WO2008139574A1 - Crystalline form of lactam compound and process for producing the same - Google Patents

Abstract

It is intended to provide a crystal of a lactam compound having storage stability, good handleability or the like which is suitable as a pharmaceutical such as an excellent sugar transport enhancer or a hypoglycemic agent. A crystal of a compound represented by the formula (I) of the invention or a pharmaceutically acceptable salt thereof is useful as a pharmaceutical such as a sugar transport enhancer or a hypoglycemic agent.

Description

 Specification

 Crystal form of lactam compound and method for producing the same

 The present invention relates to a crystal of a ratata compound excellent in storage stability and the like, a medicament containing the crystal, a method for producing the crystal, and the like. Background art

 Formula (I)

Is a known compound and has been reported to have an excellent sugar transport enhancing action and blood glucose lowering action (for example, US Patent Application Publication No. 2 0 0 4 Z 0 0 4 8 8 4 (See specification 7). The compound represented by the formula (I) is useful as a pharmaceutical agent such as a therapeutic agent for diabetes.

 -On the other hand, the crystal form of the compound is often preferable to amorphous in terms of characteristics such as storage stability.

In particular, compounds that are active pharmaceutical ingredients have important properties that are further desired in addition to biological activity, and stable crystal forms can meet these requirements. Important properties include, for example, purity, storage stability (eg to avoid the production of pharmaceutical formulations containing degradation products), stability during the manufacturing process of the pharmaceutical formulation (eg grinding process), final formulation Stability (for example, is important because it affects the shelf life), and low hygroscopicity (for example, high hygroscopicity causes fluctuations in the content of active ingredients per weight). In terms of purity, if the crystal form of a compound is available, purification can be facilitated by recrystallization. Disclosure of the invention

 However, the lactam compound crystals represented by formula (I) have not been reported so far.

 As a result of intensive studies to solve the above problems, the present inventors have succeeded in obtaining a crystal containing a compound represented by the formula (I). Furthermore, the inventors have found that the obtained crystal is excellent in storage stability, and have completed the present invention.

 That is, the present invention provides crystals of a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof, a medicament containing the same, a method for producing the same, and the like.

 That is, the present invention is as follows.

 (1) Formula (I)

 (I)

Or a pharmaceutically acceptable salt thereof.

 (2) The crystal according to (1) above, which is an anhydrous crystal.

 (3) Formula (1— 1)

Hi ' ¹ )

A compound crystal represented by:

 (4) The crystal according to (1) or (3) above, having a characteristic peak at diffraction angles (20) = 12.4, 21.8 and 26.3 in powder X-ray diffraction.

(5) In powder X-ray diffraction, diffraction angle (26) = 1.1.4, 12.4, 15.3, 19.1, 20.2, 20.8, 21.8, 23.6 and 26. Features 3 The crystal according to the above (1), (3) or (4) having a typical peak.

 (6) The crystal according to the above (1), (3), (4) or (5) having an endothermic peak in the range of 228 to 234 ° C. in differential scanning calorimetry.

 (7) The crystal according to (1) above, which is a hydrate crystal.

 (8) Formula (I 1 2)

 'xH 0

 (1-2)

(In the formula, X is a number from 0 to :!)

A compound crystal represented by:

 (9) The crystal according to (8) above, wherein X force is 0.6 to I.

 (10) In powder X-ray diffraction, diffraction angles (20) = 1.3.6, 1 6.:! To 1 6. 2 and 2 7.4 with the characteristic peaks (1), (8) Or (9) The crystal described.

 (1 1) In powder X-ray diffraction, diffraction angle (20) = 9.7 to 9.8, 13 · 6, 16. 1 to 16.2, 1, 9.4 to 1 9. 6., 20. 8 The crystal according to the above (1), (8), (9) or (10) having a peak characteristic to ˜20.9, 22.5 to 22.6 and 27.4.

 (12) X-ray powder diffraction has characteristic peaks at diffraction angles (20) = 9.8, 13.6, 16.1, 19.6, 20.8, 22.6 and .27.4 The crystal according to the above (1), (8), (9), (10) or (11).

 (13) In differential scanning calorimetry, it has an endothermic peak in the range of 204-210 ° C. (1), (8), (9), (10), (11) or (12) fe crystal.

 (14) A medicament comprising the crystal according to any one of (1) to (1 3) above.

(15) The medicament according to (14) above, which is a sugar transport enhancing agent. (1 6) The medicament according to (1 4) above, which is a hypoglycemic agent.

 (1 7) Prophylaxis and / or treatment of diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diuretic macroangiopathy, impaired glucose tolerance, or obesity 1 4) The pharmaceutical according to any one of (1 6).

 (18) The crystal according to (1) above, which is a solvate crystal.

 (1 9) The crystal according to (1 8) above, which is an ethyl acetate solvate crystal.

 1)

• 1/2 CH ₃ COOC ₂ H ₅

 (1-3)

A compound crystal represented by:

 (2 1) In powder X-ray diffraction, diffraction angle (2 Θ) = 5.8, 1 1. 6, 1 8. 4, 1 9. 5, 20. 5, 2 1. 0, 2 1-9 and 22. The crystal according to (1) or (20) above, which has a characteristic peak at 8.

 (2 2) The crystal according to the above (1 8), which is an anisosolvate crystal.

 1)

A crystal of a compound represented by '1/2 C ₆ H ₅ OCH ₃ .

 (24) In powder X-ray diffraction, diffraction angle (2 0) = 5. 8, 1 1. 6, 1 8. 4, 1 9. 3, 20. 4, 2 1. 0, 2 1. 8 and 22 The crystal according to (1) or (23), which has a peak characteristic to 8.

(2 5) The crystal according to (18), which is a benzonitrile solvate crystal. -Five)

■ 1/2 C ₆ H ₅ CN

 (1-5)

A compound crystal represented by:

 (27) In powder X-ray diffraction, diffraction angle (2 Θ) = 6.2, 12. 4, 17.6, 18. 2, 20. 2, 20. 4, 20. 8, 21 · 3 and 24. 2. The crystal according to (1) or (26) above, which has a characteristic peak in 2.

 (28) The crystal according to (18), which is a tetrahydrofuran solvate crystal.

 1)

A compound crystal represented by:

 (30) In powder X-ray diffraction, diffraction angle (20) = 7.1, 14. 4, 19.

The crystal according to (1) or (29) above, which has characteristic peaks at 9, 21.3, 22.5 and 23.7.

 (31) The crystal according to (18), which is a toluene hydrate.

(32) Equation (I 1 7)

 ■ C6H5CH3

 (1-7)

A compound crystal represented by:

 (33) Powder X-ray diffraction, characterized by diffraction angle (2 Θ) = 5.9, 8. 3, 1 1. 8, 14.5, 18.5, 21.3, 22.9 and 29.6 The crystal according to (1) or (32), which has a typical peak.

 (34) Formula (I)

(I)

A step of cooling a solution containing the compound represented by the above (2)

The manufacturing method of the crystal | crystallization in any one.

 (35) Formula (I)

(I)

The manufacturing method of the crystal | crystallization in any one of said (2)-(6) including the process of adding a poor solvent to the solution containing the compound represented by these.

(36) Formula (I)

 (I)

The manufacturing method of the crystal | crystallization in any one of said (2)-(6) including the process of desolvating the solvate crystal | crystallization of the compound represented by these.

 (37) Formula (I)

 (I)

A step of cooling a solution containing the compound represented by the above (7)

The manufacturing method of the crystal | crystallization in any one of.

 (38) Formula (I)

 (I)

The manufacturing method of the crystal | crystallization in any one of said (7)-(13) including the process of adding a poor solvent to the solution containing the compound represented by these.

 (39) The method for producing a crystal according to any one of (7) to (13) above, comprising a step of adding water to the crystal according to any one of (2) to (6) above.

 (40).

Including a step of adding water to the crystal according to any one of (31) to (33) above. The method for producing a crystal according to any one of the above (7) to (13), the crystal of the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has high storage stability. Therefore, a drug containing the compound represented by the above formula (I) excellent in stability or a drug substance or standard substance for manufacturing a drug excellent in stability is provided.

 Since the type I crystal (described later) of the present invention is an anhydrous crystal, it is very easy to handle, for example, when used as a drug substance or a standard substance for pharmaceutical production.

 Since the type I crystal (described later) of the present invention has little change in water content within a certain range of water content, it is very easy to handle, for example, when used as a drug substance in pharmaceutical production. In addition, since the I-type crystal of the present invention does not change its crystal form even when water is added, it is possible to provide a drug substance suitable for a preparation using water in the production process. Brief Description of Drawings

 FIG. 1 is a diagram showing a powder X-ray diffraction spectrum of an ethyl acetate hydrate crystal obtained in Example 2 and a crystal after desolvating it (measured by apparatus B (described later)). FIG. 2 is a graph showing a powder X-ray diffraction spectrum of the anisosolvate crystal obtained in Example 3 and the crystal after desolvation of the crystal (measured by apparatus B).

 FIG. 3 is a diagram showing a powder X-ray diffraction spectrum of the benzonitrile hydrate crystal obtained in Example 4 after removing the solvent (measured by apparatus B).

 FIG. 4 is a diagram showing a powder X-ray diffraction spectrum of the tetrahydrofuran solvate crystal obtained in Example 20 (measured with apparatus A (described later)).

 FIG. 5 is a diagram showing a powder X-ray diffraction spectrum of the toluene solvate crystal obtained in Example 21 (measured by apparatus A).

 FIG. 6 shows a powder X-ray spectrum of the type I crystal (measured by apparatus A). FIG. 7 is a diagram showing a differential scanning calorimetry (DSC) chart of the I-type crystal. FIG. 8 is a diagram showing the results of water vapor adsorption / desorption measurement of the type I crystal.

FIG. 9 is a diagram showing a powder X-ray diffraction spectrum of a type II crystal (measured by apparatus B). FIG. 10 is a diagram showing a differential scanning calorimetry (DSC) chart of a type II crystal.

 Fig. 11 shows the powder X-ray diffraction spectrum of I-type crystals measured under vacuum (measured with apparatus B).

 FIG. 12 is a diagram showing the results of water vapor adsorption / desorption measurement of II type crystals.

 FIG. 13 is a diagram showing the change over time in the water content of the I-type crystal. BEST MODE FOR CARRYING OUT THE INVENTION

 The present invention relates to a crystal of a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical containing the same, a production method thereof, and the like. Hereinafter, embodiments of the present invention will be described in detail.

1. Crystal of compound represented by formula (I) or pharmaceutically acceptable salt thereof and process for producing the same

 The first aspect of the present invention relates to a crystal of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof (sometimes referred to as “the crystal of the present invention”). The present invention also relates to a method for producing the crystal of the present invention. The crystal of the present invention introduces a solution containing a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof (sometimes referred to as “compound of the present invention”) to a supersaturated state, It can be manufactured by analyzing. Hereinafter, the compound of the present invention, the crystal of the present invention, and the production method thereof will be described in detail.

