Method for producing pyrazolopyrimidine compound and synthetic intermediate thereof

Abstract

Provided are a method for producing a pyrazolopyrimidine compound useful as an NLRP3 inflammasome inhibitor or a salt thereof, a synthetic intermediate thereof, and a method for producing the synthetic intermediate. Provided is a method for producing a compound represented by formula [11], a pharmaceutically acceptable salt thereof, or a hydrate thereof by using a compound represented by formula [10] (in formula [10], R1 is a halogen) or a pharmaceutically acceptable salt thereof.

Description

Method for producing pyrazolopyrimidine compounds and their synthetic intermediates

[0001] The present invention relates to a method for producing pyrazolopyrimidine compounds or salts thereof that are useful as NLRP3 inflammasome inhibitors, a synthetic intermediate thereof, and a method for producing the synthetic intermediate thereof.

[0002] NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) is a pattern recognition receptor belonging to the NLR (NOD-like receptors) family. Activated NLRP3 associates with the adapter protein ASC (Apoptosis-associated speck-like protein containing a caspase recruitment domain) and the cysteine ​​protease caspase 1 through protein-protein interactions to form the NLRP3 inflammasome, an intracellular protein complex.

[0003] Patent Document 1 describes compounds useful as NLRP3 inflammasome inhibitors

[11] This has been disclosed.

[0004] International Public Gazette WO2024 / 048519

[0005] The present invention provides a method for producing pyrazolopyrimidine compounds or salts thereof that are useful as NLRP3 inflammasome inhibitors, a synthetic intermediate thereof, and a method for producing the synthetic intermediate thereof.

[0006] The present invention includes the following embodiments: Clause 1: Formula

[10] (In the formula, R １ Using a compound of (which is a halogen) or a pharmaceutically acceptable salt thereof, formula

[11] A method for producing a compound or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

[0007] Item 2: Using a compound of formula

[10] or a pharmaceutically acceptable salt thereof, formula [11a] The method according to item 1, comprising the step of obtaining a compound of formula [11a] or a pharmaceutically acceptable salt thereof, and the step of obtaining a compound of formula

[11] or a pharmaceutically acceptable salt thereof from the compound of formula [11a] or a pharmaceutically acceptable salt thereof.

[0008] Item 3: The method according to item 2, wherein 1-propanol is used in the step of obtaining a compound of formula

[11] or a pharmaceutically acceptable salt thereof from the compound of formula [11a] or a pharmaceutically acceptable salt thereof.

[0009] Item 4: The method according to any one of items 1 to 3, further comprising the step of recrystallizing a compound of formula

[11] or a pharmaceutically acceptable salt thereof, or a hydrate thereof, using 1-propanol.

[0010] Item 5: A compound of formula [9] or a pharmaceutically acceptable salt thereof, and a compound of formula [4] (wherein each R １ is independently halogen) or a pharmaceutically acceptable salt thereof, to obtain a compound of formula

[10] or a pharmaceutically acceptable salt thereof. The method according to any one of items 1 to 4.

[0011] Item 6: The method according to any one of items 1 to 5, wherein R １ is chlorine.

[0012] Item 7: The method according to item 5 or 6, comprising the step of obtaining a compound of formula [4] or a pharmaceutically acceptable salt thereof using a compound of formula [3] or a pharmaceutically acceptable salt thereof.

[0013] Item 8: A compound of formula [8] (wherein R ２ is C １－４ alkyl) or a pharmaceutically acceptable salt thereof, to obtain a compound of formula [9] or a pharmaceutically acceptable salt thereof. The method according to any one of items 5 to 7.

[0014] Item 9: A compound of formula [6] (wherein R ２ is as defined above, and R ３ is halogen) or a pharmaceutically acceptable salt thereof, and a compound of formula [7] A process for obtaining a compound of formula [8] or a pharmaceutically acceptable salt thereof, using a compound, cyclopropylboronic acid pinacol ester or potassium cyclopropyltrifluoroborate, as described in item 8.

[0015] Item 10: R ２ The method according to item 8 or 9, wherein R is methyl.

[0016] Item 11: R ３ The method according to item 9 or 10, wherein R is bromine.

[0017] The method according to any one of items 9 to 11, using a compound of formula [7].

[0018] Item 13: Formula

[10] (wherein R １ is as defined above) or a pharmaceutically acceptable salt thereof.

[0019] Item 14: R １ The compound according to item 13 or a pharmaceutically acceptable salt thereof, wherein R is chlorine.

[0020] Item 15: A compound of formula [3] or a pharmaceutically acceptable salt thereof.

[0021] Item 16: Formula [8] (wherein R ２ is as defined above) or a pharmaceutically acceptable salt thereof.

[0022] Item 17: R ２ The compound according to item 16 or a pharmaceutically acceptable salt thereof, wherein R is methyl.

[0023] Item 18: Formula [6] (wherein R ２ and R ３ are as defined above) or a pharmaceutically acceptable salt thereof.

[0024] Item 19: R ２ The compound according to item 18 or a pharmaceutically acceptable salt thereof, wherein R is methyl.

[0025] Item 20: R ３ The compound according to item 18 or 19 or a pharmaceutically acceptable salt thereof, wherein R is bromine.

[0026] Figure 1 shows multiplexed recordings of the powder X-ray diffraction pattern of compound [3]. The vertical axis shows the diffraction intensity (cps: counts per second), and the horizontal axis shows the diffraction angle 2θ (°). Figure 2 shows multiplexed recordings of the powder X-ray diffraction pattern of compound [6a]. The vertical axis shows the diffraction intensity (cps: counts per second), and the horizontal axis shows the diffraction angle 2θ (°). Figure 3 shows multiplexed recordings of the powder X-ray diffraction pattern of compound [8a]. The vertical axis shows the diffraction intensity (cps: counts per second), and the horizontal axis shows the diffraction angle 2θ (°). Figure 4 shows multiplexed recordings of the powder X-ray diffraction pattern of compound [10a]. The vertical axis shows the diffraction intensity (cps: counts per second), and the horizontal axis shows the diffraction angle 2θ (°). Figure 5 shows multiplexed recordings of the powder X-ray diffraction pattern of the crystal (α-crystal) of compound [11a]. The vertical axis shows diffraction intensity (cps: counts per second), and the horizontal axis shows the diffraction angle 2θ (°). Figure 6 shows multiple recordings of the powder X-ray diffraction pattern of the crystalline (β-crystal) form of compound

[11] . The vertical axis shows diffraction intensity (cps: counts per second), and the horizontal axis shows the diffraction angle 2θ (°). Figure 7 shows multiple recordings of the powder X-ray diffraction pattern of the crystalline (γ-crystal) form of compound [11a]. The vertical axis shows diffraction intensity (cps: counts per second), and the horizontal axis shows the diffraction angle 2θ (°).

[0027] The definitions of terms used herein are as follows:

[0028] In this specification, for example, the compound of formula

[11] may be referred to as compound

[11] .

[0029] Examples of halogens include fluorine, chlorine, bromine, and iodine. Preferably, chlorine or bromine is used.

[0030] C １－４ Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Methyl is preferred.

