Method for producing 6-aminopyrazolopyrimidine compound and synthetic intermediate thereof

Abstract

Provided are: a method for producing a 6-aminopyrazolopyrimidine compound or a salt thereof which is useful as an NLRP3 inflammasome inhibitor; a synthetic intermediate of the method; and a method for producing the synthetic intermediate. Provided is a method for producing a compound represented by formula (4) or a pharmaceutically acceptable salt thereof by using a compound represented by formula (3) (wherein R1 represents a halogen atom) or a pharmaceutically acceptable salt thereof.

Description

Method for producing 6-aminopyrazolopyrimidine compounds and their synthetic intermediates

[0001] The present invention relates to a method for producing a 6-aminopyrazolopyrimidine compound or a salt thereof that is useful as an NLRP3 inflammasome inhibitor, 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 [4] This has been disclosed.

[0004] International Public Gazette WO2023 / 032987

[0005] The present invention provides a method for producing a 6-aminopyrazolopyrimidine compound or a salt thereof that is useful as an NLRP3 inflammasome inhibitor, a synthetic intermediate thereof, and a method for producing the synthetic intermediate thereof.

[0006] The present invention includes the following embodiments: Clause 1: Formula [3] (In the formula, R １ Using a compound of (which is a halogen) or a pharmaceutically acceptable salt thereof, formula [4] A method for producing a compound or a pharmaceutically acceptable salt thereof.

[0007] Claim 2: The method according to Claim 1, comprising the step of adding an acid to a compound of formula [3] or a pharmaceutically acceptable salt thereof to obtain a compound of formula [4] or a pharmaceutically acceptable salt thereof.

[0008] Item 3: The method according to item 2, wherein the acid is formic acid.

[0009] Item 4: The method according to items 1 to 3, further comprising the step of recrystallizing the compound of formula [4] or a pharmaceutically acceptable salt thereof using a mixed solvent of alcohol and water.

[0010] Item 5: The method according to item 4, wherein the alcohol is 1-propanol.

[0011] Term 6: Formula [1] Compounds of or pharmaceutically acceptable salts thereof and formula [2] (In the formula, R １ The method according to any one of claims 1 to 5, comprising the step of reacting a compound of (where each is independently a halogen) or a pharmaceutically acceptable salt thereof to obtain a compound of formula [3] or a pharmaceutically acceptable salt thereof.

[0012] Item 7: The method of item 6, wherein tetrahydrofuran is used in the step of obtaining a compound of formula [3] or a pharmaceutically acceptable salt thereof.

[0013] Item 8: The method according to any one of items 1 to 7, further comprising the step of purifying a compound of formula [3] or a pharmaceutically acceptable salt thereof into crystals.

[0014] Claim 9: The method according to any one of claims 6 to 8, wherein the compound of formula [1] or a pharmaceutically acceptable salt thereof is the hydrochloride salt of the compound of formula [1].

[0015] Item 10: R １ The method according to any one of items 1 to 9, wherein is chlorine.

[0016] Item 11: The method according to any one of items 1 to 10, wherein water is used in the reaction step described in item 1, the reaction step described in item 6, or the crystallization step of the compound of formula [3] or a pharmaceutically acceptable salt thereof.

[0017] Term 12: Formula [3] Compounds of or pharmaceutically acceptable salts thereof.

[0018] Item 13: R １ A compound or a pharmaceutically acceptable salt thereof, wherein the compound is chlorine, as described in item 12.

[0019] Item 4A: A method for producing a compound of formula [4] or a pharmaceutically acceptable salt thereof by recrystallizing the compound of formula [4] or a pharmaceutically acceptable salt thereof using a mixed solvent of alcohol and water.

[0020] Item 5A: The method according to item 4A, characterized in that the total amount of the mixed solvent used relative to the weight of the compound of formula [4] or a pharmaceutically acceptable salt thereof is less than the amount used when recrystallizing using alcohol or water alone.

[0021] Item 6A: The method according to item 4A or 5A, wherein the alcohol is 1-propanol.