(Compound of the present invention and production method thereof)

Formula (I)

Is a compound disclosed in US Patent Application Publication No. 2 0 0 4/0 0 4 8 8 4 7, and has excellent sputum transport enhancing action, clot lowering action and the like. The compound represented by the formula (I) may be a pharmaceutically acceptable salt. The pharmaceutically acceptable salt means a salt that can be used as a medicine. However, those which do not take the salt form are preferred.

 Examples of the salt of the compound represented by the formula (I) include acid addition salts such as inorganic acid salts, organic acid salts, and sulfonic acid salts; Al force metal salts, Al force earth metal salts, metal salts, ammonia salts And base addition salts. Examples of inorganic acid salts include hydrochloride, hydrobromide, sulfate, phosphate, and the like. Examples of the organic acid salt include carbonate, acetate, benzoate, oxalate, maleate, fumarate, tartrate, kenate, and the like. Examples of the sulfonate include methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like. Examples of alkali metal salts include sodium salts, potassium salts, and lithium salts. Examples of alkaline earth metal salts include calcium salts and magnesium salts. Examples of the metal salt include an aluminum salt.

 The compound represented by the formula (Γ) can be produced according to the method disclosed in US Patent Application Publication No. 2 0 0 4/0 0 4 8 8 4 7 or a method analogous thereto. More specifically, it can be produced, for example, according to the method disclosed in Reference Example 1 described later or a method analogous thereto. .

(Crystal of the present invention and production method thereof)

 Formula (I)

 (I)

The crystal of the compound represented by or a pharmaceutically acceptable salt thereof is a hydrate or a solution. It may be a solvate. Such a hydrate or solvate is also included in the “crystal of the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof”. Examples of the hydrate include a compound represented by the formula (1-2).

 Examples of the solvate include an ethyl acetate solvate, a carsol solvate, a benzo-tolyl solvate, a tetrahydrofuran solvate, a toluene solvate, and the like, and a compound represented by the formula (I-13) Ethyl acetate solvate), compound represented by formula (I 1-4) (anisolate solvate), compound represented by formula (I 1-5) (benzonitrile solvate), formula (I 1-6) A compound represented by the formula (tetrahydrofuran solvate) and a compound represented by the formula (1-7) (toluene solvate) are preferred.

 The crystal of the present invention which is a hydrate crystal not only contains moisture as water of crystallization, but can also contain moisture as adhering water due to moisture absorption, for example. Such a water-containing crystal is also included in the crystal of the present invention.

 Moreover, even if the crystal of the present invention which is not a hydrate crystal is, for example, an anhydrous crystal, it can be converted to a water-containing crystal containing water as adhering water due to moisture absorption. Such a water-containing crystal is also included in the crystal of the present invention.

 The water content of the crystal of the present invention is not necessarily constant depending on drying conditions, storage conditions, and the like. However, regardless of the water content, all are included in the crystal of the present invention. The water content can be measured in accordance with a known method such as a forceful Fischer method.

 The crystal of the present invention can be produced, for example, by a method including the following steps.

 (Process 1)

 A compound represented by formula (I) or a pharmaceutically acceptable salt thereof is used as an appropriate solvent.

Dissolve in (good solvent) and concentrate if necessary.

 (Process 2)

 A solution containing the compound represented by the formula (I) obtained in step 1 or a pharmaceutically acceptable salt thereof, for example, (1) adding a poor solvent, or (2) cooling, etc. The method leads to a supersaturated state and precipitates crystals.

 (Process 3)

The crystals precipitated in step 2 are isolated and dried. Anhydrous crystals can also be produced by desolvating solvate crystals. Solvent removal can be performed by heating, reduced pressure, or the like, but is preferably by heating.

 As a method for concentrating the solution containing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, for example, using a rotary evaporator or the like while heating at normal pressure or reduced pressure. Examples include a method of evaporating the solvent and concentrating.

 The good solvent for the compound represented by the formula (I) or a salt thereof means a solvent that dissolves the compound of the present invention well within the range of room temperature to boiling point. The good solvent preferably includes a solvent having a saturated solubility at room temperature of about 0.1 mg / m or more, and more preferably a solvent of about l mg Zm 1 or more. For the compound represented by the formula (I) that does not take the form of a salt, examples of such a good solvent include methanol, ethanol, propanol, butanol, octanol and the like having 1 to 8 carbon atoms. And dimethylenolesulphoxide, dimethylenolenolemamide, formamide, benzonitrile, acetonitrile, ethyl acetate, acetone, 2-butanone, tetrahydrofuran, diisopropylamine, dichloromethane, etc., preferably ethanolol, Propanol, butanol, dimethinolesnoreoxide, dimethenolenole amide, formamide or benzonitrile.

 The poor solvent of the compound represented by the formula (I) or a salt thereof is defined in relation to the good solvent used and can be miscible with the good solvent, but the compound of the present invention is dissolved in comparison with the good solvent. It means a solvent that is difficult to understand. Examples of the poor solvent include a solvent in which the saturation solubility of the target compound at room temperature is 1/10 or less of the good solvent, and a solvent in which 1100 or less is more preferable. When the above-mentioned good solvent is used in the compound represented by the formula (I) that does not take the form of a salt, examples of such a poor solvent include water, ether, isoptinole acetate, butinoreamine, toluene, Examples include anisol, black mouth form, mouth hexane, hexane and the like.

The supersaturated state is obtained by, for example, dissolving a compound represented by the formula (I) in a solvent heated (for example, 60 to 90 ° C.) and concentrating as necessary to obtain a saturated solution. This can be achieved by gradually cooling the liquid (eg, from 0 to 30 ° C.). Of the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof before cooling The concentration may be any concentration that can be brought to a supersaturated state by cooling even if it does not reach a saturated state, but is preferably a saturated state.

 In addition, the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is dissolved in a good solvent to obtain a saturated solution, and the resulting saturated solution is gradually added with a poor solvent to be supersaturated. It can also be in a state.

 Hereinafter, the crystal of the present invention and the production method thereof will be described more specifically.

(Crystal of the compound represented by the formula (I-1))

 Formula (1 -1)

dD

The crystal of the compound represented by formula (I) is an anhydrous crystal of the compound represented by the formula (I). In the powder X-ray diffraction obtained by irradiation with copper Κα rays (wavelength λ = 54 Å), the diffraction angle ( 26) = 12.4, 21.8 and 26.3, and more specifically diffraction angle (20) = 1 · 4, 1 2. 4, 1 5. 3, 1 9. 1, 20. 2 , 20. 8, 21.8, 23.6 and 26..3 (measured using the device 後 述 described later, hereinafter simply referred to as “device A”). Further, the crystal has an endothermic signal in the range of about 210 to 250 ° C. in the differential scanning calorimetry (DSC), and the endothermic peak temperature is about 228 to 234 ° C. Such a crystal of a compound represented by the formula (I 1 1) may be referred to as “type I crystal”.

 Type I crystals are anhydrous crystals, but may contain water as adhering water depending on storage conditions. The amount of water is not always constant depending on drying conditions and storage conditions. The water content of type I crystals is usually in the range of about 0-2.5% at room temperature. Such I-type crystals are included in the crystal represented by the formula (I-1) of the present invention regardless of the amount of water.

Type I crystals are, for example, heated compounds represented by formula (I) (for example, about 60 ° C) Dissolved in dichloromethane to obtain a saturated solution, and the obtained saturated solution was gradually cooled.

(For example, up to 0 to 10 ° C.) and allowed to stand in a cooled state (for example, 1 to 20 days).

 In addition, the type I crystal is produced, for example, by removing the solvate crystal of the compound represented by the formula (I) by a method such as heating (for example, 1550-220 ° C). It can also be done. As the solvate crystal, for example, an ethyl acetate solvate crystal, an anisol solvate crystal, a benzo-tolyl solvate crystal and the like can be suitably used. A crystal, a crystal of a compound represented by the formula (1-4), or a crystal of a compound represented by the formula (1-5) is preferable. Solvate crystals can be produced according to the method described below. Examples of the solvent removal method include methods such as heating and reduced pressure, and a method using heating is preferred. The heating temperature is usually about 1550 to 2200 ° C, preferably about 1600 to 1700 ° C. When the degree of crystallinity is low, the degree of crystallinity can be increased by a method such as heating (for example, about 2 10 ° C). Furthermore, the type I crystal is obtained by, for example, adding a poor solvent (for example, heptane) to a solution obtained by dissolving the compound represented by the formula (I) in ethanol (preferably a saturated solution) at 30 ° C. or less. It can also be produced by adding crystallization.

 Since type I crystals have high storage stability, they can be suitably used, for example, as drugs (for example, sugar transport enhancing agents, hypoglycemic agents, antidiabetic agents, etc.), drug substances, and the like. In addition, since it has low hygroscopicity, it can be suitably used as a standard product used for pharmaceutical production, for example. .

 In addition, since the type I crystal can be rapidly transferred to the type I I crystal by adding water, it can also be used for the production of the type I I crystal.

(Crystal of the compound represented by the formula (I 1 2))

Formula (1-2)

XH ₂ 0

 (1-2)

(In the formula, X represents the same meaning as described above.)

The crystal of the compound represented by formula (I) is a hydrate crystal of the compound represented by the formula (I). In the powder X-ray diffraction obtained by irradiation with copper Κα rays (wavelength; 1 = 1.54 angstrom) , Diffraction angle (2 0) = 1 3.6, 1 6. 1 to 1 6. 2 and 2 7.4 have characteristic peaks (measured using device 後 述 described later, hereinafter simply “device Β” May be indicated). In differential scanning calorimetry (DSC), it has an endothermic signal in the range of about 190 to 240 ° C, and the endothermic peak temperature is about 204 to 210 ° C. Such a crystal of the compound represented by the formula (1-2) may be referred to as “II type crystal”.

 I Although type I crystals are hydrate crystals, the crystal water is relatively easy to enter and exit, and the value of X in formula (1-2) is not necessarily constant depending on the drying conditions and storage conditions. X is preferably 0.6-1 and more preferably 0.7-0.9. Furthermore, even if the type I I crystal is a type I I crystal containing the maximum amount of crystal water (x = .l), it can further contain water as adhering water. Such a water-containing crystal of type I I crystal is also included in the type I I crystal of the present invention.

 The water content of type I crystals is usually about 0% to 12%, more preferably about 0 to 7%, and particularly preferably about 3 to 5%. I Type I crystals stabilize at room temperature at a relative humidity of about 40-80% and a moisture content of about 3-5% (ie, X is about 0.6-1).

The powder X-ray diffraction obtained by irradiation with copper Κα rays (wavelength λ = 54 Å) will be described in more detail. When the moisture content of the compound represented by the formula (I 1 2) changes, the relative intensity of the peak in powder X-ray diffraction, the diffraction angle (2Θ), etc. change continuously. Is reversible. The extent of this change The crystal structure is stable to changes in the amount of water, even though they all show almost the same pattern.

