Crystal of griseofulvin compound, method for purifying said compound, and production method relating to said compound

Abstract

The present invention relates to crystals of (1'S,6'R)-7-chloro-2',4-dimethoxy-6'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3H-spiro[1]benzofuran-2,1'-cyclohexa[2]ene]-3,4'-dione (compound 6).

Description

Crystals of griseofulvin compounds, purification method for said compounds, and production method for said compounds

[0001] The present invention relates to crystals of a griseofulvin compound, a method for purifying said compound, and a method for producing said compound.

[0002] The applicant has previously reported that griseofulvin compounds are useful as compounds having primarily central anti-inflammatory activity, and that pharmacologically acceptable salts thereof and their medical uses (Patent Document 1).

[0003] In recent years, with the progress of research, a relationship between psychiatric disorders, neurodegenerative diseases, and inflammation has been reported (Non-Patent Documents 1 and 2). It has been reported that stress increases the production of inflammatory cytokines from microglia, and that patients with psychiatric disorders (depression, schizophrenia, etc.) have high levels of cytokines (e.g., TNFα) in the blood, suggesting the involvement of brain inflammation in psychiatric disorders. It has also been suggested that proteins thought to be the cause of neurodegenerative diseases, such as Alzheimer's disease, induce brain inflammation by activating microglia.

[0004] Japanese Patent No. 7102426

[0005] Akira Moji, "Neuroinflammation Hypothesis of Psychiatric Disorders," Journal of Psychiatry and Neurology, 2012, Vol. 114, No. 2, pp. 124-133 Akio Suzukimura, "Neurodegenerative Diseases, Neuroinflammation and Microglia," Clinical Neurology 2014, Vol. 54, No. 12, pp. 1119-1121

[0006] The present invention aims to provide a method for industrially producing griseofulvin compound (Compound 6), which has been difficult to produce on an industrial scale until now, by improving each step of the production method. To date, obtaining Compound 2, which is generated during the production of Compound 6 and will be described later, has been difficult due to the difficulty of isolating the reaction mixture after the reaction and the need for further purification by column chromatography, making industrial production difficult. Furthermore, obtaining crystals of Compound 6 has been difficult because it requires selective production of stable crystals from two types of crystals, the structure of which is unclear, and the conditions must be set so as to prevent the formation of other crystals. The inventors of the present application have continued their intensive research to solve these problems, and as a result, have solved the problems and completed the present invention.

[0007] Below is an overview of the method for producing Compounds 1 to 6 and the names of each process.

[0008]

[0009] In particular, the inventors of the present application have combined (1) a method for efficiently removing impurities produced in Step 1 with (2) a method for removing impurities derived from the raw materials by liquid separation operation through liquid property control, thereby making it possible to obtain highly pure Compound 2 by precipitating a solid without performing purification by column chromatography.

[0010] Furthermore, the inventors of the present application have discovered that it is difficult to selectively obtain the desired crystals of a griseofulvin compound (Compound 6), but by using an appropriate solvent, it is possible to produce the desired crystals.

[0011] The present invention is described below: [1] A crystal of (1'S,6'R)-7-chloro-2',4-dimethoxy-6'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-3,4'-dione (Compound 6) having the following structure:

[0012]

[0013] [2] The crystal according to [1] above, which is a Form 1 crystal having peaks (in the range of ±0.2°) at diffraction angles (2θ(°)) of 12.3, 15.6, 18.3, 22.3, and 22.9 in powder X-ray diffraction. [3] The crystal according to [1] above, which is a Form 1 crystal having peaks (in the range of ±0.2°) at diffraction angles (2θ(°)) of 12.32, 15.64, 18.32, 22.32, and 22.90 in powder X-ray diffraction. [4] The crystal according to [1] above, which is a Form 1 crystal having the X-ray diffraction pattern shown below.

[0014]

[0015] [5] The crystal according to [1], which is a Form 2 crystal having peaks (including a range of ±0.2°) at diffraction angles (2θ(°)) of 5.5, 7.1, 11.2, 26.7, and 27.0 in powder X-ray diffraction. [6] The crystal according to [1], which is a Form 2 crystal having peaks (including a range of ±0.2°) at diffraction angles (2θ(°)) of 5.46, 7.12, 11.24, 26.74, and 27.03 in powder X-ray diffraction. [7] The crystal according to [1], which is a Form 2 crystal having the X-ray diffraction pattern shown below.

[0016]

[0017] [8] A method for purifying (1'S,6'R)-7-chloro-2',4-dimethoxy-6'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-3,4'-dione (Compound 6) having the following structure:

[0018]

[0019] A method for purifying Compound 6, comprising dissolving Compound 6 in an organic solvent, treating it with activated carbon, and crystallizing it from the organic solvent to obtain the crystals described in any one of [2] to [4] above. [9] A method for purifying Compound 6 described in [8] above, comprising the following steps (i) to (iv) in this order: (i) dissolving Compound 6 in ethyl acetate to obtain an ethyl acetate solution of Compound 6, adding activated carbon thereto and stirring, and then filtering off the activated carbon; (ii) stirring the solution obtained in (i) while heating, and then distilling off the solvent; (iii) adding isopropyl alcohol to the substance obtained in (ii) again, stirring the mixture while heating, and then distilling off the solvent; and (iv) washing the solid obtained in (iii) with isopropyl alcohol and drying it to obtain the crystals.

[10] A method for producing (1'S,6'R)-7-chloro-6-hydroxy-2',4-dimethoxy-6'-methyl-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-3,4'-dione (Compound 2) having the following structure from (1'S,6'R)-7-chloro-2',4,6-trimethoxy-6'-methyl-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-3,4'-dione (Compound 1) having the following structure,

[0020]

[0021] A method for producing Compound 2, comprising the following steps (i) to (iii) in this order: (i) stirring Compound 1 and tetrabutylammonium iodide under heating to obtain a reaction solution; (ii) adding activated carbon, water, and hydrochloric acid to the reaction solution obtained in (i), filtering, and then extracting, back-extracting, and extracting again in that order; and (iii) filtering again, and then concentrating to obtain Compound 2.

[11] A pharmaceutical composition comprising the crystal according to any one of [1] to [7] above.

[0022] The present invention improves the manufacturing method of griseofulvin compounds, which has been difficult to produce on an industrial scale until now, thereby enabling industrial production. Furthermore, the present invention is the first to successfully obtain stable Form 1 crystals of griseofulvin compound (Compound 6).

