Method for producing triazine derivative, and intermediate for production of said derivative

Abstract

The present invention relates to a method for producing imeglimin that is useful as a pharmaceutical; an intermediate for the production of the imeglimin; and a method for producing the intermediate.

Description

Method for producing triazine derivatives and intermediates for producing the same

[0001] This disclosure relates to a method for producing imeglimin, which is useful as a pharmaceutical, a manufacturing intermediate thereof, and a method for producing said manufacturing intermediate.

[0002] As methods for producing imeglimin and related substances, for example, the methods described in Patent Document 1 and Patent Document 2 are known.

[0003] WO2012 / 072663WO2023 / 209729

[0004] Several studies have been conducted on industrial manufacturing methods for imeglimin, which is useful as a pharmaceutical. However, these methods are still not sufficient in terms of operability, robustness, and quality control, and there is room for improvement. To address the above issues, the present invention provides a method for manufacturing imeglimin, which is useful as a pharmaceutical. More specifically, it provides an excellent industrial manufacturing method that produces optically active imeglimin represented by formula (4) in a small number of steps, with simplicity, high reproducibility, high yield, and low cost.

[0005] This invention was made to solve the aforementioned problems and provides a method for producing imeglimin, which is useful as a pharmaceutical.

[0006] In other words, the present invention provides an excellent industrial manufacturing method for producing an optically active imeglimin salt represented by the following formula (4) (hereinafter also referred to as the compound represented by formula (4), compound (4), compound 4, or (4)) in a small number of steps, simply, with high yield and at low cost.

[0007] Furthermore, the present invention provides an excellent industrial production method for producing an optically active imeglimine salt represented by formula (4) from an optically active imeglimine tartrate represented by formula (3) (hereinafter also referred to as the compound represented by formula (3), the compound of formula (3), compound (3), compound 3, or (3)) in fewer steps, in a simple, high-yield, and inexpensive manner.

[0008] More specifically, in one embodiment, in the presence of an inexpensive base, acetaldehyde represented by the following formula (1a) (hereinafter also referred to as the compound represented by formula (1a), the compound of formula (1a), compound 1a, or (1a)), which is also inexpensive, is reacted with a compound represented by the following formula (1) (hereinafter also referred to as compound 1 or (1)) to produce a production intermediate (2) (hereinafter also referred to as the compound represented by formula (2), the compound of formula (2), compound 2, or (2)) (Step 1). Further, without isolating the intermediate (2), the intermediate (3) can be stereoselectively produced by reacting it with tartaric acid or a tartaric acid derivative (Step 2). Furthermore, it has been found that the optically active salt (4) of imiglimin can be produced simply, in a high yield, and at a low cost in a small number of steps by reacting the intermediate (3) with an ammonium salt (Production Method 1).

[0009] That is, the present disclosure typically provides the following.

[0010] [Item 1] A method for producing a compound represented by the following formula (4): (wherein HX ２ represents an organic acid or an inorganic acid), the method comprising a step of reacting a compound represented by the following formula (3): [wherein R １ and R ２ are each independently a hydrogen atom, optionally substituted C １－６ alkyl, optionally substituted C ６－１０ aryl, or optionally substituted -C(=O)R ３ and R ３ is optionally substituted C １－６ alkyl or optionally substituted C ６－１０ aryl. ] with a salt selected from the group consisting of an ammonium salt, sodium halide, potassium halide, and calcium halide.

[0011] [Item 2] HX ２The method for producing the product according to item 1, wherein the product is hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), phosphoric acid, acetic acid, trifluoroacetic acid, salicylic acid, or (L)-(-)-alpha-bromocamphor-8-sulfonic acid.

[0012] [Section 3] HX ２ The manufacturing method described in item 2, wherein the substance is hydrochloric acid (HCl).

[0013] [Item 4] The compound represented by formula (4) is (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride, (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine acetate, (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine trifluoroacetate, (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydroiodide, (+)-2-amino-3,6-dihydro-4-dimethylamino-6- A method for producing a product according to any one of claims 1 to 3, wherein the product is methyl-1,3,5-triazine salicylate, (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrobromide, (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine[(1S,2S,7S)-2-bromo-7-methyl-3-oxobicyclo[2.2.1]heptan-7-yl]methanesulfonate, or (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine phosphate.

[0014] [Item 5] The method for producing the product according to item 4, wherein the compound represented by formula (4) is (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride.

[0015] [Item 6] The manufacturing method according to any one of items 1 to 5, wherein the salt reacted with the compound represented by formula (3) is an ammonium salt.

[0016] [Item 7] The method for producing the compound according to item 6, wherein the salt reacted with the compound represented by formula (3) is ammonium chloride, ammonium bromide, ammonium iodide, ammonium dihydrogen phosphate, ammonium acetate, ammonium trifluoroacetate, ammonium salicylate, or ammonium (L)-(-)-alphabromocamphor-8-sulfonate.

[0017] [Item 8] The manufacturing method according to item 7, wherein the salt is ammonium chloride.

[0018] [Item 9] The manufacturing method according to any one of items 1 to 5, wherein the salt is sodium chloride or potassium chloride.

[0019] [Clause 10] The method for producing a product according to any one of Clauses 1 to 9, wherein the reaction is carried out in the presence of a reaction solvent selected from the group consisting of alcoholic solvents, esteric solvents, etheric solvents, water, and mixed solvents thereof.

[0020] [Item 11] The manufacturing method according to item 10, wherein the reaction solvent is an alcohol-based solvent.

[0021] [Item 12] Formula (5) in the compound of formula (3) precipitated during the reaction: (In the formula, R １ and R ２ The manufacturing method according to any one of claims 1 to 11, further comprising the step of removing by-products from a compound represented by (the same as in claim 1) and then performing crystallization.

[0022] [Clause 13] The manufacturing method according to Clause 12, wherein crystallization is carried out in the presence of a crystallization solvent selected from the group consisting of alcohol-based solvents, ester-based solvents, ether-based solvents, water, and mixed solvents thereof.

[0023] [Item 14] The manufacturing method according to item 13, wherein the crystallization solvent is an alcohol-based solvent, an ether-based solvent, or water.

[0024] [Item 15] The manufacturing method according to item 13, wherein the crystallization solvent is a mixed solvent of an alcohol-based solvent, an ether-based solvent, and water.

