Crystalline form of amino acid derivatives and method for producing the same

Abstract

Providing a crystalline form that is stable in the pharmaceutical use environment of a prodrug compound of an amino acid derivative. 【Solution】A crystal of (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7 decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid having at least one of the physical properties (a) to (c) below. (a) Having peaks at 2θ = 10.8°, 14.5°, 19.4°, and 21.8° in powder X-ray diffraction (Cu-Kα); (b) In the infrared absorption spectrum (ATR method), characteristic absorption bands are at 3310 cm -1 , 1762 cm -1 , 1731 cm -1 , 1583 cm -1 and 1236 cm -1 ; or (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is at 225 - 235 °C.

Description

[Technical Field]

[0001] The present invention relates to (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7 This invention relates to crystalline polymorphs of decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid or pharmaceutically acceptable salts thereof, and methods for producing the same. More specifically, it relates to, for example, mGlu2 and mGlu3 receptors belonging to subgroup II of metabolically active glutamate (mGlu) receptors, which are effective in treating and preventing mood disorders (including depression and bipolar disorder), anxiety disorders, cognitive impairment, developmental disorders, Alzheimer's disease, Parkinson's disease, motor disorders associated with muscle rigidity, sleep disorders, Huntington's disease, eating disorders, drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral failure, cerebral edema, spinal cord injury, head injury, inflammation, immune-related diseases, etc. (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (hereinafter sometimes referred to as the parent compound or compound (B)), which acts as a gonist, is a prodrug of (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7 This invention relates to the crystalline polymorphism of decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid (hereinafter sometimes referred to as compound (A)) and a method for producing the same. Furthermore, the present invention relates to a crystalline polymorph of a prodrug, in which the mucosal absorption, such as oral absorption, is enhanced and the in vivo exposure of the parent compound is increased by prodrug formulation of the parent compound, which is a compound that acts on metabotropic glutamate receptors, and to a method for producing the same. [Background technology]

[0002] Metabotropic glutamate receptors are classified into three groups based on amino acid sequence homology, signal transduction mechanisms, and pharmacological properties. Among these, group II metabotropic glutamate receptors (mGlu2 and mGlu3 receptors) are G protein-coupled receptors that bind to adenylcyclase and suppress the forskolin-stimulating accumulation of cyclic adenosine monophosphate (cAMP) (Non-Patent Literature 1). Furthermore, group II metabotropic glutamate receptors are mainly located in the presynaptic regions of the glutamatergic nervous system and function as autoreceptors, thereby suppressing the excessive release of glutamate (Non-Patent Literature 2, Non-Patent Literature 3). Compounds that antagonize group II metabotropic glutamate receptors are thought to be effective in the treatment or prevention of acute and chronic psychiatric and neurological disorders, and (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives are compounds that have a strong antagonistic effect on group II metabotropic glutamate receptors.

[0003] However, these compounds exhibited poor oral absorption in monkeys, and it was anticipated that they would also be poorly absorbed in humans. Therefore, to improve the membrane permeability, including oral absorption, of the compounds, prodrug formulation was performed by attaching small modifying groups such as alkyl or acyl groups to the carboxyl or amino groups of the compounds. As a prodrug, a compound is desired that exists stably as a prodrug before absorption, whose absorption is improved by prodrug conversion, and which is rapidly converted to an active form chemically or enzymatically in the small intestine, liver, and / or plasma during and / or after absorption. Regarding the prodrug formulation of (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives, after repeated studies, it has been reported that by creating a prodrug with an ester bond at the 2-position of the (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-alkoxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivative, an ideal compound with significantly improved oral absorption was obtained. Specifically, (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid was prodrug'd (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1. 13,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid has also been reported (Patent Document 1).

[0004] Furthermore, from a pharmaceutical perspective, there is a demand for compounds that are easy to handle on an industrial scale and possess excellent physical properties that ensure storage stability. [Prior art documents] [Patent Documents]

[0005] [Patent Document 1] WO2017 / 183734 [Non-patent literature]

[0006] [Non-Patent Document 1] Trends Pharmacol. Sci., 14, 13-20, 1993. [Non-Patent Document 2] Neuropharmacol.,40,20-27,2001. [Non-Patent Document 3] Eur. J. Pharmacol., 356, 149-157, 1998.

