chemical formula 3; 3) A step of reacting the compound represented by 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) The step of reacting hydrazine or its hydrate with the compound represented by the chemical formula 5 to obtain the compound represented by the following chemical formula 6; and 5) A step of producing the compound represented by chemical formula 1 in situ from the compound represented by chemical formula 6, A method for producing a compound represented by chemical formula 1, which contains the following:

[0669] [ka]

[0670] [ka]

[0671] (In the above chemical formula 3, R is a C1-C6 linear or branched alkyl or benzyl group.)

[0672] [ka]

[0673] (In the above chemical formula 4, X is F, Cl, Br, or I.)

[0674] [ka]

[0675] (In the above chemical formula 5, R is a C1-C6 linear or branched alkyl or benzyl.)

[0676] [ka]

[0677] [ka]

[0678] (In the above chemical formula 7, R is a C1-C6 linear or branched alkyl or benzyl group.)

[0679] [ka]

[0680] (In the above chemical formula 8, R is a C1-C6 linear or branched alkyl or benzyl, and X is F, Cl, Br, or I.)

[0681] Example A36. A method for producing a compound represented by the following chemical formula 1, 1) A step of preparing a compound represented by the following chemical formula 3 from a compound represented by the following chemical formula 2 in the presence of aniline and a reducing agent; 2) A step of reacting the compound represented by 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) The step of reacting hydrazine or its hydrate with the compound represented by chemical formula 5 to obtain the compound represented by the following chemical formula 6; and 4) A step of producing the compound represented by chemical formula 1 in situ from the compound represented by chemical formula 6, A method for producing a compound represented by chemical formula 1, which contains the following:

[0682] [ka]

[0683] [ka]

[0684] (In the above chemical formula 2, R is a C1-C6 alkyl or benzyl.)

[0685] [ka]

[0686] (In the above chemical formula 3, R is a C1-C6 linear or branched alkyl or benzyl group.)

[0687] [ka]

[0688] (In the above chemical formula 4, X may be F, Cl, Br, or I.)

[0689] [ka]

[0690] (In the above chemical formula 5, R is a C1-C6 linear or branched alkyl or benzyl.)

[0691] [ka]

[0692] Example A37. A method for producing a compound represented by the following chemical formula 1, 1) The step of reacting hydrazine or its hydrate with a compound represented by the following chemical formula 5 to obtain a compound represented by the following chemical formula 6; and 2) A step of producing the compound represented by chemical formula 1 in situ from the compound represented by chemical formula 6 below, A method for producing a compound represented by chemical formula 1, which contains the following:

[0693] [ka]

[0694] [ka]

[0695] (In the above chemical formula 5, R is a C1-C6 linear or branched alkyl or benzyl.)

[0696] [ka]

[0697] Implementation Example A38. In Implementation Example A37, The method for producing the compound represented by the chemical formula 5 is as follows: A method for producing the compound represented by chemical formula 1, comprising the step of reacting a compound represented by the following chemical formula 3 with a compound represented by the following chemical formula 4 in the presence of a base to produce the compound represented by chemical formula 5:

[0698] [ka]

[0699] (In the above chemical formula 3, R is a C1-C6 linear or branched alkyl or benzyl group.)

[0700] [ka]

[0701] (In the above chemical formula 4, X is F, Cl, Br, or I).

[0702] Implementation Example A39. In Implementation Example A37, The method for producing the compound represented by the chemical formula 5 is as follows: The steps of: reacting the compound represented by chemical formula 8 with aniline in the presence of a base to produce the compound represented by chemical formula 3; and The method includes the step of reacting a compound represented by the following chemical formula 3 with a compound represented by the following chemical formula 4 in the presence of a base to produce the compound represented by the chemical formula 5. A method for producing the compound represented by the above chemical formula 1:

[0703] [ka]

[0704] (In the above chemical formula 3, R is a C1-C6 linear or branched alkyl or benzyl group.)

[0705] [ka]

[0706] (In the above chemical formula 4, X is F, Cl, Br, or I.)

[0707] [ka]

[0708] (In the above chemical formula 8, R is a C1-C6 linear or branched alkyl or benzyl, and X is F, Cl, Br, or I).

[0709] Implementation Example A40. In Implementation Example A37, The method for producing the compound represented by the chemical formula 5 is as follows: A step of preparing a compound represented by chemical formula 8 using a halogenating reagent from a compound represented by chemical formula 7 below; A step of reacting the compound represented by chemical formula 8 with aniline in the presence of a base to produce the compound represented by the following chemical formula 3; The method includes the step of reacting the compound represented by chemical formula 3 with the compound represented by chemical formula 4 in the presence of a base to produce the compound represented by chemical formula 5. A method for producing the compound represented by the above chemical formula 1:

[0710] [ka]

[0711] (In the above chemical formula 3, R is a C1-C6 linear or branched alkyl or benzyl group.)

[0712] [ka]

[0713] (In the above chemical formula 4, X is F, Cl, Br, or I.)

[0714] [ka]

[0715] (In the above chemical formula 7, R is a C1-C6 linear or branched alkyl or benzyl group.)

[0716] [ka]

[0717] (In the above chemical formula 8, R is a C1-C6 linear or branched alkyl or benzyl, and X is F, Cl, Br, or I).

[0718] Implementation Example A41. In Implementation Example A37, The method for producing the compound represented by the chemical formula 5 is as follows: The steps of producing a compound represented by the following chemical formula 3 from a compound represented by the following chemical formula 2 in the presence of aniline and a reducing agent; and The method includes the step of reacting the compound represented by chemical formula 3 with the compound represented by the following chemical formula 4 in the presence of a base to produce the compound represented by the following chemical formula 5. A method for producing the compound represented by the above chemical formula 1:

[0719] [ka]

[0720] (In the above chemical formula 2, R is a C1-C6 alkyl or benzyl.)

[0721] [ka]

[0722] (In the above chemical formula 3, R is a C1-C6 linear or branched alkyl or benzyl group.)

[0723] [ka]

[0724] (In the above chemical formula 4, X is F, Cl, Br, or I).

[0725] Realization Example B1. The X-ray powder diffraction pattern contains diffraction peaks at three or more diffraction angles selected from the group consisting of diffraction angles (2θ±0.2°) of 7.83°, 14.52°, 17.11°, 18.08°, 19.59°, 21.41°, and 23.56°, and is the crystalline form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by the following chemical formula 1:

[0726] [ka]

[0727] Implementation Example B2. In Implementation Example B1, The X-ray powder diffraction pattern further includes diffraction peaks at one or more diffraction angles selected from the group consisting of diffraction angles (2θ±0.2°) of 15.64°, 17.54°, 20.77°, 21.04°, 23.26°, 24.23°, and 30.37°, for crystal form I.

[0728] Implementation Example B3. In Implementation Example B1, Crystal form I, 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°.

[0729] Implementation Example B4. In any one of Implementation Examples B1 to B3, Crystal form I, which exhibits an endothermic peak between 134°C (±0.5°C) and 142°C (±0.5°C) during differential scanning calorimetry (DSC) analysis when the heating rate is 10°C / min.

[0730] Implementation Example B5. In any one of Implementation Examples B1 to B4, Crystal form I, which exhibits an endothermic peak at 138°C (±3°C) during differential scanning calorimetry (DSC) analysis when the heating rate is 10°C / min.

[0731] Implementation Example B6. In any one of Implementation Examples B1 to B5, Crystalline form I, when analyzed by differential scanning calorimetry (DSC) at a heating rate of 10°C / min, exhibits an endothermic peak at an onset temperature of 134.64°C (±0.5°C) and at 138.27°C (±0.5°C).

[0732] Realization Example B7. The X-ray powder diffraction pattern contains three or more diffraction peaks selected from the group consisting of diffraction angles (2θ±0.2°) of 7.83°, 12.22°, 19.02°, 19.67°, 21.39°, 22.35°, and 26.42°, and is the crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by the following chemical formula 1:

[0733] [ka]

[0734] Implementation Example B8. In Implementation Example B7, Crystal form II, 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 (2θ±0.2°) of 11.39°, 11.77°, 13.26°, 15.72°, 16.60°, 18.27°, 19.35°, 20.67°, 24.56°, 27.34°, and 33.72°.

[0735] Implementation Example B9. In Implementation Example B7, Crystal form II, 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 (2θ±0.2°) 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°.

[0736] Implementation Example B10. In any one of Implementation Examples B7 to B9, Crystal form II, which exhibits an endothermic peak between 125°C (±0.5°C) and 135°C (±0.5°C) during differential scanning calorimetry (DSC) analysis when the heating rate is 10°C / min.