[0023] The powder X-ray diffraction pattern of Form 1 crystal of Compound 6 is shown. The vertical axis shows intensity (cps) and the horizontal axis shows diffraction angle (2θ (°)). The powder X-ray diffraction pattern of Form 2 crystal of Compound 6 is shown. The vertical axis shows intensity (cps) and the horizontal axis shows diffraction angle (2θ (°)).

[0024] The present invention will be described in detail below. In this specification, Compound 1 will also be referred to as Compound 1. Similarly, Compounds 2 to 6 will also be referred to as Compounds 2 to 6, respectively.

[0025] The method for producing Compounds 1 to 6 will be explained below, step by step.

[0026] [Step 1] This step (Step 1) is a step for producing Compound 2 from Compound 1.

[0027]

[0028] In this step, Compound 1, a solvent, and reagents are placed in a reaction vessel and reacted. Reagents used in this step include tetrabutylammonium iodide, tetrabutylammonium bromide, tetrabutylammonium chloride, and potassium iodide. Solvents used in this step include organic solvents such as pyridine, N-methylmorpholine, and N-methylimidazole. The reaction temperature in this step is typically about 100°C to 120°C. The reaction time in this step is typically about 10 to 25 hours, and preferably about 10 to 20 hours.

[0029] This process is characterized by the following post-reaction treatment: Compound 1 is purified by a basic separation operation to remove it into an organic layer, and then crystals of Compound 2 are obtained by crystallization. The purification may also include a step of acidifying the solution to precipitate the polymerized compound as tar, which is then removed by trapping it in activated carbon.

[0030] This step may, for example, be a method comprising the following steps (i) to (iii) in this order: (i) obtaining a reaction solution by stirring Compound 1 and tetrabutylammonium iodide while heating, (ii) adding activated carbon, water, and hydrochloric acid to the reaction solution obtained in (i), filtering, and then extracting, back-extracting, and extracting again in this order, and (iii) filtering again and concentrating to obtain Compound 2.

[0031] In the above (i), the amount of tetrabutylammonium iodide is preferably 50 to 100 parts by mass, more preferably 75 to 85 parts by mass, relative to 100 parts by mass of Compound 1. In the above (i), the heating temperature is preferably 100°C to 120°C. In the above (i), the stirring time is preferably 10 to 25 hours, more preferably 10 to 20 hours.

[0032] In the above (ii), the amount of activated carbon added is preferably 10 to 40 parts by mass, more preferably 20 to 30 parts by mass, per 100 parts by mass of Compound 1. In the above (ii), the amount of water added is preferably 300 to 2000 parts by mass, more preferably 500 to 1500 parts by mass, per 100 parts by mass of Compound 1. Water may be added all at once or in stages. When added in stages, it is preferable that the total amount added satisfies the above value. In the above (ii), the amount of hydrochloric acid added is preferably 250 to 350 parts by mass, more preferably 280 to 320 parts by mass, per 100 parts by mass of Compound 1. After the addition of hydrochloric acid, it is preferable that the pH be 2 to 3. In the above (ii), filtration methods include single plate filtration, filter bag filtration, and centrifugal filtration.

[0033] In the above (iii), the filtration method includes single plate filtration, filter bag filtration, and centrifugal filtration, and the concentration method includes vacuum concentration.

[0034] [Step 2] This step (Step 2) is a step of producing Compound 3 from Compound 2.

[0035]

[0036] In this step, Compound 2, a solvent, and reagents are placed in a reaction vessel and reacted. The order in which these are added to the reaction solution does not matter. Reagents used in this step include triflation agents such as trifluoroacetic anhydride and trifluoromethanesulfonic anhydride, and bases such as organic bases like triethylamine, diisopropylethylamine, and pyridine. Solvents used in this step include acetonitrile and methylene chloride. The reaction temperature in this step is typically between -5°C and 5°C. The reaction time in this step is typically between 30 minutes and 1 hour.

[0037] This step is characterized by the following post-reaction treatment: The reaction is stopped, the aqueous layer is removed by a separation operation, and then crystals of Compound 3 are obtained by crystallization. Before the separation operation, water may be added to quench the triflation agent.

[0038] [Step 3] This step (Step 3) is a step of producing Compound 4 from Compound 3.

[0039]

[0040] In this step, Compound 3, a solvent, and reagents are placed in a reaction vessel and reacted. Reagents used in this step include palladium coupling agents such as palladium acetate and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, organic bases such as diisopropylethylamine, organophosphorus compounds such as Xantphos, and the coupling partner 2,4,6-trichlorophenyl formate. Solvents used in this step include organic solvents such as toluene. The reaction temperature in this step is typically about 80°C to 100°C. The reaction time in this step is typically about 30 minutes to 1 hour.

[0041] This process is characterized by the following post-reaction treatment. When a palladium coupling agent is used, the palladium is removed by treatment with activated carbon and silica gel, and then crystallization is performed to obtain Compound 4 crystals. If necessary, recrystallization is performed for purification. Palladium can be efficiently removed during crystallization by adding an adsorbent such as N-acetyl-L-cysteine.

[0042] [Step 4] This step (Step 4) is a step of producing Compound 5 from Compound 4.

[0043]

[0044] In this step, Compound 4, a solvent, and reagents are placed in a reaction vessel and reacted. The reagents used in this step include acetylhydrazine, and organic bases such as 1,4-diazabicyclo{2.2.2}octane, 4-dimethylaminopyridine, and imidazole, as well as 2,4,6-trichlorophenyl. The solvents used in this step include organic solvents such as ethyl acetate, tetrahydrofuran, acetonitrile, and dimethylacetamide. The reaction temperature in this step is typically between -10°C and 25°C. The reaction time in this step is typically between 4 and 24 hours.

[0045] This step is characterized by the following post-reaction treatment: If a base is used in the weakly acidic separation treatment, the base is removed, and then crystals of Compound 5 are obtained by crystallization.

[0046] [Step 5] This step is a step for producing Compound 6 from Compound 5.

[0047]

[0048] In this step, Compound 5, a solvent, and reagents are placed in a reaction vessel and reacted. The reagents used in this step include condensing agents such as paratoluenesulfonyl chloride, diethyl 3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl phosphate, and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate. The bases include organic bases such as triethylamine, 1,4-diazabicyclo{2.2.2}octane, and tetramethylethylenediamine, and inorganic bases such as potassium carbonate. Solvents used in this step include organic solvents such as acetonitrile, dimethylacetamide, acetone, tetrahydrofuran, and ethyl acetate. The reaction temperature in this step is typically between 15°C and 30°C. The reaction time in this step is typically between 30 minutes and 3 hours.