Summary of the Invention

Problems to be Solved by the Invention

[0007] An object of the present invention is to provide a prodrug that acts on group 2 metabotropic glutamate receptors, such as a therapeutic or prophylactic agent for neuropsychiatric diseases such as schizophrenia, anxiety disorders and related diseases, depression, bipolar disorder, epilepsy, developmental disorders, sleep disorders, etc., and neurological diseases such as drug addiction, cognitive impairment, Alzheimer's disease, Huntington's disease, Parkinson's disease, movement disorders associated with muscle rigidity, cerebral ischemia, cerebral insufficiency, spinal cord disorders, head injuries, etc., which are considered to involve group 2 metabotropic glutamate receptors. The present invention aims to provide a crystalline form that is preferable in the usage environment as a pharmaceutical or a pharmaceutical raw material in terms of improving mucosal absorbability such as oral absorbability of a parent compound that acts on group 2 metabotropic glutamate receptors, increasing the in vivo exposure amount, and having storage stability and ease of handling of the prodrug, and a method for producing the same.

Means for Solving the Problems

[0008] As a result of intensive studies on a prodrug having (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid (hereinafter sometimes referred to as compound (B)) as a parent compound, (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7 decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid (hereinafter sometimes referred to as compound (A)) was found to enhance mucosal absorbability such as oral absorbability as a prodrug and increase the in vivo exposure amount of the parent compound. Furthermore, the inventors discovered that a crystal of the compound or a pharmaceutically acceptable salt thereof having excellent physical properties can be provided, and thus completed the present invention.

[0009]

Chemical formula

[0010]

Chem.

[0011] That is, one aspect of the invention of the present application is (1) A D-form crystal of (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7 decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid having at least one of the following physical properties (a) to (c). (a) Having peaks at 2θ = 10.8°, 14.5°, 19.4°, and 21.8° in powder X-ray diffraction (Cu-Kα); (b) In the infrared absorption spectrum (ATR method), characteristic absorption bands are at 3310 cm -1 , 1762 cm -1 , 1731 cm -1 , 1583 cm -1 and 1236 cm -1 ; or (c) In differential thermal analysis / thermogravimetry (TG / DTA), an endothermic peak is at 225 - 235 °C. Moreover, another aspect of the invention of the present application is (2) A method for producing a D-form crystal of the compound (A) according to (1), characterized by dissolving (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7 decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid in a lower alcohol, acetonitrile, ethyl acetate, alkylamine, or a mixed solvent thereof, and then adding C 5-8 saturated hydrocarbon or water and crystallizing at 15 - 40 °C, and drying the obtained crystals.

Advantages of the Invention

[0012] The present invention provides a prodrug of (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]bicyclo[3.1.0]hexane-2,6-dicarboxylic acid, which has excellent group II metabotropic glutamate receptor antagonist activity. 3,7 It has become possible to provide crystals of decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid. These crystals are stable at temperatures around room temperature and have excellent storage stability. Furthermore, they do not undergo crystal form changes even when subjected to formulation operations such as grinding, making them easy to handle and confirming their potential as a useful pharmaceutical raw material. [Brief explanation of the drawing]

[0013] [Figure 1] The powder X-ray diffraction pattern of the D-form crystal of compound (A) is shown. [Figure 2] The differential thermal analysis / thermomass measurement curves for the D-type crystals of compound (A) are shown. [Figure 3] The infrared absorption spectrum (ATR method) of the D-form crystal of compound (A) is shown. [Figure 4] The powder X-ray diffraction pattern of the A-type crystal of compound (A) is shown. [Figure 5] The differential thermal analysis / thermomass measurement curves for the A-type crystal of compound (A) are shown. [Figure 6] The powder X-ray diffraction pattern of the B-type crystal of compound (A) is shown. [Figure 7] The differential thermal analysis / thermomass measurement curve for the B-type crystal of compound (A) is shown. [Figure 8] The powder X-ray diffraction pattern of the C-type crystal of compound (A) is shown. [Figure 9] The differential thermal analysis / thermomass measurement curves for the C-type crystals of compound (A) are shown. [Figure 10]The powder X-ray diffraction pattern of the crystalline compound (A) methanesulfonate is shown. [Figure 11] The powder X-ray diffraction pattern of the crystalline compound (A) benzenesulfonate is shown. [Figure 12] The powder X-ray diffraction pattern of the phosphate crystalline compound (A) is shown. [Modes for carrying out the invention]

