catalyst

Abstract

To provide a novel catalyst for use in the reaction between leucoquinizalins and aldehydes. [Solution] A catalyst for use in the reaction of leucoquinizarin or a derivative thereof with an aldehyde, comprising a compound having both a secondary amino group or a tertiary amino group and a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aralkyloxycarbonyl group.

Description

[Technical Field]

[0001] This invention relates to a catalyst. [Background technology]

[0002] Leucoquinizalins have many uses as raw materials or intermediates for pigments, dyes, physiologically active substances, pharmaceuticals, or redox flow battery materials. Furthermore, it is known that leucoquinizarians can be subjected to a Marschalk reaction using an aldehyde to produce novel quinizarian derivatives having a structure in which an alkyl group is introduced to the 2nd or 3rd carbon atom of the quinizarian. Such quinizarian derivatives are useful as dyes, and like leucoquinizarians, they are also expected to be used as raw materials or intermediates for other dyes, pigments, physiologically active substances, pharmaceuticals, or redox flow battery materials.

[0003] In this specification, "leucoquinizarians" is a concept that encompasses leucoquinizarians and their derivatives unless otherwise specified. Similarly, unless otherwise specified, "quinizalins" is a concept that encompasses quinizalins and their derivatives.

[0004] One method for reacting leucoquinizalins with aldehydes is to use piperidinium acetate (C5H) as a catalyst. 10 A method using NH·HO-(O=)C-CH3 (a salt formed by the reaction of piperidine and acetic acid) has been disclosed (see Non-Patent Document 1). [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Charles Lewis “Aldol Condensation of Leucoquinizarin” J. Org. Chem., Vol.35, No.9, 1970, pp2938-2942. [Overview of the project] [Problems that the invention aims to solve]

[0006] However, the catalyst disclosed in Non-Patent Document 1 is only piperidinium acetate, and other catalysts besides piperidinium acetate have not been sufficiently investigated to date. Therefore, there has been a need for the development of novel catalysts for use in the reaction between leucoquinizalins and aldehydes.

[0007] The object of this invention is to provide a novel catalyst for use in the reaction between leucoquinizalins and aldehydes. [Means for solving the problem]

[0008] To solve the above problems, the present invention adopts the following configuration. [1] A catalyst for use in the reaction of leucoquinizalin or a derivative thereof with an aldehyde, The catalyst is a catalyst comprising a compound having both a secondary amino group or a tertiary amino group and a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aralkyloxycarbonyl group. [2] The leucoquinizalin or its derivative is the following general formula (11)

[0009] [ka] (In the formula, R 11 and R 12 Each is independently a hydrogen atom or a monovalent organic group, however, R 11 and R 12 At least one of them is a hydrogen atom. The catalyst described in [1] is a compound represented by [1]. [3] The aldehyde is the following general formula (13)

[0010] [ka] (wherein R 13 represents an alkyl group, an aryl group, an aralkyl group, a heteroaryl group or a heteroarylalkyl group, and one or two or more hydrogen atoms in said alkyl group, aryl group, aralkyl group, heteroaryl group and heteroarylalkyl group may be substituted with a halogen atom, a hydroxyl group, a carboxy group, an amino group, a hydrazino group, a hydrazono group, a nitro group, a nitroso group, a cyano group, an isocyano group, a cyanate group, an amidino group, a diazo group, a mercapto group or a sulfo group, and one carbon atom, or two or more non-adjacent carbon atoms, in said alkyl group, aryl group, aralkyl group, heteroaryl group and heteroarylalkyl group may be substituted, alone or together with the hydrogen atom bonded to said carbon atom, with an oxygen atom, a sulfur atom, a nitrogen atom, a carbonyl group, a carbonyloxy group, an oxycarbonyl group, a group represented by the general formula -C(=O)-N(-R 91 )-, or a group represented by the general formula -N(-R 91 )-C(=O)-; R 91 is a hydrogen atom or an alkyl group.) The catalyst according to [1] or [2], which is a compound represented by [4] The catalyst is represented by the following general formula (2)

