JP7548506B2 - Amine detection agent - Google Patents

Description

Article 30, Paragraph 2 of the Patent Act applies Publication 1: The Journal of Organic Chemistry, 2020, vol. 85, pp. 13177-13190 https://pubs. acs. org/toc/joceah/85/20? sortBy=DATE September 17, 2020

The present invention relates to an amine detection agent, in particular a regenerative amine detection agent. The present invention also relates to a method for detecting amines using the amine detection agent, and a method for regenerating a used amine detection agent.

Amines, such as ammonia and amino acids, are essential substances in both industrial and pharmaceutical development. Therefore, amine detection agents are used in reactions involving amines to check the progress and completion of the reaction.
In addition, some amines are flammable or explosive, and some, such as aromatic amines, are carcinogenic, and there are concerns that they may cause environmental pollution or have an adverse effect on the human body if they are discharged into the atmosphere or rivers. Therefore, amine detection agents are used to confirm that exhaust gases and wastewater do not contain amines such as ammonia.
Known amine detection agents include ninhydrin reagent used for detecting primary amines and Nessler's reagent used for detecting ammonia.

Furthermore, in the field of pharmaceutical development, medium-sized molecule drugs such as peptides, which are intermediate between small molecule drugs and antibody drugs, are attracting much attention as next-generation pharmaceuticals that can solve the problems of small molecule drugs, such as low activity and specificity, and strong toxicity and side effects, as well as the problem of antibody drugs, such as high production costs.
As a method for synthesizing peptides, a solid-phase peptide synthesis method is generally known. In the solid-phase peptide synthesis method, for example, the C-terminus of a peptide or a first amino acid with a protected N-terminus is bound to a bead-shaped resin such as polystyrene or polyacrylamide directly or via a linker. Then, deprotection and a condensation reaction of the N-protected amino acid or the N-protected peptide are repeated to extend the peptide chain, and finally, the synthetic peptide is deprotected and cut out from the solid-phase surface to obtain the desired peptide.
In solid-phase peptide synthesis, it is necessary to elongate the peptide chain as designed. Therefore, every time a condensation reaction of N-protected amino acids or the like is performed, a Kaiser test is performed by taking out a part of the resin beads to confirm that the condensation reaction is completed (that no deprotected free amino groups are present). The Kaiser test is a method for detecting primary amino groups that utilizes a color reaction in which ninhydrin and primary amino groups combine to produce Ruhemann's purple, which is obtained by adding a ninhydrin solution, a potassium cyanide solution, and a phenol solution to the taken-out resin beads and heating at 110°C for 5 minutes.
In recent years, a method for detecting free amino groups in solid-phase peptide synthesis has been proposed, which utilizes a color reaction in which N-hydroxyphthalimide or N,N-dihydroxypyromellitimide is reacted with an amine to produce a yellow to red product (see Non-Patent Document 1).

Hiroyuki Konno et al., Organic Letters, 2020, Vol. 22, pp. 3309-3312

The Kaiser test has the problem of using potassium cyanide and phenol, which are toxic substances, and the Nessler reagent also has the problem of using mercury iodide, which is also toxic, so there is a need for the development of a safe amine detection drug that does not use toxic substances.
The Nessler reagent cannot be used to detect amines other than ammonia, and the Kaiser test has the problem that it is difficult to use for detecting secondary or tertiary amines because primary and secondary amino groups show different colors.
Furthermore, detection of free amino groups using the Kaiser reagent in solid-phase peptide synthesis requires removing the resin and heating it every time an N-protected amino acid is reacted, which is time-consuming and laborious, and makes it difficult to automate the detection.
In addition, since the reaction between ninhydrin and an amino group is irreversible, the sample subjected to detection cannot be recovered, resulting in a low peptide yield, and since the used reagent cannot be recycled, there are problems in that it is not environmentally friendly.

In the method described in Non-Patent Document 1, it is reported that when a pale yellow resin having an immobilized N-unprotected peptide is contacted with a dimethylformamide solution of hydroxyphthalimide or N,N-dihydroxypyromellitimide, the resin turns orange, and when the colored resin is washed with dimethylformamide, it returns to its pale yellow color.
However, quantitative evaluation is difficult in the method of Non-Patent Document 1 because the resin, not the solution, is colored. In addition, since the structure of the color-producing molecule differs depending on the structure of the amino acid to be detected, there is also a problem that the color (absorption wavelength of the solution) differs depending on the type of amino acid to be detected.

In view of the above problems, the present invention aims to provide an amine detection agent that is highly safe, can detect amines having secondary or tertiary amino groups as well as amines having primary amino groups, and is recyclable and environmentally friendly.
Another object of the present invention is to provide an amine detection agent that exhibits a single color and fluorescence regardless of the type of amino group, and that enables quantitative detection of amino groups by measuring the absorbance of a solution into which the colored and fluorescent molecules have diffused.
Another object of the present invention is to provide a simple method for detecting amines using the above-mentioned amine detection reagent, which does not require a heating step or the like, and a method for regenerating a used amine detection reagent.

As a result of extensive research into achieving the above object, the inventors discovered that salts of specific polycyclic aromatic amine compounds can be used as detection agents for amines, and thus completed the present invention.

式（Ａ）乃至（Ｄ）中、Ｒ^１、Ｒ^１１、Ｒ^２１及びＲ^３１は、夫々独立して、

を表し、
Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８及びＲ^９は、夫々独立して、水素原子、炭素原子数１乃至４のアルキル基、フェニル基又は１乃至５個の基Ｙ^２で置換されていてもよいフェニル基を表し、
Ｙ^１及びＹ^２は、夫々独立して、炭素原子数１乃至４のアルキル基、炭素原子数１乃至４のアルコキシ基、炭素原子数１乃至４のハロアルキル基、ハロゲン原子、フェニル基、ナフチル基、ビニル基、ニトロ基、シアノ基又は置換されていてもよいアミノ基を表し、
ｍは、０乃至４の整数を表す。
［２］前記多環式芳香族アミン化合物が、下記式（１）乃至下記式（１２）で表される多環式芳香族アミン化合物からなる群から選択される化合物である、［１］に記載のアミン類検出薬。

［３］前記塩が、ハロゲン化水素塩である、［１］又は［２］に記載のアミン類検出薬。［４］前記塩のｐＫａが、０．１乃至１２の範囲である、［１］乃至［３］の何れか一つに記載のアミン類検出薬。
［５］ペプチド固相合成法における遊離アミノ基の検出に使用するための［１］乃至［４］の何れか１つに記載のアミン類検出薬。
［６］アミン類を、［１］乃至［５］の何れか一つに記載のアミン類検出薬に接触させる工程、及び該接触工程により生じる多環式芳香族アミン化合物の呈色に基いて、該アミン化合物を検出する工程、を含む、アミン類の検出方法。
［７］前記アミン類が、アミノ酸、ペプチド、アミノ酸誘導体、遊離アミノ基を有する糖類、一級アミン、二級アミン、三級アミン及びこれらの樹脂工程物からなる群から選択される少なくとも一種のアミン化合物である、［６］に記載の方法。
［８］前記アミン類が、ペプチド固相合成法における、Ｃ末端が樹脂に固定された樹脂固
定アミノ酸、樹脂固定ペプチド及び樹脂固定アミノ酸誘導体から選択される少なくとも一種のアミン類である、［６］又は［５］に記載のアミン類の検出方法。
［９］アミン類の検出に使用した［１］乃至［５］の何れか一項に記載のアミン類検出薬の再生方法であって、アミン類を［１］又は［５］に記載のアミン類検出薬に接触させることにより、呈色又は変色した式（Ａ）乃至下記式（Ｄ）からなる群から選択される多環式芳香族アミン化合物を生じさせた後、更にハロゲン化水素、硫酸、亜硫酸、硝酸、亜硝酸、及びカルボン酸からなる群から選択される酸を接触させる工程、及び該接触工程により、該多環式芳香族アミン化合物を、呈色成分である多環式芳香族アミン化合物のハロゲン化水素塩、硫酸塩、亜硫酸塩、硝酸塩、亜硝酸塩、及びカルボン酸塩からなる群から選択される塩に変換する工程、を含む、再生方法。
［１０］下記式（Ｅ）乃至下記式（Ｈ）で表される多環式芳香族アミン化合物、又はそのハロゲン化水素塩、硫酸塩、亜硫酸塩、硝酸塩、亜硝酸塩、及びカルボン酸塩からなる群から選択される塩。

式中、Ｒ^４１、Ｒ^５１、Ｒ^６１及びＲ^７１は、夫々独立して

を表し、
Ｒ^４２及びＲ^４３は、夫々独立して、水素原子、炭素原子数１乃至４のアルキル基、フェニル基もしくは１乃至５個の基Ｙ^４で置換されていてもよいフェニル基を表し（但し、Ｒ^４２及びＲ^４３が、同時に水素原子を表す場合を除く。）、
Ｒ^４４、Ｒ^４５、Ｒ^４６、Ｒ^４７、Ｒ^４８及びＲ^４９は、夫々独立して、水素原子、炭素原子数１乃至４のアルキル基、フェニル基又は１乃至５個の基Ｙ^４で置換されていてもよいフェニル基を表し、
Ｙ^４及びＹ^５は、夫々独立して、炭素原子数１乃至４のアルキル基、炭素原子数１乃至４のアルコキシ基、炭素原子数１乃至４のハロアルキル基、ハロゲン原子、フェニル基、ナフチル基、ビニル基、ニトロ基、シアノ基又は置換されていてもよいアミノ基を表し、
ｎは、０乃至４の整数を表す。
［１１］前記化合物が、下記式（１）乃至下記式（６）、下記式（１０）乃至下記式（１２）で表される化合物である、［１０］に記載の化合物、又はそのハロゲン化水素塩、硫酸塩、亜硫酸塩、硝酸塩、亜硝酸塩、及びカルボン酸塩からなる群から選択される塩。

That is, the present invention relates to the following inventions [1] to [11].
[1] An amine detection agent comprising, as a color component, a salt that may be selected from the group consisting of hydrogen halide salts, sulfate salts, sulfite salts, nitrate salts, nitrite salts, and carboxylate salts of a polycyclic aromatic amine compound selected from the group consisting of the following formulas (A) to (D):

In formulae (A) to (D), R ¹ , R ¹¹ , R ²¹ and R ³¹ each independently represent

represents
^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R8 and ^R9 each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group or a phenyl group optionally substituted by 1 to 5 groups ^Y2 ;
^Y1 and ^Y2 each independently represent an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, a halogen atom, a phenyl group, a naphthyl group, a vinyl group, a nitro group, a cyano group, or an optionally substituted amino group;
m represents an integer of 0 to 4;
[2] The amine detection agent according to [1], wherein the polycyclic aromatic amine compound is a compound selected from the group consisting of polycyclic aromatic amine compounds represented by the following formulas (1) to (12):

[3] The amine detection agent according to [1] or [2], wherein the salt is a hydrogen halide salt. [4] The amine detection agent according to any one of [1] to [3], wherein the salt has a pKa in the range of 0.1 to 12.
[5] The amine detection agent according to any one of [1] to [4], which is used for detecting free amino groups in a solid-phase peptide synthesis method.
[6] A method for detecting amines, comprising: a step of contacting amines with the amine detection agent according to any one of [1] to [5]; and a step of detecting the amine compound based on the color change of the polycyclic aromatic amine compound produced by the contacting step.
[7] The method according to [6], wherein the amines are at least one amine compound selected from the group consisting of amino acids, peptides, amino acid derivatives, sugars having a free amino group, primary amines, secondary amines, tertiary amines, and resin products thereof.
[8] The method for detecting amines according to [6] or [5], wherein the amines are at least one type of amines selected from a resin-immobilized amino acid, a resin-immobilized peptide, and a resin-immobilized amino acid derivative, the C-terminus of which is immobilized on a resin, in a solid-phase peptide synthesis method.
[9] A method for regenerating the amine detection agent according to any one of [1] to [5] used for detecting amines, the regeneration method comprising the steps of: contacting amines with the amine detection agent according to [1] or [5] to produce a polycyclic aromatic amine compound selected from the group consisting of formula (A) to the following formula (D) that has been colored or changed in color; and then contacting the polycyclic aromatic amine compound with an acid selected from the group consisting of hydrogen halide, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, and carboxylic acid; and converting the polycyclic aromatic amine compound into a salt selected from the group consisting of hydrogen halide, sulfate, sulfite, nitrate, nitrite, and carboxylate of the polycyclic aromatic amine compound, which is a color-producing component, by the contacting step.
[10] A polycyclic aromatic amine compound represented by the following formula (E) to formula (H), or a salt thereof selected from the group consisting of a hydrogen halide salt, a sulfate salt, a sulfite salt, a nitrate salt, a nitrite salt, and a carboxylate salt:

In the formula, R ⁴¹ , R ⁵¹ , R ⁶¹ and R ⁷¹ each independently represent

represents
R ⁴² and R ⁴³ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, or a phenyl group which may be substituted with 1 to 5 groups Y ⁴ (excluding the case where R ⁴² and R ⁴³ simultaneously represent a hydrogen atom);
R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , R ⁴⁷ , R ⁴⁸ and R ⁴⁹ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group or a phenyl group which may be substituted by 1 to 5 groups Y ⁴ ;
^Y4 and ^Y5 each independently represent an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, a halogen atom, a phenyl group, a naphthyl group, a vinyl group, a nitro group, a cyano group, or an optionally substituted amino group;
n represents an integer of 0 to 4.
[11] The compound according to [10], which is a compound represented by the following formulas (1) to (6), or the following formulas (10) to (12), or a salt thereof selected from the group consisting of a hydrogen halide salt, a sulfate salt, a sulfite salt, a nitrate salt, a nitrite salt, and a carboxylate salt.

According to the present invention, it is possible to provide an amine detection agent that can detect amines having a primary to tertiary amino group safely and simply in a short time, and that is also recyclable and environmentally friendly, and a method for regenerating the same.
Furthermore, the present invention can provide an amine detection agent capable of quantitatively detecting amino groups.

FIG. 1 shows the absorption spectra of the compound (2) and the hydrochloride salt (2) of Example 13 by ultraviolet-visible spectroscopy (UV-vis). FIG. 2 shows the ultraviolet-visible spectroscopy (UV-vis) absorption spectra of the compound (3) and the hydrochloride salt (3) of Example 14. FIG. 3 shows the absorption spectra of compound (12) and the hydrochloride salt (12) of Example 15 by ultraviolet-visible spectroscopy (UV-vis). FIG. 4(a) is an absorption spectrum by ultraviolet-visible spectroscopy (UV-vis) of the hydrochloride salt (2) to which the primary amine of Example 16 was added, and FIG. 4(b) is a graph showing the increase in absorbance of compound (2) relative to the amount of primary amine added. FIG. 5(a) is an ultraviolet-visible spectroscopy (UV-vis) absorption spectrum of the hydrochloride salt (2) to which the secondary amine of Example 17 was added, and FIG. 5(b) is a graph showing the increase in absorbance of compound (2) relative to the amount of secondary amine added. FIG. 6(a) is an absorption spectrum by ultraviolet-visible spectroscopy (UV-vis) of the hydrochloride salt (2) to which the tertiary amine of Example 18 was added, and FIG. 6(b) is a graph showing the increase in absorbance of compound (2) relative to the amount of tertiary amine added. FIG. 7 is an ultraviolet-visible spectroscopy (UV-vis) absorption spectrum of the hydrochloride salt (6) reacted with the amine of Example 19. FIG. 8 is an ultraviolet-visible spectroscopy (UV-vis) absorption spectrum of the hydrochloride salt (8) reacted with the amine of Example 20. FIG. 9 is an IR spectrum of compound (7) reacted with hydrogen chloride and ammonia in Example 21. FIG. 10 is an IR spectrum of compound (8) reacted with hydrogen chloride and ammonia in Example 22.

式（Ａ）乃至（Ｄ）中、Ｒ^１、Ｒ^１１、Ｒ^２１及びＲ^３１は、夫々独立して、

を表す。
上記式中、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８及びＲ^９は、夫々独立して、水素原子、炭素原子数１乃至４のアルキル基、フェニル基又は１乃至５個の基Ｙ^２で置換されていてもよいフェニル基を表し、Ｙ^１及びＹ^２は、夫々独立して、炭素原子数１乃至４のアルキル基、炭素原子数１乃至４のアルコキシ基、炭素原子数１乃至４のトリハロアルキル基、ハロゲン原子、フェニル基、ナフチル基、ビニル基、ニトロ基、シアノ基又は置換されていてもよいアミノ基を表し、ｍは、０乃至４の整数を表す。 The amine detection agent of the present invention contains, as a color component, a salt that can be selected from the group consisting of hydrohalides, sulfates, sulfites, nitrates, nitrites, and carboxylates of a polycyclic aromatic amine compound selected from the group consisting of the following formulas (A) to (D):

In formulae (A) to (D), R ¹ , R ¹¹ , R ²¹ and R ³¹ each independently represent

Represents.
In the above formula, ^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R8 and ^R9 each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group or a phenyl group which may be substituted with 1 to 5 groups ^Y2 ; ^Y1 and ^Y2 each independently represent an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a trihaloalkyl group having 1 to 4 carbon atoms, a halogen atom, a phenyl group, a naphthyl group, a vinyl group, a nitro group, a cyano group or an amino group which may be substituted; and m represents an integer of 0 to 4.

Specific examples of the alkyl group having 1 to 4 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a s-butyl group, and a t-butyl group. Specific examples of the alkoxy group having 1 to 4 carbon atoms include a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, a s-butoxy group, and a t-butoxy group.
Examples of halogen atoms include fluorine, chlorine, bromine and iodine atoms.
Examples of the trihaloalkyl group having 1 to 4 carbon atoms include the above-mentioned alkyl group having 1 to 4 carbon atoms in which one or all hydrogen atoms have been substituted with the above-mentioned halogen atoms, such as a trifluoromethyl group and a trifluoroethyl group.
Examples of the amino group which may have a substituent include an amino group and an amino group substituted with the above-mentioned alkyl group having 1 to 4 carbon atoms, such as a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group, and an ethylmethylamino group.

