Method for producing centanafadine

Abstract

The present invention addresses the problem of finding a method for reliably producing (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, wherein crystalline polymorphs can be controlled with industrially easy operations. Provided is a method for producing a crystalline form of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, the method comprising: step (a) for heating and dissolving (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride in a solvent including an alcohol-based solvent; step (b) for cooling the dissolved product of step (a) to a temperature, at which crystals of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride precipitate, to nucleate the crystals; step (c) for heating a mixture containing the crystals obtained by nucleation to a temperature at which only a specific crystalline form selectively remains; and step (d) for cooling the mixture heated in step (c) to obtain the crystalline form.

Description

Technical Field

[0001] The present invention relates to a method for producing a crystalline form of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

Background Art

[0002] (1R,5S)-1-(Naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, also known as (+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, is a useful compound (generic name: centanafadine) having inhibitory activity against norepinephrine reuptake, dopamine reuptake, and serotonin (5-HT) reuptake (Patent Documents 1 and 2).

[0003] The hydrochloride salt of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane (hereinafter also referred to as "Compound 1"):

Chemical Formula

[0004] Compound 1 is produced as crystalline form A by purifying its crude crystals (Patent Documents 2, 3, and 4). However, these purification methods require complex processes such as repeated heating, dissolution, and drying using several types of organic solvents, or it is difficult to control crystal polymorphs with little difference in solubility when another crystal polymorph is mixed during the purification process. There were problems as an industrial purification method, including reproducibility.

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0006] (1R,5S)-1-(Naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, one of the problems is to find a stable production method that can control crystal polymorphs with an industrially easy operation.

Means for Solving the Problems

[0007] As a result of intensive research, the present inventors have found that crystalline form A can be stably purified by refluxing, nucleation, and subsequent reheating treatment during the purification process of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, and have completed the present invention.

[0008] In one aspect, there is provided a method for producing crystalline form A of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, comprising: step (a) of heating and dissolving (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride in a solvent containing an alcoholic solvent; step (b) of cooling the dissolved product of step (a) to a temperature at which crystals of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride precipitate to nucleate the crystals; step (c) of heating the mixture containing the crystals obtained by nucleation to a temperature at which only a specific crystal form selectively remains; and step (d) of cooling the mixture heated in step (c) to obtain the crystal form.

Advantages of the Invention

[0009] According to the present invention, by an industrially easy operation of heating, nucleating, and reheating (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride under specific conditions, it is possible to selectively and stably produce the thermodynamically metastable crystalline form A with good reproducibility.

Brief Description of the Drawings

[0010]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Mode for Carrying Out the Invention

[0011] Some specific embodiments are exemplified below. [Item 1] Step (a) of heating and dissolving (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride in a solvent containing an alcoholic solvent, step (b) of cooling the dissolved product of step (a) to a temperature at which crystals of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride precipitate to nucleate the crystals, step (c) of heating the mixture containing the crystals obtained by nucleation to a temperature at which only specific crystal forms remain selectively in the solid state, and step (d) of cooling the mixture heated in step (c) to obtain the crystal form, A method for producing crystal form A of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

[0012] [Item 2] The production method according to Item 1, wherein the heating temperature in step (a) is a temperature exceeding 77°C.

[0013] [Item 3] The production method according to Item 1 or 2, wherein the temperature in step (b) is 30 to 60°C.

[0014] [Item 4] The production method according to any one of Items 1 to 3, wherein the temperature in step (c) is 65°C or higher and lower than the boiling point of the solvent.

[0015] In the present specification, examples of the alcoholic solvent include methanol, ethanol, propanol, isopropanol, butanol, isobutanol, and a mixed solvent of two or more of them in any ratio. Preferably, it is ethanol, isopropanol, or a mixed solvent of ethanol and another alcoholic solvent. More preferably, it is ethanol.

[0016] In this specification, the solvent containing an alcoholic solvent is a mixed solvent of an alcoholic solvent and water in any ratio.

[0017] The amount of the solvent containing an alcoholic solvent in step (a) is, for example, 8 to 12 times the volume (mL) relative to the weight (g) of Compound 1. Preferably, it is 10 to 11 times the volume.

[0018] The heating temperature in step (a) is the temperature at which the solvent containing Compound 1 is completely refluxed and Compound 1 in the reaction vessel is substantially completely dissolved. For example, it is the reflux temperature of the solvent containing Compound 1. Substantially completely dissolving Compound 1 means that not only Compound 1 in the solvent but also Compound 1 adhering to the reaction vessel wall is dissolved. By substantially completely dissolving Compound 1, the crystal form of Compound 1 can be reproducibly controlled, and the amount of contamination of undesirable crystal polymorphs can be reduced. Preferably, it is a temperature exceeding 77°C. More preferably, it is 79 to 82°C.