[0022] Term 7A: Formula [1] Compounds of or pharmaceutically acceptable salts thereof and formula [2] (In the formula, R １ By reacting a compound of (each of which is independently a halogen) or a pharmaceutically acceptable salt thereof, formula [3] is obtained. (In the formula, R １ The method according to any one of claims 1 to 3 or 4A to 6A, comprising the step of obtaining a compound of (a halogen) or a pharmaceutically acceptable salt thereof, and further comprising the step of optionally using a compound of formula [3] or a pharmaceutically acceptable salt thereof to produce a compound of formula [4] or a pharmaceutically acceptable salt thereof.

[0023] Item 8A: The method of item 7A, wherein tetrahydrofuran is used in the step of obtaining a compound of formula [3] or a pharmaceutically acceptable salt thereof.

[0024] Item 9A: The method according to any one of items 4A to 8A, further comprising the step of purifying a compound of formula [3] or a pharmaceutically acceptable salt thereof into crystals.

[0025] Claim 10A: The method according to any one of claims 7A to 9A, wherein the compound of formula [1] or a pharmaceutically acceptable salt thereof is the hydrochloride salt of the compound of formula [1].

[0026] Item 11A: The method according to any one of items 1 to 3 or 4A to 10A, wherein water is used in the reaction step described in item 1, any of the reaction steps described in item 7A, or in the crystallization step of the compound of formula [3] or a pharmaceutically acceptable salt thereof.

[0027] Item 12A: The method according to any one of Items 1 to 3 or 4A to 11A, wherein water is used in any of the reaction steps described in Item 7A.

[0028] Item 13A: The method according to Item 12A, characterized in that the generation of impurities is reduced by the use of water.

[0029] Item 14A: R １ The method according to any one of Items 1 to 3 or 4A to 13A, wherein R is chlorine.

[0030] Figure 1 shows a multiple recording of the powder X-ray diffraction pattern of compound [3a]. The vertical axis represents the diffraction intensity (cps: counts per second), and the horizontal axis represents the diffraction angle 2θ (°). Figure 2 shows a multiple recording of the powder X-ray diffraction pattern of compound [4]. The vertical axis represents the diffraction intensity (cps: counts per second), and the horizontal axis represents the diffraction angle 2θ (°).

[0031] The definitions of the terms in this specification are as follows.

[0032] In this specification, for example, the compound of formula [4] may be referred to as compound [4]. [[ID=!19]]

[0033] Examples of the halogen include fluorine, chlorine, bromine, and iodine. Preferably, it is chlorine.

[0034] It seems there might be a small formatting issue with line ID 19 in the original text which was not translated as it's likely a typo (the "!19" in the translation). If this was a mistake in the original, please correct it for a more accurate translation.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.

[0035] 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 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.

[0036] 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.

[0037] 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.

[0038] The compounds or salts thereof according to the present invention may exist as tautomers. In that case, the compounds or salts 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.

[0039] The compounds or salts thereof according to the present invention may have a carbon-carbon double bond. In that case, the compounds or salts 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 or salts thereof according to the present invention may have stereoisomers that should be recognized as cis / trans isomers. In that case, the compounds or salts 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 or salts thereof according to the present invention may have one or more chiral carbons. In that case, the compounds or salts 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 or salts thereof according to the present invention may exist as atropisomers. In that case, the compounds or salts thereof according to the present invention may exist as individual atropisomers or a mixture of atropisomers, and include these. The compounds or salts thereof according to the present invention may simultaneously contain multiple structural features that give rise to the above isomers. Furthermore, the compound or salt thereof according to the present invention may contain the above-mentioned isomers in any proportion.

[0040] 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.

[0041] The separation of each single enantiomer from a mixture of enantiomers can be carried out by methods well known in the art. For example, from a mixture of enantiomers and a mixture of diastereomers formed by reacting with a compound known as a chiral auxiliary, which is a substantially pure enantiomer, standard methods such as fractional crystallization or chromatography can be used to separate an isomer ratio-enhanced or substantially pure single diastereomer. The separated diastereomer can be converted to the desired enantiomer by cleaving and removing the added chiral auxiliary. Also, a mixture of enantiomers can be directly separated by a chromatography method using a chiral stationary phase, which is well known in the art. Alternatively, either enantiomer can also be obtained by using a substantially pure optically active starting material or by performing stereoselective synthesis (asymmetric induction) using a chiral auxiliary or an asymmetric catalyst on a prochiral intermediate.