[0031] In this specification, a pharmaceutically acceptable salt is any salt known in the art that does not impose excessive toxicity. Specifically, this includes salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases. Various forms of pharmaceutically acceptable salts are well known in the art and are described, for example, in the following references: (a) Berge et al., J. Pharma. Sci., 66, pp. 1-19 (1977), (b) Stahl et al., "Handbook of Pharmaceutical Salt: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002), (c) Paulekuhn et al., J. Med. Chem. 50, pp. 6665-6672 (2007). By reacting the compounds described herein with inorganic acids, organic acids, inorganic bases, or organic bases according to methods known to the present, pharmaceutically acceptable salts thereof can be obtained.

[0032] Examples of salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, or sulfuric acid. Examples of salts with organic acids include salts with acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetate, ethane-1,2-disulfonic acid, dodecyl sulfate, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycolylarsanilic acid, hexylresorcinic acid, hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, Examples include salts with malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitrate, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectinic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, theoclic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid, or glutamic acid.

[0033] Examples of salts with inorganic bases include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, or ammonium. Examples of salts with organic bases include salts with arecoline, betaine, choline, cremisole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine, or lysine.

[0034] The compounds or salts thereof according to the present invention may exist as solvates. A solvate is a compound or salt thereof according to the present invention in which a solvent molecule is coordinated. The solvate may be any pharmaceutically acceptable solvate, such as a hydrate, acetate, acetone, ethanol, or dimethyl sulfoxide of the compound or salt thereof according to the present invention. Specifically, examples include hemihydrates, monohydrates, dihydrates, monoacetates, monoacetates, monoacetones, or monoethanolates of the compound or salt thereof according to the present invention, or 2 / 3 ethanolates of the monohydrate, monoacetone, or dihydrochloride of the sodium salt of the compound or salt thereof according to the present invention. These solvates can be obtained according to known methods.

[0035] Formula

[11] Examples of compounds represented by or their pharmaceutically acceptable salts, or their hydrates, include the following compounds: Or, These are some examples.

[0036] The compounds, salts thereof, or solvates thereof according to the present invention may exist as tautomers. In that case, the compounds, salts thereof, or solvates thereof according to the present invention include individual tautomers or mixtures of tautomers. For example, the following formula: The structure described above is, unless otherwise noted, (1) (2) (3) (4) (5) It means that they exist and / or can be written as a mixture thereof.

[0037] The compounds, salts thereof, or solvates thereof according to the present invention may have a carbon-carbon double bond. In that case, the compounds, salts thereof, or solvates thereof according to the present invention may exist as an E-isomer, a Z-isomer, or a mixture of the E-isomer and the Z-isomer, and include these. The compounds, salts thereof, or solvates thereof according to the present invention may have stereoisomers that should be recognized as cis / trans isomers. In that case, the compounds, salts thereof, or solvates thereof according to the present invention may exist as a cis-isomer, a trans-isomer, or a mixture of the cis-isomer and the trans-isomer, and include these. The compounds, salts thereof, or solvates thereof according to the present invention may have one or more chiral carbons. In that case, the compounds, salts thereof, or solvates thereof according to the present invention may exist as a single enantiomer, a single diastereomer, a mixture of enantiomers, or a mixture of diastereomers, and include these. The compounds, salts thereof, or solvates thereof according to the present invention may exist as atropisomers. In that case, the compounds, salts thereof, or solvates thereof according to the present invention may exist as individual atropisomers or a mixture of atropisomers, and include these. The compound, salt thereof, or solvate thereof according to the present invention may simultaneously contain multiple structural features that give rise to the above-mentioned isomers. Furthermore, the compound, salt thereof, or solvate thereof according to the present invention may contain the above-mentioned isomers in any proportion.

[0038] Diastereomer mixtures can be separated into their individual diastereomers by conventional methods such as chromatography and crystallization. Alternatively, each diastereomer can be synthesized using stereochemically monolithic starting materials or through stereoselective reactions.

[0039] The separation of each single enantiomer from a mixture of enantiomers can be carried out by methods well known in this field. For example, from a mixture of enantiomers and a diastereomer mixture formed by reacting a substantially pure enantiomer known as a chiral auxiliary, a single diastereomer with an increased isomer ratio or substantially pure can be separated by standard methods such as fractional crystallization or chromatography. The separated diastereomer can then be converted to the desired enantiomer by removing the added chiral auxiliary through cleavage. Alternatively, the mixture of enantiomers can be directly separated by chromatography using a chiral stationary phase, a method well known in this field. Or, one of the enantiomers can be obtained by using substantially pure optically active starting materials, or by stereoselective synthesis (asymmetric induction) of a prochiral intermediate using a chiral auxiliary or an asymmetric catalyst.

[0040] The absolute configuration can be determined by X-ray crystallography of the crystalline product or intermediate. If necessary, a crystalline product or intermediate derived with a reagent having a known chiral center configuration may be used.

[0041] The compound or salt thereof, or solvate thereof, according to the present invention may be crystalline, amorphous, or a mixture thereof.

[0042] The compound or salt thereof, or solvate thereof, according to the present invention, contains an isotopic element ( ２ H(D), ３ H, １１ C, １３ C, １４ C, １３ N, １５ N, １５ O, １８ O, １８ F, ３５ S, １２３ It may be labeled with (I, etc.). For example, if the compound according to the present invention has a methyl group, the methyl group is -CD ３The base can be substituted, and compounds obtained in this manner are also included in the present invention. Compounds labeled with isotopes, their salts, or their solvates may be useful in pharmaceuticals, pharmacokinetic studies, in vitro and / or in vivo assays, and / or diagnostics (positron emission tomography (PET), single-photon emission computed tomography (SPECT), etc.). Compounds labeled with isotopes can be prepared using isotope-labeled compounds instead of unisotopically labeled compounds according to known methods or the methods described herein.

[0043] The compound, salt thereof, or solvate thereof according to the present invention is preferably a substantially purified compound, salt thereof, or solvate thereof. More preferably, it is a compound, salt thereof, or solvate thereof purified to a purity of 80% or higher.

[0044] A method for producing the compound, its salt, or its solvate according to the present invention is illustrated below. In each step, the reaction may be carried out in a solvent. The compound obtained in each step can be isolated and purified by known methods such as distillation, recrystallization, or column chromatography, as needed, but in some cases, the process may proceed to the next step without isolation or purification. In this specification, the reaction temperature may include the temperature described ± 5°C, preferably ± 2°C.

[0045] [Manufacturing Method 1] Manufacturing of compound [4] (In the formula, R １ Each of them is an independent halogen, and R ４ Each is independently C １－４ (It is alkyl.)

[0046] Step 1 Compound [3] or a salt thereof can be produced by carrying out Step 1-1 shown below, concentrating the resulting reaction solution, and then carrying out Step 1-2. Step 1-1: Compound [1] or a salt thereof is reacted in a solvent in the presence of a reactant. Examples of reactants include sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, ammonia, sodium amide, a mixture of ammonium chloride and sodium methoxide, etc. A preferred reactant is sodium bis(trimethylsilyl)amide. The amount of reactant used is, for example, 1.0 to 5.0 equivalents relative to compound [1], preferably 1.1 to 1.3 equivalents. Examples of solvents include water, methanol, ethanol, isopropanol, tetrahydrofuran, cyclopentyl methyl ether, 1,4-dioxane, toluene, and mixtures thereof. A preferred solvent is tetrahydrofuran. The reaction temperature is, for example, -40°C to 40°C, preferably -20°C to 5°C. The reaction time is, for example, 1 to 48 hours, preferably 1 to 12 hours.

