Method for producing 2-aminobenzooxazole, 2-aminobenzothiazole, and derivatives thereof

Abstract

To provide a production method capable of industrially mass-producing 2-aminobenzooxazole, 2-aminobenzothiazole, and their derivatives.SOLUTION: A method for producing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, the method comprising a reaction step of reacting a compound represented by formula (II) with a compound represented by formula (III) in the presence of a protonic acid and a solvent, and an isolation step of isolating the compound represented by formula (I) from the reaction mixture resulting from the reaction step. (R1, R2, R3, R4: H, halogen, cyano, nitro, R5, R5-O-, R5-S-, R5-C(=O)-, R5-C(=S)- or the like; R5: substituted or unsubstituted C1-20 alkyl, substituted or unsubstituted C3-12 cycloalkyl, substituted or unsubstituted C5-20 aryl or the like; X: O, S).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present disclosure relates to methods for making 2-aminobenzoxazoles and 2-aminobenzothiazoles and derivatives thereof. [Background technology]

[0002] It is known that 2-aminobenzoxazole, 2-aminobenzothiazole, and their derivatives can be used as components of functional chemical substances (e.g., pharmaceuticals and their intermediates). Therefore, methods for industrially producing 2-aminobenzoxazole, 2-aminobenzothiazole, and their derivatives have been investigated.

[0003] Non-Patent Document 1 proposes a method for producing 2-aminobenzoxazole by reacting 2-aminophenol with dicyandiamide in the presence of a Lewis acid. [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] O. Grytsai, et al., Tetrahedron letters, 59, 1642-1645 (2018) Summary of the Invention

[0005] However, in the method of Non-Patent Document 1, after completion of the reaction, a complex is formed between the basic substance 2-aminobenzoxazole and the Lewis acid, and therefore, complicated steps are required, such as a step of decomposing the complex by adding an aqueous sodium bicarbonate solution or the like, and a subsequent step of extracting 2-aminobenzoxazole with an organic solvent, etc. Therefore, the method of Non-Patent Document 1 is not suitable for industrial mass production of 2-aminobenzoxazole and the like.

[0006] Therefore, one object of the present disclosure is to provide a new technical means for industrially mass-producing 2-aminobenzoxazole and the like.

[0007] After extensive research, the present inventors have unexpectedly found that 2-aminobenzoxazole and its derivatives can be industrially mass-produced by reacting 2-aminophenol with dicyandiamide in the presence of a protonic acid. Furthermore, they have found that this method can be used to industrially mass-produce not only 2-aminobenzoxazole and its derivatives, but also 2-aminobenzothiazole and its derivatives. The present disclosure is based on these findings.

[0008] According to one embodiment of the present disclosure, a compound represented by formula (I): [ka] (In the formula, R 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen, cyano, nitro, R 5 , R 5 -O-, R 5 -S-, R 5 -C(=O)-, R 5 -C(=S)-, R 5 -OC(=O)-, R 5 -S(=O2)-O-, R 5 -C(=O)-NR 6 - and NR 6 R 7 - selected from the group consisting of R 5 are the same or different at each occurrence and represent a substituted or unsubstituted linear or branched alkyl having 1 to 20 carbon atoms, a substituted or unsubstituted cyclic alkyl having 3 to 12 carbon atoms, a substituted or unsubstituted aryl having 5 to 20 carbon atoms, or a substituted or unsubstituted heteroaryl having 5 to 20 carbon atoms, R 6 and R 7each independently represents hydrogen, a substituted or unsubstituted linear or branched alkyl having 1 to 20 carbon atoms, a substituted or unsubstituted cyclic alkyl having 3 to 12 carbon atoms, a substituted or unsubstituted aryl having 5 to 20 carbon atoms, or a substituted or unsubstituted heteroaryl having 5 to 20 carbon atoms; X is O or S) or a pharmaceutically acceptable salt thereof, comprising the steps of: Compounds of formula (II): [ka] (wherein each substituent is as defined in the compound represented by formula (I)). and a compound of formula (III): [ka] in the presence of a protonic acid and a solvent; and an isolation step of isolating the compound represented by formula (I) from the reaction mixture obtained in the above step; A method is provided, comprising:

[0009] According to the present disclosure, it becomes possible to industrially mass-produce 2-aminobenzoxazole and the like.

[0010] According to one embodiment of the present disclosure, a method for producing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof includes a reaction step of reacting a compound represented by formula (II) with a compound represented by formula (III) in the presence of a protonic acid and a solvent, and an isolation step of isolating the compound represented by formula (I) from the reaction mixture obtained in the reaction step. The use of a protonic acid and a compound represented by formula (III) in the production of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof is advantageous in that it can eliminate the cumbersome steps (e.g., extraction with an organic solvent) required in the method described in Non-Patent Document 1. The method of the present disclosure also has the advantage of eliminating the need for environmentally hazardous compounds (e.g., cyanogen bromide) used in other conventional methods (e.g., T. Nagano, et al., Journal of American Chemical Society, 75, 2770-2771 (1953)). Each reaction is described in detail below.

[0011] [ka]

[0012] [Reaction step of reacting a compound represented by formula (II) with a compound represented by formula (III) in the presence of a protonic acid and a solvent] According to one embodiment of the present disclosure, in the production of a compound represented by formula (I), a reaction step (also referred to as "step (1)" in the present disclosure) is carried out in which a compound represented by formula (II) and a compound represented by formula (III) are reacted in the presence of a protonic acid and a solvent. The present disclosure is advantageous in that the compound represented by formula (I) or a pharmaceutically acceptable salt thereof can be produced without using a Lewis acid, which requires a complicated post-treatment step.

[0013] (Compound represented by formula (I) or a pharmaceutically acceptable salt thereof) In the present disclosure, the compound represented by formula (I) has the following structure: [ka] (In the formula, R 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen, cyano, nitro, R 5 , R 5 -O-, R 5 -S-, R 5 -C(=O)-, R 5 -C(=S)-, R 5 -OC(=O)-, R 5 -S(=O2)-O-, R 5 -C(=O)-NR 6 - and NR 6 R 7 - selected from the group consisting of R 5 are the same or different at each occurrence and represent a substituted or unsubstituted linear or branched alkyl having 1 to 20 carbon atoms, a substituted or unsubstituted cyclic alkyl having 3 to 12 carbon atoms, a substituted or unsubstituted aryl having 5 to 20 carbon atoms, or a substituted or unsubstituted heteroaryl having 5 to 20 carbon atoms, R 6 and R 7 each independently represents hydrogen, a substituted or unsubstituted linear or branched alkyl having 1 to 20 carbon atoms, a substituted or unsubstituted cyclic alkyl having 3 to 12 carbon atoms, a substituted or unsubstituted aryl having 5 to 20 carbon atoms, or a substituted or unsubstituted heteroaryl having 5 to 20 carbon atoms; X is O or S) It is expressed as:

[0014] In the present disclosure, "halogen" includes, but is not limited to, fluorine, chlorine, bromine, iodine, and the like.

[0015] In the present disclosure, examples of "linear or branched alkyl having 1 to 20 carbon atoms" include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, and eicosyl.

[0016] The substituted linear or branched alkyl having 1 to 20 carbon atoms means the linear or branched alkyl having 1 to 20 carbon atoms substituted with one or more identical or different optional substituents (including, but not limited to, for example, halogen, alkyl having 1 to 20 carbon atoms, ester, amide, etc.).

[0017] In the present disclosure, the "cyclic alkyl having 3 to 12 carbon atoms" is not particularly limited as long as it is a cyclic alkyl having 3 to 12 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and decahydronaphthyl.

[0018] The substituted cyclic alkyl having 3 to 12 carbon atoms means the above cyclic alkyl having 3 to 12 carbon atoms substituted with one or more identical or different arbitrary substituents (including, but not limited to, halogen, alkyl having 1 to 20 carbon atoms, ester, amide, etc.).