[0049] This process is characterized by the following post-reaction treatment: After removing the base component by liquid separation, crude crystals of Compound 6 are obtained by crystallization. If necessary, recrystallization is performed for purification. A common organic solvent can be used as the solvent for crystallization, and preferred examples include isopropyl alcohol and acetone.

[0050] The crystals of Compound 6 include Form 1 crystals and Form 2 crystals. The characteristics of each crystal are described below.

[0051] When producing Form 1 crystals of Compound 6, it is preferable to produce Form 1 crystals of Compound 6 by dissolving Compound 6 in an organic solvent, treating with activated carbon, and then crystallizing from the organic solvent.

[0052] The organic solvent is preferably an alcohol-based solvent.

[0053] A more preferred method for producing Form 1 crystals of Compound 6 is a method comprising the following steps (i) to (iv) in this order: (i) dissolving Compound 6 in ethyl acetate to obtain an ethyl acetate solution of Compound 6, adding activated carbon thereto and stirring, and then filtering off the activated carbon; (ii) stirring the solution obtained in (i) while heating, and then distilling off the solvent; (iii) adding isopropyl alcohol to the substance obtained in (ii) again, stirring the mixture while heating, and then distilling off the solvent; and (iv) washing the solid obtained in (iii) with isopropyl alcohol and drying it to obtain the crystals.

[0054] By producing Form 1 crystals using the above method, it is possible to crystallize without using water.

[0055] In the ethyl acetate solution of Compound 6 described in (i) above, the concentration of Compound 6 in the solution is preferably 1 to 6%, more preferably 4 to 5%, by mass. In (i) above, activated carbon is preferably added in an amount of 3 to 30 parts by mass, more preferably 5 to 15 parts by mass, per 100 parts by mass of Compound 6. In (i) above, isopropyl alcohol may be added to the ethyl acetate solution of Compound 6. In this case, isopropyl alcohol is preferably added in an amount of 400 to 1400 parts by mass, more preferably 600 to 800 parts by mass, per 100 parts by mass of Compound 6. In (i) above, it is preferable to add activated carbon to the ethyl acetate solution of Compound 6 and then stir the mixture. The stirring temperature is preferably 5 to 50°C, more preferably 15 to 30°C. The stirring time is preferably 10 to 180 minutes, more preferably 20 to 40 minutes. In (i) above, methods for filtering out the activated carbon include single-plate filtration, filter bag filtration, and centrifugal filtration.

[0056] In the above (ii), the heating temperature is preferably 30 to 70° C., more preferably 40 to 50° C. In the above (ii), examples of the method for distilling off the solvent include vacuum concentration.

[0057] In the above (iii), when isopropyl alcohol is added to the substance obtained in (ii), the isopropyl alcohol is added in a ratio of preferably 500 to 1500 parts by mass, more preferably 700 to 800 parts by mass, per 100 parts by mass of Compound 6. In the above (iii), the heating temperature is preferably 30 to 70°C, more preferably 40 to 50°C. In the above (iii), examples of the method for distilling off the solvent include vacuum concentration.

[0058] In the above (iv), when washing, isopropyl alcohol is used in a ratio of preferably 100 to 500 parts by mass, more preferably 200 to 300 parts by mass, per 100 parts by mass of Compound 6. In the above (iv), drying methods include vacuum drying. The temperature during drying is preferably 20 to 70°C, more preferably 30 to 50°C. It is preferable to dry until the residual solvent is below a specified value.

[0059] By the method described above, the desired crystals of Compound 6 can be produced efficiently.

[0060] Form 1 crystals of Compound 6 (also simply referred to herein as "Form 1 crystals") have peaks at diffraction angles (2θ(°)) of 12.3, 15.6, 18.3, 22.3, and 22.9 (including a range of ±0.2°) in powder X-ray diffraction. Form 1 crystals preferably have peaks at diffraction angles (2θ(°)) of 19.2, 20.7, 24.2, 26.6, and 29.3 (including a range of ±0.2°) in powder X-ray diffraction. Form 1 crystals more preferably have peaks at diffraction angles (2θ(°)) of 10.0, 19.7, 27.9, and 28.3 (including a range of ±0.2°) in powder X-ray diffraction.

[0061] The Form 1 crystal preferably has peaks at diffraction angles (2θ(°)) of 12.32, 15.64, 18.32, 22.32, and 22.90 (including a range of ±0.2°) in powder X-ray diffraction. The Form 1 crystal more preferably has peaks at diffraction angles (2θ(°)) of 19.16, 20.73, 24.18, 26.59, and 29.31 (including a range of ±0.2°) in powder X-ray diffraction. The Form 1 crystal even more preferably has peaks at diffraction angles (2θ(°)) of 10.04, 19.69, 27.91, and 28.29 (including a range of ±0.2°) in powder X-ray diffraction.

[0062] Form 2 crystals of Compound 6 (also simply referred to herein as "Form 2 crystals") have peaks at diffraction angles (2θ(°)) of 5.5, 7.1, 11.2, 26.7, and 27.0 (including a range of ±0.2°) in powder X-ray diffraction. Form 2 crystals preferably further have peaks at diffraction angles (2θ(°)) of 9.1, 10.5, 19.8, 21.4, and 27.8 (including a range of ±0.2°) in powder X-ray diffraction.

[0063] The Form 2 crystal preferably has peaks at diffraction angles (2θ(°)) of 5.46, 7.12, 11.24, 26.74, and 27.03 (including a range of ±0.2°) in powder X-ray diffraction. The Form 2 crystal more preferably has peaks at diffraction angles (2θ(°)) of 9.10, 10.48, 19.83, 21.44, and 27.80 (including a range of ±0.2°) in powder X-ray diffraction.

[0064] Unless otherwise specified, powder X-ray diffraction analysis values ​​herein are those obtained using Cu-Kα radiation. When X-rays other than Cu-Kα radiation are used, 2θ (°) varies according to the formula 2d sin θ = nλ (d is the distance between two planes, n is an arbitrary integer, and λ is the wavelength of the X-rays). However, these are merely essentially equivalent ways of expressing the crystals of the present invention and are included within the scope of the present invention, which can be easily understood by those skilled in the art of crystallography. Furthermore, the relative intensities of the peaks shown in these charts may vary depending on, for example, the degree of crystallization of the sample or the preparation method. While 2θ (°) does not vary substantially, it may vary within an error range (generally ±0.2°) recognized by those skilled in the art of crystallography. Regarding characteristic peaks of powder X-ray diffraction expressed as 2θ angles, another embodiment shows ±0.1°.