[0047] Step 1-2: The concentrate of the reaction solution obtained in Step 1-1 is reacted with compound [2] or a salt thereof in a solvent. A base (e.g., sodium bis(trimethylsilyl)amide, sodium methoxide, etc.) may be added as needed. Examples of solvents include water, methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, cyclopentyl methyl ether, toluene, dimethyl sulfoxide, and mixtures thereof. A preferred solvent is methanol. The reaction temperature is, for example, 0°C to 100°C, preferably 45°C to 65°C. The reaction time is, for example, 1 hour to 48 hours, preferably 6 hours to 20 hours. Compound [1] or a salt thereof may be commercially available or produced from a commercially available product by a known method. Compound [2] or a salt thereof may be commercially available or produced from a commercially available product by a known method.

[0048] Step 2 Compound [4] or a salt thereof can be produced by reacting compound [3] or a salt thereof in a solvent in the presence of a reactant. The reactant is added in several stages, for example, in two stages. Water may be added to the solvent as needed. An endothermic reagent (for example, disodium hydrogen phosphate dodecahydrate) may be added during post-treatment. Examples of reactants include phosphorus oxychloride, thionyl chloride, oxalyl chloride, phenyl phosphodichloride, phosphorodichloride anhydride, phosphoryl bromide, etc. A preferred reactant is phosphorus oxychloride. The amount of reactant used is, for example, 1 to 18 equivalents relative to compound [3], preferably 1 to 14 equivalents. Examples of solvents include N,N-dimethylformamide, N,N-dibutylformamide, toluene, benzene, chlorobenzene, dichlorobenzene, dichloroethane, and mixed solvents thereof. A preferred solvent is a mixed solvent of N,N-dimethylformamide and toluene. The reaction temperature is, for example, 0°C to 100°C, preferably 10°C to 60°C. The reaction time is, for example, 1 hour to 72 hours, preferably 10 hours to 50 hours.

[0049] [Manufacturing Method 2] Manufacturing of Compound [8] (In the formula, R ２ is C １－４ It is alkyl, R ３ (It is a halogen.)

[0050] Step 3 Compound [6] or a salt thereof can be produced by reacting compound [5] or a salt thereof with a reactant in a solvent in the presence of a base. Examples of bases include N,N-diisopropylethylamine, triethylamine, tributylamine, 1,1,3,3-tetramethylguanidine, 1,8-diazabicyclo[5.4.0]-7-undecene, potassium carbonate, etc. A preferred base is N,N-diisopropylethylamine. The amount of base used is, for example, 2 to 5 equivalents relative to compound [5], preferably 2.5 to 3.5 equivalents. Examples of reactants include methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, butyl chloroformate, etc. A preferred reactant is methyl chloroformate. The amount of reactant used is, for example, 1.0 to 4.0 equivalents relative to compound [5], preferably 1.0 to 1.1 equivalents. Examples of solvents include tetrahydrofuran, cyclopentyl methyl ether, acetonitrile, methyl-tert-butyl ether, toluene, methylene chloride, and mixtures thereof. Tetrahydrofuran is a preferred solvent. The reaction temperature is, for example, -40°C to 50°C, preferably -30°C to 20°C. The reaction time is, for example, 0.1 hours to 24 hours, preferably 0.5 hours to 16 hours. Compound [5] or its salt may be commercially available or produced from a commercially available product by a known method.

[0051] Step 4 Compound [8] or a salt thereof can be produced by reacting compound [6] or a salt thereof with compound [7] or a derivative thereof (e.g., pinacol cyclopropylboronic acid ester and potassium cyclopropyltrifluoroborate) in a solvent in the presence of a catalyst and a base. The amount of compound [7] or a derivative thereof used is, for example, 1 to 5 equivalents relative to compound [6], preferably 1 to 3 equivalents. Examples of catalysts include palladium acetate, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct, tetrakis(triphenylphosphine)palladium(O), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride, 1,3,5,7-tetramethyl-8-phenyl-2,4,6-trioxa-8-phosphineadamantane, 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl, 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl, tris(dibenzylideneacetone)dipalladium(O), and [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate. A preferred catalyst is palladium acetate or 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl. The amount of catalyst used is, for example, 0.001 to 0.5 equivalents relative to compound [7], preferably 0.01 to 0.03 equivalents. Examples of bases include tripotassium phosphate, cesium carbonate, potassium carbonate, potassium fluoride, lithium hydroxide, etc. A preferred base is tripotassium phosphate. The amount of base used is, for example, 2 to 5 equivalents relative to compound [6], preferably 3 to 4 equivalents. Examples of solvents include water, toluene, 1,2-dimethoxyethane, 1,4-dioxane, cyclopentyl methyl ether, chlorobenzene, dichlorobenzene, and mixed solvents thereof. A preferred solvent is a mixed solvent of toluene and water. The reaction temperature is, for example, 0°C to 120°C, preferably 70°C to 90°C.The reaction time is, for example, 1 to 48 hours, preferably 5 to 20 hours. Compound [7] or a salt thereof may be prepared from a commercially available product by known methods.

[0052] [Manufacturing Method 3] Manufacturing of Compound

[11] (In the formula, R １ and R ２ (This is synonymous with the definition above.)

[0053] Step 5 Compound [9] or a salt thereof can be produced by reacting compound [8] or a salt thereof in a solvent in the presence of a base and an antioxidant. Examples of bases include potassium hydroxide, sodium hydroxide, lithium hydroxide, and tetrabutylammonium hydroxide. A preferred base is potassium hydroxide. The amount of base used is, for example, 1.0 to 6.0 equivalents relative to compound [8], preferably 3.0 to 5.0 equivalents. Examples of antioxidants include sodium thiosulfate pentahydrate, N-acetyl-L-cysteine, and 2,6-di-tert-butyl-4-methylphenol. A preferred antioxidant is sodium thiosulfate pentahydrate. The amount of antioxidant used is, for example, 0.1 to 1.0 equivalents relative to compound [8], preferably 0.15 to 0.25 equivalents. Examples of solvents include water, 2-ethoxyethanol, methanol, ethanol, 1-propanol, 2-propanol, cyclopentyl methyl ether, tetrahydrofuran, dimethyl sulfoxide, and mixtures thereof. A preferred solvent is a mixture of water and 2-ethoxyethanol. The reaction temperature is, for example, 0°C to 80°C, preferably 30°C to 55°C. The reaction time is, for example, 1 hour to 24 hours, preferably 3 hours to 10 hours.

[0054] Step 6 Compound

[10] or a salt thereof can be produced by reacting compound [9] or a salt thereof (which may be the crude product obtained in Step 5) with compound [4] or a salt thereof in a solvent in the presence of a base. If necessary, an antioxidant (e.g., 2,6-di-tert-butyl-4-methylphenol) may be added. Examples of bases include triethylamine, N,N-diisopropylethylamine, diisopropylamine, tributylamine, 1,1,3,3-tetramethylguanidine, 1,8-diazabicyclo[5,4,0]-7-undecene, potassium carbonate, and tripotassium phosphate. A preferred base is N,N-diisopropylethylamine. The amount of base used is, for example, 1.5 to 5.0 equivalents relative to compound [4], preferably 2.0 to 4.0 equivalents. Examples of solvents include water, methanol, ethanol, tetrahydrofuran, toluene, cyclopentyl methyl ether, acetonitrile, 1,2-dimethoxyethane, ethyl acetate, dimethylformamide, and mixtures thereof. Preferred solvents are a mixture of water, tetrahydrofuran, and cyclopentyl methyl ether, or a mixture of water and cyclopentyl methyl ether. The reaction temperature is, for example, 0°C to 80°C, preferably 15°C to 35°C. The reaction time is, for example, 1 hour to 48 hours, preferably 12 hours to 24 hours.