[0014] The following describes specific embodiments for carrying out the present invention. The compound of the present invention is (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid (compound (A)) has the chemical structure shown below.

[0015] [ka]

[0016] The D-form crystal of compound (A) has at least one of the following physical properties (a) to (c). (a) Having peaks at 2θ = 10.8°, 14.5°, 19.4°, and 21.8° in powder X-ray diffraction (Cu-Kα); or (b) In the infrared absorption spectrum (ATR method), the characteristic absorption band is 3310 cm⁻¹. -1 , 1762cm -1 , 1731cm -1 , 1583cm -1 and 1236cm -1 Located in; or (c) In differential thermal analysis / thermal mass measurement (TG / DTA), the endothermic peak is located at 225-235°C. The powder X-ray diffraction pattern of the D-type crystal of compound (A) is shown in Figure 1, the differential thermal analysis / thermomass measurement curve is shown in Figure 2, and the infrared absorption spectrum is shown in Figure 3. As can be seen from Figures 1-3, the D-form crystals of compound (A) produced by the manufacturing method of the present invention are basically high-purity crystals. High crystal purity is desirable, and preferably they are substantially free of other crystal forms. As shown in the examples described later, the D-form crystals of compound (A) produced by the manufacturing method of the present invention can be reproducibly obtained as single crystals with consistent quality, and can be stably supplied as active pharmaceutical ingredient crystals used in the manufacture of pharmaceuticals and pharmaceutical raw materials, possessing excellent physical properties for storage stability.

[0017] Next, a method for producing D-form crystals of compound (A) will be described. The D-form crystals of the present invention can be obtained by the following recrystallization operation. For example, after heating and dissolving compound (A) in a predetermined organic solvent, the crystals can be precipitated by slow cooling, or by adding a predetermined poor solvent and then slow cooling. The precipitated crystals can then be separated from the solvent by filtration, centrifugation, etc., and dried to obtain D-form crystals of compound (A). Recrystallization may be repeated not only once but two or more times, but usually only once is performed. The specified organic solvent used to dissolve the raw material compound (A) before recrystallization is, for example, a lower alcohol, ethyl acetate, diC 1-4 Examples include common organic solvents such as alkyl ethers, acetone, acetonitrile, THF, DMF, and DMSO, or organic bases such as triethylamine and diisopropylethylamine as alkylamines, or mixed solutions of these organic solvents. The predetermined poor solvent to be added afterward is, for example, water, C 5-8 Examples include saturated hydrocarbons and acetic acid.

[0018] Examples of lower alcohols include methanol, ethanol, 1-propanol, and 2-propanol. Ji C 1-4 Examples of alkyl ethers include diethyl ether, diisopropyl ether, and butyl-methyl ether.

[0019] C 5-8Examples of saturated hydrocarbons include pentane, hexane, heptane, and octane. Hexane or heptane are preferred.

[0020] The concentration at which compound (A) dissolves is 1 to 50% by mass. Here, mass% refers to the mass percentage of D-form crystals of compound (A) in the solution or suspension. The crystallization of compound (A) into D-form crystals is usually carried out at 0 to 100°C. The drying of the D-form crystals of compound (A) is usually carried out at temperatures below 100°C.