 When the water content is about 0-5% (ie, when X is about 0-1.0), the type II crystal has a diffraction angle (2Θ) = 9.7-7.9.8, 13. 6, 16. 1-16. 2, 19. 4-19. 6, 20. 8-20. 9, 22.5-22. 6 and 27.4 show characteristic peaks (device Β)

 More specifically, when the water content is about 3 to 5% (ie, when X is about 0.6 to 1.0), the diffraction angle (26) = 9.8,13.6, 16. Has characteristic peaks at 1, 1 9. 6, 20. 8, 22. 6 and 27.4 (apparatus Β). For example, when the water content is about 0%, the diffraction angle (2 Θ) = 9.7, 1 3. 6, 14. ◦, 16. 2, 19. 4, 19. 9, 20. 9. 2) Has characteristic peaks at 5 and 27.4 (apparatus Β).

 Such II type crystals are included in the crystal of the compound represented by the formula (I-2) of the present invention regardless of the amount of water.

 Type II crystals can be obtained by, for example, heating a compound represented by the formula (I) (eg, about 70 to 80 ° C.) or alcohol having 1 to 8 carbon atoms (eg, ethanol, absolute ethanol, butanol). ) To obtain a saturated solution, and the resulting saturated solution is gradually cooled (for example, to 0 to 30 ° C.) and allowed to stand in the cooled state (for example, 1 to 60 days). it can. After cooling the solution containing the compound represented by the formula (I), a poor solvent may be added.

 In addition, the I-type crystal can be produced, for example, by dissolving the compound represented by the formula (I) in a good solvent to obtain a saturated solution, and gradually adding a poor solvent to the obtained saturated solution. After the poor solvent is added to the solution containing the compound represented by the formula (I), the solution may be cooled (for example, 0 to 10 ° C.), and is preferably cooled. Furthermore, it is preferable to store the cooled solution refrigerated (for example, 1 to 60 days at 0 to 1 °). As the good solvent used, methanol, ethanol, propanol, dimethyl sulfoxide, dimethylformamide, formamide, or the like is preferable. As the poor solvent, water, ether, isobutyl acetate and the like are preferable.

Furthermore, the type II crystal can also be produced, for example, by adding water to the type I crystal to form a slurry to be transferred to the type II crystal. The type II crystal can also be produced, for example, by adding water to a toluene solvate crystal of the compound represented by the formula (I) to form a slurry and transferring it to a type II crystal.

 Furthermore, the type II crystal is obtained by, for example, adding a poor solvent (eg, heptane) at 60 ° C. to a solution (preferably a saturated solution) obtained by dissolving the compound represented by the formula (I) in ethanol. It can also be produced by adding crystallization and cooling crystallization to 10 ° C.

 The I type I crystal can also be produced, for example, by removing a suitable solvate crystal of the compound represented by the formula (I) by a method such as heating. Furthermore, a type II crystal having a preferred moisture content is obtained by allowing a type II crystal from which water has been removed by, for example, heat drying to store and absorb moisture under normal conditions, preferably under humidified conditions. Therefore, it can be suitably manufactured.

 Alternatively, a type II crystal having a preferred moisture content can be suitably obtained by storing and releasing moisture of a type II crystal having a higher moisture content under normal conditions, preferably under low humidity conditions. Can be manufactured.

 Alternatively, a type I I crystal having a preferred water content can be suitably produced by heating and drying a type I I crystal having a higher water content to an appropriate level.

 Since type I crystals have high storage stability, they can be suitably used, for example, as pharmaceuticals (for example, sugar transport enhancing agents, hypoglycemic agents, antidiabetic agents, etc.), active pharmaceutical ingredients, and the like.

 In addition, type II crystals have a particularly favorable water content. Type II crystals have little change in water content under normal conditions (for example, in the environment during pharmaceutical production). Agents, antihyperglycemic agents, antidiabetic agents, etc.), and active pharmaceutical ingredients.

(Crystal of compound represented by formula (I 1 3))

Formula (I 1 3)

 ■ 1/2 CH3COOC2H5

 (1-3)

The crystal of the compound represented by formula (I) is an ethyl acetate solvate crystal of the compound represented by the formula (I), which is obtained by irradiation with copper Κ _α rays (wavelength λ = 1.54 angstroms). Diffraction peaks (2Θ) = 5.8, 1 1. 6, 1 8. 4, 1 9.5, 20. 5, 21.0, 21.9 and 22.8 (apparatus

Β)

 The water content of the crystal of the compound represented by the formula (I-13) is not necessarily constant depending on the drying conditions and storage conditions.

 The crystal of the compound represented by the formula (I 1 3) is obtained by, for example, dissolving a compound represented by the formula (I) in ethyl acetate heated (for example, about 50 to 80 ° C.) to obtain a saturated solution. The obtained saturated solution is gradually cooled (for example, to 0 to 30 ° C.) and allowed to stand in the cooled state (for example, 1 to 7 days).

 The crystal of the compound represented by the formula (I-13) is desolvated by heating (for example, about 160 ° C.) and transitions to the I-type crystal. Therefore, it can be used for the production of the I-type crystal. .

(Crystal of compound represented by formula (I 1-4))

 -Four)

■ 1/2 C ₆ H ₅ OCH ₃

 (1-4)

The crystal of the compound represented by formula (I) is a solvate crystal of the compound represented by formula (I). Yes, in powder X-ray diffraction obtained by irradiation of copper Ko! Line (wavelength = 1.54 angstroms), diffraction angle (2 Θ) = 5.8, 1 1. 6, 1 8. 4, 1 9. 3, 20. 4, 2 1. 0, 2 1. 8 and 2 2. 8

Β)

 The water content of the crystal of the compound represented by the formula (I-14) is not necessarily constant depending on the drying conditions and storage conditions.

 The crystal of the compound represented by formula (I-14) is prepared by, for example, dissolving the compound represented by formula (I) in a good solvent to form a saturated solution, and gradually adding anisol to the obtained saturated solution. Can be produced. It can also be produced by refrigerated storage (for example, 0 to 10 ° C. for 1 to 60 days) after adding the sole. The good solvent used is preferably dimethylformamide.

 The crystal of the compound represented by the formula (1-3) is desolvated by heating (for example, about 170 ° C.) and transitions to the I-type crystal. Therefore, it can be used for the production of the I-type crystal. it can.

(Crystal of compound represented by formula (1-5))

 1)

■ 1/2 C ₆ H ₅ CN

 (1-5)

The crystal of the compound represented by formula (I) is a benzo-tolyl hydrate crystal of the compound represented by the formula (I), and is obtained by powder X-ray diffraction obtained by irradiation with copper Κα rays (wavelength λ = 54 Å). , Diffraction angle (2 0) = 6. 2, 1 2. 4, 1 7. 6, 1 8.

Has characteristic peaks at 2, 20. 2, 20. 4, 20. 8, 2 1. 3 and 24.2 (device 装置).

The water content of the crystal of the compound represented by the formula (I 1-5) is not necessarily constant depending on the drying conditions and storage conditions. The crystal of the compound represented by the formula (I 1-5) is, for example, dissolved in benzonitrile obtained by heating (for example, about 70 to 90 ° C.) the compound represented by the formula (I) to form a saturated solution, The obtained saturated solution can be gradually cooled (for example, to 0 to 10 ° C.) and allowed to stand in the cooled state (for example, for 1 to 30 days).

 The crystal of the compound represented by the formula (1-5) is desolvated by heating (for example, about 170 ° C.) and transitions to the type I crystal. Therefore, it can be used for the production of the type I crystal. it can.

(Formula (I 1-6)

 1)

■ C ₄ H ₈ 0

 (1-6)

The crystal of the compound represented by formula (I) is a tetrahydrofuran hydrate crystal of the compound represented by formula (I). In the powder X-ray diffraction obtained by irradiation with copper Κα rays (wavelength = 1.54 angstroms). Diffraction angle (2Θ) = 7.1, 14.4, 19.9, 21.3, 22.5 and 23.7 have characteristic peaks (apparatus Α).

 The amount of water in the crystal of the compound represented by formula (1-6) is not necessarily constant depending on the drying conditions and storage conditions.

 The crystal of the compound represented by the formula (1-6) is, for example, dissolved in benzonitrile obtained by heating the compound represented by the formula (I) (for example, about 55 to 75 ° C) to form a saturated solution. The obtained saturated solution can be gradually cooled (for example, to 0 to 30 ° C.) and allowed to stand in the cooled state (for example, for 1 to 30 days).

(Crystal of the compound represented by the formula (I-7))

Formula (1-7)

 "C6H5CH3

 (1-7)

The crystal of the compound represented by the formula is a toluene solvate crystal of the compound represented by the formula (I), and is obtained by powder X-rays obtained by irradiation with copper K-wire (wavelength; 1 = 1.54 angstrom). In diffraction, diffraction angles (2 Θ) = 5.9, 8. 3, 11. 8, 14.5, 1 8.5, 21. 3, 22. 9 and 29.6 have characteristic peaks ( Device A).

 The moisture content of the crystal of the compound represented by the formula (I-7) is not necessarily constant depending on the drying conditions and storage conditions.

 Crystals of the compound represented by the formula (I-7) are obtained by adding toluene to a solution (preferably a saturated solution) obtained by dissolving the compound represented by the formula (I) in ethanol. Then, it can be produced by cooling crystallization (for example, up to 10 ° C.).

 Since the crystal of the compound represented by the formula (I 17) can be transferred to the II type crystal by adding water, it can be used for the production of the II type crystal.

 In the present invention, the peak value and the relative intensity value of the diffraction angle. (2Θ) of the powder X-ray diffraction pattern can allow an experimental error. More specifically, the 20 values described in the present invention are accurate in the range of 0.2 under the same measurement conditions. That is, when determining whether or not a crystal is a crystal according to the present invention, the range of ± 0.2 of the 26 values of the characteristic peak of 2 Θ 1S crystal of the present invention obtained experimentally for the crystal. If it is within the range, it is recognized as the same peak.

2. A medicine containing the crystal of the present invention

Since the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has excellent sugar transport enhancing action, hypoglycemic action, etc., the crystal of the present invention has a sugar transport enhancing action. Agent; hypoglycemic agent; diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetes It is useful as a medicine for the prevention and / or treatment of pathologic retinopathy, diabetic macroangiopathy, impaired glucose tolerance, or obesity.

 When the crystal of the present invention is used as a medicine, it can be used as a pharmaceutical composition, for example, orally, parenterally, intravenously, buccally, rectally, vaginally, transdermally, via the nasal route or via inhalation. Although it can, it is preferably administered orally. Pharmaceutical compositions for oral administration include tablets (including sugar-coated tablets, coated tablets, dry-coated tablets, sublingual tablets, intraoral patches, orally disintegrating tablets), pills, capsules (hard capsules, soft capsules) , Capsules, microcapsules), powders, granules, fine granules, troches, liquids (including syrups, emulsions and suspensions). Examples of the pharmaceutical composition for parenteral administration include injections, creams, ointments, suppositories and the like. Such a pharmaceutical composition can be produced, for example, by mixing with a pharmaceutically acceptable excipient, carrier, etc. according to a conventional method.