[0019] The heating time in step (a) is the time until the solvent containing Compound 1 is completely refluxed and Compound 1 in the reaction vessel is substantially completely dissolved. The heating time is, for example, at least 5 minutes. Preferably, it is 10 minutes or more.

[0020] Nucleation in step (b) means that crystals of Compound 1 are nucleated. The crystals may be any one of crystal form A, crystal form B, and crystal form C of Compound 1 or a mixture thereof in any ratio of two or more. The mixture may contain any other crystal form at less than, for example, 20% by weight, 10% by weight, 5% by weight, 3% by weight, 2% by weight, 1% by weight, 0.1% by weight, or 0.01% by weight relative to the main crystal form.

[0021] The temperature at which crystals precipitate in step (b) is preferably the temperature at which crystals of Compound 1 containing crystal form A of Compound 1 precipitate. For example, it is 20 to 60°C. Preferably, it is 30 to 60°C. More preferably, it is 60°C.

[0022] The cooling time in step (b) is, for example, 10 minutes or more. Preferably it is 40 minutes or more.

[0023] The temperature at which only a specific crystal form in step (c) selectively remains in the solid state is preferably the temperature at which crystal form A of compound 1 selectively remains in the solid state, and is the temperature at which crystal forms other than crystal form A of compound 1 are substantially completely dissolved. In certain embodiments, the temperature at which only a specific crystal form selectively remains in the solid state is a temperature at which the specific crystal form may contain less than 5 wt%, less than 3 wt%, less than 2 wt%, less than 1 wt%, less than 0.1 wt%, or less than 0.01 wt% of any other crystal form relative to the main crystal form. The temperature is, for example, less than the boiling point of a solvent containing an alcohol-based solvent of 65°C or higher. Preferably it is 65°C to 72°C. More preferably it is 70°C.

[0024] The heating time in step (c) is the time at which crystal forms other than crystal form A of compound 1 are substantially completely dissolved. For example, it is at least 30 minutes or more and less than 10 hours. Preferably it is 60 minutes or more and 7 hours or less.

[0025] The cooling temperature in step (d) is, for example, 0 to 20°C. Preferably it is 10°C.

[0026] The cooling time in step (d) is, for example, 2 to 12 hours.

[0027] Crystal form A may exhibit at least 3, for example at least 5, for example at least 7, for example at least 9 selected from the group consisting of 2θ values of 12.22 ± 0.2°, 13.75 ± 0.2°, 15.38 ± 0.2°, 16.51 ± 0.2°, 17.11 ± 0.2°, 18.46 ± 0.2°, 19.40 ± 0.2°, 20.44 ± 0.2°, 20.65 ± 0.2°, 22.85 ± 0.2° and 25.62 ± 0.2° in powder X-ray diffraction measurement (XRPD) using a Cu wire. In one embodiment, crystal form A exhibits an XRPD pattern substantially shown in FIG. 1, FIG. 3, FIG. 5 or FIG. 7. Crystal form A may also exhibit, for example, an onset temperature of the endothermic peak of 247.07 ± 1.0 °C in differential thermal - thermogravimetric measurement (TGA / DSC). In one embodiment, crystal form A exhibits a TGA / DSC pattern substantially shown in FIG. 2, FIG. 4, FIG. 6 or FIG. 8.

[0028] Crystal form B of Compound 1 that can be formed by the nucleation in step (b) can also be produced, for example, using the method disclosed in Patent Document 2, and may exhibit any XRPD pattern or TGA / DSC pattern of crystal form B described in the same document.

[0029] Crystal form C of Compound 1 that can be formed by the nucleation in step (b) can also be produced, for example, using the method disclosed in Patent Document 2, and may exhibit any XRPD pattern or TGA / DSC pattern of crystal form C described in the same document.

[0030] [Method for Producing Crystal Form A] The crude product of Compound 1 can be produced using the method disclosed in any of Patent Documents 2 to 4. The crude product of Compound 1 is heated and dissolved in a solvent containing an alcohol-based solvent, then cooled, activated carbon is added and reheated. After the reheated mixture is filtered while hot, the obtained precipitate is washed with the solvent containing the alcohol-based solvent, the filtrate is heated until Compound 1 is substantially completely dissolved, and then cooled to the temperature at which crystals of Compound 1 precipitate. Then, it is reheated and the mixture is stirred, and then cooled. The obtained precipitated crystals are collected by filtration, washed with an alcohol-based solvent, and dried to obtain crystal form A of Compound 1.