[0019] In the present disclosure, "aryl having 5 to 20 carbon atoms" refers to an aromatic hydrocarbon group having 5 to 20 carbon atoms. The aryl having 5 to 20 carbon atoms may be monocyclic or polycyclic (for example, bicyclic or tricyclic). Examples of the aryl having 5 to 20 carbon atoms include, but are not limited to, phenyl, naphthyl, etc.

[0020] The substituted aryl having 5 to 20 carbon atoms means the above aryl having 5 to 20 carbon atoms substituted with one or more identical or different optional substituents (including, but not limited to, halogen, alkyl having 1 to 20 carbon atoms, ester, amide, etc.).

[0021] In the present disclosure, "heteroaryl having 5 to 20 carbon atoms" refers to an aromatic hydrocarbon group having 5 to 20 carbon atoms and containing at least one heteroatom (e.g., oxygen atom, nitrogen atom, sulfur atom). The heteroaryl having 5 to 20 carbon atoms may be monocyclic or polycyclic (e.g., bicyclic or tricyclic). Examples of the heteroaryl having 5 to 20 carbon atoms include, but are not limited to, furyl, thienyl, pyridyl, indolyl, quinolyl, isoquinolyl, and imidazolyl.

[0022] The substituted heteroaryl having 5 to 20 carbon atoms means the above heteroaryl having 5 to 20 carbon atoms substituted with one or more identical or different optional substituents (including, but not limited to, halogen, alkyl having 1 to 20 carbon atoms, ester, amide, etc.).

[0023] In the present disclosure, the term "ester group" refers to a group represented by the group -COOR', where R' is an alkyl group having 1 to 20 carbon atoms.

[0024] In the present disclosure, an "amide group" refers to a group represented by the group -C(O)NR'R'', where R' and R'' are each independently selected from the group consisting of a hydrogen atom and an alkyl group having 1 to 20 carbon atoms. Examples of the amide group include, but are not limited to, methylamide, ethylamide, propylamide, isopropylamide, butylamide, pentylamide, neopentylamide, hexylamide, heptylamide, octylamide, nonylamide, decylamide, dimethylamide, diethylamide, dipropylamide, diisopropylamide, dibutylamide, dipentylamide, dineopentylamide, dihexylamide, diheptylamide, dioctylamide, dinonylamide, didecylamide, ethylmethylamide, methylpropylamide, and ethylpropylamide.

[0025] Pharmaceutically acceptable salts of the compound of formula (I) are not particularly limited as long as they are pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include, but are not limited to, acid addition salts with inorganic acids (including, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, etc.) or organic acids (including, but not limited to, formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.).

[0026] According to one embodiment of the present disclosure, X is O.

[0027] According to one embodiment of the present disclosure, R 1 is hydrogen, halogen, R 5 and R is selected from the group consisting of 5 is a substituted or unsubstituted straight or branched alkyl having 1 to 20 carbon atoms. 1is selected from the group consisting of hydrogen, chlorine, and linear or branched alkyl having 1 to 10 carbon atoms (preferably linear or branched alkyl having 1 to 5 carbon atoms, more preferably linear alkyl having 1 to 3 carbon atoms, and even more preferably methyl). According to a preferred embodiment of the present disclosure, R 1 is hydrogen.

[0028] According to one embodiment of the present disclosure, R 2 is hydrogen, halogen (preferably chlorine) and R 5 According to one embodiment of the present disclosure, R 2 is hydrogen, halogen (preferably chlorine) and R 5 and R is selected from the group consisting of 5 is a substituted or unsubstituted straight or branched alkyl having 1 to 20 carbon atoms. 2 is selected from the group consisting of hydrogen, chlorine, and linear or branched alkyl having 1 to 10 carbon atoms (preferably linear or branched alkyl having 1 to 5 carbon atoms, more preferably linear alkyl having 1 to 3 carbon atoms, and even more preferably methyl). According to a preferred embodiment of the present disclosure, R 2 is hydrogen.

[0029] According to one embodiment of the present disclosure, R 3 is hydrogen, halogen (preferably chlorine) and R 5 According to one embodiment of the present disclosure, R 3 is hydrogen, halogen (preferably chlorine) and R 5 and R is selected from the group consisting of 5 is a substituted or unsubstituted straight or branched alkyl having 1 to 20 carbon atoms. 3 is selected from the group consisting of hydrogen, chlorine, and linear or branched alkyl having 1 to 10 carbon atoms (preferably linear or branched alkyl having 1 to 5 carbon atoms, more preferably linear alkyl having 1 to 3 carbon atoms, and even more preferably methyl). According to a preferred embodiment of the present disclosure, R 3 is hydrogen.

[0030] According to one embodiment of the present disclosure, R 4 is hydrogen, halogen, R 5 and R is selected from the group consisting of 5 is a substituted or unsubstituted straight or branched alkyl having 1 to 20 carbon atoms. 4 is selected from the group consisting of hydrogen, chlorine, and linear or branched alkyl having 1 to 10 carbon atoms (preferably linear or branched alkyl having 1 to 5 carbon atoms, more preferably linear alkyl having 1 to 3 carbon atoms, and even more preferably methyl). According to a preferred embodiment of the present disclosure, R 4 is hydrogen.

[0031] According to one embodiment of the present disclosure, R 1 and R 4 are each independently hydrogen, halogen, or R 5 and R is selected from the group consisting of 5 is a substituted or unsubstituted straight or branched alkyl having 1 to 20 carbon atoms. 1 and R 4 are each independently selected from the group consisting of hydrogen, chlorine, and linear or branched alkyl having 1 to 10 carbon atoms (preferably linear or branched alkyl having 1 to 5 carbon atoms, more preferably linear alkyl having 1 to 3 carbon atoms, and even more preferably methyl). According to a preferred embodiment of the present disclosure, R 1 is hydrogen and R 4 is hydrogen.

[0032] According to one embodiment of the present disclosure, R 2 and R 3 are each independently hydrogen, halogen (preferably chlorine), and R 5 According to one embodiment of the present disclosure, R 2 and R 3 are each independently hydrogen, halogen (preferably chlorine), and R 5 and R is selected from the group consisting of 5are each independently a substituted or unsubstituted straight or branched alkyl having 1 to 20 carbon atoms. 2 and R 3 are each independently selected from the group consisting of hydrogen, chlorine, and linear or branched alkyl having 1 to 10 carbon atoms (preferably linear or branched alkyl having 1 to 5 carbon atoms, more preferably linear alkyl having 1 to 3 carbon atoms, and even more preferably methyl). According to a preferred embodiment of the present disclosure, R 2 is hydrogen and R 3 is hydrogen.

[0033] According to one embodiment of the present disclosure, X is O and R 1 is hydrogen and R 4 is hydrogen.

[0034] According to one embodiment of the present disclosure, X is O and R 1 is hydrogen and R 2 is hydrogen, halogen (preferably chlorine) and R 5 and R is selected from the group consisting of 4 is hydrogen. According to one embodiment of the present disclosure, X is O and R 1 is hydrogen and R 2 is hydrogen, halogen (preferably chlorine) and R 5 and R is selected from the group consisting of 5 is a substituted or unsubstituted linear or branched alkyl having 1 to 20 carbon atoms, and R 4 is hydrogen. According to one embodiment of the present disclosure, X is O and R 1 is hydrogen and R 3 is selected from the group consisting of hydrogen, chlorine, and linear or branched alkyl having 1 to 10 carbon atoms (preferably linear or branched alkyl having 1 to 5 carbon atoms, more preferably linear alkyl having 1 to 3 carbon atoms, and even more preferably methyl), and R 4 is hydrogen. According to one embodiment of the present disclosure, X is O and R 1 is hydrogen and R 2 is hydrogen and R 4 is hydrogen.