[0011]

Chemical Formula

[0012] [ka] (In the formula, R 211 , R 221 and R 212 Each is independently a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, however, R 211 and R 221At least one of the elements is the alkyl group, and one or more hydrogen atoms in the alkyl group may be substituted with a halogen atom or a hydroxyl group, and one or more non-adjacent carbon atoms in the alkyl group may, alone or together with a hydrogen atom bonded to the carbon atom, be an oxygen atom, a sulfur atom, a nitrogen atom, a carbonyl group, a carbonyloxy group, an oxycarbonyl group, or a group of the general formula -C(=O)-N(-R 921 A group represented by -, or the general formula -N(-R 921 It may also be substituted with a group represented by )-C(=O)-; R 921 is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms; R 241 , R 251 and R 252 Each of these is independently a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, an alkoxycarbonyl group having 2 to 11 carbon atoms, an aryloxycarbonyl group having 7 to 13 carbon atoms, or an aralkyloxycarbonyl group having 8 to 14 carbon atoms; R 242 These are halogen atoms, hydroxyl groups, carboxyl groups, alkoxycarbonyl groups having 2 to 11 carbon atoms, aryloxycarbonyl groups having 7 to 13 carbon atoms, or aralkyloxycarbonyl groups having 8 to 14 carbon atoms; n 21 n is an integer between 0 and 5. 21 If n is 2 or greater, 21 Individual R 251 They may be the same or different from each other; n 22 and n 23 Each of these is an independent integer between 0 and 2, where n 22 +n 23 The ranges from 1 to 4; n 24 n is an integer between 0 and 3. 24 If n is 2 or 3, 24 Individual R 252 They may be the same or different from each other; n 25 n is an integer between 0 and 6. 25 If n is 2 or greater, 25 Individual R242 They may be the same or different from each other; R 231 and R 232 (These are a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 13 carbon atoms.) The catalyst described in [4] is a compound represented by [4]. [Effects of the Invention]

[0013] The present invention provides a novel catalyst for use in the reaction between leucoquinizalins and aldehydes. [Brief explanation of the drawing]

[0014] [Figure 1] These are imaging data obtained by STEM-EDS for the precious metal solid catalyst obtained in Manufacturing Example 1. [Figure 2] This graph shows the change in the yield of the compound in Example 10 over time. [Modes for carrying out the invention]

[0015] In this specification, the unit of concentration "M" means "mol / L".

[0016] ◎Catalyst A catalyst according to one embodiment of the present invention (which may be referred to as "catalyst (b1)" herein) is a catalyst for use in the reaction of a leucoquinizarin or a derivative thereof with an aldehyde, The catalyst comprises a compound (sometimes referred to as "compound (b10)" herein) having both a secondary or tertiary amino group and a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aralkyloxycarbonyl group.

[0017] In this specification, "secondary amino group" means a monovalent group having a structure in which only one of the two hydrogen atoms (one hydrogen atom) in the amino group (-NH2) is replaced by a group other than a hydrogen atom. Similarly, a "tertiary amino group" refers to a monovalent group in which both hydrogen atoms in the amino group are replaced by a group other than a hydrogen atom.

[0018] By reacting leucoquinizalins with an aldehyde using the catalyst (b1), a quinizalin derivative having a structure in which a group derived from the aldehyde is introduced to the carbon atom at position 2 or 3 of the quinizalin is obtained. This reaction is classified as a Marschalk reaction, and seemingly, the hydrogen atom in the ring containing the carbonyl group among the three fused rings in the leucoquinizalin is replaced by the group derived from the aldehyde. At this time, the reaction between the leucoquinizalins and the aldehyde is accelerated by the catalyst (b1), which further reduces the amount of residual leucoquinizalins (the starting material) and further increases the amount of the quinizalin derivative (the product). The resulting quinizalin derivatives may be useful as raw materials or intermediates for pigments, dyes, bioactive substances, pharmaceuticals, or redox flow battery materials.