Example

[0031] The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto. Also, the measurement conditions of the analytical instruments used in the examples are shown below. 1. Chemical purity test by HPLC Column: Kinetex R Polar C18 (100 mm x 3.0 mm, 2.6μm) (Phenomenex R ) Column temperature: 40°C Wavelength: 254 nm Mobile phase: Solution A: Acetonitrile Solution B: 20 mM ammonium formate aqueous solution Composition:

Table 1

[0032] 2. Optical purity test by HPLC Column: Shiseido chiral CD-Ph (250 mm x 4.6 mm, 5μm) Column temperature: 30°C Wavelength: 222 nm Mobile phase: 50 mmol / L sodium heptanesulfonate buffer (pH 3.0) / acetonitrile mixture (6:4) Flow rate: 1.5 mL / min Injection volume: 5 μL

[0033] 3. Powder X-ray diffraction measurement (XRPD) Measuring instrument manufacturer (model): Shimadzu Corporation (XRD-6000) X-ray source: Cu Voltage / current: 35 kV / 20 mA Measurement range: 2θ, 3~40° Measurement speed: 5° / min

[0034] 4. Differential thermal and thermogravimetric measurement (TGA / DSC) Measuring instrument manufacturer (model): METTLER TOLEDO AG (TGA / DSC1) Heating rate: 5 °C / min Temperature range: 25 - 300 °C Atmospheric gas: Dry nitrogen Flow rate: 50 mL / min Sample 6.7600 mg Result Mode: Abscissa Unit

[0035] [Example 1] Production of crystalline form A of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (Compound 1) (1) [Chemical formula] Under a nitrogen atmosphere, the crude product of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (20.0 g, 0.081 mol) was added to a mixture of ethanol (178.2 mL) and water (1.8 mL), and refluxed for 10 minutes or more to confirm dissolution. After cooling until the reflux subsided, activated carbon (2.0 g) was added and refluxed for 30 minutes or more. After hot filtration, it was washed with a mixture of ethanol (19.8 mL) and water (0.2 mL), and the filtrate was refluxed again for 10 minutes or more at complete reflux (79 °C) to confirm dissolution. After cooling to 60 °C, it was heated to 70 °C again and stirred for 60 minutes or more. After cooling to 10 °C, the precipitated crystals were collected by filtration, washed with ethanol (40.0 mL), and dried at 40 °C to obtain the title compound as a white to slightly yellow solid (14.80 g, yield 74.00%, chemical purity 99.65%, optical purity 100.00% ee). 1H-NMR (400 MHz, DMSO-d6) δ: 1.22 - 1.23 (1H, m), 1.45 - 1.48 (1H, m), 2.23 - 2.24 (1H, m), 3.41 - 3.43 (1H, m), 3.51 - 3.52 (1H, m), 3.58 - 3.61 (1H, m), 3.76 - 3.79 (1H, m), 7.39 (1H, dd, J = 1.8, 8.2 Hz), 7.49 (1H, ddd, J = 1.4, 6.9, 6.9 Hz), 7.51 (1H, ddd, J = 1.4, 6.9, 6.9 Hz), 7.82 (1H, d, J = 1.8 Hz), 7.88 (2H, dd, J = 1.4, 6.9 Hz), 7.89 (1H, d, J = 8.2 Hz), 9.71 (2H, br.s) The XRPD and TGA / DSC of the obtained solid were measured, and it was confirmed that it was crystalline form A. The results are shown in the following table and Figures 1 and 2.