[0737] Implementation Example B11. In any one of Implementation Examples B7 to B10, Crystal form II, which exhibits an endothermic peak at 130°C (±5°C) during differential scanning calorimetry (DSC) analysis when the heating rate is 10°C / min.

[0738] Implementation Example B12. In any one of Implementation Examples B7 to B11, Crystalline form II, when the heating rate is 10°C / min, exhibits endothermic peaks at an onset temperature of 125.61°C (±0.5°C) and 130.43°C (±0.5°C) during differential scanning calorimetry (DSC) analysis.

[0739] Implementation Example B13.(a) N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by the following chemical formula 1 is converted to ethyl acetate, ethanol, methanol, isopropyl alcohol, butyl alcohol, methyl tert-butyl The steps of obtaining a solution by dissolving in a solvent selected from the group consisting of 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 step of producing a solid from the solution, A method for producing the compound represented by the above chemical formula 1, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide crystalline form I:

[0740] [ka]

[0741] Implementation Example B14. In Implementation Example B13, in step (a), the solvent is A method for producing a substance, comprising one or more alcohols selected from the group consisting of ethanol, methanol, isopropyl alcohol, and butyl alcohol, ethyl acetate, or a mixture of the alcohols and ethyl acetate.

[0742] Implementation Example B15. In Implementation Example B14 or 15, (a) the step of obtaining the solution is: (a1) The step of adding a compound represented by chemical formula 1 to the solvent to obtain a mixture; and (a2) A method for producing the mixture, comprising the step of heating the mixture to a temperature exceeding 40°C.

[0743] Implementation Example B16. In any one of Implementation Examples B13 to B15, the step of generating the solid in step (b) is: (b1) Adding one or more alcohols selected from the group consisting of ethanol, methanol, isopropyl alcohol, and butyl alcohol to the solution of step (a); and (b2) The step further includes stirring after adding alcohol in step (b1), Manufacturing method.

[0744] Implementation Example B17. In Implementation Example B16, steps (b1) and (b2) are performed at a temperature exceeding 40°C. Manufacturing method.

[0745] Implementation Example B18. In Implementation Example B16 or B17, before performing step (a), The steps include: dissolving the compound represented by chemical formula 1 in dichloromethane, then performing primary concentration to produce a concentrated residue; and The method further includes the step of adding ethyl acetate to the concentrated residue and performing a secondary concentration. Manufacturing method.

[0746] Example B19.(a) A step of preparing a mixture by adding N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-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, isopropyl alcohol, butyl alcohol, diisopropyl ether, tetrahydrofuran, heptane, hexane, and mixtures thereof; (b) A step of heating the mixture to a temperature of 40°C or lower to obtain a solution; and (c) The method includes the step of producing a solid from the solution at a temperature of 40°C or lower. A method for producing crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is represented by the above chemical formula 1:

[0747] [ka]

[0748] Implementation Example B20. A method for production in which, in step (a) of Implementation Example B19, the solvent is ethanol, isopropanol, or a mixture thereof.

[0749] Implementation Example B21. In Implementation Example B19 or B20, before performing step (a), The compound represented by the chemical formula 1 is dissolved in dichloromethane, and then the mixture is concentrated to produce a concentrated residue; The method further includes the step of adding ethanol to the concentrated residue and performing a secondary concentration. Manufacturing method.

[0750] Implementation Example B22.(a) The amorphous N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by the following chemical formula 1 is converted to methyl tert-butyl ether (MTBE), heptane, octane, hexane, pentane, and The steps of adding to a solvent selected from the group consisting of these mixtures to form a slurry; and (b) The step of obtaining a solid from the slurry, A method for producing crystalline form III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is represented by the chemical formula 1:

[0751] [ka]

[0752] Implementation Example B23. In Implementation Example B22, the solvent in step (a) is methyl tert-butyl ether (MTBE), heptane, or a mixture thereof. Manufacturing method.

[0753] Implementation Example B24. A manufacturing method in which, in Implementation Example B22 or B23, the step of (a) forming a slurry is carried out for 3 to 20 days.

[0754] Implementation Example B25. A manufacturing method in which, in any one of Implementation Examples B22 to B24, (b) the step of obtaining a solid includes the step of filtering the slurry.

[0755] Implementation Example B26. In any one of Implementation Examples B28 to B31, the steps of (a) forming a slurry and (b) obtaining a solid are performed at a temperature of 30°C or lower. The manufacturing method. [Examples]

[0756] The present invention will be described in detail below with reference to examples to aid in understanding the present invention. However, the following examples are merely illustrative of the content of the present invention, and the scope of the present invention is not limited to these examples. The examples of the present invention are provided to give a more complete explanation of the present invention to a person of average knowledge in the industry.

[0757] <Example 1> Preparation of methyl 6-(chloromethyl)nicotinate (8a)

[0758] [ka]

[0759] Methyl 6-methylnicotinate (380 g, 7a) and dichloromethane (5.7 L) were added to the reaction chamber, and trichloroisocyanuric acid (701 g) was added in installments at 15-22°C for 1 hour. The mixture was stirred at 17-22°C for 2-4 hours, then cooled to below 5°C and filtered. The filtered solid was washed with dichloromethane (760 mL) to remove insoluble solids. 20% sodium sulfite aqueous solution (1.9 L) was gradually added to the filtrate obtained through filtration at below 25°C, and the mixture was stirred at 20-25°C for 1 hour. The stirred mixture was filtered by Celite filtration and washed with dichloromethane (760 mL), after which the organic layer was separated. The separated organic layer was washed with distilled water (1.9 L) and 10% sodium chloride aqueous solution (1.9 L) in sequence, and water was removed using sodium sulfate (380 g). The reactants were concentrated and the solvent removed to obtain the title compound (466.6 g, 100% yield) with an HPLC purity of 93.08%.

[0760] 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)

[0761] <Example 2> Preparation of Methyl 6-((phenylamino)methyl)nicotinate (3a)

[0762] [ka]

[0763] In the reaction chamber, methyl 6-(chloromethyl)nicotinate (466.6g, 8a) prepared in Example 1, sodium bicarbonate (422.3g), potassium iodide (125.19g), dimethylacetamide (1.4L), and aniline (468.21g) were added. The reaction was carried out with stirring at 25-30°C for 3 hours. After the reaction, the temperature was cooled to room temperature, and ethyl acetate (3.7 L) and 10% ammonium chloride aqueous solution (2.3 L) were added and stirred for 0.5 hours. The organic layer was separated and washed with 15% ammonium chloride aqueous solution (2.3 L) and 9% sodium bicarbonate aqueous solution (2.3 L) in sequence, and the solvent was concentrated and removed.

[0764] Methanol (2.3 L) was added to the concentrated residue, and the residue was dissolved at 45-50°C. After cooling to room temperature, the mixture was stirred for 2 hours. Distilled water (2.3 L) was gradually added to the reaction mixture at room temperature, and the mixture was stirred for 2 hours. After stirring, the temperature was cooled to 0-5°C, and the mixture was stirred for 1-2 hours before filtration. The solid obtained by filtration was washed with distilled water (930 mL) and vacuum-dried for 12 hours to obtain the title compound (501.2 g, yield: 82.4%) with an HPLC purity of 95.54%.

[0765] 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)

[0766] <Example 3> Preparation of Methyl 6-((1,1-dioxide-N-phenylthiomorpholine-4-carboxamide)methyl)nicotinate (5a)

[0767] [ka]

[0768] Methyl 6-((phenylamino)methyl)nicotinate (500g, 3a), thiomorpholine-4-carbonyl chloride 1,1-dioxide (469g, 4a), N,N-diisopropylethylamine (DIPEA, 346.8g), and toluene (1.5L) prepared in Example 2 were added to the reaction chamber, and the mixture was heated to 75-85°C and stirred for 2-3 hours.

[0769] After cooling the temperature to 20-30°C, dichloromethane (3.5 L) was added and the mixture was stirred at room temperature for 0.5-1 hour. The organic layer was separated, and 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 using 10% ammonium chloride aqueous solution (2.5 L) and distilled water (2.5 L) in sequence.

[0770] After concentrating the reaction mixture and removing the solvent, methanol (2.5 L) was added and the mixture was stirred at 55-65°C for 2-3 hours. After cooling the temperature to 45-55°C, methyl tert-butyl ether was added. 4 L of tert was gradually added and stirred at 35-45°C for 1-2 hours. The temperature was cooled to 0-5°C and stirred for 1-2 hours before filtration. The solid obtained by filtration was methyl tert-butyl ester. The sample was washed with 1 L of ester and vacuum-dried for 6 hours to obtain the title compound (731.7 g, yield: 87.9%) with an HPLC purity of 99.65%.