[0019] In this specification, unless otherwise specified, when a particular compound is assumed to have a structure in which one or more hydrogen atoms are substituted with groups other than hydrogen atoms, a compound having such a substituted structure will be referred to as a "derivative" of the particular compound described above. In this specification, unless otherwise specified, the term "group" includes not only atomic groups formed by the bonding of multiple atoms, but also single atoms.

[0020] <<Compound (b10)>> The compound (b10) has both a secondary amino group or a tertiary amino group and a carboxyl group (-C(=O)-OH), an alkoxycarbonyl group, an aryloxycarbonyl group, or an aralkyloxycarbonyl group. Compound (b10) has either a secondary amino group or a tertiary amino group, or both, in one molecule, and the total number of secondary and tertiary amino groups is 1 or 2 or more. In particular, it is preferable that the total number is 1, that is, that compound (b10) has only one secondary amino group or one tertiary amino group in one molecule. Compound (b10) has one or more groups selected from the group consisting of carboxyl groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and aralkyloxycarbonyl groups in one molecule, and the total number of carboxyl groups, alkoxycarbonyl groups, aryloxycarbonyl groups, and aralkyloxycarbonyl groups is 1 or 2 or more. In particular, it is preferable that the total number is 1, that is, that compound (b10) has only one carboxyl group, alkoxycarbonyl group, aryloxycarbonyl group, or aralkyloxycarbonyl group in one molecule.

[0021] More specifically, as compound (b10), for example, a compound having both a secondary amino group and a carboxyl group, a compound having both a secondary amino group and an alkoxycarbonyl group, a compound having both a secondary amino group and an aryloxycarbonyl group, a compound having both a secondary amino group and an aralkyloxycarbonyl group, Examples include compounds having both a tertiary amino group and a carboxyl group, compounds having both a tertiary amino group and an alkoxycarbonyl group, compounds having both a tertiary amino group and an aryloxycarbonyl group, and compounds having both a tertiary amino group and an aralkyloxycarbonyl group.

[0022] In the alkoxycarbonyl group of compound (b10), the alkyl group bonded to the oxygen atom in the oxycarbonyl group (-C(=O)-O-) may be linear, branched, or cyclic, and may have both a linear structure (linear or branched) and a cyclic structure. In the case where the alkyl group is cyclic, the cyclic structure may be monocyclic or polycyclic. The number of carbon atoms in the alkyl group is preferably 1 to 30, and more preferably 1 to 20.

[0023] The number of carbon atoms in the linear or branched (i.e., linear) alkyl group in the alkoxycarbonyl group is preferably 1 to 20. Examples of such chain-like alkyl groups include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, n-hexyl group, 2-methylpentyl group, 3-methylpentyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, and 3-methyl Examples include hexyl group, 2,2-dimethylpentyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 3,3-dimethylpentyl group, 3-ethylpentyl group, 2,2,3-trimethylbutyl group, n-octyl group, isooctyl group, 2-ethylhexyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, and eicosyl group. The number of carbon atoms in the chain-like alkyl group is more preferably 1 to 10, and may be any of 1 to 8, 1 to 6, or 1 to 4.

[0024] The number of carbon atoms in the cyclic alkyl group (cycloalkyl group) or other alkyl group having a cyclic structure in the alkoxycarbonyl group is preferably 3 to 20. Examples of such cyclic alkyl groups include monocyclic or polycyclic alkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group, cyclodecyl group, norbornyl group, isobornyl group, 1-adamantyl group, 2-adamantyl group, tricyclodecyl group, decahydro-1-naphthyl group, and decahydro-2-naphthyl group. Examples of alkyl groups having both a linear and a cyclic structure include monovalent groups having a structure in which one or more hydrogen atoms (-H) in the linear or branched alkyl group are substituted with the cyclic alkyl group. The number of carbon atoms in the alkyl group having the cyclic structure is more preferably 3 to 10, and may be any of 3 to 5, 5 to 7, or 7 to 10.