[0025] [Section 16] R １ and R ２ However, H is X ２A manufacturing method according to any one of claims 1 to 15, wherein is Cl.

[0026] [Item 17] The following formula (1): (In the formula, X １ Compounds represented by (where represents halogen) are subjected to the following reaction in the presence of a base: (1a) By reacting it with the compound represented by the following formula (2): Prepare a compound represented by, or a pharmaceutically acceptable salt thereof, and further, formula (5): (In the formula, R １ and R ２ A manufacturing method according to any one of claims 1 to 16, comprising the step of reacting a compound represented by (the same as in claim 1) with a compound represented by formula (3).

[0027] [Item 18] The manufacturing method according to item 17, wherein the base used in the step of reacting the compound of formula (1) with the compound of formula (1a) is an organic base or an inorganic base.

[0028] [Item 19] The manufacturing method according to item 18, wherein the base is an inorganic base.

[0029] [Clause 20] The method for producing the inorganic base according to Clause 19, wherein the inorganic base is sodium hydroxide or potassium hydroxide.

[0030] [Item 21] The manufacturing method according to item 20, wherein the inorganic base is potassium hydroxide.

[0031] [Clause 22] The method for producing the compound according to any one of Clauses 17 to 21, wherein the reaction between the compound of formula (1) and the compound of formula (1a) is carried out in the presence of an alcoholic solvent.

[0032] [Clause 23] The method for producing the product according to any one of claims 17 to 22, further comprising the step of removing by filtration the salt precipitated during the reaction of the compound of formula (1) and the compound of formula (1a).

[0033] [Clause 24] The method for producing a compound represented by formula (1a) dropwise over 0.5 to 10 hours, as described in any one of Clauses 17 to 23.

[0034] [Clause 25] The method for producing a compound according to any one of Clauses 17 to 24, wherein the compound represented by formula (5) is L-(+)-tartaric acid.

[0035] [Clause 26] A method for producing the compound of formula (2) or a pharmaceutically acceptable salt thereof from the compound of formula (5), wherein the reaction is carried out in the presence of an alcoholic solvent, as described in any one of claims 17 to 25.

[0036] In this disclosure, one or more of the above features are intended to be provided in combinations other than those explicitly stated. Further embodiments and advantages of this disclosure will be apparent to those skilled in the art, by reading and understanding the detailed description below as necessary.

[0037] According to the manufacturing method of the present invention, compared to known manufacturing methods, it is possible to produce optically active imeglimin salts (4) useful as pharmaceuticals in high yield and high purity with fewer isolation steps.

[0038] The present disclosure is described below in best form. Throughout this specification, singular expressions should be understood to include the concept of their plural form unless otherwise specified. Accordingly, singular articles (for example, "a," "an," and "the" in English) should be understood to include the concept of their plural form unless otherwise specified. Furthermore, terms used herein should be understood to have the meaning commonly used in the art unless otherwise specified. Accordingly, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains. In case of any conflict, this specification (including definitions) shall prevail.

[0039] Since the compounds of this disclosure may also exist in the form of solvates (e.g., hydrates), the compounds represented by formulas (1), (2), (3), and (4) or their tautomers, or solvates (e.g., hydrates) of pharmaceutically acceptable salts thereof as needed, are also included in the compounds of this disclosure.

[0040] The compounds represented by formulas (1), (2), (3), (4), and (5) may have one or more chiral carbon atoms and may exhibit geometric isomerism and axial chirality, thus existing as several stereoisomers. In this disclosure, these stereoisomers, mixtures thereof, and racemates are also included in the compounds of this disclosure.

[0041] Furthermore, one or more compounds represented by formulas (1), (2), (3), (4), and (5) １ H (hydrogen atom) ２ Deuterium converters converted to H (D: deuterium atom) are also included in the compounds represented by formulas (1), (2), (3), (4), and (5).

[0042] Compounds represented by formulas (1), (3), (4), and (5) obtained as crystals, or their tautomers, or pharmaceutically acceptable salts thereof as needed, may have crystalline polymorphisms, and the disclosed compounds include all crystalline forms.

[0043] This disclosure is described in detail below.

[0044] In this specification, the term "salt of imeglimine" refers to an acid addition salt formed by imeglimine and an acid. Specific examples of acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, formate, acetate, trifluoroacetate, oxalate, propionate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, malonate, salicylate, camphor sulfonate, and (L)-(-)-alpha-bromocamphor-8-sulfonate (see, for example, S.M. Berge et al. "Pharmaceutical Salts" J. Pharma. Sci, 66: pp. 1-19 (1977)). Preferably, tartrates, hydrochlorides, hydrobroms, hydroiodides, phosphates, acetates, trifluoroacetates, salicylates, and (L)-(-)-alpha-bromocamphor-8-sulfonates are used. Most preferably, hydrochlorides are used. Acids that can be used to form salts are HX as used herein. １ HX ２ It can be described as follows.

[0045] One aspect of this disclosure is (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride (i.e., the compound represented by formula (4a)). The IUPAC nomenclature name of this compound is (6R)-N ２ , N ２ It is 6-trimethyl-3,6-dihydro-1,3,5-triazine-2,4-diamine monohydrochloride. The CAS registration number for this compound is [775351-61-6]. In this specification, this compound is also referred to as imeglimin hydrochloride.

[0046] One embodiment of the present disclosure is (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine acetate. In this specification, the compound is also referred to as imeglimine acetate.

[0047] One embodiment of the present disclosure is (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazinetrifluoroacetate. In this specification, the compound is also referred to as imeglimin trifluoroacetate.

[0048] One aspect of this disclosure is (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydroiodide. In this specification, the compound is also referred to as imeglimin hydroiodide.

[0049] One embodiment of this disclosure is (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine salicylate. In this specification, the compound is also referred to as imeglimin salicylate.

[0050] One aspect of this disclosure is (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrobromide. In this specification, the compound is also referred to as imeglimine hydrobromide.

[0051] One aspect of the present disclosure is (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine[(1S,2S,7S)-2-bromo-7-methyl-3-oxobicyclo[2.2.1]heptan-7-yl]methanesulfonate. In this specification, the compound is also referred to as imeglimin(L)-(-)-alpha-bromocamphor-8-sulfonate.