 Examples of pharmaceutically acceptable excipients and carriers include, for example, excipients in solid preparations, binders, disintegrating agents, lubricants; solvents in liquid preparations, solubilizers, suspending agents. , Buffers, thickeners, emulsifiers, etc. In addition, formulation additives such as coloring agents, seasonings, and antioxidants can be used as necessary.

 Examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, arsenic starch, dextrin, crystalline cellulose (for example, microcrystalline cellulose), low-substituted hydroxypropylcellulose, carboxy Examples include methylcellulose sodium, gum arabic, dextrin, pullulan, light anhydrous carboxylic acid, synthetic aluminum silicate and magnesium aluminate metasilicate. Examples of binders include pregelatinized starch, sucrose, gelatin, macrogol, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydrange Droxypropylcellulose (HPC), Hydroxypropylmethylcellulose (HP MC), Polyvinylpyrrolidone (Ρ

V P).

Disintegrants include, for example, lactose, sucrose, starch, carboxymethyl cellulose, canolepoxymethinorescenellose calcium, cross-linked polyvinylino pyrrolidone, force norellose sodium, croscarmellose sodium, canoleboxoxymethinorester These include sodium sodium, light anhydrous caustic acid, low-substituted hydroxypropyl cellulose, cation exchange resin, partially pregelatinized starch, and corn starch. Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, tanolec, waxes, colloidal silica, DL-leucine, sodium lauryl sulfate, magnesium lauryl sulfate, macrogol, and aerosil.

 Solvents include, for example, water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, medium chain fatty acid triglyceride (MCT), vegetable oil (eg safflower oil, sesame oil, corn oil, olive oil) Cottonseed oil, soy lecithin, etc.).

 Examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, trenosylose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium tamate, sodium salicylate, Examples thereof include sodium acetate. Examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; Hydrophilic polymers such as Polyvinylenopyrrolidone, Canoleboxymethinoresenorelose sodium, Metinorece / Rerose, Hydroxymethy / Recenorelose, Hydroxy Shetinorecellulose, Hydroxypropyl Cellulose; Polysorbates And polyoxyethylene hydrogenated castor oil.

 Examples of the buffer include buffer solutions such as phosphate, acetate, carbonate, citrate, and the like.

Examples of the thickener include natural gums and cellulose derivatives. Examples of the emulsifier include fatty acid esters (for example, sucrose fatty acid ester, glycerin fatty acid ester, sorbitan fatty acid ester, propylene glycol fatty acid ester, etc.), wax (for example, beeswax, rapeseed hydrogenated oil, safra-hydrogenated oil, palm Hydrogenated oil, sitosterol, stigmasterol, force mpesterol, brush casterol, cacao butter powder, carnauba wax, rice wax, molasses, paraffin, etc.), lecithin (eg egg yolk lecithin, large Bean lecithin).

 Examples of colorants include water-soluble edible tar dyes (eg, edible red No. 2 oppi 3, edible yellow No. 4 and 5, edible blue No. 1 oppi No. 2, etc., water insoluble Lake pigments (eg, aluminum salts of the above-mentioned water-soluble edible tar pigments), natural pigments (eg, J3—power rotin, chlorophyll, bengara, etc.).

 Examples of the sweetening agent include sucrose, lactose, sodium saccharin, dipotassium glycyrrhizinate, aspartame, stevia and the like.

 Examples of the antioxidant include sulfite, ascorbic acid and alkali metal salts thereof, alkaline earth metal salts, and the like.

 Tablets, granules, fine granules, etc. can be coated by a known method using a coating substrate for the purpose of masking taste, improving light stability, improving appearance or enteric properties, etc. Good. Examples of the coating base include a sugar coating base, a water-soluble film coating base, and an enteric film coating base.

 Examples of the sugar coating base include sucrose, and one or more kinds selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.

 Examples of water-soluble film coating bases include celluloses such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), ethinore senorelose, hydroxenochinoselenose, and methino lech dorochichinenoselenose. Polymers: Polyvinylacetal Jetylaminoacetate, Aminoalkyl methacrylate copolymer E (Eudragit E (registered trademark)) Synthetic polymers such as polyvinylpyrrolidone; Polysaccharides such as pullulan I can get lost.

Examples of enteric film coating bases include cellulosic polymers such as hydroxypropylmethylenorerose phthalate, hydroxypropinoremethylolosenolose acetate succinate, carboxymethylethyl cellulose, and cellulose acetate phthalate; Methacrylic acid copolymer L (Eudragit L (registered trademark)), Methacrylic acid copolymer LD (Eudragit L 1 3 0 D 5 5 (registered trademark)) Methacrylic acid copolymer S (Eudragit S (registered trademark)), etc. Talaric acid polymers; natural products such as shellac.

 These coating bases may be coated singly or as a mixture of two or more kinds in an appropriate ratio, or two or more kinds may be sequentially coated. The content of the crystal of the present invention in the medicament of the present invention is usually 0.01 to 100% by weight, preferably 1 to 99% by weight.

 In the compound of the present invention contained as an active ingredient in the medicament of the present invention, the proportion of the compound of the present invention that takes the form of crystals is preferably 50% or more, more preferably 95% or more. Particularly preferably, it is 98% or more.

 The dose of the crystal of the present invention may be within the range of the effective amount of the crystal of the present invention, such as a sugar transport enhancing action and a hypoglycemic action, and also varies depending on the target disease, administration subject, administration method, symptoms, etc. However, it is usually from about 0.001 to about 100 Omg per day per kilogram of body weight.

 More specifically, for example, when administered orally to a diabetic patient for the purpose of treating diabetes, about 0.01 to 100 mg of crystals of the present invention per day per kg of body weight, Preferably, 0.05 to 50 mg, more preferably 0.:! To 10 mg is applied. When administered parenterally, per day per kilogram of body weight, the crystals of the present invention are about 0.001 to 5 Omg, preferably 0.005 to 2 Omg, more preferably 0.01 to 1 Omg. Administer. Example.

 The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to these examples.

[Analysis conditions]

 The analysis in the following examples and test examples was conducted according to a conventional method using the following measuring apparatus.

 (1) Powder X-ray crystal diffraction

Device A:

Nippon Philips Co., Ltd. (currently Spectris Co., Ltd.) X 'PERT— M PD Or

Device B:

Rigaku Co., Ltd. R I NT 21 00 S

 Humidity controller: Shinei Co., Ltd. SRH-1R

 Drying conditions: measured while drying the sample under reduced pressure

 Humidity conditions: Measure humidity by placing saturated salt solution

 (2) Differential scanning calorimetry

Equipment: Seiko Instruments Inc. (Seiko Instr ume n ts In c.) DSC6200

 Reference: Empty aluminum pan

Sampling time: 0.2 seconds

Temperature increase rate: 10 ° CZ min

 (3) Water vapor adsorption / desorption measurement

Equipment: Nippon Bell Co., Ltd. BELSORP— 18

(4) One NMR and ¹³ C-NMR

Equipment: Bruker AVANCE 400

 PARIAN (VAR I AN) MARCURY 300

 (5) E S I—MS

Device: Thermo Quest TSQ 700 or Nihon Waters Z Q 2000

[Reference Example 1]

(1R, 8R, dish)-9-(2-hydroxyacetyl)-8-phenyl-2,5,9-triazatrisic [8.4.0.0 ³ ' ⁷ ] tetradeca-3 (7) -nin-6-one Synthesis of (compound represented by formula (I))

 (Step 1) Synthesis of 4-hydroxy-2-oxo-1, 2, 5-dihydro-1 H-pyrrole-3-strong rubonic acid methyl ester

In a 150 L reactor equipped with a stirrer, 29.3 L of methyl acetate, 4500 g (26.44 mol) of monoethyl ester monomalate malonate, 3690 g of glycine ethyl ester hydrochloride (26.4½ ol) was added. 2.25 L of methyl acetate was used for washing. The mixture was heated to 32 ° C, and 5490 g (99.4%, 26. 45 raol) of dicyclohexyl carpositimide dissolved in 2.51 L of methyl acetate was added over 1 hour and 19 minutes. . For washing, 0.90 L of methyl acetate was used. After stirring at 30 ° C for 20 hours, the precipitated solid was separated by a centrifuge and washed with 18 L of methyl acetate at 30 ° C.

 The filtrate was concentrated under reduced pressure until the liquid volume reached 27.3 L, 22.5 L of methanol was added, and the filtrate was concentrated under reduced pressure until the liquid volume reached 13.5 L. Further, 22.5 L of methanol was added, and after concentration under reduced pressure until the liquid volume became 15 L, 31.06 L of methanol was added. To this solution was added 5.48 L (26.98 mol) of a 28% sodium methoxide / methanol solution at 60 ° C, and the mixture was washed with 10.62 L of methanol. After stirring at 64 ° C for 5 hours, the mixture was cooled to 30 ° C and 15.96 L (31. 89 mol) of 2M hydrochloric acid was added. The solid precipitated after stirring at 30 ° C for 16 hours was separated by a centrifuge and washed with 21.31 L of a 30 ° C aqueous methanol solution (70% v / v). The obtained wet solid was dried under reduced pressure at 60 ° C. for 19 hours to obtain 3487 g of the title compound.

_{¾ NMR (400MHz, DMS0_d 6)} : δ 3. 63 (s, 3H, methyl ester), 3. 84 (s, 2H, 5- CH2).

 ESI-MS: ra / z 158 (M + H) +, 156 (M-H)-

(Step 2) 4-[(1 R, 2 R) 1 -2-aminocyclohexylamino] 1-3-ringoline 1-one hydrochloride synthesis

600 g of the compound obtained in Step 1 was added to 4.5 L of dimethylformamide and washed with 0.3 L of dimethylformamide. The mixture was heated to 100 ° C., 103 ml of water was added dropwise, and the mixture was stirred for 10 minutes. The this operation 5 batches performed each reaction, 5 to obtain a dimethylformamidine de solution ^D C to the cooled dimethyl Chiruhorumuami de 6. continue addition to OIL 4-hydroxy-2- Okiso 3 pylori emissions. Each patch was washed with 0.55 L of dimethylformamide.