[0021] The crystalline form of the compound of the present invention can be administered orally or parenterally. The dosage forms include tablets, capsules, granules, powders, lozenges, ointments, creams, transdermal patches, emulsions, suspensions, suppositories, and injections, all of which can be manufactured using conventional pharmaceutical techniques (for example, methods specified in the 17th edition of the Japanese Pharmacopoeia). These dosage forms can be appropriately selected according to the patient's symptoms, age, weight, and the purpose of treatment. These formulations can be manufactured by compounding a composition containing the compound of the present invention with pharmacologically acceptable carriers, i.e., excipients (e.g., crystalline cellulose, starch, lactose, mannitol), binders (e.g., hydroxypropylcellulose, polyvinylpyrrolidone), lubricants (e.g., magnesium stearate, talc), disintegrants (e.g., carboxymethylcellulose calcium), and other pharmacologically acceptable additives. The compound of the present invention can be administered to adult patients orally or parenterally in doses of 0.001 to 500 mg once or several times a day. This dose can be appropriately increased or decreased depending on the type of disease being treated, the patient's age, weight, symptoms, etc. [Examples]

[0022] Next, the present invention will be described in more detail with reference examples, examples, and test examples, but the present invention is not limited to these. Powder X-ray radiation was measured using SmartLab (Rigaku). Differential thermal analysis / thermal mass measurement (TG / DTA) was performed using a Thermo plus EvoTG8120 (RIGAKU). The infrared absorption spectrum was measured using IRAffinity-1 (Shimadzu Corporation). Water vapor adsorption measurements were performed using the DVS-1 Advantage (Surface Measurement Systems). In the reference examples and examples, room temperature refers to approximately 25°C. (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7 ]decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid (compound (A)) can be obtained, for example, by the same method as in Example 4 of Patent Document 1 (WO2017 / 183734).

[0023] Example 1 (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7 Method for producing D-form crystals of decane-1-carbonyl oxyethoxy}carbonyl bicyclo[3.1.0]hexane-6-carboxylic acid (compound (A))

[0024] (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7466 g of decane-1-carbonyl)oxyethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid was mixed with ethyl acetate (1.87 kg) and triethylamine (462 g) and heated to an ambient temperature of 54°C until dissolved. The solution was filtered through a cartridge filter to remove impurities and washed with ethyl acetate (0.48 kg). While maintaining an ambient temperature of around 75°C, heptane (2.39 kg) was added dropwise to the filtrate. The mixture was stirred at around 75°C for more than 30 minutes, and then stirred for approximately 20 hours while gradually cooling to around 20°C. After filtering the suspension, it was washed with a mixed solution of ethyl acetate / heptane (1 / 9, 1.93 kg). The resulting solid was dried under reduced pressure to obtain D-form crystals of compound (A) (417 g, white solid).

[0025] Example 2 The powder X-ray diffraction pattern of the D-type crystal of compound (A) obtained by the method of Example 1 was measured using a Rigaku powder X-ray diffractometer (SmartLab) with Cu-Kα rays as the X-ray source. Peaks were observed around 2θ = 10.8 degrees, 14.5 degrees, 19.4 degrees, and 21.8 degrees, confirming the good crystallinity of the D-type crystal. Infrared spectra were collected using a Shimadzu Fourier transform infrared spectrophotometer (IRAffinity-1) with total internal reflection (ATR) method, 45 integrations, and a resolution of 2 cm. -1 The measurement was taken under the following conditions: 3310cm -1 , 1762cm -1 , 1731cm -1 , 1583cm -1 and 1236cm -1 A peak was observed in the vicinity. The melting point was measured using a Rigaku differential thermometer (Thermo plus EVO TG8120) and equivalent equipment under atmospheric pressure, from room temperature to approximately 250°C at a heating rate of 10°C / min. As a result, an endothermic peak originating from melting was observed between 225 and 235°C. The hygroscopic properties were measured using a Surface Measurement Systems water vapor adsorption analyzer (DVS-1 Advantage) under room temperature, atmospheric pressure, and nitrogen flow conditions. Before measurement, the sample was dried at 60°C for 2 hours. The mass change was measured at 5% intervals during the process of increasing the relative humidity from 0%RH to 95%RH and then decreasing it to 5%RH. The equilibrium condition was set to move to the next humidity level when the mass change of 0.01% per minute ceased. Hygroscopicity (DVS) measurements revealed that the D-form crystals of compound (A) were non-hygroscopic and showed no change in crystal form due to humidity. Solid stability tests revealed that the D-form crystals of compound (A) were stable in the solid state, with quantitative values ​​of 99.8%, 99.4%, and 100.4% (compared to initial values) after 4 weeks at 65°C, 3 months at 40°C and 75% RH, and 3 weeks at room temperature after light irradiation (FL3000 lx). Furthermore, the D-form crystals of compound (A) did not undergo any changes in crystal shape or crystallinity due to crushing or tableting.