[0055] Step 7 Compound

[11] or a salt thereof, or a hydrate thereof, can be produced by reacting compound

[10] or a salt thereof in a solvent in the presence of an acid. Activated carbon (e.g., Carboraffin®) may be added as needed. Examples of acids include formic acid, acetic acid, trifluoroacetic acid, and hydrochloric acid. Formic acid is preferred. The amount of acid used is, for example, 1.0 to 40 equivalents, preferably 4.0 to 16 equivalents, relative to compound

[10] . Examples of solvents include water, acetonitrile, tetrahydrofuran, ethanol, 1-propanol, 2-propanol, dimethyl sulfoxide, and mixed solvents thereof. A preferred solvent is a mixed solvent of acetonitrile and water (e.g., a volume ratio of 100:1 to 1:1, preferably 50:1 to 2:1). The reaction temperature is, for example, 0°C to 80°C, preferably 30°C to 60°C. The reaction time is, for example, 1 to 48 hours, preferably 3 to 24 hours.

[0056] [Manufacturing Method 4] Manufacturing of Compound

[11]

[0057] Compound

[11] can be produced by stirring compound [11a] in a solvent, cooling, and then stirring again. Cooling and stirring may be repeated two or more times. Examples of solvents include ethanol, 1-propanol, acetonitrile, ethyl acetate, and mixtures thereof. The preferred solvent is 1-propanol. The amount of solvent used is, for example, 2 to 20 times the weight of compound [11a], preferably 3 to 6 times. The stirring temperature before cooling is, for example, 10°C to 60°C, preferably 20°C to 50°C. The stirring temperature after cooling is, for example, -10°C to 35°C, preferably 0°C to 10°C. The stirring time is, for example, 0.5 hours to 24 hours, preferably 1 hour to 20 hours. More preferably, 1 hour to 4 hours, or 5 hours to 16 hours.

[0058] Purification of Compound

[11] Compound

[11] or its salt can be purified by dissolving Compound

[11] or its salt, or its hydrate, in a solvent and then recrystallizing it. During recrystallization, stirring under cooling may be performed two or more times. During recrystallization, filtration and concentration operations may be performed. Activated carbon (e.g., Carboraffin®) may be added as needed. Examples of solvents include ethanol, 1-propanol, ethyl acetate, n-hexane, cyclohexane, n-heptane, and mixtures thereof. The preferred solvent is 1-propanol. The amount of solvent used is, for example, 5 to 20 times the weight of Compound

[11] , preferably 6 to 10 times. The dissolution temperature is, for example, 70°C to 120°C, preferably 75°C to 90°C. The stirring temperature under cooling is, for example, -15°C to 60°C, preferably -5°C to 55°C. The stirring time is, for example, 0.5 hours to 72 hours, preferably 2 hours to 50 hours. It is more preferable to carry out a recrystallization step after the step of producing compound

[11] from compound [11a].

[0059] The characteristics of this manufacturing method include, for example, the following: (1) In step 2, compound [4], for example, compound [4a] (1) When manufacturing the compound [5], post-processing can be carried out safely by using disodium hydrogen phosphate or its hydrate, which has an endothermic effect, in the post-processing step. (2) By protecting the hydrazine portion of compound [5] with an alkyl ester (e.g., methyl ester), the decomposition of the product during deprotection can be suppressed, and the purity and yield of compound [9] can be increased. (3) Step 6 can be carried out using a solution containing the synthesized compound [9] so that compound [9], which may be mutagenic, does not need to be handled as a powder. (4) By stirring and recrystallizing in 1-propanol, physicochemically high-purity crystals (β crystals) of compound

[11] can be obtained.

[0060] Methods for producing the compound, salt thereof, or solvate thereof according to the present invention will be specifically described by examples. However, the present invention is not limited to these examples.

[0061] The measuring device and measurement conditions used in this embodiment are shown below.

[0062] １ H-NMR and １３ The C-NMR spectrum is DMSO-d ６ In the above, tetramethylsilane was used as an internal standard for measurement, and the total δ value is expressed in ppm. Unless otherwise specified, measurements were taken using 400 MHz and 100 MHz NMR spectrometers. The symbols in the examples have the following meanings: s: singlet d: doublet t: triplet dd: double doublet ddd: double double doublet tt: triple triplet br: broad m: multiplet J: coupling constant

[0063] ​The X-ray diffraction pattern of the sample was measured by powder X-ray diffraction. Measurement equipment: Empiren (Spectris) Measurement conditions: Measurement mode: HTS transmission method Cathode: Copper X-ray tube current and voltage: 45kV, 40mA Sample plate vibration amplitude: x-axis, 4mm Mirror: Focusing mirror Solar slit on the incident side: 0.04rad Sample mask: 4mm Divergent slit on the incident side: 1 / 2° Scattering slit on the incident side: 1 / 2° Filter on the receiving side: None Solar slit on the receiving side: 0.04rad Divergent slit on the receiving side: None Detector: PIXcel1D Detector mode: Scanning Effective width of detector: 3.3482° Scanning axis: Goniometric Scanning mode: Continuous Scanning range: 3° to 25° Time per unit step: 9.4 seconds Repeat measurement: 3 times

[0064] [Example 1] Preparation of 2-(4-cyclopropyl-2,6-dimethylphenyl)-6-(1-methyl-1H-pyrazole-3-yl)-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one (compound

[11] )

[0065] Process 1 Under a nitrogen atmosphere, a solution of sodium bis(trimethylsilyl)amide in tetrahydrafuran (39.6% by weight, 103.8 kg) was added dropwise to a solution of compound [1] (20.0 kg, 186.7 mol) in tetrahydrafuran (106.0 kg) over 6 hours and 50 minutes at a temperature of -6.0°C to -5.0°C. The reaction mixture was stirred at -8.8°C to -5.1°C for 2 hours, and then methanol (79.0 kg) was added dropwise over 4 hours and 50 minutes at a temperature of -8.9°C to 2.5°C. After standing for 7 hours and 30 minutes at a temperature of -9.8°C to -0.3°C, the solution was concentrated. Methanol (79.0 kg) was added to the filtrate for concentration, and then methanol (15.8 kg) was added. Compound [2a] (37.0 kg) was added to this solution, and then the mixture was stirred at a temperature of 45.0°C to 56.9°C for 18 hours and 20 minutes. Concentrated hydrochloric acid (3.9 kg) and water (100.0 kg) were sequentially added to this reaction mixture, and the mixture was stirred at 20.4°C to 24.0°C for 1 hour. Further addition of concentrated hydrochloric acid (19.5 kg) and water (100.0 kg) was performed, and the mixture was stirred at a temperature of 19.1°C to 24.3°C for 14 hours. The resulting suspension was filtered and washed sequentially with a mixture of methanol (15.8 kg) and water (60.0 kg), followed by water (50 L or more). The resulting solid was dried under reduced pressure to obtain compound [3] (34.1 kg, 177.4 mol) in 92.1% yield. 1 ¹H-NMR (400MHz, DMSO-d6) δ: 11.62 (2H, br), 7.86 (1H, d, J = 2.8 Hz), 6.93 (1H, d, J = 2.0 Hz), 5.24 (1H, s), 3.94 (3H, s). ¹³C-NMR (100MHz, DMSO-d6) δ: 166.7, 152.0, 143.8, 133.1, 106.4, 88.6, 39.2 For the obtained compound [3], the diffraction angle 2θ and diffraction intensity were measured by powder X-ray diffraction. The obtained spectra are shown in Figure 1. The peaks in Figure 1 are as shown in the table below.

