Oxazole compound crystal

Abstract

To provide a crystal of an oxazole compound that has specific inhibitory activity against PDE4, and that shows excellent stability.SOLUTION: A crystal of an oxazole compound represented by formula (5), the crystal having peaks at diffraction angles 2θ(°)=9.6±0.2, 19.1±0.2, and 21.2±0.2 in an X-ray powder diffraction pattern measured using CuKα characteristic X-rays.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a novel crystal of an oxazole compound and a method for producing the same. [Background technology]

[0002] Patent Documents 1 and 2 report oxazole compounds with specific inhibitory activity against phosphodiesterase 4 (PDE4) and methods for producing the same. PDE4 is the predominant PDE in inflammatory cells. Inhibition of PDE4 increases intracellular cAMP levels, which downregulates inflammatory responses by regulating the expression of TNF-α, IL-23, and other inflammatory cytokines. Increased cAMP levels also increase anti-inflammatory cytokines such as IL-10. Therefore, the oxazole compounds are considered suitable for use as anti-inflammatory agents. For example, they are considered useful for suppressing skin eczema and dermatitis, including atopic dermatitis. Patent Document 3 describes an ointment that stably contains an oxazole compound with specific inhibitory activity against PDE4 and can be efficiently absorbed into the skin. The contents of Patent Documents 1 to 3 are incorporated herein by reference. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2007 / 058338 (Patent Publication No. 2009-515872) [Patent Document 2] International Publication No. 2014 / 034958 (Patent Publication No. 2015-528433) [Patent Document 3] International Publication No. 2017 / 115780 Summary of the Invention [Problem to be solved by the invention]

[0004] An object of the present invention is to provide a crystal of an oxazole compound having PDE4 inhibitory activity (specifically, an oxazole compound represented by the following formula (5)), which has superior stability. [Means for solving the problem]

[0005] The present inventors have discovered a method for preparing a hitherto unreported type of crystal using a specific oxazole compound having PDE4 inhibitory activity, and have further found that the novel crystal has superior stability. Further improvements have led to the completion of the present invention.

[0006] The present invention encompasses, for example, the subject matter described in the following paragraphs. Section 1. Formula (5):

[0007] [ka]

[0008] A crystal of an oxazole compound represented by the formula: In the powder X-ray diffraction pattern measured using CuKα characteristic X-rays, the diffraction angle 2θ (°) = Crystals with peaks at 9.6±0.2, 19.1±0.2, and 21.2±0.2. Item 2. Item 1. The crystal according to Item 1, further comprising a peak at one, two, or three diffraction angles 2θ (°) selected from the group consisting of 12.6±0.2, 22.8±0.2, and 26.0±0.2 in a powder X-ray diffraction pattern measured using CuKα characteristic X-rays. Section 3. Item 3. The crystal according to Item 2, further comprising a peak at one or more diffraction angles 2θ (°) 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 a powder X-ray diffraction pattern measured using CuKα characteristic X-rays. Section 4. Formula (5):

[0009] [ka]

[0010] A crystal of an oxazole compound represented by the formula: In the infrared absorption spectrum measured by the potassium bromide tablet method, the wave number (cm -1 )=3380±5, 2980±5, 1651±2, 1501±2, 1258±2, 1121±2, and 754±2, crystalline. Section 5. In the infrared absorption spectrum measured by the potassium bromide tablet method, the wave number (cm -1 4. The crystal according to any one of items 1 to 3, having infrared absorption bands at λ / 3, λ / 4, λ / 5, λ / 6, λ / 7, λ / 8, λ / 9, λ / 10, λ / 11, λ / 20, λ / 32, λ / 25, λ / 36, λ / 40, λ / 25, λ / 36, λ / 25 ... Section 6. Furthermore, in an infrared absorption spectrum measured by the potassium bromide tablet method, one or more wavenumbers (cm) selected from the group consisting of 1601±2, 1537±2, 1302±2, 1234±2, 1107±2, 1026±2, and 627±2 are -1 Item 6. The crystal according to Item 4 or 5, having an infrared absorption band in Section 7. Item 7. The crystal according to any one of Items 1 to 6, having a melting point of 75 to 90°C. Section 8. Formula (5):