[0025] In the aryloxycarbonyl group of compound (b10), the aryl group bonded to the oxygen atom in the oxycarbonyl group may be monocyclic or polycyclic. The number of carbon atoms in the aryl group is preferably 6 to 22.

[0026] Examples of aryl groups in the aforementioned aryloxycarbonyl group include phenyl group, 1-naphthyl group, 2-naphthyl group, 4-methylphenyl group (p-tolyl group), 3-methylphenyl group (m-tolyl group), 2-methylphenyl group (o-tolyl group), 2,3-dimethylphenyl group (2,3-xylyl group), 2,4-dimethylphenyl group (2,4-xylyl group), 2,5-dimethylphenyl group (2,5-xylyl group), 2,6-dimethylphenyl group (2,6-xylyl group), 3,4-dimethylphenyl group (3,4-xylyl group), 3,5-dimethylphenyl group (3,5-xylyl group), 2,4,6-trimethylphenyl group (mesityl group), 4-ethylphenyl group, 3-ethylphenyl group, 2-ethylphenyl group, indenyl group, phenantrenyl group, pyrenyl group, and the like. The aryl group in the aryloxycarbonyl group may also be a monovalent group having a structure in which one or more hydrogen atoms in the aforementioned aryl group are further substituted with the alkyl group or aryl group.

[0027] The number of carbon atoms in the aryl group in the aryloxycarbonyl group is more preferably 6 to 18, and may be any of 6 to 14, 6 to 12, or 6 to 8. Particularly preferred aryl groups include, for example, phenyl groups.

[0028] In the aralkyloxycarbonyl group of compound (b10), the aralkyl group bonded to the oxygen atom in the oxycarbonyl group is a monovalent group having a structure in which one hydrogen atom bonded to the carbon atom in the alkyl group is substituted with the aryl group. The aromatic ring in the aralkyl group may be monocyclic or polycyclic. The number of carbon atoms in the aralkyl group is preferably 7 to 23.

[0029] The number of carbon atoms in the aralkyloxycarbonyl group is more preferably 7 to 19, and may be any of 7 to 15, 7 to 13, and 7 to 9. Preferred aralkyl groups include, for example, benzyl group (phenylmethyl group), phenethyl group (2-phenylethyl group), 3-phenylpropyl group, 4-phenylbutyl group, 1-naphthylmethyl group, and 2-naphthylmethyl group. Particularly preferred aralkyl groups include, for example, benzyl groups.

[0030] The catalyst (b1) is based on the following general formula (2)

[0031] [ka] (In the formula, X 1 is an alkylene group, and one or more hydrogen atoms in the alkylene group may be substituted with halogen atoms, hydroxyl groups, carboxyl groups, alkoxycarbonyl groups, aryloxycarbonyl groups, or aralkyloxycarbonyl groups; R 21 and R 22 Each is independently a hydrogen atom or an alkyl group, however, R 21 and R 22At least one of the elements is the alkyl group, and one or more hydrogen atoms in the alkyl group may be substituted with a halogen atom or a hydroxyl group, and one or more non-adjacent carbon atoms in the alkyl group may, alone or together with a hydrogen atom bonded to the carbon atom, be an oxygen atom, a sulfur atom, a nitrogen atom, a carbonyl group, a carbonyloxy group, an oxycarbonyl group, or a group of the general formula -C(=O)-N(-R 92 A group represented by -, or the general formula -N(-R 92 It may also be substituted with a group represented by )-C(=O)-; R 92 is a hydrogen atom or an alkyl group; R 21 and R 22 If R is the alkyl group, 21 and R 22 They may be bonded to each other to form a ring; X 1 And the alkyl group R 21 or R 22 These elements may be joined to each other to form a ring; R 23 (This is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group.) Preferably, the compound consists of the compound represented by (which may be referred to as "compound (2)" in this specification). In other words, compound (b10) is preferably compound (2).

