METHOD FOR PRODUCING A PHARMACEUTICAL COMPOSITION COMPRISING AN OXAZOLE COMPOUND CRYSTAL

Description

1 / 22 METHOD FOR PRODUCING A PHARMACEUTICAL COMPOSITION COMPRISING AN OXAZOLE COMPOUND CRYSTAL Separated from BR112020019377-1, filed on April 3, 2019. TECHNICAL FIELD

[0001] The present invention relates to a new crystal of an oxazole compound, a method for producing the same, etc. BACKGROUND OF THE INVENTION

[0002] PTL 1 and 2 report an oxazole compound having specific inhibitory activity against phosphodiesterase 4 (PDE4), and a method for producing the oxazole compound. PDE4 is predominant in inflammatory cells. Inhibition of PDE4 increases intracellular cAMP levels, and increased cAMP levels downregulate the inflammatory response by regulating the expression of TNF-α, IL-23, or other inflammatory cytokines. Increases in cAMP levels also increase anti-inflammatory cytokines, such as IL-10. Thus, the oxazole compound is thought to be appropriate for use as an anti-inflammatory agent. For example, the oxazole compound is thought to be useful for reducing or eliminating eczema or dermatitis, including atopic dermatitis. PTL 3 shows a balm that stably contains an oxazole compound having specific inhibitory activity against PDE4, and which can be efficiently absorbed into the skin. Exposures PTL1 to 3 are incorporated herein by reference in their entirety.LIST OF QUOTATIONS. Patent Literature

[0003] PTL 1: W02007 / 058338 (JP2009-515872A)

[0004] PTL 2: WO2014 / 034958 (JP2015-528433A)

[0005] PTL 3: WO2017 / 115780 SUMMARY OF THE INVENTION TECHNICAL PROBLEM Petition 870260078249, dated 05 / 08 / 2026, p. 9 / 74 2 / 22

[0006] An object of the present invention is to provide a crystal of an oxazole compound (specifically, an oxazole compound represented by formula (5) below) that has specific inhibitory activity against PDE4, and that shows more excellent stability. SOLUTION TO THE PROBLEM

[0007] The present inventors have verified a method for preparing a new type of crystal not previously reported, using a specific oxazole compound having inhibitory activity against PDE4, and have also verified that the new type of crystal has excellent stability. The inventors have further made modifications and completed the present invention.

[0008] Specifically, the present invention covers, for example, the following subject matter.

[0009] Item 1. A crystal of an oxazole compound represented by formula (5) F

[0010] in which the crystal has peaks at diffraction angles 20(°) of 9.6 ± 0.2, 19.1 ± 0.2, and 21.2 ± 0.2 in a powder X-ray diffraction pattern measured using characteristic CuKa X-rays.

[0011] Item 2. The crystal according to Item 1, wherein the crystal still has one, two, or three peaks at one, two, or three diffraction angles 20(°) selected from the group consisting of 12.6 ± 0.2, 22.8 ± 0.2, and 26.0 ± 0.2 in the powder X-ray diffraction pattern measured using characteristic CuKa X-rays.

[0012] Item 3. The crystal according to Item 2, wherein the crystal still has one or more peaks at one or more diffraction angles 20(°) selected from the group consisting of 10.4 ± 0.2, 11.9 ± 0.2, 15.0 ± Petition 870260078249, dated 05 / 08 / 2026, page 10 / 74 3 / 22 0.2, 15.9 ± 0.2, 19.7 ± 0.2, 24.7 ± 0.2, and 27.6 ± 0.2 in the powder X-ray diffraction pattern measured using characteristic CuKa X-rays.

[0013] Item 4. A crystal of an oxazole compound represented by formula (5) F

[0014] wherein the crystal has infrared absorption bands at wavenumbers (cm-1) of 3380 ± 5, 2980 ± 5, 1651 ± 2, 1501 ± 2, 1258 ± 2, 1121 ± 2, and 754 ± 2 in an infrared absorption spectrum measured using a potassium bromide disk method.

[0015] Item 5. The crystal according to any one of Items 1 to 3, wherein the crystal has infrared absorption bands at wavenumbers (cm⁻¹) of 3380 ± 5, 2980 ± 5, 1651 ± 2, 1501 ± 2, 1258 ± 2, 1121 ± 2, and 754 ± 2 in an infrared absorption spectrum measured by a potassium bromide disk method.

[0016] Item 6. The crystal according to Item 4 or 5, wherein the crystal still has one or more infrared absorption bands at one or more wavenumbers (cm-1) selected from the group consisting of 1601 ± 2, 1537 ± 2, 1302 ± 2, 1234 ± 2, 1107 ± 2, 1026 ± 2, and 627 ± 2 in the infrared absorption spectrum measured by the potassium bromide disk method.

[0017] Item 7. The crystal according to any one of Items 1 to 6, wherein the crystal has a melting point of 75 to 90°C.

[0018] Item 8. A crystal of an oxazole compound represented by formula (5) Petition 870260078249, dated 05 / 08 / 2026, page 11 / 74 4 / 22 (5)

[0019] in which the crystal has a melting point of 75 to 90°C.

[0020] Item 9. A pharmaceutical composition comprising the crystal according to any one of Items 1 to 8.