[0035] According to one embodiment of the present disclosure, X is O and R 1 is hydrogen and R 3 is hydrogen, halogen (preferably chlorine) and R 5 and R is selected from the group consisting of 4 is hydrogen. According to one embodiment of the present disclosure, X is O and R 1 is hydrogen and R 3 is hydrogen, halogen (preferably chlorine) and R 5 and R is selected from the group consisting of 5 is a substituted or unsubstituted linear or branched alkyl having 1 to 20 carbon atoms, and R 4 is hydrogen. According to one embodiment of the present disclosure, X is O and R 1 is hydrogen and R 3 is selected from the group consisting of hydrogen, chlorine, and linear or branched alkyl having 1 to 10 carbon atoms (preferably linear or branched alkyl having 1 to 5 carbon atoms, more preferably linear alkyl having 1 to 3 carbon atoms, and even more preferably methyl), and R 4 is hydrogen. According to one embodiment of the present disclosure, X is O and R 1 is hydrogen and R 3 is hydrogen and R 4 is hydrogen.

[0036] According to one embodiment of the present disclosure, X is O and R 1 is hydrogen and R 2 and R 3 are each independently hydrogen, halogen (preferably chlorine), and R 5 and R is selected from the group consisting of 4 is hydrogen. According to one embodiment of the present disclosure, X is O and R 1 is hydrogen and R 2 and R 3 are each independently hydrogen, halogen (preferably chlorine), and R 5 and R is selected from the group consisting of 5 are each independently a substituted or unsubstituted linear or branched alkyl having 1 to 20 carbon atoms, and R 4is hydrogen. According to one embodiment of the present disclosure, X is O and R 1 is hydrogen and R 2 and R 3 are each independently selected from the group consisting of hydrogen, chlorine, and linear or branched alkyl having 1 to 10 carbon atoms (preferably linear or branched alkyl having 1 to 5 carbon atoms, more preferably linear alkyl having 1 to 3 carbon atoms, and even more preferably methyl); R 4 is hydrogen. According to one embodiment of the present disclosure, X is O and R 1 is hydrogen and R 2 is hydrogen and R 3 is hydrogen and R 4 is hydrogen.

[0037] (Compound represented by formula (II)) According to one embodiment of the present disclosure, the compound of formula (II) has the following structure: [ka] wherein each substituent is as defined in the present disclosure. It is expressed as:

[0038] According to one embodiment of the present disclosure, the compound represented by formula (II) has the following structure: [ka] wherein each substituent is as defined in the present disclosure. It is expressed as:

[0039] According to one embodiment of the present disclosure, the compound represented by formula (II) has the following structure: [ka] wherein each substituent is as defined in the present disclosure. It is expressed as:

[0040] The amount of the compound represented by formula (II) used in the above step (1) is not particularly limited as long as the object of the present disclosure can be achieved.

[0041] The compound represented by formula (II) may be commercially available or may be synthesized by any method.

[0042] (Compound represented by formula (III)) According to one embodiment of the present disclosure, the compound of formula (III) has the following structure: [ka] It is said to be dicyandiamide represented by the formula:

[0043] The compound represented by formula (III) may be commercially available or may be synthesized by any method.

[0044] The amount of the compound represented by formula (III) used in the above step (1) is not particularly limited as long as the object of the present disclosure can be achieved. The amount of the compound represented by formula (III) is, for example, 0.5 to 10 moles, preferably 0.8 to 5 moles, more preferably 1 to 2 moles, based on 1 mole of the compound represented by formula (II), from the viewpoint of improving the yield of the compound represented by formula (I), suppressing the production of by-products, and / or economic efficiency.

[0045] (protonic acid) The "protonic acid" in the present disclosure is not particularly limited as long as it is an acid capable of donating a proton. Examples of protonic acids include, but are not limited to, inorganic acids such as nitric acid, sulfuric acid, hydrogen chloride, hydrobromic acid, and phosphoric acid; organic acids such as methanesulfonic acid and paratoluenesulfonic acid; and solutions thereof in any solvent (e.g., a solvent described below) (e.g., hydrogen chloride dissolved in ethanol). These may be used alone or in any combination of two or more. From the viewpoint of low-cost implementation, it is preferable that the protonic acid contains hydrochloric acid. From the viewpoint of producing the compound represented by formula (I) in higher yield and / or selectivity, it is preferable that the protonic acid is an organic acid (preferably methanesulfonic acid).

[0046] The amount of protonic acid used in the above step (1) is not particularly limited as long as the object of the present disclosure can be achieved. The amount of protonic acid is, for example, 0.1 to 10 moles, preferably 0.3 to 5 moles, and more preferably 1 to 2 moles, based on 1 mole of the compound represented by formula (II). The amount of protonic acid is, for example, 0.1 to 10 moles, preferably 0.3 to 5 moles, and more preferably 1 to 2 moles, based on 1 mole of the compound represented by formula (III).

[0047] (solvent) The solvent used in the above step (1) is not particularly limited as long as it can achieve the object of the present disclosure, and may be, for example, a protic solvent or an aprotic solvent. In the present disclosure, a "protic solvent" refers to a solvent having proton-donating properties. In the present disclosure, an "aprotic solvent" refers to a solvent having no proton-donating properties. Examples of the solvent include, but are not limited to, protic solvents such as water, methanol, ethanol, 1-propanol, isopropyl alcohol, 1-butanol, 2-butanol, t-butanol, pentanol, hexanol, 1-octanol, 2-octanol, ethylene glycol, ethylene glycol monomethyl ether, propylene glycol monomethyl ether, propylene glycol monobutyl ether, propylene glycol, and methyl lactate; hexane, cyclohexane, heptane, octane, decane, dodecane, decalin, acetone, cyclohexanone, 2-butanone, dimethoxyethane, monomethyl ether, ethyl acetate, butyl acetate, Examples of suitable aprotic solvents include diglyme, triglyme, propylene glycol monomethyl ether monoacetate (PGMEA), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone, tetrahydrofuran, anisole, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, chlorobenzene, dichlorobenzene, benzene, toluene, xylene, ethylbenzene, mesitylene, tetralin, methylnaphthalene, 1,2-dimethoxyethane, diethyl ether, acetonitrile, dimethyl sulfoxide, and 1,4-dioxane. These may be used alone or in any combination of two or more. From the viewpoint of further improving the yield and / or selectivity of the compound represented by formula (I), the solvent preferably contains an aprotic solvent, more preferably contains an aprotic polar solvent, and more preferably contains 1,2-dimethoxyethane.

[0048] The amount of the solvent is not particularly limited as long as the object of the present disclosure can be achieved. The amount of the solvent is, for example, 1 to 100 parts by mass, preferably 3 to 50 parts by mass, and more preferably 5 to 30 parts by mass, based on 1 part by mass of the compound represented by formula (II). In particular, an amount of the solvent of 3 parts by mass or more (preferably 5 parts by mass or more) based on 1 part by mass of the compound represented by formula (II) is advantageous from the viewpoint of suppressing by-products (e.g., 2-guanidinobenzoxazole or a derivative thereof, 2-guanidinobenzothiazole or a derivative thereof).

[0049] (Reaction temperature) The reaction temperature in the step (1) is not particularly limited as long as the object of the present disclosure can be achieved. The reaction temperature is, for example, 0°C to 150°C, preferably 10°C to 120°C, and more preferably 50°C to 90°C, from the viewpoint of further improving the yield and / or selectivity of the compound represented by formula (I), suppressing by-products, and / or economic efficiency. According to one embodiment of the present disclosure, the reaction temperature in the step (1) is the reflux temperature of the solvent.

[0050] According to one embodiment of the present disclosure, the step (1) is carried out under reflux conditions of the solvent.