[0066] The compound of formula [3] is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5) at diffraction angles (2θ) of 11.1±0.2°, 13.3±0.2°, 18.9±0.2°, 21.2±0.2°, or 23.8±0.2°, as measured using CuKα emission. Preferably, the compound of formula [3] is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5) at diffraction angles (2θ) of 11.1±0.1°, 13.3±0.1°, 18.9±0.1°, 21.2±0.1°, or 23.8±0.1°, as measured using CuKα emission. More preferably, the compound of formula [3] is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5) at diffraction angles (2θ) of 11.1±0.06°, 13.3±0.06°, 18.9±0.06°, 21.2±0.06°, or 23.8±0.06°, measured using CuKα radiation.

[0067] Process 2 Under a nitrogen atmosphere, phosphorus oxychloride (32.6 kg) was added dropwise over 2 hours and 30 minutes at a temperature ranging from 19.2°C to 30.2°C to a mixture of compound [3] (34.1 kg, 177.4 mol), N,N-dimethylformamide (129.6 kg), and toluene (15.0 kg). This reaction mixture was stirred for 20 hours and 40 minutes at a temperature ranging from 19.9°C to 27.6°C. To this reaction mixture, phosphorus oxychloride (326.5 kg) was added dropwise at a temperature ranging from 19.9°C to 46.7°C, and the mixture was stirred for 20 hours and 40 minutes at a temperature ranging from 45.0°C to 50.9°C. The resulting reaction solution was added to a mixture of disodium hydrogen phosphate dodecahydrate (1080.4 kg) and water (648 L) over 5 hours and 50 minutes at a temperature ranging from 0.3°C to 28.2°C. The mixture was then washed with acetonitrile (26.6 kg) and stirred for 15 hours and 20 minutes. The precipitated solid was filtered off under reduced pressure and washed twice with water (50 L). The obtained solid was mixed with water (853 L) and stirred at 17.7°C to 18.3°C for 2 hours and 20 minutes. This suspension was filtered and washed with water (50 L or more). The obtained solid was dried under reduced pressure to obtain compound [4a] (37.75 kg, 146.8 mol) in 87.0% yield.1 13C-NMR (100MHz, DMSO-d6) δ: 10.28 (1H, s), 7.92 (1H, d, J = 2.4 Hz), 7.04 (1H, d, J = 2.0 Hz), 4.00 (3H, s). 186.6, 161.9, 160.4, 146.6, 133.4, 121.9, 108.9, 39.5

[0068] Process 3 Under a nitrogen atmosphere, methyl chloroformate (15.0 kg) was added dropwise over 2 hours and 40 minutes at a temperature ranging from -2.6°C to 7.9°C to a mixture of compound [5a] (38.0 kg, 151.0 mol), N,N-diisopropylethylamine (58.5 kg), and tetrahydrofuran (168.9 kg). The reaction mixture was stirred for 1 hour. Water (38.0 kg) was added to the resulting mixture over 1 hour and 10 minutes at a temperature ranging from 12.7°C to 22.6°C. This solution was stirred for more than 20 minutes to separate the organic layer. The resulting organic layer was washed with an aqueous sodium chloride solution (20% by weight, 38.0 kg), the aqueous layer was drained, and the solution was concentrated under reduced pressure. Methanol (90.3 kg) was added to this concentrate, and the solution was concentrated under reduced pressure again. Methanol (33.1 kg) was added to the resulting concentrate. Water (76.0 kg) was added dropwise to the obtained solution over 30 minutes at a temperature ranging from 48.9°C to 51.2°C, and then the mixture was stirred for 30 minutes at a temperature ranging from 27.8°C to 30.4°C. The precipitated solid was filtered and washed with a mixture of methanol (36.1 kg) and water (30.4 kg). The obtained solid was dried under reduced pressure to obtain compound [6a] (38.0 kg, 139.1 mol) in 92.1% yield. 1 H-NMR (400MHz, DMSO-d6) δ: 9.08 (1H, s), 7.07 (2H, s), 6.56 (1H, s), 3.52 (3H, s), 2.23 (6H, s). 13¹³C-NMR (100MHz, DMSO-d6) δ: 157.4, 144.4, 130.5, 130.2, 112.8, 51.6, 18.3 For the obtained compound [6a], the diffraction angle 2θ and diffraction intensity were measured by powder X-ray diffraction. The obtained spectrum is shown in Figure 2. The peaks in Figure 2 are as shown in the table below.

[0069] The compound of formula [6a] is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5) at diffraction angles (2θ) of 11.8±0.2°, 15.1±0.2°, 18.2±0.2°, 21.3±0.2°, or 24.6±0.2°, as measured using CuKα emission. Preferably, the compound of formula [6a] is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5) at diffraction angles (2θ) of 11.8±0.1°, 15.1±0.1°, 18.2±0.1°, 21.3±0.1°, or 24.6±0.1°, as measured using CuKα emission. More preferably, the compound of formula [6a] is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5) at diffraction angles (2θ) of 11.8±0.06°, 15.1±0.06°, 18.2±0.06°, 21.3±0.06°, or 24.6±0.06°, as measured using CuKα radiation.

[0070] Process 4 Under a nitrogen atmosphere, water (74.0 kg) was added dropwise at a temperature of 26.7°C to 33.0°C to a mixture of compound [6a] (18.50 kg, 67.7 mol), compound [7] (11.64 kg, 135.0 mol), tripotassium phosphate (50.3 kg), palladium acetate (0.30 kg), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (0.56 kg), and toluene (128.2 kg). After purging with nitrogen under reduced pressure, the mixture was stirred at 79.5°C to 89.0°C for 6 hours and 50 minutes. After draining the aqueous layer, ethyl acetate (116.9 kg) and activated carbon (Carborafin®) (3.70 kg, manufactured by Osaka Gas Chemical Co., Ltd.) were added, and the mixture was stirred at a temperature of 27.6°C to 30.4°C for 1 hour. This suspension was filtered through activated carbon and washed with ethyl acetate (49.9 kg). The filtrate was washed twice with a mixed solution of water (92.5 kg), potassium hydroxide (0.88 kg), and N-acetyl-L-cysteine ​​(2.21 kg), and then washed with water (92.5 kg). The organic layer was concentrated and then subjected to three concentration substitutions with methanol (approximately 88 kg). Methanol (24.4 kg) and tetrahydrofuran (16.4 kg) were added, and water (120.2 kg) was added over 1 hour at a temperature ranging from 21.9°C to 26.8°C. After stirring for 2 hours at 24.7°C to 25.5°C, the precipitated solid was filtered and washed with a mixed solution of methanol (14.6 kg) and water (37.0 kg). The obtained solid was dried under reduced pressure to obtain compound [8a] (14.7 kg, 62.7 mol) in 92.8% yield. 1 H-NMR (400MHz, DMSO-d6) δ: 8.95 (1H, s), 6.59 (2H, s), 6.27 (1H, s), 3.50 (3H, s), 2.21 (6H, s), 1.73 (1H, tt, J = 8.4, 5.2 Hz), 0.76 (2H, ddd, J = 8.4, 6.8, 4.4 Hz), 0.53 (2H, ddd, J = 6.4, 5.2, 4.0 Hz) 13¹¹C-NMR (100MHz, DMSO-d6) δ: 157.3, 142.3, 136.2, 127.7, 125.5, 51.3, 18.4, 14.2, 8.4 For the obtained compound [8a], the diffraction angle 2θ and diffraction intensity were measured by powder X-ray diffraction. The obtained spectrum is shown in Figure 3. The peaks in Figure 3 are as shown in the table below.

