Method for detecting amine compound, amine compound detection agent, and thiazole derivative

Abstract

Provided is a method for detecting an amine compound which makes it possible to detect an amine compound by using an electrochemical measurement. This method for detecting an amine compound includes: contacting a specimen and an isothiocyanate compound having a phenanthrenequinone skeleton with one another; and detecting a thiazole derivative, which is formed from the isothiocyanate compound and an amine compound contained in the specimen.

Description

Method for detecting amine compounds, agent for detecting amine compounds, and thiazole derivatives

[0001] The present invention relates to a method for detecting an amine compound, a detecting agent for an amine compound, and a thiazole derivative.

[0002] Various color reactions and the like are known as methods for detecting amine compounds. For example, Japanese Patent Application Laid-Open No. 2016-023957 proposes a method for quantifying amino acids in a sample by electrochemical measurement. In addition, Inorg. Chem. 2016, 55, 3616-3623 discusses a method for electrochemically detecting redox-inactive compounds using a compound having an anthraquinone structure.

[0003] An object of one aspect of the present invention is to provide a method for detecting an amine compound, which enables the detection of an amine compound by electrochemical measurement.

[0004] A first aspect is a method for detecting an amine compound, comprising: bringing a sample into contact with an isothiocyanate compound having a phenanthrenequinone skeleton; and detecting a thiazole derivative formed from an amine compound contained in the sample and the isothiocyanate compound.

[0005] The second aspect is a detection agent for an amine compound, which contains an isothiocyanate compound having a phenanthrenequinone skeleton represented by the following formula (1): １０１ and R １０３ From R １０８ each independently represents a hydrogen atom or at least one substituent selected from the group consisting of a substituted or unsubstituted hydrocarbon group, a nitro group, a cyano group, a halogen atom, a hydroxy group, an alkoxy group, an acyl group, an alkoxycarbonyl group, and a carboxy group.

[0006]

[0007] The third aspect is a thiazole derivative represented by the following formula (2): ２０３ From R ２０８R each independently represents a hydrogen atom or at least one substituent selected from the group consisting of a substituted or unsubstituted hydrocarbon group, a nitro group, a cyano group, a halogen atom, a hydroxy group, an alkoxy group, an acyl group, an alkoxycarbonyl group, and a carboxy group. ２１１ and R ２１２ each independently represents a hydrogen atom or a substituted or unsubstituted hydrocarbon group.

[0008]

[0009] According to one aspect of the present invention, there can be provided a method for detecting an amine compound, which enables the detection of an amine compound by electrochemical measurement.

[0010] 1A and 1B are diagrams showing an example of the results of absorbance measurement in this embodiment, a diagram showing an example of the results of electrochemical measurement in this embodiment, and a diagram showing another example of the results of electrochemical measurement in this embodiment.

[0011] In this specification, the term "process" refers not only to an independent process, but also to a process that cannot be clearly distinguished from other processes, as long as the intended purpose of the process is achieved. Furthermore, the upper and lower limits of the numerical ranges described in this specification can be arbitrarily selected and combined from the numerical values ​​exemplified as numerical ranges. Hereinafter, embodiments of the present invention will be described with reference to the drawings. However, the embodiments described below exemplify the amine compound detection method, amine compound detection agent, and thiazole derivative for embodying the technical concept of the present invention, and the present invention is not limited to the amine compound detection method, amine compound detection agent, and thiazole derivative described below.

[0012] 1. Method for detecting an amine compound The method for detecting an amine compound of the first embodiment includes a first step of contacting a sample with an isothiocyanate compound having a phenanthrenequinone skeleton (hereinafter also simply referred to as an "isothiocyanate compound"), and a second step of detecting a thiazole derivative formed from the amine compound and the isothiocyanate compound contained in the sample.

[0013] In the first step, a sample is contacted with an isothiocyanate compound. This results in the formation of a thiazole derivative from the amine compound to be detected and the isothiocyanate compound present in the sample. The formed thiazole derivative has a partial structure derived from the amine compound and a redox-active phenanthrenequinone structure, making it possible to detect the amine compound by electrochemical measurement. Furthermore, since the thiazole derivative has a partial structure derived from the amine compound, it makes it possible to identify the amine compound by electrochemical measurement. In one aspect, the method for detecting an amine compound may include a method for quantitatively analyzing an amine compound, or may include a method for identifying an amine compound.

[0014] The thiazole derivative formed from an amine compound and an isothiocyanate compound can be considered to be formed, for example, by an addition reaction of the amine compound to the isothiocyanate group, followed by a ring-closing reaction of the thiourea group to the phenanthrene skeleton, or by the concerted progress of these reactions.

[0015] The origin of the sample is not particularly limited as long as it can contain an amine compound. Examples of the origin of the sample include living organisms, food, environmental samples, etc. Examples of living organisms include mammals (e.g., humans, monkeys, mice, rats, rabbits, cows, pigs, horses, goats, and sheep), birds, and other animals, insects, mollusks, microorganisms, and plants. Examples of samples derived from living organisms include blood (e.g., whole blood, serum, plasma, etc.), urine, sweat, and saliva. The sample may be subjected to an appropriate pretreatment depending on its origin. Examples of pretreatment include centrifugation, extraction, and filtration. The concentration of the amine compound in the sample may be, for example, 1 nM to 1 M, preferably 1 μM to 1 mM.