[0021] Item 10. The pharmaceutical composition according to Item 9, for use in the treatment and / or prevention of eczema or dermatitis (preferably atopic dermatitis).

[0022] Item 11. The pharmaceutical composition according to Item 9 or 10, which is a balm. ADVANTAGEOUS EFFECTS OF THE INVENTION

[0023] A more stable crystal of a specific oxazole compound having inhibitory activity against PDE4 can be provided. In particular, since the crystal has a higher melting point than a conventional crystal of the specific oxazole compound, it has high thermal stability, and this is advantageous. BRIEF DESCRIPTION OF DRAWINGS

[0024] Fig. 1 shows an X-ray powder diffraction pattern of a type A crystal of compound (5), which is measured using characteristic CuKa X-rays.

[0025] Fig. 2 shows an infrared absorption spectrum of a type A crystal of compound (5), which is measured using a potassium bromide disk method.

[0026] Fig. 3 shows an X-ray powder diffraction pattern of a B-type crystal of compound (5), which is measured using characteristic CuKa X-rays.

[0027] Fig. 4 shows an infrared absorption spectrum of a type B crystal of compound (5), which is measured using a potassium bromide disk method. Petition 870260078249, dated 05 / 08 / 2026, page 12 / 74 5 / 22 DESCRIPTION OF MODALITIES

[0028] Embodiments of the present invention are detailed below.

[0029] The oxazole compound crystal in the present invention includes an oxazole compound crystal represented by formula (5) below. F

[0030] The oxazole compound has specific inhibitory activity against PDE4, and is effective as an anti-inflammatory agent, etc. In this descriptive report, the oxazole compound represented by formula (5) is sometimes referred to as compound (5). Compound (5) is N-[2-(difluoromethoxy-3-isopropoxyphenyl)oxazol-4-yl methyl]-2-ethoxybenzamide.

[0031] Compound (5) can be produced by a known process (for example, a method described in any of PTL 1 to 3). However, crystal forms of compound (5) produced by known methods are different from the crystal form of compound (5) covered in the present invention. In this descriptive report, the former crystal form is sometimes referred to as type A, and the latter crystal form is sometimes referred to as type B. Specifically, the crystal of compound (5) produced by a known method is a type A crystal, and the crystal of compound (5) covered in the present invention is a type B crystal.

[0032] A type B crystal is a compound crystal (5) that has one or more of the following characteristics. Between characteristics (i) to (iii) below, a type B crystal preferably has at least one characteristic, more preferably at least two characteristics (i.e., characteristics (i) and (ii), characteristics (ii) and (iii), or characteristics (iii) and (i)), and even more preferably has all three characteristics. Characteristic (i): Characteristic X-ray diffraction pattern of Petition 870260078249, dated 05 / 08 / 2026, p. 13 / 74 6 / 22 Dust

[0033] The type B crystal preferably has peaks at diffraction angles of 96 ± 0.2, 19.1 ± 0.2, and 21.2 ± 0.2 in the powder X-ray diffraction pattern measured by characteristic CuKa X-rays. Of these three peaks, the intensity of the peak at a diffraction angle of 19.1 ± 0.2 (sometimes referred to as peak

[12] ) is preferably the lowest. The intensity of the peak at a diffraction angle of 21.2 ± 0.2 (sometimes referred to as peak

[16] ) is preferably the broadest. The peak at a diffraction angle of 9.6 ± 0.2 is sometimes referred to as peak [2].

[0034] The ratio of peak intensity

[12] and peak

[16] (peak

[16] / peak

[12] ) is preferably about 1.5 to 2.5, more preferably about 1.6 to 2.4 or 1.7 to 2.3, and even more preferably about 1.8 to 2.2, or about 1.9 to 2.1. The ratio of peak intensity

[12] and peak [2] (peak [2] / peak

[12] ) is preferably 1.5 to 1.75.

[0035] It is still preferable to have one, two, or three peaks at one, two, or three diffraction angles 20(°) selected from the group consisting of 12.6 ± 0.2, 22.8 ± 0.2, and 26.0 ± 0.2, in addition to the three peaks above (peaks [2],

[12] , and

[16] ). The peak at a diffraction angle 20(°) of 12.6 ± 0.2 is sometimes referred to as peak [6]. The peak at a diffraction angle 20(°) of 22.8 ± 0.2 is sometimes referred to as peak

[18] . The peak at a diffraction angle 20(°) of 26.0 ± 0.2 is sometimes referred to as peak

[20] .

[0036] In the most preferred embodiment, the type B crystal has all peaks [6],

[18] and

[20] , in addition to peaks [2],

[12] , and

[16] . In this case, the intensity of each of the peaks [6],

[18] , and

[20] is preferably less than the intensity of peak

[12] . In addition, the intensity of peak

[20] is preferably the greater of the intensities of peaks [6],

[18] , and

[20] .