[0071] The compound of formula [8a] is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5) at diffraction angles (2θ) of 6.5±0.2°, 10.7±0.2°, 12.6±0.2°, 19.3±0.2°, or 23.1±0.2°, as measured using CuKα emission. Preferably, the compound of formula [8a] is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5) at diffraction angles (2θ) of 6.5±0.1°, 10.7±0.1°, 12.6±0.1°, 19.3±0.1°, or 23.1±0.1°, as measured using CuKα emission. More preferably, the compound of formula [8a] is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5) at diffraction angles (2θ) of 6.5±0.06°, 10.7±0.06°, 12.6±0.06°, 19.3±0.06°, or 23.1±0.06°, as measured using CuKα radiation.

[0072] Process 5 Under an argon atmosphere, a mixture of compound [8a] (28.4 kg, 121.2 mol), sodium thiosulfate pentahydrate (3.83 kg), 2-ethoxyethanol (40 kg), and water (28 kg) was subjected to argon purging under reduced pressure. Then, potassium hydroxide (94.1% by weight, 28.9 kg) was added in five portions over 2 hours at a temperature ranging from 7°C to 19°C. The solution was subjected to argon purging under reduced pressure and stirred for 4 hours and 40 minutes at a temperature ranging from 35°C to 47°C. The solution was subjected to argon purging under reduced pressure, cyclopentyl methyl ether (122 kg) and water (57 kg) were added, and then subjected to argon purging under reduced pressure. Acetic acid (29.1 kg) was added to this solution at a temperature ranging from 7°C to 15°C, and the organic layer was separated and washed with water (28 kg). 2,6-di-tert-butyl-4-methylphenol (2.7 kg) and cyclopentyl methyl ether (24 kg) were added to this solution and the mixture was purged with argon under reduced pressure. The resulting cyclopentyl methyl ether solution of compound [9] was used in the next step at a yield of 100%.

[0073] Process 6 Under a nitrogen atmosphere, N,N-diisopropylethylamine was added to a mixture of compound [4a] (28.9 kg, 121.2 mol), cyclopentyl methyl ether (130 kg), tetrahydrofuran (78 kg), and water (29 kg) at a temperature of 21°C to 22°C. This solution was stirred under reduced pressure and nitrogen purged for 30 minutes. To this solution, the cyclopentyl methyl ether solution of compound [9] obtained in the previous step was added over a period of 4 hours and 20 minutes or more at a temperature of 21°C to 31°C. After stirring for 16 hours at a temperature of 24°C to 27°C, the mixture was heated and stirred for 1 hour at a temperature of 60°C to 63°C. After cooling to below 35°C over 1 hour and 10 minutes, water (58 kg) was added dropwise over 1 hour at a temperature of 27°C to 30°C, and the mixture was stirred for 1 hour and 20 minutes at a temperature of 15°C to 27°C. This suspension was stirred at a temperature of 2 to 10°C for 1 hour. The precipitated solid was filtered off and sequentially washed with cyclopentyl methyl ether (124 kg) and water (145 kg) at temperatures below 10°C to obtain wet crystals (52.1 kg) of compound [10a]. The obtained wet crystals were used in the next step without further purification. 1H-NMR (400MHz, DMSO-d6) δ: 8.71 (1H, s), 7.91 (1H, d, J = 2.4 Hz), 6.97 (1H, d, J = 2.4 Hz), 6.97 (2H, s), 3.98 (3H, s), 1.95 (6H, s), 1.94 (1H, m), 0.99 (2H, ddd, J = 8.4, 6.8, 4.4 Hz), 0.74 (2H, ddd, J = 6.4, 4.8, 4.0 Hz) 13 ¹¹C-NMR (100MHz, DMSO-d6) δ: 159.2, 158.5, 149.1, 145.3, 144.4, 136.1, 134.6, 133.3, 131.4, 124.9, 106.4, 106.0, 39.1, 16.9, 14.7, 9.5 For the obtained compound [10a], the diffraction angle 2θ and diffraction intensity were measured by powder X-ray diffraction. The obtained spectrum is shown in Figure 4. The peaks in Figure 4 are as shown in the table below.

[0074] The compound of formula [10a] is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5) at diffraction angles (2θ) of 12.6±0.2°, 17.0±0.2°, 19.8±0.2°, 22.9±0.2°, or 24.6±0.2°, as measured using CuKα emission. Preferably, the compound of formula [10a] is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5) at diffraction angles (2θ) of 12.6±0.1°, 17.0±0.1°, 19.8±0.1°, 22.9±0.1°, or 24.6±0.1°, as measured using CuKα emission. More preferably, the compound of formula [10a] is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5) at diffraction angles (2θ) of 12.6±0.06°, 17.0±0.06°, 19.8±0.06°, 22.9±0.06°, or 24.6±0.06°, measured using CuKα radiation.

[0075] Process 7 Under a nitrogen atmosphere, a mixture of wet crystals of compound [10a] (52.1 kg), acetonitrile (101 kg), and water (3.0 kg) was mixed with formic acid (35 kg) at a temperature of 11°C to 18°C. The solution was stirred at 30°C to 35°C for 23 hours. After cooling, the solution was stirred at 15°C for 30 minutes. Water (58 kg) was added to this reaction mixture over 40 minutes at a temperature of 8°C to 10°C, and the mixture was stirred for 1 hour and 50 minutes. Water (202 kg) was added to this suspension over 50 minutes, and the mixture was stirred at 10°C to 11°C for 1 hour and 20 minutes. The precipitated solid was filtered and washed with water (173 kg). The obtained solid was dried under reduced pressure to obtain crystals of compound [11a] (α-crystal, 32.2 kg, 85.2 mmol) in a yield of 75.8% from compound [4a]. The diffraction angle 2θ and diffraction intensity were measured for the obtained compound [11a] (α-crystal) by powder X-ray diffraction. The obtained spectrum is shown in Figure 5. The peaks in Figure 5 are as shown in the table below.

[0076] The compound (α-crystal) of formula [11a] is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5) at diffraction angles (2θ) of 8.9±0.2°, 11.1±0.2°, 16.9±0.2°, 19.4±0.2°, or 24.6±0.2°, as measured using CuKα radiation. Preferably, the compound (α-crystal) of formula [11a] is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5) at diffraction angles (2θ) of 8.9±0.1°, 11.1±0.1°, 16.9±0.1°, 19.4±0.1°, or 24.6±0.1°, as measured using CuKα radiation. More preferably, the compound of formula [11a] (α crystal) is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5 peaks) at diffraction angles (2θ) of 8.9±0.06°, 11.1±0.06°, 16.9±0.06°, 19.4±0.06°, or 24.6±0.06°, measured using CuKα radiation.