[0026] Reference Example 1 (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7 Method for producing A-type crystals of decane-1-carbonyl oxyethoxy}carbonyl bicyclo[3.1.0]hexane-6-carboxylic acid (compound (A))

[0027] (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7 1 g of decane-1-carbonyl)oxyethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid was purified by silica gel column chromatography (YMC C18, H2O / MeCN = 95 / 5~5 / 95). The fraction containing the target product was concentrated under reduced pressure, and acetonitrile was added again and stirred. By filtering off the precipitate, A-type crystals of compound (A) (0.85 g) were obtained.

[0028] Reference example 2 The powder X-ray diffraction pattern of the A-type crystal of compound (A) obtained by the method in Reference Example 1 was measured, and peaks were observed around 2θ = 12.2 degrees and 12.6 degrees. Differential thermal analysis / thermal mass measurement revealed an endothermic peak originating from melting at 225-235°C.

[0029] Reference Example 3 (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7 Method for producing B-type crystals of decane-1-carbonyl oxyethoxy}carbonyl bicyclo[3.1.0]hexane-6-carboxylic acid (compound (A))

[0030] (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7 30 mg of decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid crystals of form A were added to 1 mL of 2-propanol and shaken at 25°C for 1 week. After centrifugation (3000 rpm, 10 min), the supernatant was removed and the mixture was dried under reduced pressure at room temperature to obtain crystals of compound (A) of form B.

[0031] Reference example 4 The powder X-ray diffraction pattern of the B-type crystal of compound (A) obtained by the method in Reference Example 3 was measured, and peaks were observed around 2θ = 7.4 degrees and 11.6 degrees. Differential thermal analysis / thermal mass measurement was also performed, and an endothermic peak originating from melting was observed between 225 and 235°C.

[0032] Reference Example 5 (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7 Method for producing C-type crystals of decane-1-carbonyl oxyethoxy}carbonyl bicyclo[3.1.0]hexane-6-carboxylic acid (compound (A))

[0033] (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7 30 mg of A-type crystals of decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid were mixed with ethyl acetate (1 mL) and shaken at 25°C for 1 week. After centrifugation (3000 rpm, 25°C, 10 min), the supernatant was removed and the mixture was dried under reduced pressure at room temperature to obtain C-type crystals of compound (A).

[0034] Reference example 6 The powder X-ray diffraction pattern of the C-type crystal of compound (A) obtained by the method of Reference Example 5 was measured, and peaks were observed around 2θ = 7.0 degrees, 9.9 degrees, 12.0 degrees, and 13.5 degrees. Differential thermal analysis / thermal mass measurement revealed an endothermic peak originating from melting at 225-235°C.

[0035] Reference Example 7 (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7 Method for producing crystals of decane-1-carbonyl oxyethoxy}carbonyl bicyclo[3.1.0]hexane-6-carboxylic acid (compound (A)) methanesulfonate

[0036] [ka]

[0037] (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,70.5 g of decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid was mixed with 1.9 mL of THF. Under ice cooling, 0.069 mL of methanesulfonic acid was added and the mixture was stirred for 1 hour, after which the solvent was removed under reduced pressure. Acetone and hexane were added to the residue and the mixture was stirred at room temperature. By filtering the precipitated solid, methanesulfonate crystals of compound (A) (0.412 g) were obtained.