[0042] The absolute configuration can be determined by X-ray crystal analysis of a crystalline product or intermediate. In that case, a crystalline product or intermediate derivatized with a reagent having an asymmetric center of known configuration may be used as necessary.

[0043] The compound according to the present invention or a salt thereof may be a crystal, an amorphous substance, or a mixture thereof.

[0044] The compound according to the present invention or a salt thereof may be labeled with isotope elements ( ２ H (D), ３ H, １１ C, １３ C, １４ C, １３ N, １５ N, １５ O, １８ O, １８ F, ３５ S, １２３ I, etc.). For example, when 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 or salts thereof 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.

[0045] The compound or salt thereof according to the present invention is preferably a substantially purified compound or salt thereof. More preferably, it is a compound or salt thereof purified to a purity of 80% or higher.

[0046] A method for producing a compound or a salt thereof 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, and 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.

[0047] Manufacturing method 1: Preparation of compound [4]

[0048] Process 1 (In the formula, R １(Each of these is an independent halogen) Compound [3] or a salt thereof can be produced by reacting compound [1] or a salt thereof with compound [2] or a salt thereof in a solvent in the presence of a base. Examples of bases include triethylamine, tributylamine, N,N-diisopropylethylamine, diisopropylamine, 1,1,3,3-tetramethylguanidine, 1,8-diazabicyclo[5.4.0]undeca-7-ene, potassium carbonate, and tripotassium phosphate. A preferred base is N,N-diisopropylethylamine. The amount of base used is, for example, 1.0 to 5.0 equivalents relative to compound [2], preferably 2.0 to 4.0 equivalents. The amount of compound [1] used is, for example, 0.9 to 2.0 equivalents relative to compound [2], preferably 0.95 to 1.1 equivalents. Examples of solvents include water, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 1-pentanol, 2-ethoxyethanol, tetrahydrofuran, cyclopentyl methyl ether, dimethoxyethane, toluene, acetonitrile, dimethylacetamide, and mixed solvents thereof. A preferred solvent is a mixed solvent of water and tetrahydrofuran (for example, a volume ratio of 1:1 to 1:9, preferably 1:8). The reaction temperature is, for example, 0°C to 80°C, preferably 15°C to 40°C. The reaction time is, for example, 1 hour to 48 hours, preferably 1 hour to 6 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.

[0049] Purification of the compound of formula [3] The compound of formula [3] can be purified by stirring in a solvent. Examples of solvents include water, 1-propanol, 2-propanol, acetonitrile, tetrahydrofuran, cyclopentyl methyl ether, toluene, and mixed solvents thereof. A preferred solvent is a mixed solvent of water and acetonitrile (for example, in a volume ratio of 1:2 to 2:1), and toluene may be added to the mixed solvent. The amount of solvent used is, for example, 10 to 50 times the weight of compound [3], preferably 20 to 30 times. The stirring temperature is, for example, 0°C to 80°C, preferably 20°C to 45°C. The stirring time is, for example, 0.5 hours to 24 hours, preferably 0.5 hours to 2 hours.

[0050] Process 2 (In the formula, R １ (This is the same as the definition above.) Compound [4] or a salt thereof can be produced by reacting compound [3] or a salt thereof in a solvent in the presence of an acid. Examples of acids include formic acid, hydrochloric acid, acetic acid, trifluoroacetic acid, etc. The preferred acid is formic acid. The amount of acid used is, for example, 1.0 to 30 equivalents relative to compound [3], preferably 5.0 to 15 equivalents. Examples of solvents include water, acetonitrile, 2-propanol, dimethyl sulfoxide, tetrahydrofuran, and mixed solvents thereof. The preferred solvent is a mixed solvent of acetonitrile and water (for example, a volume ratio of 1:1 to 1:9, preferably 2:3). The reaction temperature is, for example, 0°C to 100°C, preferably 20°C to 60°C. The reaction time is, for example, 1 to 24 hours, preferably 1 to 6 hours.