[0051] In the step (1), the compound represented by formula (II), the compound represented by formula (III), the protonic acid, and the solvent may be added to a reactor simultaneously or in any order. In the step (1), it is preferable that the compound represented by formula (II), the compound represented by formula (III), and the solvent are added to a reactor and refluxed, and then the protonic acid is added to the reaction system and further refluxed.

[0052] The above step (1) preferably includes a step of adding a protonic acid to the reaction system in multiple batches. Adding a protonic acid to the reaction system in multiple batches is advantageous from the viewpoint of suppressing by-products (e.g., a compound represented by formula (IV) described below (e.g., 2-guanidinobenzoxazole or a derivative thereof, 2-guanidinobenzothiazole or a derivative thereof)). In the present disclosure, "adding a protonic acid to the reaction system in multiple batches" means a method in which the entire amount of the protonic acid is not added to the reaction system at once, and is intended to encompass not only sequential or continuous addition of the protonic acid, but also a method in which a constant amount of the protonic acid is added to the reaction system over time. Therefore, according to one embodiment of the present disclosure, in the above step (1), the addition rate of the protonic acid is adjusted in advance so that the amount of the compound represented by formula (I) produced is greater than the amount of the compound represented by formula (IV) described below.

[0053] According to one embodiment of the present disclosure, the protonic acid is added to the reaction system over a period of 0.5 to 12 hours (preferably 1 to 8 hours, more preferably 1 to 5 hours).

[0054] (Reaction time) The reaction time in step (1) is not particularly limited as long as it is capable of achieving the object of the present disclosure. The reaction time in step (1) refers to the time when the compound represented by formula (II), the compound represented by formula (III), the solvent, and the entire amount of protonic acid are present in the reaction system. Therefore, the reaction time does not include the time when the protonic acid is added to the reaction system in multiple batches. The reaction time is, for example, 0.5 to 48 hours, preferably 1 to 24 hours, and more preferably 1 to 10 hours, from the viewpoint of further improving the yield and / or selectivity of the compound represented by formula (I), suppressing by-products, and / or economic efficiency.

[0055] According to one embodiment of the present disclosure, the rate of addition of the protonic acid in the above step (1) is, for example, 10 to 100 mmol / h, preferably 15 to 70 mmol / h, and more preferably 20 to 50 mmol / h, assuming that the initial concentrations of the compound represented by formula (II) and the compound represented by formula (III) are 2.3 mol / L and 3.6 mol / L, respectively.

[0056] [Sulfonic Acid Reaction Step of Reacting the Reaction Mixture with Sulfonic Acid] According to one embodiment of the present disclosure, in the production of the compound represented by formula (I), a sulfonic acid reaction step (also referred to as "step (2)" in the present disclosure) in which the reaction mixture obtained in step (1) is reacted with sulfonic acid may be carried out after step (1) and before the isolation step described below. The inclusion of step (2) in the method of the present disclosure is advantageous in that the purity of the compound represented by formula (I) can be improved. Furthermore, carrying out step (2) is particularly advantageous in that by-products are precipitated as sparingly soluble salts, which can be easily removed by filtration or the like.

[0057] (sulfonic acid) The sulfonic acid used in the above step (2) includes, but is not limited to, sulfuric acid, methanesulfonic acid, paratoluenesulfonic acid, benzenesulfonic acid, etc., and these may be used alone or in any combination of two or more. The sulfonic acid preferably contains sulfuric acid from the viewpoint of forming a poorly soluble salt with the by-product compound represented by formula (IV) (preferably 2-guanidinobenzoxazole or a derivative thereof, 2-guanidinobenzothiazole or a derivative thereof).

[0058] The amount of sulfonic acid used in the above step (2) is not particularly limited as long as the object of the present disclosure can be achieved. The amount of sulfonic acid is, for example, 0.01 to 10 mol, preferably 0.03 to 3 mol, and more preferably 0.1 to 1 mol, based on 1 mol of the compound represented by formula (II).

[0059] (Reaction temperature) The reaction temperature in step (2) is not particularly limited as long as the object of the present disclosure can be achieved. The reaction temperature is, for example, 0°C to 150°C, preferably 10°C to 120°C, and more preferably 50°C to 90°C, from the viewpoint of further improving the yield and / or selectivity of the compound represented by formula (I), suppressing by-products, and / or economic efficiency. According to one embodiment of the present disclosure, the reaction temperature in step (2) is the reflux temperature of the solvent.

[0060] According to one embodiment of the present disclosure, the step (2) is carried out under reflux conditions of the solvent.

[0061] (Reaction time) The reaction time in the step (2) is not particularly limited as long as the object of the present disclosure can be achieved. The reaction time is, for example, 0.1 to 24 hours, preferably 0.3 to 12 hours, and more preferably 0.5 to 6 hours, from the viewpoint of further improving the yield and / or selectivity of the compound represented by formula (I), suppressing by-products, and / or economic efficiency.

[0062] [Isolation step for isolating the compound represented by formula (I)] According to one embodiment of the present disclosure, in the production of the compound represented by formula (I), an isolation step (also referred to as "step (3)" in the present disclosure) is carried out to isolate the compound represented by formula (I) from the reaction mixture obtained in the above step.

[0063] The above step (3) is not particularly limited as long as it is a method capable of isolating the compound represented by formula (I). Examples of isolation methods include, but are not limited to, filtration, recrystallization, evaporation, etc., which may be used alone or in any combination of two or more. Furthermore, the above isolation may be repeated for the purpose of improving the purity of the compound represented by formula (I), etc.

[0064] According to one embodiment of the present disclosure, step (3) comprises cooling the reaction mixture obtained in step (1) or (2) and separating the filtrate from the precipitate. Cooling the reaction mixture is advantageous in that by-products (e.g., a compound represented by formula (IV) described below (e.g., 2-guanidinobenzoxazole or a derivative thereof, 2-guanidinobenzothiazole or a derivative thereof) are precipitated, thereby increasing the purity of the compound represented by formula (I) contained in the filtrate. In particular, since the compound represented by formula (I) and 2-guanidinobenzoxazole or a derivative thereof and / or 2-guanidinobenzothiazole or a derivative thereof are not easily separated by chromatography or the like, the separation step is particularly advantageous in that the precipitated by-products can be easily separated by filtration or the like.

[0065] According to one embodiment of the present disclosure, the separation is filtration.

[0066] According to one embodiment of the present disclosure, step (3) includes obtaining the compound represented by formula (I) from the filtrate. It is believed that the filtrate of the reaction mixture obtained by step (1) or (2) contains a large amount of the compound represented by formula (I). Therefore, the compound represented by formula (I) may be isolated by removing part or all of the solvent from the filtrate. Examples of methods for removing the solvent include distillation under reduced pressure (e.g., evaporation). Alternatively, the compound represented by formula (I) may be isolated by adding any solvent (e.g., water) to the residue obtained by removing part or all of the solvent, cooling, and recrystallizing.

[0067] According to a preferred embodiment of the present disclosure, step (3) comprises reacting the filtrate with an acid. Reacting the filtrate with an acid in step (3) advantageously allows by-products (e.g., the compound represented by Formula (IV)) contained in the filtrate to be precipitated as poorly soluble salts, thereby further improving the purity of the compound represented by Formula (I). The acid used in this step is not particularly limited, but examples include strong acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, hydroiodic acid, and hydrogen peroxide; and weak acids such as acetic acid, phosphoric acid, and oxalic acid. These may be used alone or in any combination of two or more. According to one embodiment of the present disclosure, the acid used in this step comprises a strong acid (preferably at least one selected from the group consisting of hydrochloric acid and sulfuric acid). The amount of acid used in this step may be, for example, 0.1 to 20 mol, preferably 0.5 to 10 mol, and more preferably 1 to 5 mol, based on 1 mol of the compound represented by Formula (I). According to a preferred embodiment of the present disclosure, the amounts of acid used in this step may be 0-10 mol of hydrochloric acid and 0.1-3 mol of sulfuric acid, preferably 0.5-5 mol of hydrochloric acid and 0.3-2 mol of sulfuric acid, more preferably 1-3 mol of hydrochloric acid and 0.5-0.7 mol of sulfuric acid.