[0771] 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)

[0772] <Example 4> Preparation of N-((5-(hydrazinecarbonyl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (6)

[0773] [ka]

[0774] Methyl 6-((1,1-dioxide-N-phenylthiomorpholine-4-carboxamide)methyl)nicotinate (700g, 5a) prepared in Example 3, hydrazine monohydrate (434.3g), methanol (2.8L), and distilled water (1.4L) were added to the reaction chamber, and the mixture was heated to 58-68°C and stirred for 3-5 hours.

[0775] After cooling the temperature to 20-30°C, the mixture was stirred for 1 hour, and anhydrous ethanol (2.8 L) was gradually added to the reaction. The temperature was cooled to 0-5°C, the mixture was stirred for 1 hour, and then filtered. The solid obtained by filtration was washed with anhydrous ethanol:distilled water mixture (5:1 (v:v), 1.4 L), and vacuum-dried at 50-55°C for 12 hours to obtain the primary purified title compound.

[0776] The primary purified title compound and dichloromethane (4.9 L) were added to the reaction chamber, stirred at 25-35°C for 2 hours, and then cooled to 0-5°C. The cooled mixture was stirred for 1 hour and then filtered. The filtered solid was washed with dichloromethane (1.4 L) and vacuum-dried at 50-55°C for 12 hours to obtain the title compound (631.5 g, yield: 90.2%) with an HPLC purity of 99.63%.

[0777] TLC (MC / MeOH = 10 / 1): Rf 0.2 1H 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)

[0778] <Example 5> Preparation of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (1) and its crystalline form I

[0779] [ka]

[0780] Imidazole (303.73 g) and dichloromethane (0.9 L) were added to reaction chamber 1, and the temperature was cooled to 0-10°C. Difluoroacetic anhydride (776.5 g) was gradually added to the cooled mixture while maintaining a temperature of 25°C or lower, and the mixture was stirred at room temperature for 1-2 hours.

[0781] In addition, N-((5-(hydrazinecarbonyl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (600 g, 6) and dichloromethane (2.7 L) prepared in Example 4 were added to the other reaction chamber 2, and the temperature was cooled to below 0°C.

[0782] The mixture from reaction section 1 was gradually added to the mixture from reaction section 2, which had been cooled to below 0°C, while maintaining a temperature of -10-5°C. After the addition was complete, the temperature was raised to 35-40°C and stirred for 3-4 hours. After stirring, it was cooled to room temperature, and 3 L of 10% ammonium chloride aqueous solution was added, followed by stirring for 0.5 hours. The organic layer was separated, 3 L of 9% sodium bicarbonate aqueous solution was added, and the mixture was stirred for 0.5 hours. After separating the organic layer, it was washed with 3 L of distilled water. 600 g of sodium sulfate was added to the organic layer and water was removed while stirring for 0.5 hours. After filtration and concentration of the solvent, the title compound represented by chemical formula 1 (689 g) with an HPLC purity of 99.60% was obtained.

[0783] The compound represented by chemical formula 1 obtained as described above was further concentrated by injecting ethyl acetate (600 mL). Ethyl acetate (900 mL) and anhydrous ethanol (1.2 L) were added to the concentrated residue and the mixture was heated to 55-65°C to dissolve it. Anhydrous ethanol (2.4 L) was added and the mixture was stirred at 40-50°C for 3 hours to precipitate a solid. Anhydrous ethanol (2.4 L) was added and the mixture was stirred at 40-50°C for 2-4 hours, then cooled to below 5°C and stirred for an additional hour before being filtered. The filtered solid was washed with anhydrous ethanol (1.2 L) and vacuum dried at 35-40°C for 6 hours to obtain crystalline form I (632.3 g, yield 91.7%) of the compound represented by chemical formula 1 with an HPLC purity of 99.84%.

[0784] The NMR analysis results of the compound represented by chemical formula 1 obtained in Example 5 are as follows:

[0785] 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)

[0786] Furthermore, the X-ray powder diffraction (XRPD) pattern of crystal form I obtained in Example 5 is shown in Figure 2 and Table 1, and the differential scanning calorimetry (DSC) analysis results are shown in Figure 3.

[0787] [Table 1]

[0788] <Example 6> Preparation of Methyl 6-((phenylamino)methyl)nicotinate (3a)

[0789] [ka]

[0790] Methyl 6-formyl nicotinate (180 g, 2a) and dichloromethane (900 mL) were added to reaction chamber 1, and aniline (101.5 g) was gradually added while maintaining a temperature of 10-30°C, after which the mixture was stirred at a temperature of 20-30°C for 1-2 hours.

[0791] In addition, sodium triacetoxyborohydride (346.5 g) and dichloromethane (1.62 L) were added to the other reaction chamber 2, and the mixture was cooled to a temperature of 5°C or lower.

[0792] The mixture from reaction section 1 was gradually added to the mixture from reaction section 2, which had been cooled to below 5°C, while maintaining a temperature of below 10°C. After addition, any small amount of mixture remaining in reaction section 1 was washed with dichloromethane (180 mL) and added to reaction section 2. After addition was complete, the temperature was raised to 15-25°C and stirred for 2-3 hours. After stirring, 1.8 L of 1N hydrochloric acid aqueous solution and 360 mL of 9% sodium bicarbonate aqueous solution were gradually added in sequence, and the mixture was stirred at 20-30°C for 0.5 hours. The organic layer was separated, and 1.44 L of 9% sodium bicarbonate aqueous solution was added, followed by stirring for 0.5 hours. After separating the organic layer, it was washed with 1.8 L of 10% sodium chloride aqueous solution. Water was removed from the organic layer using sodium sulfate (180 g), and the solvent was filtered and concentrated to obtain the title compound (264.07 g, yield 100%) with an HPLC purity of 99.01%.

[0793] 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)

[0794] <Example 7> Preparation of Methyl 6-((1,1-dioxide-N-phenylthiomorpholine-4-carboxamide)methyl)nicotinate (5a)

[0795] [ka]

[0796] The reaction site contains methyl 6-((phenylamino)methyl)nicotinate (264.07 g, 3a), thiomorpholine-4-carbonyl chloride (280 g, 4a), N,N-diisopropylethylamine (DIPEA, 281.7 g), and the following: Luen (3.43 L) was added, and after raising the temperature to 90-100°C, it was stirred for 2-3 hours.

[0797] After cooling the temperature to 65-70°C, distilled water (792 mL) was added and the mixture was stirred at 65-70°C for 1 hour. 2-butanol (792 mL) was added to the reaction mixture at 65-70°C, and after cooling the temperature to 35-40°C, dichloromethane (528 mL) was added and the mixture was stirred at 35-40°C for 0.5 hours. The organic layer was separated, filtered by Celite, 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. After separating the organic layer, it was washed with 10% ammonium chloride aqueous solution (2.6 L) and then distilled water (1.3 L).

[0798] After concentrating the reactants and removing the solvent, methanol (1.3 L) was added and the mixture was stirred at 55-65°C for 2 hours. After cooling to 50-55°C, methyl tert-butyl ether was added. (2.1 L) was gradually added and stirred at 35-45°C for 1 hour. The temperature was cooled to 0-5°C and stirred for 1-2 hours before filtration. The solid obtained by filtration was methyl tert-butyl ether. The sample was washed with 528 mL of water and vacuum-dried for 6 hours to obtain the title compound (372 g, yield: 84.6%) with an HPLC purity of 99.72%.

[0799] 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)

[0800] <Example 8> Preparation of N-((5-(hydrazinecarbonyl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (6)

[0801] [ka]

[0802] Methyl 6-((1,1-dioxide-N-phenylthiomorpholine-4-carboxamide)methyl)nicotinate (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 chamber, and the mixture was heated to 58-68°C and stirred for 3-5 hours.

[0803] After cooling the temperature to 20-30°C, the mixture was stirred for 1 hour, and anhydrous ethanol (2.22 L) was gradually added to the reaction mixture. The temperature was cooled to 0-5°C, and after stirring for 1 hour, the mixture was filtered. The solid obtained by filtration was washed with anhydrous ethanol:distilled water mixture (5:1 (v / v), 740 mL), and vacuum-dried at 50-55°C for 12 hours to obtain the primary purified title compound.