[0016] The amine compound to be detected contained in the sample may be any amine compound containing at least one of a primary amino group and a secondary amino group. Examples of the amine compound include aliphatic amines having an aliphatic group with 1 to 20 carbon atoms, and aromatic amines having an aromatic group with 6 to 20 carbon atoms. The amine compound contained in the sample may be a single type or a mixture of two or more types.

[0017] The aliphatic group in the aliphatic amine may be a saturated aliphatic group or an unsaturated aliphatic group. The aliphatic group may be linear, branched, cyclic, or a combination thereof. The carbon number of the aliphatic group may preferably be 1 to 12. The aliphatic group may have a substituent. Examples of the substituent in the aliphatic group include a carboxy group, a hydroxy group, an amino group, a halogen atom, an aryl group, a heteroaromatic ring group, a sulfanyl group, an alkylsulfanyl group, a guanidyl group, a carboxamide group, and an imidazolyl group. The aliphatic group may contain at least one substituent selected from the group consisting of these. The alkyl group in the alkylsulfanyl group may have, for example, 1 to 3 carbon atoms and may be linear or branched. Examples of the aryl group as a substituent in the aliphatic group include a phenyl group and a naphthyl group. Examples of the heteroaromatic ring group as a substituent in the aliphatic group include an indolyl group and an imidazolyl group. The aryl group and heteroaromatic ring group as the substituent in the aliphatic group may further have a substituent, such as an alkyl group having 1 to 3 carbon atoms, a hydroxy group, or a halogen atom.

[0018] The number of carbon atoms in the aromatic group of the aromatic amine may preferably be 6 to 10. Examples of the aromatic group in the aromatic amine include a phenyl group, a naphthyl group, anthracene, and phenanthrene. The aromatic group in the aromatic amine may have a substituent. Examples of the substituent in the aromatic group include a saturated or unsaturated aliphatic group having 1 to 6 carbon atoms, a halogen atom, and an alkoxy group having 1 to 6 carbon atoms.

[0019] The amine compound to be detected may include, for example, an amino acid. The amino acid may be any compound having an amino group and a carboxy group, and may be a natural amino acid or a non-natural amino acid. Examples of natural amino acids include glycine, alanine, isoleucine, leucine, methionine, valine, phenylalanine, tryptophan, tyrosine, asparagine, cysteine, glutamine, serine, threonine, aspartic acid, glutamic acid, arginine, lysine, histidine, proline, β-alanine, citrulline, and theanine. Examples of non-natural amino acids include D-amino acids. The amino acid to be detected may be a derivative such as an ester or amide.

[0020] The amine compound to be detected may have a structure represented by the following formula (3), for example.

[0021]

[0022] In formula (3), R ３１１ and R ３１２ may each independently be a hydrogen atom or a substituted or unsubstituted hydrocarbon group, and preferably R ３１１ and R ３１２ At least one of R may be a substituted or unsubstituted hydrocarbon group. ３１１ and R ３１２ The hydrocarbon groups represented by the following formula may be bonded to each other to form a 5-membered or 6-membered ring. ３１１ and R ３１２ When the hydrocarbon groups represented by the following formula (I) are bonded to each other to form a 5-membered or 6-membered ring, the 5-membered or 6-membered ring may contain a heteroatom such as an oxygen atom or a sulfur atom. ３１１ or R ３１２ The hydrocarbon group represented by R may be an aliphatic group or an aromatic group. ３１１ or R ３１２The aliphatic group represented by the formula (I) may have, for example, 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms. The aliphatic group may be a saturated aliphatic group or an unsaturated aliphatic group. The aliphatic group may be linear, branched, cyclic, or a combination thereof. The aliphatic group may have at least one substituent. Examples of the substituent in the aliphatic group include a carboxy group, a hydroxy group, an amino group, a halogen atom, an aryl group which may have a substituent, a heteroaromatic ring group which may have a substituent, a sulfanyl group, an alkylsulfanyl group, a guanidyl group, a carboxamide group, and an imidazolyl group. The alkyl group in the alkylsulfanyl group may have, for example, 1 to 3 carbon atoms, and may be linear or branched. Examples of the aryl group as a substituent in the aliphatic group include a phenyl group and a naphthyl group. Examples of the heteroaromatic ring group as a substituent in the aliphatic group include an indolyl group and an imidazolyl group. The aryl group and heteroaromatic ring group as the substituent in the aliphatic group may further have a substituent, such as an alkyl group having 1 to 3 carbon atoms, a hydroxy group, or a halogen atom.

[0023] R ３１１ or R ３１２ The aromatic group represented by the formula (I) may have, for example, 6 to 20 carbon atoms, preferably 6 to 10 carbon atoms. Examples of the aromatic group include a phenyl group, a naphthyl group, anthracene, and phenanthrene. The aromatic group may have at least one substituent. Examples of the substituent in the aromatic group include a saturated or unsaturated aliphatic group having 1 to 6 carbon atoms, a halogen atom, and an alkoxy group having 1 to 6 carbon atoms.

[0024] The isothiocyanate compound may be a phenanthrenequinone having an isothiocyanate group. The phenanthrenequinone may be, for example, 9,10-phenanthrenequinone, 1,4-phenanthrenequinone, etc. The substitution position of the isothiocyanate group may be, for example, the 2-position, the 3-position, the 4-position, etc., and preferably the 2-position. The phenanthrenequinone constituting the isothiocyanate compound may have a substituent in addition to the isothiocyanate group. The substituent that the phenanthrenequinone may have will be described later.