[0037] In addition to the four to six peaks above (three pi peaks Petition 870260078249, dated 05 / 08 / 2026, page 14 / 74 7 / 22 cos [2],

[12] , and

[16] ; and one, two, or three peaks selected from the group consisting of peaks [6],

[18] , and

[20] ), it is still preferable to have one or more peaks at one or more (2, 3, 4, 5, 6, or 7) diffraction angles 20(°) selected from the group consisting of 10.4 ± 0.2, 11.9 ± 0.2, 15.0 ± 0.2, 15.9 ± 0.2, 19.7 ± 0.2, 24.7 ± 0.2, and 27.6 ± 0.2. The intensity of each of these one to seven peaks is preferably less than the intensity of each of the four to six peaks mentioned above. A type B crystal having peaks [2],

[12] ,

[16] , and peaks [6],

[18] , and

[20] is particularly preferred; as well as peaks at diffraction angles 20(°) of 10.4 ± 0.2, 11.9 ± 0.2, 15.0 ± 0.2, 15.9 ± 0.2, 19.7 ± 0.2, 24.7 ± 0.2 and 27.6 ± 0.2. Characteristic (ii): Characteristic infrared absorption spectrum

[0038] The type B crystal preferably has infrared absorption bands at wavenumbers (cm1) of 3380 ± 5, 2980 ± 5, 1651 ± 2, 1501 ± 2, 1258 ± 2, 1121 ± 2, and 754 ± 2 in the infrared absorption spectrum measured by a potassium bromide disk method. Of these infrared absorption bands, an infrared absorption band at a wavenumber (cnr1) of 1651 ± 2 is particularly a characteristic band of the type B crystal. These infrared absorption bands are derived from infrared absorption of characteristic functional groups present in compound (5), which is more specifically explained below. (The wavelength described to the right of the cut in the following description is the wavelength of the infrared absorption band of the type A crystal described below).

[0039] 3380 (cm'1): secondary amide stretching vibration NH

[0040] 2980 (cm1): stretch vibration -Chh

[0041] 1651 / 1643 (cm1): C=O amide stretching vibration

[0042] 1501 / 1503 (cm1): aromatic stretching vibration C=C Petition 870260078249, dated 05 / 08 / 2026, page 15 / 74 8 / 22

[0043] 1258 / 1261, 1121 / 1119 (cm1): stretching vibration -CF2

[0044] 754 / 758 (cm1): out-of-plane bending vibration of benzene CH

[0045] In addition to such characteristic infrared absorption bands, the type B crystal preferably has one or more infrared absorption bands at one or more (2, 3, 4, 5, 6, or 7) wavenumbers (cm1) selected from the group consisting of 1601 ± 2, 1537 ± 2, 1302 ± 2, 1234 ± 2, 1107 ± 2, 1026 ± 2, and 627 ± 2.

[0046] In the infrared absorption spectrum, the wavenumber error (cm1) of one or more (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13) infrared absorption bands may be ± 4, ± 3, ± 2, or ± 1. Characteristic (iii): Characteristic melting point

[0047] The melting point of type B crystal is preferably 75 to 90°C. The lower limit of this range may be 76°C, 77°C, 78°C, 79°C, or 80°C. The upper limit of this range may be 89°C, 88°C, 87°C, 86°C, 85°C, or 84°C. The melting point is preferably 77 to 88°C, more preferably 78 to 86°C, even more preferably 79 to 85°C, and particularly preferably 80 to 84°C.

[0048] The melting point is the value measured according to Method I in Section 2.60 of the Japanese Pharmacopoeia, seventeenth edition.

[0049] Type B crystal can be prepared by leaving type A crystal to stand for a long period of time at a temperature higher than room temperature. More specifically, type B crystal can be prepared by allowing type A crystal to stand preferably at 40 to 60°C, more preferably 45 to 55°C, and even more preferably at 48 to 52°C, for preferably 3 months or more, and more preferably 4 months or more or 5 months or more. The upper limit of the static period is not particularly limited, as far as type B crystal can be obtained; and it is, for example, about 6 or 7 Petition 870260078249, dated 05 / 08 / 2026, p. 16 / 74 9 / 22 months. Type A crystal is preferably left to rest in hermetically sealed or airtight containers. Furthermore, type A crystal is preferably left to rest under conditions unaffected by light (e.g., a light-protected condition; more specifically, in a light-blocking amber bottle).

[0050] Type A crystal can be prepared by a known method as described above, for example, by a method described in any of PTL 1 to 3. Although there is no particular limitation, type A crystal can be prepared by preparing compound (5) according to the reaction formula described in PTL 3, and precipitating the compound crystal (5). The resulting precipitated crystal can be dried, and then used as type A crystal. The dried type A crystal is particularly preferred as the type A crystal that is left to stand at a temperature higher than room temperature for a long period of time, and used for the preparation of type B crystal. 2) Concentrated HCl Purification * DIPEA: diisopropyl ethyl amine, CPME: cyclopentyl methyl ether, DMF: N,N-dimethylformamide, 2-EBA: 2-ethoxybenzoic acid, WSC: 1-ethyl-3-(3-dimethylaminopropyl)carbo diimide hydrochloride Petition 870260078249, dated 05 / 08 / 2026, p. 17 / 74 10 / 22