[0068] According to a preferred embodiment of the present disclosure, step (3) comprises, after the step of reacting the filtrate with an acid, a step of separating the filtrate (e.g., by filtration). According to a preferred embodiment of the present disclosure, step (3) comprises, after the step of reacting the filtrate with an acid, a step of separating the filtrate (e.g., by filtration), and a step of cooling the filtrate to recrystallize the compound represented by formula (I).

[0069] [Other processes] In the method of the present disclosure, other steps (neutralization; solvent extraction; purification by chromatography, etc.) may be carried out as necessary at any position before, during, or after each of the above steps.

[0070] [Compound represented by formula (IV)] According to one embodiment of the present disclosure, the method of the present disclosure comprises the step of producing a by-product, a compound represented by formula (IV): [ka] wherein each substituent is as defined in the present disclosure. The compound represented by formula (IV) has a similar structure to the compound represented by formula (I), and separation using chromatography or the like is considered difficult. Therefore, the method of the present disclosure is particularly advantageous in that it can suppress contamination with the compound represented by formula (IV), which is difficult to separate using conventional methods.

[0071] The molar ratio of the compound represented by formula (I) obtained by the method of the present disclosure to the by-product compound represented by formula (IV) (compound represented by formula (IV) / compound represented by formula (I)) is, for example, 0 to 0.25, preferably 0 to 0.1, and more preferably 0 to 0.05.

[0072] [Uses of the compound represented by formula (I)] The compounds of formula (I) produced by the methods of the present disclosure may be used as is or may be used, for example, as intermediates for producing other compounds (e.g., pharmaceuticals).

[0073] The present disclosure encompasses the following: [1] A compound represented by formula (I): [ka] (In the formula, R 1 , R 2 , R 3 and R 4 are each independently hydrogen, halogen, cyano, nitro, R 5 , R 5 -O-, R 5 -S-, R 5 -C(=O)-, R 5 -C(=S)-, R 5 -OC(=O)-, R 5 -S(=O2)-O-, R 5 -C(=O)-NR 6 - and NR 6R 7 - selected from the group consisting of R 5 are the same or different at each occurrence and represent a substituted or unsubstituted linear or branched alkyl having 1 to 20 carbon atoms, a substituted or unsubstituted cyclic alkyl having 3 to 12 carbon atoms, a substituted or unsubstituted aryl having 5 to 20 carbon atoms, or a substituted or unsubstituted heteroaryl having 5 to 20 carbon atoms, R 6 and R 7 each independently represents hydrogen, a substituted or unsubstituted linear or branched alkyl having 1 to 20 carbon atoms, a substituted or unsubstituted cyclic alkyl having 3 to 12 carbon atoms, a substituted or unsubstituted aryl having 5 to 20 carbon atoms, or a substituted or unsubstituted heteroaryl having 5 to 20 carbon atoms; X is O or S) or a pharmaceutically acceptable salt thereof, comprising the steps of: Compounds of formula (II): [ka] (wherein each substituent is as defined in the compound represented by formula (I)). and a compound of formula (III): [ka] in the presence of a protonic acid and a solvent; and an isolation step of isolating the compound represented by formula (I) from the reaction mixture obtained in the above step; A method comprising: [2] The method according to [1], wherein X is O. [3]R 1 is hydrogen and R 4 The method according to [1] or [2], wherein [4]R 2 and R 3 are each independently hydrogen, halogen, and R 5 and R is selected from the group consisting of 5The method according to any one of [1] to [3], wherein is a substituted or unsubstituted linear or branched alkyl having 1 to 20 carbon atoms. [5] The method according to any one of [1] to [4], wherein the protonic acid is hydrochloric acid or methanesulfonic acid. [6] The method according to any one of [1] to [5], wherein the amount of the protonic acid is 0.1 to 10 moles based on 1 mole of the compound represented by formula (I). [7] The method according to any one of [1] to [6], wherein the solvent comprises an aprotic solvent. [8] The method according to any one of [1] to [7], wherein the solvent comprises 1,2-dimethoxyethane. [9] The method according to any one of [1] to [8], wherein the amount of the solvent is 1 to 50 parts by mass based on 1 part by mass of the compound represented by formula (I).

[10] The method according to any one of [1] to [9], wherein the reaction step is carried out under reflux conditions of the solvent.

[11] The method according to any one of [1] to

[10] , wherein the reaction step comprises adding the protonic acid to the reaction system in multiple batches.

[12] The method according to any one of [1] to

[11] , further comprising a sulfonic acid reaction step of reacting the reaction mixture obtained in the reaction step with sulfonic acid after the reaction step and before the isolation step.

[13] The method according to

[12] , wherein the amount of sulfonic acid is 0.1 to 1 mole based on 1 mole of the compound represented by formula (I).

[14] The method according to

[12] or

[13] , wherein the sulfonic acid reaction step is carried out under reflux conditions of the solvent.

[15] The method according to any one of [1] to

[14] , wherein the isolation step comprises a step of cooling the reaction mixture obtained in the reaction step and separating the filtrate from the precipitate.

[16] The method according to

[15] , wherein the separation is filtration.

[17] The method according to claim 16, wherein the isolation step comprises obtaining the compound represented by formula (I) from the filtrate. [Example]

[0074] The method of the present disclosure will be described in more detail below using examples. However, the following examples are not intended to limit the method of the present disclosure in any way. Unless otherwise specified, percentages and ratios described herein are by mass. Furthermore, unless otherwise specified, units and measurement methods described herein are in accordance with the provisions of the Japanese Industrial Standards (JIS).

[0075] The following instruments were used to measure the properties of the examples and reference examples described below. 1 H nuclear magnetic resonance spectrum ( 1 H NMR): JNM-ECZ400S (JEOL) 13 C nuclear magnetic resonance spectrum ( 13 C NMR): JNM-ECZ400S (JEOL) Internal standard: tetramethylsilane

[0076] [Example 1: Preparation of 2-aminobenzoxazole 1] [ka]

[0077] 5.0 g (46 mmol) of 2-aminophenol (Tokyo Chemical Industry Co., Ltd.) and 4.0 g (48 mmol, 1.0 equivalent relative to 2-aminophenol) of dicyandiamide (Tokyo Chemical Industry Co., Ltd.) were added to 30 mL of ethanol and refluxed at 78-81 °C. 5 mL (57 mmol, 1.2 equivalent relative to 2-aminophenol) of concentrated hydrochloric acid (35%) was added all at once (i.e., no dropwise addition time) and then refluxed for an additional 4 hours (i.e., 4 hours of post-reaction time). The resulting reaction solution was cooled to 5 °C and the precipitate was removed by suction filtration. The resulting filtrate was concentrated using a rotary evaporator, followed by the addition of 50 mL of water and refluxing. 12 mL of 10% aqueous sodium hydroxide was added, cooled to 5 °C, and the crystals were filtered off by suction. The resulting crystals were washed with water and dried under reduced pressure to obtain 2-aminobenzoxazole (A) and the by-product 2-guanidinobenzoxazole (B). The yields of A and B are calculated by dividing the yield of the mixture obtained (i.e., the yield of the mixture of (A) and (B) obtained) and 1 The results were calculated based on the integral ratio of H NMR. The results are shown in Table 1.