[0011] [ka]

[0012] A crystal of an oxazole compound represented by the formula: It is crystalline and has a melting point of 75-90°C. Section 9. A pharmaceutical composition comprising the crystal according to any one of Items 1 to 8. Section 10. Item 10. The pharmaceutical composition according to Item 9, for treating and / or preventing skin eczema or dermatitis (preferably atopic dermatitis). Section 11. Item 11. The pharmaceutical composition according to Item 9 or 10, which is an ointment. [Effects of the Invention]

[0013] The present invention provides a more stable crystal of a specific oxazole compound having PDE4 inhibitory activity. In particular, the crystal has a higher melting point than conventional crystals of the specific oxazole compound, and is therefore advantageous in that it has higher thermal stability. [Brief explanation of the drawings]

[0014] [Figure 1] 1 shows a powder X-ray diffraction pattern of the A-type crystal of compound (5) measured using CuKα characteristic X-rays. [Figure 2] 1 shows an infrared absorption spectrum of type A crystals of compound (5) measured by the potassium bromide tablet method. [Figure 3] 1 shows a powder X-ray diffraction pattern of the B-type crystal of compound (5) measured using CuKα characteristic X-rays. [Figure 4] 1 shows an infrared absorption spectrum of type B crystals of compound (5) measured by the potassium bromide tablet method. DETAILED DESCRIPTION OF THE INVENTION

[0015] Each embodiment of the present invention will be described in further detail below.

[0016] The crystalline oxazole compound included in the present invention is represented by the following formula (5):

[0017] [ka]

[0018] The oxazole compound has a specific inhibitory effect on PDE4 and is useful as an anti-inflammatory agent. In this specification, the oxazole compound represented by formula (5) may be referred to as compound (5). Compound (5) is N-[2-(4-difluoromethoxy-3-isopropoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide.

[0019] Compound (5) can be produced by known methods (for example, the methods described in any of Patent Documents 1 to 3). However, the crystalline form of compound (5) produced by any known method differs from the crystalline form of compound (5) encompassed by the present invention. In this specification, the former crystalline form may be referred to as Type A, and the latter crystalline form as Type B. That is, the crystalline form of compound (5) produced by known methods is Type A crystal, and the crystalline form of compound (5) encompassed by the present invention is Type B crystal.

[0020] The B-type crystal is, for example, a crystal of compound (5) having one or more of the following characteristics: Preferably, it has at least one of the following characteristics (i) to (iii), more preferably at least two of them (i.e., it has characteristics (i) and (ii), or (ii) and (iii), or (iii) and (i)), and even more preferably it has all three of them.

[0021] Feature (i): Unique powder X-ray diffraction pattern The B-type crystal preferably has peaks at diffraction angles 2θ(°)=9.6±0.2, 19.1±0.2, and 21.2±0.2 in a powder X-ray diffraction pattern measured using CuKα characteristic X-rays. Of these three peaks, the peak at diffraction angle 2θ(°)=19.1±0.2 (sometimes referred to as peak

[12] ) has the smallest intensity. It is preferable that the intensity of the peak at a diffraction angle 2θ(°)=21.2±0.2 (sometimes referred to as peak

[16] ) is the greatest. The peak at a diffraction angle 2θ(°)=9.6±0.2 is sometimes referred to as peak [2].

[0022] Furthermore, the ratio of the intensities of peak

[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 about 1.7 to 2.3, and even more preferably about 1.8 to 2.2 or about 1.9 to 2.1. Furthermore, the ratio of the intensities of peak

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

[12] ) is preferably about 1.5 to 1.75.

[0023] In addition to these three peaks (peaks [2],

[12] , and

[16] ), it is more preferable to have peaks at one, two, or three diffraction angles 2θ (°) selected from the group consisting of 12.6±0.2, 22.8±0.2, and 26.0±0.2. The peak at a diffraction angle 2θ (°) = 12.6±0.2 is sometimes referred to as peak [6]. The peak at a diffraction angle 2θ (°) = 22.8±0.2 is sometimes referred to as peak

[18] . The peak at a diffraction angle 2θ (°) = 26.0±0.2 is sometimes referred to as peak

[20] .