[0051] Purification of the compound of formula [4] The compound of formula [4] can be purified by dissolving the compound of formula [4] in a solvent and then recrystallizing it. Examples of solvents include alcohols (e.g., methanol, ethanol, 1-propanol, 2-propanol, mixed solvents thereof, etc.), water, ethyl acetate, mixed solvents thereof, etc. A preferred solvent is a mixed solvent of 1-propanol and water (e.g., a volume ratio of 100:1 to 1:4, preferably 9:1 to 3:1). The amount of solvent used is, for example, 5 to 50 times the weight of compound [4], preferably 13 to 30 times. The crystallization temperature is, for example, 70°C to 130°C, preferably 80°C to 95°C. The recrystallization time is, for example, 1 to 72 hours, preferably 2 to 24 hours.

[0052] The following are some of the features of this manufacturing method: (1) Compound [4] can be produced with a small number of steps. (2) By adding water to the reaction system in step 1 of manufacturing method 1, side reactions occur, for example This suppresses compound [3], for example, compound [3a] This allows for the production of compound [3a] and compound [5] in high yield and high chemical purity. Impurities that may be generated in step 1 of manufacturing method 1 include compounds [5] and [6], which are products of the side reaction. For example, in step 1 of manufacturing method 1, when water was added to the reaction system, the yields of compound [3a] and compound [5] were 93.6% and 6.4%, respectively, while the yields when water was not added were 47.5% and 52.5%, respectively. (3) When water is used in the manufacturing process and crystallization process of compound [3], for example, compound [3a], and in the manufacturing process of compound [4], drying of compound [3a] is unnecessary, and compound [4] can be produced in a short time. (4) In step 1 of manufacturing method 1, the filtration time can be shortened by using tetrahydrofuran as the solvent. (5) In step 2 of manufacturing method 1, by adding acid to the reaction system, the reaction is accelerated and the decomposition of the product is suppressed, and compound [4] can be produced in high yield. Furthermore, the addition of the acid is also effective in removing coloring impurities, and a white compound [4] can be obtained. (6) By using a mixed solvent of alcohol (e.g., 1-propanol) and water in the recrystallization step of compound [4], which has low solubility in various solvents, the amount of solvent used can be reduced. As an example, the solubility of compound [4] in various solvents and the solubility profile of compound [4] in a water / 1-propanol mixed solvent are shown below. Solubility of compound [4] in various solvents Solubility profile of compound [4] in a water / 1-propanol mixed solvent

[0053] A method for producing the compound or salt thereof according to the present invention will be specifically described by example. However, the present invention is not limited to these examples.

[0054] The meanings of the abbreviations used herein are as follows: BDPH-HC: 4-bromo-2,6-dimethylphenylhydrazine hydrochloride DMPA: 4,6-dichloro-2-(4-morpholinyl)-5-pyridinecarboxaldehyde

[0055] The measuring device and measurement conditions used in this embodiment are shown below.

[0056] ​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 br: broad m: multiplet J: coupling constant

[0057] 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

[0058] [Example 1] 2-(4-bromo-2,6-dimethylphenyl)-6-morpholino-2,5-dihydro-4H-pyrazolo[3,4-d]pyrimidine-4-one) (Preparation of Compound [4])

[0059] Process 1 Under a nitrogen atmosphere, N,N-diisopropylethylamine (178 kg) was added to a suspension of DMPA (compound [2a]) (120 kg, 457.9 mol), tetrahydrofuran (425 kg), and water (120 kg) at a temperature of 24.7°C to 25.8°C. Then, a suspension of BDPH-HC (compound [1a]) (115 kg) and tetrahydrofuran (320 kg) was added in eight portions over 1 hour and 40 minutes at a temperature of 25.4°C to 30.4°C. After washing with tetrahydrofuran (110 kg), the mixture was stirred at 22.3°C to 26.1°C for 1 hour and 10 minutes. A mixed solution of acetonitrile (370 kg) and water (840 kg) was added dropwise to the reaction mixture over 30 minutes at a temperature of 22.3°C to 25.3°C, and the mixture was stirred for 1 hour. The precipitated solid was filtered and washed sequentially with a mixed solution of acetonitrile (370 kg) and water (240 kg), followed by acetonitrile (560 kg) to obtain the crude product of compound [3a] (258.9 kg). The obtained compound was used in the next step without further purification.