[0051] The powder X-ray diffraction pattern, infrared absorption spectrum, and melting point of the type A crystal are described below. The type A crystal particularly has characteristic diffraction angles of 5.8 ± 0.2, 11.6 ± 0.2, 17.1 ± 0.2, 23.1 ± 0.2 and 26.1 ± 0.2 in the powder X-ray diffraction pattern measured with characteristic CuKa X-rays. The type A crystal may still have one or more peaks at one or more diffraction angles 20(°) selected from the group consisting of 10 ± 0.2, 13.2 ± 0.2, 16.1 ± 0.2, 18.5 ± 0.2, 22.2 ± 0.2, and 26.7 ± 0.2. The type A crystal has particularly infrared absorption bands at wavenumbers (cnr1) of 3380 ± 5, 2980 ± 5, 1643 ± 2, 1503 ± 2, 1261 ± 2, 1119 ± 2, and 758 ± 2 in the infrared absorption spectrum measured through a potassium bromide disk process.Type A crystals may still have one or more infrared absorption bands at one or more wavenumbers (cm⁻¹) selected from the group consisting of 1601 ± 2, 15637 ± 2, 1296 ± 2, 1229 ± 2, 1047 ± 2, 939 ± 2, and 617 ± 2. The melting point of type A crystals (measured according to Method 1 in Section 2.60 of the Japanese Pharmacopoeia, Seventeenth Edition) is about 56 to 60°C.

[0052] The present invention also comprises a pharmaceutical composition containing type B crystal. The pharmaceutical composition, for example, contains a pharmaceutically acceptable carrier and type B crystal. Such carriers are not particularly limited, and known carriers may be used. The pharmaceutical composition is sometimes referred to as the pharmaceutical composition of the present invention.

[0053] The pharmaceutical composition of the present invention is particularly effective for reducing or eliminating eczema and dermatitis, in particular for reducing or eliminating atopic dermatitis. The pharmaceutical composition of the present invention can be used as a preventive and / or treatment agent for these diseases. Petition 870260078249, dated 05 / 08 / 2026, page 18 / 74 11 / 22

[0054] The form of the pharmaceutical composition of the present invention is not particularly limited. Examples include agents applied externally to the skin, oral formulations, injections, and the like. Of these, agents applied externally to the skin are preferred, and balms are particularly preferred. In a balm, it is preferable that type (B) crystal (I) be dissolved in a base component, and that the base component comprise balm base (III) and solvent (II) for dissolving compound (5).

[0055] A balsam is more preferred in which solvent (II) containing dissolved type B crystal (I) is dissolved or dispersed in the form of droplets in balsam base (III).

[0056] Type B crystal (I) can be dissolved in solvent (II) by heating. Type B crystal (I) is preferably dissolved by heating at a temperature higher than the melting point of type B crystal. For example, heating and dissolution can be carried out at 75°C or more, 76°C or more, 77°C or more, 78°C or more, 79°C or more, 80°C or more, 81°C or more, 82°C or more, 83°C or more, 84°C or more, 85°C or more, 86°C or more, 87°C or more, 88°C or more, 89°C or more, or 90°C or more. The upper limit of the heating temperature is not particularly restricted, as long as the compound effects (5) are obtained. For example, the temperature is 100°C or less, 99°C or less, 98°C or less, 97°C or less, 96°C or less, 95°C or less, 94°C or less, 93°C or less, 92°C or less, or 91°C or less.

[0057] Although there is no particular limitation, type B (I) crystal is present in the balsam in an amount of preferably 0.01 to 10 parts by weight, more preferably 0.05 to 7.5 parts by weight, even more preferably 0.1 to 5 parts by weight, per 100 parts by weight of the balsam.

[0058] As established above, type B (I) crystal is preferably Petition 870260078249, dated 05 / 08 / 2026, page 19 / 74 12 / 22 dissolved in solvent (II). The solvent is preferably a polar compound that is liquid at room temperature. Specific examples of solvents include ethylene carbonate, propylene carbonate, benzyl alcohol, triacetin, diethyl sebacate, diisopropyl sebacate, diethyl adipate, diisopropyl adipate, isostearic acid, olive oil, hexyl dodecanol, decyl Ia oleate, isostearyl alcohol, and isopropyl myristate. Ethylene carbonate, propylene carbonate, benzyl alcohol, and triacetin are most preferable, and propylene carbonate and triacetin are even more preferable. Of these, propylene carbonate is preferred. These solvents may be used alone, or in a combination of two or more. In particular, it is preferable to use ethylene carbonate or propylene carbonate with benzyl alcohol and / or triacetin.

[0059] The solvent (II) is present in the balsam in an amount preferably more than 2 parts by weight, more preferably 2.1 parts by weight or more, and even more preferably 2.2 parts by weight or more, per part by weight of type B crystal (I). The upper limit of the amount of solvent (II) is not particularly limited, so far as the effect of the present invention is produced. For example, the upper limit is preferably 30 parts by weight or less, more preferably 20 parts by weight or less, and even more preferably 15 parts by weight or less.

[0060] Solvent (II) is present in the balsam in an amount of preferably 0.1 to 50 parts by weight, more preferably 0.2 to 25 parts by weight, and even more preferably 0.5 to 20 parts by weight, per 100 parts by weight of the balsam.

[0061] The type B crystal solution in the solvent is preferably dissolved or dispersed in the form of droplets in balsam (III) base, and more preferably dispersed in the form of droplets in balsam (III) base. Petition 870260078249, dated 05 / 08 / 2026, page 20 / 74 13 / 22

[0062] Balsam bases known for use in the production of balms may be used as a balm base (III). Examples of balm bases include hydrocarbons, and more specific examples include grease bases, particularly natural wax, petroleum wax, and other hydrocarbons. Examples of natural wax include beeswax (e.g., unbleached beeswax, non-chemically bleached beeswax, and chemically bleached beeswax), and carnauba wax. Examples of petroleum wax include liquid paraffin and petrolatum (e.g., white petrolatum and yellow petrolatum). Balsam bases may be used alone, or in a combination of two or more.