[0078] 2-Aminobenzoxazole (A): 1 H NMR (400MHz, DMSO-d6): δ6.95(t,J=7.4Hz,1H),7.09(t,J=7.4Hz,1H),7.19(d,J=7.8Hz,1H),7.31(d,J=7.8Hz,1H),7.36(s,2H). 13 C NMR (101MHz, DMSO-d6): δ108.4,115.2,119.9,123.5,143.6,148.0,162.7. MP:125-127℃

[0079] 2-Guanidinobenzoxazole (B): 1 H NMR (400MHz, DMSO-d6): δ7.01(t,J=7.2Hz,1H),7.10(t,J=7.2Hz,1H),7.24(br s,4H),7.28(d,J=8.0Hz,1H),7.32(d,J=8.0Hz,1H). 13 C NMR (101MHz, DMSO-d6): δ108.6,115.4,120.9,123.1,142.6,146.6,159.9,166.4. mp:185-187℃

[0080] [Example 2: Preparation of 2-aminobenzoxazole 2] 2-Aminobenzoxazole was produced in the same manner as in Example 1, except that concentrated hydrochloric acid was added dropwise over 1 hour and then refluxed for an additional 3 hours after the completion of the addition (i.e., the post-reaction time was 3 hours). The results are shown in Table 1.

[0081] [Example 3: Preparation of 2-aminobenzoxazole 3] 2-Aminobenzoxazole was produced in the same manner as in Example 1, except that concentrated hydrochloric acid was added dropwise over 6 hours and refluxed for an additional hour after the completion of the addition (i.e., the post-reaction time was 1 hour). The results are shown in Table 1.

[0082] [Example 4: Preparation of 2-aminobenzoxazole 4] 2-Aminobenzoxazole was produced in the same manner as in Example 1, except that methanol (reflux temperature: 68° C.) was used instead of ethanol. The results are shown in Table 1.

[0083] [Example 5: Preparation of 2-aminobenzoxazole 5] 2-Aminobenzoxazole was produced in the same manner as in Example 1, except that tetrahydrofuran (THF, reflux temperature: 64°C) was used instead of ethanol and the post-reaction time was 6 hours. The results are shown in Table 1.

[0084] [Example 6: Preparation of 2-aminobenzoxazole 6] 2-Aminobenzoxazole was produced in the same manner as in Example 1, except that 1,2-dimethoxyethane (DME, reflux temperature: 83° C.) was used instead of ethanol. The results are shown in Table 1.

[0085] [Reference Example 1: Preparation of 2-aminobenzoxazole 7 (use of Lewis acid)] 20 mL of 1,2-dimethoxyethane was added to 5.0 g (46 mmol) of 2-aminophenol and 6.0 g (69 mmol) of dicyandiamide and refluxed. A solution of 11.5 mL (92 mmol) of trifluoroborane diethyl ether methanesulfone complex diluted with 10 mL of 1,2-dimethoxyethane was added dropwise over 3 hours, followed by refluxing for an additional 4 hours. The resulting reaction mixture was cooled to room temperature and quenched by the addition of saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated to obtain a mixture containing 2-aminobenzoxazole (A). 50 mL of water and 5 mL of concentrated hydrochloric acid were added to the resulting mixture and refluxed until the mixture was completely dissolved. 25 mL of 10% aqueous sodium hydroxide was added, cooled to 5°C, and the crystals were filtered off by suction filtration. The obtained crystals were washed with water to obtain 2-aminobenzoxazole (A) (1.3 g, yield 21%). The results are shown in Table 1.

[0086] [Table 1]

[0087] [Example 7: Preparation of 2-aminobenzoxazole 8] [ka]

[0088] 20 mL of ethanol was added to 5.0 g (46 mmol) of 2-aminophenol and 4.0 g (48 mmol, 1.0 equivalent relative to 2-aminophenol) of dicyandiamide, and the mixture was refluxed (reflux temperature: 83°C). A mixture of 3.6 mL of methanesulfonic acid (55 mmol, 1.2 equivalent relative to 2-aminophenol) dissolved in 10 mL of ethanol was added dropwise over 3 hours, followed by reflux for an additional 4 hours (i.e., a post-reaction time of 4 hours). The resulting reaction solution was cooled to 5°C, and the precipitate was removed by suction filtration. The resulting filtrate was concentrated using a rotary evaporator, followed by addition of 50 mL of water and reflux. 12 mL of 10% aqueous sodium hydroxide solution was added, cooled to 5°C, and the crystals were filtered off by suction. The resulting crystals were washed with water and dried under reduced pressure to obtain 2-aminobenzoxazole (A) and the by-product 2-guanidinobenzoxazole (B). The yields of A and B were calculated based on the yield of the resulting mixture and the 1 The results were calculated based on the integral ratio of H NMR. The results are shown in Table 2.

[0089] [Example 8: Preparation of 2-aminobenzoxazole 9] 2-Aminobenzoxazole was produced in the same manner as in Example 7, except that dioxane (reaction temperature: 90° C.) was used instead of ethanol. The results are shown in Table 2.

[0090] Example 9: Preparation of 2-aminobenzoxazole 10 2-Aminobenzoxazole was produced in the same manner as in Example 7, except that 1,2-dimethoxyethane (reflux temperature: 83°C) was used instead of ethanol, the dropwise addition time was 1.5 hours, and the post-reaction time was 6 hours. The results are shown in Table 2.

[0091] Example 10: Preparation of 2-aminobenzoxazole 11 2-Aminobenzoxazole was produced in the same manner as in Example 7, except that the amount of methanesulfonic acid used was changed to 92 mmol (2.0 equivalents relative to 2-aminophenol) and 1,2-dimethoxyethane (reflux temperature: 83°C) was used instead of ethanol. The results are shown in Table 2.

[0092] Example 11: Preparation of 2-aminobenzoxazole 12 2-Aminobenzoxazole was produced in the same manner as in Example 7, except that the amount of methanesulfonic acid used was changed to 92 mmol (2.0 equivalents relative to 2-aminophenol), the amount of dicyandiamide used was changed to 69 mmol (1.5 equivalents relative to 2-aminophenol), and 1,2-dimethoxyethane (reflux temperature: 83°C) was used instead of ethanol. The results are shown in Table 2. The purity (HPLC) of 2-aminobenzoxazole obtained in Example 11 was 97.5%.

[0093] [Table 2]

[0094] [Examples 12 to 14: Preparation of 2-aminobenzoxazole derivatives] [ka]

[0095] A 2-aminophenol derivative (46 mmol) having the substituents listed in Table 3 and 6.0 g of dicyandiamide (69 mmol, 1.5 equivalents relative to the 2-aminophenol derivative) were added to 20 mL of 1,2-dimethoxyethane and refluxed. A solution of 6 mL of methanesulfonic acid (92 mmol, 2.0 equivalents relative to the 2-aminophenol derivative) dissolved in 10 mL of 1,2-dimethoxyethane was added dropwise over 3 hours, followed by refluxing for an additional 4 hours. The resulting reaction solution was cooled to 5°C and the precipitate (the sulfate salt of B) was removed by suction filtration. The resulting filtrate was concentrated using a rotary evaporator, followed by addition of 50 mL of water and refluxing. 15 mL of 10% aqueous sodium hydroxide solution was added, cooled to 5°C, and the crystals were filtered off by suction. The resulting crystals were washed with water and dried under reduced pressure to obtain the 2-aminobenzoxazole derivative (A). The results are shown in Table 3.