Table 2

[0036] [Example 2] (1R,5S)-1-(Naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (Compound 1), Preparation of crystalline form A (2) Under a nitrogen atmosphere, the crude product of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (20.0 g, 0.081 mol) was added to a mixed solution of ethanol (178.2 mL) and water (1.8 mL), and refluxed for more than 10 minutes to confirm dissolution. It was cooled until the reflux subsided, activated carbon (2.0 g) was added, and refluxed for more than 30 minutes. After filtration while hot, it was washed with a mixed solution of ethanol (19.8 mL) and water (0.2 mL), and the filtrate was refluxed again completely (79 °C) for more than 10 minutes to confirm dissolution. After cooling to 51 °C, it was heated to 70 °C again and stirred for more than 60 minutes. After cooling to 10 °C, the precipitated crystals were collected by filtration, washed with ethanol (40.0 mL), and dried at 40 °C to obtain the title compound as a white to slightly yellow solid (14.55 g, yield 72.75%, chemical purity 100.00%, optical purity 99.81% ee). 1 1H-NMR (400 MHz, DMSO-d6) δ: 1.22 - 1.23 (1H, m), 1.45 - 1.48 (1H, m), 2.23 - 2.24 (1H, m), 3.41 - 3.43 (1H, m), 3.51 - 3.52 (1H, m), 3.58 - 3.61 (1H, m), 3.76 - 3.79 (1H, m), 7.39 (1H, dd, J = 1.8, 8.2 Hz), 7.49 (1H, ddd, J = 1.4, 6.9, 6.9 Hz), 7.51 (1H, ddd, J = 1.4, 6.9, 6.9 Hz), 7.82 (1H, d, J = 1.8 Hz), 7.88 (2H, dd, J = 1.4, 6.9 Hz), 7.89 (1H, d, J = 8.2 Hz), 9.71 (2H, br.s) The XRPD and TGA / DSC of the obtained solid were measured, and it was confirmed to be crystal form A. The results are shown in the following table and Figures 3 and 4.

Table 3

[0037] [Example 3] Production of Crystal Form A of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (Compound 1) (3) Under a nitrogen atmosphere, the crude product of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (20.0 g, 0.081 mol) was added to a mixture of ethanol (178.2 mL) and water (1.8 mL), and refluxed for more than 10 minutes to confirm dissolution. After cooling until the reflux subsided, activated carbon (2.0 g) was added and refluxed for more than 30 minutes. After hot filtration, it was washed with a mixture of ethanol (19.8 mL) and water (0.2 mL), and the filtrate was refluxed again completely (79 °C) for more than 10 minutes to confirm dissolution. After cooling to 60 °C, it was heated to 72 °C again and stirred for more than 60 minutes. After cooling to 10 °C, the precipitated crystals were collected by filtration, washed with ethanol (40.0 mL), and dried at 40 °C to obtain the title compound as a white to slightly yellow solid (12.69 g, yield 63.45%, chemical purity 100.00%, optical purity 99.78% ee). 1 1H-NMR (400 MHz, DMSO-d6) δ: 1.22 - 1.23 (1H, m), 1.45 - 1.48 (1H, m), 2.23 - 2.24 (1H, m), 3.41 - 3.43 (1H, m), 3.51 - 3.52 (1H, m), 3.58 - 3.61 (1H, m), 3.76 - 3.79 (1H, m), 7.39 (1H, dd, J = 1.8, 8.2 Hz), 7.49 (1H, ddd, J = 1.4, 6.9, 6.9 Hz), 7.51 (1H, ddd, J = 1.4, 6.9, 6.9 Hz), 7.82 (1H, d, J = 1.8 Hz), 7.88 (2H, dd, J = 1.4, 6.9 Hz), 7.89 (1H, d, J = 8.2 Hz), 9.71 (2H, br.s) The XRPD and TGA / DSC of the obtained solid were measured to confirm that it was Crystal Form A. The results are shown in the following table and Figures 5 and 6.

Table 4

[0038] [Example 4] (1R,5S)-1-(Naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (Compound 1), Preparation of Crystal Form A (4) Under a nitrogen atmosphere, a crude product of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (20.0 g, 0.081 mol) was added to a mixed solution of isopropanol (190.0 mL) and water (10.0 mL), and refluxed for 10 minutes or more to confirm dissolution. It was cooled until the reflux subsided, activated carbon (2.0 g) was added, and refluxed for 30 minutes or more. After filtration while hot, it was washed with a mixed solution of isopropanol (19.0 mL) and water (1.0 mL), and the filtrate was refluxed again completely (82 °C) for 10 minutes or more to confirm dissolution. After cooling to 30 °C, it was heated again to 66 °C and stirred for 60 minutes or more. After cooling to 10 °C, the precipitated crystals were collected by filtration, washed with isopropanol (40.0 mL), and dried at 40 °C to obtain the title compound as a white to slightly yellow solid (13.46 g, yield 67.30%, chemical purity 100.00%, optical purity 99.62% ee). 1 H-NMR (400 MHz, DMSO-d6) δ: 1.22 - 1.23 (1H, m), 1.45 - 1.48 (1H, m), 2.23 - 2.24 (1H, m), 3.41 - 3.43 (1H, m), 3.51 - 3.52 (1H, m), 3.58 - 3.61 (1H, m), 3.76 - 3.79 (1H, m), 7.39 (1H, dd, J = 1.8, 8.2 Hz), 7.49 (1H, ddd, J = 1.4, 6.9, 6.9 Hz), 7.51 (1H, ddd, J = 1.4, 6.9, 6.9 Hz), 7.82 (1H, d, J = 1.8 Hz), 7.88 (2H, dd, J = 1.4, 6.9 Hz), 7.89 (1H, d, J = 8.2 Hz), 9.71 (2H, br.s) The XRPD and TGA / DSC of the obtained solid were measured, and it was confirmed to be Crystal Form A. The results are shown in the following table and Figures 7 and 8.