[0032] In the general formula (2), X 1 This is an alkylene group. The aforementioned X 1 The alkylene group in this context refers to a divalent group having a structure in which one hydrogen atom is removed from the alkyl group mentioned above as being bonded to the oxygen atom in the alkoxycarbonyl group. More specifically, it is as follows:

[0033] X 1The alkylene group in may be linear, branched, or cyclic, and may have both a linear structure (linear or branched) and a cyclic structure. In the case where the alkylene group is cyclic, the cyclic structure may be monocyclic or polycyclic. The number of carbon atoms in the alkylene group is preferably 1 to 30, and more preferably 1 to 20.

[0034] The linear or branched alkylene group preferably has 1 to 10 carbon atoms, and may be any of 1 to 8, 1 to 6, 1 to 4, 1 to 3, or 1 to 2 carbon atoms. Examples of such chain-like alkylene groups include methylene group, ethylene group, propylene group (methylethylene group), trimethylene group, tetramethylene group, 1-methyltrimethylene group, 2-methyltrimethylene group, 1,2-dimethylethylene group, 1,1-dimethylethylene group, ethylethylene group, pentamethylene group, 1-methyltetramethylene group, 2-methyltetramethylene group, 1,1-dimethyltrimethylene group, 1,2-dimethyltrimethylene group, 1,3-dimethyltrimethylene group, 1-ethyltrimethylene group, 2-ethyltrimethylene group, 1-methyl-2-ethylethylene group, n-propylethylene group, hexamethylene group, 1-methylpentamethylene group, 2-methylpentamethylene group, and 3-methyl Examples include pentamethylene group, 1,1-dimethyltetramethylene group, 1,2-dimethyltetramethylene group, 1,3-dimethyltetramethylene group, 1,4-dimethyltetramethylene group, 2,3-dimethyltetramethylene group, 2,2-dimethyltetramethylene group, 1-ethyltetramethylene group, 2-ethyltetramethylene group, 1-methyl-2-ethyltrimethylene group, 1-methyl-3-ethyltrimethylene group, 2-methyl-3-ethyltrimethylene group, 1-methyl-1-ethyltrimethylene group, 2-methyl-2-ethyltrimethylene group, 1,2,3-trimethyltrimethylene group, 1,1,2,2-tetramethylethylene group, heptamethylene group, octamethylene group, nonamethylene group, decamethylene group, etc.

[0035] The number of carbon atoms in the alkylene group having a cyclic structure, such as the cyclic alkylene group (cycloalkylene group), is preferably 3 to 20, more preferably 3 to 10, and may be any of 3 to 5, 5 to 7, or 7 to 10. Examples of such cyclic alkylene groups include monocyclic or polycyclic alkylene groups such as cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, cyclooctylene, cyclononylene, cyclodecylen, and decahydronaphthalenediyl. Alkylene groups having both a linear and a cyclic structure include divalent groups having a structure in which one or more hydrogen atoms (-H) in the linear or branched alkylene group described above are substituted with a cyclic alkyl group. Here, the cyclic alkyl group is the same as the cyclic alkyl group mentioned above that is bonded to the oxygen atom in the alkoxycarbonyl group.

[0036] X 1 In the alkylene group, one or more hydrogen atoms may or may not be substituted with a halogen atom, a hydroxyl group, a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aralkyloxycarbonyl group. X 1 Examples of halogen atoms as substituents in this compound include fluorine atoms, chlorine atoms, bromine atoms, iodine atoms, and the like. X 1 Examples of substituents in the compound (b10) include the same alkoxycarbonyl group, aryloxycarbonyl group, and aralkyloxycarbonyl group as described above.

[0037] In the above general formula (2), R 21 and R 22 Each of these is independently either a hydrogen atom or an alkyl group. The aforementioned R 21 and R22 Examples of the alkyl group in the above include the same alkyl groups as those exemplified as being bonded to an oxygen atom in the alkoxycarbonyl group described above.