(1R, 2R)-1,2-Diaminocyclohexane 2180g (19.09raol) was dissolved in dimethylformamide 7,5L, cooled to 6 ° C and 6M hydrochloric acid 3.18L (19.09mol) Added at 18 ° C. 18 L of the 4-hydroxy-2-oxo-1-pyrroline solution obtained above was added dropwise thereto. Seed crystals of the title compound (for example, obtained in the same manner as this method without using seed crystals) 11. 45 g (content 88.4%) was added, and the remaining 17 L of the solution was added dropwise. wash Dimethylformamide 0.6 L was used. After stirring at 6 ° C for 1 hour, 21.04 L of toluene was added dropwise over 45 minutes, and the mixture was further stirred for 21 hours. The precipitated solid was separated with a centrifugal separator, washed with 12 L of a 10 ° C dimethylformamide toluene mixed solution (volume ratio 50:50), and then washed with 12 L of toluene. The obtained wet solid was dried under reduced pressure at 60 ° C. for 16 hours to obtain 3924 g of the title compound.

¾ 匪 R (400MHz, DMSO-d ₆ ): δ 1.21 (m, 3H, cyclohexyl), 1.44 (ra, 1H, cyclohexyl), 1.67 (m, 2H, cyclohexyl), 1.93 (m, 1H, cyclohexyl), 2.05 (m, 1H, cyclohexyl), 2.90 (m, 1H, 2, — H), 3.08 (m, 1H, 1, 1 H), 3.79 (dd, 2H, J = 16, 7, 43.5Hz, 5— CH2 ), 4.58 (s, 1H, 3-H), 6.67 (brs, 1H, NH), 6.89 (m, 1H, NH), 8.23 (brs, 2H, NH2)

¹³ C NMR (100 MHz, DMSO—d ₆ ): δ 23.2, 23.7, 29.0, 30.6, 45.9, 53.4, 55.3,

86.6, 163.4, 176.7.

ESI-MS: m / z 196 (M + H) +, 194 (MH)-(Step 3) (1R, 8R, 10R)-8-phenyl-2,5,9-triazatricyclo [8,4.0 .0 ³ ' ⁷ ] Synthesis of Tetradeca-3 (7) -en-6-one

 27.8 g of the compound obtained in step 2 in 150 mL of methanol (content 89.8 ° 107.7 mmol),

20.7 mL (102. lmmol) of 28% sodium methoxide / methanol solution and 442 mg (5.4 mmol) of sodium acetate were added and stirred for 30 minutes.

 To this mixture was added benzaldehyde 12. OmL (118.5 mmol), and the mixture was heated and stirred at 60 ° C. for 14 hours, and then concentrated under reduced pressure to about 130 mL. The precipitated sodium chloride was filtered and washed with 42.4 mL of methanol, and the filtrate was concentrated under reduced pressure to a liquid volume of about 10 mL.

 The procedure of adding 260 mL of 2-propanol and concentrating under reduced pressure was performed in three steps, and then the liquid volume was adjusted to about llOmL. The obtained liquid was kept at 50 ° C for 1 hour, cooled to 10 ° C over about 4 hours, and further kept at 10 ° C for about 10 hours. The precipitated solid was filtered and washed with 84.9 mL of 2-propanol cooled to 10 ° C. The obtained wet solid was dried under reduced pressure at 60 ° C. to obtain 21.40 g (content 88.3%) of the title compound.

¾ Rei R (300MHz, DMS0-d ₆ ): δ 0.50-3.40 (10mm, m), 3.69 (1H, d, J = 16.0Hz), 3.84 (1H, d, J = 16.0Hz), 4.79 (1H, s), 6.32 (1H, s), 6.75 (1H, s), 7.10-7.30 (5H, m). ESI-MS: m / z 284 (M + H) + (Step 4) (1R, 8R, 10R) -5,9-bis (2-acetoxyacetyl) -8-phenyl-2,5,9-triazatricyclo [8.4.0.0 ³ ' ⁷ ] Synthesis of tetradeca-3 (7) -en-6-one

 To 130 mL of acetonitrile, 17.1 mL (159. 1 mmol) of acetylacetyl chloride was added at 10 ° C., followed by 19.50 g (content 92.3%, 63.5 mmol) of the compound obtained in Step 3. To this, 24 mL (172.2 mmol) of triethylamine dissolved in 50 mL of acetonitrile was added dropwise at 10 to 13 ° C. over 1 hour. After stirring at 10 ° C for 3 hours, 108 mL of water was added to stop the reaction. Acetonitrile was distilled off under reduced pressure, followed by extraction with ethyl acetate, and the organic layer was washed with an aqueous sodium bicarbonate solution (6.9 wt%) and concentrated under reduced pressure. Ethyl acetate was added to the concentrated solution and concentrated under reduced pressure twice, and then ethyl acetate was added so that the liquid volume became about llOmL. After raising the temperature to 55 ° C, add 18 mg of seed crystals of the title compound (for example, obtained in the same manner as this method without using seed crystals), hold for 1 hour at 55 ° C, and then add heptane (5% 2-propanol Contained) 123 mL was added dropwise over 1 hour. It was kept at 55 ° C for 1 hour, cooled to 10 ° C over about 4.5 hours, and further kept at 10 ° C for about 8 hours. The precipitated solid was filtered and washed with 36 mL of an ethyl acetate-heptane mixed solution (volume ratio 40:60) cooled to 10 ° C. The obtained wet solid was dried under reduced pressure at 60 ° C. to obtain 24.12 g (content 97.0%) of the title compound.

¾ NMR (400MHz, MeOH-d ₄ ) δ: 0.76 (1Η, br-dd), 1.14 (1H, br-dd), 1.23 (1H, br-dd), 1.34 (1H, br-d), 1.58 ( 2H, br—dx2), 2.08 (1H, br—d), 2.10 (3H, s), 2.15 (3H, s), 2.59 (1H, br-dd), 2.90 (1H, ddd), 4.19 (1H, ddd), 4.35 (1H, d), 4.41 (1H, d), 4.77 (1H, d), 5.17 (1H, d), 5.17 (2H, s), 5 · 78 (1H, br—s), 7.37 (1H, dd), 7.41 (4H, m).

¹³ C NMR (100 MHz, MeOH-d ₄ ) δ: 29.18, 35.09, 48.91, 56.50, 59.05, 61.04, 63.74, 64.89, 95.22, 128.92, 129.27, 129.82, 138.53, 159.77, 167.85, 169.04, 171.71, 172.30, 172.39 .

ESI- MS: ra / z 484 (M + H) ⁺ , 482 (M-H)

(Step 5) (1R, 8R, 10R) - 9-(2 - hydroxy § cetyl) -8 - Hue - Honoré - 2, 5, 9 - tri Azatorishikuro [8.4.0.0 ^{3 '7]} tetradec - 3 (7) Synthesis of -en-6-one (compound represented by formula (I)) To the ethanol 86 mL, add 22.16 g of the compound obtained in step 4 (content: 9 ° 0 °, 44.5 mmol), 28% sodium methoxide / methanol solution 1.6 raL (8. Ommol), and add at 25 ° C for 1 hour. Stir. After concentration under reduced pressure, ethanol was added to adjust the solution weight to 58.4 g. After raising the temperature to 50 ° C., 109.7 mL of water was added dropwise over 1 hour, and 15 mg of the title compound seed crystal (for example, obtained in the same manner as in this method without using the seed crystal) was added. After cooling to 40 ° C over 1 hour and holding at 40 ° C for 1 hour, 54.8 mL of water was added dropwise over 1 hour. It was kept at 40 ° C for 1 hour, cooled to 10 ° C over 3 hours, and further kept at 10 ° C for 5.2 hours. The precipitated solid was filtered and washed with ethanol / water mixed solution cooled to 10 ° C (volume ratio 25:75) 30. ImL. The obtained wet solid was dried under reduced pressure at 60 ° C. to obtain 14.33 g of the title compound.

¾ negation _{R (300MHz, DMSO- d 6)} :.. Δ 0. 50-2 72 (9H, m), 3. 75-4 05 (4H, m), 4. 42 (1H, m), 4. 72 (lH, m), 5.54 (1H, s), 6.74 (1H, s), 6.80 (1H, s), 7.22-7.37 (5H, m).

ESI-MS: m / z 342 (M + H) + [Example 1]

Production of type I crystals by crystallization from dichloromethane solution

 (1R, 8R, 10R)-9-(2-Hydroxycetinole) -8-Fueninole-2, 5, 9-Triazatricyclo [8. 4. 0. 03, 7] Tetradeca-3 (7 ) About 20-30 mg of -en-6-one was dissolved in about 3 mL of dichloromethane heated to about 60 ° C. Then, it was left to stand in a refrigerator (about 0 to 10 ° C) for 10 days, and the precipitated crystals were collected by suction filtration using a Kiriyama funnel. The crystals were vacuum-dried at about 60 ° C. to obtain about 13 mg of crystals. A powder X-ray diffraction spectrum of the obtained crystal was measured and confirmed to be an I-type crystal.

[Example 2]

Production of type I crystals by desolvation of ethyl acetate solvate crystals

 (Step 1) Production of ethyl acetate hydrate crystals

(1R, 8R, 10R)-9- (2-Hydroxycetyl) -8-phenyl-2,5,9-triazatricyclo [8. 4. 0. 03, 7] tetradeca-3 (7) 6-on about 15-20 mg about 7-8. Dissolved in about 1.5 mL of ethyl acetate heated to C. Then, it was left to stand at room temperature for 1 day, and the precipitated crystals were collected by suction filtration using a Kiriyama funnel. About 60 ° C After vacuum drying, about 5 mg of crystals were obtained.

A powder X-ray diffraction spectrum (FIG. 1) and ¹ H-NMR spectrum of the obtained crystals were measured and confirmed to be about 0.5 ethyl acetate.

— NMR (400MH z, CD ₃ OD) δ = 0.7 5-0. 8 1 (1 Η, m), 1. 07-1. 16 (1 Η, m), 1. 22— 1. 37 (2Η , m), 1.26 (1.5H, t, J = 7.1 Hz), 1.58 (2H, d, J = 1 1. OH z), 2.03 (1.5H, s), 2 05 (1 H, d, J = 1 1.8H z), 2. 66-2. 90 (2H, m), 4.01 (2H, dd, J = 3 1. 7, 17. 0Hz), 4. 09-4. 1 3 (1 H, m), 4. 1 2-4. 1 9 (2H, m), 4.62 (1H, d, J = 1 5. 2H z), 5. 72 (1 H, s), 7. 30-7. 41 (5H, m).

(Step 2) Desolvation of ethyl acetate solvate crystals

 The ethyl acetate hydrate crystals obtained in Step 1 were heated to about 160 ° C. to remove the solvent. As a result of measuring the powder X-ray diffraction spectrum of the obtained crystal, it was confirmed to be a type I crystal (Fig. 1).

[Example 3]

Preparation of type I crystals by desolvation of anisolate crystals

 (Step 1) Manufacture of a solvate crystal.

 (1R, 8R, 10R)-9- (2-Hydroxycetyl) 8-phenyl-2,5,9-triazatricyclo [8.4.0.03, 7] tetradeca-3 (7) -en-6-one About 96 Omg was dissolved in about 9 mL of dimethylformamide at room temperature and filtered through a filter to prepare a saturated solution. While stirring with a stirrer, about 1 HI of this saturated solution was gradually added with anisole (total of about 2.5 mL), and the crystals precipitated immediately after the addition were collected by suction filtration using a Kiriyama funnel. The crystals were vacuum dried at about 60 ° C. to obtain about 10 Omg of crystals.