[0024] It is particularly preferred that the B-type crystal has all of the peaks [6],

[18] , and

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

[12] , and

[16] . In this case, it is preferred that the peak intensities of the peaks [6],

[18] , and

[20] are all smaller than the peak intensity of the peak

[12] . Furthermore, it is preferred that the peak intensity of the peak

[20] is the largest among the peak intensities of the peaks [6],

[18] , and

[20] .

[0025] Furthermore, in addition to the four to six peaks (the three peaks [2],

[12] , and

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

[18] , and

[20] ), it is even more preferable to have peaks at one or more (2, 3, 4, 5, 6, or 7) diffraction angles 2θ (°) 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 intensities of these one to seven peaks are preferably all smaller than the intensities of the four to six peaks. Particularly preferred is type B crystal, which has peaks [2],

[12] , and

[16] , and peaks [6],

[18] , and

[20] , and also has peaks at diffraction angles 2θ (°) = 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.

[0026] Feature (ii): Unique infrared absorption spectrum Type B crystals have a wave number (cm) in the infrared absorption spectrum measured by the potassium bromide tablet method. -1 )=3380±5, 2980±5, 1651±2, 1501±2, 1258 It is preferable that the compound has infrared absorption bands at wave numbers (cm ). -1 The infrared absorption band at λ / (π / π) = 1651 ± 2 is a band that is particularly characteristic of type B crystals. These infrared absorption bands are derived from the infrared absorption of characteristic functional groups present in compound (5), and more specifically, are as follows: (Note that the wavelengths shown to the right of the symbol " / " below are the wavelengths of the infrared absorption bands in type A crystals described below.) 3380(cm -1 ): Secondary amide NH stretching vibration 2980(cm -1 ): -CH2 stretching vibration 1651 / 1643(cm -1 ): Amide C=O stretching vibration 1501 / 1503(cm -1): Aromatic C=C stretching vibration 1258 / 1261, 1121 / 1119 (cm -1 ): -CF2 stretching vibration 754 / 758(cm -1 ): Benzene CH out-of-plane bending vibration

[0027] In addition to these characteristic infrared absorption bands, one or more (2, 3, 4, 5, 6, or 7) wavenumbers (cm) selected from the group consisting of 1601±2, 1537±2, 1302±2, 1234±2, 1107±2, 1026±2, and 627±2 are also present. -1 ) more preferably has an additional infrared absorption band.

[0028] In the infrared absorption spectrum, the wave numbers (cm) of one or more (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13) infrared absorption bands -1 ) may have an error of ±4, ±3, ±2, or ±1.

[0029] Feature (iii): characteristic melting point The melting point of the B-type crystals 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.

[0030] The melting point is a value measured by Method 1 described in Section 2.60 of the 17th Edition of the Japanese Pharmacopoeia.

[0031] Type B crystals can be prepared by allowing Type A crystals to stand for a long period of time at a temperature higher than room temperature. More specifically, they can be prepared, for example, by allowing them to stand at preferably 40 to 60°C, more preferably 45 to 55°C, and even more preferably 48 to 52°C, for preferably 3 months or more, more preferably 4 months or more, or 5 months or more. The upper limit of the standing period is not particularly limited as long as Type B crystals are obtained, but examples include approximately 6 or 7 months. The standing period is preferably carried out in an airtight or sealed state. It is also preferably carried out in a state where it is not affected by light (for example, in a light-shielding state, more specifically, in a light-shielding brown bottle).

[0032] Furthermore, type A crystals can be prepared by known methods as described above, for example, by the methods described in any of Patent Documents 1 to 3. Without any particular limitation, type A crystals can be prepared, for example, by preparing compound (5) according to the following reaction scheme described in Patent Document 3, and then precipitating crystals of compound (5). The obtained precipitated crystals can be dried and used as type A crystals, and the dried type A crystals are particularly preferred as type A crystals to be used for preparing type B crystals by leaving them at a temperature higher than room temperature for a long period of time.