[0065] Due to the nature of the data, the values ​​of powder X-ray diffraction analysis should not be interpreted strictly because the crystal lattice spacing and overall pattern are important in determining the identity of the crystal, and the relative intensities may vary somewhat depending on the direction of crystal growth, particle size, and measurement conditions.

[0066] The crystal of this embodiment may be a crystal consisting of only Form 1 crystal, or a crystal consisting of only Form 2 crystal, or may be a mixture of Form 1 crystal and Form 2 crystal.

[0067] This embodiment also relates to a pharmaceutical composition comprising the crystal of this embodiment. The pharmaceutical composition of this embodiment contains at least Form 1 crystal or Form 2 crystal in part. For example, when the pharmaceutical composition contains Form 1 crystal, a crystalline form other than Form 1 crystal (e.g., Form 2 crystal) may also be present. The proportion of Form 1 crystal contained in the pharmaceutical composition may be in the range of 0.01% by mass to 99.9% by mass, for example, 0.01% by mass or more, 0.1% by mass or more, 1% by mass or more, 10% by mass or more, 50% by mass or more, 90% by mass or more, 95% by mass or more, 98% by mass or more, 99% by mass or more, 99.5% by mass or more, 99.6% by mass or more, 99.7% by mass or more, 99.8% by mass or more, or 99.9% by mass or more, based on the total active ingredient contained in the pharmaceutical composition. Whether Form 1 crystal is contained in the pharmaceutical composition can be confirmed by the instrumental analysis methods described herein (e.g., powder X-ray diffraction, etc.).

[0068] The instruments used for the various analyses and measurements and their conditions are listed below. X-ray diffraction measurement (XRD) Instrument used for measurement: Rigaku MiniFlex 600 X-ray source: CuKα Method: Reflection method Tube voltage: 40 kV Tube current: 15 mA Scan range: 3°-40° Scan speed: 10°C / min Sampling width: 0.02° Rotation: Yes Sample amount: Approximately 5 mg

[0069] The present invention will now be described in detail with reference to examples, but is not limited thereto. Tetramethylsilane was used as an internal standard in magnetic resonance spectroscopy (NMR), and the abbreviations for multiplicities are: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad.

[0070] Example 1 Preparation of (1'S,6'R)-7-chloro-6-hydroxy-2',4-dimethoxy-6'-methyl-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-3,4'-dione (Compound 2)

[0071]

[0072] Example 1-1: Under a nitrogen atmosphere, pyridine (688.0 kg), (1'S,6'R)-7-chloro-2',4,6-trimethoxy-6'-methyl-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-3,4'-dione (Compound 1: 87.5 kg, 248 mol), and tetrabutylammonium iodide (73.3 kg, 198 mol) were added to a reaction vessel. The internal temperature was adjusted to 117°C and the mixture was stirred under reflux for 21 hours. After cooling the reaction solution to 20°C, water (1313.2 kg) and ethyl acetate (1181.0 kg) were added and the mixture was stirred for 5 minutes. After allowing to stand for 18 hours, the lower layer (aqueous layer) was removed and transferred to another reaction vessel. Water (438.0 kg) was added to the upper layer (organic layer), stirred for 5 minutes, and then allowed to stand for 1 hour. The lower layer (aqueous layer) was removed and matched the aqueous layer that had been transferred earlier. Water (438.2 kg) was added to the upper layer (organic layer), stirred for 5 minutes, and then allowed to stand for 1.5 hours. The lower layer (aqueous layer) was removed and matched the aqueous layer that had been transferred earlier. The organic layer was discarded.

[0073] The combined aqueous layer was adjusted to 20°C, and activated carbon (17.5 kg) and ethyl acetate (398.6 kg) were added. Concentrated hydrochloric acid was then added to adjust the pH to 2.0. This slurry was stirred for 1.5 hours, after which the solids were removed by filtration, and the filtrate was obtained. The filtered solids were washed with water (175.0 kg) and then ethyl acetate (395.5 kg). This washing solution was combined with the previous filtrate. The combined solution was adjusted to an internal temperature of 20°C, stirred for 5 minutes, then allowed to stand for 1 hour. The lower layer (aqueous layer) was removed and discarded. Water (438.4 kg) was added to the upper layer (organic layer), stirred for 5 minutes, and then allowed to stand for 20 minutes. The lower layer (aqueous layer) was removed and discarded. Water (438.0 kg) was then added to the upper layer (organic layer), stirred for 5 minutes, and allowed to stand for 5 minutes. The lower layer (aqueous layer) was removed and discarded. Thereafter, 10% saline (467.7 kg) was added to the upper layer (organic layer), and after stirring for 5 minutes, the mixture was allowed to stand for 5 minutes, and the lower layer (aqueous layer) was extracted and discarded.

[0074] The resulting upper layer (organic layer) was concentrated under reduced pressure until the volume of the reaction mixture reached 88 L. Ethyl acetate (283.4 kg) was added to this solution, and the mixture was concentrated under reduced pressure again until the volume of the reaction mixture reached 88 L. Ethyl acetate (276.4 kg) was then added to this solution, and the mixture was concentrated under reduced pressure again until the volume of the reaction mixture reached 88 L. Ethyl acetate (106.2 kg) was added to this solution, and the internal temperature was adjusted to 50 °C to remove any adhering to the reactor walls with solvent vapor. The internal temperature was then cooled to 0 °C, and the precipitated solid was collected by filtration. This solid was washed with ethyl acetate (117.9 kg) cooled to 0 °C and dried to obtain the title compound (Compound 2: 15.1 kg, 44.6 mol) as a solid. The physical properties of the resulting title compound (Compound 2) are as follows: 1 H NMR (500 MHz, CD3CN): δ 8.65 (br, 1H), 6.28 (s, 1H), 5.54 (s, 1H), 3.86 (s, 3H), 3.62 (s, 3H), 2.76 - 2.84 (m, 2H), 2.32 - 2.39 (m, 1H), 0.87 (d, J = 3.0 Hz, 3H)

[0075] (Example 1-2) Under a nitrogen atmosphere, pyridine (1800.0 L), (1'S,6'R)-7-chloro-2',4,6-trimethoxy-6'-methyl-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-3,4'-dione (Compound 1: 600.0 kg, 1.70 kmol), and tetrabutylammonium iodide (502.6 kg, 0.735 kmol) were added to a reaction vessel, and the internal temperature was adjusted to 100°C and stirred for 21 hours. After that, the reaction solution was cooled to 25°C. Activated carbon (180.0 kg) and water (3600.0 L) were added to another reaction vessel, and the reaction solution was added thereto, followed by ethyl acetate (3600 L). Finally, concentrated hydrochloric acid was added to adjust the pH to 2.0.