[0804] The primary purified title compound and dichloromethane (1.85 L) were added to the reaction chamber, and the mixture was stirred at 25-35°C for 2 hours, then cooled to 0-5°C. The cooled mixture was stirred for 1 hour and then filtered. The filtered solid was washed with dichloromethane (740 mL) and vacuum-dried at 50-55°C for 12 hours to obtain the title compound (333 g, yield: 90%) with an HPLC purity of 99.56%.

[0805] TLC (MC / MeOH = 10 / 1): Rf 0.2 1H 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)

[0806] <Example 9> Preparation of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (1) and its crystalline form I

[0807] [ka]

[0808] Imidazole (164.83 g) and dichloromethane (1.3 L) were added to reaction chamber 1, and the temperature was cooled to 0-10°C. Difluoroacetic anhydride (421.4 g) was gradually added to the cooled mixture while maintaining a temperature of 20°C or lower, and the mixture was stirred at room temperature for 1-2 hours.

[0809] In addition, N-((5-(hydrazinecarbonyl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (325.6 g, 6) and dichloromethane (1.63 L) prepared in Example 8 were added to the other reaction chamber 2, and the temperature was cooled to below 0°C.

[0810] The mixture in the reaction part 1 was gradually added while maintaining the temperature at -10 - 0 °C with the mixed solution in the reaction part 2 cooled to 0 °C or below. After the addition was completed, the temperature was raised to 35 - 40 °C, and then stirred for 3 - 4 hours. After stirring, it was cooled to room temperature, and after adding 10% aqueous ammonium chloride solution (3.26 L), it was stirred for 0.5 hours. The organic layer was separated, after adding 9% aqueous sodium hydrogen carbonate solution (3.26 L), it was stirred for 0.5 hours, and after separating the organic layer, it was washed with distilled water (1.63 L). Sodium sulfate (326 g) was added to the organic layer and stirred for 0.5 hours to remove moisture. After filtration and concentration of the solvent, the title compound (374 g) represented by Chemical Formula 1 with an HPLC purity of 99.69% was obtained.

[0811] Ethyl acetate (326 mL) was injected into the compound represented by Chemical Formula 1 obtained as described above for additional concentration. Ethyl acetate (326 mL) and absolute ethanol (1.3 L) were added to the concentrated residue, and the temperature was raised to 50 - 60 °C to dissolve it. Additional absolute ethanol (1.95 L) was added, and after stirring at 45 - 50 °C for 3 hours, it was cooled to 5 °C or below and filtered. The solid obtained by filtration was washed with absolute ethanol (652 mL) and vacuum dried at 35 - 40 °C for 6 hours to obtain the title compound (343.2 g, yield 91.8%) with an HPLC purity of 99.83%.

[0812] The results of NMR analysis of the compound represented by Chemical Formula 1 obtained in Example 9 are as follows.

[0813] 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)

[0814] The X-ray powder diffraction (XRPD) patterns of crystal form I obtained in Example 9 are shown in Figure 4 and Table 2, and the differential scanning calorimetry (DSC) analysis results are shown in Figure 5.

[0815] [Table 2]

[0816] <Example 10> Preparation of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (compound represented by chemical formula 1) and its crystalline form I Construction

[0817] Imidazole (1.61 kg) and dichloromethane (15.9 L) were added to reaction chamber 1, and the temperature was cooled to 5-10°C. Difluoroacetic anhydride (4.12 kg) was gradually added to the cooled mixture while maintaining a temperature of 30°C or lower, and the mixture was stirred at room temperature for 1 hour.

[0818] In addition, N-((5-(hydrazinecarbonyl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (3.18 kg) and dichloromethane (15.9 L) were added to the other reaction chamber 2, and the temperature was cooled to below 0°C.

[0819] The mixture from reaction section 1 was gradually added to the mixture from reaction section 2, which had been cooled to below 0°C, while maintaining a temperature of below 5°C. After the addition was complete, the temperature was raised to 35-40°C for 1 hour, followed by stirring for 2 hours. After confirming the completion of the reaction by HPLC, the mixture was cooled to room temperature, and 10% ammonium chloride aqueous solution (31.8 L) was added, followed by stirring for 0.5 hours. The organic layer was separated, and 9% sodium bicarbonate aqueous solution (31.8 L) was added, followed by stirring for 0.5 hours. After that, the organic layer was washed with distilled water (15.9 L) after separation. Sodium sulfate (3.18 kg) was added to the organic layer, and water was removed while stirring for 0.5 hours. The mixture was then filtered and the solvent was concentrated to obtain the title compound (3.65 kg), represented by chemical formula 1, with an HPLC purity of 99.69%.

[0820] As described above, 3.65 kg of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by chemical formula 1, was injected with ethyl acetate (3.18 L) and further concentrated. Ethyl acetate (3.18 L) and ethanol (12.72 L) were added to the concentrated residue and the mixture was heated to 50-55°C to dissolve. Ethanol (19.08 L) was added, and the mixture was stirred at 50-55°C for 1.5 hours, then cooled to below 5°C and filtered. The solid obtained by filtration was washed with ethanol (6.36 L) and vacuum-dried for 14 hours to obtain the title compound (N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide crystal form I) (3.38 kg, yield 92.3%) with an HPLC purity of 99.90%.

[0821] The X-ray powder diffraction (XRPD) patterns of crystal form I obtained in Example 10 are shown in Figure 6 and Table 3.

[0822] [Table 3]

[0823] <Example 11> Preparation of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (compound represented by chemical formula 1) and its crystalline form II

[0824] Imidazole (405.4 g) and dichloromethane (4.45 L) were added to reaction chamber 1, and the temperature was cooled to 0-5°C. Difluoroacetic anhydride (1.04 kg) was gradually added to the cooled mixture while maintaining a temperature of 0-10°C, and the mixture was stirred at room temperature for 1 hour.

[0825] In addition, N-((5-(hydrazinecarbonyl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (890 g) and dichloromethane (8.9 L) were added to the other reaction chamber 2, and the temperature was cooled to 0-5°C.

[0826] The mixture from reaction section 1 was gradually added to the cooled mixture from reaction section 2 while maintaining a temperature of 0-5°C. After the addition was complete, the temperature was raised to 35-40°C for 1 hour, followed by stirring for 4 hours. After confirming the completion of the reaction by HPLC, the mixture was cooled to room temperature, and 10% ammonium chloride aqueous solution (8.9 L) was added, followed by stirring for 0.5 hours. The organic layer was separated, and 9% sodium bicarbonate aqueous solution (8.9 L) was added, followed by stirring for 0.5 hours. The organic layer was then separated again and washed with distilled water (4.45 L). Sodium sulfate (890 g) was added to the organic layer, and water was removed while stirring for 0.5 hours. The mixture was then filtered and the solvent concentrated to obtain the title compound, which is represented by chemical formula 1.

[0827] As described above, the compound N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (1022.4g), represented by chemical formula 1, was injected with ethanol (2L) and concentrated. Ethanol (7.15L) was added to the concentrated residue, and the mixture was heated to 35-40°C and stirred for 13 hours. The precipitated mixture during stirring was filtered. 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-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide crystal form II) (985.8 g, yield 96.4%) with an HPLC purity of 99.6%.

[0828] The X-ray powder diffraction (XRPD) patterns of crystal form II obtained in Example 11 are shown in Figure 7 and Table 4, and the differential scanning calorimetry (DSC) analysis results are shown in Figure 8.

[0829] [Table 4]

[0830] <Example 12> Amorphous N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine Preparation of -4-carboxamide 1,1-dioxide (compound represented by chemical formula 1) and crystalline form III

[0831] Imidazole (15.2 g) and dichloromethane (150 mL) were added to reaction chamber 1, and the temperature was cooled to 5-10°C. Difluoroacetic anhydride (38.8 g) was gradually added to the cooled mixture while maintaining a temperature of 20°C or lower, and the mixture was stirred at room temperature for 1 hour.

[0832] In addition, N-((5-(hydrazinecarbonyl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (30 g) and dichloromethane (150 mL) were added to the other reaction chamber 2, and the temperature was cooled to 0-5°C.