Examples of the hydrogen halide salt include hydrogen fluoride salt, hydrogen chloride salt, hydrogen bromide salt and hydrogen iodide salt, and the hydrogen chloride salt (hydrochloride salt) is preferred.
The carboxylate is not particularly limited, but examples thereof include salts of monovalent carboxylic acids such as acetates, propionic acid, hexanoic acid, octanoic acid, and 2-ethylhexanoic acid; salts of monovalent hydroxycarboxylic acids such as lactic acid; salts of divalent carboxylic acids such as succinates, maleates, fumarates, azelaates, and oxalates; salts of divalent hydroxycarboxylic acids such as malates and tartrates; salts of trivalent carboxylic acids such as aconitates; and salts of trivalent hydroxycarboxylic acids such as citric acid. Preferred examples include acetates, citrates, and tartrates.
It is believed that the polycyclic aromatic amine compound forms an ammonium salt by combining with an acid such as hydrogen halide, sulfuric acid, sulfurous acid, thiosulfuric acid, nitric acid, nitrous acid, or carboxylic acid. The reaction between the polycyclic amine compound and the acid can be appropriately controlled depending on the valence of the base of the polycyclic aromatic amine compound (e.g., the number of amino groups) and the valence of the acid.
For example, when a polycyclic aromatic amine compound has two or more amino groups, one molecule of the polycyclic aromatic amine compound can form a salt with one or the same number of monovalent acids, such as hydrogen halides, as the amino groups. When quantitative analysis is performed, the polycyclic aromatic amine compound of the present invention is preferably one that forms a salt with one molecule of a monovalent acid, such as hydrogen halide.

The amine detection agent of the present invention preferably contains, as a color component, a salt selected from the group consisting of hydrohalides, sulfates, sulfites, nitrates, nitrites, and carboxylates of polycyclic aromatic amine compounds represented by the following (1) to (12).

Amines that can be detected by the amine detection agent of the present invention are not limited as long as they have an amino group, and examples thereof include amino acids, peptides, amino acid derivatives, sugars having a free amino group, other primary amines, secondary amines and tertiary amines, and also include those amines fixed to a solid such as a resin.
Examples of amines immobilized on a solid such as a resin include, but are not limited to, resin-immobilized amino acids having a free amino group and whose C-terminus is immobilized on a resin, resin-immobilized peptides, and resin-immobilized amino acid derivatives in solid-phase peptide synthesis.

Specific examples of amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, cystine, hydroxyproline, hydroxylysine, dihydroxyphenylalanine, thyroxine, phosphoserine, desmosine, β-alanine, sarcosine, ornithine, creatine, γ-aminobutyric acid, theanine, kainic acid, domoic acid, and ibotenic acid, as well as N-alkylated amino acids thereof.

Specific examples of amino acid derivatives include serotonin, noradrenaline, adrenaline, tyramine, dopamine, and N-alkylated amino acid derivatives thereof.
Specific examples of sugars having a free amino group include D-glucosamine, D-galactosamine, neuraminic acid, hyaluronic acid, chondroitin sulfate, heparan sulfate, heparin, and N-alkylated sugars.

Specific examples of primary amines include aliphatic amines such as methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, isobutylamine, sec-butylamine, tert-butylamine, n-pentylamine, n-hexylamine, n-heptylamine, n-octylamine, n-nonylamine, n-decylamine, n-undecylamine, n-dodecylamine, n-tridecylamine, n-tetradecylamine, n-pentadecylamine, n-hexadecylamine, n-heptadecylamine, n-octadecylamine, n-nonadecylamine, and n-eicosylamine; alicyclic amines such as cyclopentylamine and cyclohexylamine; aralkyl amines such as benzylamine and phenethylamine; aniline, p-n-butylamine, etc. Examples of aromatic amines include anilines such as diphenylamine, p-tert-butylaniline, p-n-octylaniline, p-n-decylaniline, p-n-dodecylaniline, and p-n-tetradecylaniline; naphthylamines such as 1-naphthylamine and 2-naphthylamine; aminoanthracenes such as 1-aminoanthracene and 2-aminoanthracene; aminoanthraquinones such as 1-aminoanthraquinone; aminobiphenyls such as 4-aminobiphenyl and 2-aminobiphenyl; aminofluorenes such as 2-aminofluorene, 1-amino-9-fluorenone, and 4-amino-9-fluorenone; aminoindanes such as 5-aminoindan; aminoisoquinolines such as 5-aminoisoquinoline; and aminophenanthrenes such as 9-aminophenanthrene. Further examples include N-(tert-butoxycarbonyl)-1,2-ethylenediamine, N-(tert-butoxycarbonyl)-1,3-propylenediamine, N-(tert-butoxycarbonyl)-1,4-butylenediamine, N-(tert-butoxycarbonyl)-1,5-pentamethylenediamine, N-(tert-butoxycarbonyl)-1,6-hexamethylenediamine, N-(2-hydroxyethyl)amine, N-(3-hydroxypropyl)amine, N-(2-methoxyethyl)amine, and N-(2-ethoxyethyl)amine.

Specific examples of secondary amines include dimethylamine, diethylamine, di-n-propylamine, diisopropylamine, di-n-butylamine, diisobutylamine, di-sec-butylamine, di-n-pentylamine, ethylmethylamine, methyl-n-propylamine, methyl-n-butylamine, methyl-n-pentylamine, methyl-n-octylamine, methyl-n-decylamine, methyl-n-dodecylamine, methyl-n-tetradecylamine, methyl-n-hexadecylamine, and methyl-n-octadecylamine. Examples of the amine include aliphatic amines such as ethyl isopropylamine, ethyl-n-butylamine, ethyl-n-pentylamine, ethyl-n-octylamine, di-n-hexylamine, di-n-octylamine, di-n-dodecylamine, di-n-hexadecylamine, and di-n-octadecylamine; alicyclic amines such as dicyclohexylamine; aralkyl amines such as dibenzylamine; aromatic amines such as diphenylamine; and nitrogen-containing heterocyclic compounds such as phthalimide, pyrrole, piperidine, piperazine, and imidazole. Further examples include bis(2-hydroxyethyl)amine, bis(3-hydroxypropyl)amine, bis(2-ethoxyethyl)amine, and bis(2-propoxyethyl)amine.

Specific examples of tertiary amines include aliphatic amines such as trimethylamine, triethylamine, tri-n-propylamine, tri-n-butylamine, tri-n-pentylamine, tri-n-hexylamine, tri-n-octylamine, tri-n-dodecylamine, dimethylethylamine, dimethyl-n-butylamine, dimethyl-n-hexylamine, dimethyl-n-octylamine, dimethyl-n-decylamine, diethyl-n-decylamine, dimethyl-n-dodecylamine, dimethyl-n-tetradecylamine, dimethyl-n-hexadecylamine, dimethyl-n-octadecylamine, and dimethyl-n-eicosylamine; and nitrogen-containing heterocyclic compounds such as pyridine, pyrazine, pyrimidine, quinoline, 1-methylimidazole, 4,4'-bipyridyl, and 4-methyl-4,4'-bipyridyl.

The resin to which the amines are fixed is not particularly limited, and examples thereof include resins having functional groups such as amino groups, carboxyl groups, and hydroxyl groups from the viewpoint of introducing amines or linkers that bind them. Examples of such resins include polyoxyalkylene polyols (e.g., polyethylene glycol, polypropylene glycol, etc.), polyvinyl alcohol, polyacrylic acid, polyacrylic acid esters, polyesters (e.g., polyethylene terephthalate, polyethylene naphthalate, polybutylene terephthalate, polybutylene naphthalate, etc.), polyolefins (e.g., polyethylene, polypropylene, ethylene-propylene copolymers, etc.), polyvinyl chloride, polystyrene, and resins that combine two or more of these (e.g., copolymers thereof). As these resins, those in the form of beads are preferable. Resins that can be used as magnetic beads can also be used.

The amine detection agent of the present invention can be used in the form of a powder or granule of the salt of the polycyclic aromatic amine compound, or in the form of a uniform solution or dispersion of the salt of the polycyclic aromatic amine compound.
When used as a solid, it can be mixed with other powders as long as it does not inhibit the detection of amines. Preferably, an inactive salt such as potassium bromide is used.
When used in the form of a solution or dispersion, examples of the solvent include the following inert solvents. Preferred examples include water, lower alcohols such as methanol, ethanol, and propanol, and ethers such as methyl ethyl ether, diethyl ether, 1,4-dioxane, and tetrahydrofuran. These solvents can be used alone or in combination of two or more.
When used in the form of a solution or dispersion, it may contain a known buffer to the extent that it does not inhibit the detection of amines, such as Clark-Labs buffer, Sorenson buffer, Kolthoff buffer, Michaelis buffer, McIlvaine buffer, Britton-Robinson buffer, Carmody buffer, Gomori buffer, Bates-Bauer buffer, and DeLoree-King buffer.

<Method for detecting amines>
The method for detecting amines of the present invention comprises the steps of contacting amines with the above-mentioned amine detection agent, and detecting the amines based on the coloration of the amine compound produced by the contacting step.

A conventional method can be used to contact an amine with the amine-detecting agent.
For example, a gas sample is brought into contact with a solid salt of a polycyclic aromatic amine compound in a sealed container. If the sample contains amines, a color reaction occurs in which the polycyclic aromatic amine compound is produced, and the amines can be detected.
Also included is a method of adding a solid, liquid or gas sample to a solution in which a salt of a polycyclic aromatic amine compound has been dissolved, or a method of directly adding a solid salt of a polycyclic aromatic amine compound to a liquid sample. When amines are contained in the sample, the resulting polycyclic aromatic amine compound diffuses into the solution, causing a change in the color of the solution, allowing the amines to be detected.

The polycyclic aromatic amine compound used in the present invention is a push-pull type π-extended polycyclic aromatic amine compound having a trifluoromethyl group, which is a strong electron-withdrawing group, and an amino group, which is an electron-donating group, in the π-conjugated ring, and thus develops color (fluorescence). On the other hand, the salt of the polycyclic aromatic amine compound does not have push-pull type π-extended polycyclic aromaticity and is a colorless or light-colored compound (for example, light yellow or light brown derived from the amino group) because the amino group site has an ammonium cation structure that does not have electron-donating properties.
The amine detection agent of the present invention brings a colorless or light-colored salt of a polycyclic aromatic amine compound into contact with amines, and a color reaction occurs in which the salt is desalted to produce a colored or fluorescent polycyclic aromatic amine compound. This changes the color of the polycyclic aromatic amine compound or the solution into which it has been diffused, allowing the presence or absence of amines to be detected visually.
On the other hand, if the sample does not contain amines having an amino group, no polycyclic aromatic amine compounds are produced and the amine detection agent does not develop color, so that the amine detection agent of the present invention is effective in detecting amines.

Here, the solution of the salt of the polycyclic aromatic amine compound may be partially desalted depending on the type of solvent used and its pH, and may be a colored solution in which the polycyclic aromatic amine compound and its salt are dispersed in an equilibrium state. By contacting the solution with amines, the concentration of the polycyclic aromatic amine compound increases and the color of the solution darkens, making it possible to detect the amines.

In addition, since the acid dissociation constant (pKa) of the salt of the polycyclic aromatic amine compound differs depending on its structure, the equilibrium state between the polycyclic aromatic amine compound and its salt in the solution can be adjusted by adjusting the type of solvent and pH. In addition, the salt of the polycyclic aromatic amine compound to be used can be selectively used based on the solvent and pH of the sample. For the quantification of amines, it is preferable to use an amine detection agent that is colorless (white) or light colored under the detection conditions. For example, for solid-phase synthesis of peptides, a solvent with a pH near neutral that does not affect resin beads is used, so it is preferable to use a salt of a polycyclic aromatic amine compound with a pKa in the range of 5.0 to 11.0, preferably 5.8 to 7.5.

However, in the detection of amines having an acid dissociation constant lower than that of the salt of the polycyclic aromatic amine compound of the present invention, the equilibrium is biased toward the production of the salt of the polycyclic aromatic amine compound rather than the production of the salt of the amines, so that accurate quantification of the amines may not be possible. Therefore, it is preferable to use an amine detection agent containing a halogen salt of a polycyclic aromatic amine compound having an acid dissociation constant lower than that of the amines to be detected.
For example, it is preferable to use a salt of a polycyclic aromatic amine compound having a pKa in the range of 0.1 to 12.0, preferably in the range of 5.0 to 11.0, and more preferably in the range of 5.8 to 7.5. Within this range, the salt of the polycyclic aromatic amine compound of the present invention is not completely desalted in the solvent and does not interfere with the formation of salts of the amines to be detected.

In addition, conventional amine detection agents utilize the coloration caused by the binding of the detection agent and amines, so there are limitations on the amines that can be detected, and different colors are produced depending on the type of amine to be detected. For example, the Kaiser test utilizes a coloration reaction in which ninhydrin reacts with a primary amino group (-NH ₂ ) to produce Ruhemann's purple, so there is a problem that it cannot be applied to the detection of amines that do not have a primary amino group (-NH ₂ ). However, the amine detection agent of the present invention detects amines based on the color of the polycyclic aromatic amine compound produced by desalting or the color of the solution into which it is diffused, so it has the advantage of being able to detect any type of amine and showing a single coloration.

In addition, in a color reaction in which a colored product is generated by binding (covalent or ionic bonds) between a conventional amine detection agent and an amine, the color (absorption spectrum) of the product varies depending on the type of amine, making it difficult to perform a quantitative reaction. Also, in the detection of amino acids such as resin-immobilized peptides, the resin, not the solution, is colored, making it difficult to perform a quantitative reaction.
However, the amine detection agent of the present invention produces a single desalted polycyclic aromatic amine compound regardless of the type of amine to be detected, and diffuses into the solution, so that the amount of amines contained in the sample can be quantified from the concentration of the amine detection agent in the solution measured using a conventional method such as ultraviolet-visible spectroscopy.

The content of polycyclic aromatic amine compounds contained in the amine detection agent of the present invention may vary depending on the sample to be detected and the shape of the detection agent, but when used as a solution, for example, the concentration after mixing with the sample is, for example, 0.01 μM to 100 mM, preferably 0.1 to 100 μM.

<Method for regenerating amine detection reagent>
The method for regenerating an amine detection agent includes a step of contacting amines with the amine detection agent to produce a polycyclic aromatic amine compound, and then further contacting the polycyclic aromatic amine compound with an acid selected from the group consisting of hydrogen halides, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, and carboxylic acid, and a step of converting the polycyclic aromatic amine compound into a salt selected from the group consisting of hydrogen halides, sulfates, sulfites, nitrates, nitrites, and carboxylates of the polycyclic aromatic amine compound, which is a color-developing component, by the contacting step.

The polycyclic aromatic amine compound obtained by desalting through the reaction with amines can be easily reacted with an equivalent or excess amount of acid to produce a salt of the corresponding polycyclic aromatic amine compound. The salt of the polycyclic aromatic amine compound thus produced can be purified by a known method to easily regenerate the amine detection agent.
The Kaiser test that has been used up to now is an irreversible reaction, making it extremely difficult to regenerate ninhydrin. However, the amino detection drug of the present invention can be easily recovered and recycled after detection of amines, and is therefore extremely environmentally friendly.

As a method for contacting the polycyclic aromatic amine compound with an acid, a known method can be used.
For example, there can be mentioned a method in which a solid polycyclic aromatic amine compound is contacted with a gaseous acid until a white or pale solid is obtained.
Another method includes a method in which a gaseous, liquid or solid acid, or a solution of an acid dissolved in an inert solvent described below is added to a solution in which the polycyclic aromatic amine compound has been dispersed until the solution becomes transparent, and the obtained solution is purified by distilling off the solvent.

<Application to solid-phase peptide synthesis>
The amine detection agent of the present invention is suitable for use in place of the Kaiser test for detecting unreacted free amino groups in solid phase peptide synthesis.
The amine detection agent of the present invention can be used in a solid-phase peptide synthesis method including, for example, a step of preparing a resin having an N-terminal protected amino acid (or peptide) fixed thereto, a step of deprotecting the resin-fixed amino acid (or peptide) and condensing the N-protected amino acid, a step of washing the resin and then contacting the resin with the amine detection agent of the present invention to detect the presence or absence of a free amino group, a step of again condensing the N-protected amino acid based on the detection result or a step of condensing the next deprotected and N-protected amino acid, and a step of repeating the above detection and reaction steps until the desired peptide chain is obtained, and then a step of recovering the peptide from the resin.

In the amine detection agent of the present invention, after the condensation reaction of N-protected amino acids, the resin (solid phase) is washed and the amine detection agent solution of the present invention is added to the solid phase, thereby making it possible to detect the presence or absence of free amino groups for all peptides (amino acids) immobilized on the resin. In other words, the detection accuracy of free amino groups is higher than that of the Kaiser test, which can only be used for detection of some resins.
In the case where no free amino groups are present, the amine detection agent of the present invention does not desalt and the solution does not become colored. In this case, the amine detection agent is recovered and the next elimination and condensation reaction of the N-protected amino acid can be carried out simply by washing the solid phase.
On the other hand, if free amino groups are present, a solution in which the colored polycyclic aromatic amine compound is dispersed after desalting is obtained. In this case, the condensation reaction of the N-protected amino acid can be carried out again simply by recovering the amine detection agent and washing the solid phase.

In other words, in the method of the present invention, in order to detect free amino groups, it is not necessary to take out a part of the resin as in the Kaiser test, nor is it necessary to carry out a heating step for a color reaction. In addition, the next step can be carried out simply by washing the resin (solid phase). Therefore, there is no decrease in yield due to peptide elongation, and peptide synthesis can be carried out easily in a short time, making it economically superior. In addition, when a column with a stopcock or the like is used for solid-phase peptide synthesis, peptides can be synthesized in one pot by using the amine detection agent of the present invention, which is expected to enable the automation of peptide synthesis.

In addition, the amount of remaining amino groups can be quantified by measuring the absorption spectrum of the solution of the amine detection agent recovered as described above using an ultraviolet-visible spectrophotometer or the like. In addition, the recovered amine detection agent can be easily regenerated and reused using the method described above.