[0063] Balsam base (III) is present in the balsam in an amount of preferably 5 to 5000 parts by weight, more preferably 10 to 2500 parts by weight, and even more preferably 20 to 1000 parts by weight, per part by weight of type B crystal (I).

[0064] Balsam base (III) is present in the balsam in an amount of preferably 50 to 99 parts by weight, more preferably 70 to 98 parts by weight, and even more preferably 80 to 97 parts by weight, per 100 parts by weight of the balsam.

[0065] Balsam base (III) preferably comprises at least beeswax. The beeswax for use is preferably beeswax that is not chemically bleached; including, for example, beeswax that is not chemically bleached (non-chemically bleached beeswax), and beeswax that is not bleached (non-bleached beeswax).

[0066] Beeswax is present in the balsam in an amount of preferably 0.05 to 50 parts by weight, more preferably 0.1 to 40 parts by weight, and even more preferably 0.2 to 35 parts by weight, per part by weight of type B (I) crystal.

[0067] Beeswax is present in the balm in a quantity Petition 870260078249, dated 05 / 08 / 2026, p. 21 / 74 14 / 22 preferably 0.1 to 10 parts by weight, more preferably 0.2 to 9 parts by weight, even more preferably 0.4 to 8 parts by weight, even more preferably 0.5 to 7.5 parts by weight, and particularly preferably 1 to 5 parts by weight, per 100 parts by weight of balsam.

[0068] When other balsam bases are combined with beeswax, the combination is not particularly limited. However, for example, the combination preferably comprises beeswax and at least one selected member of the group consisting of petrolatum (preferably white petrolatum), liquid paraffin, and paraffin.

[0069] In addition to the balsam base, the balsam may comprise other additives for use in balsams (in particular, pharmaceutical additives), such as flavor components, colorants, preservatives, absorption enhancers including higher alkene acids (e.g., oleic acid), or medications effective for the treatment of other skin diseases.

[0070] As set forth above, the balsam of the present invention is preferably a balsam in which solvent (II), in which type B crystal (I) is dissolved, is dissolved or dispersed in the form of droplets in a balsam base (III). Examples of the method for producing this balsam include a method comprising preparing a solution of component (I) in component (II), and mixing the solution with component (III) with stirring. Mixing with stirring can be carried out with, for example, a homogenizer, a paddle mixer, or a combination of these mixers.

[0071] When using multiple types of balsam bases (component (III)), it is preferable to mix the multiple balsam bases beforehand. In the formulation of component (III) containing multiple types of balsam bases, it is preferable to mix the balsam bases with Petition 870260078249, dated 05 / 08 / 2026, page 22 / 74 15 / 22 Heating to melt solids, such as beeswax. For example, when beeswax and other balsam bases are used in combination, the beeswax and other balsam bases are preferably mixed beforehand, preferably with heating.

[0072] In the case of a balm in which component (II), in which component (I) is dissolved, is dispersed in the form of droplets in component (III), the particle size of the droplets observed with a polarizing microscope is 100 µm or less, preferably about 40 micrometers or less, more preferably about 25 micrometers or less, and even more preferably about 20 micrometers or less. In particular, preferably there are no droplets having a particle size of more than 100 micrometers, more preferably no droplets having a particle size of more than 40 micrometers, and even more preferably no droplets having a particle size of more than 20 micrometers. A desired average particle size of the droplets is obtained by adjusting the stirring rate at which the solution is mixed with component (III) with stirring.

[0073] In this descriptive report, the term “comprising” includes “essentially consisting of” and “consisting of”. The present invention covers all combinations of the elements described in this descriptive report.

[0074] The characteristics (properties, structures, functions, etc.) that are explained in the embodiments of the present invention can be combined in any way to specify the subject matter included in the present invention. Specifically, the present invention covers all subject matter that includes various embodiments of the combinable characteristics described in this descriptive report. EXAMPLES Petition 870260078249, dated 05 / 08 / 2026, page 23 / 74 16 / 22

[0075] The present invention is described in more detail below. However, the present invention is not limited to the following examples. In the following reaction schemes, when a compound is represented numerically, the compound may be referred to as “compound (numerical number)”. For example, a compound represented as “3” may be referred to as “compound (3)”. Also, in the following reaction schemes, the compound represented as “5” is the same as compound (5) described above. Synthesis of Oxazole Compound (Type A Crystal)

[0076] Compound (5) (white powder) was prepared according to the method shown in PTL 1 Example 352 (W02007 / 058338). Composite Data (5)

[0077] N-({2-[4-difluoromethoxy)-3-isopropoxy phenyl] oxazol-4-yl} methyl)-2-ethoxy benzamide: white powder. 1H NMR (400 MHz, CDCI3): δ = 8.56 (br s, 1H, NH), 8.23 ​​(dd, J = 7.6 Hz, 1.6 Hz, 1H, ArH), 7.66 (s, 1H, ArH), 7.63 (d, J = 2.0 Hz, 1H, ArH), 7.58 (dd, J = 8.4 Hz, 2.0 Hz, 1H, ArH), 7.44-7.39 (m, 1H, ArH), 7.21 (d, J = 8.0 Hz, 1H, ArH), 7.08-7.04 (m, 1H, ArH), 6.94 (d, J = 8.0 Hz, 1H, ArH), 6.61 (t, J = 75.2Hz, 1H, CHF2) Hz, 6H, 2CH3).