The powder X-ray diffraction spectrum (Fig. 2) and ¹ H-NMR spectrum of the obtained crystals were measured, and it was confirmed that the obtained crystals were about 0.5 sol.

'H-NMR (40 OMH z, CD ₃ OD) δ = 0.75-0.78 (1 H, m), 1. 09- 1.13 (1H, m), 1. 26— 1. 33 (2H, m),

1. 58 (2H, d, J = 1 1.5 H z), 2. 05 (1H, d, J = 1 2.6

Hz), 2.66-2.90 (2H, m), 3.80 (1.5 H, s), 4.0

2 (2H, dd, J = 29.9, 16.9Hz), 4. 12-4.16 (2H, m), 4.62 (1H, d, J = 15.2Hz), 5. 72 (1 H, s), 6. 90-6. 93 (1.5 H, m), 7.25-7.29 (1 H, m), 7.25 1 7.41 (5H, m) .

(Step 2) Desolvation of solvate crystals

 The solvate crystals obtained in Step 1 were heated to about 170 ° C to remove the solvent, and the powder X-ray diffraction spectrum of the obtained crystals was measured. It was confirmed to be a type I crystal (Fig. 2).

[Example 4]

Preparation of type I crystals by desolvation of benzonitrile solvate crystals

 (Step 1) Production of benzonitrile solvate crystals

 (1R, 8R, 10R) -9- (2-Hydroxycetyl) -8-phenol-2,5,9-triazatric port [8.4.0.03, 7] tetradeca-3 (7) -en-6 -About 270-300 mg of ON was dissolved in about 2 mL of benzo-tolyl heated to about 79 ° C. After that, it was left to stand for 17 days in a refrigerator (about 0.0 to 10 ° C.), and the precipitated crystals were collected by suction filtration using a Kiriyama funnel. The crystals were vacuum-dried at about 60 ° C. to obtain about 11 mg of crystals.

A powder X-ray diffraction spectrum (Fig. 3) and ¹ H-NMR spectrum of the obtained crystal were measured and confirmed to be about 0.5 benzoethryl.

'H-NMR (40 OMH z, CD ₃ OD) δ = 0.7 1—0.8 1 (1 H, m), 1.06— 1.16 (1 H, m), 1.22 — 1 37 (2H, m), 1.58 (2H, d, J = 1 1. 8H z), 2. 05 (1 H, d, J = 1 2.6 Hz), 2. 66-2. 90 (2H, m), 4.01 (2H, dd, J = 32.2, 17. OH z), 4.1 3-4. 16 (2H, m), 4.62 (1 H, d, J = 15.2H z), 5.72 (1H, s), 7.30-7.40 (5H, m) _: 7.55-7.76 (2.5H, m). (Step 2) Desolvation of benzonitrile solvate crystals

 The benzonitrile solvate crystal obtained in Step 1 was heated to about 170 ° C to remove the solvent, and as a result of measuring powder X-ray diffraction, it was confirmed to be a type I crystal (Fig. 3).

[Example 5]

Production of type I crystals by crystallization from aqueous solution.

 (1R, 8R, 10R) -9 (2-Hydroxycetyl) 8-Fueru 2, 5, 9-Triazatric port [8.4.0.03, 7] Tetrade force-3 (7) -Yen-6 -About 1000 mg of ON was dissolved in about 1 65 mL of water heated to about 80 ° C. Then, it was refrigerated for 2 days (about 0 to 10 ° C), and the precipitated crystals were collected by suction filtration using a Kiriyama funnel. The crystals were vacuum-dried at about 60 ° C to obtain about 56 Omg crystals. A powder X-ray diffraction spectrum of the obtained crystal was measured to confirm that it was an I-type crystal. [Example 6]

Production of type I crystals by crystallization from ethanol solution ''

 (1R, 8R, 10R) -9- (2-Hydroxycetyl) -8-phenyl-2,5,9-triazatricyclo [8.4.0.03, 7] tetradeca-3 (7) -en-6-one approx. 790-860 mg was dissolved in about 2 mL of ethanol heated to about 77 ° C. Then, it was allowed to stand at room temperature for 1 day, and further refrigerated for 14 days (about 0 to .10 ° C). The precipitated crystals were collected by suction filtration using a Kiriyama funnel. The crystals were vacuum dried at about 60 ° C. to obtain about 51 Omg of crystals. The powder X-ray diffraction spectrum of the obtained crystal was measured and confirmed to be II type crystal. [Example 7]

Production of type I crystals by crystallization from absolute ethanol solution

(1R, 8R, 10R) -9- (2-Hydroxycetyl)-8-phenyl-2,5,9-triazatricyclo [8.4.0.03, 7] tetradeca-3 (7) -en-6-one approx. Approximately 78 to 460 mg. Dissolved in about 1 mL of absolute ethanol heated to C. Then, leave it at room temperature for 3 days, and store it in the refrigerator for another 5 days (about 0 ~ 10 ° C), and suck the precipitated crystals with a Kiriyama funnel. Filtered and collected. The crystals were vacuum dried at about 60 ° C. to obtain about 4 Omg crystals. A powder X-ray diffraction spectrum of the obtained crystal was measured and confirmed to be a type II crystal. [Example 8]

Production of type I crystals by crystallization from butanol solutions.

 (1R, 8R, 10R) -9- (2-Hydroxycetyl) -8-phenyl-2,5,9-triazatric port [8.4.0.03, 7] tetradec-3 (7) -en-6-one About 190-200 mg was dissolved in about 1.5 mL of butanol heated to about 78 ° C. Then, it was left to stand at room temperature for 2 days, and the precipitated crystals were collected by suction filtration using a Kiriyama funnel. The crystals were vacuum-dried at about 60 ° C. to obtain about 1 10 mg of crystals. After refrigerated for about 1 and a half months (about 0 to 10 ° C), the powder X-ray diffraction spectrum of the obtained crystal was measured to confirm that it was an I I type crystal. [Example 9]

Production of type I crystals by adding water to methanol solutions.

 (1R, 8R, 10R) -9- (2-Hydroxycetyl) -8_phenyl-2,5,9-triazatricyclo [8.4.0.03, 7] tetradeca-3 (7) -en-6- About 17 mg of ON was dissolved in about 3 mL of methanol at room temperature and filtered through a filter to prepare a saturated solution. While stirring with a stirrer, slowly add water to about 1 mL of this saturated solution (about 2 mL in total) and store in the refrigerator for about 1 day (about o to io ° c). Using suction filtration, it was collected. The crystals were vacuum dried at about 60 ° C. to obtain about 2 Omg of crystals. A powder X-ray diffraction spectrum of the obtained crystal was measured and confirmed to be an I-type crystal.

[Example 10]

Preparation of type I crystals by adding water to ethanol solutions.

(1R, 8R, 10R) -9- (2-Hydroxycetyl) -8-phenenole-2,5,9-triazatricyclo [8.4.0.03,7] tetradeca-3 (7) -en-6-one approx. 28 Omg was dissolved in about 2.5 mL of ethanol at room temperature and filtered through a filter to prepare a saturated solution. Star ^ "La Gradually add water to about 1 mL of this saturated solution while stirring at the same time (about 2.5 mL in total) and store in the refrigerator for 1 day. The precipitated crystals were collected by suction filtration using a Kiriyama funnel. . The crystals were vacuum-dried at about 60 ° C for 1 B to obtain about 70 mg of crystals. A powder X-ray diffraction spectrum of the obtained crystal was measured and confirmed to be a type II crystal.

[Example 1 1]

Preparation of type I crystals by the addition of ether to ethanol solutions.

 (1R, 8R, 10R) _ 9- (2-Hydroxycetyl)-8-phenyl-2, 5, 9-triazatricyclo [8.4.0.03, 7] tetradeca-3 (7) -en-6- About 28 Omg of ON was dissolved in about 2.5 mL of ethanol at room temperature and filtered through a filter to prepare a saturated solution. While stirring with a stirrer, ether is gradually added to about ImL of this saturated solution (about 5 mL in total), and refrigerated for 1 day (about 0 to 10 ° C). And suction filtered. The crystals were vacuum-dried at about 60 ° C for 1 to 3 ¾ to obtain a trace amount of crystals. A powder X-ray diffraction spectrum of the obtained crystal was measured and confirmed to be an I-type crystal.

[Example 1 2]

Production of type I crystals by adding water to propanol solutions.

 (1R, 8R, 10R) -9- (2-Hydroxyacetyl) -8-phenyl-2,5,9-triazatricyclo [8.4.0.03,7] tetradeca-3 (7) -en-6-one approx. 15 Omg was dissolved in about 1.5 mL of propanol at room temperature and filtered through a filter to prepare a saturated solution. While stirring with a stirrer, gradually add water to about 1.5 mL of this saturated solution (total of about 2 OmL) and store in a refrigerator for about 6 days (about 0 to 10 ° C). The solution was collected by suction filtration using a funnel. The crystals were vacuum dried at about 60 ° C. overnight to obtain about 5 Omg of crystals. A powder X-ray diffraction spectrum of the obtained crystal was measured and confirmed to be II type crystal.

[Example 1 3]

Preparation of type I crystals by addition of ether to propanol solutions.

(1R, 8R, 10R) -9- (2-Hydroxycetyl) -8-phenyl-2,5,9-triazatrici Chromium [8.4.0.03, 7] tetradeca-3 (7) -en-6-one About lO Omg was dissolved in about ImL of propanol at room temperature and filtered through a filter to prepare a saturated solution. While stirring with a stirrer, ether is gradually added to about 1 mL of this saturated solution (about 5 mL in total) and stored refrigerated for 8 days (about 0 to 10 ° C). Using suction filtration, it was collected. The crystals were vacuum dried at about 60 ° C. to obtain about 50 mg of crystals. A powder X-ray diffraction spectrum of the obtained crystal was measured and confirmed to be a type II crystal.

[Example 14]

Preparation of type I crystals by addition of isobutyl acetate to propanol solutions.

 (1R, 8R, 10R)-9- (2-Hydroxycetyl) -8-phenyl-2,5,9-triazatricyclo [8.4.0.03, 7] tetradeca-3 (7) -en-6- About 90 Omg of ON was dissolved in about 8 mL of propanol at room temperature and filtered through a filter to prepare a saturated solution. While stirring with a stirrer, gradually add isoptil acetate to about 1 mL of this saturated solution (about 30 mL in total) and store in the refrigerator for 8 days (about 0 to 10 ° C). Using suction filtration, it was collected. The crystals were vacuum dried at about 60 ° C. to obtain about 5 mg of crystals. A powder X-ray diffraction spectrum of the obtained crystal was measured to confirm that it was an I-type crystal. [Example 1 5]

Preparation of type I crystals by adding water to dimethyl sulfoxide solution.