[0077] Process 8 Under a nitrogen atmosphere, crystalline compound [11a] (α-crystal, 32.1 kg, 84.8 mol) and 1-propanol (77 kg) were mixed and stirred for 5 hours and 10 minutes at a temperature of 35°C to 45°C. This reaction mixture was stirred for 15 hours and 10 minutes at a temperature of 24°C to 35°C, then cooled and stirred for 1 hour and 30 minutes at a temperature of 4°C to 10°C. The precipitated solid was filtered and washed with 1-propanol (26 kg) below 10°C to obtain the crude product of compound

[11] (35.1 kg). The obtained wet crystals were used in the next step without further purification.

[0078] Step 8-1: Crystal Isolation of Compound

[11] Under a nitrogen atmosphere, wet crystals of Compound

[11] obtained in the previous step (35.1 kg), activated carbon (Carborafin®) (1.6 kg, manufactured by Osaka Gas Chemical Co., Ltd.), and 1-propanol (257 kg) were mixed and stirred for 2 hours and 10 minutes at a temperature of 75°C to 81°C. This suspension was filtered to remove the activated carbon, then washed with 1-propanol (128 kg) and the filtrate was concentrated. 103 kg of 1-propanol was added to the concentrate and it was concentrated again. 39.2 kg of 1-propanol was added to the resulting concentrate and stirred for 30 minutes at a temperature of 75°C to 90°C. After confirming that the solid was completely dissolved, the solution was filtered to remove dust and washed with 1-propanol (26 kg) at a temperature of 75°C or higher. The resulting solution was cooled to below 55°C over 40 minutes, and then stirred for 3 hours at a temperature of 47°C to 55°C. After confirming the precipitation of the solid, the suspension was cooled to below 25°C over 2 hours and 10 minutes, and then stirred at a temperature of 19°C to 25°C for 13 hours and 50 minutes. This suspension was cooled to below 10°C over 1 hour, and then stirred at a temperature of 1°C to 10°C for 3 hours and 40 minutes. The precipitated solid was filtered and washed twice with 1-propanol (26 kg) at a temperature of below 10°C. The obtained solid was dried under reduced pressure to obtain crystals of compound

[11] (β-crystal, 26.5 kg, 73.5 mol) in a yield of 86.8% from compound [11a]. 1H-NMR (400MHz, DMSO-d6) δ: 11.23 (1H, s), 8.70 (1H, s), 7.90 (1H, d, J = 2.4 Hz), 6.97 (2H, s), 6.96 (1H, d, J = 2.4 Hz), 3.98 (3H, s), 1.97 (6H, s), 1.94 (1H, m), 0.99 (2H, ddd, J = 8.0, 6.4, 4.4 Hz), 0.77 (2H, ddd, J = 6.4, 5.2, 4.0 Hz) 13 ¹¹C-NMR (100MHz, DMSO-d6) δ: 159.4, 158.5, 149.0, 145.3, 144.5, 136.2, 134.6, 133.2, 131.4, 124.9, 106.4, 105.9, 39.1, 16.9, 14.7, 9.5 For the obtained compound

[11] (β crystal), the diffraction angle 2θ and diffraction intensity were measured by powder X-ray diffraction. The obtained spectrum is shown in Figure 6. The peaks in Figure 6 are as shown in the table below.

[0079] The compound (β crystal) of formula

[11] is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5) at diffraction angles (2θ) of 4.8±0.2°, 10.8±0.2°, 15.5±0.2°, 18.5±0.2°, or 23.0±0.2°, as measured using CuKα emission. Preferably, the compound (β crystal) of formula

[11] is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5) at diffraction angles (2θ) of 4.8±0.1°, 10.8±0.1°, 15.5±0.1°, 18.5±0.1°, or 23.0±0.1°, as measured using CuKα emission. More preferably, the compound of formula

[11] (β crystal) is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5 peaks) at diffraction angles (2θ) of 4.8±0.06°, 10.8±0.06°, 15.5±0.06°, 18.5±0.06°, or 23.0±0.06°, measured using CuKα radiation.

[0080] [Example 2] Another method for producing compound

[11] Process 1 Under a nitrogen atmosphere, a mixture of compound [8a] (19.53 kg, 83.3 mol), sodium thiosulfate pentahydrate (4.14 kg), 2-ethoxyethanol (54.5 kg), and water (19.5 kg) was purged with nitrogen under reduced pressure, and then potassium hydroxide (approximately 86.1% by weight, 21.7 kg) was added over 50 minutes at a temperature ranging from 8.0°C to 18.4°C. This solution was stirred for 5 hours at a temperature ranging from 34.5°C to 41.3°C. N-acetyl-L-cysteine ​​(4.08 kg) and citric acid (1.60 kg) were added to this reaction mixture at a temperature ranging from 27.9°C to 34.3°C, and the mixture was stirred for 1 hour at a temperature ranging from 28.9°C to 29.2°C. Cyclopentyl methyl ether (84.4 kg), acetic acid (17.0 kg), and water (39.0 kg) were sequentially added in the range of 12.2°C to 24.2°C, and the mixture was stirred for 20 minutes in the range of 15.0°C to 17.5°C, after which the aqueous layer was drained. The resulting organic layer was washed with water (19.5 kg), 2,6-di-tert-butyl-4-methylphenol (3.67 kg) was added, the mixture was filtered, and washed with cyclopentyl methyl ether (84.1 kg). After standing at 3°C ​​for 10 minutes, the aqueous layer was drained. To the resulting organic layer, a hydrochloric acid solution of cyclopentyl methyl ether (4N, 19.0 kg) was added over 1 hour and 10 minutes in the range of 1.0°C to 6.9°C, and the mixture was stirred for 1 hour in the range of 0.8°C to 4.3°C. The precipitated solid was filtered and washed with cyclopentyl methyl ether (101.0 kg). The obtained solid was dried under reduced pressure to obtain compound [9a] (15.6 kg) in a yield of 88.3%. 1 H-NMR (400MHz, DMSO-d6) δ: 9.61 (3H, br), 6.78 (2H, s), 3.79 (1H, br), 2.34 (6H, s), 1.82 (1H, tt, J = 8.4, 5.2 Hz), 0.90 (2H, ddd, J = 8.4, 6.8, 4.4 Hz), 0.62 (2H, ddd, J = 6.8, 5.6, 4.4 Hz) 13C-NMR (100MHz, DMSO-d6) δ: 142.6, 137.8, 135.0, 125.4, 17.8, 14.5, 9.2

[0081] Process 2 Under a nitrogen atmosphere, a mixture of compound [4a] (15.0 kg), 2,6-di-tert-butyl-4-methylphenol (0.64 kg), cyclopentyl methyl ether (51 kg), water (38 kg), and N,N-diisopropylethylamine (30.2 kg) was subjected to reduced pressure and nitrogen purging. To this solution, a suspension of compound [9a] (12.4 kg) and cyclopentyl methyl ether (104 kg) was added in five portions over 2 hours and 20 minutes at a temperature range of 0.7°C to 6.7°C. After adding cyclopentyl methyl ether (104 kg) at 25°C over 10 minutes, the mixture was stirred for 21 hours at a temperature range of 20°C to 33°C. The precipitated solid was filtered and washed sequentially with cyclopentyl methyl ether (52 kg) and water (60 kg). To the obtained solid, acetonitrile (59 kg) was added to the suspension, to which water (45 kg) was added dropwise over 40 minutes at a temperature of 19°C to 20°C, and the mixture was stirred at 20°C to 21°C for 1 hour and 40 minutes. After filtering off the precipitated solid, it was washed with water (60 kg) to obtain wet crystals of compound [10a]. The obtained wet crystals were used in the next step without further purification.