[0076] This slurry was stirred at an internal temperature of 25°C for 2 hours, after which the solids were removed by filtration. The solids were washed with ethyl acetate (1200.0 L) and then water (600.0 L), and the filtrate and washings were combined. The combined solution was adjusted to an internal temperature of 25°C, stirred for 5 minutes, and then allowed to stand for 13 hours. The lower layer (aqueous layer) was removed and discarded. Water (3000.0 L) was added to the upper layer (organic layer), stirred for 5 minutes, and then allowed to stand for 40 minutes. The lower layer (aqueous layer) was removed and discarded. Water (3000.0 L) was then added to the upper layer (organic layer), stirred for 5 minutes, and then allowed to stand for 1 hour. The lower layer (aqueous layer) was removed and discarded.

[0077] Ethyl acetate (3000.0 L) and water (3000.0 L) were then added to the upper layer (organic layer), and the pH was adjusted to 10.0 using 48% aqueous sodium hydroxide. This solution was stirred for 5 minutes and then allowed to stand for 18 hours. The lower layer (aqueous layer) was removed and transferred to another reaction vessel. Water (1800.0 L) was added to the upper layer (organic layer), stirred for 5 minutes, and then allowed to stand for 15 minutes. The lower layer (aqueous layer) was removed and matched with the aqueous layer previously transferred. Water (1800.0 L) was then added to the upper layer (organic layer), stirred for 5 minutes, and then allowed to stand for 40 minutes. The lower layer (aqueous layer) was removed and matched with the aqueous layer previously transferred. The organic layer was discarded.

[0078] Ethyl acetate (5400.0 L) was added to the combined aqueous layer, followed by the addition of concentrated hydrochloric acid to adjust the pH to 3.0. The solution was stirred for 5 minutes and then allowed to stand for 40 minutes, after which the lower (aqueous) layer was removed and discarded. Next, 10% brine (3000.0 kg) was added to the upper (organic) layer and stirred for 1 hour. The solids were then removed by filtration, washed with ethyl acetate (600.0 L), and the filtrate and wash were combined.

[0079] The combined solution was allowed to stand for 17 hours, after which the lower layer (aqueous layer) was removed and discarded. The resulting organic layer was concentrated under reduced pressure until the volume of the solution in the system reached 1800 L. Ethyl acetate (2100.0 L) was added to this solution, and the solution was again concentrated under reduced pressure until the volume of the solution in the system reached 1800 L. Ethyl acetate (1200.0 L) was then added to this solution, and the solution was again concentrated under reduced pressure until the volume of the solution in the system reached 1800 L. The concentrated solution was adjusted to an internal temperature of 0°C and stirred for 17 hours, after which the precipitated solid was filtered. This solid was washed with ethyl acetate (900.0 L) cooled to 0°C and dried to obtain the title compound (Compound 2: 90.49 kg, 267 mol) as a solid.

[0080] Example 2 Preparation of (1'S,6'R)-7-chloro-2',4-dimethoxy-6'-methyl-3,4'-dioxo-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]en]-6-yl trifluoromethanesulfonate (Compound 3)

[0081]

[0082] Example 2-1: Under a nitrogen atmosphere, acetonitrile (153.1 kg), (1'S,6'R)-7-chloro-6-hydroxy-2',4-dimethoxy-6'-methyl-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-3,4'-dione (Compound 2: 28.0 kg, 82.7 mol), and pyridine (11.9 kg) were added to a reaction vessel and the temperature was adjusted to -5°C while stirring. Trifluoromethanesulfonic anhydride (32.7 kg, 116 mol) was added dropwise to this solution so that the internal temperature did not exceed 0°C, and the mixture was then stirred at an internal temperature of -2°C for 1 hour. 20% brine (96.0 kg) was added to the reaction solution, the internal temperature was adjusted to 20°C, the mixture was stirred for 10 minutes, and the mixture was allowed to stand for 10 minutes. The lower layer (aqueous layer) was then removed and discarded. The resulting organic layer was concentrated under reduced pressure until the volume of the liquid in the system reached 112 L and stirred at an internal temperature of 25 °C for 1 hour to precipitate a solid. Water (82.6 kg) was added dropwise to this slurry over 2 hours, and after stirring for 30 minutes, the precipitated solid was filtered. This solid was washed with a mixture of acetonitrile (32.8 kg) and water (84.0 kg) and dried to obtain the title compound (30.5 kg, 64.8 mol) as a solid. To purify this solid, methanol (72.0 kg) and water (60.6 kg) were added to a reaction vessel under a nitrogen atmosphere and the internal temperature was adjusted to 25 °C. The title compound (Compound 3: 30.3 kg, 64.4 mol) was added to this solution, stirred for 2 hours, and the precipitated solid was filtered. This solid was washed with a mixture of methanol (43.3 kg) and water (36.5 kg) and dried to obtain the title compound (Compound 3: 28.7 kg, 61.0 mol) as a solid. The physical properties of the title compound (Compound 3) were as follows: 1 H NMR (500 MHz, CD3CN): δ 6.77 (s, 1H), 5.58 (s, 1H), 3.94 (s, 3H), 3.63 (s, 3H), 2.87 (m, 1H), 2.76 (m, 1H), 2.40 - 2.43 (m, 1H), 0.89 (s, 3H)

[0083] Example 2-2: Under a nitrogen atmosphere, acetonitrile (560.0 L) and pyridine (46.70 kg) were added to a reaction vessel, and trifluoromethanesulfonic anhydride (99.95 kg, 354 mol) was added dropwise while maintaining the internal temperature below 5°C. After stirring at an internal temperature of 0°C for 1 hour, (1'S,6'R)-7-chloro-6-hydroxy-2',4-dimethoxy-6'-methyl-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-3,4'-dione (Compound 2: 80.00 kg, 236 mol) was quickly added and stirred for 1 hour. 15% brine (240.0 kg) was added to the solution, which was stirred for 5 minutes and allowed to stand for 15 minutes. The lower layer (aqueous layer) was then removed and discarded. Acetonitrile (200.0 L) was added to the resulting organic layer, which was then concentrated under reduced pressure until the volume of the liquid in the system reached 400 L and stirred at an internal temperature of 25 °C for 1 hour. Water (320.0 L) was then added dropwise over 2 hours, and the mixture was stirred for 14 hours. The precipitated solid was then filtered. This solid was washed with a mixture of acetonitrile (200.0 L) and water (200.0 L) and dried to obtain the title compound (Compound 3: 86.43 kg, 184 mol).