[0025] The isothiocyanate compound may be, for example, a compound represented by the following formula (1): When the isothiocyanate compound has a specific structure, the thiazole derivative can be produced more efficiently.

[0026]

[0027] In formula (1), R １０１ and R １０３ From R １０８are each independently a hydrogen atom or at least one substituent selected from the group consisting of a substituted or unsubstituted hydrocarbon group, a nitro group, a cyano group, a halogen atom, a hydroxy group, an alkoxy group, an acyl group, an alkoxycarbonyl group, and a carboxy group. The hydrocarbon group in the substituent may be an aliphatic group or an aromatic group. The aliphatic group may be a saturated aliphatic group or an unsaturated aliphatic group. The aliphatic group may be linear, branched, cyclic, or a combination thereof. The aliphatic group may have, for example, 1 to 12 carbon atoms, preferably 1 to 6 or 1 to 3 carbon atoms. Examples of substituents in the aliphatic group include halogen atoms and aryl groups. The aromatic group may have, for example, 6 to 20 carbon atoms, preferably 6 to 10 carbon atoms. Examples of substituents in the aromatic group include halogen atoms and aliphatic groups having 1 to 3 carbon atoms. The alkoxy group as a substituent may have an aliphatic group having 1 to 6 carbon atoms, preferably an aliphatic group having 1 to 3 carbon atoms. The acyl group as a substituent may have an aliphatic group having 1 to 6 carbon atoms, preferably an aliphatic group having 1 to 3 carbon atoms. The alkoxycarbonyl group as a substituent may have an aliphatic group having 1 to 6 carbon atoms, preferably an aliphatic group having 1 to 3 carbon atoms.

[0028] The isothiocyanate compound represented by formula (1) is R １０１ and R １０３ From R １０８ At least four of the isothiocyanate groups selected from the group consisting of at least R １０１ may be a hydrogen atom, and R １０１ and R １０３ From R １０８ may all be hydrogen atoms.

[0029] The isothiocyanate compound can be synthesized by, for example, nitrating phenanthrenequinone or a derivative thereof, reducing the nitro group to convert it to an amino group, and then converting the amino group to an isothiocyanate group. For details of the synthesis method, see, for example, Chem. Mater. 2015, 27, 3568; Inorg. Chem. 2016, 55, 3616.

[0030] The contact of the specimen with the isothiocyanate compound in the first step may be carried out in a liquid medium. Examples of the liquid medium include aprotic polar solvents such as tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide, and dimethylacetamide, water, and combinations thereof. The specimen and the isothiocyanate compound in the first step may be contacted by mixing the specimen with a solution of the isothiocyanate compound. The concentration of the isothiocyanate compound in the solution of the isothiocyanate compound may be, for example, 10 mM or more and 50 mM or less, and preferably 20 mM or more and 30 mM or less.

[0031] When the sample is brought into contact with the isothiocyanate compound, a reaction catalyst may be present, if necessary. Examples of the reaction catalyst include tertiary amines such as triethylamine, diisopropylethylamine, and N-methylmorpholine. When a reaction catalyst is used in the contact of the sample with the isothiocyanate compound, the amount of the catalyst added may be, for example, 1 to 20, preferably 5 to 12, in terms of molar ratio relative to the isothiocyanate compound.

[0032] The contact temperature between the specimen and the isothiocyanate compound may be, for example, 10° C. or higher and 80° C. or lower, and preferably 20° C. or higher or 40° C. or lower. The contact time between the specimen and the isothiocyanate compound may be, for example, 1 minute or higher and 120 minutes or lower, and preferably 5 minutes or higher or 90 minutes or lower.

[0033] The first step may optionally include a purification step of separating the thiazole derivative from the reaction product obtained by contacting the sample with the isothiocyanate compound, which may include, for example, precipitation by adding a poor solvent such as water, filtration, washing with water, etc.

[0034] In the second step, a thiazole derivative formed from an amine compound and an isothiocyanate compound contained in the sample is detected. The thiazole derivative to be detected may be a compound having a thiazole structure containing a partial structure derived from the amine compound and a phenanthrenequinone structure derived from the isothiocyanate compound, or may be a fused ring compound of a thiazole containing a partial structure derived from the amine compound and a phenanthrenequinone.

[0035] The thiazole derivative may be, for example, a compound represented by the following formula (2): When the thiazole derivative has a specific structure, it can exhibit specific redox behavior depending on the structure of the amine compound.

[0036]

[0037] In formula (2), R ２０３ From R ２０８ may each independently be a hydrogen atom or at least one substituent selected from the group consisting of a substituted or unsubstituted hydrocarbon group, a nitro group, a cyano group, a halogen atom, a hydroxy group, an alkoxy group, an acyl group, an alkoxycarbonyl group, and a carboxy group. ２０３ From R ２０８ The details of the substituent represented by any one of R in formula (1) are as follows: １０３ The same applies to the substituents represented by the above.

[0038] The thiazole derivative represented by formula (2) is R ２０３ From R ２０８ At least four, preferably at least five selected from R ２０３ From R ２０８ may all be hydrogen atoms.