[0833] The mixture from reaction section 1 was gradually added to the cooled mixture from reaction section 2 while maintaining a temperature of 0-5°C. After the addition was complete, the temperature was raised to 35-40°C and stirred for 3 hours. After confirming the completion of the reaction by HPLC, the mixture was cooled to room temperature, 300 mL of 10% ammonium chloride aqueous solution was added, and the mixture was stirred for 0.5 hours. The organic layer was separated, 300 mL of 9% sodium bicarbonate aqueous solution was added, and the mixture was stirred for 0.5 hours. The organic layer was then separated again and washed with 150 mL of distilled water. 30 g of sodium sulfate was added to the organic layer and the mixture was stirred for 0.5 hours to remove water. After filtration and concentration of the solvent, the compound represented by chemical formula 1 was vacuum-dried at room temperature for 14 hours to obtain 34.46 g of the compound represented by chemical formula 1 in amorphous solid form.

[0834] 20 g of the amorphous solid compound represented by chemical formula 1 is mixed with methyl tert-butyl ether. 400 mL of tert-butyl ether (MTBE) was added, and the slurry was allowed to stand at 20-25°C for 24 hours before being filtered. The resulting solid was washed with methyl tert-butyl ether (MTBE, 40 mL). The compound was purified and vacuum-dried for 14 hours to obtain the title compound (N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide crystal form III) (18.6 g, yield 93%) with an HPLC purity of 99.86%.

[0835] The X-ray powder diffraction (XRPD) patterns of crystal form III obtained from Example 12 are shown in Figure 9 and Table 5, and the differential scanning calorimetry (DSC) analysis results are shown in Figure 10.

[0836] [Table 5]

[0837] On the other hand, the X-ray powder diffraction (XRPD) pattern of the amorphous compound represented by chemical formula 1, used in the manufacturing process of crystalline form III, is shown in Figure 11.

[0838] <Manufacturing example>

[0839] Manufacturing Example 1. N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carb Amorphous production of xamide 1,1-dioxide

[0840] 20 g of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (compound represented by chemical formula 1) was dissolved in 400 mL of dichloromethane and then concentrated. Vacuum drying was performed at 20-30°C for 14 hours to obtain 20 g of amorphous (melting point: 129.5°C) of the title compound (N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide with an HPLC purity of 99.77%. The X-ray powder diffraction (XRPD) pattern is shown in Figure 12, and the differential scanning calorimetry (DSC) analysis results are shown in Figure 13.

[0841] Example 13. Preparation of crystalline form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide

[0842] 34.5 g of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (compound represented by chemical formula 1) was dissolved completely in 600 mL of dichloromethane, and then concentrated. Ethyl acetate (30 mL) was added to the concentrated residue and concentrated again. Then, 30 mL of ethyl acetate and 120 mL of ethanol were added, and the mixture was heated to 50-55°C to dissolve it. An additional 180 mL of ethanol was added, and the mixture was stirred at 50-55°C for 3 hours to precipitate the solid. After that, the mixture was cooled to below 5°C and filtered. The solid obtained by filtration was washed with ethanol (60 mL) and vacuum-dried for 14 hours to obtain the title compound (crystal form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide) (32.5 g, yield 94.3%, melting point: 138.3 °C) with HPLC purity of 99.91%. The X-ray powder diffraction (XRPD) pattern of crystal form I is shown in Figure 14 and Table 6, and the differential scanning calorimetry (DSC) analysis results are shown in Figure 15.

[0843] [Table 6]

[0844] Example 14. Preparation of crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide

[0845] After completely dissolving 23 g of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (a compound represented by chemical formula 1) in 400 mL of dichloromethane, the solution was concentrated. Ethanol (40 mL) was then injected into the concentrated residue. After concentration, ethanol (140 mL) was added, and the temperature was raised to 35-40°C to dissolve the compound and prepare a solution, which was then stirred for 1-2 hours. The solid precipitated during stirring was filtered. The filtered solid was dried for 14 hours to obtain the title compound (N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide crystal form II) (20.9 g, yield 91%, melting point: 130.4°C) with HPLC purity of 99.6%. The X-ray powder diffraction (XRPD) pattern of crystal form II is shown in Figure 16 and Table 7, and the differential scanning calorimetry (DSC) analysis results are shown in Figure 17.

[0846] [Table 7]

[0847] Example 15. Preparation of crystalline form III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide

[0848] The amorphous solid state obtained in the manufacturing example is N-((5-(5-(difluoromethyl)-1,3 Add 20g of 4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide (compound represented by chemical formula 1) to methyl tert-butyl ether (MTBE, 400mL) and heat at 20-25°C. The slurry was filtered after 24 hours. The solid obtained by filtration was methyl tert-butyl ether. The sample was washed with tereol (MTBE, 40 mL) and vacuum-dried for 14 hours to obtain the title compound (N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide crystal form III) (18.5 g, yield 92.5%, melting point: 125.0 °C) with HPLC purity of 99.8%. The X-ray powder diffraction (XRPD) pattern of crystal form III is shown in Figure 18 and Table 8, and the differential scanning calorimetry (DSC) analysis results are shown in Figure 19.

[0849] [Table 8]

[0850] <Example of experiment>

[0851] Experimental Example 1. Crystallographic stability and accelerated stability tests for amorphous, crystalline forms I, II, and III.

[0852] The crystalline form of a compound can change to other crystalline forms depending on the surrounding environment, and such crystalline forms that are fragile in terms of crystalline stability can easily undergo crystalline form changes and exist in multiple crystalline forms. In this case, the pharmacokinetic properties of the final drug may change, and unexpected reactions in pharmacokinetics may be induced. Therefore, the N-((5-(5-(difluoro produced in the above manufacturing example) Crystal stability and accelerated stability tests (accelerated conditions: 40°C ± 2°C, 75% RH ± 5%) were performed on amorphous, crystalline form I, crystalline form II, and crystalline form III of methyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide. After 6 months, purity and X-ray powder diffraction (XPRD) patterns were further confirmed, and the analytical results are shown in Table 9.

[0853] [Table 9]

[0854] As shown in Table 9 above, crystal forms I, II, and III exhibit excellent crystal stability, maintaining their purity and crystal form stably for six months, and were confirmed to be easy to store.

[0855] However, in the case of amorphous material, although there was no change in purity for 3 months under accelerated conditions, it was confirmed that it easily converted to crystalline form I, and that the purity decreased to 94.6% after 6 months. Based on the above observations, it was confirmed that amorphous material has relatively low stability.

[0856] Therefore, it can be seen that crystal forms I, II, and III according to the present invention exhibit excellent stability to the extent that they can be used in pharmaceuticals, and that their crystal form is stably maintained during the manufacturing of pharmaceuticals, and that they can be stored for a long period of time without changes in pharmacological effect, safety, and pharmacokinetic properties, thus enabling the maintenance of excellent therapeutic effects over a long period of time, and that they are also remarkably economical.

[0857] Experimental Example 2. Hygroscopicity Test

[0858] Hygroscopic compounds are easily susceptible to moisture absorption, making them difficult to handle and unsuitable for formulation due to their poor flowability. Furthermore, their fragile stability limits their long-term storage, and their inconsistent content makes it difficult to obtain reproducible results.

[0859] Therefore, the hygroscopicity of the N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide crystalline form according to the present invention was evaluated. The hygroscopicity of the crystalline form of this invention was confirmed using a moisture adsorption analyzer (dynamic vapor sorption, DVS), and the results were compared with those for amorphous compounds, as shown in Table 10 and Figures 20-23.

[0860] <Moisture adsorption analysis (Dynamic Vapor Sorption, DVS)>

[0861] Using a moisture adsorption analyzer (dynamic vapor sorption, DVS) (Surface Measurement Systems' DVS Intrinsic model), the relative humidity was gradually changed from 0% to 95% in 10% increments at 25°C, and the mass changes of crystalline and amorphous materials were measured under dm / dt (delta mass / delta time) conditions. The mass changes due to the humidity changes are shown in Figures 20 (crystalline form I), 21 (crystalline form II), 22 (crystalline form III), and 23 (amorphous), and the confirmation of hygroscopicity through mass changes at 25°C / 80%RH is shown in Table 10 below.

[0862] [Table 10]

[0863] As can be seen in Figures 20 to 23, crystalline forms I, II, and III according to the present invention stably maintain an anhydrous state without being affected by changes in ambient relative humidity. However, in the case of amorphous forms, compared to crystalline forms, it tended to absorb about 1% to 2.5% of moisture at high relative humidity (70-90% RH).

[0864] Furthermore, as can be seen in Table 10, the crystalline forms I, II, and III of the invention maintained a substantially stable moisture content by weight even at a relative humidity of 80%, while the amorphous form was found to absorb moisture, resulting in an increase in moisture content by weight.