[0084] Example 3 Preparation of 2,4,6-trichlorophenyl (1'S,6'R)-7-chloro-2',4-dimethoxy-6'-methyl-3,4'-dioxo-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-6-carboxylate (Compound 4)

[0085]

[0086] Toluene (69.0 kg), diisopropylethylamine (5.30 kg, 41.0 mol), and (1'S,6'R)-7-chloro-2',4-dimethoxy-6'-methyl-3,4'-dioxo-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]en]-6-yl trifluoromethanesulfonate (Compound 3: 16.00 kg, 34.0 mol) were added to a reaction vessel under a nitrogen atmosphere. The mixture was degassed until the dissolved oxygen concentration reached 0.5 ppm or less (as measured by a dissolved oxygen meter). Xantphos (1.97 kg, 3.40 mol) and palladium acetate (380 g, 1.69 mol) were then added, and the mixture was degassed again until the dissolved oxygen concentration reached 0.5 ppm or less (as measured by a dissolved oxygen meter). After adjusting the internal temperature to 92°C, a solution of 2,4,6-trichlorophenyl formate (9.2 kg, 40.8 mol) in toluene (69.0 kg) was added dropwise over 30 minutes and stirred at the same temperature for 1 hour. The reaction mixture was cooled to an internal temperature of 25°C, and 10% brine (171.0 kg) was added. The mixture was stirred for 5 minutes, allowed to stand for 5 minutes, and the lower layer (aqueous layer) was removed and discarded. Activated carbon (1.60 kg) and silica gel (11.5 kg) were added to the upper layer (organic layer) and stirred for 14 hours. The resulting slurry was filtered, and the solids were washed with toluene (69.0 kg). The filtrate and washings were combined. The resulting solution was concentrated under reduced pressure until the volume of the system reached 48 L. Acetonitrile (125.0 kg) was added, and the mixture was again concentrated under reduced pressure until the volume of the system reached 48 L. Acetonitrile (125.0 kg) was added, and the mixture was concentrated under reduced pressure until the volume of the liquid in the system reached 48 L. Then, acetonitrile (88.0 kg) and N-acetyl-L-cysteine ​​(0.83 kg, 5.09 mol) were added, and the mixture was stirred at an internal temperature of 25 °C for 1 hour. Water (160.0 kg) was then added dropwise over 1 hour, followed by stirring for 9 hours. The precipitated solid was collected by filtration. This solid was washed with a mixture of acetonitrile (25.0 kg) and water (32.0 kg) and dried to obtain the title compound (Compound 4: 15.05 kg, 27.6 mol).To purify this solid, dimethylacetamide (141.0 kg), N-acetyl-L-cysteine ​​(1.80 kg, 11.0 mol), and the title compound (Compound 4: 15.00 kg, 27.5 mol) were added to a reaction vessel under a nitrogen atmosphere and stirred at an internal temperature of 20 °C for 3 hours. The resulting slurry was filtered, and the collected solid was washed with dimethylacetamide (42.0 kg). The filtrate and washings were combined. Water (38.0 kg) was added dropwise to the combined solution at an internal temperature of 30 °C or below, and the mixture was stirred at an internal temperature of 25 °C for 3 hours. Water (38.0 kg) was then added dropwise over 1 hour, and the mixture was stirred for 9 hours. The precipitated solid was then filtered. The solid was washed with a mixture of dimethylacetamide (41.0 kg) and water (17.0 kg) and dried to obtain the title compound (Compound 4: 10.58 kg, 19.4 mol). The physical properties of the obtained title compound (Compound 4) are as follows: 1 H NMR (500 MHz, CD3CN): δ 7.67 (s, 2H), 7.28 (s, 1H), 5.59 (s, 1H), 4.00 (s, 3H), 3.64 (s, 3H), 2.76 - 2.95 (m, 2H), 2.43 (d, 1H), 0.91 (s, 3H)

[0087] Example 4 Preparation of (1'S,6'R)-N'-acetyl-7-chloro-2',4-dimethoxy-6'-methyl-3,4'-dioxo-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-6-carbohydrazide (Compound 5)

[0088]

[0089] (Example 4-1) Under a nitrogen atmosphere, acetonitrile (100 mL) and 2,4,6-trichlorophenyl (1'S,6'R)-7-chloro-2',4-dimethoxy-6'-methyl-3,4'-dioxo-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-6-carboxylate (Compound 4: 10.0 g, 18.3 mmol) were added to a reaction vessel and the internal temperature was adjusted to 0° C. Then, acetylhydrazine (5.43 g, 73.3 mmol) and 1,4-diazabicyclo{2.2.2}octane (6.16 g, 54.9 mmol) were added, and the mixture was stirred at an internal temperature of 0° C. for 4.5 hours. Next, acetonitrile (150 mL), water (15 mL), and 20% brine (50 mL) were added so that the internal temperature did not exceed 5°C. The pH was adjusted to 5.0 with concentrated hydrochloric acid, followed by stirring for 5 minutes and standing for 5 minutes. The lower (aqueous) layer was then removed and discarded. To the upper (organic) layer, 20% brine (50 mL) was added so that the internal temperature did not exceed 5°C. The mixture was stirred for 5 minutes and stood for 5 minutes. The lower (aqueous) layer was then removed and discarded. This upper (organic) layer was subjected to the same procedure of adding 20% ​​brine, stirring, standing, and then removing the lower (aqueous) layer once more. The upper (organic) layer was then concentrated under reduced pressure until the volume of the liquid in the system reached 50 mL. Acetonitrile (250 mL) was added to the concentrated solution, and the solution was concentrated under reduced pressure until the volume of the liquid in the system reached 50 mL. The solids that had formed in the system were then removed by filtration. The solid collected by filtration was washed with acetonitrile (30 mL), and the title compound obtained in Example 4-2 (Compound 5: 1.00 mg) was added to the combined filtrate and washings, followed by stirring for 21 hours. The internal temperature of this slurry was adjusted to 60°C and stirred for 1 hour to remove any deposits on the reactor wall, and then cooled to an internal temperature of 25°C. tert-Butyl acetate (100 mL) was added to this slurry, followed by concentration under reduced pressure until the volume of the liquid in the system was 50 mL. tert-Butyl acetate (100 mL) was then added again, and the internal temperature of the slurry was adjusted to 60°C and stirred for 1 hour to remove any deposits on the reactor wall, followed by cooling to an internal temperature of 25°C. The liquid in the system was concentrated under reduced pressure until the volume of the liquid in the system was 50 mL, followed by stirring for 2 hours at an internal temperature of 25°C, and then the precipitated solid was filtered.This solid was washed with tert-butyl acetate (50 mL) and dried to obtain the title compound as a solid (Compound 5: 6.80 g, 16.1 mmol). The physical properties of the title compound (Compound 5) obtained are as follows: 1 H NMR (500 MHz, DMSO-d6): δ 10.57 (br, 1H), 10.15 (br, 1H), 7.52 (s, 1H), 5.66 (s, 1H), 3.94 (s, 3H), 3.64 (s, 3H), 2.86 - 2.89 (m, 1H), 2.63 - 2.69 (m, 1H), 2.42 (m, 1H), 1.92 (s, 3H), 0.82 (m, 3H)