[0039] R ２１１ and R ２１２may each independently be a hydrogen atom or a substituted or unsubstituted hydrocarbon group, and preferably R ２１１ and R ２１２ At least one of R may be a substituted or unsubstituted hydrocarbon group. ２１１ and R ２１２ The hydrocarbon groups represented by the following formula may be bonded to each other to form a 5-membered or 6-membered ring. ２１１ and R ２１２ When the hydrocarbon groups represented by the following formula (I) are bonded to each other to form a 5-membered or 6-membered ring, the 5-membered or 6-membered ring may contain a heteroatom such as an oxygen atom or a sulfur atom within the ring. ２１１ or R ２１２ The details of the substituted or unsubstituted hydrocarbon group represented by R in formula (3) are as follows: ３１１ or R ３１２ The same applies to the substituted or unsubstituted hydrocarbon group represented by the following formula:

[0040] The detection of the thiazole derivative in the second step can be carried out, for example, by visual observation of a color change, ultraviolet-visible absorption spectrum measurement, electrochemical measurement, etc. As will be described later, the isothiocyanate compound and the thiazole derivative each have a maximum absorption wavelength in the visible region, and the maximum absorption wavelengths are significantly different from each other, so that the detection of the thiazole derivative can be determined by visual observation.

[0041] The detection of the thiazole derivative in the second step may include ultraviolet-visible absorption spectroscopy. Thiazole derivatives formed from amine compounds have a maximum absorption wavelength in a specific wavelength range, and therefore, the thiazole derivatives can be detected by ultraviolet-visible absorption spectroscopy. That is, the presence of an amine compound in an absorbance measurement sample prepared from an analyte and an isothiocyanate compound can be detected by having a maximum absorption wavelength in a specific wavelength range. Furthermore, by measuring the absorbance at the maximum absorption wavelength, the concentration of the thiazole compound in the absorbance measurement sample can be quantitatively or semi-quantitatively determined. Absorbance measurement can be performed, for example, using an ultraviolet-visible spectrophotometer.

[0042] The thiazole derivative may have an absorption maximum in the range of 500 nm to 600 nm, preferably in the range of 510 nm to 550 nm. On the other hand, the isothiocyanate compound may have an absorption maximum in the range of 400 nm to less than 500 nm, preferably in the range of 420 nm to 460 nm. The difference between the absorption maximum of the thiazole derivative and the absorption maximum of the isothiocyanate compound may be, for example, 40 nm to 200 nm, preferably 80 nm to 150 nm.

[0043] The absorption maximum wavelength of the thiazole derivative may be shifted to a longer wavelength in the presence of a basic compound. In this case, a change in color tone can be visually confirmed by adding a basic compound to a solution of the thiazole derivative. The thiazole derivative whose absorption maximum wavelength is shifted to a longer wavelength in the presence of a basic compound may have, for example, a carboxy group as a substituent. Examples of basic compounds include aliphatic tertiary amines such as triethylamine, diisopropylethylamine, and N-methylmorpholine. The amount of the longer wavelength shift of the absorption maximum wavelength of the thiazole derivative in the presence of a basic compound may be, for example, 5 nm or more and 100 nm or less, and preferably 10 nm or more and 50 nm or less.

[0044] The detection of the thiazole derivative in the second step may include electrochemical measurement. Since the thiazole derivative formed from the amine compound has a phenanthrenequinone skeleton, the thiazole derivative can be detected by electrochemical measurement. Furthermore, the thiazole derivative has a partial structure derived from the amine compound, and since the electrochemical behavior changes due to this partial structure, it becomes possible to identify or to some extent infer the structure of the amine compound. Detection of the thiazole derivative by electrochemical measurement can be carried out by cyclic voltammetry using, for example, a commonly used electrochemical measurement device equipped with a working electrode, a counter electrode, and a reference electrode.

[0045] Examples of materials for the working electrode used in electrochemical measurements include glassy carbon (GC), gold, platinum, silver, nickel, and graphite. Examples of materials for the counter electrode include platinum, gold, and nickel. The reference electrode can be appropriately selected from commercially available reference electrodes. Examples of reference electrodes include aqueous reference electrodes such as Ag / AgCl electrodes and calomel electrodes; Ag / Ag ＋ In detecting a thiazole derivative, for example, a glassy carbon working electrode, a platinum counter electrode, and a non-aqueous reference electrode may be used.

[0046] The sample for electrochemical measurement to be subjected to electrochemical measurement may contain an organic solvent, an electrolyte, etc. Examples of the organic solvent include nitrile-based solvents such as acetonitrile, propionitrile, and benzonitrile; amide-based solvents such as dimethylformamide and dimethylacetamide; and sulfoxide-based solvents such as dimethyl sulfoxide. Examples of the electrolyte include tetraethylammonium perchlorate, tetrabutylammonium perchlorate, and tetraethylammonium tetrafluoroborate (TEABF ４ ), tetrabutylammonium tetrafluoroborate (TBABF ４ ) and the like.

[0047] The thiazole derivative may exhibit a reversible oxidation-reduction wave in cyclic voltammetry measurement. That is, the thiazole derivative may be a oxidation-reduction system having a stable structure. Furthermore, the oxidation-reduction wave exhibited by the thiazole derivative may have three oxidation peaks, namely, a first oxidation peak, a second oxidation peak, and a third oxidation peak, in order from the low potential side. The first oxidation peak and the second oxidation peak may be derived from, for example, the phenanthrenequinone skeleton constituting the thiazole derivative. Furthermore, the third oxidation peak may be derived from, for example, the thiazole ring structure. The presence of an amine compound in the sample can be detected when an electrochemical measurement sample prepared from an analyte and an isothiocyanate compound exhibits an oxidation peak derived from the thiazole ring structure.