(1R, 8R, 10R) -9- (2-Hydroxycetyl) -8-phenolinore 2, 5, 9-triazatricyclo [8.4.0.03, 7] tetradeca-3 (7) -ene -6- About 184 Omg of ON was dissolved in about 3.5 mL of dimethyl sulfoxide at room temperature and filtered through a filter to prepare a saturated solution. While stirring with a stirrer, gradually add water to about ImL of this saturated solution (total of about 0.8mL) and store in a refrigerator for about 1 day (about 0 to 10 ° C). Suction the precipitated crystals using a Kiriyama funnel. Filtered and collected. The crystals were vacuum dried at about 60 ° C. overnight to obtain about 21 Omg of crystals. A powder X-ray diffraction spectrum of the obtained crystal was measured and confirmed to be a type II crystal. [Example 16]

Preparation of type I crystals by adding water to dimethylformamide solution.

 (1R, 8R, 10R) -9- (2-Hydroxycetyl) -8-Fer-2, 5, 9-Triazatricyclo [8.4.0.03, 7] Te 1, Rade force-3 (7) About 96 Omg of N-6-one was dissolved in about 9 mL of dimethylformamide at room temperature and filtered through a filter to prepare a saturated solution. While stirring with a stirrer, gradually add water to about 1 mL of this saturated solution (about 2 OmL in total) and store in the refrigerator for 6 days (about 0 to 10 ° C). The precipitated crystals are suction filtered using a Kiriyama funnel. And collected. The crystals were vacuum dried at about 60 ° C. to obtain about 4 Omg of crystals. The powder X-ray diffraction spectrum of the obtained crystal was measured and confirmed to be II type crystal.

[Example 1 7]

Preparation of type I crystals by adding water to formamide solution.

 (1R, 8R, 10R) -9- (2-Hydroxycetyl)-8 -Ferr-2,5,9 -Triazatricyclo [8.4.0.03, 7] tetrade force-3 (7) -En-6 _ About 1 3 Omg of ON was dissolved in about 1.5 mL of formamide at room temperature and filtered through a filter to prepare a saturated solution. While stirring with a stirrer, gradually add water to about 1 mL of this saturated solution (about 20 mL in total) and store in a refrigerator for about 14 days (about 0 to 10 ° C). Using suction filtration, it was collected. The crystals were vacuum-dried at about 60 ° C. to obtain about 25 mg of crystals. A powder X-ray diffraction spectrum of the obtained crystal was measured and confirmed to be an I-type crystal.

[Example 18]

 Production of type I crystals by adding water to type I crystals

Add approximately 5 mL of water to approximately 100 mg of each sample of type I crystal, stir at approximately 25 ° C for 10 minutes, 1 hour, 2 hours, 3 hours, and 4 hours respectively in a supersaturated state, then filter, Crystals were obtained by vacuum drying at about 60 ° C. Powder X-ray diffraction was measured for each crystal and all were confirmed to be type II crystals. [Example 1 9] Addition of water to type II crystals

 About 5 mL of water was added to approximately 10 mg of a sample of type II crystals, stirred at approximately 25 ° C for 4 hours in a supersaturated state, filtered, and vacuum dried at approximately 60 ° C overnight to obtain crystals. . The powder was measured by powder X-ray diffraction and confirmed to be II type crystal. As a result, it was confirmed that the I-type crystals did not transfer when water was added.

[Example 20]

Production of tetrahydrofuran solvate crystals

 (1R, 8R, 10R)-9- (2-Hydroxycetyl) -8 -Fer-2, 5, 9 -Triazatricyclo [8.4.0.03, 7] Tetradeca-3 (7) -Yen -6- About 10 to 2 Omg of ON was dissolved in about 1.5 mL of tetrahydrofuran heated to about 65 ° C. Then, it was left to stand at room temperature for 1 day, and the precipitated crystals were collected by suction filtration using a Kiriyama funnel. The crystals were vacuum-dried at about 60 ° C to obtain about 6 mg of crystals.

The obtained crystals were measured by powder X-ray diffraction spectrum (FIG. 4) and ¹ H-NMR spectrum, and confirmed to be a tetrahydrofuran solvate.

'Η- -NMR (4 0 OMH z, CD ₃ OD) δ = 0.75-0.78 (1 H, m), 1.0 0-1. 1 6 (1 H, m), 1 22 1 1. 3 6 (2H, m),

1. 58 (2H, d, J = 1 0. 3H z), 1. 8 7 1 1. 9 1 (2H, m),

2. 0 5 (1 H, d, J = 1 2.6 Hz), 2. 6 6 1 2. 8 9 (2H, m),

3. 73- 3. 76 (2H, m), 4.0 2 (2H, d d, J = 3 1. 4, 1 '

OH z), 4.1 2-4. 1 6 (2H, m), 4.6 2 (1 H, d, J = 1 5.

2H z), 5. 7 2 (1 H, s), 7. 3 0-7. 4 1 (5 H, m).

[Example 2 1]

Manufacture of tolene hydrate crystals by adding toluene to ethanol solution

(1R, 8R, 10R) -9- (2-hydroxyacetyl) -8-phenol-2,5,9-triazatricyclo [8, 4.0.03, obtained by the method described in Reference Example 1 [7] Tetrade force-3 (7) -en-6-one 20 5 g was dissolved in 55 5 mL of ethanol at about 55 ° C. While stirring with a stirrer, 2038 mL of toluene was added to this solution at 50 ° C., and when type II crystals were inoculated, crystallization occurred. Add 7mL of toluene 73 After the addition, it was cooled to 1 ° C. and aged overnight. The precipitated crystals were separated using a centrifugal filter. A part of the crystals (1.2 g) was vacuum dried at 40 ° C for a while to obtain 1. O g crystals. Powder X-ray diffraction spectrum (Fig. 5) and ¹ H-NM R spectrum of the obtained crystals were measured and confirmed to be toluene solvate crystals. — NMR (400MHz, DMSO— d ₆ ) 6 = 0.50-2.72 (9H, m), 2. 30 (2.6 H, s), 3. 75-3. 99 (4H, m), 4 42-4. 4 7 (lH, m), 4. 74-4. 77 (1 H, m), 5. 56 (1H, s), 6. 77 (1H, s), 6. 83 (1H , s), 7.23-7.37 (5H, m), 7.23-7.29 (4.3H, m).

[Example 22]

 Production of type I crystals from toluene solvate crystals

 80 of about 250 g of toluene hydrate prior to drying, obtained in the same manner as described in Example 21. C. Vacuum dried. When the powder X-ray diffraction spectrum was measured, the dried crystals remained as the Tolen hydrate. 1370 mL of water was added to the dried crystals, and the mixture was stirred in a slurry state at 25 ° C. for 1.5 hours, and then separated by a centrifugal filter. The powder X-ray diffraction spectrum of the crystal obtained by vacuum drying at 60 ° C overnight was measured, and it was confirmed that it was converted to II type crystal. [Example 23].

 I Manufacture of type I crystals

 54 g of type I I crystals obtained in the same manner as in Example 22 was melted at 68 ° C. in a mixed solvent of 102 mL of ethanol and 51 mL of water. After filtration, the mixture was cooled to 50 ° C. or lower, and 14 mL of water was added with stirring with a stirrer to inoculate type I I crystals. After aging at 40 ° C. for 1.5 hours, crystallization occurred. Further, 140 mL of water was added and cooled to 10 ° C. The precipitated crystals were suction filtered using a Kiriyama funnel and dried to an appropriate level (12 hours at 30 ° C. 2 kPa) to obtain 50 g of dried crystals. The obtained crystals were confirmed to be II-type crystals containing about 4% water from the moisture measurement by the force-fisher method and the measurement of the powder X-ray diffraction spectrum.

In addition, after sufficient drying, type II with a water content of about 0% was obtained in the same manner as above. Crystals could also be obtained.

[Example 24]

Preparation of type I crystals by addition of heptane to ethanol solution

 (1R, 8R, 10R) -9- (2-Hydroxyacetyl) -8-phenol-2,5,9-triazatricyclo [8.4.0.03,7] tetradeca-3 (7) -en-6 -2 g of ON was dissolved in 3 2 OmL of ethanol at 45 ° C and then cooled to 30 ° C. While stirring with a stirrer at 30 ° C, 464 mL of heptane was added, and then type I crystals were inoculated. Further, 1 76 mL of heptane was added, and after crystallization was confirmed, the mixture was aged at 30 ° C for 1 hour. Subsequently, after adding 640 mL of heptane and aging for 1 hour, the mixture was cooled to 10 ° C. and stirred for one hour. The precipitated crystals were collected by suction filtration using a Kiriyama funnel. The crystals were vacuum-dried at 60 ° C. to obtain 32 g of crystals. A powder X-ray diffraction spectrum of the obtained crystal was measured and confirmed to be an I-type crystal. [Example 2 5]

Preparation of type I crystals by addition of heptane to ethano-nore solutions.

(1R, 8R, 10R) -9- (2-Hydroxyacetyl)-8 -Ferle 2, 5, 9-Triazatrisic [8.4.0.03, 7] Tetradeca-3 (7) -En-6 -After dissolving 5 g of ON in 22 mL of ethanol at 60 ° C, 47 mL of heptane was added while stirring with a stirrer to inoculate type I crystals. After aging for 1 hour at 60 ° C, crystallization was confirmed. After cooling to 50 ° C. and further adding 19 mL of heptane, the mixture was cooled to 10 ° C. and stirred. The precipitated crystals were collected by suction filtration using a Kiriyama funnel. The crystals were vacuum-dried at 60 ° C for 1 B to obtain 4.3 g of crystals. A powder X-ray diffraction spectrum of the obtained crystal was measured to confirm that it was an II type crystal.

[Test Example 1]

 Physical property data of type I crystals

Fig. 6 shows the powder X-ray diffraction spectrum of the type I crystal, and Fig. 7 shows the differential scanning calorimetry (DSC) chart. [Test Example 2]

 Water vapor adsorption / desorption measurement of type I crystals

 About 10 Omg of type I crystals were collected and dried in a vacuum at about 50 ° C. Then, the moisture adsorption amount was measured at a constant temperature of about 25 using a fully automatic water vapor adsorption measuring device. As a result, the amount of moisture adsorbed continuously increased with increasing relative humidity. The results are shown in FIG.

[Test Example 3]

 Storage stability test of type I crystals

 It preserve | saved in the constant temperature and humidity tank of 25 degreeC60% RH and 40 degreeC75% RH. Storage at 25 ° C 60% RH was carried out for up to 18 months. Storage at 40 ° C and 75% RH was completed in 6 months. In any condition, no significant increase or decrease in impurities was observed after storage.