[0052] One embodiment of this disclosure is (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine phosphate. In this specification, the compound is also referred to as imeglimin phosphate.

[0053] The "base" used in the step of reacting the compound of formula (1) with the compound of formula (1a) includes both organic bases and inorganic bases.

[0054] Specific examples of "organic bases" include, but are not limited to, sodium tert-butoxide, potassium tert-butoxide, sodium methoxide, triethylamine, N,N,N',N'-tetramethylethane-1,2-diamine, N,N-dimethylaniline, N,N-diisopropylethylamine, N-methylpyrrolidine, N-methylpiperidine, piperidine, 1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]-5-nonene, 1,8-diazabicyclo[5.4.0]-7-undecene, N-methylmorpholine, diazabicycloundecene, methylamine, ethylamine, diisopropylamine, 4-dimethylaminopyridine, 2,6-ruditine, pyrimidine or pyridine, or mixtures thereof. More preferably, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N,N,N',N'-tetramethylethane-1,2-diamine, 1,4-diazabicyclo[2.2.2]octane, N-methylpiperidine, pyrimidine, or pyridine are mentioned. Even more preferably, sodium tert-butoxide, potassium tert-butoxide, triethylamine, diisopropylethylamine, N,N,N',N'-tetramethylethane-1,2-diamine, 1,4-diazabicyclo[2.2.2]octane, N-methylpiperidine, pyrimidine, or pyridine are mentioned. Most preferably, sodium tert-butoxide, potassium tert-butoxide, triethylamine, and N,N-diisopropylethylamine are mentioned.

[0055] Specific examples of "inorganic bases" include, but are not limited to, ammonia, lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, or cesium carbonate, or mixtures thereof. Preferably, lithium hydroxide, sodium hydroxide, and potassium hydroxide are used. Most preferably, potassium hydroxide is used.

[0056] HX ２ The term "acid" as expressed by this expression includes both organic and inorganic acids.

[0057] "Organic acids" include organic acids and Lewis acids, and specific examples include formic acid, acetic acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid, trichloroacetic acid, dichloroacetic acid, difluoroacetic acid, citric acid, oxalic acid, tartaric acid, salicylic acid, camphorsulfonic acid, (L)-(-)-alpha-bromocamphor-8-sulfonic acid, 1,1'-bi(2-naphthol), hydrogen phosphate-1,1'-binaphthyl-2,2'-diyl, hydrogen phosphate Examples include, but are not limited to, 3,3'-bis(2,4,6-triisopropylphenyl)-1,1'-binaphthyl-2,2'-diyl, or hydrogen phosphate 3,3'-bis(triphenylsilyl)-1,1'-binaphthyl-2,2'-diyl, trifluoroborane diethyl ether complex, trimethylsilyl chloride, diethylaluminum chloride, zinc bromide, tetrachlorotitanium, magnesium bromide diethyl ether complex, or mixtures thereof.

[0058] Specific examples of "inorganic acids" include, but are not limited to, hydrochloric acid (HCl), hydrobromic acid (HBr), hydroiodic acid (HI), nitric acid, phosphoric acid, sulfuric acid, or mixtures thereof. Preferably, hydrochloric acid (HCl) and hydrobromic acid (HBr) are used. Most preferably, hydrochloric acid (HCl) is used.

[0059] "Ammonium salt" refers to ammonium ions NH ４ ＋The ionic compound consists of an organic acid ion or an inorganic acid ion, and specific examples include, but are not limited to, ammonium chloride, ammonium bromide, ammonium iodide, ammonium nitrate, ammonium dihydrogen phosphate, ammonium sulfate, ammonium bicarbonate, ammonium formate, ammonium acetate, ammonium trifluoroacetate, ammonium salicylate, (L)-(-)-alpha-bromocamphor-8-sulfonate ammonium, or mixtures thereof. Preferably, ammonium chloride, ammonium bromide, ammonium iodide, ammonium dihydrogen phosphate, ammonium acetate, ammonium trifluoroacetate, ammonium salicylate, and (L)-(-)-alpha-bromocamphor-8-sulfonate ammonium. Most preferably, ammonium chloride is used.

[0060] An "alcohol-based solvent" refers to a compound containing one or more hydroxyl groups in its molecule, which is a liquid at the reaction temperature and has the property of dissolving or dispersing the reaction substrate. Specific examples of "alcohol-based solvents" include methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 3-methyl-1-butanol, 2-methyl-1-propanol, and tert-butyl alcohol. Preferably, methanol, ethanol, and 2-propanol are used. More preferably, ethanol is used.

[0061] An "ether-based solvent" refers to a compound containing one or more ether bonds in its molecule, which is a liquid at the reaction temperature and has the property of dissolving or dispersing the reaction substrate. Specific examples of "ether-based solvents" include diethyl ether, tetrahydrofuran, methyl-tert-butyl ether (MTBE), and 1,4-dioxane. Preferably, methyl-tert-butyl ether is used as the "ether-based solvent."

[0062] An "ester-based solvent" refers to a compound containing one or more ester bonds in its molecule, which is a liquid at the reaction temperature and has the property of dissolving or dispersing the reaction substrate. Specific examples of "ester-based solvents" include ethyl acetate and isopropyl acetate. Ethyl acetate is preferably used as the "ester-based solvent." The solvents used in the production method of the present invention may be, for example, "alcohol-based solvents," "ether-based solvents," and "ester-based solvents" individually, or they may be used in mixtures.

[0063] In this specification, the number of carbon atoms in the definition of a "substituent" is defined as, for example, "C １－６ It may also be written as "C １－６ The term "alkyl" is synonymous with alkyl groups having 1 to 6 carbon atoms. Furthermore, in this specification, substituents that are not explicitly defined as "may be substituted," "may be substituted," or "substituted" refer to "unsubstituted" substituents. For example, "C １－６ "Alkyl" means "unsubstituted".

[0064] "C １－６ "Alkyl" refers to alkyl groups with 1 to 6 carbon atoms. ６ "Alkyl" refers to an alkyl group with six carbon atoms. The same applies to other numbers.