<Method for synthesizing polycyclic aromatic amine compounds and their salts>
The present invention also relates to a method for producing a polycyclic aromatic amine compound selected from the group consisting of formulas (A) to (D) and a salt thereof selected from the group consisting of a hydrogen halide salt, a sulfate salt, a sulfite salt, a nitrate salt, a nitrite salt, and a carboxylate salt thereof. For example, a polycyclic aromatic amine can be obtained by the following production method.

(Production of compounds represented by formulae (A1) to (D1))

The compounds represented by formulae (A1) to (D1) can be produced by the following method.

The compound represented by formula (A1) can be synthesized by a known method (for example, the method described in U.S. Patent No. 8,106,206). For example, it can be obtained by subjecting 1,3-phenylenediamine to a cyclization reaction with hexafluoroacetylacetone.

The compounds represented by formulas (B1) and (C1) can be obtained as a mixture, for example, by subjecting 2,7-naphthylenediamine to a cyclization reaction with hexafluoroacetylacetone. The resulting mixture can be purified and isolated by a known method, for example, silica gel column chromatography.

1,3-phenylenediamine and hexafluoroacetylacetone can be commercially available products.
2,7-Diaminonaphthalene may be commercially available or may be synthesized by reacting 2,7-dihydroxynaphthalene with aqueous ammonia in the presence of sodium hydrogen sulfite in a sealed tube according to the Bucherer reaction.
Instead of the 2,7-diaminonaphthalene used in the reaction, it is preferable to use a protected form in which one of the amino groups of 2,7-diaminonaphthalene is selectively protected with a tosyl group or the like. The protected form can be obtained, for example, by reacting 2,7-diaminonaphthalene with 0.9 to 1.2 equivalents of paratoluenesulfonyl chloride (tosyl chloride) in a pyridine solvent at room temperature. After the cyclization reaction, the compound represented by formula (B1) and (C1) can be obtained by deprotection in the presence of a base.

These reactions can be carried out, for example, according to the Combes-quinoline reaction, for example, in the presence of a catalyst in an inert solvent.

Catalysts include acid catalysts that can be used in the Combes-quinoline reaction, such as sulfonic acids including aliphatic sulfonic acids such as methanesulfonic acid, and aromatic sulfonic acids such as p-toluenesulfonic acid, benzenesulfonic acid, and xylenesulfonic acid; mineral acids such as sulfuric acid, oleum, and phosphoric acid; carboxylic acids such as formic acid, acetic acid, propionic acid, and trifluoroacetic acid; Lewis acids such as boron trifluoride-tetrahydrofuran (THF) complex, aluminum chloride, and zinc chloride; and solid acids such as montmorillonite K-10 and sulfated zirconia, with montmorillonite K10 being preferred.

The inert solvent may be any solvent that does not participate in the reaction, such as ethers such as water, diethyl ether, diisopropyl ether, dibutyl ether, tert-butyl methyl ether, cyclopentyl methyl ether (CPME), tetrahydrofuran (THF), 2-methyltetrahydrofuran, 1,4-dioxane, and dimethoxyethane; saturated hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, and tetralin; carbonates such as ethylene carbonate, propylene carbonate, dimethyl carbonate, diethyl carbonate, ethyl methyl carbonate, and 4-fluoroethylene carbonate; methyl acetate, ethyl acetate, propyl acetate, butyl acetate, and propionate. Examples of suitable solvents include esters such as methyl ester, ethyl propionate, methyl butyrate, and γ-lactone; amides such as N,N-dimethylformamide (DMF), dimethylacetamide (DMAc), and N-methylpyrrolidone (NMP); ureas such as N,N,N',N'-tetramethylurea (TMU) and N,N'-dimethylpropyleneurea (DMPU); alcohols such as dimethylsulfoxide (DMSO), methanol, ethanol, isopropyl alcohol, butanol, octanol, benzyl alcohol, ethylene glycol, propylene glycol, diethylene glycol, triethylene glycol, and 2,2,2-trifluoroethanol; and halogenated hydrocarbons such as dichloromethane, trichloromethane, and dichloroethane. These may be used alone or in any combination. 1,4-dioxane is preferred.

The reaction temperature is from 0°C to the reflux temperature of the solvent, preferably from 60°C to 100°C. The reaction time varies depending on the reaction temperature, but is from 5 minutes to 168 hours, preferably from 10 minutes to 24 hours.

The compound represented by formula (D1) can be obtained, for example, by reacting a compound represented by formula (D11) (wherein X represents a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom) obtained by reacting 2,4-bis(trifluoromethyl)imidazo[1,2-α][1,8]naphthyridine with a halogenating agent, with a boron compound represented by formula (13). The resulting mixture can be purified and isolated by a known method, for example, silica gel column chromatography.

2,4-bis(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridine can be synthesized according to a method known per se, for example (Noboru Koga et al., Org. Lett., 2012, vol. 14, no. 24, pp. 6282-6285, and Yefeng Tang et al., Org. Biomol. Chem., 2014, vol. 12, pp. 2344-2348). For example, 2-amino-5,7-bis(trifluoromethyl)-1,8-naphthyridine obtained by cyclization reaction of 2,6-diaminopyridine with hexafluoroacetylacetone can be further cyclized with bromoacetaldehyde to obtain the compound.

The compound represented by formula (D11) can be synthesized by a known method, for example, a method similar to the Wohl-Ziegler reaction, for example, in an inert solvent using a halogenating agent such as N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide, bromine, or sulfuryl chloride. Furthermore, the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile to the reaction.

で表される基が挙げられる。収率の観点から式（ＩＩ）で示される基が好ましい。
式（Ｄ１１）で表される化合物は、ホウ素化合物に対して０．５～３．０モル当量を用いることが好ましい。
式（１３）で表されるホウ素化合物としては、好ましくは４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）アニリンが挙げられる。 As the boron compound represented by formula (13), commercially available or known compounds can be used.
In the formula, examples of -B(OR ⁵¹ ) ₂ include -B(OH) ₂ , -B(OMe) ₂ , -B(OEt) ₂ , -B(OPr) ₂ , -B(OBu) ₂ and -B(OPh) _2. Two OR ⁵¹ and a boron atom may form a ring, and in that case, examples of B(OR ⁵¹ ) ₂ include

From the viewpoint of yield, the group represented by formula (II) is preferred.
The compound represented by formula (D11) is preferably used in an amount of 0.5 to 3.0 molar equivalents relative to the boron compound.
The boron compound represented by the formula (13) is preferably 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.

The reaction between the compound represented by formula (D11) and the boron compound represented by formula (13) can be carried out, for example, according to the Suzuki-Miyaura cross-coupling reaction, for example, in the presence of a catalyst, in an inert solvent, at a temperature range of 0°C to the reflux temperature of the solvent, for 5 minutes to 168 hours.

The catalyst may be a palladium catalyst, as described below, preferably tetrakis(triphenylphosphine)palladium(0).

The base includes the bases described below, and preferable examples include metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, and cesium carbonate.
There is no particular limitation on the amount of base used. For example, the molar ratio of base to boron compound is in the range of 1:2 to 10:1, preferably 1:1 to 4:1.

The inert solvent may be any of the inert solvents listed above, preferably water, ether, amide, alcohol, or a mixture thereof, more preferably a mixture of water and 1,4-dioxane.

The reaction temperature is from 0° C. to the reflux temperature of the solvent, preferably from 40° C. to the reflux temperature of the solvent.
The reaction time varies depending on the reaction temperature, but is from 5 minutes to 168 hours, preferably from 10 minutes to 48 hours.

Here, by using a compound represented by formula (15) described later instead of the boron compound represented by formula (13), a compound represented by formula (D2) or (D3) (wherein R ⁴ , R ⁵ and Y ¹ have the same meanings as above) can be synthesized.

(Production of amine compounds represented by formulae (A2) to (D2) and (A3) to (D3))

上記方法で得られた式（Ａ１）で表される化合物を、不活性溶媒中、触媒及び塩基の存在下、上記式（１４）（式中、Ｘはフッ素原子、塩素原子、臭素原子又はヨウ素原子を表し、Ｒ^２は上記と同じ意味を表す。）で表されるハロゲン化合物と反応させて、式（Ａ２）（式中、Ｒ^２は上記と同じ意味を表す。）で表される化合物を得ることができる。 The compounds represented by the above formulae (A2) and (A3) can be produced by the following method.

The compound represented by formula (A1) obtained by the above method can be reacted with a halogen compound represented by formula (14) (wherein X represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and ^R2 has the same meaning as above) in an inert solvent in the presence of a catalyst and a base to obtain a compound represented by formula (A2) (wherein ^R2 has the same meaning as above).

さらに、上記方法で得られた式（Ａ２）で表される化合物を、不活性溶媒中、触媒及び塩基の存在下、上記式（１５）（式中、Ｘ及びＲ^３は上記と同じ意味を表す。）で表されるハロゲン化合物と反応させて、式（Ａ３）（式中、Ｒ^３は上記と同じ意味を表す。）で表される多環式芳香族アミン化合物を得ることができる。
式（Ａ３）中のＲ^２及びＲ^３が同じ基を表す場合、式（Ａ１）で表される多環式芳香族アミン化合物に、２当量以上、好ましくは２乃至１０当量の上記式（１４）で表されるハロゲン化合物を反応させることで、式（Ａ３）で表される芳香族アミン化合物を得ること
もできる。
同様に、式（Ａ１）で表される多環式芳香族アミン化合物に代えて、式（Ｂ１）乃至（Ｄ１）で表される多環式芳香族アミン化合物を使用することで、式（Ｂ２）乃至（Ｄ２）、及び式（Ｂ３）乃至（Ｄ３）で表される多環式芳香族アミン化合物を製造することができる。

Furthermore, the compound represented by formula (A2) obtained by the above method can be reacted with a halogen compound represented by formula (15) (wherein X and ^R3 have the same meanings as above) in an inert solvent in the presence of a catalyst and a base to obtain a polycyclic aromatic amine compound represented by formula (A3) (wherein ^R3 has the same meaning as above).
When ^R2 and ^R3 in formula (A3) represent the same group, the aromatic amine compound represented by formula (A3) can also be obtained by reacting the polycyclic aromatic amine compound represented by formula (A1) with 2 equivalents or more, preferably 2 to 10 equivalents of the halogen compound represented by formula (14).
Similarly, by using the polycyclic aromatic amine compound represented by formulae (B1) to (D1) instead of the polycyclic aromatic amine compound represented by formula (A1), the polycyclic aromatic amine compounds represented by formulae (B2) to (D2) and formulae (B3) to (D3) can be produced.

As the halogen compound represented by the above formula (14) and the halogen compound represented by the above formula (15), commercially available or known compounds can be used, and preferred examples include methyl iodide, ethyl iodide, propyl iodide, isopropyl iodide, butyl iodide, 2-methylpropyl iodide, tert-butyl iodide, bromobenzene, 4-tert-butyl-1-bromobenzene, and 4-methoxy-1-bromobenzene.

These reactions can be carried out in accordance with known methods such as the Buchwald-Hartwig amination reaction, the Goldberg amination reaction, and the Jordan-Ullmann-Goldberg reaction, and are carried out, for example, in the presence of a catalyst, a base, and a ligand in an inert solvent.

As the catalyst, for example, a palladium catalyst or a copper catalyst can be used.
As the palladium catalyst, a palladium catalyst having a phosphine-based ligand or a complex formed by mixing a palladium catalyst precursor with a phosphine-based ligand can be used. The complex formed by mixing a palladium catalyst precursor with a phosphine-based ligand can be prepared in the reaction system, or in some cases, can be prepared separately and added to the reaction system.

Examples of palladium catalysts having phosphine ligands include tetrakis(triphenylphosphine)palladium(0), bis(tri-tert-butylphosphine)palladium(0), bis(tricyclohexylphosphine)palladium(0), bis[1,2-bis(diphenylphosphino)ethane]palladium(0), bis(tricyclohexylphosphine)palladium(0), dichlorobis(triphenylphosphine)palladium(II), bis(triphenylphosphine)palladium(II) diacetate, dichloro[1,2-bis(diphenylphosphino)ethane]palladium(II), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II), dichloro[1,3-bis(diphenylphosphino)propane]palladium(II), dichlorobis(tri-O-tolylphosphine)palladium(II), etc. Preferred are dichlorobis(triphenylphosphine)palladium, tetrakistriphenylphosphinepalladium(0), and tris(dibenzylideneacetone)dipalladium.

Examples of palladium catalyst precursors include dichlorobis(acetonitrile)palladium(II), dichlorodiaminepalladium(II), dichlorobis(benzonitrile)palladium(II), dichloro(1,5-cyclooctadiene)palladium(II), allylpalladium chloride dimer(II), bis(2-methylallyl)palladium chloride dimer(II), bis(dibenzylideneacetone)palladium(0), tris(dibenzylideneacetone)(chloroform)dipalladium(0), acetylacetonepalladium(II), palladium acetate(II), palladium trifluoroacetate(II), palladium trifluoromethanesulfonate(II), palladium chloride(II), and palladium-supported carbon. Palladium chloride(II) and palladium acetate(II) are preferred. Palladium acetate(II) is more preferred.

Examples of the phosphine ligand include trimethylphosphine, tri-n-butylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, trimethoxyphosphine, triethoxyphosphine, triphenylphosphine, and triphenoxyphosphine.
Examples of the phosphine include tri(o-tolylphosphine), tris(2-methylphenoxy)phosphine, tris(4-methylphenyl)phosphine, tris(4-methoxyphenyl)phosphine, 1,2-bis(diphenylphosphino)ethane, 1,2-bis(diphenylphosphino)propane, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, 4,5-bis(diphenylphosphino)-9,9'-dimethylxanthene, bis(diphenylphosphino)-1,1'-binaphthyl, and 1,1'-bis(diphenylphosphino)ferrocene. Triphenylphosphine is more preferable.
The amount of the phosphine-based ligand used is 10 molar equivalents or less, preferably 5 molar equivalents or less, more preferably 3 molar equivalents or less, and 0.01 molar equivalents or more, preferably 0.1 molar equivalents or more, more preferably 1 molar equivalent or more, relative to the catalyst precursor. The amount of the phosphine-based ligand used can be any combination of the upper and lower limits described above.

Examples of copper catalysts include copper(I) iodide, copper(I) bromide, copper(I) chloride, copper(II) acetate, and copper(II) sulfate. Examples of ligands include trans-N,N'-dimethylcyclohexane-1,2-diamine.

Examples of bases include metal hydroxide salts such as sodium hydroxide, potassium hydroxide, calcium hydroxide, and barium hydroxide; metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, and cesium carbonate; metal acetates such as potassium acetate and sodium acetate; metal phosphates such as potassium phosphate and sodium phosphate; metal fluoride salts such as sodium fluoride, potassium fluoride, calcium fluoride, and cesium fluoride; metal alkoxides such as sodium methoxide, potassium methoxide, sodium ethoxide, potassium isopropyl oxide, and potassium tert-butoxide; and organic bases such as triethylamine, N,N-dimethylaniline, N,N-dimethylpiperazine, and N-methylpiperazine. Potassium tert-butoxide is preferred.

As the inert solvent, the above-mentioned inert solvents can be used, and aromatic hydrocarbons such as toluene are particularly preferred.
The reaction temperature is from room temperature to the reflux temperature of the solvent, preferably from 80° C. to the reflux temperature of the solvent. The reaction time varies depending on the reaction temperature, but is 5 minutes to 48 hours, preferably 4 to 12 hours.

(Production of compounds represented by formulae (A5) to (D5))

The compound represented by formula (A5) can be produced by the following method.

The compound represented by formula (A4) can be produced by a known method (e.g., the method described in U.S. Patent No. 8,106,206) using the compound represented by formula (A1) obtained by the above method. For example, the amino group of the compound represented by formula (A1) is reacted with a nitrite salt in an inert solvent in the presence of an acid to form a diazonium group, which is then reacted with an iodide salt to obtain the compound represented by formula (A4).
The obtained compound represented by formula (A4) can be reacted with a boron compound represented by formula (16) (wherein R ⁴ , R ⁵ and Y ¹ have the same meanings as above, and R ⁵¹ has the same meanings as above) to obtain a compound represented by formula (A5) (wherein R ⁴ , R ⁵ and Y ¹ have the same meanings as above).
Similarly, by using the compounds represented by formulae (B1) to (D1) instead of the compound represented by formula (A1), the compounds represented by formulae (B5) to (D5) can be obtained.

The nitrite preferably includes sodium nitrite.
The acid includes sulfuric acid, hydrochloric acid, methanesulfonic acid, trifluoroacetic acid, etc., and preferably sulfuric acid.
Examples of iodide salts include potassium iodide, sodium iodide, and lithium iodide, with potassium iodide being preferred.
For example, the diazonium salt can be formed by adding dropwise an aqueous solution of a nitrite to a sulfuric acid solution of the compound represented by formula (A1) to (D1) while maintaining the temperature at 5° C. or lower.
The iodination reaction can be carried out by adding an aqueous solution of iodide salt to a solution of diazonium salt at 5°C or below, and then at a temperature between 60°C and 100°C.

As the boron compound represented by formula (16), commercially available or known compounds can be used.
In the formula, R ⁴ , R ⁵ , Y ¹ and -B(OR ⁵¹ ) ₂ have the same meanings as above.
It is preferable to use 0.5 to 3.0 molar equivalents of 2,4-bis(trifluoromethyl)-7-iodoquinone relative to the boron compound represented by formula (12).
The compound represented by the formula (12) is preferably 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.

These reactions can be carried out, for example, in accordance with the Suzuki-Miyaura cross-coupling reaction, for example, in the presence of a catalyst, in an inert solvent, at a temperature range of 0°C to the reflux temperature of the solvent, for 5 minutes to 168 hours.

The palladium catalyst includes the above-mentioned palladium catalysts.
Examples of the palladium catalyst having a phosphine ligand include the above-mentioned palladium catalysts, and preferably, dichlorobis(triphenylphosphine)palladium(II) and tetrakis(triphenylphosphine)palladium(0). More preferably, tetrakis(triphenylphosphine)palladium(0) is used.
The palladium catalyst precursor may be the above-mentioned palladium catalyst precursor, preferably palladium(II) chloride or palladium(II) acetate, more preferably palladium(II) acetate.
The phosphine ligand includes the above-mentioned phosphine ligands, and preferably includes triphenylphosphine, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, or 1,1'-bis(diphenylphosphino)ferrocene.
The amount of the phosphine ligand used is the same as above.