[0096] 2-amino-5-methylbenzoxazole (R 3 =Me, R 4 =H): 1 H NMR (400MHz, DMSO-d6): δ2.31(s,3H),6.75(d,J=7.8Hz,1H),7.00(s,1H),7.16(d,J=7.8Hz,1H),7.27(s,2H). 13 C NMR (101MHz, DMSO-d6): δ21.0,107.7,115.7,120.4,132.4,143.7,146.1,162.8. mp:136-138℃

[0097] 2-guanidino-5-methylbenzoxazole (R 3 =Me, R 4 =H): 1 H NMR (400MHz, DMSO-d6): δ2.33(s,3H),6.82(d,J=8.0Hz,1H),7.08(s,1H),7.16(br s,4H),7.17(d,J=8.0Hz,1H). 13C NMR (101MHz, DMSO-d6): δ21.1,101.0,115.7,121.5,132.0,142.7,144.7,159.8,166.5. mp:244-247℃

[0098] 2-amino-6-methylbenzoxazole (R 3 =H, R 4 =Me): 1 H NMR (400MHz, DMSO-d6): δ2.33(s,3H),6.90(d,J=8.2Hz,1H),7.06(d,J=8.2Hz,1H),7.13(s,1H),7.22(s,2H). 13 C NMR (101MHz, DMSO-d6): δ21.0,108.9,114.8,124.1,129.3,141.2,148.1,162.4. mp: 164-166℃

[0099] 2-guanidino-6-methylbenzoxazole (R 3 =H, R 4 =Me): 1 H NMR (400MHz, DMSO-d6): δ2.34(s,3H),6.92(d,J=7.8Hz,1H),7.11(br s,4H),7.14(s,1H),7.15(d,J=7.8Hz,1H). 13 C NMR (101MHz, DMSO-d6): δ21.7,109.0,114.9,123.7,130.3,140.2,146.8,160.0,166.1. mp:194-197℃

[0100] 2-amino-5-chlorobenzoxazole (R 3 =Cl, R 4 =H): 1H NMR (400MHz, DMSO-d6): δ6.97(dd,J=8.4,2.0Hz,1H),7.22(d,J=2.0Hz,1H),7.33(d,J=8.4Hz,1H),7.59(s,2H). 13 C NMR (101MHz, DMSO-d6): δ109.4,114.9,119.5,127.7,145.3,146.7,163.9. mp:182-185℃

[0101] 2-guanidino-5-chlorobenzoxazole (R 3 =Cl, R 4 =H): 1 H NMR (400MHz, DMSO-d6): δ7.03(dd,J=8.0,2.4Hz,1H),7.25(br s,4H),7.32(d,J=2.4Hz,1H),7.34(d,J=8.0Hz,1H). 13 C NMR (101MHz, DMSO-d6): δ109.6,114.9,120.4,127.2,144.2,145.4,160.0,167.4. mp:234-236℃

[0102] [Table 3]

[0103] [Example 15: Purification of 2-aminobenzoxazole derivatives] 2.0 g of 2-aminobenzoxazole (14 mmol as 2-aminobenzoxazole) containing 8.3 mol% 2-guanidinobenzoxazole was dissolved in 20 mL of ethanol, and 2.4 mL (27 mmol) of 35% hydrochloric acid and 0.5 mL (9 mmol) of concentrated sulfuric acid were added sequentially and stirred at room temperature. The solution was cooled to 5°C with stirring to crystallize the sulfate salt of 2-guanidinobenzoxazole. The crystals were separated by suction filtration, and the filtrate was concentrated on a rotary evaporator. 30 mL of water was added to the residue and refluxed, and 10 mL of 10% aqueous sodium hydroxide solution was added and cooled to 5°C with stirring to crystallize 2-aminobenzoxazole. The crystals were separated by suction filtration, washed with water, and then dried under reduced pressure at 40°C for 2 hours to obtain 2-aminobenzoxazole (1.3 g, yield: 71%).

[0104] [Example 16: Preparation of 2-aminobenzoxazole derivative 13 (implementation of sulfonic acid reaction step)] [ka]

[0105] 20 mL of ethanol was added to 5.0 g (46 mmol) of 2-aminophenol and 6.0 g (69 mmol, 1.5 equivalents relative to 2-aminophenol) of dicyandiamide and refluxed. A solution of 5 mL (57 mmol, 1.2 equivalents relative to 2-aminophenol) of concentrated hydrochloric acid (35%) diluted with 10 mL of ethanol was added dropwise over 3 hours, followed by refluxing for an additional 2 hours. 1 mL (19 mmol, 0.4 equivalents relative to 2-aminophenol) of sulfuric acid was added and refluxed for 1 hour. The resulting reaction solution was cooled to 5°C, and the precipitate was removed by suction filtration. The filtrate was concentrated using a rotary evaporator, followed by addition of 50 mL of water and refluxing. 12 mL of 10% aqueous sodium hydroxide solution was added, cooled to 5°C, and the crystals were filtered off by suction. The resulting crystals were washed with water and dried under reduced pressure to obtain 2-aminobenzoxazole (3.1 g, yield: 50%).

[0106] Example 17: Preparation of 2-aminobenzothiazole [ka]

[0107] 20 mL of ethanol was added to 5.8 g (46 mmol) of 2-aminothiophenol and 6.0 g (69 mmol, 1.5 equivalents relative to 2-aminothiophenol) of dicyandiamide and refluxed. A solution of 5 mL (57 mmol, 1.2 equivalents relative to 2-aminothiophenol) of concentrated hydrochloric acid (35%) diluted with 10 mL of ethanol was added dropwise over 3 hours, followed by refluxing for an additional 2 hours. 1 mL (19 mmol) of sulfuric acid was added and refluxed for 1 hour. The resulting reaction solution was cooled to 5°C and the precipitate (the sulfate salt of B) was removed by suction filtration. The filtrate was concentrated using a rotary evaporator, followed by addition of 50 mL of water and refluxing. 12 mL of 10% aqueous sodium hydroxide solution was added, cooled to 5°C, and the crystals were filtered off by suction. The resulting crystals were washed with water and dried under reduced pressure to obtain 2-aminobenzothiazole (A) (6.0 g, yield: 86%).

[0108] 2-Aminobenzothiazole: 1 H NMR (400MHz, DMSO-d6): δ7.00(t,J=7.6Hz,1H),7.20(t,J=7.6Hz,1H),7.32(d,J=8.0Hz,1H),7.43(s,2H),7.64(d,J=8.0Hz,1H). 13 C NMR (101MHz, DMSO-d6): δ117.7,120.8,120.9,125.4,130.9,152.8,166.4. MP:125-127℃

[0109] 2-Guanidinobenzothiazole: 1 H NMR (400MHz, DMSO-d6): δ7.06(t,J=7.2Hz,1H),7.14(br s,4H),7.24(t,J=7.6Hz,1H),7.43(d,J=8.0Hz,1H),7.65(d,J=7.6Hz,1H). 13C NMR (101MHz, DMSO-d6): δ118.3,120.7,121.6,125.2,130.2,152.0,158.1,174.0. mp:165-167℃

[0110] The results of Examples 1 to 14 and 16 indicate that a compound represented by formula (I) (a compound represented by formula (II) (a compound represented by formula (III) (dicyandiamide)) was reacted with a compound represented by formula (II) (a compound represented by formula (III)) in the presence of a protonic acid (e.g., hydrochloric acid, methanesulfonic acid) to produce a compound represented by formula (I) (a compound represented by formula (III)) in the presence of a protonic acid (e.g., hydrochloric acid). Furthermore, the results of Example 17 indicate that a compound represented by formula (I) (a compound represented by formula (II)) (a compound represented by formula (III)) in the presence of a protonic acid (e.g., hydrochloric acid) was reacted with a compound represented by formula (III) (dicyandiamide) to produce a compound represented by formula (I). Therefore, the method of the present disclosure is believed to be capable of producing a compound represented by formula (I) (a compound represented by formula (I)) without using a Lewis acid, which requires a complicated treatment step. Furthermore, the method of the present disclosure is believed to be advantageous in that it can produce a compound represented by formula (I) in a yield comparable to or higher than that of the method using a Lewis acid (Reference Example 1). Furthermore, the method of the present disclosure is believed to be particularly advantageous in that by-products can be easily removed by filtration.