[0038] Reference example 8 The powder X-ray diffraction pattern of the crystalline compound (A) methanesulfonate obtained by the method in Reference Example 7 was measured, and peaks were observed around 2θ = 7.7 degrees and 15.2 degrees.

[0039] Reference Example 9 (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7 Method for producing crystals of decane-1-carbonyl oxyethoxy}carbonyl bicyclo[3.1.0]hexane-6-carboxylic acid (compound (A))benzenesulfonate

[0040] [ka]

[0041] (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7 0.05 g of decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid was mixed with 0.3 mL of THF. Benzoyl benzenesulfonic acid (0.018 mL) was added under ice cooling and the mixture was stirred for 1 hour, after which the solvent was removed under reduced pressure. Diisopropyl ether was added to the residue and the mixture was stirred at room temperature for 16 hours. By filtering the precipitated solid, 0.025 g of benzenesulfonate crystals of compound (A) was obtained.

[0042] Reference example 10 The powder X-ray diffraction pattern of the crystalline compound (A) benzenesulfonate obtained by the method of Reference Example 9 was measured, and peaks were observed around 2θ = 5.6 degrees and 7.9 degrees.

[0043] Reference Example 11 (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7 Method for producing crystals of decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid (compound (A)) phosphate

[0044] [ka]

[0045] (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7 To a solution of decane-1-carbonyl)oxyethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid (0.020 g) in THF (1.0 mL), phosphoric acid (0.002 mL) was added and the mixture was stirred at room temperature for 16 hours. After removing the solvent under reduced pressure, IPE was added and the mixture was stirred at room temperature. By filtering the precipitated solid, phosphate crystals of compound (A) (0.011 g) were obtained.

[0046] Reference example 12 The powder X-ray diffraction pattern of the crystalline compound (A) phosphate obtained by the method in Reference Example 11 was measured, and peaks were observed around 2θ = 4.2 degrees and 13.3 degrees. [Industrial applicability]

[0047] According to the present invention, (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 3,7The present invention provides a crystalline form of decane-1-carbonyl)oxy]ethoxy}carbonyl)bicyclo[3.1.0]hexane-6-carboxylic acid that is preferable in terms of storage stability and ease of handling for use as a pharmaceutical or pharmaceutical raw material, as well as a method for producing the same. The crystalline form of the present invention can be used as a therapeutic and preventive agent for diseases regulated by group II metabotropic glutamate receptor antagonism, such as mood disorders (including depression and bipolar disorder), anxiety disorders, cognitive impairment, developmental disorders, Alzheimer's disease, Parkinson's disease, motor disorders associated with muscle rigidity, sleep disorders, Huntington's disease, eating disorders, drug addiction, epilepsy, cerebral infarction, cerebral ischemia, cerebral failure, cerebral edema, spinal cord injury, head trauma, inflammation, and immune-related diseases.

Claims

1. (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ３，７ Crystals of decane-1-carbonyl oxyethoxy}carbonyl bicyclo[3.1.0]hexane-6-carboxylic acid. (a) In powder X-ray diffraction (Cu-Kα), peaks are found at 2θ = 10.8°, 14.5°, 19.4°, and 21.8°; (b) In the infrared absorption spectrum (ATR method), the characteristic absorption band is 3310 cm⁻¹. －１ , 1762cm －１ , 1731cm －１ , 1583cm －１ and 1236 cm －１ Located in; or, (c) In differential thermal analysis / thermomass analysis (TG / DTA), the endothermic peak is located at 225–235°C.

2. Lower alcohol, acetonitrile, ethyl acetate, alkylamine, or a mixture thereof, (1R,2R,3R,5R,6R)-2-amino-6-fluoro-3-[(4-fluorophenyl)methoxy]-2-({(1S)-1-[(tricyclo[3.3.1.1 ３，７ After dissolving decane-1-carbonyl oxyethoxy}carbonyl bicyclo[3.1.0]hexane-6-carboxylic acid, C ５－８ A method for producing crystals according to claim 1, characterized by crystallization by adding saturated hydrocarbons or water and slowly cooling, and then drying the obtained crystals.

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