The base includes the above-mentioned bases, and preferably includes metal carbonates such as sodium carbonate, potassium carbonate, lithium carbonate, and cesium carbonate.
There is no particular limitation on the amount of base used. For example, the molar ratio of the base to the boron compound is in the range of 1:2 to 10:1, preferably 1:1 to 4:1.

The inert solvent may be any of the inert solvents listed above, preferably water, ether, amide, alcohol, or a mixture thereof, more preferably a mixture of water and 1,4-dioxane.

The reaction temperature is from 0° C. to the reflux temperature of the solvent, preferably from 40° C. to the reflux temperature of the solvent.
The reaction time varies depending on the reaction temperature, but is from 5 minutes to 168 hours, preferably from 10 minutes to 48 hours.

(Production of compounds represented by formulae (A6) to (D6))

The compound represented by the above formula (A6) can be produced by the following method.

For example, the compound represented by formula (A4) obtained above can be reacted with a guanidine compound represented by formula (17) (wherein ^R6 to ^R9 have the same meanings as above) in an inert solvent in the presence of a base and a catalyst to obtain a polycyclic aromatic amine compound represented by formula (A6) (wherein ^R6 to ^R9 have the same meanings as above).
By using the compounds represented by the formulae (B4) to (D4) instead of the compound represented by the formula (A4), the compounds represented by the formulae (B6) to (D6) can be obtained.

The guanidine represented by the formula (17) can be a commercially available or known guanidine. Specific examples thereof include guanidine, 1-methylguanidine, 1-ethylguanidine, 1-propylguanidine, 1-butylguanidine, 1-tert-butylguanidine, 1-phenylguanidine, 1,1-dimethylguanidine, 1,1-diethylguanidine, 1,1-dipropylguanidine, 1,1-dibutylguanidine, 1,1-tert-butylguanidine, 1,1-diphenylguanidine, 1,3-dimethylguanidine, 1,3-diethylguanidine, 1,3-dipropylguanidine, 1,3-dibutylguanidine, 1, 3-tert-guanidine, 1,3-diphenylguanidine, 1,1,3,3-tetramethylguanidine, 1,1,3,3-tetraethylguanidine, 1,1,3,3-tetrapropylguanidine, 1,1,3,3-tetrabutylguanidine, 1,1,3,3-tetratert-butylguanidine, 1,1,3,3-tetraphenylguanidine, 1,3-bis(4-chlorophenyl)guanidine, 1,3-bis(4-fluorophenyl)guanidine, 1,3-bis(4-methylphenyl)guanidine, 1,3-bis(4-ethylphenyl)guanidine, 1,3-bis(4-propylphenyl)guanidine, 1,3-bis(4
1,3-bis(4-hexylphenyl)guanidine, 1,3-bis(4-methoxyphenyl)guanidine, 1,3-bis(2-methoxyphenyl)guanidine, 1,3-bis(2-ethoxyphenyl)guanidine, 1,3-bis(2-ethoxyphenyl)guanidine, 1,3-bis(4-(trifluoromethyl)phenyl)guanidine, 1-phenyl-3-(2-(trifluoromethyl)phenyl)guanidine, 1,3-bis(2-methyl-4-nitrophenyl)guanidine, 1-phenyl-3-(4-(trifluoromethyl)phenyl)guanidine, [0113] Examples of such guanidine include 1,3-bis(1-naphthyl)guanidine, 1,3-bis(2-naphthyl)guanidine, and 1,3-bis(1,1'-biphenyl-4-yl)guanidine, and preferably include 1,3-diphenylguanidine, 1,3-bis(4-methoxyphenyl)guanidine, 1,3-bis(4-(trifluoromethyl)phenyl)guanidine, and 1-phenyl-3-(4-(trifluoromethyl)phenyl)guanidine.

The catalyst includes the above-mentioned palladium catalysts, and preferably includes a combination of palladium (II) acetate and xanthophos.
The base includes the above-mentioned bases, and preferable examples include sodium carbonate, potassium carbonate, cesium carbonate, and the like.
The above reaction can be carried out in a solvent, and examples of the solvent include the above-mentioned inert solvents, and preferably toluene.
The reaction temperature is from 0° C. to the reflux temperature of the solvent, preferably from 80° C. to the reflux temperature of the solvent.
The reaction time varies depending on the reaction temperature, but is from 5 minutes to 168 hours, preferably from 10 minutes to 8 hours.

(Production of compounds represented by formulae (A7) to (D7) and (A8) to (D8))

The amine compound represented by formula (A8) can be produced by the following method.

For example, the compound represented by formula (A1) obtained above can be reacted with a guanidinylating agent represented by formula (18) (wherein R ⁵² and R ⁵³ each independently represent a hydrogen atom or a protecting group) in an inert solvent in the presence of a base to obtain a compound represented by formula (A7) (wherein R ⁵² to R ⁵³ have the same meaning as above). When the groups R ⁵² and R ⁵³ are protecting groups, the compound represented by formula (A8) can be obtained by deprotecting them.
Moreover, by using the compounds represented by the formulae (B1) to (D1) instead of the compound represented by the formula (A1), the compounds represented by the formulae (B8) to (D8) can be obtained.

Protective groups that can be used include known ones, such as N-protective groups derived from cyanamide, S-alkylisothiourea, O-alkylisourea, aminoiminomethanesulfonic acid, 3,5-dimethyl-1-guanylpyrazole, and 1H-pyrazole-1-carboxamidine.

In the formula, the compound represented by formula (18) is exemplified as a guanidinylating agent, but other known guanidinylating agents can also be used, such as 1-amidinopyrazole hydrochloride, 1-carbamimidoyl-1,2,4-triazole hydrochloride, 1-(N-Boc-amidino)-pyrazole, 1-(N-Cbz-amidino)-pyrazole, 1-[N,N'-(Di-Boc)amidino]pyrazole, Examples of the di-Boc-amino]pyrazole include 1-[N,N'-(Di-Cbz)amidino]pyrazole, N,N'-di-Boc-S-methylisothiourea, 1,3-di-Boc-thiourea, Goodman's drug, and 1,2,3-tri-Boc-guanidine, and preferred examples include 1-[N,N'-(di-Boc)amidino]pyrazole and 1-[N,N'-(di-Cbz)amidino]pyrazole.
When a protected form is used, the target compound can be obtained by deprotecting the protected form with an acid such as trifluoroacetic acid after completion of the reaction.

The base used in the reaction includes the above-mentioned bases, and preferred are tertiary amines such as triethylamine, N,N-dimethylaniline, N,N-dimethylpiperazine, and N-methylpiperazine.
The inert solvent used in the reaction may be the same as those mentioned above, and preferably 1,4-dioxane.
The reaction temperature is from 0° C. to the reflux temperature of the solvent, preferably from 30° C. to the reflux temperature of the solvent.
The reaction time varies depending on the reaction temperature, but is from 5 minutes to 168 hours, preferably from 48 hours to 120 hours.

(Production of compounds represented by formulae (A10) to (D10))

上記で得られた式（Ａ１）で表される多環式芳香族アミン化合物に、式（１９）（式中、Ｒ^６は上記と同じ意味を表す。）で表されるイソチオシアネート化合物を反応させて、式（Ａ９）（式中、Ｒ^６は上記と同じ意味を表す。）で表されるチオウレア化合物を得ることができる。次いで、式（Ａ９）で表されるチオウレア化合物に、式（２０）（Ｒ^８は上記と同じ意味を表す。）で表されるアミン化合物を反応させて、式（Ａ１０）で表される多環式芳香族アミン化合物を得ることができる。
上記式中、式（Ａ１）で表される多環式芳香族アミン化合物に代えて、式（Ｂ１）乃至（Ｄ１）で表される化合物を使用することで、式（Ｂ１０）乃至（Ｄ１０）で表される多環式芳香族アミン化合物を得ることができる。 The polycyclic aromatic amine compound represented by formula (A10) can be produced by the following method.

The polycyclic aromatic amine compound represented by formula (A1) obtained above can be reacted with an isothiocyanate compound represented by formula (19) (wherein ^R6 has the same meaning as above) to obtain a thiourea compound represented by formula (A9) (wherein ^R6 has the same meaning as above). Next, the thiourea compound represented by formula (A9) can be reacted with an amine compound represented by formula (20) (wherein ^R8 has the same meaning as above) to obtain a polycyclic aromatic amine compound represented by formula (A10).
In the above formula, by using the compounds represented by the formulae (B1) to (D1) instead of the polycyclic aromatic amine compound represented by the formula (A1), it is possible to obtain the polycyclic aromatic amine compounds represented by the formulae (B10) to (D10).

Preferred examples of the isothiocyanate represented by formula (19) include methyl isothiocyanate, ethyl isothiocyanate, propyl isothiocyanate, butyl isothiocyanate, tert-butyl isothiocyanate, and phenyl isothiocyanate, and preferably phenyl isothiocyanate.

Examples of the amine compound represented by formula (20) include methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine, sec-butylamine, tert-butylamine, and aniline, and preferably n-propylamine.
The base includes the above-mentioned bases, and preferably includes triethylamine.

The synthesis reaction of the compound represented by formula (A9) can be carried out in a solvent, and examples of the solvent include the above-mentioned inert solvents, and preferably acetonitrile.
The reaction temperature is from 0° C. to the reflux temperature of the solvent, preferably from 30° C. to the reflux temperature of the solvent.
The reaction time varies depending on the reaction temperature, but is from 5 minutes to 168 hours, preferably from 12 hours to 36 hours.

The synthesis reaction of the compound represented by formula (A10) can be carried out in a solvent in the presence of a base and a condensing agent.

As the condensing agent, known ones can be used, for example, N,N'-disubstituted carbodiimides such as N,N'-dicyclohexylcarbodiimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSC) hydrochloride, and preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.
The amount of the condensing agent used is usually 0.5 to 5 mol, preferably 0.8 to 3 mol, and more preferably 1.0 to 1.2 mol, per 1 mol of the compound represented by Compounds (A1) to (D1).

The solvent may be the above-mentioned inert solvent, preferably acetonitrile.
The base includes the above-mentioned bases, and preferably includes tertiary amines such as triethylamine, N,N-dimethylaniline, N,N-dimethylpiperazine, and N-methylpiperazine.
The reaction temperature is from 0° C. to the reflux temperature of the solvent, preferably from 50° C. to the reflux temperature of the solvent.
The reaction time varies depending on the reaction temperature, but is from 5 minutes to 168 hours, preferably from 8 hours to 36 hours.

The salt of the polycyclic aromatic amine compound of the present invention selected from the group consisting of formulas (A) to (D) can be obtained by adding a gaseous, liquid or solid acid, or a solution of the acid dissolved in the inert solvent, to a solid of a polycyclic aromatic amine compound selected from the group consisting of formulas (A) to (D) above or a solution containing the same.

A gaseous acid is added, for example, in an amount of 1 to 10 equivalents, preferably 1 to 3 equivalents, until the color of the colored solid of the polycyclic aromatic amine compound selected from the groups represented by (A) to (D) above does not change (until the color becomes white or pale), thereby obtaining a hydrohalide salt of the polycyclic aromatic amine compound selected from the groups represented by (A) to (D).
Alternatively, for example, 1 to 10 equivalents, preferably 1 to 3 equivalents, of a gaseous, liquid or solid acid, or an acid solution dissolved in the above-mentioned inert solvent can be added until the color of the colored solution into which the polycyclic aromatic amine compound selected from the group represented by the above formulas (A) to (D) has been diffused no longer changes (until the solution becomes colorless or pale), and then the solvent is distilled off and the solution is dried in vacuum to obtain a salt of the polycyclic aromatic amine compound selected from the group consisting of the formulas (A) to (D).
The resulting salt of the polycyclic aromatic amine compound can be purified, if necessary, by a known method such as silica gel chromatography.

The acid that can be used is the same as that described above, and is preferably hydrogen chloride or hydrochloric acid.
The solvent may be any solvent capable of dissolving a polycyclic aromatic amine compound selected from the group consisting of formulae (A) to (D), and examples thereof include the above-mentioned solvents. Preferred examples thereof include water, lower alcohols such as methanol, ethanol, and propanol, and ethers such as methyl ethyl ether, diethyl ether, 1,4-dioxane, and tetrahydrofuran.

式中、Ｒ^４１、Ｒ^５１、Ｒ^６１及びＲ^７１は、夫々独立して

を表す。
Ｒ^４２及びＲ^４３は、夫々独立して、水素原子、炭素原子数１乃至４のアルキル基、フェニル基もしくは１乃至５個の基Ｙ^４で置換されていてもよいフェニル基を表す。但し、Ｒ^４２及びＲ^４３が、同時に水素原子を表す場合を除く。
Ｒ^４４、Ｒ^４５、Ｒ^４６、Ｒ^４７、Ｒ^４８及びＲ^４９は、夫々独立して、水素原子、炭素原子数１乃至４のアルキル基、フェニル基又は１乃至５個の基Ｙ^５で置換されていてもよいフェニル基を表す。
Ｙ^４及びＹ^５は、夫々独立して、炭素原子数１乃至４のアルキル基、炭素原子数１乃至４のアルコキシ基、炭素原子数１乃至４のハロアルキル基、ハロゲン原子、フェニル基、ナフチル基、ビニル基、ニトロ基、シアノ基又は置換されていていてもよいアミノ基を表し、ｎは、０乃至４の整数を表す。
炭素原子数１乃至４のアルキル基としては、上述したアルキル基が挙げられる。 Preferably, the present invention relates to a novel polycyclic aromatic amine compound represented by the following formulas (E) to (H), or a salt thereof.

In the formula, R ⁴¹ , R ⁵¹ , R ⁶¹ and R ⁷¹ each independently represent

Represents.
R ⁴² and R ⁴³ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group, or a phenyl group which may be substituted with 1 to 5 groups Y ⁴ , except when R ⁴² and R ⁴³ simultaneously represent a hydrogen atom.
R ⁴⁴ , R ⁴⁵ , R ⁴⁶ , R ⁴⁷ , R ⁴⁸ and R ⁴⁹ each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group or a phenyl group which may be substituted with 1 to 5 groups Y ⁵ .
^Y4 and ^Y5 each independently represent an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, a halogen atom, a phenyl group, a naphthyl group, a vinyl group, a nitro group, a cyano group, or an amino group which may be substituted; and n represents an integer of 0 to 4.
Examples of the alkyl group having 1 to 4 carbon atoms include the alkyl groups described above.

Specific examples of the polycyclic aromatic amine compounds represented by the above formulas (E) to (H) include polycyclic aromatic amines represented by the following formulas (1) to (6) and (10) to (12), but are not limited thereto.

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to the following examples.
In the examples, reagents used for synthesis and preparation of samples were purchased from the following manufacturers.
(1) N,N-Dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline: Tokyo Chemical Industry Co., Ltd. (2) Sodium carbonate: Nacalai Tesque, Inc. (3) 1,4-Dioxane: Nacalai Tesque, Inc. (4) Tetrakis(triphenylphosphine)palladium(0): Tokyo Chemical Industry Co., Ltd. (5) 1,3-Diphenylguanidine: Tokyo Chemical Industry Co., Ltd. (6) Cesium carbonate: Fujifilm Wako Pure Chemical Industries, Ltd. (7) Toluene: Fujifilm Wako Pure Chemical Industries, Ltd. (8) Palladium(II) acetate: Tokyo Chemical Industry Co., Ltd. (9) Xanthophos: Sigma Aldrich Dritch (10) N,N'-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine: Tokyo Chemical Industry Co., Ltd. (11) Triethylamine: Nacalai Tesque Co., Ltd. (12) Dichloromethane: Kanto Chemical Co., Ltd. (13) Trifluoroacetic acid: Tokyo Chemical Industry Co., Ltd. (14) Phenyl isocyanate: Tokyo Chemical Industry Co., Ltd. (15) Acetonitrile: Kanto Chemical Co., Ltd. or Nacalai Tesque Co., Ltd. (16) n-Propylamine: Nacalai Tesque Co., Ltd. (17) 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride: Tokyo Chemical Industry Co., Ltd. (18) 1M Hydrochloric acid/diethyl ether: Tokyo Chemical Industry Co., Ltd. (19) Methanol: Nacalai Tesque, Inc. (20) Ethyl acetate: Nacalai Tesque, Inc. (21) Hexane: Nacalai Tesque, Inc. (22) Pyridine: Nacalai Tesque, Inc. (23) Bromobenzene: Nacalai Tesque, Inc. (24) Diethyl ether: Nacalai Tesque, Inc. (25) Chloroform: Nacalai Tesque, Inc. (26) Dichloromethane complex of [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(DPPF)Cl ₂ /CH ₂ Cl ₂ ): Tokyo Chemical Industry Co., Ltd. (27) Bis(diphenylphosphino)ferrocene (DPPF): Tokyo Chemical Industry Co., Ltd. (28) N-bromosuccinimide: Nacalai Tesque Co., Ltd. (29) Sodium thiosulfate: Nacalai Tesque Co., Ltd. (30) Sodium bicarbonate: Nacalai Tesque Co., Ltd. (31) 4-iodoaniline: Tokyo Chemical Industry Co., Ltd. (32) Potassium acetate: Nacalai Tesque Co., Ltd. (33) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane): Tokyo Chemical Industry Co., Ltd. (34) Anhydrous magnesium sulfate Nacalai Tesque Co., Ltd. (35) Tetrakis(triphenylphosphine)palladium (0): Tokyo Chemical Industry Co., Ltd.