[0090] (Example 4-2) Obtaining Compound 5 seed crystals Under a nitrogen atmosphere, acetonitrile (25 mL), 2,4,6-trichlorophenyl(1'S,6'R)-7-chloro-2',4-dimethoxy-6'-methyl-3,4'-dioxo-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-6-carboxylate (Compound 4: 5.0 g, 9.15 mmol), acetylhydrazine (746 mg, 10.1 mmol), and 1,4-diazabicyclo{2.2.2}octane (2.05 g, 18.3 mmol) were added to a reaction vessel and stirred at room temperature for 17 hours. The reaction solution was then concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography. The fractions containing the title compound (Compound 5) were collected and concentrated to dryness to obtain an amorphous solid. Acetonitrile (12 mL) and isopropyl ether (36 mL) were added to the amorphous solid, which was then filtered. The solid was dried to obtain the title compound (Compound 5: 3.07 g, 7.26 mmol) as crystals.

[0091] Example 5 Preparation of Form 1 Crystals of (1'S,6'R)-7-chloro-2',4-dimethoxy-6'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-3,4'-dione (Compound 6)

[0092] The present inventors have discovered a method for selectively obtaining two types of crystals (Form 1 and Form 2) of Compound 6 by the following procedure.

[0093] Under a nitrogen atmosphere, acetone (34.0 kg), (1'S,6'R)-N'-acetyl-7-chloro-2',4-dimethoxy-6'-methyl-3,4'-dioxo-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-6-carbohydrazide (Compound 5: 8.60 kg, 20.3 mol), and tetramethylethylenediamine (4.73 kg, 40.7 mol) were added to a reaction vessel, followed by the addition of p-toluenesulfonyl chloride (4.65 kg, 24.4 mol) so that the internal temperature did not exceed 30°C. The reaction mixture was stirred at an internal temperature of 25°C for 1.5 hours, after which ethyl acetate (192.9 kg) was added and the internal temperature was adjusted to 5°C. To this solution, 1 mol / L hydrochloric acid (43.8 kg) was added so that the internal temperature did not exceed 10°C, followed by stirring for 5 minutes and standing for 5 minutes. The lower layer (aqueous layer) was then removed and discarded. To the upper layer (organic layer), 1 mol / L hydrochloric acid (43.8 kg) was again added so that the internal temperature did not exceed 10°C, followed by stirring for 5 minutes and standing for 5 minutes. The lower layer (aqueous layer) was then removed and discarded. 5% aqueous sodium bicarbonate solution (45.2 kg) was added to the upper layer (organic layer), and the internal temperature was adjusted to 20°C. After stirring for 5 minutes and standing for 5 minutes, the lower layer (aqueous layer) was removed and discarded. Purified water (43.0 kg) was then added to the upper layer (organic layer), followed by stirring for 5 minutes and standing for 5 minutes. The lower layer (aqueous layer) was then removed and discarded. This procedure was repeated twice. Activated carbon (0.86 kg) was added to the upper layer (organic layer) and stirred at an internal temperature of 25°C for 30 minutes. The solids were removed by filtration and washed with ethyl acetate (38.6 kg). The filtrate and washings were combined. The combined solution was concentrated under reduced pressure to a volume of 86 L. Isopropyl alcohol (67.2 kg) was added, and the mixture was concentrated under reduced pressure again to a volume of 86 L. The internal temperature was adjusted to 25°C and stirred for 10 hours, after which it was further concentrated under reduced pressure to a volume of 43 L. Isopropyl alcohol (33.6 kg) was added to the concentrated solution, and the mixture was concentrated under reduced pressure again to a volume of 43 L. The internal temperature was adjusted to 60°C and stirred for 30 minutes to remove any residue from the reactor walls. The internal temperature was then cooled to 25°C over 1 hour, stirred for 2 hours, and then cooled to 0°C over another 2 hours. After stirring at the same temperature for 16 hours, the precipitated solid was filtered.This solid was washed with isopropyl alcohol (20.1 kg) and dried to obtain the title compound (Compound 6: 6.55 kg, 16.2 mol) as a solid. This is also referred to as crude crystals of Compound 6. To purify this solid, ethyl acetate (143.5 kg) and the title compound (Compound 6: 6.40 kg, 15.8 mol) were added to a reaction vessel under a nitrogen atmosphere and stirred at an internal temperature of 25 °C until complete dissolution. Activated carbon (0.64 kg) was then added and stirred for 30 minutes. This slurry was filtered, and the remaining solid was washed with ethyl acetate (45.9 kg). The filtrate and washings were combined. The combined solution was concentrated under reduced pressure until the volume of the system reached 64 L, and isopropyl alcohol (50.0 kg) was added. The internal temperature was adjusted to 45 °C and stirring was continued. After confirming complete dissolution of the crystals, the system was concentrated under reduced pressure until the volume of the system reached 77 L, ensuring that the internal temperature did not fall below 40 °C. After stirring for 15 hours at an internal temperature of 45°C, isopropyl alcohol (50.0 kg) was added and the mixture was concentrated under reduced pressure until the volume of the liquid in the system reached 64 L, while maintaining the internal temperature above 40°C. After stirring for 1.5 hours at an internal temperature of 45°C, additional isopropyl alcohol (50.0 kg) was added and the mixture was concentrated under reduced pressure until the volume of the liquid in the system reached 64 L, while maintaining the internal temperature above 40°C. After stirring for 1 hour at an internal temperature of 45°C, the mixture was cooled to 25°C over 1 hour. After stirring for 12 hours at the same temperature, the precipitated solid was filtered. The solid was washed with isopropyl alcohol (15.0 kg) and dried to obtain purified crystals of Form 1 of the title compound (Compound 6: 5.59 kg, 13.8 mol). The physical properties of the resulting title compound (purified crystals of Form 1 of Compound 6) are as follows: 1 H NMR (500 MHz, CDCl3): δ7.26 (s, 1H), 5.58 (s, 1H), 4.03 (s, 3H), 3.64 (s, 3H), 2.97 - 3.03 (m, 1H), 2.86 - 2.94 (m, 1H), 2.71 (s, 3H), 2.46 - 2.51 (m, 1H), 0.98 - 0.99 (m, 3H)