[0865] Therefore, crystal forms I, II, and III according to the present invention are stable crystal forms with low hygroscopicity, can be maintained stably for a long period of time without being affected by ambient humidity, do not require separate storage conditions during storage, can maintain stably physicochemical properties without being affected by ambient moisture, are advantageous for formulation, yield formulations with excellent content uniformity, and can maintain excellent therapeutic effects stably for a long period of time, thus demonstrating that they are crystal forms with outstanding reproducibility and economic efficiency.

[0866] Experimental Example 3. Residual Solvent Removal Test for Amorphous, Crystalline Forms I, II, and III

[0867] All residual solvents have no therapeutic benefit and must be removed to a level that meets product specifications, Good Manufacturing Practices (GMP), or other quality standards. The formulation must not contain residual solvents at levels exceeding those permitted by safety data. Furthermore, residual levels must be regulated in accordance with ICH guidelines to protect patients from potential adverse reactions caused by the toxicity of residual solvents. Therefore, residual solvent management is crucial, as is the management of flexible substances in the final API, and the efficiency of residual solvent removal can vary significantly depending on the crystalline form. Accordingly, the degree of residual solvent removal for amorphous and crystalline forms was evaluated.

[0868] N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-di The degree of residual solvent removal for amorphous oxides, crystalline forms I, II, and III was tested, and the results are shown in Table 11 below.

[0869] In the residual solvent removal experiment described above, vacuum drying was performed at a temperature of 20-30°C, and humidified drying was performed at a temperature of 20-30°C and a relative humidity of 80-90%. For amorphous materials, humidified drying was performed after vacuum drying as described in Production Example 1.

[0870] [Table 11]

[0871] As shown in Table 11 above, it was found that the crystalline forms I, II, and III of the present invention can have residual solvent removed to below the ICH guideline standards by general vacuum drying alone, making them suitable as raw materials for pharmaceuticals. In contrast, it was confirmed that the amorphous form is difficult to remove residual solvent to below the ICH specified value even after vacuum drying and further humidification drying. In other words, it was confirmed that the crystalline forms I, II, and III of the present invention can effectively remove residual solvent compared to the amorphous form.

[0872] Therefore, the crystalline forms I, II, and III of the present invention are safe from the toxicity of residual solvents, meet excellent standards as raw materials for pharmaceuticals, do not require complex processes for the removal of residual solvents, can be easily used as pharmaceuticals, are suitable for mass production, and can achieve excellent therapeutic effects and safety.

[0873] Experimental Example 4. NMR Analysis Test

[0874] NMR analysis was performed on N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide prepared through the above-mentioned Production Example 1. The NMR spectrum was analyzed using a Bruker 700 MHz nuclear magnetic resonance spectrometer, and the results are shown in Figure 24. 1 1H NMR) and 25( 13 The results were shown in the 13C NMR spectrum.

[0875] In this invention, the conditions for performing X-ray powder diffraction analysis, thermal analysis, and high-performance liquid chromatography (HPLC) are as follows.

[0876] 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) with a detector. After charging the sample in the XRPD sample holder, measurements were taken at various angles (2θ). Source: CuKα, λ=1.5406Å; Generator: 40kV-40mA; Detector: PSD, Lynx Eye; DongShinFinetek DS-20. Unless otherwise specified herein, X-ray powder diffraction analysis is performed using the CuKα described above. These measurements were performed using radiation; for example, the X-ray powder diffraction (XRPD) patterns in Tables 1 to 8 were measured using CuKα radiation.

[0877] 2.Thermal analysis Examples 1-12 Differential scanning calorimetry (DSC) analysis was performed using a thermal analyzer (manufacturer: Netzsch, model name: DSC204 F1 Phoenix). Approximately 1–10 mg of sample was weighed and placed in an aluminum pan with a lid. The sample was evaluated using a linear heating lamp with a temperature range of 25°C to 400°C at a rate of 10°C / min.

[0878] Examples 13-15 Differential scanning calorimetry (DSC) analysis was performed using thermal analyzers (Manufacturer: METTLER TOLEDO, Model: DSC 823e (Crystal Form I, Crystal Form II) / Manufacturer: Netzsch, Model: DSC204 F1 Phoenix (Crystal Form III, Amorphous)). Approximately 1–10 mg of sample was weighed and placed in an aluminum pan with a lid. The sample was evaluated using a linear heating lamp with a temperature range of 25°C to 400°C at a rate of 10°C / min.

[0879] 3. High-performance liquid chromatography (HPLC) -Detector: Ultraviolet external absorbance spectrophotometer (detection wavelength 245 nm) - Column: Waters Cortecs C18+ (3.0 x 100 mm, 2.7 μm) - Column temperature: 35℃ -Flow rate: 0.7mL / min -Injection volume: 2.0μL -Mobile phase A: 0.1% Acetic acid in Water -Mobile phase B: 0.1% Acetic acid in Acetonitrile -Diluent:Mobile phase A:Mobile phase B = 50:50 (v / v) -Sample concentration: 0.5 mg / mL -Mobile phase conditions:

[0880] [Table 12]

[0881] 4. Hygroscopic analysis Moisture adsorption analysis (dynamic vapor sorption, DVS) A moisture adsorption analyzer (dynamic vapor sorption, DVS, Surface Measurement Systems' DVS Intrinsic model) was used to analyze moisture levels from 0%RH to 95%RH at 25°C. The relative humidity was gradually changed in 10% increments from 0% to 95%, and the dm / dt (delta mass / delta) ratio was calculated. The mass change of the crystalline or amorphous material was measured under the condition of (a time).

Claims

1. A method for producing a compound represented by the following chemical formula 1, comprising the step of producing a compound represented by the following chemical formula 1 in situ from a compound represented by the following chemical formula 6: 【Chemistry 1】 【Chemistry 2】

2. The manufacturing method according to claim 1, wherein the step of producing the compound represented by chemical formula 1 from the compound represented by chemical formula 6 is carried out in the presence of a base.

3. The manufacturing method according to claim 2, wherein the base contains imidazole.

4. The manufacturing method according to claim 1, wherein the compound represented by chemical formula 1 is produced using at least one selected from the compounds represented by chemical formula A and chemical formula B below and the compound represented by chemical formula 6 as reactants: 【Transformation 3】 In the aforementioned chemical formula B, X １ is F, Cl, Br, or I.

5. The step of producing the compound represented by chemical formula 1 from the compound represented by chemical formula 6 is: a) A step of preparing a reaction unit 1 containing a compound represented by the following chemical formula A or B and a base; and b) The manufacturing method according to claim 1, comprising the step of mixing the reaction unit 1 and the reaction unit 2 containing the compound represented by the chemical formula 6 to produce the compound represented by the chemical formula 1: 【Chemistry 4】 In the aforementioned chemical formula B, X １ is F, Cl, Br, or I.

6. The manufacturing method according to claim 5, wherein step a) is to mix a mixture containing a base and a solvent with a compound represented by chemical formula A or chemical formula B.

7. Step a) is, A step of preparing a mixture containing a base and a solvent; and The manufacturing method according to claim 5, comprising the step of adding the compound represented by chemical formula A or chemical formula B to the mixture.

8. The manufacturing method according to claim 7, further comprising the step of preparing a mixture containing the base and a solvent, and then cooling the mixture to 0 to 10°C.

9. The manufacturing method according to claim 5, further comprising the step of adding the compound represented by chemical formula A or chemical formula B to the mixture and then stirring.

10. In step b) above, the reaction unit 2 is The manufacturing method according to claim 5, comprising the compound represented by the chemical formula 6 and a solvent.

11. The manufacturing method according to claim 5, wherein the step of mixing the reaction section 2 and the reaction section 1 in step b) is the step of adding the reaction section 1 to the reaction section 2.

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

13. The manufacturing method according to claim 12, further comprising the step of raising the temperature to 20 to 45°C after mixing in step b).

14. Hydrazine (N) is used in the presence of a solvent containing a C1-C6 linear or branched alcohol, or a mixture of a C1-C6 linear or branched alcohol and water. ２ H ４ A method for producing the compound represented by the following chemical formula 6, comprising the steps of producing the compound represented by the following chemical formula 6 from the hydrate thereof and the compound represented by the following chemical formula 5: 【Transformation 5】 【Transformation 6】 In the above chemical formula 5, R is a C1-C6 linear or branched alkyl or benzyl group.

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

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

1.

17. The manufacturing method according to claim 14, wherein R is methyl.

18. A method for producing a compound represented by chemical formula 5, comprising the 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 produce a compound represented by chemical formula 5: 【Transformation 7】 【Transformation 8】 【Chemistry 9】 In chemical formulas 3 and 5, R is a C1-C6 linear or branched alkyl or benzyl, and in chemical formula 4, X is F, Cl, Br, or I.