The following equipment was used for sample preparation and analysis of physical properties.
(1) Infrared spectrophotometer (IR)
Equipment: JASCO 420FT-IR
(2) Nuclear magnetic resonance apparatus (NMR)
Apparatus: AVANCE 300M manufactured by Bruker Biospin
AVANCE 600 manufactured by Bruker Biospin
(3) High-resolution mass spectrometer (HRMS (ESI))
Equipment: JMP-T100LP manufactured by JEOL Datum Co., Ltd.
(4) UV-Visible Absorption Spectrometer: V760 manufactured by JASCO Corporation
(5) pH measuring device: Horiba Ltd. pH meter D51, pH electrode 9618S-10D

シュレンク管に２，４－ビス（トリフルオロメチル）－７－ヨードキノリン（４６．０ｍｇ，０．１１８ｍｍｏｌ）、Ｎ，Ｎ－ジメチル－４－（４，４，５，５－テトラメチル－１，３，２－ジオキサボロラン－２－イル）アニリン（３０．６ｍｇ，０．１２４ｍｍｏｌ）、炭酸ナトリウム（１８．８ｍｇ，０．１７７ｍｍｏｌ）を加え、１，４－ジオキサン（１ｍＬ）と水（０．４ｍＬ）により溶解した。溶液を凍結脱気後、窒素雰囲気下、テトラキス（トリフェニルフォスフィン）パラジウム（０）（５．５ｍｇ，４．８μｍｏｌ）を加え、６０℃にて４時間撹拌した。反応終了後、酢酸エチルと水を加え、分液操作を行った。得られた有機相を無水硫酸マグネシウムにより乾燥後、ろ過し、溶媒を減圧下留去することで粗生成物を得た。得られた粗生成物はシリカゲルカラムクロマトグラフィー（３％酢酸エチル／ヘキサン溶液）により精製し、目的化合物（１）（４８．２ｍｇ，当量）を黄色の蛍光性固体として得た。
融点（Mp）: 164-167 ℃; ¹H NMR (600 MHz, CDCl₃): δ 8.47 (d, J = 1.9 Hz, 1H), 8.20 (dd, J = 8.9, 1.9 Hz, 1H), 8.09 (dd, J = 8.9, 1.9 Hz, 1H), 7.92 (s, 2H), 7.71
(d, J = 8.9 Hz, 2H), 6.84 (d, J = 8.9 Hz, 2H), 3.05 (s, 6H); ¹³C NMR (150 MHz, CDCl₃): δ 150.9, 148.9, 147.6 (q, J = 35.2 Hz), 144.2, 136.2 (q, J = 32.3 Hz), 129.5, 128.1 (2C), 125.8, 125.7, 124.1, 123.0 (q, J = 273.0 Hz), 122.0, 121.1 (q, J =273.6 Hz), 112.9, 112.6 (2C), 40.3 (2C); ¹⁹F NMR (282 MHz, CDCl₃): δ -61.5
(d, J = 1.4 Hz), -67.7; IR (KBr): 1610, 1510, 1449, 1364, 1274, 1250, 1200, 1137, 1097, 898, 813 cm^-1; HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₉H₁₅F₆N₂, 385.1139;
found, 385.1136. Example 1: Synthesis of 4-(2,4-bis(trifluoromethyl)quinolin-7-yl)-N,N-dimethylaniline (compound (1)) and its hydrochloride (hydrochloride (1))

2,4-bis(trifluoromethyl)-7-iodoquinoline (46.0 mg, 0.118 mmol), N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (30.6 mg, 0.124 mmol), and sodium carbonate (18.8 mg, 0.177 mmol) were added to a Schlenk flask, and dissolved in 1,4-dioxane (1 mL) and water (0.4 mL). The solution was freeze-degassed, and then tetrakis(triphenylphosphine)palladium(0) (5.5 mg, 4.8 μmol) was added under a nitrogen atmosphere, and the mixture was stirred at 60° C. for 4 hours. After the reaction was completed, ethyl acetate and water were added, and a separation operation was performed. The obtained organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography (3% ethyl acetate/hexane solution) to obtain the target compound (1) (48.2 mg, equivalent) as a yellow fluorescent solid.
Melting point (Mp): 164-167 ℃; ¹ H NMR (600 MHz, CDCl ₃ ): δ 8.47 (d, J = 1.9 Hz, 1H), 8.20 (dd, J = 8.9, 1.9 Hz, 1H), 8.09 (dd, J = 8.9, 1.9 Hz, 1H), 7.92 (s, 2H), 7.71
(d, J = 8.9 Hz, 2H), 6.84 (d, J = 8.9 Hz, 2H), 3.05 (s, 6H); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 150.9, 148.9, 147.6 (q, J = 35.2 Hz), 144.2, 136.2 (q, J = 32.3 Hz), 129.5, 128.1 (2C), 125.8, 125.7, 124.1, 123.0 (q, J = 273.0 Hz), 122.0, 121.1 (q, J =273.6 Hz), 112.9, 112.6 (2C), 40.3 (2C ); ^19F NMR (282 MHz, _CDCl3 ): δ -61.5
(d, J = 1.4 Hz), -67.7; IR (KBr): 1610, 1510, 1449, 1364, 1274, 1250, 1200, 1137, 1097, 898, 813 cm ^-1 ; HRMS (ESI) m/z: [M + H] ⁺ calcd for C ₁₉ H ₁₅ F ₆ N ₂ , 385.1139;
Found, 385.1136.

Compound (1) was dissolved in methanol to obtain a yellow solution. 0.5 mL of a 1 mol/L solution of hydrochloric acid in diethyl ether was added to obtain a transparent solution. The solvent was removed to obtain a white solid, which was then dried in a vacuum to obtain the hydrochloride salt (1).

シュレンク管に２，４－ビス（トリフルオロメチル）－７－ヨードキノリン（１９６ｍｇ，０．５０１ｍｍｏｌ）、１，３－ジフェニルグアニジン（１２７ｍｇ，０．６０１ｍｍｏｌ）、炭酸セシウム（６５２ｍｇ，２．００ｍｍｏｌ）を加え、トルエン（５ｍＬ）により溶解した。溶液を凍結脱気後、窒素雰囲気下、酢酸パラジウム（５．６ｍｇ，２４．９μｍｏｌ）とキサントフォス（１４．５ｍｇ，２５．１μｍｏｌ）を加え、１００℃にて２時間撹拌した。反応終了後、酢酸エチルと水を加え、分液操作を行った。得られた有機相を無水硫酸マグネシウムにより乾燥後、ろ過し、溶媒を減圧下留去することで粗生成物を得た。得られた粗生成物はシリカゲルカラムクロマトグラフィー（１３％酢酸エチル／ヘキサン溶液）により精製し、目的化合物（２）（２４８ｍｇ，当量）を黄色の非晶体として得た。
¹H NMR (600 MHz, CDCl₃): δ 7.94 (s, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.57 (s, 1H), 7.30 (t, J = 7.7 Hz, 4H), 7.23 (t, J = 7.7 Hz, 4H), 7.09 (t, J = 7.3 Hz, 2H), 6.44 (br s, 2H); ¹³C NMR (150 MHz, CDCl₃): δ 150.4, 149.2, 147.1 (q, J = 35.2
Hz), 145.6, 139.7, 135.9 (q, J = 32.1 Hz), 129.5 (4C), 128.4, 124.4, 124.2 (2C), 122.8 (q, J = 273.4 Hz), 121.9 (4C), 121.0 (q, J = 273.7 Hz), 119.3, 118.8, 111.4 (2C); ¹⁹F NMR (282 MHz, CDCl₃): δ -61.4 (d, J = 1.7 Hz), -67.6; IR (KBr): 3419, 1645, 1584, 1541, 1497, 1446, 1278, 1214, 1138, 1095, 985, 886, 750, 693 cm^-1; HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₄H₁₇F₆N₄, 475.1357; found, 475.1355. Example 2: Synthesis of 2,4-bis(trifluoromethyl)-7-(N,N'-diphenylguanidyl)quinoline (compound (2)) and its hydrochloride salt (2)

2,4-bis(trifluoromethyl)-7-iodoquinoline (196 mg, 0.501 mmol), 1,3-diphenylguanidine (127 mg, 0.601 mmol), and cesium carbonate (652 mg, 2.00 mmol) were added to a Schlenk flask, and dissolved in toluene (5 mL). The solution was freeze-degassed, and then palladium acetate (5.6 mg, 24.9 μmol) and xanthophos (14.5 mg, 25.1 μmol) were added under a nitrogen atmosphere, and the mixture was stirred at 100° C. for 2 hours. After the reaction was completed, ethyl acetate and water were added, and a separation operation was performed. The obtained organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (13% ethyl acetate/hexane solution), and the target compound (2) (248 mg, equivalent) was obtained as a yellow amorphous body.
¹ H NMR (600 MHz, CDCl ₃ ): δ 7.94 (s, 1H), 7.79 (s, 1H), 7.69 (s, 1H), 7.57 (s, 1H), 7.30 (t, J = 7.7 Hz, 4H), 7.23 (t, J = 7.7 Hz, 4H), 7.09 (t , J = 7.3 Hz, 2H), 6.44 (br s, 2H); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 150.4, 149.2, 147.1 (q, J = 35.2
Hz), 145.6, 139.7, 135.9 (q, J = 32.1 Hz), 129.5 (4C), 128.4, 124.4, 124.2 (2C), 122.8 (q, J = 273.4 Hz), 121.9 (4C), 121.0 (q, J = 273.7 Hz), 119.3, 118.8, 111.4 (2C); ¹⁹ F NMR (282 MHz, CDCl ₃ ): δ -61.4 (d, J = 1.7 Hz), -67.6; IR (KBr): 3419, 1645, 1584, 1541, 1497, 1446, 1214, 1138, 1095, 985, 886, 750, 693 cm ^-1 ; HRMS (ESI) m/z: [M + H] ⁺ calcd for C ₂₄ H ₁₇ F ₆ N ₄ , 475.1357; found, 475.1355.

Compound (2) was dissolved in methanol to obtain a yellow solution. 0.5 mL of a 1 mol/L solution of hydrochloric acid in diethyl ether was added to obtain a transparent solution. The solvent was removed to obtain a white solid, which was then dried in a vacuum to obtain the hydrochloride salt (2).

２，４－ビス（トリフルオロメチル）－７－アミノキノリン（１４０ｍｇ，０．５００ｍｍｏｌ）、Ｎ，Ｎ’－ビス（ｔｅｒｔ－ブトキシカルボニル）－１Ｈ－ピラゾール－１－カルボキサミジン（３１０ｍｇ，０．９９９ｍｍｏｌ）、トリエチルアミン（１３９μＬ，１．００ｍｍｏｌ）を１，４－ジオキサン（５ｍＬ）で溶解し、窒素雰囲気下、５０℃にて３日間撹拌した。反応液に酢酸エチルを加え、１Ｍ塩酸と飽和食塩水で順次洗浄した。得られた有機相を無水硫酸マグネシウムにより乾燥後、ろ過し、溶媒を減圧下留去することで粗生成物を得た。得られた粗生成物はシリカゲルカラムクロマトグラフィー（３％酢酸エチル／ヘキサン溶液）により精製し、目的化合物（３）のＢｏｃ保護体（５０．０ｍｇ，１９％）を白色の固体として得た。
Mp: 156-159 ℃; ¹H NMR (600 MHz, CDCl₃): δ 11.67 (s, 1H), 10.85 (s, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.20 (dd, J = 9.2, 2.0 Hz, 1H), 8.17 (dd, J = 9.4, 1.2 Hz, 1
H), 7.91 (s, 1H), 1.57 (s, 9H), 1.55 (s, 9H); ¹³C NMR (150 MHz, CDCl₃): δ 163.2, 153.4, 153.3, 148.0 (q, J = 35.2 Hz), 140.0, 136.1 (q, J = 32.2 Hz), 126.1, 124.6, 122.8 (q, J = 273.4 Hz), 121.0 (q, J = 273.6 Hz), 120.73, 120.70, 112.9, 84.4, 80.4, 28.12 (3C), 28.06 (3C); ¹⁹F NMR (282 MHz, CDCl₃): δ -61.4, -67.7; IR (KBr): 1719, 1652, 1416, 1372, 1327, 1279, 1147, 1102 cm^-1; HRMS (ESI) m/z: [M +
Na]⁺ calcd for C₂₂H₂₄F₆N₄NaO₄, 545.1599; found, 545.1592. Example 3: Synthesis of 2,4-bis(trifluoromethyl)-7-guanidylquinoline (compound (3)) and its hydrochloride (hydrochloride (3))

2,4-Bis(trifluoromethyl)-7-aminoquinoline (140 mg, 0.500 mmol), N,N'-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (310 mg, 0.999 mmol), and triethylamine (139 μL, 1.00 mmol) were dissolved in 1,4-dioxane (5 mL) and stirred at 50° C. under a nitrogen atmosphere for 3 days. Ethyl acetate was added to the reaction solution, and the solution was washed successively with 1M hydrochloric acid and saturated saline. The obtained organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (3% ethyl acetate/hexane solution) to obtain the Boc-protected product of the target compound (3) (50.0 mg, 19%) as a white solid.
Mp: 156-159 ℃; ¹ H NMR (600 MHz, CDCl ₃ ): δ 11.67 (s, 1H), 10.85 (s, 1H), 8.58 (d, J = 2.0 Hz, 1H), 8.20 (dd, J = 9.2, 2.0 Hz, 1H), 8.17 (dd, J = 9 .4, 1.2 Hz, 1
¹³ C NMR (150 MHz, CDCl ₃ ): δ 163.2, 153.4, 153.3, 148.0 (q, J = 35.2 Hz), 140.0, 136.1 (q, J = 32.2 Hz), 126.1, 124.6, 122.8 (q, J = 273.4 Hz), 121.0 (q, J = 273.6 Hz), 120.73, 120.70, 112.9, 84.4, 80.4, 28.12 (3C), 28.06 (3C); ^F NMR (282 MHz, CDCl ₃ ): δ -61.4, -67.7; IR (KBr): 1719, 1652, 1416, 1372, 1327, 1279, 1147, 1102 cm ^-1 ; HRMS (ESI) m/z: [M +
Na] ⁺ calcd for C ₂₂ H ₂₄ F ₆ N ₄ NaO ₄ , 545.1599; found, 545.1592.

Subsequently, the Boc-protected compound (3) (33.3 mg, 63.7 μmol) was dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was neutralized with saturated aqueous NaHCO ₃ solution and extracted three times with ethyl acetate. The obtained organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (ethyl acetate) using amino silica gel, and the target compound (3) (19.6 mg, 96%) was obtained as a pale yellow solid.
Mp: 179-182 ℃; ft. ¹ H NMR (600 MHz, CD ₃ CN): δ 8.06 (dd, J = 9.1, 2.1 Hz, 1H), 7.89 (s, 1H), 7.56 (d, J = 2.2 Hz, 1H), 7.45 (dd, J = 9.1, 2.2 Hz, 1H), 4.77 (br s, 2 × NH ₂ ); ¹³ C NMR (150 MHz, CD ₃ CN): δ 155.8, 154.3, 151.1, 147.6 (q, J = 34.9 Hz), 136.2 (q, J = 32.0 Hz), 131.6, 125.1, .3 (q, J = 272.5 Hz), 122.4 (q,
¹⁹ F NMR (282 MHz, CD ₃ OD): δ -62.9 (d, J = 1.8 Hz), -69.2; IR (KBr): 3463, 1648, 1587, 1448, 1277, 1241, 1134, 1114, 892 cm ^-1 ; HRMS (ESI) m/z: [M + H] ⁺ calcd for C ₁₂ H ₉ F ₆ N ₄ , 323.0731; found, 323.0726.

Compound (3) was dissolved in methanol to obtain a pale yellow solution. 0.5 mL of a 1 mol/L solution of hydrochloric acid in diethyl ether was added to obtain a transparent solution. The solvent was removed to obtain a white solid, which was then dried in a vacuum to obtain the hydrochloride salt (3).

１，３－ビス（トリフルオロメチル）ベンゾ［ｆ］キノリン－９－アミン（３３．０ｍｇ，９９．９μｍｏｌ）、フェニルイソチオシアネート（３５．９μＬ，０．３００ｍｍｏｌ）をアセトニトリル（１ｍＬ）で溶解し、窒素雰囲気下、６０℃にて２４時間撹拌した。反応後、反応液を室温まで冷やし、ヘキサンを加えてろ過した。ろ紙上の固体を回収し、乾燥することでチオウレア中間体を得た。このチオウレア中間体をアセトニトリル（１ｍＬ）で溶解し、トリエチルアミン（４１．６μＬ，０．３００ｍｍｏｌ）、ｎ－プロピルアミン（１６．４μＬ，０．２００ｍｍｏｌ）、１－（３－ジメチルアミノプロピル）－３－エチルカルボジイミドヒドロクロリド塩酸塩（２３．０ｍｇ，０．１２０ｍｍｏｌ）を加え、窒素雰囲気下、室温にて１６時間撹拌した。反応液を酢酸エチルで希釈後、水で洗浄した。得られた有機相を無水硫酸マグネシウムにより乾燥後、ろ過し、溶媒を減圧下留去することで粗生成物を得た。得られた粗生成物はアミノシリカゲルを用いたシリ
カゲルカラムクロマトグラフィー（１０％酢酸エチル／ヘキサン溶液）と通常のシリカゲルカラムクロマトグラフィー（５０％酢酸エチル／ヘキサン溶液、２０％メタノール／酢酸エチル溶液）により精製し、目的化合物（４）（３９．０ｍｇ，収率８０％）を黄色の固体として得た。
Mp: 140-142 ℃; ¹H NMR (600 MHz, CDCl₃): δ 8.40 (s, 1H), 8.14 (s, 1H), 8.03 (d,
J = 8.9 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 8.3, 1.2 Hz, 1H), 7.36-7.31 (m, 2H), 7.16-7.09 (m, 3H), 4.30 (br s, 1H), 3.36 (t, J = 7.2 Hz, 2H), 1.63 (sep, J = 7.2 Hz, 2H), 0.97 (t, J = 7.5 Hz, 3H); ¹³C
NMR (150 MHz, CDCl₃): δ 150.6, 148.8, 146.4 (q, J = 35.8 Hz), 135.3 (q, J = 32.7 Hz), 133.6, 130.1, 129.6 (2C), 129.3, 128.2, 126.6 (2C), 125.8, 124.5, 123.9 (q, J = 273.5 Hz), 123.7, 123.3 (2C), 121.2 (q, J = 273.3 Hz), 121.1 (2C), 115.1, 43.7, 22.9, 11.5; ¹⁹F NMR (282 MHz, CDCl₃): δ -57.9, -67.5; IR (KBr): 3435, 1619, 1589, 1418, 1334, 1271, 1192, 1137, 843 cm^-1; HRMS (ESI) m/z: [M + H]⁺calcd
for C₂₅H₂₁F₆N₄, 491.1670; found, 491.1661. Example 4: Synthesis of 1,3-bis(trifluoromethyl)benzo[f]quinoline-9-N-phenyl-N'-normal-propylguanidine (compound (4)) and its hydrochloride salt (4)