[0048] The three oxidation peaks exhibited by the thiazole derivative by electrochemical measurement may exhibit specific potentials depending on the partial structure derived from the amine compound. The potential of the first oxidation peak (hereinafter also referred to as the first oxidation potential) may be, for example, −1.100 V or more and −0.950 V or less, and preferably −1.050 V or more and −0.960 V or less. The potential of the second oxidation peak (hereinafter also referred to as the second oxidation potential) may be, for example, −0.500 V or more and −0.300 V or less, and preferably −0.450 V or more and −0.350 V or less. The potential of the third oxidation peak (hereinafter also referred to as the third oxidation potential) may be, for example, 0.700 V or more and 1.000 V or less, and preferably 0.800 V or more and 0.950 V or less. The potentials of each oxidation peak are measured using ferrocene as the reference potential.

[0049] The structure of an amine compound can be identified by utilizing the fact that a thiazole derivative exhibits an oxidation potential corresponding to the partial structure derived from the amine compound. For example, the potential of each oxidation peak exhibited by a thiazole derivative formed from a specific amine compound can be measured in advance and compared with the potential of each oxidation peak exhibited by a thiazole derivative formed from a sample, thereby identifying the structure of the amine compound. Here, the potential of each oxidation peak may be a value obtained from a single electrochemical measurement or may be the arithmetic average of oxidation potentials obtained from multiple electrochemical measurements. The oxidation peak potentials to be compared may be a combination of the first oxidation potential, the second oxidation potential, and the third oxidation potential, a combination of the first oxidation potential and the second oxidation potential, or a combination of the second oxidation potential and the third oxidation potential. For example, the relationship between the first oxidation potential and the second oxidation potential obtained from each electrochemical measurement may be two-dimensionally plotted, and the structure of the amine compound may be identified from the distribution pattern. Furthermore, for example, the first oxidation potential may be used as a reference, and the difference between the second oxidation potential and the third oxidation potential may be used as the comparison target.

[0050] The detection agent for amine compounds of the second embodiment contains an isothiocyanate compound having a phenanthrenequinone skeleton represented by the above formula (1). The isothiocyanate compound has a specific structure, which allows it to react with the amine compound to be detected and efficiently produce a thiazole derivative having a partial structure derived from the amine compound. Details of the isothiocyanate compound represented by formula (1) are as described above.

[0051] The thiazole derivative of the third aspect is represented by the above formula (2). A thiazole derivative having a partial structure derived from an amine compound, which is a detection target, can be used to identify the detection target. Details of the thiazole derivative represented by formula (2) are as described above.

[0052] The present invention may include the following aspects <1> to <7>.

[0053] <1> A method for detecting an amine compound, comprising: contacting a sample with an isothiocyanate compound having a phenanthrenequinone skeleton; and detecting a thiazole derivative formed from an amine compound contained in the sample and the isothiocyanate compound.

[0054] <2> The detection method according to <1>, wherein the detection of the thiazole derivative includes measuring absorbance.

[0055] <3> The detection method according to <1> or <2>, wherein the detection of the thiazole derivative includes electrochemical measurement.

[0056] <4> The detection method according to any one of <1> to <3>, wherein the isothiocyanate compound is represented by the following formula (1):

[0057]

[0058] In formula (1), R １０１ and R １０３ From R １０８ each independently represents a hydrogen atom or at least one substituent selected from the group consisting of a substituted or unsubstituted hydrocarbon group, a nitro group, a cyano group, a halogen atom, a hydroxy group, an alkoxy group, an acyl group, an alkoxycarbonyl group, and a carboxy group.

[0059] <5> The detection method according to any one of <1> to <4>, wherein the thiazole derivative is represented by the following formula (2):

[0060]

[0061] In formula (2), R ２０３ From R ２０８ R each independently represents a hydrogen atom or at least one substituent selected from the group consisting of a substituted or unsubstituted hydrocarbon group, a nitro group, a cyano group, a halogen atom, a hydroxy group, an alkoxy group, an acyl group, an alkoxycarbonyl group, and a carboxy group. ２１１ and R ２１２ R each independently represents a hydrogen atom or a substituted or unsubstituted hydrocarbon group. ２１１ and R ２１２ The hydrocarbon groups represented by the following formula may be bonded to each other to form a 5- or 6-membered ring.

[0062] <6> A detection agent for an amine compound, comprising an isothiocyanate compound having a phenanthrenequinone skeleton represented by the following formula (1):

[0063]

[0064] In formula (1), R １０１ and R １０３ From R １０８ each independently represents a hydrogen atom or at least one substituent selected from the group consisting of a substituted or unsubstituted hydrocarbon group, a nitro group, a cyano group, a halogen atom, a hydroxy group, an alkoxy group, an acyl group, an alkoxycarbonyl group, and a carboxy group.