[0078] The powder X-ray diffraction pattern of the white powder obtained from compound (5) was measured using characteristic CuKa X-rays. More specifically, the measurement was conducted under the following conditions.

[0079] Measuring device - XRD-6000 (Shimadzu Corporation)

[0080] Operating conditions - Voltage: 35.0 kV, Current: 20.0 mA, Peak Sampling: 0.0200°

[0081] Fig. 1 and Table 1 show the measurement results. Petition 870260078249, dated 05 / 08 / 2026, page 24 / 74 17 / 22 TABLE 1 Strongest peak number 3 peaks 2 theta (deg) d (A) I / Il FWHM (deg) Intensity (counts) Integrated Intensity (counts) 1 4 11.5469 7.65742 100 0.2406 869 11021 2 19 23.0346 3.85799 63 0.3511 544 11211 3 21 25.9597 3.42952 30 0.3355 262 4458 # Peak data no. List 2 theta d I / Ϊ1 FWHM Intensity Integrated (deg) (A) (deg) (counts) (counts) 1 5.8157 15.18438 19 0.1860 169 1999 2 10.2509 8.62243 11 0.2728 93 1422 3 11.1800 7.90788 9 0.1714 77 1471 4 11.5469 7.65742 100 0.2406 869 11021 5 13.2725 6.66548 7 0.3450 59 1156 6 14.7100 6.01718 6 0.2600 49 759 7 15.1487 5.84390 10 0.2254 85 1002 8 15.8200 5.59740 6 0.2400 48 679 9 16.1346 5.48896 16 0.3827 139 2601 10 17.0431 5.19836 23 0.2738 199 3292 11 17.4200 5.08673 4 0.0000 39 0 12 17.7200 5.00128 6 0.2450 53 899 13 18.5686 4.77458 13 0.3293 116 2029 14 19.0800 4.64775 4 0.3600 35 612 15 20.7400 4.27935 17 0.4300 144 2826 16 21.1400 4.19927 13 0.4134 115 2014 17 21.4800 4.13356 9 0.2216 74 844 1Θ 22.2421 3.99362 14 0.3008 124 2136 19 23.0346 3.85799 63 0.3511 544 11211 20 25.2853 3.51945 10 0.5627 85 2603 21 25.9597 3.42952 30 0.3355 262 4458 22 26.5000 3.36081 4 0.2240 35 412 23 26.7020 3.33585 10 0.3040 90 1212 24 27.6400 3.22473 3 0.2000 26 351 25 28.0070 3.18331 4 0.2740 39 598 26 29.2200 3.05386 5 0.4480 41 855 27 29.4600 3.02952 5 0.1658 46 405 28 31.1971 2.86468 5 0.3408 46 1047.

[0082] The infrared absorption spectrum of the white powder obtained from compound (5) was measured using the potassium bromide disk method. More specifically, the measurement was conducted under the following conditions.

[0083] Measuring device - IR Prestige-21 (Shimadzu Corporation)

[0084] Operating conditions - Cumulative number: 16, Resolution: 4 cm'1

[0085] Fig. 2 shows the measurement results.

[0086] The melting point of the white powder obtained from compound (5) was measured in accordance with Method 1 in Section 2.60 of the Japanese Pharmacopoeia, Seventeenth Edition. Petition 870260078249, dated 05 / 08 / 2026, p. 25 / 74 18 / 22

[0087] More specifically, the measurement was conducted under the following conditions.

[0088] Measuring device - M-565 (BUCHI)

[0089] Operating conditions - The white compound powder (5) was placed in a dry capillary tube to form a layer with a thickness of 2.5 to 3.5 mm. The bath fluid was gradually heated to 48°C, and the capillary tube containing the white powder was inserted. Subsequently, the temperature was increased at a rate of about 3°C ​​per minute, and when the temperature reached 53°C, the temperature was increased at a rate of about 1°C per minute; samples were then observed.

[0090] Measurement results confirmed that the melting point of the white powder (type A crystal) of compound (5) was approximately 56 to 60°C.

[0091] Compound (5) crystals prepared according to the method shown in PTL 2 (WO2014 / 034958) (in particular, Example 1 (1-10): compound 1) and the method shown in PTL 3 (WO2017 / 115780) (in particular, Production Example 4 (compound (11))) using the type A crystal thus obtained as a seed crystal both had the same characteristics as above, and were thus considered to be type A crystals. Preparation 1 of Type B Crystal