[0060] Step 1-1 Crystallization of Compound [3a] Under a nitrogen atmosphere, water (970 kg) was added dropwise to a suspension of the crude product of Compound [3a] (258.9 kg), acetonitrile (1100 kg), and toluene (83 kg) at a temperature of 21.2°C to 27.1°C for 1 hour, and then stirred at a temperature of 29.5°C to 36.1°C for 1 hour. The solid was filtered and washed sequentially with a mixed solution of acetonitrile (380 kg) and water (240 kg), and then with acetonitrile (570 kg) to obtain wet crystals of Compound [3a] (254.5 kg). The obtained wet crystals were used in the next step without further purification. 1¹H-NMR (400MHz, DMSO-d6) δ: 10.38 (1H, d, J = 2.8 Hz), 9.95 (1H, s), 7.21 (1H, d, J = 2.8 Hz), 7.10 (2H, s), 3.72 (2H, m), 3.56 (2H, m), 3.46 (4H, m), 2.22 (6H, s). For compound [3a] synthesized by the same method, the diffraction angle 2θ and diffraction intensity were measured by powder X-ray diffraction. The obtained spectrum is shown in Figure 1. The peaks in Figure 1 are as shown in the table below.

[0061] The compound of formula [3a] 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 14.5±0.2°, 15.7±0.2°, 19.1±0.2°, 20.3±0.2°, or 21.9±0.2°, as measured using CuKα emission. Preferably, the compound of formula [3a] 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 14.5±0.1°, 15.7±0.1°, 19.1±0.1°, 20.3±0.1°, or 21.9±0.1°, as measured using CuKα emission. More preferably, the compound of formula [3a] 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 14.5±0.06°, 15.7±0.06°, 19.1±0.06°, 20.3±0.06°, or 21.9±0.06°, measured using CuKα radiation.

[0062] Process 2 Under a nitrogen atmosphere, wet crystals of compound [3a] (254.5 kg) were added in two portions over 30 minutes at a temperature ranging from 26.8°C to 30.5°C to a mixed solution of formic acid (300 kg), acetonitrile (280 kg), and water (240 kg). The mixture was then stirred at 45.0°C to 53.4°C for 5 hours and 40 minutes. A solution prepared by dissolving sodium chloride (26 kg) in water (1800 kg) was added dropwise to the reaction mixture over 1 hour at a temperature ranging from 22.0°C to 28.4°C, and the mixture was stirred at 22.0°C to 28.1°C for 1 hour. The precipitated solid was filtered and washed with a mixed solution of acetonitrile (190 kg) and water (480 kg), followed by water (730 kg). The resulting solid was dried under reduced pressure to obtain the crude product of compound [4] (157.7 kg, 390.1 mol). It was obtained from DMPA (compound [2a]) in a yield of 85.2%.