[0065] <7> A thiazole derivative represented by the following formula (2):

[0066]

[0067] In formula (2), R ２０３ From R ２０８R each independently represents a hydrogen atom or at least one substituent selected from the group consisting of a substituted or unsubstituted hydrocarbon group, a nitro group, a cyano group, a halogen atom, a hydroxy group, an alkoxy group, an acyl group, an alkoxycarbonyl group, and a carboxy group. ２１１ and R ２１２ R each independently represents a hydrogen atom or a substituted or unsubstituted hydrocarbon group. ２１１ and R ２１２ The hydrocarbon groups represented by the following formula may be bonded to each other to form a 5- or 6-membered ring.

[0068] In other aspects, the present invention includes use of the isothiocyanate compound represented by formula (1) in a method for detecting amine compounds, use of the isothiocyanate compound represented by formula (1) in the production of a detection agent for amine compounds, and use of the isothiocyanate compound represented by formula (1) in the method for detecting amine compounds. The present invention also includes use of the thiazole derivative represented by formula (2) in the method for detecting amine compounds, and use of the thiazole derivative represented by formula (2) in the method for detecting amine compounds.

[0069] The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

[0070] The measurement conditions in the following Examples and Comparative Examples are as follows: Proton nuclear magnetic resonance spectrum ( １ H-NMR was measured using a nuclear magnetic resonance spectrometer manufactured by Bruker. The chemical shift reference was tetramethylsilane. Mass spectrometry (MS) was measured by ESI-TOF using a Bruker "Compact".

[0071] Synthesis Example 1 As shown in the following scheme, an isothiocyanate compound having a phenanthrenequinone skeleton (PQ-2-NCS) was synthesized using 9,10-phenanthrenequinone (PQ) as a starting material with reference to the descriptions in Chem. Mater. 2015, 27, 3568. and Inorg. Chem. 2016, 55, 3616.

[0072]

[0073] Example 1 300 mg (1.13 mmol) of an isothiocyanate compound (PQ-2-NCS) was added to 48 mL of THF (stabilizer-free, manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) and completely dissolved to prepare a PQ-2-NCS solution. 296.7 mg (2.26 mmol) of L-leucine (manufactured by Tokyo Chemical Industry Co., Ltd.) and 1.57 mL (11.34 mmol) of triethylamine (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) were dissolved in 24 mL of ultrapure water to prepare a sample. The sample was added to the PQ-2-NCS solution and stirred at room temperature for 1 hour. Next, 10 mL of 1 M hydrochloric acid and 50 mL of ultrapure water were added to this solution. The precipitated substance was collected by suction filtration, washed with ultrapure water, and then air-dried to obtain 330 mg of thiazole derivative A-1 as a black powder.

[0074] Regarding the obtained thiazole derivative A-1, １ H-NMR measurement and MS measurement were carried out.

[0075] １ H-NMR (400MHz, DMSO-d ６ ) δ (ppm): 12.75 (br, 1H), 8.71 (d, 1H), 8.22 (d, 1H), 8.15 (d, 1H), 7.99 (dd, 1H), 7.68-7.85 (m, 2 H), 7.45 (t, 1H), 4.50 (br, 1H), 1.71-1.83 (m, 1H), 1.62-1.69 (m, 2H), 0.96 (d, 3H), 0.92 (d, 3H) MS (ESI-TOF): m / z=393.08, calcd for C ２１ H １７ N ２ O ４ S [M-H] － 393.09

[0076] Example 2 Thiazole derivative A-2 was obtained in the same manner as in Example 1, except that L-phenylalanine was used instead of L-leucine.

[0077] １ H-NMR (400MHz, DMSO-d ６ ​​) δ (ppm): 12.95 (br, 1H), 8.80 (d, 1H), 8.22 (d, 1H), 8.17 (d, 1H), 7.98 (dd, 1H), 7.68-7.74 (m, 2H), 7.44 (s, 1H), 7.27-7.31 (m, 4H), 7.18-7.24 (m, 1H), 4.71-4.76 (m, 1H), 3.25 (dd, 1H), 3.04 (dd, 1H) MS (ESI-TOF): m / z=427.07, calcd for C ２４ H １５ N ２ O ４ S [M-H] － 427.08

[0078] Example 3 Thiazole derivative A-3 was obtained in the same manner as in Example 1, except that L-isoleucine was used instead of L-leucine.

[0079] １ H-NMR (400MHz, DMSO-d ６ ) δ (ppm): 12.77 (br, 1H), 8.63 (d, 1H), 8.23 ​​(d, 1H), 8.15 (d, 1H), 7.99 (dd, 1H), 7.73 (t, 1H), 7.69 ( d, 1H), 7.45 (t, 1H), 4.50 (m, 1H), 1.94 (m, 1H), 1.53 (m, 1H), 1.34 (m, 1H), 0.98 (d, 3H), 0.92 (t, 3H) MS (ESI-TOF): m / z=393.09, calcd for C ２１ H １７ N ２ O ４ S [M-H] － 393.09

[0080] Example 4 Thiazole derivative A-4 was obtained in the same manner as in Example 1, except that L-valine was used instead of L-leucine.

[0081] １ H-NMR (400MHz, DMSO-d ６ ​​) δ (ppm): 12.80 (br, 1H), 8.63 (d, 1H), 8.23 ​​(d, 1H), 8.16 (d, 1H), 8.00 (d, 1H), 7.74 (t, 1H), 7.70 (d, 1H), 7.46 (t, 1H), 4.47 (m, 1H), 2.23 (m, 1H), 1.02 (d, 6H) MS (ESI-TOF): m / z=379.08, calcd for C ２０ H １５ N ２ O ４ S [M-H] － 379.08

[0082] Example 5 Thiazole derivative A-5 was obtained in the same manner as in Example 1, except that histamine dihydrochloride was used instead of L-leucine.