19. The manufacturing method according to claim 18, wherein R is methyl and X is Cl.

20. The manufacturing method according to 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 manufacturing method according to claim 18, further comprising the step of purifying a compound represented by chemical formula 5.

22. The purification step involves methanol, ethanol, isopropyl alcohol, butyl alcohol, methyl tert-butyl ether (MTBE), diisopropyl ether, hep The manufacturing method according to claim 21, wherein the process is carried out under a solvent selected from the group consisting of tan, hexane, and mixtures thereof.

23. The steps of preparing a compound represented by the chemical formula 8 using a halogenating agent from a compound represented by the chemical formula 7 below; and The process includes the step of reacting a compound represented by the following chemical formula 8 with aniline in the presence of a base to produce a compound represented by the following chemical formula 3. Method for producing the compound represented by the following chemical formula 3: 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 In chemical formulas 3, 7, and 8, R is a C1-C6 linear or branched alkyl or benzyl, and in chemical formula 8, X is F, Cl, Br, or I.

24. The manufacturing method according to claim 23, wherein R is methyl and X is Cl.

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

26. The method for producing the compound represented by the chemical formula 8, wherein X is Cl, and the halogenating reagent is N-chlorosuccinimide (NCS), trichloroisocyanuric acid (TCCA), or a mixture thereof.

27. The manufacturing method according to 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 for producing the product according to claim 24, wherein the step of reacting the compound represented by chemical formula 8 with aniline is carried out in the presence of potassium brominated, potassium iodide, tetrabutylammonium bromide (TBAB), or a mixture thereof.

29. A method for producing the compound represented by the chemical formula 8a below, comprising the step of using only trichloroisocyanuric acid (TCCA) reagent alone with the compound represented by the chemical formula 7 below to produce the compound represented by the chemical formula 8a below: 【Chemistry 13】 【Chemistry 14】 In the chemical formulas 7 and 8a, R is a C1-C6 linear alkyl or benzyl group.

30. A method for producing the compound represented by chemical formula 3, comprising the step of reacting the compound represented by the following chemical formula 8 with aniline in the presence of a base to produce the compound represented by the following chemical formula 3: 【Chemistry 15】 【Chemistry 16】 In chemical formulas 3 and 8, R is a C1-C6 linear or branched alkyl or benzyl group, and in chemical formula 8, X is F, Cl, Br, or I.

31. The manufacturing method according to 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 for producing the product according to claim 30, wherein the step of reacting the compound represented by chemical formula 8 with aniline is carried out in the presence of potassium brominated, potassium iodide, tetrabutylammonium bromide (TBAB), or a mixture thereof.

33. A method for producing a compound represented by chemical formula 3, comprising the step of producing a compound represented by chemical formula 3 from a compound represented by chemical formula 2 in the presence of aniline and a reducing agent: 【Chemistry 17】 [Chemistry 18] In the aforementioned chemical formula 2 or 3, R is a C1-C6 linear or branched alkyl or benzyl group.

34. The step of producing the compound represented by chemical formula 3 from the compound represented by chemical formula 2 is: A step of producing a mixture containing the compound represented by the chemical formula 2 and aniline; and The manufacturing method according to claim 33, comprising the step of reacting the mixture with a reducing agent.

35. The step of producing the compound represented by chemical formula 3 from the compound represented by chemical formula 2 is: A step of preparing a reaction unit 1 containing a compound represented by chemical formula 2, aniline, and a solvent; and The manufacturing method according to claim 33, comprising the step of mixing a reaction section 2 containing a reducing agent and a solvent with the reaction section 1.

36. The reducing agent is sodium borohydride (NaBH ４ ), sodium borohydride (NaBH ３ CN), and sodium borotriacetoxyhydride (NaBH(OAc) ３ The manufacturing method according to claim 33, wherein at least one is selected from the group consisting of ).

37. The manufacturing method according to claim 33, wherein the step of producing the compound represented by chemical formula 3 from the compound represented by chemical formula 2 is carried out in the presence of an acid.

38. A method for producing a compound represented by the following chemical formula 1, 1) A step of preparing a compound represented by the chemical formula 8 using a halogenating reagent from a compound represented by the chemical formula 7 below; 2) A step of reacting the compound represented by chemical formula 8 with aniline in the presence of a base to produce the compound represented by chemical formula 3; 3) A step of reacting a compound represented by chemical formula 3 and a compound represented by chemical formula 4 in the presence of a base to obtain a compound represented by chemical formula 5; 4) The step of reacting hydrazine or its hydrate with a compound represented by the following chemical formula 5 to obtain a compound represented by the following chemical formula 6; and 5) A step of producing a compound represented by the following chemical formula 1 in situ from a compound represented by the following chemical formula 6, A method for producing a compound represented by chemical formula 1, which contains the following: 【Chemistry 19】 【Chemistry 20】 (In the above chemical formula 3, R is a C1-C6 linear or branched alkyl or benzyl group.) 【Chemistry 21】 (In the above chemical formula 4, X is F, Cl, Br, or I.) 【Chemistry 22】 (In the above chemical formula 5, R is a C1-C6 linear or branched alkyl or benzyl group.) 【Chemistry 23】 【Chemistry 24】 (In the above chemical formula 7, R is a C1-C6 linear or branched alkyl or benzyl (It is a ru) 【Chemistry 25】 (In the above chemical formula 8, R is a C1-C6 linear or branched alkyl or benzyl, and X is F, Cl, Br, or I).

39. A method for producing a compound represented by the following chemical formula 1, 1) A step of producing a compound represented by the following chemical formula 3 from a compound represented by the following chemical formula 2 in the presence of aniline and a reducing agent; 2) A step of reacting a compound represented by the following chemical formula 3 with a compound represented by the following chemical formula 4 in the presence of a base to obtain a compound represented by the following chemical formula 5; 3) The step of reacting hydrazine or its hydrate with a compound represented by the following chemical formula 5 to obtain a compound represented by the following chemical formula 6; and 4) A step of producing a compound represented by the following chemical formula 1 in situ from a compound represented by the following chemical formula 6, A method for producing a compound represented by chemical formula 1, which contains the following: 【Chemistry 26】 【Chemistry 27】 (In the above chemical formula 2, R is a C1-C6 alkyl or benzyl.) 【Chemistry 28】 (In the above chemical formula 3, R is a C1-C6 linear or branched alkyl or benzyl group.) 【Chemistry 29】 (In the above chemical formula 4, X may be F, Cl, Br, or I.) 【Transformation 30】 (In the above chemical formula 5, R is a C1-C6 linear or branched alkyl or benzyl group.) 【Chemistry 31】

40. A method for producing a compound represented by the following chemical formula 1, 1) The step of reacting hydrazine or its hydrate with a compound represented by the following chemical formula 5 to obtain a compound represented by the following chemical formula 6; and 2) A step of producing a compound represented by the following chemical formula 1 in situ from a compound represented by the following chemical formula 6, A method for producing a compound represented by chemical formula 1, which contains the following: 【Chemistry 32】 【Transformation 33】 (In the above chemical formula 5, R is a C1-C6 linear or branched alkyl or benzyl group.) 【Transformation 34】

41. The method for producing the compound represented by the chemical formula 5 is as follows: A method for producing the compound represented by chemical formula 1 according to claim 40, comprising the step of reacting a compound represented by the following chemical formula 3 with a compound represented by the following chemical formula 4 in the presence of a base to produce the compound represented by chemical formula 5: 【Chemistry 35】 (In the above chemical formula 3, R is a C1-C6 linear or branched alkyl or benzyl group.) 【Transformation 36】 (In the above chemical formula 4, X is F, Cl, Br, or I).

42. The method for producing the compound represented by the chemical formula 5 is as follows: The steps of: reacting a compound represented by chemical formula 8 with aniline in the presence of a base to produce a compound represented by chemical formula 3; and A method for producing the compound represented by chemical formula 1 according to claim 40, comprising the step of reacting a compound represented by the following chemical formula 3 with a compound represented by the following chemical formula 4 in the presence of a base to produce the compound represented by chemical formula 5: 【Chemistry 37】 (In the above chemical formula 3, R is a C1-C6 linear or branched alkyl or benzyl group.) 【Transformation 38】 (In the above chemical formula 4, X is F, Cl, Br, or I.) 【Chemistry 39】 (In the above chemical formula 8, R is a C1-C6 linear or branched alkyl or benzyl, and X is F, Cl, Br, or I).