Table 5

[0039] [Reference Example 1] Under a nitrogen atmosphere, a crude product of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (16.0 g, 0.065 mol) was added to a mixed solution of ethanol (198.0 mL) and water (2.0 mL), and completely refluxed (79 °C) for 10 minutes or more to confirm dissolution. After cooling to 60 °C, 4.0 g of crystalline form A was added. It was heated to 70 °C again and stirred for 60 minutes. After cooling to 10 °C, the precipitated crystals were collected by filtration, washed with ethanol (40.0 mL), and dried at 40 °C to obtain a white solid (yield 78.1%, chemical purity 99.94%, optical purity 99.99% ee). From the start of the reaction to the collection of the crystals by filtration, changes in crystal habit and particle size were observed using Particle View (PVM V819; Mettler Toledo Co., Ltd.) and Particle track (FBRM G400; Mettler Toledo Co., Ltd.). When heated to 70 °C again, crystals remained, and there were no changes in crystal particle size or crystal habit during stirring at 70 °C for 60 minutes, and no crystal form transition was observed. The XRPD of the solid obtained after purification was measured, and it was confirmed to be crystalline form A.

[0040] [Reference Example 2] Under a nitrogen atmosphere, a crude product of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (16.0 g, 0.065 mol) was added to a mixed solution of ethanol (198.0 mL) and water (2.0 mL), and completely refluxed (79 °C) for 10 minutes or more to confirm dissolution. After cooling to 60 °C, 4.0 g of crystalline form B was added. It was heated to 70 °C again and stirred for 60 minutes. After cooling to 10 °C, the precipitated crystals were collected by filtration, washed with ethanol (40.0 mL), and dried at 40 °C to obtain a white solid (yield 76.5%, chemical purity 99.95%, optical purity 100% ee). From the start of the reaction to the filtration of the crystals, changes in crystal habit and particle size were observed using Particle View (PVM V819; Mettler Toledo Co., Ltd.) and Particle track (FBRM G400; Mettler Toledo Co., Ltd.). When crystalline form B was added, plate-like crystalline form B without the thickness of columnar crystalline form A was observed. However, when heated to 70 °C again, the crystals completely dissolved and were not observed. Columnar crystalline form A was observed in the observation immediately before filtration of the precipitated crystals after cooling to 10 °C. The XRPD of the solid obtained after purification was measured and confirmed to be crystalline form A. Note that crystalline form B added in Reference Example 2 was obtained by the following method. Under a nitrogen atmosphere, crystalline form A (20.0 g, 0.081 mol) of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride was added to water (200.0 mL) and stirred at 25 °C. After cooling to 10 °C, the precipitated crystals were collected by filtration, washed with ethanol (10.0 mL), and dried at 40 °C to obtain a white solid (yield 76.02%, chemical purity 99.93%, optical purity 99.99% ee). The XRPD of the solid obtained after purification was measured and confirmed to be crystalline form B.

Industrial Applicability

[0041] According to the present invention, crystalline form A of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride can be selectively and stably produced by an industrially easy operation.

Claims

1. Step (a) of heating and dissolving (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride in a solvent containing an alcoholic solvent, step (b) of cooling the dissolved product in step (a) to a temperature at which crystals of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride precipitate to nucleate the crystals, step (c) of heating the mixture containing the crystals obtained by nucleation to a temperature at which only a specific crystal form selectively remains in the solid state, and step (d) of cooling the mixture heated in step (c) to obtain the crystal form, a method for producing crystal form A of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride, wherein crystal form A exhibits 2θ values of 13.75±0.2°, 20.65±0.2°, and 25.62±0.2° in powder X-ray diffraction measurement (XRPD) using a Cu wire.

2. The production method according to claim 1, wherein the heating temperature in step (a) is a temperature exceeding 77°C.

3. The production method according to claim 1 or 2, wherein the temperature in step (b) is 30 to 60°C.

4. The production method according to any one of claims 1 to 3, wherein the temperature in step (c) is 65°C or higher and lower than the boiling point of the solvent.

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