[0083] １ H-NMR (400MHz, DMSO-d ６ ) δ (ppm): 11.96 (br, 1H), 10.30 (s, 1H), 8.48 (d, 1H), 8.28 (br, 1H), 8.17-8.24 (m, 2H), 8 .07-8.15 (m, 2H), 7.88-7.95 (m, 2H), 7.60 (s, 1H), 6.90 (s, 1H), 3.77 (d, 1H), 2.83 (t, 1H) MS (ESI-TOF): m / z=375.08, calcd for C ２０ H １５ N ４ O ２ S [M ＋ H] ＋ 375.09

[0084]

[0085] Synthesis Example 2 As shown in the following scheme, 2-aminoanthraquinone (AQ-2-NH ２ Using AQ-2-NCS as a starting material, an isothiocyanate compound having an anthraquinone skeleton (AQ-2-NCS) was synthesized with reference to the description in Inorg. Chem. 2016, 55, 3616.

[0086]

[0087] ​Comparative Example 1 A reaction product B-1 of a sample containing L-leucine and an isothiocyanate compound (AQ-2-NCS) was obtained in the same manner as in Example 1, except that an isothiocyanate compound having an anthraquinone skeleton (AQ-2-NCS) was used instead of the isothiocyanate compound having a phenanthrenequinone skeleton (PQ-2-NCS).

[0088] Regarding the obtained reaction product B-1, １ H-NMR and MS measurements were carried out. The resulting reaction product B-1 was the thiourea derivative shown below.

[0089] １ H-NMR (400MHz, DMSO-d ６ ) δ (ppm): 12.83 (br, 1H), 10.33 (s, 1H), 8.58 (s, 1H), 8.42 (d, 1H), 8.09-8.23 (m, 4H), 7.91-7.99 (m, 3H) , 4.92 (m, 1H), 1.75 (m, 3H), 0.89 (t, 6H) MS (ESI-TOF): m / z=395.11, calcd for C ２１ H １９ N ２ O ４ S [M-H] － 395.11

[0090] Comparative Example 2 A reaction product B-2 of the specimen and the isothiocyanate compound (AQ-2-NCS) was obtained in the same manner as in Comparative Example 1, except that L-phenylalanine was used instead of L-leucine.

[0091] １ H-NMR (400MHz, DMSO-d ６ ) δ (ppm): 13.10 (br, 1H), 10.50 (s, 1H), 8.58 (d, 1H), 8.28 (d, 1H), 8.20-8.25 (m, 2H), 8.14 (d, 1H), 8.06 (dd , 1H), 7.90-7.96 (m, 2H), 7.32-7.36 (m, 2H), 7.24-7.27 (m, 3H), 5.15 (m, 1H), 3.27 (m, 1H), 3.09-3.14 (m, 1H) MS (ESI-TOF): m / z=429.09, calcd for C ２４ H １７ N​​２ O ４ S [M-H] － 429.09

[0092]

[0093] Absorption spectra were measured for the thiazole derivatives A-1 to A-5, reaction products B-1 and B-2, PQ-2-NCS, and AQ-2-NCS obtained above. Samples for absorbance measurement were prepared using acetonitrile as a solvent so that each concentration was 50 μM.

[0094] The absorption spectrum of each of the prepared samples for absorbance measurement (3 mL) was measured using an ultraviolet-visible spectrophotometer (UV1800, manufactured by Shimadzu Corporation). ３ N(-) is shown in Table 1. In addition, the absorbance measurement samples of the thiazole derivatives A-1 to A-5 and the reaction products B-1 and B-2 were treated with triethylamine (Et ３ The absorption spectrum was also measured after adding 100 μL of Et ３ N(+) is shown in Table 1. Furthermore, the absorption spectra of the thiazole derivative A-1 and PQ-2-NCS are shown in Figure 1. In Figure 1, the absorption spectrum of PQ-2-NCS is shown by a dotted line, the absorption spectrum of the thiazole derivative A-1 is shown by a solid line, and the absorption spectrum of the thiazole derivative A-1 to which triethylamine has been added is shown by a dashed line.

[0095]

[0096] The results in Table 1 show that the thiazole derivatives obtained by the reaction of an amine compound with an isothiocyanate compound have a significantly longer absorption maximum wavelength than the compounds obtained in the comparative examples. That is, the thiazole derivatives obtained in the examples exhibit a greater change in color and improved color visibility. Furthermore, when an amine acid is used as the amine compound, the addition of a base (triethylamine) further extends the absorption maximum wavelength.

[0097] Electrochemical Measurement 1 Electrochemical measurements (cyclic voltammetry measurements) were carried out on the thiazole derivatives A-1 to A-4, reaction products B-1 and B-2, PQ-2-NCS, and AQ-2-NCS obtained above. ４ Each compound was dissolved in a 2,4-dichloro-1,4-dichloro- ...