[0063] Step 2-1 Crystallization of Compound [4] Under a nitrogen atmosphere, the crude product of Compound [4] (78.8 kg, 194.9 mmol), 1-propanol (630 kg), and water (240 kg) were mixed and heated to 85.0°C to 88.3°C to dissolve the solid. This solution was filtered to remove dust and washed with a mixed solution of 1-propanol (95 kg) and water (39 kg) (to be used at 75°C or higher). The resulting reaction mixture was stirred at 71.2°C to 82.2°C for 40 minutes, then water (550 kg) was added dropwise over 40 minutes in the range of 75.7°C to 82.4°C, and the mixture was stirred at 68.7°C to 75.0°C for 1 hour. Water (630 kg) was added dropwise over 1 hour and 20 minutes in the range of 70.2°C to 71.0°C, and the mixture was stirred at 70.4°C to 70.9°C for 1 hour. The resulting reaction solution was cooled to below 10°C and stirred at 4.1°C to 10.0°C for 1 hour. The precipitated solid was filtered and washed with water (320 kg) below 10°C. The resulting solid was dried under reduced pressure to obtain crystalline compound [4] (74.4 kg, 184.0 mol) in a yield of 94.8%. 1H-NMR (400MHz, DMSO-d6) δ: 10.98 (1H, br), 8.51 (1H, s), 7.51 (2H, s), 3.67 (4H, dd, J = 5.6, 4.0 Hz), 3.55 (4H, dd, J = 5.6, 4.4 Hz), 1.98 (6H, s). 13C-NMR (100MHz, DMSO-d6) δ: 160.5, 160.1, 153.5, 138.3, 137.9, 131.0, 130.7, 122.1, 103.3, 65.7, 45.7, 16.7 For compound [4] synthesized using the same method, the diffraction angle 2θ and diffraction intensity were measured by powder X-ray diffraction. The obtained spectra are shown in Figure 2. The peaks in Figure 2 are as shown in the table below.

[0064] The compound of formula [4] 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 6.9±0.2°, 10.7±0.2°, 15.0±0.2°, 22.0±0.2°, or 23.6±0.2°, as measured using CuKα radiation. Preferably, the compound of formula [4] 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 6.9±0.1°, 10.7±0.1°, 15.0±0.1°, 22.0±0.1°, or 23.6±0.1°, as measured using CuKα radiation. More preferably, the compound of formula [4] 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 6.9±0.06°, 10.7±0.06°, 15.0±0.06°, 22.0±0.06°, or 23.6±0.06°, as measured using CuKα radiation.

[0065] The compound or salt according to the present invention is useful as a synthetic intermediate for producing compound [4]. Furthermore, the production method according to the present invention includes a method for stably producing compound [4] with good chemical purity. Moreover, since the production method according to the present invention can stably produce compound [4] in good yield, it is useful as an industrial large-scale synthesis method. The method for producing the synthetic intermediate of compound [4] includes a method for stably producing compound [3a], which is a synthetic intermediate of compound [4], with good chemical purity.

Claims

1. Formula [3] (In the formula, R １ Using a compound of (which is a halogen) or a pharmaceutically acceptable salt thereof, formula [4] A method for producing a compound or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, comprising the step of obtaining a compound of formula [4] or a pharmaceutically acceptable salt thereof by adding an acid to a compound of formula [3] or a pharmaceutically acceptable salt thereof.

3. The method according to claim 2, wherein the acid is formic acid.

4. Using a mixed solvent of alcohol and water, formula [4] A method for producing the compound of formula [4] or a pharmaceutically acceptable salt thereof by recrystallizing the compound or a pharmaceutically acceptable salt thereof.

5. The method according to claim 4, characterized in that the total amount of the mixed solvent used relative to the weight of the compound of formula [4] or a pharmaceutically acceptable salt thereof is less than the amount used when recrystallizing using alcohol or water alone.

6. The method according to claim 4 or 5, wherein the alcohol is 1-propanol.

7. Formula [1] Compounds of or pharmaceutically acceptable salts thereof and formula [2] (In the formula, R １ The method according to any one of claims 1 to 6, comprising the step of reacting a compound of (where each is independently a halogen) or a pharmaceutically acceptable salt thereof to obtain a compound of formula [3] or a pharmaceutically acceptable salt thereof, and further comprising the step of using the compound of formula [3] or a pharmaceutically acceptable salt thereof as appropriate to obtain a compound of formula [4] or a pharmaceutically acceptable salt thereof.

8. The method according to claim 7, wherein the compound of formula [1] or a pharmaceutically acceptable salt thereof is the hydrochloride salt of the compound of formula [1].

9. The method according to any one of claims 1 to 8, wherein water is used in any reaction step described in claim 7.

10. The method according to claim 9, characterized in that the generation of impurities is reduced by the use of water.

11. R １ The method according to any one of claims 1 to 10, wherein is chlorine.

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

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

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