[0038] Provided that R 21 and R 22 at least one of which is the alkyl group. That is, R 21 and R 22 examples of combinations include a combination of a hydrogen atom and an alkyl group, a combination of an alkyl group and a hydrogen atom, and a combination of two or more alkyl groups.

[0039] R 21 and R 22 one or two or more hydrogen atoms in the alkyl group may or may not be substituted with a halogen atom or a hydroxyl group (-OH). R 21 and R 22 examples of the halogen atom as a substituent in the above include those the same as the halogen atom as a substituent in X 1 described above. The substitution position of the hydrogen atom in the alkyl group is not particularly limited. The number of substituted hydrogen atoms in the alkyl group is preferably 1 to 3.

[0040] R 21 and R 22 one carbon atom, or two or more non-adjacent carbon atoms in the alkyl group, may be, alone or together with hydrogen atoms bonded to said carbon atoms, replaced by an oxygen atom (-O-), a sulfur atom (-S-), a nitrogen atom (-N=, (-N(-)-)), a carbonyl group (-C(=O)-), a carbonyloxy group (-C(=O)-O-), an oxycarbonyl group (-O-C(=O)-), a group represented by general formula -C(=O)-N(-R 92 )-, or a group represented by general formula -N(-R 92 )-C(=O)-, or may not be substituted. As used herein, the expression that a carbon atom is substituted with a substituent together with the hydrogen atom bonded thereto includes, for example, an embodiment in which a methylene group (-CH2-) or a methine group (-CH(-)-) is substituted with a substituent. The substitution positions of carbon atoms in the alkyl group are not particularly limited, as long as they are not adjacent carbon atoms to each other. The number of substituted carbon atoms in the alkyl group is preferably 1 to 3.

[0041] In the general formula above, R 92 is a hydrogen atom or an alkyl group. For the aforementioned R 92 examples of the alkyl group include the same alkyl groups as those exemplified as being bonded to the oxygen atom in the alkoxycarbonyl group described above.

[0042] When R 21 and R 22 are the aforementioned alkyl groups, R 21 and R 22 may be bonded to each other to form a ring together with the nitrogen atom to which they are bonded.

[0043] As used herein, the expression that alkyl groups are bonded to each other to form a ring means that hydrogen atoms in these alkyl groups are removed, and the carbon atoms from which the hydrogen atoms have been removed are bonded to each other, thereby newly forming a ring structure together with the group to which these alkyl groups are bonded (in the case of R 21 and R 22 , a nitrogen atom). Bonding between these alkyl groups may occur at one site, or may occur at two or more sites. When bonding between alkyl groups occurs at one site, the formed ring is a monocyclic ring; when bonding between alkyl groups occurs at two sites, the formed ring is a bicyclic ring.

[0044] When the alkyl groups in R 21 and R 22 form a ring, bonding between the alkyl groups preferably occurs at one site or two sites. The bonding positions of these alkyl groups are not particularly limited. The number of ring members (the number of atoms forming the ring skeleton) of the ring formed by the bonding of these alkyl groups is preferably 5 to 8, and may be any of 5 to 6, 6 to 7, or 7 to 8.

[0045] X 1 And the alkyl group R 21 or R 22 These elements may be bonded to each other, forming a ring together with the nitrogen atom to which they are bonded. X 1 (Alkylene group) and R 21 or R 22 When the alkyl group and the alkyl group form a ring, the bond between the alkylene group and the alkyl group may occur at one location or at two or more locations, and it is preferable that the bond occurs at one or two locations. The bonding positions of these alkylene groups and alkyl groups are not particularly limited. The number of ring members (the number of atoms forming the ring skeleton) of the ring formed by the bonding of these alkylene groups and alkyl groups is preferably 5 to 8, and may be any of 5 to 6, 6 to 7, and 7 to 8.