[0033] [ka]

[0034] The powder X-ray diffraction pattern, infrared absorption spectrum, and melting point of the A-type crystal are described below. In the powder X-ray diffraction pattern measured using CuKα characteristic X-rays, the A-type crystal has characteristic peaks, particularly at diffraction angles 2θ (°) = 5.8±0.2, 11.6±0.2, 17.1±0.2, 23.1±0.2, and 26.1±0.2. Furthermore, the A-type crystal may also have peaks at one or more diffraction angles 2θ (°) selected from the group consisting of 10.2±0.2, 13.2±0.2, 16.1±0.2, 18.5±0.2, 22.2±0.2, and 26.7±0.2. In the infrared absorption spectrum measured by the potassium bromide tablet method, the A-type crystal has characteristic peaks, particularly at wavenumbers (cm -1) = 3380 ± 5, 2980 ± 5, 1643 ± 2, 1503 ± 2, 1261 ± 2, 1119 ± 2, and 758 ± 2. Furthermore, the compound has one or more wavenumbers (cm) selected from the group consisting of 1601 ± 2, 1537 ± 2, 1296 ± 2, 1229 ± 2, 1047 ± 2, 939 ± 2, and 617 ± 2. -1 The melting point of the A-type crystals (measured by Method 1 described in 2.60 of the Japanese Pharmacopoeia, Seventeenth Edition) is about 56 to 60°C.

[0035] The present invention also includes a pharmaceutical composition containing the B-type crystals. The pharmaceutical composition contains, for example, a pharmaceutically acceptable carrier and the B-type crystals. Such a carrier is not particularly limited, and any known carrier can be used. The pharmaceutical composition may also be referred to as the pharmaceutical composition of the present invention.

[0036] The pharmaceutical composition of the present invention is particularly useful for suppressing skin eczema or dermatitis, and is particularly useful for suppressing atopic dermatitis, and can be used, for example, as an agent for preventing and / or treating these diseases.

[0037] The form of the pharmaceutical composition of the present invention is not particularly limited, and examples thereof include topical skin preparations, oral preparations, and injections. Of these, topical skin preparations are preferred, and ointments are particularly preferred. As an ointment, the (I)B-type crystals are preferably dissolved in a base component and contained therein. The base components include (II) a solvent for dissolving compound (5), and (III) an ointment base.

[0038] More preferably, the ointment is an ointment in which (I) the type B crystals are dissolved in (II) a solvent, and (III) the ointment base is dissolved or dispersed as droplets.

[0039] The (I) B-type crystals may be dissolved in the (II) solvent by heating. When dissolving by heating, it is preferable to heat to a temperature equal to or higher than the melting point of the B-type crystals. For example, the B-type crystals can be dissolved by heating at 75°C or higher, 76°C or higher, 77°C or higher, 78°C or higher, 79°C or higher, 80°C or higher, 81°C or higher, 82°C or higher, 83°C or higher, 84°C or higher, 85°C or higher, 86°C or higher, 87°C or higher, 88°C or higher, 89°C or higher, or 90°C or higher. The upper limit of the heating temperature is not particularly limited as long as the effects of compound (5) are exhibited, and examples include 100°C or lower, 99°C or lower, 98°C or lower, 97°C or lower, 96°C or lower, 95°C or lower, 94°C or lower, 93°C or lower, 92°C or lower, and 91°C or lower.

[0040] Although not particularly limited, the (I) B-type crystals are contained in the ointment in an amount of preferably 0.01 to 10 parts by weight, more preferably 0.05 to 7.5 parts by weight, and even more preferably 0.1 to 5 parts by weight, per 100 parts by weight of the ointment.