[0065] "C １－６ "Alkyl" refers to a linear or branched saturated hydrocarbon group with 1 to 6 carbon atoms. １－６ Preferably, "C" is used as the alkyl group. １－４ Examples include "alkyl", and more preferably "C １－３ "Alkyl" is one example. １－３ Specific examples of "alkyl" include, for example, methyl, ethyl, propyl, 1-methylethyl, etc. １－４ A specific example of "alkyl" is, for example, the aforementioned "C １－３ In addition to the examples listed for "alkyl," other examples include butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, etc. １－６A specific example of "alkyl" is, for example, the aforementioned "C １－４ In addition to the examples listed for "alkyl," other examples include pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, and hexyl.

[0066] "C ６－１０ "Aryl" refers to an aromatic hydrocarbon ring group with 6 to 10 carbon atoms. ６－１０ Specific examples of "aryl" include, for example, phenyl, 1-naphthyl, and 2-naphthyl. Phenyle is preferred.

[0067] Examples of "halogen atoms" include fluorine atoms, chlorine atoms, bromine atoms, or iodine atoms. Fluorine atoms and chlorine atoms are preferred.

[0068] In this specification, the number of substituents on a group defined as “may be substituted” is not particularly limited as long as they are substituted, and can be zero, one, or more. Furthermore, unless otherwise indicated, the description of each group also applies when that group is a part of or a substituent of another group.

[0069] In this specification, the substituents in "may be substituted..." can be appropriately selected depending on the group being substituted. For example, "may be substituted C １－６ "Alkyl" refers to the C which may be substituted with halogen atoms, phenyl groups, methoxy groups, hydroxyl groups, etc., at any substituted position. １－６ This refers to alkyl groups, and examples include methyl group, ethyl group, n-propyl group, isopropyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2-methoxyethyl group, and benzyl group. Preferably, it is a methyl group, ethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2-methoxyethyl group, or benzyl group.

[0070] For example, "C may be replaced" ６－１０ "Aryl" means C at any replaceable position. １－６The C may be substituted with alkyl, halogen atoms, phenyl groups, methoxy groups, hydroxyl groups, etc. ６－１０ This refers to aryl groups, such as toluyl groups, anisoyl groups, phenol groups, and chlorophenyl groups. Preferably, it is a toluyl group or anisoyl group.

[0071] In this specification, when referring to solvents, etc., the expression "at least one independently selected from..." is understood to mean that if two or more of these options are selected, the expression includes a mixture of those two or more options.

[0072] As used herein, unless otherwise specified, the term “pharmaceutically acceptable salt” means a salt prepared from a pharmaceutically acceptable acid (including inorganic and organic acids). Furthermore, “a pharmaceutically acceptable salt as needed” means that it may optionally be a pharmaceutically acceptable salt; for example, in the production of intermediates, a salt that is not pharmaceutically acceptable may be used up to a certain stage. Pharmaceutically acceptable salts include, but are not limited to, salts with acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethensulfonic acid, formic acid, fumaric acid, fluoroacid, gluconic acid, glutamic acid, glucorenic acid, galacturonic acid, glycidic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucinic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, propionic acid, phosphoric acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid.

[0073] "Purification" refers to any act that increases the purity of a target substance and reduces the concentration of other substances below the concentration before the purification process. Various methods are used for purification, including precipitation, recrystallization, sublimation, distillation, solvent extraction, use of molecular sieves, and application of various chromatography techniques. Filtration using filter paper or Celite is not included in the definition of purification.

[0074] The present disclosure will now be described in more detail by reference to preferred embodiments, but the technical scope of the present disclosure is not limited to these preferred embodiments. Furthermore, modifications may be made without departing from the scope of the present disclosure.

[0075] X １ X means halogen atom. １ Preferred embodiments include fluorine atoms, chlorine atoms, bromine atoms, or iodine atoms. １ A more preferred embodiment includes a chlorine atom, a bromine atom, or an iodine atom. １ A more preferred embodiment is a chlorine atom.

[0076] HX ２ HX means organic acid or inorganic acid. ２ Preferred embodiments include hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), nitric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, salicylic acid, or (L)-(-)-alphabromocamphor-8-sulfonic acid. ２ More preferred embodiments include hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), phosphoric acid, acetic acid, trifluoroacetic acid, salicylic acid, or (L)-(-)-alphabromocamphor-8-sulfonic acid. ２ A more preferred embodiment is hydrochloric acid (HCl).

[0077] In equation (3), R １ and R ２ Each of these independently consists of a hydrogen atom and a C atom which may be substituted. １－６ Alkyl, optionally substituted C ６－１０ Aryl or possibly substituted -C(=O)R ３ And R ３ C may be substituted. １－６ Alkyl or optionally substituted C ６－１０ It is an arrow. -C(=O)R ３ Specific examples include acetyl groups, benzoyl groups, toluyl groups, and anisoyl groups.

[0078] R １ , R ２and R ３ "C which may be substituted" １－６ The substituents of "alkyl" include halogen atoms and C １－６ Alkyloxy or C ６－１０ C may be substituted with aryl. １－６ This means alkyl, halogen atom, phenyl group, methoxy group, cyano group, or hydroxyl group, and the C １－６ The alkyl group may be substituted at any substituted position, for example, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2-methoxyethyl group, a methoxy group, a cyano group, a benzyl group, and the like. Preferably, it is a methyl group, an ethyl group, a 2-methoxyethyl group, a methoxy group, a cyano group, or a benzyl group.

[0079] R １ and R ２ "C which may be substituted" ６－１０ The substituents of "aryl" include halogen atoms and C １－６ Alkyloxy or C ６－１０ C may be substituted with aryl. １－６ This means alkyl, halogen atom, phenyl group, methoxy group, cyano group, or hydroxyl group, and the C ６－１０ The aryl group may be substituted at any of its substitutable positions, such as a fluorine atom, chlorine atom, methyl group, ethyl group, n-propyl group, isopropyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2-methoxyethyl group, or benzyl group. Preferably, the methyl group, ethyl group, methoxy group, 2-methoxyethyl group, or benzyl group is used.

[0080] R １ and R ２ Preferably, a hydrogen atom, a methyl group, and -C(=O)R ３ It is, and more preferably, a hydrogen atom.