[0092] Type A crystal (12 g) was placed in an amber glass bottle. The glass bottle was sealed and stored for 3 months in an incubator (50 ± 2°C). The X-ray diffraction pattern of the powder and the infrared absorption spectrum of the powder (crystal) collected after storage were measured as above. Fig. 3 and Table 2 show the X-ray diffraction pattern of the powder, and Fig. 4 shows the infrared absorption spectrum. The melting point was also measured as in the method above, except that “48°C” was changed to “72°C”, and “53°C” Petition 870260078249, dated 05 / 08 / 2026, page 26 / 74 19 / 22 was changed to “77°C”. The melting point was found to be around 84°C. TABLE 2 # Peak number 3 peaks 2 most strong theta no. (deg) 1 16 21.1479 2 2 9.5562 3 12 19.0600 i Peak data List 2 theta no. (deg) 1 9.1600 2 9.5562 3 10.3752 4 11.5800 5 11.8351 6 12.5573 7 14.9711 8 15.6200 9 15.8818 10 17.5600 11 18.5400 12 19.0600 13 19.3000 14 19.6942 15 20.8600 16 21.1479 17 22.3600 18 22.7003 19 24.6375 20 25.9103 21 26.2200 22 27.5105 23 28.4600 24 29.2200 25 29.4183 26 31.6000 27 31.8200 28 34.1400 29 34.3200 d I / Il FWHM (A) (deg) 4.19772 100 0.2253 9.24764 82 0.2303 4.65258 50 0.2757 d I / Il t'WHM (A) (deg) 9.64672 6 0.2200 9.24764 B2 0.2303 8.51941 11 0.2162 7.63560 3 0.2934 7.47159 11 0.1837 7.04346 22 0.2259 5.91282 9 0.2178 5.66862 5 0.2134 5.57576 12 0.2487 5.04649 4 0.2500 4.78189 4 0.2600 4.65258 50 0.2757 4.59526 26 0.1952 4.50416 14 0.2776 4.25500 25 0.2542 4.19772 100 0.2253 3.97283 11 0.2734 3.91404 24 0.2776 3.61050 7 0.3250 3.43595 36 0.2628 3.39607 17 0.2284 3.23962 6 0.2510 3.13366 3 0.2400 3.05386 3 0.2200 3.03372 4 0.2367 2.82907 3 0.3000 2.81001 3 0.3466 2.62418 4 0.5200 2.61082 4 0.1534 Integrated Intensity (counts) (counts) 876 9915 717 8537 437 5663 Integrated Intensity (counts) (counts) 54 1412 717 8537 99 1244 28 456 97 881 194 2554 83 1024 42 500 109 1469 37 688 34 765 437 5 663 224 2180 127 1874 216 3633 876 9915 94 1318 206 3116 63 1121 312 4427 148 1607 52 807 30 413 30 288 38 4 63 27 62 8 30 4 66 36 818 37 255

[0093] These results revealed that the powder X-ray diffraction pattern, infrared absorption spectrum, and melting point of the crystal collected after storage were all different from those of type A crystal. This crystal was named “type B crystal”.

[0094] As described above, type B crystal has a higher melting point than type A crystal. This fact confirmed that type B crystal has more excellent thermal stability. Prior to this analysis, a recrystallization method was performed using various solvents to search for crystals with more excellent stability than type A crystal; however, different types of crystals could not be found. Surprisingly, however, it was clarified that type B crystal, Petition 870260078249, dated 05 / 08 / 2026, page 27 / 74 20 / 22, which has greater stability (in particular, thermal stability), can be prepared by allowing type A crystals to rest at a temperature higher than room temperature for an extended period of time. Preparation 2 of Type B Crystal

[0095] Analysis was conducted to further prepare the type B crystal using the type B crystal obtained as a seed crystal. More specifically, the type B crystal was prepared as follows, according to the method shown in PTL 3 (WO2017 / 115780).

[0096] 20.00 g (66.8 mmol) of compound (1) and 17.28 g (134 mmol) of diisopropylamine were added to 300 ml of ethyl acetate, and the mixture was cooled. 11.48 g (100 mmol) of methanesulfonyl chloride were poured in and stirred at 10 to 30°C for 1 hour. 17.41 g (200 mmol) of lithium bromide were added, and the mixture was stirred at 20 to 35°C for 1 hour. 100 ml of water were added to the reaction solution, and the mixture was separated, followed by concentration of the organic layer under reduced pressure. 300 ml of ethyl acetate were added to the concentrated residue to dissolve the residue, and the solution was again concentrated under reduced pressure. 200 ml of N,N-dimethylformamide and 17.33 g (93.6 mmol) of potassium phthalimide were added to the concentrated residue and reacted at 75–85°C for 1 hour. 200 ml of water were added to the reaction solution to precipitate crystals.The precipitated crystals were collected by filtration and dried at 80°C, yielding 27.20 g. Petition 870260078249, dated 05 / 08 / 2026, page 28 / 74 21 / 22 (yield: 95.01%) of compound (3). F

[0097] 20.00 g (46.7 mmol) of compound (3), and 40 mL of a 40% aqueous solution of methyl amine, 40 mL of methanol, and 100 mL of water were mixed and reacted for 30 minutes under reflux. 200 mL of cyclopentyl methyl ether (CPME) and 20 mL of a 25% aqueous solution of sodium hydroxide were added to the reaction solution, and the temperature was adjusted to 65–75°C, followed by separation. A mixture of 100 mL of water and 20.00 g of sodium chloride was added to the organic layer, and the temperature was adjusted to 65–75°C again, followed by separation. 5 mL of concentrated hydrochloric acid were added to the organic layer to precipitate crystals. The precipitated crystals were collected by filtration, so that 27.58 g of compound (4) were obtained as a wet crystal.