 The results are shown in Table 1 (25 ° C 60% RH) and Table 2 (40 ° C75% RH). [table 1 ]

[Table 2]

Loss on drying (%) 0.3 0.7 0.8

 Quantitative (%) 99.9 99.9 99.9

 Powder X-ray Type I crystal Type I crystal Type I crystal

[Test Example 4]

 I Physical properties data of type I crystals

 Fig. 9 shows a powder X-ray crystal diffraction spectrum of a type II crystal (water content of about 3-5%), and differential scanning calorimetry (DS C) of the type II crystal obtained by the method described in Example 5 Figure 10 shows these charts. In the DSC chart, a broad endothermic peak with a peak near 90 degrees is considered to correspond to the disappearance of water, and supports the fact that this crystal is a hydrated substance.

 In addition, powder X-ray diffraction was measured by changing the humidity conditions stepwise from vacuum to ambient humidity conditions, and a continuous spectrum shift was confirmed. Fig. 11 shows the results of powder X-ray diffraction measurements after standing for 60 minutes under vacuum.

[Test Example 5

 I Water vapor adsorption / desorption measurement of type I crystals

 About 100 ig of type II crystals obtained by the method described in Example 6 were collected, vacuum-dried overnight at about 50 ° C, and then used at a constant temperature of about 25 ° C using a fully automatic water vapor adsorption measuring device. Then, the moisture adsorption amount was measured. As a result, the amount of moisture adsorbed increased continuously with increasing relative humidity, but the rate of increase tended to decrease from around 4%. The results are shown in FIG.

[Test Example 6]

 I Moisture content of type I crystals over time

From the results of moisture absorption / desorption measurement in Test Example 5, it was recognized that the type II crystal was most stable when the water content was around 4-5%. Therefore, the type II crystal (sample 1) with a water content of 4-5% A well-dried type II crystal (specimen 2) was stored at a constant relative humidity of 11% RH to 84% RH, and the change in moisture content over time was confirmed. For sample 1, after confirming that the initial moisture content was 4.4%, about 11% RH (under a saturated solution of lithium chloride monohydrate), about 33% RH (magnesium chloride hexahydrate) ) And about 84% RH (under a saturated solution of potassium chloride) in an open system. The water content of each specimen was measured after 1, 6 and 26 hours of storage.

 The specimen that was vacuum-dried at 60 ° C for 2 hours was designated as specimen 2, and the water content was measured and confirmed to be 0.2%. After that, it was stored in an open system at about 60% RH (in a constant temperature and humidity chamber of 25 ° C 60% RH) and 84% RH (under a saturated solution of potassium chloride). The water content of each specimen was measured after 1, 6 and 26 hours of storage.

 The Karl Fischer measurement device (Mitsubishi Chemical Corporation CA-06) was used for the measurement of water content.

 The results are shown in Fig. 13.

 As a result, the specimen with the initial moisture content of 4.4% (Sample 1) is 3-5 ° / at any relative humidity. It was confirmed that the crystal was easy to handle, having a moisture content within a certain range, having little fluctuation in moisture content, and being hardly affected by humidity during weighing. In addition, it was confirmed that the dried crystals became water-containing crystals having a water content in the above range under normal or humid conditions.

[Test Example 7]

 I Storage stability test of type I crystals

 I Type I crystals were stored in a thermostatic chamber at 25 ° C 60% RH and 40 ° C 75% RH. 2 Storage at 5 ° C6 0% RH was performed for up to 12 months. Four

Storage at 0 ° C7 5% RH ended the study in 6 months. Under any condition, no significant increase or decrease in impurities was observed after storage.

 The results are shown in Table 3 (25 ° C 60% RH) and Table 4 (40 ° C 75% RH).

 [Table 3]

3.9 4.0 3.9 40 3.8 Determination (%) 99.6 99.7 100.3 100.4 99.8 Powder X-ray Type II crystal Type II crystal Type II crystal Type II crystal Type II crystal

[Table 4]

[Test Example 8]

 I Storage stability test for type I crystals (under severe conditions)

 Type II crystals open in a constant temperature and humidity chamber at 80 ° C / 90% RH, 25 ° C / 40% RH, 60 ° C / 90% RH, or 60 ° CZ Saved with. Storage was performed for up to 3 months. As a result, no significant increase or decrease in impurities was observed after storage under any of the conditions.

 The results are shown in Table 5 (80 ° C / 90 ° / oRH), Table 6 (25 ° C / 40% RH), Table 7 (60 ° C / 90% RH), and Table 8 (60 ° C / now) Humidity)

[Table 5] 80 ° C / 90% RH

[Table 6] 25 ° C / 40% RH

[Table 7] 60 ° C / 90% RH

[Table 8] Humidity at 60 ° CZ (low humidity)

*) There is a slight peak value shift based on the moisture content change as described above. As can be seen from the above test example, type II crystals (containing about 3-5% water) have high storage stability, and have a wide range of temperatures as described above. And does not produce impurities under humidity. Although it shows slight changes under high temperature and low humidity conditions, it is basically a stable crystal that does not change its water content or powder X-ray pattern, and is extremely useful for pharmaceutical production. Industrial applicability

 Since the crystal of the compound represented by the formula (I) or the pharmaceutically acceptable salt thereof of the present invention has high storage stability, production of a medicament containing the compound represented by the formula (I), etc. Useful for.

 Since the crystals of the compound represented by the formula (1-1) of the present invention are anhydrous crystals, they are useful as drug substances and standard substances in pharmaceutical production.

 The crystal represented by the formula (1-2) of the present invention is extremely useful for pharmaceutical production and the like because the change in water content is small.

Claims

Claim Formula (I)

 (I)

Or a pharmaceutically acceptable salt thereof.

 2. The crystal according to claim 1, which is an anhydrous crystal.

 3. Formula (I 1 1)

 (1-1)

A compound crystal represented by:

4. In powder X-ray diffraction, diffraction angle (2 Θ) = 1 2.4, 21.8 and 2

6. The crystal according to claim 1 or 3, which has a characteristic peak in 3.

 5. In powder X-ray diffraction, diffraction angle (20) = 1.1.4, 12.4, 15.

The crystal according to claim 1, 3 or 4 having peaks characteristic of 3, 19.1, 20.2, 20.8, 21.8, 23.6 and 26.3.

6. The crystal according to claim 1, 3, 4 or 5, further having an endothermic peak in the range of 228 to 234 ° C in differential scanning calorimetry.

 7. The crystal according to claim 1, which is a hydrate crystal.

8. Formula (I 1 2)

"XH ₂ 0

 (1-2)

(In the formula, x is a number from 0 to 1.)

A compound crystal represented by:

 9. The crystal according to claim 8, wherein X is 0.6 to 1.

10. The crystal according to claim 1, 8 or 9, which has a characteristic peak at diffraction angle (20) = 13.6, 16. 1-16.2 and 27.4 in powder X-ray diffraction.

1 1. In powder X-ray diffraction, diffraction angle (20) = 9.7 to 9.8, 13.6, 16.1 to 16.2, 19.4 to 19.6, 20.8 to 20. The crystal according to claim 1, 8, 9 or 10 having peaks characteristic of 9, 22.5 to 22.6 and 27.4.

 1 2. In powder X-ray diffraction, the diffraction angle (26) = 9. 8, 13. 6, 16. 1, 19. 19. 20, 20. 8, 22. 6 and 27.4. A crystal according to claim 1, 8, 9, 10, or 11.

 13. The crystal according to claim 1, further comprising an endothermic peak in a range of 204 to 210 ° C. in differential scanning calorimetry.

 14. A pharmaceutical comprising the crystal according to any one of claims 1 to 13.

 15. The medicament according to claim 14, which is an agent for enhancing sugar transport.

 16. The medicament according to claim 14, which is a hypoglycemic agent.

 17. It is a prophylactic and therapeutic agent for diabetes, diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic macroangiopathy, impaired glucose tolerance, or obesity. The medicament according to any one of the above.

18. The crystal according to claim 1, which is a solvate crystal.

19. The crystal according to claim 18, which is an ethyl acetate solvate crystal.

20. Formula (I 1 3)

 ■ 1/2 CH3COOC2H5

 (1-3)

A compound crystal represented by:

 21. In powder X-ray diffraction, diffraction angle (20) = 5. 8, 1 1. 6, 18. 4, 1 9. 5, 20. 5, 21. 0, 21.9 and 22.8 21. The crystal according to claim 1 or 20, which has a unique peak.

 22. The crystal according to claim 18, wherein the crystal is an anisosolvate crystal.

 1)

■ 1/2 C ₆ H ₅ OCH ₃

 (1-4)

A compound crystal represented by:

 24. In powder X-ray diffraction, diffraction angle (26) = 5.8, 1 1, 6, 18 4, 1 9. 3, 20. 4, 21.0, 21.8 and 22.8 24. The crystal according to claim 1 or 23, which has a peak.

 25. The crystal according to claim 18, which is a benzonitrile solvate crystal.

26. Formula (I 1 5)

A compound crystal represented by:

 27. In powder X-ray diffraction, diffraction angle (20) = 6.2, 12. 4, 1 7. 6, 18. 2, 20. 2, 20. 4, 20. 8, 21. 3 and 24.2 27. The crystal according to claim 1 or 26, wherein the crystal has a special peak.

28. The crystal according to claim 18, which is a tetrahydrofuran solvate crystal.

 1)

■ C ₄ H ₈ 0

 (1-6)

A compound crystal represented by:

 30. In powder X-ray diffraction, the diffraction angle (20) = 7.1, 14.4, 1, 9, 9, 21.3, 22.5 and 23.7 have characteristic peaks at claim 1 or The crystal according to 29.

 31. The crystal according to claim 18, wherein the crystal is a Toruen sum.

 1)

 ■ U6H5 Ηΐ3

 (1-7)

A compound crystal represented by:

 33. In powder X-ray diffraction, diffraction angle (2 Θ) = 5.9, 8. 3, 1 1. 8, 14. 5, 18. 5, 21. 3, 22. 9 and 29.6 The crystal according to claim 1 or 32, which has a large peak.

34. Formula (I)

 (I)

The manufacturing method of the crystal | crystallization in any one of Claims 2-6 including the process of cooling the solution containing the compound represented by these.

35. Formula (I)

(I)

The manufacturing method of the crystal | crystallization in any one of Claims 2-6 including the process of adding a poor solvent to the solution containing the compound represented by these.

36. Formula (I)

(I)

The method for producing a crystal according to any one of claims 2 to 6, comprising a step of desolvating the solvate crystal of the compound represented by formula (1).

3 7. Formula (I)

 (I)

The method for producing a crystal according to any one of claims 7 to 13, comprising a step of cooling a solution containing the compound represented by formula (1).

38. Formula (I)

(I)

The manufacturing method of the crystal | crystallization in any one of Claims 7-13 including the process of adding a poor solvent to the solution containing the compound represented by these.

 39. The method for producing a crystal according to any one of claims 7 to 13, comprising a step of adding water to the crystal according to any one of claims 2 to 6.

 40 .. The method for producing a crystal according to any one of claims 7 to 13, comprising a step of adding water to the crystal according to any one of claims 31 to 33.