43. The method for producing the compound represented by the chemical formula 5 is as follows: A step of preparing a compound represented by the chemical formula 8 using a halogenating reagent from a compound represented by the chemical formula 7 below; A step of reacting the compound represented by chemical formula 8 with aniline in the presence of a base to produce the compound represented by the following chemical formula 3; A method for producing the compound represented by chemical formula 1 according to claim 40, comprising the step of reacting a compound represented by the following chemical formula 3 with a compound represented by the following chemical formula 4 in the presence of a base to produce a compound represented by chemical formula 5: 【Chemistry 40】 (In the above chemical formula 3, R is a C1-C6 linear or branched alkyl or benzyl group.) 【Chemistry 41】 (In the above chemical formula 4, X is F, Cl, Br, or I.) 【Chemistry 42】 (In the above chemical formula 7, R is a C1-C6 linear or branched alkyl or benzyl group.) 【Chemistry 43】 (In the above chemical formula 8, R is a C1-C6 linear or branched alkyl or benzyl, and X is F, Cl, Br, or I).

44. The method for producing the compound represented by the chemical formula 5 is as follows: A step of producing a compound represented by the following chemical formula 3 from a compound represented by the following chemical formula 2 in the presence of aniline and a reducing agent; and A method for producing the compound represented by chemical formula 1 according to claim 40, comprising the step of reacting the compound represented by chemical formula 3 with the compound represented by the following chemical formula 4 in the presence of a base to produce the compound represented by the following chemical formula 5: 【Chemistry 44】 (In the above chemical formula 2, R is a C1-C6 alkyl or benzyl.) 【Chemistry 45】 (In the above chemical formula 3, R is a C1-C6 linear or branched alkyl or benzyl group.) 【Chemistry 46】 (In the above chemical formula 4, X is F, Cl, Br, or I).

45. Crystal form I of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by the following chemical formula 1, has an X-ray powder diffraction pattern containing diffraction peaks at three or more diffraction angles selected from the group consisting of diffraction angles of 7.85°, 14.54°, 17.14°, 18.09°, 19.62°, 21.41°, and 23.58° (2θ ± 0.2°): 【Chemistry 47】

46. The crystal 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. Crystal form I according to claim 45, further comprising 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° in the X-ray powder diffraction pattern.

48. When the heating rate is 10°C / min, the differential scanning calorimetry (DSC) analysis will be performed at 132°C (±0 Crystal form I according to claim 45, which has an endothermic peak between 5°C and 143°C (±0.5°C).

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

50. Crystal form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by the following chemical formula 1, has an X-ray powder diffraction pattern containing three or more diffraction peaks selected from the group consisting of diffraction angles (2θ ± 0.2°) of 7.83°, 12.22°, 19.02°, 19.67°, 21.40°, 22.35°, and 26.44°: 【Chemistry 48】

51. Crystal form II according to claim 50, further comprising diffraction peaks at one or more diffraction angles selected from the group consisting of diffraction angles (2θ ± 0.2°) 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° in the X-ray powder diffraction pattern.

52. Crystal form II according to claim 50, further comprising diffraction peaks at one or more diffraction angles selected from the group consisting of diffraction angles (2θ±0.2°) 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° in the X-ray powder diffraction pattern.

53. Crystal form II according to claim 50, wherein, when the heating rate is 10°C / min, the differential scanning calorimetry (DSC) analysis shows an endothermic peak between 124°C (±0.5°C) and 138°C (±0.5°C).

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

55. Crystal form III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, represented by the following chemical formula 1, whose X-ray powder diffraction pattern contains diffraction peaks at three or more diffraction angles selected from the group consisting of diffraction angles of 8.75°, 10.98°, 12.44°, 16.86°, 22.92°, and 28.49° (2θ ± 0.2°): 【Chemistry 49】

56. Crystal form III according to claim 55, 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 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. Crystal form III according to claim 55, 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 (2θ ± 0.2°) 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°.

58. Crystal form III according to claim 55, wherein, when the heating rate is 10°C / min, the differential scanning calorimetry (DSC) analysis shows an endothermic peak between 120°C (±0.5°C) and 130°C (±0.5°C).

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

60. (a) N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by the following chemical formula 1 is mixed with ethyl acetate, ethanol, methanol, isopropyl alcohol, butyl alcohol, methyl tert-butyl ether (MT The steps of obtaining a solution by dissolving in a solvent selected from the group consisting of BE), 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 step comprising producing a solid from the solution, A method for producing the compound represented by the chemical formula 1, N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide crystalline form I: [Transformation 50]

61. In step (a) above, the solvent is The method for producing the product according to claim 60, wherein the product is one or more alcohols selected from the group consisting of ethanol, methanol, isopropyl alcohol, and butyl alcohol, ethyl acetate, or a mixture of the alcohols and ethyl acetate.

62. (a) The step of obtaining the solution is: (a1) The step of adding a compound represented by chemical formula 1 to the solvent to obtain a mixture; and (a2) The manufacturing method according to claim 60, comprising the step of heating the mixture to a temperature exceeding 40°C.

63. The step of producing the solid in step (b) above is: (b1) Adding one or more alcohols selected from the group consisting of ethanol, methanol, isopropyl alcohol, and butyl alcohol to the solution of step (a); and (b2) The manufacturing method according to claim 60, further comprising the step of stirring after the addition of alcohol in step (b1).

64. The manufacturing method according to claim 63, wherein steps (b1) and (b2) are carried out at a temperature exceeding 40°C.

65. Before performing step (a), The steps include: dissolving the compound represented by chemical formula 1 in dichloromethane, then performing primary concentration to produce a concentrated residue; and The manufacturing method according to claim 60, further comprising the step of adding ethyl acetate to the concentrated residue and performing a secondary concentration.

66. The compound represented by the aforementioned chemical formula 1 is The manufacturing method according to claim 60, which involves producing a compound represented by the following chemical formula 1 in situ from a compound represented by the following chemical formula 6: 【Chemistry 51】

67. (a) A step of preparing a mixture by adding N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-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, isopropyl alcohol, butyl alcohol, diisopropyl ether, tetrahydrofuran, heptane, hexane, and mixtures thereof; (b) The step of heating the mixture to a temperature of 40°C or lower to obtain a solution; and (c) The method includes the step of producing a solid from the solution at a temperature of 40°C or lower. A method for producing crystalline form II of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is the compound represented by the chemical formula 1: 【Chemistry 52】

68. The manufacturing method according to claim 67, wherein in step (a), the solvent is ethanol, isopropanol, or a mixture thereof.

69. Before performing step (a), The step of dissolving the compound represented by the chemical formula 1 in dichloromethane, followed by primary concentration to produce a concentrated residue; The manufacturing method according to claim 67, further comprising the step of adding ethanol to the concentrated residue and performing secondary concentration.

70. The compound represented by the aforementioned chemical formula 1 is The manufacturing method according to claim 67, which involves producing a compound represented by the following chemical formula 1 in situ from a compound represented by the following chemical formula 6: 【Chemistry 53】 【Chemistry 54】

71. (a) Amorphous N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide represented by the following chemical formula 1 is methyl tert-butylated. A step of adding to a solvent selected from the group consisting of tel(MTBE), heptane, octane, hexane, pentane, and mixtures thereof to form a slurry; and (b) The step of obtaining a solid from the slurry, A method for producing the crystalline form III of N-((5-(5-(difluoromethyl)-1,3,4-oxadiazole-2-yl)pyridine-2-yl)methyl)-N-phenylthiomorpholine-4-carboxamide 1,1-dioxide, which is the compound represented by the chemical formula 1: 【Transformation 55】

72. The solvent in step (a) is methyl tert-butyl ether (MTBE), heptate The manufacturing method according to claim 71, wherein the manufacturing method is n, or a mixture thereof.

73. The manufacturing method according to claim 71, wherein the step of (a) forming a slurry is carried out for 12 hours to 20 days.

74. (b) The manufacturing method according to claim 71, wherein the step of obtaining a solid further comprises the step of filtering the slurry.

75. The manufacturing method according to claim 71, wherein the steps of (a) forming a slurry and (b) obtaining a solid are carried out at a temperature of 30°C or lower.

76. The step of producing an amorphous form of the compound represented by the chemical formula 1 is: A step of producing the compound represented by chemical formula 1 in-situ from the compound represented by chemical formula 6 below; and The manufacturing method according to claim 71, comprising the step of vacuum drying the compound represented by the chemical formula 1: 【Transformation 56】 【Chemistry 57】

Images