[0046] In the above general formula (2), R 23 This is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group. R 23 The alkyl group in this context is the same as the alkyl group mentioned above as being bonded to the oxygen atom in the alkoxycarbonyl group. R 23 The aryl group in this context is the same as the aryl group mentioned above as being bonded to the oxygen atom in the aryloxycarbonyl group. R 23 The aralkyl group in this context is the same as the aralkyl group mentioned above as being bonded to the oxygen atom in the aralkyloxycarbonyl group.

[0047] A preferred compound (2) is, for example, X 1 However, the alkylene group is a chain-like (linear or branched) alkylene group having 1 to 10 carbon atoms, and one or more hydrogen atoms in the alkylene group may be substituted with halogen atoms, hydroxyl groups, carboxyl groups, alkoxycarbonyl groups, aryloxycarbonyl groups, or aralkyloxycarbonyl groups. R 21 and R 22 However, each is independently a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, provided that R 21 and R 22 At least one of the elements is the alkyl group, and one or more hydrogen atoms in the alkyl group may be substituted with a halogen atom or a hydroxyl group, and one or more non-adjacent carbon atoms in the alkyl group may, alone or together with a hydrogen atom bonded to the carbon atom, be an oxygen atom, a sulfur atom, a nitrogen atom, a carbonyl group, a carbonyloxy group, an oxycarbonyl group, or a group of the general formula -C(=O)-N(-R 92 A group represented by -, or the general formula -N(-R 92 The group may be substituted with a group represented by )-C(=O)-, R 92 is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, R 21 and R 22 If R is the alkyl group, 21 and R 22 They may be bonded to each other to form a ring with 5 to 8 members. X 1 And the alkyl group R 21 or R 22 These elements may be bonded to each other to form a ring with 5 to 8 members. R 23 However, compound (2) is a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 13 carbon atoms.

[0048] The aforementioned compound (2) is the following general formula (21) or (22)

[0049] [ka] (In the formula, R 211 , R 221 and R 212 Each is independently a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, however, R 211 and R 221 At least one of the elements is the alkyl group, and one or more hydrogen atoms in the alkyl group may be substituted with a halogen atom or a hydroxyl group, and one or more non-adjacent carbon atoms in the alkyl group may, alone or together with a hydrogen atom bonded to the carbon atom, be an oxygen atom, a sulfur atom, a nitrogen atom, a carbonyl group, a carbonyloxy group, an oxycarbonyl group, or a group of the general formula -C(=O)-N(-R 921 A group represented by -, or the general formula -N(-R 921 It may also be substituted with a group represented by )-C(=O)-; R 921 is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms; R 241 , R 251 and R 252 Each of these is independently a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, an alkoxycarbonyl group having 2 to 11 carbon atoms, an aryloxycarbonyl group having 7 to 13 carbon atoms, or an aralkyloxycarbonyl group having 8 to 14 carbon atoms; R 242 These are halogen atoms, hydroxyl groups, carboxyl groups, alkoxycarbonyl groups having 2 to 11 carbon atoms, aryloxycarbonyl groups having 7 to 13 carbon atoms, or aralkyloxycarbonyl groups having 8 to 14 carbon atoms; n 21 n is an integer between 0 and 5. 21 If n is 2 or greater, 21 Individual R 251 They may be the same or different from each other; n 22 and n 23 Each of these is an independent integer between 0 and 2, where n 22 +n 23 The ranges from 1 to 4; n24 n is an integer between 0 and 3. 24 If n is 2 or 3, 24 Individual R 252 They may be the same or different from each other; n 25 n is an integer between 0 and 6. 25 If n is 2 or greater, 25 Individual R 242 They may be the same or different from each other; R 231 and R 232 (These are a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 13 carbon atoms.) It is preferable that the compounds are represented by (which may be referred to as "compound (21)" and "compound (22)" respectively in this specification). In other words, the catalyst (b1) is preferably composed of compound (21) or compound (22). Compound (21) is X 1 And the alkyl group R 21 or R 22 (2) is a compound that does not have a nitrogen-containing ring and in which these compounds are not involved in the bonding between them. Compound (22) is X 1 And the alkyl group R 22 The two elements are bonded to each other to form a ring, resulting in a compound (2) having a nitrogen-containing ring.