[0041] The (I)B-type crystals are preferably dissolved in a (II) solvent. The solvent is preferably a polar compound that is liquid at room temperature. More specifically, preferred examples include ethylene carbonate, propylene carbonate, benzyl alcohol, triacetin, diethyl sebacate, diisopropyl sebacate, diethyl adipate, diisopropyl adipate, isostearic acid, olive oil, hexyldodecanol, decyl oleate, isostearyl alcohol, and isopropyl myristate. More preferred examples include ethylene carbonate, propylene carbonate, benzyl alcohol, and triacetin, with propylene carbonate and triacetin being even more preferred. Among these, propylene carbonate is preferred. The solvent may be used alone or in combination of two or more. It is particularly preferred to use ethylene carbonate or propylene carbonate alone, or to use ethylene carbonate or propylene carbonate in combination with benzyl alcohol and / or triacetin.

[0042] The ointment contains the (II) solvent in an amount of 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 the (I) type B crystals. The upper limit is not particularly limited as long as the effects of the present invention are obtained, but is, for example, 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.

[0043] The ointment contains 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 of the solvent (II) relative to 100 parts by weight of the ointment.

[0044] The solution in which the type B crystals are dissolved in a solvent is preferably dissolved or dispersed as droplets in (III) an ointment base, and more preferably dispersed as droplets in (III) an ointment base.

[0045] (III) As the ointment base, known ointment bases used in the manufacture of ointments can be used, such as hydrocarbons. More specifically, examples include oily bases, particularly natural wax, petroleum wax, and other hydrocarbons. Examples of natural waxes include beeswax (unbleached beeswax, non-chemically bleached white beeswax, chemically bleached white beeswax, etc.) and carnauba wax. Examples of petroleum waxes include paraffin and microcrystalline wax. Examples of other hydrocarbons include liquid paraffin, petrolatum (white petrolatum, yellow petrolatum, etc.), etc. The ointment base can be used alone or in combination of two or more.

[0046] The ointment contains 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 of (III) ointment base per part by weight of (I) type B crystals.

[0047] The ointment contains (III) an ointment base 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 ointment.

[0048] The ointment base (III) preferably contains at least beeswax. As the beeswax, it is preferable to use beeswax that has not been chemically bleached, such as non-chemically bleached beeswax (non-chemically bleached beeswax) or unbleached beeswax (unbleached beeswax).

[0049] The ointment contains 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 of beeswax per part by weight of the (I) B-type crystals.

[0050] The ointment contains 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 of beeswax per 100 parts by weight of the ointment.

[0051] When other ointment bases are used in combination with beeswax, there are no particular limitations, but it is preferable that they include at least one selected from the group consisting of petrolatum (preferably white petrolatum), liquid paraffin, and paraffin, and beeswax.

[0052] In addition to the above ointment base, other additives (especially pharmaceutical additives) that can be used in ointments, such as fragrances, coloring agents, preservatives, and absorption enhancers such as higher alkenoic acids (e.g., oleic acid, etc.), as well as drugs effective for other skin diseases, may also be included.

[0053] As described above, the ointment of the present invention preferably has a structure in which (I) the B-type crystals are dissolved in (II) a solvent, and the solvent is dissolved or dispersed as droplets in (III) an ointment base. For example, an ointment having such a structure can be produced by dissolving (I) in (II) to prepare a solution, and then stirring and mixing the solution with (III). For stirring and mixing, a homomixer, a paddle mixer, or a combination thereof can be used.

[0054] Regarding (III), when multiple types of ointment bases are used, it is preferable to mix them in advance. In the preparation, it is preferable to heat and mix them in order to dissolve solids such as beeswax. For example, when beeswax and other ointment bases are used in combination, it is preferable to mix the beeswax and other ointment bases in advance, and it is preferable to heat and mix them during mixing.

[0055] Furthermore, when the ointment has a structure in which (I) is dissolved and (II) is dispersed as droplets in (III), the particle size of the droplets is 100 μm or less when observed under a polarizing microscope. It is preferably about 40 μm or less, more preferably about 25 μm or less, and even more preferably about 20 μm or less. In particular, it is preferable that there are no droplets larger than 100 μm, more preferably there are no droplets larger than 40 μm, and even more preferably there are no droplets larger than 25 μm. It is more preferable that no droplets are present, and even more preferable that no droplets larger than 20 μm are present. The particle size of the droplets can be adjusted to a desired average particle size by adjusting the stirring speed when stirring and mixing the solution and (III).