1,3-bis(trifluoromethyl)benzo[f]quinolin-9-amine (33.0 mg, 99.9 μmol) and phenylisothiocyanate (35.9 μL, 0.300 mmol) were dissolved in acetonitrile (1 mL) and stirred at 60° C. under a nitrogen atmosphere for 24 hours. After the reaction, the reaction solution was cooled to room temperature, hexane was added, and the mixture was filtered. The solid on the filter paper was collected and dried to obtain a thiourea intermediate. This thiourea intermediate was dissolved in acetonitrile (1 mL), and triethylamine (41.6 μL, 0.300 mmol), n-propylamine (16.4 μL, 0.200 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride hydrochloride (23.0 mg, 0.120 mmol) were added, followed by stirring at room temperature for 16 hours under a nitrogen atmosphere. The reaction solution was diluted with ethyl acetate and then washed with water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (10% ethyl acetate/hexane solution) using amino silica gel and normal silica gel column chromatography (50% ethyl acetate/hexane solution, 20% methanol/ethyl acetate solution) to obtain the target compound (4) (39.0 mg, yield 80%) as a yellow solid.
Mp: 140-142 ℃; ¹ H NMR (600 MHz, CDCl ₃ ): δ 8.40 (s, 1H), 8.14 (s, 1H), 8.03 (d,
J = 8.9 Hz, 1H), 7.92 (d, J = 8.9 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 8.3, 1.2 Hz, 1H), 7.36-7.31 (m, 2H), 7.16-7.09 (m, 3H), 4 .30 (br s, 1H), 3.36 (t, J = 7.2 Hz, 2H), 1.63 (sep, J = 7.2 Hz, 2H), 0.97 (t, J = 7.5 Hz, 3H); ¹³ C
NMR (150 MHz, CDCl ₃ ): δ 150.6, 148.8, 146.4 (q, J = 35.8 Hz), 135.3 (q, J = 32.7 Hz), 133.6, 130.1, 129.6 (2C), 129.3, 128.2, 126.6 (2C), ^{1 19} F NMR (282 MHz, CDCl ₃ ): δ -57.9, -67.5; IR (KBr): 3435, 1619, 1589, 1418, 1334, 1271, 1192, 1137, 843 cm ^-1 ; HRMS (ESI) m/z: [M + H] ⁺ calcd
for C ₂₅ H ₂₁ F ₆ N ₄ , 491.1670; found, 491.1661.

Compound (4) was dissolved in methanol to obtain a pale yellow solution. 0.5 mL of a 1 mol/L solution of hydrochloric acid in diethyl ether was added to obtain a transparent solution. The solvent was removed to obtain a white solid, which was then dried in a vacuum to obtain the hydrochloride salt (4).

１，３－ビス（トリフルオロメチル）ベンゾ［ｆ］キノリン－９－アミン（８７．１ｍｇ，０．２６４ｍｍｏｌ）、Ｎ，Ｎ’－ビス（ｔｅｒｔ－ブトキシカルボニル）－１Ｈ－ピラゾール－１－カルボキサミジン（１６４ｍｇ，０．５２８ｍｍｏｌ）、トリエチルアミン（７３．２μＬ，０．５２８ｍｍｏｌ）を１，４－ジオキサン（２．６ｍＬ）で溶解し、窒素雰囲気下、５０℃にて３日間撹拌した。反応液に酢酸エチルを加え、１Ｍ塩酸と飽和食塩水で順次洗浄した。得られた有機相を無水硫酸マグネシウムにより乾燥後、ろ過し、溶媒を減圧下留去することで粗生成物を得た。得られた粗生成物はシリカゲルカラムクロマトグラフィー（５％酢酸エチル／ヘキサン溶液）により精製し、目的化合物（５）のＢｏｃ保護体（７２．８ｍｇ，収率４８％）を黄色の固体として得た。
Mp: 96-98 ℃; ¹H NMR (600 MHz, CDCl₃): δ 11.66 (s, 1H), 10.68 (s, 1H), 9.31 (s,
1H), 8.21 (s, 1H), 8.05 (dd, J = 8.9, 4.1 Hz, 1H), 8.01 (dd, J = 8.9, 3.8 Hz, 1H), 7.93 (dd, J = 8.5, 3.8 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 1.58 (s, 9H), 1.54
(s, 9H); ¹³C NMR (150 MHz, CDCl₃): δ 163.4, 153.4, 153.3, 150.6, 146.8 (q, J =
35.8 Hz), 136.3, 136.0 (q, J = 32.9 Hz), 133.3, 130.8, 129.4, 127.7, 127.4, 124.1, 123.9, 123.6 (q, J = 273.6 Hz), 121.3 (q, J = 8.0 Hz), 121.1 (q, J = 273.3 Hz), 115.4 (q, J = 6.6 Hz), 84.1, 79.8, 28.1 (6C); ¹⁹F NMR (282 MHz, CDCl₃): δ -58.2, -67.5; IR (KBr): 1720, 1646, 1415, 1370, 1332, 1278, 1152, 1060 cm^-1; HRMS
(ESI) m/z: [M + Na]⁺ calcd for C₂₆H₂₆F₆N₄NaO₄, 595.1756; found, 595.1756. Example 5: Synthesis of 1,3-bis(trifluoromethyl)benzo[f]quinoline-9-guanidine (compound (5)) and its hydrochloride salt (5)

1,3-bis(trifluoromethyl)benzo[f]quinolin-9-amine (87.1 mg, 0.264 mmol), N,N'-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (164 mg, 0.528 mmol), and triethylamine (73.2 μL, 0.528 mmol) were dissolved in 1,4-dioxane (2.6 mL) and stirred at 50° C. for 3 days under a nitrogen atmosphere. Ethyl acetate was added to the reaction solution, and the solution was washed successively with 1M hydrochloric acid and saturated saline. The obtained organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (5% ethyl acetate/hexane solution) to obtain the Boc-protected form of the target compound (5) (72.8 mg, yield 48%) as a yellow solid.
Mp: 96-98 ℃; ¹ H NMR (600 MHz, CDCl ₃ ): δ 11.66 (s, 1H), 10.68 (s, 1H), 9.31 (s,
1H), 8.21 (s, 1H), 8.05 (dd, J = 8.9, 4.1 Hz, 1H), 8.01 (dd, J = 8.9, 3.8 Hz, 1H), 7.93 (dd, J = 8.5, 3.8 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 1 .58 (s, 9H), 1.54
(s, 9H); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 163.4, 153.4, 153.3, 150.6, 146.8 (q, J =
35.8 Hz), 136.3, 136.0 (q, J = 32.9 Hz), 133.3, 130.8, 129.4, 127.7, 127.4, 124.1, 123.9, 123.6 (q, J = 273.6 Hz), 121.3 (q, J = 8.0 Hz ), 121.1 (q, J = 273.3 Hz), 115.4 (q, J = 6.6 Hz), 84.1, 79.8, 28.1 (6C); ¹⁹ F NMR (282 MHz, CDCl ₃ ): δ -58.2, -67.5; IR (KBr): 1720, 1646, 1415, 1 370, 1332, 1278, 1152, 1060 cm ^-1 ; HRMS
(ESI) m/z: [M + Na] ⁺ calcd for C ₂₆ H ₂₆ F ₆ N ₄ NaO ₄ , 595.1756; found, 595.1756.

Subsequently, the Boc-protected form of this compound (5) (40.0 mg, 69.9 μmol) was dissolved in dichloromethane (0.5 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature overnight. The reaction solution was neutralized with a saturated aqueous solution of sodium bicarbonate and extracted three times with ethyl acetate. The obtained organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (ethyl acetate) using amino silica gel, and the target compound (5) (17.2 mg, yield 66%) was obtained as a pale yellow solid.
Mp: 205-207 ℃; ¹ H NMR (600 MHz, CD ₃ CN): δ 8.30 (s, 1H), 8.26 (s, 1H), 8.18 (d,
J = 8.9 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 7.44 (d, J
= 8.4, 1.8 Hz, 1H), 5.14 (br s, 2 × NH ₂ ); ¹³ C NMR (150 MHz, CD ₃ OD): δ 157.0, 151.9, 149.2, 147.6 (q, J = 35.6 Hz), 136.7 (q, J = 32.2 Hz), ¹⁹ F NMR (282 MHz, CD ₃ OD): δ -59.3, -69.1; IR (KBr): 3426, 1648, 1597, 1451, 1334, 1278, 1194, 1151, 902 cm ^-1 ; HRMS (ESI) m/z: [M + H] ⁺ calcd for C ₁₆ H ₁₁ F ₆ N ₄ , 373.0888; found, 373.0897.

Compound (5) was dissolved in methanol by stirring to obtain a pale yellow solution. 0.5 mL of a 1 mol/L solution of hydrochloric acid in diethyl ether was added to obtain a transparent solution. The solvent was removed to obtain a white solid, which was then dried in a vacuum to obtain the hydrochloride salt (5).

Example 6 Synthesis of 4-(2,4-bis(trifluoromethyl)imidazo[1,2-a][1,8]naphthyridin-9-yl)aniline (compound (6)) and its hydrochloride salt (6) Compound (6) was synthesized according to the following scheme.

2,6-Diaminopyridine (3.0 g, 27.5 mmol) and hexafluoroacetylacetone (6.32 g, 30.4 mmol) were dissolved in acetic acid (14 mL), and concentrated sulfuric acid (0.35 mL) was added thereto. The mixture was refluxed for 24 hours, then cooled, and an aqueous solution (40 mL) of sodium hydroxide (11.0 g) was slowly added at 5°C or less. The precipitate was filtered, washed with cold water, and dried in vacuum to obtain 2,4-bis(trifluoromethyl)[1,8]naphthyridine (6a) as a white solid (5.4 g, 19.1 mmol, yield 69.3%).

Bromoacetaldehyde diethyl acetal (7.4 g, 37.5 mmol) was dissolved in water (30 mL) and hydrobromic acid (2.7 mL) was added. The mixture was refluxed for 30 minutes, cooled, and the solution was extracted with ether. The organic phase was dried over anhydrous sodium sulfate and extracted under vacuum.
The solvent was removed. The resulting bromoacetaldehyde was added to a solution of compound (6a) (1.74 g, 6.19 mmol) in ethanol (100 mL). The mixture was refluxed for 3 hours, after which the solvent was evaporated under reduced pressure. The residue was dissolved in water, basified with sodium carbonate, and extracted with dichloromethane. After drying, the organic phase was concentrated in vacuum and purified by silica gel chromatography (petroleum ether/ethyl acetate=5:1) to give 2,4-bis(trifluoromethyl)imidazo[1,2-][1,8]naphthyridine (6b) (1.83 g, 80% yield).
¹H NMR (300 MHz, MeOD): δ 8.59 (s, 1H), 8.22 (s, 1H), 7.90 (dd, J=1.7, 9.9 Hz, 1H), 7.84 (d, J=9.8 Hz, 1H), 7.68 (d, J =1.3 Hz, 1H);¹³C NMR (150 MHz, MeOD): δ 147.37 (q, J= 36.9 Hz), 145.46, 145.36, 138.87 (q, J = 33.5 Hz), 133.95, 124.76, 123.08, 122.97, 121.41, 118.53, 115.61, 114.85;¹⁹F NMR (282 MHz, CDCl₃): δ
-60.8, -67.4; IR (KBr): 3421, 1583, 1509, 1449, 1278, 1244, 1142, 1036, 826, 665 cm^-1; IR (KBr): 3050, 1464, 1447, 1319, 1294, 1273, 1231, 1198, 1159, 1132, 739 cm^-1HRMS (ESI) m/z: [M + H]⁺calcd for C₁₂H₆F₆N₃, 306.0466; found, 306.0445.

The obtained compound (6b) (1.51 g, 4.95 mmol) and N-bromosuccinimide (1.32 g, 7.42 mmol) were dissolved in acetonitrile (20 mL) and stirred at 50°C for 1 hour. The reaction solution was cooled to room temperature and the solvent was removed under vacuum. The residue was dissolved in dichloromethane and separated three times, after which the organic layer was washed with sodium thiosulfate and sodium bicarbonate. The organic layer was then filtered and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (50% ethyl acetate/n-hexane solution) to obtain 9-bromo-2,4-bis(trifluoromethyl)imidazo[1,2-α][1,8]naphthyridine (6c) (1.82 g, 96%) as a yellow solid.¹H NMR (300 MHz, MeOD): δ 8.32 (s, 1H), 7.98 (dd, J=1.8, 9.8 Hz, 1H),
7.88 (d, J=9.8 Hz, 1H), 7.75 (s, 1H);¹³C NMR (150 MHz, MeOD): δ 146.72, 146.56, 145.77 (q, J = 37.0 Hz), 138.42 (q, J = 33.5 Hz), 136.82, 126.60, 124.78, 123.14, 121.63, 119.18, 115.88, 100.46;¹⁹F NMR (282 MHz, CDCl₃): δ -61.0, -67.6; IR (KBr): 3055, 1424, 1274, 1133, 901, 713 cm^-1HRMS (ESI) m/z: [M + H]⁺calcd for C₁₂H₅BrF₆N₃, 383.9571; found, 383.9582.

4-Iodoaniline (1.0 g, 5.81 mmol), potassium acetate (2.3 g, 23.24 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.8 g, 6.97 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (5 mol%) were dissolved in 1,4-dioxane (4 mL), and the mixture was stirred at 100° C. for 17 hours. After the reaction was completed, the mixture was cooled to room temperature and separated using ethyl acetate and water. The obtained organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (99% dichloromethane/methanol solution) to obtain 4-(4,4,5,5-tetramethyl-1,3-dioxaborane-2-yl)aniline (6d) (923.8 mg, yield 78%) as a white solid.
¹ H NMR (300 MHz, CDCl ₃ ): δ 7.62 (d, J = 9.0 Hz, 2H), 6.66 (d, J = 9.0 Hz, 2H), 3.83 (br, 2H), 1.32 (s, 12H); IR (KBr): 3450, 3358, 3218, 3042, 2994, 2977, 2927, 1630, 1604, 1562, 1472, 1430, 1398, 1361, 1311, 1302, 1272, 1214, 1182, 1144, 1109, 1089, 962, 859, 7 40, 672, 658, 639, 581, 526, 507, 450 cm ^-1 ; HRMS (ESI) m/z: [M + H] ⁺ calcd for C ₁₂ H ₁₉ BNO ₂ , 220.1598; found, 220.1511.

Under a nitrogen atmosphere, compound (6c) (311.9 mg, 0.81 mmol), compound (6d) (230.0 mg, 1.05 mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mol%) were dissolved in 1,4-dioxane (5.5 mL), and 1
A 0% aqueous sodium carbonate solution (10 mL) was added. The mixture was stirred at 90° C. for 2 hours. After the reaction was completed, the mixture was cooled to room temperature and separated using dichloromethane and water. The obtained organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (50% ethyl acetate/hexane solution) to obtain compound (6) (351.2 mg, 76%) as a red solid.
^1H NMR (300 MHz, DMSO-d6): δ 8.28 (s, 1H), 7.99 (d, J = 9.7 Hz, 1H), 7.74 (dd, J = 2.07, 9.72 Hz, 1H), 7.60 (s, 1H), 7.31 (d, J = 8.52, 2H), 6. 60 (d, J = 8.58,
2H), 5.32 (s, 2H); ¹³ C NMR (150 MHz, MeOD): δ 149.5, 146.8, 146.0, 145.7 (q, J
= 37.1 Hz), 138.0 (q, J = 33.2 Hz), 134.1, 134.0, 132.4, 124.9, 124.7, 123.4, 123.1, 122.8, 120.8, 120.6, 119.5, 115.4, 115.1; ⁹ F NMR (282 MHz, CDCl ₃ ): δ -60.9 (d, J = 1.8 Hz), -67.2; IR (KBr): 3424, 3340, 3229, 1637, 1610, 1487, 1420, 1277, 1213, 1141 cm ^-1 ; HRMS (ESI) m/z: [ M + H] ⁺ calcd for C ₁₈ H ₁₁ F ₆ N ₄ , 397.0888; found, 397.0882.

Compound (6) was dissolved in methanol to obtain a yellow solution. 0.5 mL of a 1 mol/L solution of hydrochloric acid in diethyl ether was added to obtain a transparent solution. The solvent was removed to obtain a white solid, which was then dried in a vacuum to obtain the hydrochloride salt (6).

オートクレーブ中で、２，７－ジヒドロキシナフタリン（２．００ｇ、１２．５ｍｍｏｌ）及び２８％の亜硫酸水素ナトリウム（５．２０ｇ、５０．０ｍｍｏｌ）のアンモニア溶液（１００ｍＬ）を１７０℃で９時間撹拌し、次いで反応混合物を室温まで冷却し、１０％水酸化ナリウム水溶液を用いてｐＨを１２にして、沈殿物を得た。沈殿物をろ過し、洗浄し、真空乾燥して２，７－ジアミノナフタレン（１．８２ｇ、９２％）を黄褐色の固体として得た。
1H NMR (400 MHz, CDCl3) δ: 7.50 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 2.0 Hz, 2H), 6.70 (dd, J = 2.4, 8.8 Hz, 2H), 3.77 (br s,4H). Example 7: Synthesis of 1,3-bis(trifluoromethyl)benzo[f]quinolin-9-amine (compound 7) and 2,4-bis(trifluoromethyl)benzo[g]quinolin-8-amine (compound 8), as well as their hydrochlorides (7) and (8)

2,7-Dihydroxynaphthalene (2.00 g, 12.5 mmol) and 28% sodium bisulfite (5.20 g, 50.0 mmol) in ammonia (100 mL) were stirred in an autoclave at 170° C. for 9 hours, then the reaction mixture was cooled to room temperature and the pH was adjusted to 12 with 10% aqueous sodium hydroxide to give a precipitate, which was filtered, washed, and dried in vacuum to give 2,7-diaminonaphthalene (1.82 g, 92%) as a tan solid.
1H NMR (400 MHz, CDCl3) δ: 7.50 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 2.0 Hz, 2H), 6.70 (dd, J = 2.4, 8.8 Hz, 2H), 3.77 (br s,4H).