[0111] From the results of Examples 1 to 3, it is considered that the yield of the compound represented by formula (I) is higher when the protonic acid is added to the reaction system in multiple portions (for example, dropwise) than when the entire amount of the protonic acid is added to the reaction system at once. Without being bound by theory, it is believed that when a compound represented by formula (II) reacts with a compound represented by formula (III), the following reaction intermediate (a compound represented by formula (V)) is formed. In this reaction intermediate, the guanidino group is believed to be more basic than -NH2, which is directly bonded to the ring structure containing N and X. Therefore, it is believed that the protonic acid reacts preferentially to give a compound represented by formula (I) (Hypothetical Scheme I, Route 1). On the other hand, if a large amount of protonic acid is present in the reaction system, not only the guanidino group but also the -NH2 directly bonded to the ring structure containing the other N and X, which has a relatively low basicity, is thought to react, resulting in the formation of by-products (Hypothetical Scheme I, Route 2). Therefore, by adding the protonic acid in multiple portions, the reaction of the protonic acid with -NH2, which has a slow reaction rate in the compound represented by formula (I) (Hypothetical Scheme I, Route 2), is suppressed, and the reaction of the protonic acid with the guanidino group, which has a fast reaction rate in the compound represented by formula (I) is accelerated (Hypothetical Scheme I, Route 1), which is thought to further improve the yield and / or selectivity of the compound represented by formula (I).

[0112] [ka]

[0113] [ka]

[0114] From the results of Examples 1 to 6, it is believed that the use of an aprotic solvent (e.g., 1,2-dimethoxyethane) is advantageous in that it can further improve the yield and / or selectivity of the compound represented by formula (I). Without being bound by theory, it is believed that the use of a protic solvent (e.g., ethanol) facilitates the production of the by-product compound represented by formula (IV) (e.g., 2-guanidinobenzoxazole) via a reaction intermediate of a five-membered ring intermediate involving an oxonium ion (Hypothetical Scheme I, Route 3). On the other hand, it is believed that the use of an aprotic solvent (e.g., 1,2-dimethoxyethane) favors the reaction via Hypothetical Scheme I, Route 1, resulting in higher selectivity to the compound represented by formula (I). Furthermore, without being bound by theory, it is believed that the use of a water-free solvent in the method of the present disclosure can improve the yield and / or selectivity of the compound represented by formula (I).

[0115] The results of Examples 7 to 11 suggest that using methanesulfonic acid as a protonic acid is advantageous in that it can further improve the yield and / or selectivity of the compound represented by formula (I) compared to using other protonic acids (e.g., hydrochloric acid). Without being bound by theory, the use of hydrochloric acid containing water likely leads to the production of the by-product 2-guanidinobenzoxazole via a reaction intermediate of a five-membered ring intermediate involving an oxonium ion (Hypothetical Scheme I, Route 3). On the other hand, the use of methanesulfonic acid as a protonic acid without water likely leads to the reaction via Hypothetical Scheme I, Route 1, resulting in higher selectivity to the compound represented by formula (I).

[0116] From the results of Example 15, when a compound represented by formula (I) (e.g., 2-aminobenzoxazole) and a compound represented by formula (IV) (e.g., 2-guanidinobenzoxazole) coexist in a solvent (e.g., when a compound represented by formula (I) and a compound represented by formula (IV) coexist in a filtrate), it is believed that the compound represented by formula (IV) can be precipitated as a sparingly soluble salt by reacting with an acid (preferably a strong acid such as hydrochloric acid or sulfuric acid). Therefore, in the isolation step (step (3)), reacting the obtained filtrate with an acid is believed to be advantageous from the viewpoint of further improving the purity of the compound represented by formula (I).

[0117] From the results of Example 16, it is believed that further treatment with a sulfonic acid (e.g., sulfuric acid) after reacting a compound represented by formula (II) with a compound represented by formula (III) in the presence of a protonic acid is advantageous in that it can further improve the yield and / or selectivity of the compound represented by formula (I). Without being bound by theory, it is believed that further treatment with a sulfonic acid (e.g., sulfuric acid) insolubilizes by-products such as 2-guanidinobenzoxazole (e.g., forms an insoluble salt such as a sulfate), thereby increasing the selectivity of the compound represented by formula (I).

Claims

1. Compounds represented by formula (I): 【Chemistry 1】 (In the formula, R １ , R ２ , R ３ and R ４ are each independently hydrogen, halogen, cyano, nitro, R ５ , R ５ -O-, R ５ -S-, R ５ -C(=O)-, R ５ -C(=S)-, R ５ -O-C(=O)-, R ５ -S(=O ２ )-O-, R ５ —C(═O)—NR ６ - and NR ６ R ７ - selected from the group consisting of R ５ are the same or different at each occurrence and represent a substituted or unsubstituted linear or branched alkyl having 1 to 20 carbon atoms, a substituted or unsubstituted cyclic alkyl having 3 to 12 carbon atoms, a substituted or unsubstituted aryl having 5 to 20 carbon atoms, or a substituted or unsubstituted heteroaryl having 5 to 20 carbon atoms, R ６ and R ７ each independently represents hydrogen, a substituted or unsubstituted linear or branched alkyl having 1 to 20 carbon atoms, a substituted or unsubstituted cyclic alkyl having 3 to 12 carbon atoms, a substituted or unsubstituted aryl having 5 to 20 carbon atoms, or a substituted or unsubstituted heteroaryl having 5 to 20 carbon atoms; X is O or S. or a pharmaceutically acceptable salt thereof, comprising the steps of: Compounds represented by formula (II): 【Chemistry 2】 (wherein each substituent is as defined in the compound represented by formula (I)). and a compound represented by formula (III): 【Transformation 3】 in the presence of a protonic acid and a solvent; and an isolation step of isolating the compound represented by formula (I) from the reaction mixture obtained in the above step; A method comprising:

2. 2. The method of claim 1, wherein X is O.

3. R １ is hydrogen, and R ４ The method of claim 1 , wherein is hydrogen.

4. R ２ and R ３ are each independently hydrogen, halogen, and R ５ and R ５ The method according to claim 1, wherein is a substituted or unsubstituted linear or branched alkyl having 1 to 20 carbon atoms.

5. 2. The method of claim 1, wherein the protic acid is hydrochloric acid or methanesulfonic acid.

6. 2. The method according to claim 1, wherein the amount of the protonic acid is 0.1 to 10 moles based on 1 mole of the compound represented by formula (I).

7. The method of claim 1 , wherein the solvent comprises an aprotic solvent.

8. The method of claim 1 , wherein the solvent comprises 1,2-dimethoxyethane.

9. 2. The method according to claim 1, wherein the amount of the solvent is 1 to 50 parts by weight based on 1 part by weight of the compound represented by formula (I).

10. 10. The method of claim 1, wherein the reacting step is carried out under reflux conditions of the solvent.

11. 2. The method of claim 1, wherein the reaction step comprises adding the protonic acid to the reaction system in multiple portions.

12. 2. The method of claim 1, further comprising a sulfonic acid reaction step of reacting the reaction mixture obtained in the reaction step with sulfonic acid after the reaction step and before the isolation step.

13. 13. The method according to claim 12, wherein the amount of sulfonic acid is 0.1 to 1 mole based on 1 mole of the compound represented by formula (I).

14. 13. The method of claim 12, wherein the sulfonic acid reaction step is carried out under reflux conditions of the solvent.

15. The method according to any one of claims 1 to 14, wherein the isolation step comprises a step of cooling the reaction mixture obtained in the reaction step and separating the filtrate and the precipitate.

16. 16. The method of claim 15, wherein the separation is filtration.

17. 17. The method of claim 16, wherein the isolating step comprises obtaining the compound of formula (I) from the filtrate.

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