[0056] In this specification, the term "comprising" includes "consisting essentially of" and "consisting of." Furthermore, the present invention encompasses all arbitrary combinations of the constituent elements described in this specification.

[0057] Furthermore, the various characteristics (properties, structures, functions, etc.) described in each embodiment of the present invention may be combined in any way to specify the subject matter encompassed by the present invention. In other words, the present invention encompasses all subject matter consisting of any combination of the combinable characteristics described herein. [Example]

[0058] The present invention will be described in more detail below, but is not limited to the following examples. In the reaction formulas described below, when each compound is represented by a number, the compound may be referred to as "compound (number)." For example, the compound represented by "3" may be referred to as "compound (3)." In addition, in the reaction formulas below, the compound represented by "5" is the same compound as the above-mentioned compound (5).

[0059] [Synthesis of oxazole compound (A-type crystal)] Compound (5) (white powder) was prepared by the method described in Example 352 of Patent Document 1 (WO 2007 / 058338).

[0060] Compound (5) data N-({2-[4-(difluoromethoxy)-3-isopropoxyphenyl]oxazol-4-yl}methyl)-2-ethoxybenzamide : white powder. 1 H NMR (400 MHz, CDCl3): 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 = 75.2 Hz, 1H, CHF2), 4.68 (sept, J = 6.0 Hz, 1H, CH), 4.62 (d, J = 6.0 Hz, 2H, CH2), 4.17 (q, J = 6.93, 2H, CH2), 1.48 (t, J = 7.2 Hz, 3H, CH3), 1.39 (d, J = 5.6 Hz, 6H, 2CH3).

[0061] The powder X-ray diffraction pattern of the obtained white powder of compound (5) was measured using CuKα characteristic X-rays. More specifically, the measurement was performed under the following conditions. Measurement equipment: XRD-6000 (Shimadzu Corporation) Operating conditions: Voltage: 35.0kV, Current: 20.0mA, Sampling Pitch: 0.0200° The measurement results are shown in FIG.

[0062] [Table 1]

[0063] The infrared absorption spectrum of the obtained white powder of compound (5) was measured by the potassium bromide tablet method. More specifically, the measurement was performed under the following conditions. Measuring device: IR Prestige-21 (Shimadzu Corporation) Operating conditions: Number of integrations: 16, resolution: 4cm -1 The measurement results are shown in Figure 2.

[0064] The melting point of the obtained white powder of compound (5) was measured by Method 1 described in Section 2.60 of the Japanese Pharmacopoeia, Seventeenth Edition. More specifically, the measurement was performed under the following conditions. Measuring device: M-565 (BUCHI) Operating conditions: The white powder of compound (5) was placed in a dry capillary tube to form a layer thickness of 2.5 to 3.5 mm. The bath was gradually heated to 48°C, and the capillary tube containing the white powder was inserted. The temperature was then increased by approximately 3°C per minute, and the sample was then heated from 53°C at a rate of 1°C per minute, during which time the sample was observed.

[0065] As a result of the measurement, the melting point of the white powder (A-type crystal) of compound (5) was about 56 to 60°C.

[0066] The crystals of compound (5) prepared using the A-type crystals obtained as described above as seed crystals by the method described in Patent Document 2 (WO 2014 / 034958) (particularly Example 1 (1-10): Compound 1) and the method described in Patent Document 3 (WO 2017 / 115780) (particularly Production Example 4 (Compound (11))) also had similar properties to those described above, and therefore, were both A-type crystals.

[0067] [Preparation of B-type crystals 1] 12 g of the A-type crystals were placed in a brown glass bottle, sealed, and stored in an incubator (50±2°C) for 3 months. The powder (crystals) recovered after storage were subjected to the same powder X-ray diffraction pattern and infrared absorption spectrum measurements as described above. The powder X-ray diffraction pattern is shown in Figure 3 and Table 2, and the infrared absorption spectrum is shown in Figure 4. The melting point was also measured in the same manner as described above, except that "48°C" was changed to "72°C" and "53°C" to "77°C." The resulting melting point was approximately 80 to 84°C.