[0081] The salt used in Step 2 is selected from the group consisting of ammonium salts, sodium halides, potassium halides, and calcium halides, preferably ammonium chloride, ammonium bromide, ammonium iodide, ammonium dihydrogen phosphate, ammonium acetate, ammonium trifluoroacetate, ammonium salicylate, (L)-(-)-alphabromocamphor-8-sulfonate ammonium, sodium chloride, or potassium chloride, and more preferably ammonium chloride. Methods for producing the compounds of (1), (2), (3), (4), and (5) of this disclosure, or their tautomers, stereoisomers, mixtures thereof, or racemates, or pharmaceutically acceptable salts thereof as needed, or solvates thereof are described below.

[0082] Furthermore, the compounds obtained in each step can be used in the next reaction either as a reaction solution or as a composition. However, they can also be isolated from the reaction mixture according to conventional methods and easily purified by separation methods such as recrystallization, distillation, and chromatography.

[0083] In the following reactions, the symbols of the compounds have the same meaning as above unless otherwise specified.

[0084] The manufacturing method of this disclosure is described below. Starting materials not described below may be commercially available or manufactured according to methods known to those skilled in the art or similar methods.

[0085] Manufacturing method 1

[0086] Steps 1-1, 1-2, and 2 will be described below with reference to preferred embodiments, but this disclosure is not limited to these.

[0087] Regarding Step 1-1 This process involves reacting a compound represented by formula (1) with a compound represented by formula (1a) in reaction solvent 1 to obtain a compound represented by formula (2) or a pharmaceutically acceptable salt thereof.

[0088] The reaction solvent 1 used in this process is not particularly limited as long as its boiling point is equal to or greater than the reaction temperature of this reaction, but examples include alcoholic solvents, preferably methanol, ethanol, propanol, isopropanol, and isobutanol, and more preferably methanol.

[0089] The amount of reaction solvent 1 used in this process is usually 1.0 to 10 times the weight of the compound represented by formula (1) per weight, preferably 1.0 to 5 times the weight, and more preferably 1.0 to 2.0 times the weight.

[0090] The amount of compound represented by formula (1a) used is typically 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, and more preferably 1.0 to 1.8 equivalents, per equivalent of formula (1).

[0091] The base used in this process is an inorganic base, preferably lithium hydroxide, sodium hydroxide, or potassium hydroxide, and more preferably potassium hydroxide.

[0092] The amount of base used is typically 1.0 to 10.0 equivalents, preferably 1.0 to 5.0 equivalents, and more preferably 1.0 to 1.6 equivalents, per equivalent of the compound represented by formula (1).

[0093] The compound represented by formula (1a) is used in the reaction either on its own or diluted with reaction solvent 1 of this step. The amount of reaction solvent 1 used for dilution is 0.1 to 1.0 times the weight of 1 weight of the compound represented by formula (1), preferably 0.1 to 0.3 times the weight.

[0094] The compound represented by formula (1a), either in its pure form or diluted with the solvent used in this step, is added dropwise to a mixture of the base, the compound represented by formula (1), and the solvent. The dropping temperature is usually -10°C to 30°C, preferably 0°C to 10°C. The dropping time is usually 0.5 hours to 10 hours, preferably 2 hours to 5 hours. If the dropping rate is too fast, unreacted compound 1a will remain in the reaction system. As a result, a polymer is formed when compounds 1a undergo an aldol reaction, and this polymer then reacts with the compound represented by formula (1), generating various by-products. Therefore, the dropping rate is controlled so that no excess compound 1a remains.

[0095] The reaction time is usually 0.5 to 10 hours, preferably 1 to 5 hours.

[0096] The reaction temperature is typically 0°C to 40°C, preferably 0°C to 25°C, and more preferably 5°C to 25°C.

[0097] After the reaction is complete, the solid produced during the reaction is removed by filtration. The compound represented by formula (1) is present in the filtrate as a solution of reaction solvent 1. The filtration temperature is equal to the temperature defined as the reaction temperature. The washing solvent for the filtered solid is equal to reaction solvent 1, and its amount is 0.1 to 1.0 times the weight of 1 weight of the compound represented by formula (1), preferably 0.2 to 0.5 times the weight.

[0098] Regarding Steps 1-2 This process involves reacting a compound represented by formula (2) or a pharmaceutically acceptable salt thereof with tartaric acid or a tartaric acid derivative represented by formula (5) in the presence of reaction solvent 2 to obtain a compound represented by formula (3) (tartrate or tartaric acid derivative salt).

[0099] The amount of reaction solvent 2 used in this process is usually 1.5 to 20 times the weight of the compound represented by formula (2) or a pharmaceutically acceptable salt thereof, preferably 1.5 to 5 times the weight, and more preferably 1.5 to 3.0 times the weight.

[0100] The reaction solvent 2 used in this process is not particularly limited as long as its boiling point is equal to or greater than the reaction temperature of this reaction, but examples include alcoholic solvents, preferably methanol, ethanol, propanol, isopropanol, and isobutanol, and more preferably methanol.

[0101] The amount of L(+)-tartaric acid or tartaric acid derivative represented by formula (5) used is usually 0.7 to 3.0 equivalents, preferably 1.0 to 5.0 equivalents, more preferably 1.0 to 2.0 equivalents, and most preferably 1.0 to 1.6 equivalents, relative to 1 equivalent of the compound represented by formula (2) or its pharmaceutically acceptable salt.

[0102] The reaction time is usually about 0.5 to 24 hours, preferably 5 to 20 hours.

[0103] The reaction temperature is typically -10°C to 60°C, preferably -10°C to 50°C, and more preferably -5°C to 45°C.

[0104] About Step 2 This step involves adding the compound represented by formula (3) to MX in the presence of reaction solvent 3. ２ This is a step to obtain a compound represented by formula (4) by reacting a compound represented by .

[0105] The reaction solvent 3 used in this process is not particularly limited as long as its boiling point is equal to or greater than the reaction temperature of this reaction, and includes alcohol-based solvents, ester-based solvents, ether-based solvents, water, or mixtures thereof. Preferably, it is an alcohol-based solvent, more preferably methanol, ethanol, propanol, isopropanol, or isobutanol, and most preferably methanol.

[0106] In this step, crystallization may be carried out by adding a crystallization solvent. The crystallization solvent is not particularly limited as long as its boiling point is not lower than the reaction temperature of this reaction, and examples thereof include alcohol solvents, ether solvents, ester solvents, water, or a mixed solvent thereof. Preferably, they are methanol, ethanol, propanol, isopropanol, isobutanol, ethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl acetate, isopropyl acetate, or a mixed solvent thereof. More preferably, they are isopropanol, methyl tert-butyl ether, ethyl acetate, or a mixed solvent thereof.