The obtained 2,7-diaminonaphthalene (158 mg, 1.0 mmol) was dissolved in a pyridine solution (5 mL), and a pyridine solution (10 mL) of tosyl chloride (270 mg, 1.4 mmol) was added dropwise thereto over 1 hour at 0°C. The reaction mixture was warmed to room temperature and stirred overnight, and the reaction was quenched by adding water (100 mL). The obtained mixture was extracted with diethyl ether (100 mL), and the organic phase was acidified with 10% hydrochloric acid. The aqueous phase was neutralized with a sodium hydroxide solution, and extracted by adding diethyl ether.
The organic phase was collected, dried over magnesium sulfate, filtered and the solvent was evaporated in vacuo to give N-(7-aminonaphthalen-2-yl)-4-methylbenzenesulfonamide (234 mg, 75% crude yield).

Mp: 156-158℃; IR (KBr): 3406, 3339, 1636, 1516, 1346, 1320, 1159, 1091 cm- ¹ ;
1H NMR (600 MHz, CDCl3) δ: 7.67 (d, J = 8.3 Hz, 2H), 7.54 (dd, J = 6.8, 8.4 Hz,
2H), 7.27 (d, J = 1.8 Hz, 1H), 7.18 (d, J = 8.2 Hz, 2H), 6.92 (dd, J = 2.2, 8.6
Hz, 1H), 6.86 (dd, J = 2.2, 8.6 Hz, 1H), 6.83 (d, J = 1.9 Hz, 1H), 6.70 (br s, 1H), 3.87 (br s, 2H), 2.34 (s , 3H); ¹³ C{1H}NMR (150 MHz, CDCl3) δ: 144.9, 143.8, 136.1, 135.2, 134.5, 129.6 (2C), 129.1, 129.0, 127.2 (2C), 125.5, 117.7, 117.4, 116.3, 108.0, 21.5; HRMS (ESI) m/z [M + H]+ calcd for C ₁₇ H ₁₇ N ₂ O ₂ S 313.1011, found: 313.1007.

Under a nitrogen atmosphere, hexafluoroacetylacetone (1.4 mL, 9.7 mmol) and montmorillonite K10 (1.13 g) were added to a solution of N-(7-aminonaphthalen-2-yl)-4-methylbenzenesulfonamide in dry 1,4-dioxane (12 mL), and the mixture was stirred at 60°C for 10 hours. The mixture was cooled to room temperature, filtered through Celite, and the obtained filtrate was evaporated under reduced pressure to obtain a solid. Concentrated sulfuric acid (2.4 mL) was added to the obtained solid, and the mixture was stirred at 100°C for 5 hours. After neutralization with an aqueous sodium hydroxide solution, the mixture was extracted three times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated in vacuum to obtain a mixture of the target compounds (7) and (8). This mixture was purified by silica gel column chromatography (n-hexane/ethyl acetate = 20/1) to obtain a yellow solid of compound (7) (252 mg, 32%) and a red solid of compound (8) (38.0 mg, 5%).

Compound (7): Mp:132-138 ℃, IR (KBr): 3457, 3399, 1635, 1540, 1276, 1188, and 1137 cm- ¹ , 1H NMR (300 MHz, CDCl3) δ: 8.13 (s, 1H ), 8.00-7.97 (m, 2H), 7.84 (d, J = 9.0 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.16 (dd, J = 2.1, 8.5 Hz, 1H), 4.13 (br, 2H); ¹³ C{1H}NMR (150 MHz, CDCl3) δ: 150.9, 146.3 (q, 2JCF = 35.6 Hz), 145.9, 135.3 (q, 2JCF = 32.6 Hz), 133.6, 130.2, 128.6, 126.9, 124.2, 123.9 (q, 1JCF = 273.5 Hz), 123.1, 121.2 (q, 1JCF = 273 .3 Hz), 118.6, 114.8 (q, 3JCF = 7.2 Hz),
111.8 (q, 3JCF = 8.1 Hz); ¹⁹ F{1H}-NMR (282 MHz, CDCl ₃ ) δ: -58.0, -67.9; HRMS (ESI) m/z [M + H]+ calcd for C ₁₅ H ₉ F ₆ N ₂ 331.0669, found: 331.0705; anal. calcd for
C ₁₅ H ₈ F ₆ N ₂ : C, 54.56; H, 2.44; N, 8.48. Found: C, 54.60; H, 2.47; N, 8.50.

Compound (8): Mp: 228-235 ℃; IR (KBr): 3464, 3351, 1636, 1277, 1197, and 1135 cm- ¹ ; 1H NMR (600 MHz, CDCl ₃ ) δ: 8.59 (s, 2H) , 7.97 (d, J = 9.0 Hz, 1H), 7.82 (s, 1H), 7.17 (dd, J = 2.2, 8.9 Hz, 1H), 7.14 (d, J = 2.0 Hz, 1H), 4.22 (br s , 2H); ¹³ C{1H}NMR (150 MHz, CDCl ₃ ) δ: 147.4 (q, 2JCF = 35.6 Hz), 145.7, 144.5, 136.7
(q, 2JCF = 32.1 Hz), 136.6, 130.4, 129.4, 125.8, 123.7, 123.2 (q, 1JCF = 273.4 Hz), 122.7, 121.1 (q, 1JCF = 274.0 Hz), 118.1, 111.8, 1 05.2; ¹⁹ F{ 1H}NMR (282 MHz,
CDCl ₃ ) δ: -62.8, -68.4; HRMS (ESI) m/z [M + H]+ calcd for C ₁₅ H ₉ F ₆ N ₂ 331.0669, found: 331.0707; anal. calcd for C ₁₅ H ₈ F ₆ N ₂ : C, 54.56; H, 2.44; N, 8.48. Found: C,
54.78; H, 2.60; N, 8.34.

ｍ－フェニレンジアミン１．０ｇ（９．２６ｍｍｏｌ）及びモンモリロナイトＫ１０ １．５ｇを溶解したトルエン３０ｍＬ溶液に、ヘキサフルオロアセトン２．３５ｇ（１１
．３５ｍｍｏｌ）を添加し、９０℃で１時間反応させた。反応溶液を濾過し、濾液を減圧下で約１０ｍＬに濃縮した。冷却後、得られた沈殿物を濾過により集めて、２，４－ビス（トリフルオロメチル）キノリン－７－アミン（化合物（９））を黄色の固体２．５ｇ（８．９３ｍｍｏｌ、収率９６％）で得た。
また、酢酸エチル／ヘキサン混合溶媒で再結晶することで化合物（９）の黄色単結晶を得た。
化合物（９）をメタノール中で撹拌して溶解させて黄色の溶液を得た。ここに、１ｍｏｌ／Ｌの塩酸のジエチルエーテル溶液を０．５ｍＬ加えて、透明の溶液を得た。溶媒を除去して得られた白色固体を真空乾燥して、塩酸塩（９）を得た。 Example 8: Synthesis of 2,4-bis(trifluoromethyl)-7-iodoquinoline (compound (9)) and its hydrochloride salt (9)

1.0 g (9.26 mmol) of m-phenylenediamine and 1.5 g of montmorillonite K10 were dissolved in 30 mL of toluene, and 2.35 g (11 mmol) of hexafluoroacetone was added.
The reaction mixture was filtered and the filtrate was concentrated to about 10 mL under reduced pressure. After cooling, the resulting precipitate was collected by filtration to obtain 2,4-bis(trifluoromethyl)quinolin-7-amine (compound (9)) as a yellow solid (2.5 g, 8.93 mmol, 96% yield).
In addition, yellow single crystals of compound (9) were obtained by recrystallization from a mixed solvent of ethyl acetate/hexane.
Compound (9) was dissolved in methanol by stirring to obtain a yellow solution. 0.5 mL of a 1 mol/L solution of hydrochloric acid in diethyl ether was added thereto to obtain a transparent solution. The solvent was removed to obtain a white solid, which was then dried in vacuum to obtain hydrochloride (9).

シュレンク管に２，４－ビス（トリフルオロメチル）－７－ヨードキノリン（１１３ｍｇ、０．２８９ｍｍｏｌ）、１，３－ビス（４－（トリフルオロメチル）フェニル）グアニジン（１２１ｍｇ、０．３４８ｍｍｏｌ）、炭酸セシウム（３７７ｍｇ、１．１６ｍｍｏｌ）及びトルエン（３ｍＬ）を加えて溶解した。溶液を凍結脱気後、窒素雰囲気下、酢酸パラジウム（３．２ｍｇ、１４μｍｏｌ）とキサントフォス（８．４ｍｇ、１５μｍｏｌ）を加え、１００℃にて１時間撹拌した。反応終了後、酢酸エチルと水を加え、分液操作を行った。得られた有機相を無水硫酸マグネシウムにより乾燥後、ろ過し、溶媒を減圧下留去することで粗生成物を得た。得られた粗生成物はシリカゲルカラムクロマトグラフィー（１０％酢酸エチル／ヘキサン溶液）により精製し、目的化合物（７６．４ｍｇ、４３％）を薄い黄色の非晶体として得た。
¹H NMR (600 MHz, CD₃CN): δ 8.00 (br d, J = 9.0 Hz, 1H), 7.87 (s, 2H), 7.59 (br d, J = 6.8 Hz, 1H), 7.44 (d, J = 7.4 Hz, 4H), 7.23 (br s, 4H); ¹³C NMR (150 MHz,
CD₃CN): δ 150.0, 147.9 (q, J = 35.1 Hz), 145.7, 146.2 (q, J= 32.4 Hz), 131.9, 129.4, 126.75 (2C), 126.72 (2C), 125.4 (q, J = 270.2 Hz, 2C), 125.0 (2C), 124.2 (q, J = 32.2 Hz, 2C), 123.9 (q, J = 274.2 Hz), 122.0 (q, J = 274.4 Hz), 121.1 (4C), 120.1, 112.9 (2C); ¹⁹F NMR (282 MHz, CD₃CN): δ -62.1, -62.3, -68.3; IR (KBr): 3427, 1603, 1523, 1450, 1325, 1279, 1215, 1116, 1068, 835, 666 cm^-1; HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₆H₁₅F₁₂N₄, 611.1105; found, 611.1126. Example 9: Synthesis of 2-(2,4-bis(trifluoromethyl)quinolin-7-yl)-1,3-bis(4-(trifluoromethyl)phenyl)guanidine (compound (10)) and its hydrochloride salt (10)

2,4-bis(trifluoromethyl)-7-iodoquinoline (113 mg, 0.289 mmol), 1,3-bis(4-(trifluoromethyl)phenyl)guanidine (121 mg, 0.348 mmol), cesium carbonate (377 mg, 1.16 mmol) and toluene (3 mL) were added to a Schlenk flask and dissolved. The solution was freeze-degassed, and then palladium acetate (3.2 mg, 14 μmol) and xanthophos (8.4 mg, 15 μmol) were added under a nitrogen atmosphere and stirred at 100° C. for 1 hour. After the reaction was completed, ethyl acetate and water were added and a separation operation was performed. The obtained organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (10% ethyl acetate/hexane solution) to obtain the target compound (76.4 mg, 43%) as a pale yellow amorphous substance.
¹ H NMR (600 MHz, CD ₃ CN): δ 8.00 (br d, J = 9.0 Hz, 1H), 7.87 (s, 2H), 7.59 (br d, J = 6.8 Hz, 1H), 7.44 (d, J = 7.4 Hz, 4H), 7.23 (br s, 4H); ¹³ C NMR (150 MHz,
CD ₃ CN): δ 150.0, 147.9 (q, J = 35.1 Hz), 145.7, 146.2 (q, J= 32.4 Hz), 131.9, 129.4, 126.75 (2C), 126.72 (2C), 125.4 (q, J = 270.2 Hz, ^{2 19} F NMR (282 MHz, CD _3CN ): δ -62.1, -62.3, -68.3; IR (KBr): 3427, 1603, 1523, 1450, 1325, 1279, 1215, 1116, 1068, 835, 666 cm ^-1 ; HRMS (ESI) m/z: [M + H] ⁺ calcd for C ₂₆ H ₁₅ F _{1 2} N ₄ , 611.1105; found, 611.1126.

Compound (10) was dissolved in methanol by stirring to obtain a yellow solution. 0.5 mL of a 1 mol/L solution of hydrochloric acid in diethyl ether was added to obtain a transparent solution. The solvent was removed to obtain a white solid, which was then dried in a vacuum to obtain the hydrochloride salt (10).

シュレンク管に２，４－ビス（トリフルオロメチル）－７－ヨードキノリン（５４．１ｍｇ、０．１３８ｍｍｏｌ）、１－フェニル－３－（４－（トリフルオロメチル）フェニル）グアニジン（４６．３ｍｇ、０．１６６ｍｍｏｌ）、炭酸セシウム（１８０ｍｇ、０．５５２ｍｍｏｌ）、及びトルエン（２ｍＬ）を加えて溶解した。溶液を凍結脱気後、窒素雰囲気下、酢酸パラジウム（１．５ｍｇ、６．７μｍｏｌ）とキサントフォス（４．０ｍｇ、６．９μｍｏｌ）を加え、１００℃にて３時間撹拌した。反応終了後、酢酸エチルと水を加え、分液操作を行った。得られた有機相を無水硫酸マグネシウムにより乾燥後、ろ過し、溶媒を減圧下留去することで粗生成物を得た。得られた粗生成物はシリカゲルカラムクロマトグラフィー（３％酢酸エチル／ジクロロメタン溶液）により精製し、目的化合物（７０．２ｍｇ、９４％）を黄色の非晶体として得た。
¹H NMR (600 MHz, CDCl₃): δ 8.05 (br d, J = 8.4 Hz, 1H), 7.97 (br s, 1H), 7.79 (s, 1H), 7.63 (br s, 1H), 7.55 (d, J= 8.0 Hz, 2H), 7.40-7.31 (m, 4H), 7.20 (d, J=
8.0 Hz, 3H), 6.38 (br s, 2H); ¹³C NMR (150 MHz, CDCl₃): δ 149.3, 147.6 (q, J =
35.0 Hz), 144.7, 138.2, 136.1 (q, J = 32.6 Hz), 129.9 (4C), 127.6, 126.54 (2C),
126.52 (2C), 125.4, 125.1 (q, J = 32.7 Hz), 124.8, 124.2 (q, J= 271.6 Hz), 123.1, 122.8 (q, J = 273.2 Hz), 121.0 (q, J = 275.4 Hz), 120.6, 118.7, 111.9 (2C); ¹⁹F NMR (282 MHz, CDCl₃): δ -61.5, -61.9, -67.5; IR (KBr): 3422, 1594, 1541, 1449, 1325, 1279, 1215, 1146, 1067, 835, 751, 666 cm^-1; HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₅H₁₆F₉N₄, 543.1231; found, 543.1221. Example 10: Synthesis of 2-(2,4-bis(trifluoromethyl)quinolin-7-yl)-1-phenyl-3-(4-(trifluoromethyl)phenyl)guanidine (compound (11)) and its hydrochloride salt (11)

2,4-bis(trifluoromethyl)-7-iodoquinoline (54.1 mg, 0.138 mmol), 1-phenyl-3-(4-(trifluoromethyl)phenyl)guanidine (46.3 mg, 0.166 mmol), cesium carbonate (180 mg, 0.552 mmol), and toluene (2 mL) were added to a Schlenk flask and dissolved. The solution was freeze-degassed, and then palladium acetate (1.5 mg, 6.7 μmol) and xanthophos (4.0 mg, 6.9 μmol) were added under a nitrogen atmosphere and stirred at 100° C. for 3 hours. After the reaction was completed, ethyl acetate and water were added and a separation operation was performed. The obtained organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (3% ethyl acetate/dichloromethane solution) to obtain the target compound (70.2 mg, 94%) as a yellow amorphous substance.
¹ H NMR (600 MHz, CDCl ₃ ): δ 8.05 (br d, J = 8.4 Hz, 1H), 7.97 (br s, 1H), 7.79 (s, 1H), 7.63 (br s, 1H), 7.55 (d, J= 8.0 Hz, 2H), 7.40-7.31 (m, 4H), 7.20 (d, J=
8.0 Hz, 3H), 6.38 (br s, 2H); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 149.3, 147.6 (q, J =
35.0 Hz), 144.7, 138.2, 136.1 (q, J = 32.6 Hz), 129.9 (4C), 127.6, 126.54 (2C),
126.52 (2C), 125.4, 125.1 (q, J = 32.7 Hz), 124.8, 124.2 (q, J= 271.6 Hz), 123.1, 122.8 (q, J = 273.2 Hz), 121.0 (q, J = 275.4 Hz), 118.7, 111.9 (2C); ¹⁹ F NMR (282 MHz, CDCl ₃ ): δ -61.5, -61.9, -67.5; IR (KBr): 3422, 1594, 1541, 1449, 1325, 1279, 1215, 1146, 1067, 751, 666 cm ^-1 ; HRMS (ESI) m/z: [M + H] ⁺ calcd for C ₂₅ H ₁₆ F ₉ N ₄ , 543.1231; found, 543.1221.

Compound (11) was dissolved in methanol by stirring to obtain a yellow solution. 0.5 mL of a 1 mol/L solution of hydrochloric acid in diethyl ether was added to obtain a transparent solution. The solvent was removed to obtain a white solid, which was then dried in a vacuum to obtain the hydrochloride salt (11).