[0068] [Table 2]

[0069] As can be seen from these results, the crystals recovered after storage showed a different powder X-ray diffraction pattern, a different infrared absorption spectrum, and a different melting point from those of type A crystals. These crystals were designated type B crystals.

[0070] As mentioned above, type B crystals have a higher melting point than type A crystals. This indicates that type B crystals have superior thermal stability. Prior to this study, a search for crystals with greater stability than type A crystals was conducted using recrystallization methods with a variety of solvents, but no different crystal forms were obtained. However, it was unexpectedly discovered that type B crystals, which have greater stability (especially thermal stability), can be prepared by leaving type A crystals at a temperature higher than room temperature for a long period of time.

[0071] [Preparation of B-type crystals 2] The obtained B-type crystals were used as seed crystals to further prepare B-type crystals. Specifically, the following method was performed according to the method described in Patent Document 3 (WO 2017 / 115780): In this way, type B crystals were prepared.

[0072] [ka]

[0073] 20.00 g (66.8 mmol) of compound (1) and 17.28 g (134 mmol) of diisopropylethylamine were added to 300 mL of ethyl acetate and cooled. 11.48 g (100 mmol) of methanesulfonyl chloride was added and stirred at 10 to 30°C for 1 hour. 17.41 g (200 mmol) of lithium bromide was then added and stirred at 20 to 35°C for 1 hour. 100 mL of water was added to the reaction mixture, and the organic layer was concentrated under reduced pressure. 300 mL of ethyl acetate was added to the concentrated residue, which was dissolved and concentrated under reduced pressure again. 200 mL of N,N-dimethylformamide and 17.33 g (93.6 mmol) of potassium phthalimide were added to the concentrated residue, and the mixture was reacted at 75 to 85°C for 1 hour. 200 mL of water was added to the reaction mixture to precipitate crystals, which were collected by filtration and dried at 80° C. to obtain 27.20 g of compound (3) (yield 95.01%).

[0074] [ka]

[0075] 20.00 g (46.7 mmol) of compound (3) was mixed with 40 mL of 40% aqueous methylamine solution, 40 mL of methanol, and 100 mL of water, and the mixture was allowed to react under reflux for 30 minutes. 200 mL of cyclopentyl methyl ether (CPME) and 20 mL of 25% aqueous sodium hydroxide solution were added to the reaction mixture, and the temperature was adjusted to 65-75°C, allowing for phase 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 again adjusted to 65-75°C, allowing for phase separation. 5 mL of concentrated hydrochloric acid was added to the organic layer to precipitate crystals. The precipitated crystals were collected by filtration, yielding 27.58 g of wet crystals of compound (4).

[0076] Wet crystals of compound (4) (46.7 mmol) were mixed with 120 mL of ethyl acetate and 7.1 mL (51.4 mmol) of triethylamine and stirred at 20-30°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 mixture and reacted at 20-30°C for 1 hour. 60 mL of water and 6 mL of concentrated hydrochloric acid were added to the reaction mixture, and the temperature was adjusted to 40-50°C for separation. The organic layer was washed with 60 mL of water and 25% hydroxide. 6 mL of aqueous sodium solution was added, and the temperature was adjusted again to 40-50°C for separation. The organic layer was concentrated under reduced pressure. 50 mL of ethanol, 20 mL of water, 6 mL of 25% aqueous sodium hydroxide solution, and 0.6 g of activated carbon were added to the concentrated residue and refluxed for 30 minutes. The activated carbon was filtered off and washed with 12 mL of ethanol. The filtrate was cooled and then 10 mg of type B crystals (seed crystals) were added to precipitate crystals. The precipitated crystals were collected by filtration and dried at 60°C to obtain 18.38 g of crystals of compound (5) (yield 88.18%).

[0077] The powder X-ray diffraction pattern, infrared absorption spectrum, and melting point of the obtained crystals were measured in the same manner as above, and all the results were similar to those of the above-mentioned type B crystals. This indicates that type B crystals can be directly synthesized by using type B crystals as seed crystals, without having to prepare type B crystals using type A crystals.

Claims

[Claim 1] The invention described in the specification.

Images