[0098] The wet crystal (46.7 mmol) of compound (4) was mixed with 120 mL of ethyl acetate and 7.1 mL (51.4 mmol) of triethylamine, and stirred at 20 to 30°C for 1 hour. 10.09 g (60.7 mmol) of 2-ethoxybenzoic acid and 11.63 g (60.7 mmol) of 1-ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC) were added to the reaction solution, and reacted at 20 to 30°C for 1 hour. 60 mL of water and 6 mL of concentrated hydrochloric acid were added to the reaction solution, and the temperature was adjusted to 40 to 50°C, followed by separation. 60 mL of water and 6 mL of a 25% aqueous sodium hydroxide solution were added to the organic layer, and the temperature was... Petition 870260078249, dated 05 / 08 / 2026, p. 29 / 74 22 / 22 again adjusted to 40 to 50°C. The mixture was separated, and the organic layer was concentrated under reduced pressure. 50 mL of ethanol, 20 mL of water, 6 mL of a 25% aqueous sodium hydroxide solution, and 0.6 g of activated charcoal were added to the concentrated residue, and the mixture was refluxed for 30 minutes. The activated charcoal was removed by filtration, and the filtrate was washed with 12 mL of ethanol. The filtrate was cooled, and 10 mg of type B crystals (one seed crystal) were added for crystal precipitation. The precipitated crystals were collected by filtration and dried at 60°C, obtaining 18.38 g (88.18%) of compound (5).

[0099] The powder X-ray diffraction pattern, the infrared absorption spectrum, and the melting point of the obtained crystal were measured as above. The results were all the same as the results above for the type B crystal. This confirmed that the type B crystal can be directly synthesized by using type B crystal as a seed crystal, without the need to prepare type B crystal by using type A crystal. Petition 870260078249, dated 05 / 08 / 2026, page 30 / 74

Claims

M3 CLAIMS 1. Method of producing a pharmaceutical composition comprising a crystal of an oxazole compound, which is represented by formula (5) F characterized in that the method comprises dissolving a crystal of the oxazole compound represented by formula (5) in a solvent, wherein the crystal has peaks at diffraction angles of 9.6 ± 0.2, 19.1 ± 0.2, and 21.2 ± 0.2 in a powder X-ray diffraction pattern measured using characteristic CuKa X-rays.

2. Production method according to claim 1, characterized in that it has one, two, or three peaks at one, two, or three diffraction angles 20(°) selected from the group consisting of 12.6 ± 0.2, 22.8 ± 0.2 and 26.0 ± 0.2 in the powder X-ray diffraction pattern measured using CuKa characteristic X-rays.

3. Production method according to claim 2, characterized in that it has one or more peaks at one or more diffraction angles 20(°) selected from the group consisting of 10.4 ± 0.2, 11.9 ± 0.2, 15.0 ± 0.2, 15.9 ± 0.2, 19.7 ± 0.2, 24.7 ± 0.2, and 27.6 ± 0.2 in the powder X-ray diffraction pattern measured using CuKa characteristic X-rays.

4. Production method according to any one of claims 1 to 3, characterized in that it has infrared absorption bands at wavenumbers (cm-1) of 3380 ± 5, 2980 ± 5, 1651 ± 2, 1501 ± 2, 1258 ± 2, 1121 ± 2, and 754 ± 2 in an infrared absorption spectrum measured using a potassium bromide disk method. Petition 870260078249, dated 05 / 08 / 2026, p. 31 / 74 2 / 3 5. Production method according to claim 4, characterized in that it has one or more infrared absorption bands at one or more wavenumbers (cnr1) selected from the group consisting of 1601 ± 2, 1537 ± 2, 1302 ± 2, 1234 ± 2, 1107 ± 2, 1026 ± 2, and 627 ± 2 in the infrared absorption spectrum measured using the potassium bromide disk method.

6. Production method according to any one of claims 1 to 5, characterized in that it has a melting point of 75 to 90°C.

7. Production method according to any one of claims 1 to 6, characterized in that it comprises dissolving the crystal in a solvent by heating to a temperature above the melting point of the crystal.

8. Production method according to claim 7, characterized in that it comprises dissolving the crystal in a solvent by heating to a temperature of 85°C or higher and 91°C or lower.

9. Production method according to any one of claims 1 to 8, characterized in that the solvent is a polar compound that is liquid at room temperature.

10. Production method according to any one of claims 1 to 9, characterized in that it comprises dissolving the crystal in a solvent, and mixing the solvent containing the dissolved crystal with a balsam base.

11. Production method according to claim 10, characterized in that the balsam base comprises a hydrocarbon.

12. Production method according to claim 10, characterized in that the base of the balsam comprises Petition 870260078249, dated 05 / 08 / 2026, page 32 / 74 3 / 3 less beeswax.

13. Production method according to any one of claims 10 to 12, characterized in that the solvent containing the crystal dissolved in the pharmaceutical composition is dissolved or dispersed in the form of droplets in the base of the balm.

14. Production method according to claim 13, characterized in that the droplets have an average particle size of 100 µm or less.

15. Production method according to any one of claims 1 to 14, characterized in that the pharmaceutical composition is a balsam and further comprises a balsam base. Petition 870260078249, dated 05 / 08 / 2026, p. 33 / 74

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