[0107] The reaction solvent 3 used in this step is usually 0.5 to 10 times by weight, preferably 0.5 to 5 times by weight, and more preferably 1.0 to 3 times by weight, based on 1 weight of the compound represented by the formula (3).

[0108] The crystallization solvent used in this step is usually 0.5 to 10 times by weight, preferably 0.5 to 5 times by weight, and more preferably 0.5 to 3 times by weight, based on 1 weight of the compound represented by the formula (3).

[0109] MX in this step ２ of X ２ The anions of X include fluorine atom, chlorine atom, bromine atom, iodine atom, H ２ PO ４ CH ３ CO ２ CF ３ CO ２ and anions of those having the structures shown below. [In the formula, * represents the bonding position with M.] The cations of M in MX in this step include ammonium, lithium, sodium, potassium, calcium, and cesium cations. MX in this step ２ The cations of M include ammonium, lithium, sodium, potassium, calcium, and cesium cations. MX in this step ２Examples include ammonium chloride, ammonium bromide, ammonium iodide, ammonium dihydrogen phosphate, ammonium acetate, ammonium trifluoroacetate, ammonium salicylate, ammonium (L)-(−)-α-bromocamphor-8-sulfonate, sodium chloride, and potassium chloride, with ammonium chloride being more preferred.

[0110] MX ２ The usage amount of MX is usually 0.8 to 10.0 equivalents, preferably 1.0 to 5.0 equivalents, and more preferably 1.0 to 1.5 equivalents with respect to 1 equivalent of the compound represented by formula (3).

[0111] The usage amount of water in this step is usually 0 to 2 weight times, preferably 0.01 to 1 weight times, and more preferably 0.01 to 0.3 weight times with respect to 1 weight of the compound represented by formula (3).

[0112] The reaction time is usually about 0.5 to 24 hours, preferably 1 to 20 hours.

[0113] The reaction temperature is usually 20°C to 65°C, preferably 45°C to 65°C.

[0114] The compound represented by formula (3) and MX ２ The solid (the salt of the tartrate anion and M or the salt of the tartrate derivative anion and M represented by formula (6)) produced by reacting the compound represented by formula (3) and the compound represented by MX can be removed by filtration. Note that the by-product from the compound represented by formula (5) in the compound of formula (3) in item 12 is the compound of formula (6). A crystallization solvent is added to the obtained filtrate to perform crystallization. Filtration can be carried out at the same temperature as the reaction temperature. The washing solvent for the solid removed by filtration can be the same solvent as reaction solvent 3. The amount of the washing solvent used is usually 0.3 to 10 weight times, preferably 0.3 to 5 weight times, and more preferably 0.5 to 3 weight times with respect to 1 weight of the compound represented by formula (3).

[0115] The operating temperature of crystallization is usually -20°C to 65°C, preferably -10°C to 40°C.

[0116] The order in which reagents and other substances are added is not limited to those listed above.

[0117] The present disclosure will be further described below with reference examples and embodiments, but these will not limit the scope of the disclosure. Furthermore, these may be modified without departing from the scope of the disclosure. The compound names shown herein do not necessarily follow IUPAC nomenclature. Compound identification was performed using high-performance liquid chromatography-mass spectrometry (LCMS), infrared absorption (IR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, high-performance liquid chromatography (HPLC), etc.

[0118] The Rt values ​​for each compound, measured under the following conditions, are shown in the table below.

[0119] In this specification, the following abbreviations may be used: Me: methyl MeOH: methanol MTBE: methyl-tert-butyl ether Rt: retention time

[0120] The room temperature is between 10°C and 30°C.

[0121] Example 1: Method for producing (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine tartrate KOH (85.5% content, 17.81 g, 271.39 mmol) and methanol (85.02 mL) were added to a 300 mL three-necked flask and stirred at 15°C. Metformin hydrochloride (44.95 g, 271.39 mmol) was added and stirred at 15°C for 1 hour. A methanol solution (11.24 mL) of acetaldehyde (90% content, 14.35 g, 325.66 mmol), which had been cooled to 5°C beforehand, was added dropwise over 3 hours. After stirring the reaction solution at 15°C for 5 hours, the precipitated solid was removed by filtration, and the filtered product was washed with methanol (22.67 mL). (L)-tartaric acid (40.73 g, 271.39 mmol) was added to the obtained filtrate and kept warm at 40°C. After adding seed crystals (4.47 mg), the mixture was stirred at 40°C for 2 hours and then cooled to 0°C over 4 hours. After incubating at 0°C for 3 hours, the mixture was filtered. The crystals were washed with methanol (56.68 mL) and then dried under reduced pressure at 50°C or below to obtain imeglimine tartrate (3a) (33.74 g, purity yield 39%, content 92.9%, HPLC Method 1). 1 H-NMR (400 MHz, DMSO-d6) δ: 8.36 (1H, s), 8.20 (1H, s), 7.25 (total 2H, brs), 4.78-4.74 (1H, m), 3.29 (2H, s), 2.98 (6H, s), 1.39 (3H, d, J = 5.2 Hz).

[0122] Example 2: Method for producing (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride Imeglimin tartrate (10 g, 32.76 mmol), ammonium chloride (1.93 g, 36.03 mmol), and methanol (27.74 mL) were added to a 100 mL three-necked flask and stirred at 60°C for 3 hours. The precipitated solid was removed by filtration, and the supernatant was washed with methanol (10.00 mL). The resulting filtrate was concentrated to a volume of 20 g, then water (0.7 g) was added at 30°C, and the mixture was stirred at the same temperature for 1.0 hour. MTBE (19.57 mL) was added dropwise over 1.5 hours, and the mixture was stirred at the same temperature for 1 hour. The mixture was cooled to 0°C over 3 hours, and then incubated at the same temperature for 11 hours. After filtering the crystals, they were washed with a pre-mixed solution of methanol (1.89 mL) and MTBE (4.05 mL), and then dried under reduced pressure at 50°C or below to obtain imeglimin hydrochloride (4a) (5.41 g, 86.2%, content 99.9% HPLC Method 1, R-isomer / S-isomer = 96 / 4 HPLC Method 2). 1 H-NMR (400 MHz, DMSO-d6) δ: 8.40 (1H, s), 8.24 (1H, s), 7.27 (2H, brs), 4.82-4.77 (1H,m), 3.02 (6H, s), 1.32 (3H, d, J = 5.8 Hz). 13 C-NMR (100 MHz, DMSO-d6) δ: 157.8, 156.3, 57.6, 36.8, 22.0 Mass (ESI + ): 156.1244 (M+H) +