[0098] Cyclic voltammetry (CV) measurements were performed using a non-aqueous reference electrode RE-7 (manufactured by BAS Co., Ltd.) as the reference electrode, a GC electrode as the working electrode, and a platinum electrode as the counter electrode, using an electrochemical measurement device (Model 660E, manufactured by BAS Co., Ltd.). The measurement range was −1.5 V to 1.2 V, and the sweep rate was 100 mV / s. Ferrocene (Fc / Fc ＋ ) was used as the reference potential. Before the measurement, nitrogen gas was bubbled for 30 seconds. CV measurement was performed six times, and the potentials of each oxidation peak in the sixth measurement are shown in Table 2. An example of a cyclic voltanogram for the thiazole derivative A-1 is shown in Figure 2.

[0099]

[0100] From the results in Table 2, a comparison of Comparative Examples 1 and 2 shows that the potentials of the first oxidation peak (first oxidation potential) were nearly identical regardless of the structure of the amine compound. Furthermore, the peak shape of the second oxidation peak was unclear. From the above, it can be seen that amine compounds cannot be distinguished by their anthraquinone skeleton. On the other hand, in the thiazole derivatives having a phenanthrenequinone skeleton according to the examples, the potentials of the second oxidation peak (second oxidation potential) and the potentials of the third oxidation peak (third oxidation potential) clearly differ depending on the structure of the amine compound. In other words, it can be seen that amine compounds can be distinguished by using the thiazole derivatives according to the examples.

[0101] Electrochemical Measurement 2: For each of the thiazole derivatives A-1 to A-4 obtained above, cyclic voltammetry (CV) measurements were performed multiple times under the same conditions as above. For thiazole derivative A-1, CV measurements were performed a total of five times for three types of samples obtained in batches a, b, and c. For thiazole derivative A-2, CV measurements were performed a total of four times for three types of samples obtained in batches d, e, and f. For thiazole derivative A-3, CV measurements were performed a total of three times for two types of samples obtained in batches g and h. For thiazole derivative A-4, CV measurements were performed two times for one type of sample obtained in batch i. The results are shown in Table 3.

[0102]

[0103] The first oxidation potential and second oxidation potential obtained by CV measurement of each thiazole derivative were plotted two-dimensionally with the first oxidation potential on the horizontal axis and the second oxidation potential on the vertical axis. The results are shown in Figure 3.

[0104] 3, although there are variations in the results for each thiazole derivative due to differences in batches and the number of measurements, the degree of variation appears to be somewhat determined by the compound. In other words, it can be said that the amine compound can be estimated to some extent from the first oxidation potential and second oxidation potential.

[0105] The disclosure of Japanese Patent Application No. 2022-090378 (filing date: June 2, 2022) is incorporated herein by reference in its entirety. All documents, patent applications, and technical standards mentioned herein are incorporated herein by reference to the same extent as if each individual document, patent application, and technical standard was specifically and individually indicated to be incorporated by reference.

Claims

1. contacting a sample with an isothiocyanate compound having a phenanthrenequinone skeleton; detecting a thiazole derivative formed from an amine compound contained in the sample and the isothiocyanate compound.

2. The method according to claim 1 , wherein the detection of the thiazole derivative comprises measuring absorbance.

3. The method according to claim 1 , wherein the detection of the thiazole derivative comprises electrochemical measurement.

4. The detection method according to claim 1 , wherein the isothiocyanate compound is represented by the following formula (1): 【Chemistry 1】 (In formula (1), R １０１ and R １０３ From R １０８ each independently represents a hydrogen atom or at least one substituent selected from the group consisting of a substituted or unsubstituted hydrocarbon group, a nitro group, a cyano group, a halogen atom, a hydroxy group, an alkoxy group, an acyl group, an alkoxycarbonyl group, and a carboxy group.

5. The detection method according to claim 1 , wherein the thiazole derivative is represented by the following formula (2): 【Chemistry 2】 (In formula (2), R ２０３ From R ２０８ each independently represents a hydrogen atom or at least one substituent selected from the group consisting of a substituted or unsubstituted hydrocarbon group, a nitro group, a cyano group, a halogen atom, a hydroxy group, an alkoxy group, a tertiary amino group, an acyl group, an alkoxycarbonyl group, and a carboxy group; R ２１１ and R ２１２ each independently represents a hydrogen atom or a substituted or unsubstituted hydrocarbon group; R ２１１ and R ２１２ may be bonded to each other to form a 5- or 6-membered ring)

6. An agent for detecting an amine compound, comprising an isothiocyanate compound having a phenanthrenequinone skeleton represented by the following formula (1): 【Chemistry 3】 (In formula (1), R １０１ and R １０３ From R １０８ each independently represents a hydrogen atom or at least one substituent selected from the group consisting of a substituted or unsubstituted hydrocarbon group, a nitro group, a cyano group, a halogen atom, a hydroxy group, an alkoxy group, an acyl group, an alkoxycarbonyl group, and a carboxy group.

7. A thiazole derivative represented by the following formula (2): 【Chemistry 4】 (In formula (2), R ２０３ From R ２０８ each independently represents a hydrogen atom or at least one substituent selected from the group consisting of a substituted or unsubstituted hydrocarbon group, a nitro group, a cyano group, a halogen atom, a hydroxy group, an alkoxy group, a tertiary amino group, an acyl group, an alkoxycarbonyl group, and a carboxy group; R ２１１ and R ２１２ each independently represents a hydrogen atom or a substituted or unsubstituted hydrocarbon group; R ２１１ and R ２１２ may be bonded to each other to form a 5- or 6-membered ring)

Images