シュレンク管に２，４－ビス（トリフルオロメチル）－７－ヨードキノリン（６２．９ｍｇ、０．１６１ｍｍｏｌ）、１，３－ビス（４－メトキシフェニル）グアニジン（５４．０ｍｇ、０．１９３ｍｍｏｌ）、炭酸セシウム（２１０ｍｇ、０．６４５ｍｍｏｌ）、及びトルエン（１．６ｍＬ）を加えて溶解した。溶液を凍結脱気後、窒素雰囲気下、酢酸パラジウム（１．８ｍｇ、８．０μｍｏｌ）とキサントフォス（４．７ｍｇ、８．１μｍｏｌ）を加え、１００℃にて３時間撹拌した。反応終了後、酢酸エチルと水を加え、分液操作を行った。得られた有機相を無水硫酸マグネシウムにより乾燥後、ろ過し、溶媒を減圧下留去することで粗生成物を得た。得られた粗生成物はシリカゲルカラムクロマトグラ
フィー（２５％酢酸エチル／ヘキサン溶液）により精製し、目的化合物（８５．３ｍｇ、９９％）を黄色の非晶体として得た。
¹H NMR (600 MHz, CDCl₃): δ 8.00 (d, J = 9.0 Hz, 1H), 7.90 (br s, 1H), 7.73 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.19 (d, J = 8.9 Hz, 4H), 6.86 (d, J = 8.9 Hz, 4H), 6.15 (br s, 2H), 3.78 (s, 6H); ¹³C NMR (150 MHz, CDCl₃): δ 156.9 (2C), 150.9, 149.5, 147.2 (q, J = 35.3 Hz), 146.9, 135.8 (q, J = 32.5 Hz), 132.1, 128.8, 124.7 (4C), 124.4 (2C), 122.9 (q, J = 275.5 Hz), 121.1 (q, J = 275.5 Hz), 119.3, 119.0, 114.7 (4C), 111.3, 55.5 (2C); ¹⁹F NMR (282 MHz, CDCl₃): δ -61.4 (d, J = 1.5 Hz), -67.4; IR (KBr): 3421, 1583, 1509, 1449, 1278, 1244, 1142, 1036, 826, 665 cm^-1; HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₆H₂₁F₆N₄O₂, 535.1569; found, 535.1549. Example 11: Synthesis of 2-(2,4-bis(trifluoromethyl)quinolin-7-yl)-1,3-bis(4-methoxyphenyl)guanidine (compound (12)) and its hydrochloride salt (12)

2,4-bis(trifluoromethyl)-7-iodoquinoline (62.9 mg, 0.161 mmol), 1,3-bis(4-methoxyphenyl)guanidine (54.0 mg, 0.193 mmol), cesium carbonate (210 mg, 0.645 mmol), and toluene (1.6 mL) were added to a Schlenk flask and dissolved. After the solution was freeze-degassed, palladium acetate (1.8 mg, 8.0 μmol) and xanthophos (4.7 mg, 8.1 μmol) were added under a nitrogen atmosphere and stirred at 100° C. for 3 hours. After the reaction was completed, ethyl acetate and water were added and a separation operation was performed. The obtained organic phase was dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (25% ethyl acetate/hexane solution) to obtain the target compound (85.3 mg, 99%) as a yellow amorphous substance.
¹ H NMR (600 MHz, CDCl ₃ ): δ 8.00 (d, J = 9.0 Hz, 1H), 7.90 (br s, 1H), 7.73 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.19 (d, J = 8.9 Hz, 4H), 6.86 (d, J = 8.9 Hz, 4H), 6.15 (br s, 2H), 3.78 (s, 6H); ¹³ C NMR (150 MHz, CDCl ₃ ): δ 156.9 (2C), 150.9, 149.5, 147.2 (q, J = 35.3 Hz), 146.9, 135.8 (q, J = 32.5 Hz), 132.1, 128.8, 124.7 (4C), 124.4 (2C), 122.9 (q, J = 275.5 Hz), 121.1 (q, J = 275.5 Hz), 119.3, 119.0, 114.7 (4C), 111.3, 55.5 (2C ⁾ ; F NMR (282 MHz, CDCl ₃ ): δ -61.4 (d, J = 1.5 Hz), -67.4; IR (KBr): 3421, 1583, 1509, 1449, 1278, 1244, 1142, 1036, 826, 665 cm ^-1 ; HRMS (ESI) m/z: [M + H ] ⁺ calcd for C ₂₆ H ₂₁ F ₆ N ₄ O ₂ , 535.1569; found, 535.1549.

Compound (12) was dissolved in methanol by stirring to obtain a yellow solution. 0.5 mL of a 1 mol/L solution of hydrochloric acid in diethyl ether was added to obtain a transparent solution. The solvent was removed to obtain a white solid, which was then dried in a vacuum to obtain the hydrochloride salt (12).

Example 12: Determination of PKa of hydrochloride of polycyclic aromatic amine compound 0.125 μmol of the above hydrochlorides (1) to (5), (7) to (12) was dissolved in 1.5 mL of 1,4-dioxane, and 3.5 mL of buffer solutions adjusted to various pH values (pH 0 to 2: hydrochloric acid buffer, pH 2 to 8: McIlvaine buffer, pH 8 to 13: sodium bicarbonate/sodium hydroxide buffer) were added thereto, and the pH of the mixture was measured. Then, the absorbance of the solutions at each pH was measured, and a pH curve was created from the absorption intensity at the absorption maximum wavelength of each hydrochloride, and the pKa of the protonated form of each compound was calculated. The calculated pKa values are shown in Table 1 below.

The hydrochlorides of each polycyclic aromatic amine of the present invention each have a different pKa (0.8 to 9.8), so that an appropriate amine detection agent can be provided based on the pH of the sample to be detected. For example, to detect free amino groups in solid-phase peptide synthesis, it is preferable to use an amine detection agent containing hydrochloride (2) to (5), (11) or (12), particularly preferably hydrochloride (2) or (12), whose pH has been adjusted to a neutral range so as not to affect the reaction.

<Measurement of Absorption Spectrum>
Example 13: Molar extinction coefficient (ε) of compound (2) and hydrochloride salt (2)
Two screw vials containing 0.0474 mg (0.100 μmol) of compound (2) were prepared, and 5 mL of methanol or 5 mL of a 3% hydrochloric acid in methanol solution was added to each vial, followed by shaking to dissolve.
Also, one vial containing 0.0511 mg (0.100 μmol) of the hydrochloride salt (2) was prepared, and methanol (5 mL) was added thereto to dissolve the salt.
The absorption spectra of these three samples are shown in FIG.

Example 14: Molar extinction coefficient (ε) of compound (3) and hydrochloride salt (3)
Three screw vials containing 0.0322 mg (0.100 μmol) of compound (3) were prepared, and 5 mL of methanol, 5 mL of n-butanol, or 5 mL of a 3% hydrochloric acid-containing methanol solution was added to each vial and the mixture was shaken to dissolve.
Also, one vial containing 0.0359 mg (0.100 μmol) of the hydrochloride salt (3) was prepared, and methanol (5 mL) was added thereto to dissolve the salt.
The absorption spectra of these four samples are shown in FIG.

Example 15: Molar extinction coefficient (ε) of compound (12) and hydrochloride salt (12)
Three screw vials containing 0.0534 mg (0.100 μmol) of compound (12) were prepared, and 5 mL of methanol, 5 mL of n-butanol, or 5 mL of a 3% hydrochloric acid-containing methanol solution was added to each vial and the mixture was shaken to dissolve.
Also, one vial containing 0.0571 mg (0.100 μmol) of the hydrochloride salt (12) was prepared, and methanol (5 mL) was added thereto to dissolve the salt.
The absorption spectra of these four samples are shown in FIG.

1 to 3, the molar absorption coefficients (ε) of the compounds (2), (3) and (12) in a methanol solution containing 3% hydrochloric acid are almost the same as the molar absorption coefficients (ε) of the hydrochloride salts (2), (3) and (12) in a methanol solution. This shows that the polycyclic aromatic amine compound of the present invention forms a hydrochloride salt of the polycyclic aromatic amine compound in the presence of hydrochloric acid.
On the other hand, the methanol solutions of the hydrochlorides (2), (3) and (12) have molar absorption coefficients (ε) of almost 0 at wavelengths longer than 380 nm, and are therefore almost colorless and transparent solutions, whereas the methanol solutions of the compounds (2), (3) and (12) have molar absorption coefficients (ε) in the wavelength region of 380 nm to 500 nm, and are therefore yellow to red solutions. In other words, it can be understood that the salts of the polycyclic aromatic amine compounds of the present invention are colored by desalting, and can change the color of the solution into which they are diffused.
It can also be understood that the desalted polycyclic aromatic amine compounds (2), (3) and (12) can be easily regenerated into the hydrochlorides of the polycyclic aromatic amine compounds (2), (3) and (12) by the addition of hydrochloric acid.

<Detection of amines>
Example 16 Detection of Primary Amines Using Compound (2) 51.086 mg of hydrochloride (2) was dissolved in 50 mL of methanol to prepare a 2.0 mM solution of hydrochloride (2) in methanol.
5 mL of this solution was dispensed into containers, and 0, 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, 1.6 and 2.0 equivalents of n-propylamine were added to the solutions in the respective containers using a microsyringe.
The absorbance of this solution was measured using a 0.2 cm cell, and the resulting absorption spectrum is shown in Figure 4(a).
FIG. 4(b) shows a graph of absorbance at a wavelength of 381 nm versus the amount of n-propylamine added.

Example 17 Detection of Secondary Amines Using Compound (2) 51.086 mg of hydrochloride (2) was dissolved in 50 mL of methanol to prepare a 2 mM solution of hydrochloride (2) in methanol.
5 mL of this solution was dispensed into containers, and 0, 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, 1.6 and 2.0 equivalents of piperidine were added to the solution in each container using a microsyringe.
The absorbance of this solution was measured using a 0.2 cm cell. The absorption spectrum obtained is shown in Figure 5(a). Figure 5(b) shows a graph of the absorbance at a wavelength of 381 nm versus the amount of piperidine added.

Example 18: Detection of tertiary amines using compound (2) 51.086 mg of hydrochloride (2) was dissolved in 50 mL of methanol to prepare a 2 mM solution of hydrochloride (2) in methanol.
5 mL of this solution was dispensed into containers, and 0, 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, 1.6 and 2.0 equivalents of triethylamine were added to the solutions in the respective containers using a microsyringe.
The absorbance of this solution was measured using a 0.2 cm cell. The absorption spectrum obtained is shown in Figure 6(a). Figure 6(b) shows a graph of absorbance at a wavelength of 381 nm versus the amount of triethylamine added.

Examples 16 to 18 show that the amine detection reagent of the present invention can quantitatively detect primary, secondary, and tertiary amines, since the absorbance increases in proportion to the amount of the amines added.
Furthermore, from Examples 16 to 18, it can be seen that the amine detection agent of the present invention can detect amines, including primary, secondary, and tertiary amines, by measuring the absorbance at the maximum absorption wavelength of a polycyclic aromatic amine compound.

Example 19: Color reaction of hydrochloride (6) 0.346 g of hydrochloride (6) was dissolved in 40 mL of methanol solution in a screw vial to prepare a 20 μmol/L solution of hydrochloride (6) in methanol. 5 mL of this solution was dispensed into six screw vials. Five equivalents of 28% aqueous ammonia (NH ₃ ), 40% aqueous methylamine solution (MeNH ₂ ), 50% aqueous dimethylamine solution (Me2NH), glycine (Gly) and proline (Pro) were added to each screw vial relative to the hydrochloride (6), and the vials were then capped and shaken to observe the color of the solution. The absorption spectrum of the solution is shown in FIG. 7.
To the solution containing the amines, 33% hydrochloric acid was further added in an amount of 5 equivalents relative to the hydrochloride salt (6), and the color of the solution was observed. The change in color of the solution is shown in Table 2 below.

Example 20: Color reaction of hydrochloride (8) The hydrochloride (8) (0.293 mg) synthesized in Example 7 was dissolved in 40 mL of methanol solution to prepare a 20 μmol/L methanol solution of hydrochloride (8). 5 mL of this solution was dispensed into six screw vials. Five equivalents of 28% aqueous ammonia (NH ₃ ), 40% aqueous methylamine solution (MeNH ₂ ), 50% aqueous dimethylamine solution (Me2NH), glycine (Gly) and proline (Pro) were added to each screw vial relative to the hydrochloride (8), and the vials were then capped and shaken. The results are shown in Table 3 below. The absorption spectrum of the solution is shown in FIG. 7.
In addition, 5 equivalents of 33% hydrochloric acid relative to the hydrochloride (8) were added to the solution containing the amines, and the color of the solution was observed. The color of the solution is shown in Table 3 below.

The hydrochloride salts (6) and (8) to which various amines had been added each showed the same color when visually observed. Moreover, as shown in Figures 7 and 8, the solutions after the addition of amines each showed approximately the same absorbance.
7 and 8 show that the amine detection agent containing the salt of the polycyclic aromatic amine compound of the present invention desalts upon contact with amines, causing a color reaction to produce the polycyclic aromatic amine compound. It was also shown that secondary amines such as dimethylamine and proline can be detected in the same manner as primary amines.
It can also be seen that the hydrochloride (6) has a higher absorbance and is more sensitive than the hydrochloride (8).
It was also shown that the amine detection reagent after amine detection can be reused by adding an excess amount of hydrogen halide to form a hydrogen halide salt.

<Detection of amines (gas)>
Example 21: Detection of ammonia gas using hydrochloride salt (7) 1 mg of compound (7) was mixed with 49 mg of potassium bromide to prepare a yellow powder sample containing 2 mass % of compound (7).
The yellow powder sample was placed in a closed container filled with hydrogen chloride gas prepared from 33% hydrochloric acid, and the color of the powder gradually faded, and after 10 minutes the color of the powder became pale. When a portion of the powder was taken out and subjected to IR measurement, the peak of compound (7) disappeared, and the peak of hydrochloride (7) was detected.
Next, the obtained light yellow powder was placed in a sealed container filled with ammonia gas prepared from 28% ammonia water, and the color of the powder turned yellow within 5 seconds. When a part of the powder was taken out and subjected to IR measurement, the peak of hydrochloride (7) disappeared, and the peak of compound (7) and the peak of ammonium chloride were detected. The result of the IR measurement is shown in Figure 9. The same color change was observed even when the same operation was repeated five times on this powder.

Example 22: Detection of ammonia gas using hydrochloride (8) 1 mg of compound (8) was mixed with 49 mg of potassium bromide to prepare an orange powder sample containing 2 mass % of compound (8).
The red powder sample was placed in a sealed container filled with hydrogen chloride gas prepared from 33% hydrochloric acid, and the color of the powder gradually faded, and after 10 minutes the color of the powder changed to light brown. When a portion of the resulting powder was taken out and subjected to IR measurement, the peak of compound (8) disappeared, and the peak of the hydrochloride salt (8) was detected.
Next, the light brown powder obtained was placed in a sealed container filled with ammonia gas prepared from 28% ammonia water, and the color of the powder changed to orange within 5 seconds. When a part of the powder was taken out and subjected to IR measurement, the peak of hydrochloride (8) disappeared, and the peaks of compound (8) and ammonium chloride were detected. The result of IR measurement is shown in Figure 10. The same operation was repeated five times on this powder, and the same color change was observed.

Examples 21 and 22 show that the amine detection agent of the present invention can be used to detect gaseous amines even in a solid or solution state. It was also shown that the amine detection agent can be easily regenerated and reused after detecting gaseous amines.

Claims (10)

An amine detection agent comprising, as a color component, a salt selected from the group consisting of hydrogen halide salts, sulfate salts, sulfite salts, nitrate salts, nitrite salts, and carboxylate salts of a polycyclic aromatic amine compound selected from the group consisting of formulas (A) to (D) below.
In formulae (A) to (D), R ¹ , R ¹¹ , R ²¹ and R ³¹ each independently represent
represents
^R2 , ^R3 , ^R4 , ^R5 , ^R6 , ^R7 , ^R8 and ^R9 each independently represent a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a phenyl group or a phenyl group optionally substituted by 1 to 5 groups ^Y2 ;
^Y1 and ^Y2 each independently represent an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a haloalkyl group having 1 to 4 carbon atoms, a halogen atom, a phenyl group, a naphthyl group, a vinyl group, a nitro group, a cyano group, or an optionally substituted amino group;
m represents an integer of 0 to 4; The amine detection agent according to claim 1, wherein the polycyclic aromatic amine compound is a compound selected from the group consisting of polycyclic aromatic amine compounds represented by the following formulas (1) to (12):
The amine detection agent according to claim 1 or 2, wherein the salt is a hydrogen halide salt. The amine detection agent according to any one of claims 1 to 3, wherein the pKa of the salt is in the range of 0.1 to 12. An amine detection agent according to any one of claims 1 to 4 for use in detecting free amino groups in a solid-phase peptide synthesis method. A step of contacting amines with the amine detection agent according to any one of claims 1 to 5, and a step of detecting the amine compounds based on the coloration of the polycyclic aromatic amine compounds produced by the contacting step.
A method for detecting amines, comprising: The method according to claim 6, wherein the amines are at least one amine compound selected from the group consisting of amino acids, peptides, amino acid derivatives, sugars having free amino groups, primary amines, secondary amines, tertiary amines, and resin products thereof. The method for detecting amines according to claim 6 or 7, wherein the amines are at least one type of amines selected from resin-immobilized amino acids, resin-immobilized peptides, and resin-immobilized amino acid derivatives, the C-terminus of which is immobilized on a resin, in a solid-phase peptide synthesis method. A method for regenerating the amine detection reagent according to any one of claims 1 to 5, which has been used for detecting amines, comprising:
a step of contacting amines with the amine detection agent according to claim 1 or claim 5 to produce a polycyclic aromatic amine compound selected from the group consisting of formula (A) to the following formula (D) that has been colored or changed in color, and then contacting the polycyclic aromatic amine compound with an acid selected from the group consisting of hydrogen halide, sulfuric acid, sulfurous acid, nitric acid, nitrous acid, and carboxylic acid; and a step of converting the polycyclic aromatic amine compound into a salt selected from the group consisting of hydrogen halide, sulfate, sulfite, nitrate, nitrite, and carboxylate of the polycyclic aromatic amine compound, which is a color-developing component, by the contacting step.
A playback method including: A polycyclic aromatic amine compound represented by any one of the following formulae (1) to (6) and (10) to (12) , or a salt thereof selected from the group consisting of a hydrogen halide salt, a sulfate salt, a sulfite salt, a nitrate salt, a nitrite salt, and a carboxylate salt.