[0123] Example 3: Method for producing (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine acetate. Imeglimine tartrate (1.5 g, 4.91 mmol), ammonium acetate (397.5 mg, 5.16 mmol), and methanol (4.2 mL) were added to a 30 mL three-necked flask and stirred at 60°C for 3 hours. The precipitated solid was removed by filtration, and the supernatant was washed with methanol (5.7 mL). The obtained filtrate was concentrated to dryness to obtain imeglimine acetate (1.15 g, 105%, content 90.9%, HPLC Method 1). 1H-NMR (400 MHz, DMSO-d6) δ: 9.48 (1H, s), 7.01 (1H, s), 4.82-4.77 (1H, m), 2.99 (6H, s), 1.68 (3H, s), 1.30 (3H, d, J = 6.0 Hz). LC-MS: Detection m / z: 156 (M+H) +

[0124] Example 4: Method for producing (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazinetrifluoroacetate Imeglimine tartrate (1.5 g, 4.91 mmol), ammonium trifluoroacetate (675.6 mg, 5.16 mmol), and methanol (4.2 mL) were added to a 30 mL three-necked flask and stirred at 60°C for 3 hours. The precipitated solid was removed by filtration, and the supernatant was washed with methanol (5.7 mL). The obtained filtrate was concentrated to dryness to obtain imeglimine trifluoroacetate (1.31 g, 99.0%, content 98.7%, HPLC Method 1). 1 H-NMR (400 MHz, DMSO-d6) δ: 8.59 (1H, s), 8.12(1H, s), 7.37(2H, brs), 4.82-4.78(1H,m), 3.02(6H, s), 1.32(3H, d, J = 6.4 Hz).

[0125] Example 5: Method for producing (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydroiodide. Imeglimine tartrate (1.5 g, 4.91 mmol), ammonium iodide (750.3 mg, 5.16 mmol), and methanol (4.2 mL) were added to a 30 mL three-necked flask and stirred at 60°C for 3 hours. The precipitated solid was removed by filtration, and the supernatant was washed with methanol (5.7 mL). The obtained filtrate was concentrated to dryness to obtain imeglimine hydroiodide (1.39 g, 99.7%, content 97.2%, HPLC Method 1). 1H-NMR (400 MHz, DMSO-d6) δ: 8.05 (1H, s), 8.01 (1H, s), 7.01 (2H, brs), 4.83-4.79 (1H,m), 3.02 (6H, s), 1.32 (3H, d, J = 6.0 Hz). LC-MS: Detection m / z: 156 (M+H) +

[0126] Example 6: Method for producing (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine salicylate. Imeglimine tartrate (3.0 g, 9.83 mmol), ammonium salicylate (1.60 g, 10.32 mmol), and methanol (8.4 mL) were added to a 50 mL three-necked flask and stirred at 60°C for 3 hours. The precipitated solid was removed by filtration, and the supernatant was washed with methanol (11.4 mL). The obtained filtrate was concentrated to dryness to obtain imeglimine salicylate (2.68 g, 93%, content 98.6%, HPLC Method 1). 1 H-NMR (400 MHz, DMSO-d6) δ: 9.44 (1H, s), 8.15 (1H, s), 7.95 (1H, brs), 7.70 (1H, dd, J = 7.2, 1.2 Hz), 7.18 (1H, dd, J = 7.2, 1.2 Hz), 6.68-6.63(2H,m), 4.83 (1H, t, J = 5.2 Hz), 3.02 (6H, s), 1.36 (3H, d, J = 5.2 Hz). LC-MS: Detection m / z: 156 (M+H) +

[0127] Example 7: Method for producing (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrobromide. Imeglimine tartrate (3.0 g, 9.83 mmol), ammonium bromide (1.011 g, 10.32 mmol), and methanol (8.4 mL) were added to a 50 mL three-necked flask and stirred at 60°C for 3 hours. The precipitated solid was removed by filtration, and the supernatant was washed with methanol (11.4 mL). The obtained filtrate was concentrated to dryness to obtain imeglimine hydrobromide (2.06 g, 89%, content 96.1%, HPLC Method 1). 1 H-NMR (400 MHz, DMSO-d6) δ: 8.12 (1H, s), 8.07 (1H, s), 7.15 (2H, brs), 4.82-4.78 (1H, m), 3.17 (6H, s), 1.32 (3H, d, J = 5.6 Hz). LC-MS: Detection m / z: 156 (M+H) +

[0128] Example 8: Method for producing (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine[(1S,2S,7S)-2-bromo-7-methyl-3-oxobicyclo[2.2.1]heptan-7-yl]methanesulfonate Imeglimine tartrate (3.0 g, 9.83 mmol), (L)-(-)-alpha-bromocamphor-8-sulfonate ammonium (3.39 g, 10.32 mmol), and methanol (8.4 mL) were added to a 50 mL three-necked flask and stirred at 60°C for 3 hours. The precipitated solid was removed by filtration, and the supernatant was washed with methanol (11.4 mL). The resulting filtrate was concentrated to dryness to obtain imeglimin (L)-(-)-alpha-bromocamphor-8-sulfonate (4.72 g, 100%, content 93.7%, HPLC Method 1). 1H-NMR (400 MHz, DMSO-d6) δ: 8.22 (1H, s), 8.04 (1H, s), 7.20 (2H, brs), 5.00 (1H, d, J = 4.3 Hz), 4.80 (1H, q, J = 5.9 Hz), 3.01-2.98 (7H, m), 2.85 (1H, d, J = 14.0 Hz), 2.41 (1H, d, J = 14.0 Hz), 2.15-2.09 (1H, m), 1.87-1.71 (2H, m), 1.32 (3H, d, J = 5.9 Hz), 1.21-1.14 (1H, m), 1.09 (3H, s), 0.82 (3H, s). LC-MS: Detection m / z: 156 (M+H) +