[0082] Process 3 Under a nitrogen atmosphere, a mixture of wet crystals of compound [10a] (22.58 kg), activated carbon (Carborafin®) (3.0 kg, manufactured by Osaka Gas Chemical Co., Ltd.), acetonitrile (30 kg), and water (15 kg) was mixed with formic acid (38 kg) and acetonitrile (6 kg) over 10 minutes at a temperature of 20°C to 27°C. The solution was stirred at 40°C to 48°C for 3 hours. The solution was cooled to below 35°C, filtered to remove the activated carbon, and washed with a mixture of acetonitrile (36 kg) and water (24 kg). Water (45 kg) was added to the filtrate over 1 hour at a temperature of 32°C to 34°C, and the mixture was stirred at a temperature of 29°C to 32°C for 15 hours and 40 minutes. Water (90 kg) was added to this reaction mixture over 1 hour at a temperature of 28°C to 29°C, and the mixture was stirred for 4 hours and 10 minutes. The precipitated solid was filtered and washed with water (75 kg). The obtained solid was dried under reduced pressure to obtain crystalline compound [11a] (γ crystal, 14.90 kg) in a yield of 67.4% from compound [4a]. The diffraction angle 2θ and diffraction intensity of the obtained compound [11a] (γ crystal) were measured by powder X-ray diffraction. The obtained spectrum is shown in Figure 7. The peaks in Figure 7 are as shown in the table below.

[0083] The compound (γ crystal) of formula [11a] is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5) at diffraction angles (2θ) of 12.1±0.2°, 13.2±0.2°, 14.6±0.2°, 17.8±0.2°, or 22.8±0.2°, as measured using CuKα radiation. Preferably, the compound (γ crystal) of formula [11a] is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5) at diffraction angles (2θ) of 12.1±0.1°, 13.2±0.1°, 14.6±0.1°, 17.8±0.1°, or 22.8±0.1°, as measured using CuKα radiation. More preferably, the compound (γ crystal) of formula [11a] is a crystal that exhibits a powder X-ray diffraction pattern having at least one peak (e.g., at least 1, 2, 3, 4, or 5 peaks) at diffraction angles (2θ) of 12.1±0.06°, 13.2±0.06°, 14.6±0.06°, 17.8±0.06°, or 22.8±0.06°, measured using CuKα radiation, for example.

[0084] Process 4 Under a nitrogen atmosphere, crystalline compound [11a] (γ crystal, 14.90 kg) and 1-propanol (71.5 kg) were mixed and stirred at a temperature of 75°C to 85°C for at least 50 minutes to dissolve the crystals. This solution was filtered to remove dust and washed with 1-propanol (11.9 kg). The resulting filtrate was heated to 75°C, then cooled to 55°C over at least 1 hour, and stirred for 22 hours and 20 minutes. This suspension was cooled to 35°C over 2 hours, and then stirred at a temperature of 26°C to 35°C for 2 hours and 10 minutes. This suspension was cooled to 10°C over 1 hour and 30 minutes, and then stirred at 3°C ​​to 10°C for 18 hours and 30 minutes. The precipitated solid was filtered and washed with 1-propanol (23.8 kg) at a temperature of 10°C or below. The obtained solid was dried under reduced pressure to obtain crystalline compound

[11] (β-crystal, 12.8 kg) in 90.5% yield from compound [11a].

[0085] The compound or salt according to the present invention is useful as a synthetic intermediate for producing compound

[11] . Furthermore, the production method according to the present invention includes a method for stably producing compound

[11] with good chemical purity. Moreover, since the production method according to the present invention can stably produce compound

[11] in good yield, it is useful as an industrial large-scale synthesis method. The method for producing the synthetic intermediate of compound

[11] includes a method for stably producing compound [4a], compound [8a], and compound [10a], which are synthetic intermediates of compound

[11] , with good chemical purity.

Claims

1. Formula [10] (In the formula, R １ Using a compound of (which is a halogen) or a pharmaceutically acceptable salt thereof, formula [11] A method for producing a compound or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

2. Using the compound of formula [10] or a pharmaceutically acceptable salt thereof, formula [11a] The method according to claim 1, comprising the steps of obtaining a compound of formula [11] or a pharmaceutically acceptable salt thereof, and obtaining a compound of formula [11] or a pharmaceutically acceptable salt thereof from a compound of formula [11a] or a pharmaceutically acceptable salt thereof.

3. Formula [9] A compound of or a pharmaceutically acceptable salt thereof, and formula [4] (In the formula, R １ The method according to claim 1 or 2, comprising the step of obtaining a compound of formula [10] or a pharmaceutically acceptable salt thereof using a compound of (where each is independently a halogen) or a pharmaceutically acceptable salt thereof.

4. R １ The method according to any one of claims 1 to 3, wherein is chlorine.

5. Formula [3] The method according to claim 3 or 4, comprising the step of obtaining a compound of formula [4] or a pharmaceutically acceptable salt thereof using a compound of the same or a pharmaceutically acceptable salt thereof.

6. Formula [8] (In the formula, R ２ is C １－４ The method according to any one of claims 3 to 5, comprising the step of obtaining a compound of formula [9] or a pharmaceutically acceptable salt thereof using a compound of (which is alkyl) or a pharmaceutically acceptable salt thereof.

7. Formula [6] (In the formula, R ２ This is synonymous with the definition in claim 6, and R ３ A compound of (which is a halogen) or a pharmaceutically acceptable salt thereof, and formula [7] The method according to claim 6, comprising the step of obtaining a compound of formula [8] or a pharmaceutically acceptable salt thereof using a compound, cyclopropylboronic acid pinacol ester, or potassium cyclopropyltrifluoroborate.

8. R ２ The method according to claim 6 or 7, wherein is methyl.

9. R ３ The method according to claim 7 or 8, wherein R is bromine.

10. The method according to any one of claims 7 to 9, wherein a compound of formula [7] is used.

11. Formula [10] (In the formula, R １ A compound of (which is defined as in Claim 1) or a pharmaceutically acceptable salt thereof.

12. R １ The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein is chlorine.

13. Formula [3] Compounds of or pharmaceutically acceptable salts thereof.

14. Formula [8] (In the formula, R ２ A compound of (which is defined as in claim 6) or a pharmaceutically acceptable salt thereof.

15. R ２ The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein the compound is methyl.

16. Formula [6] (In the formula, R ２ This is synonymous with the definition in claim 6, and R ３ A compound of (which is defined as in claim 7) or a pharmaceutically acceptable salt thereof.

17. R ２ The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein is methyl.

18. R ３ The compound according to claim 16 or 17, or a pharmaceutically acceptable salt thereof, wherein the compound is bromine.

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