[0094] For Form 1 crystals of (1'S,6'R)-7-chloro-2',4-dimethoxy-6'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-3,4'-dione (Compound 6) obtained by the method of Example 5, Table 1 lists peaks with a relative intensity of 20 or more, with the maximum peak intensity set to 100. Figure 1 shows the diffraction pattern of the powder X-ray diffraction spectrum (CuKα, λ = 1.54 Å, scanning rate = 10°C / min).

[0095] Example 6 Preparation of Form 2 Crystals of (1'S,6'R)-7-chloro-2',4-dimethoxy-6'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-3,4'-dione (Compound 6)

[0096] Under a nitrogen atmosphere, acetone (4.0 mL), (1'S,6'R)-7-chloro-2',4-dimethoxy-6'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-3,4'-dione (Compound 6: 400 mg, 0.988 mmol), and activated carbon (80 mg) were added to a reaction vessel and stirred for 1 hour. The Compound 6 used here was obtained using the same procedure as the crude crystals of Compound 6 obtained in Example 5. Note that the Compound 6 used here does not necessarily have to be obtained using the same procedure as the crude crystals of Compound 6 obtained in Example 5. The resulting slurry was filtered, and the solid was washed with acetone (4.0 mL). The filtrate and the washings were combined. The solution was concentrated under reduced pressure to a volume of 24 mL, and then water (16.0 mL) was added and stirred for 1 hour. Water (8.0 mL) was then added and stirred for 1 hour, followed by the addition of water (20.0 mL). After stirring for another hour, the precipitated solid was filtered. The solid was dried to obtain Form 2 crystals of the title compound (186.5 mg, 0.461 mmol).

[0097] For Form 2 crystals of (1'S,6'R)-7-chloro-2',4-dimethoxy-6'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-3,4'-dione obtained by the method of Example 6, Table 2 lists peaks with a relative intensity of 10 or more, with the maximum peak intensity set to 100. Figure 2 shows the diffraction pattern of the powder X-ray diffraction spectrum (CuKα, λ = 1.54 Å, scanning rate = 10°C / min).

[0098]

[0099]

[0100] It is clear that a person skilled in the art can conceive of various modifications and alterations within the scope of the claims, and it is understood that these also naturally fall within the technical scope of the present invention. Furthermore, the components in the above-described embodiments may be combined in any manner without departing from the spirit of the invention.

[0101] This application is based on a Japanese patent application (Patent Application No. 2023-215081) filed on December 20, 2023, the contents of which are incorporated herein by reference.

Claims

1. A crystal of (1'S,6'R)-7-chloro-2',4-dimethoxy-6'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-3,4'-dione (Compound 6) having the following structure.

2. The crystal according to claim 1, which is a Form 1 crystal having peaks at diffraction angles (2θ(°)) of 12.3, 15.6, 18.3, 22.3, and 22.9 (including a range of ±0.2°) in powder X-ray diffraction.

3. The crystal according to claim 1, which is a Form 1 crystal having peaks at diffraction angles (2θ(°)) of 12.32, 15.64, 18.32, 22.32, and 22.90 (including a range of ±0.2°) in powder X-ray diffraction.

4. The crystal of claim 1, which is a Form 1 crystal having the X-ray diffraction pattern shown below.

5. The crystal according to claim 1, which is a Form 2 crystal having peaks at diffraction angles (2θ(°)) of 5.5, 7.1, 11.2, 26.7, and 27.0 (including a range of ±0.2°) in powder X-ray diffraction.

6. The crystal according to claim 1, which is a Form 2 crystal having peaks at diffraction angles (2θ(°)) of 5.46, 7.12, 11.24, 26.74, and 27.03 (including a range of ±0.2°) in powder X-ray diffraction.

7. The crystal according to claim 1, which is a Form 2 crystal having the X-ray diffraction pattern shown below.

8. A method for purifying (1'S,6'R)-7-chloro-2',4-dimethoxy-6'-methyl-6-(5-methyl-1,3,4-oxadiazol-2-yl)-3H-spiro[[1]benzofuran-2,1'-cyclohex[2]ene]-3,4'-dione (Compound 6) having the following structure: A method for purifying Compound 6, comprising dissolving Compound 6 in an organic solvent, treating the compound with activated carbon, and crystallizing the compound 6 from the organic solvent to obtain the crystals according to any one of claims 2 to 4.

9. A method for purifying Compound 6 according to claim 8, comprising the steps of (i) to (iv) in this order: (i) dissolving Compound 6 in ethyl acetate to obtain an ethyl acetate solution of Compound 6, adding activated carbon thereto and stirring, and then filtering off the activated carbon; (ii) stirring the solution obtained in (i) while heating, and then distilling off the solvent; (iii) adding isopropyl alcohol to the substance obtained in (ii) again, stirring the solution while heating, and then distilling off the solvent; (iv) washing the solid obtained in (iii) with isopropyl alcohol and drying it to obtain the crystals.

10. A method for producing (1'S,6'R)-7-chloro-6-hydroxy-2',4-dimethoxy-6'-methyl-3H-spiro[[1]benzofuran-2,1'-cyclohexa[2]ene]-3,4'-dione (Compound 2) having the following structure from (1'S,6'R)-7-chloro-2',4,6-trimethoxy-6'-methyl-3H-spiro[[1]benzofuran-2,1'-cyclohexa[2]ene]-3,4'-dione (Compound 1) having the following structure, A method for producing Compound 2, comprising the steps of (i) to (iii) below in this order: (i) heating and stirring Compound 1 and tetrabutylammonium iodide to obtain a reaction solution; (ii) adding activated carbon, water, and hydrochloric acid to the reaction solution obtained in (i), filtering, and then extracting, back-extracting, and extracting again in that order; and (iii) filtering again and concentrating the resulting mixture to obtain Compound 2.

11. A pharmaceutical composition comprising the crystal according to any one of claims 1 to 7.

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