[0129] Example 9: Method for producing (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine phosphate. Imeglimin tartrate (3.0 g, 9.83 mmol), ammonium dihydrogen phosphate (1.187 g, 10.32 mmol), methanol (4.16 mL), and water (3.3 mL) were added to a 50 mL three-necked flask and stirred at 60°C for 3 hours. The precipitated solid was removed by filtration, and the supernatant was washed with methanol (11.4 mL). The obtained filtrate was concentrated to dryness to obtain imeglimin phosphate (2.458 g, 98.8%, content 93.3%, HPLC Method 1). 1 H-NMR (400 MHz, D2O) δ: 4.76-4.71 (1H, m), 2.90 (6H, s), 1.27 (3H, d, J = 6.0 Hz). LC-MS: Detection m / z: 156 (M+H) +

[0130] According to the present invention, optically active imeglimin salts useful as pharmaceuticals can be produced simply, with high yield and at low cost, using fewer steps, providing an excellent industrial production method.

Claims

1. The following formula (4): (wherein, HX ２ means an organic acid or an inorganic acid) is a method for producing a compound represented by the following formula (3): [wherein, R １ and R ２ are each independently a hydrogen atom, optionally substituted C １－６ alkyl, optionally substituted C ６－１０ aryl or optionally substituted -C(=O)R ３ ; and R ３ is optionally substituted C １－６ alkyl or optionally substituted C ６－１０ aryl.], and reacting the compound represented by the formula with a salt selected from the group consisting of an ammonium salt, sodium halide, potassium halide and calcium halide.

2. HX ２ The method for producing the product according to claim 1, wherein the product is hydrochloric acid (HCl), hydrogen bromide (HBr), hydrogen iodide (HI), phosphoric acid, acetic acid, trifluoroacetic acid, salicylic acid, or (L)-(-)-alpha-bromocamphor-8-sulfonic acid.

3. HX ２ The manufacturing method according to claim 2, wherein is hydrochloric acid (HCl).

4. The compound represented by formula (4) is (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride, (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine acetate, (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine trifluoroacetate, (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydroiodide, (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl A method for producing triazine according to any one of claims 1 to 3, wherein the salt is 1,3,5-triazine salicylate, (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrobromide, (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine[(1S,2S,7S)-2-bromo-7-methyl-3-oxobicyclo[2.2.1]heptan-7-yl]methanesulfonate, or (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine phosphate.

5. The manufacturing method according to claim 4, wherein the compound represented by formula (4) is (+)-2-amino-3,6-dihydro-4-dimethylamino-6-methyl-1,3,5-triazine hydrochloride.

6. The manufacturing method according to any one of claims 1 to 5, wherein the salt reacted with the compound represented by formula (3) is an ammonium salt.

7. The manufacturing method according to claim 6, wherein the salt reacted with the compound represented by formula (3) is ammonium chloride, ammonium bromide, ammonium iodide, ammonium dihydrogen phosphate, ammonium acetate, ammonium trifluoroacetate, ammonium salicylate, or ammonium (L)-(-)-alphabromocamphor-8-sulfonate.

8. The manufacturing method according to claim 7, wherein the salt is ammonium chloride.

9. The manufacturing method according to any one of claims 1 to 5, wherein the salt is sodium chloride or potassium chloride.

10. The manufacturing method according to any one of claims 1 to 9, wherein the reaction is carried out in the presence of a reaction solvent selected from the group consisting of alcohol-based solvents, ester-based solvents, ether-based solvents, water, and mixed solvents thereof.

11. The manufacturing method according to claim 10, wherein the reaction solvent is an alcohol-based solvent.

12. Formula (5) in the compound of formula (3) precipitated during the reaction: (In the formula, R １ and R ２ The manufacturing method according to any one of claims 1 to 11, further comprising the step of performing crystallization after removing by-products from a compound represented by (which is the same as in claim 1).

13. The manufacturing method according to claim 12, wherein crystallization is carried out in the presence of a crystallization solvent selected from the group consisting of alcohol-based solvents, ester-based solvents, ether-based solvents, water, and mixed solvents thereof.

14. The manufacturing method according to claim 13, wherein the crystallization solvent is an alcohol-based solvent, an ether-based solvent, or water.

15. The manufacturing method according to claim 13, wherein the crystallization solvent is a mixed solvent of an alcohol-based solvent, an ether-based solvent, and water.

16. R １ and R ２ However, H is X ２ The manufacturing method according to any one of claims 1 to 15, wherein is Cl.

17. The following formula (1): (In the formula, X １ Compounds represented by (where represents halogen) are subjected to the following reaction in the presence of a base: (1a) By reacting it with the compound represented by the following formula (2): Prepare a compound represented by, or a pharmaceutically acceptable salt thereof, and further, formula (5): (In the formula, R １ and R ２ A manufacturing method according to any one of claims 1 to 16, comprising the step of reacting with a compound represented by (the same as in claim 1) to obtain a compound represented by formula (3).

18. The manufacturing method according to claim 17, wherein the base used in the step of reacting the compound of formula (1) with the compound of formula (1a) is an organic base or an inorganic base.

19. The manufacturing method according to claim 18, wherein the base is an inorganic base.

20. The manufacturing method according to claim 19, wherein the inorganic base is sodium hydroxide or potassium hydroxide.

21. The manufacturing method according to claim 20, wherein the inorganic base is potassium hydroxide.

22. The method for producing the compound according to any one of claims 17 to 21, wherein the reaction between the compound of formula (1) and the compound of formula (1a) is carried out in the presence of an alcoholic solvent.

23. The manufacturing method according to any one of claims 17 to 22, further comprising the step of removing by filtration the salt precipitated during the reaction between the compound of formula (1) and the compound of formula (1a).

24. The manufacturing method according to any one of claims 17 to 23, characterized in that the total amount of the compound represented by formula (1a) is added dropwise over 0.5 to 10 hours.

25. The manufacturing method according to any one of claims 17 to 24, wherein the compound represented by formula (5) is L-(+)-tartaric acid.

26. The method for producing the compound according to any one of claims 17 to 25, wherein the reaction between the compound of formula (2) or a pharmaceutically acceptable salt thereof and the compound of formula (5) is carried out in the presence of an alcoholic solvent.

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