[0050] In the above general formula (21), R 211 and R 221 , and R in the general formula (22) 212 Each of these is independently either a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. The aforementioned R 211 , R 221 and R 212 The alkyl group in R is limited to having 1 to 10 carbon atoms. 21 and R 22 This is the same as the alkyl group in the above example.

[0051] However, R 211 and R221 At least one of them is the alkyl group. That is, R 211 and R 221 Examples of combinations include combinations of a hydrogen atom and the alkyl group, combinations of the alkyl group and a hydrogen atom, and combinations of the alkyl groups themselves.

[0052] R 211 , R 221 and R 212 In the alkyl group, one or more hydrogen atoms may be substituted with a halogen atom or a hydroxyl group, or they may not be substituted. R 211 , R 221 and R 212 The halogen atom as a substituent in is the above-mentioned X 1 Examples of substituents similar to the halogen atoms mentioned above include those found in the above-mentioned example. The substitution position of the hydrogen atom in the alkyl group is not particularly limited. The number of hydrogen atoms substituted in the alkyl group is preferably 1 to 3.

[0053] R 211 , R 221 and R 212 In the alkyl group, one or more non-adjacent carbon atoms, either alone or together with a hydrogen atom bonded to the carbon atom, may be oxygen atoms, sulfur atoms, nitrogen atoms, carbonyl groups, carbonyloxy groups, oxycarbonyl groups, or groups of the general formula -C(=O)-N(-R 921 A group represented by -, or the general formula -N(-R 921 It may or may not be substituted with a group represented by )-C(=O)-. The substitution positions of carbon atoms in the alkyl group are not particularly limited, as long as they are not adjacent carbon atoms. The number of carbon atoms substituted in the alkyl group is preferably 1 or 2.

[0054] In the above general formula, R 921 This is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms. The aforementioned R 921 The alkyl group in R is limited to having 1 to 10 carbon atoms. 92 This is the same as the alkyl group in the above example.

[0055] In the above general formula (21), R 241 and R 251 , and R in the general formula (22) 252 These are, independently, a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, an alkoxycarbonyl group having 2 to 11 carbon atoms, an aryloxycarbonyl group having 7 to 13 carbon atoms, or an aralkyloxycarbonyl group having 8 to 14 carbon atoms. R in the general formula (22) 242 These are halogen atoms, hydroxyl groups, carboxyl groups, alkoxycarbonyl groups having 2 to 11 carbon atoms, aryloxycarbonyl groups having 7 to 13 carbon atoms, or aralkyloxycarbonyl groups having 8 to 14 carbon atoms. The aforementioned R 241 , R 251 , R 242 and R 252 In the above, the alkoxycarbonyl group having 2 to 11 carbon atoms, the aryloxycarbonyl group having 7 to 13 carbon atoms, and the aralkyloxycarbonyl group having 8 to 14 carbon atoms are, respectively, limited in the number of carbon atoms as described above. 1 The substituents in are the same as the alkoxycarbonyl group, aryloxycarbonyl group, and aralkyloxycarbonyl group.

[0056] n in the general formula (21) 21 n is an integer between 0 and 5, preferably between 0 and 4, more preferably between 0 and 3, even more preferably between 0 and 2, and particularly preferably 0 or 1. 21 This range allows the catalytic activity of catalyst (b1) to be higher. n 21 If n is 2 or greater (2 to 5), 21 Individual R 251 They may be the same or different from each other. That is, n 21 Individual R 251They may all be the same, they may all be different, or they may be partially the same.

[0057] n in the general formula (22) 22 and n 23 These are each an independent integer between 0 and 2. That is, n 22 and n 23 They may be the same or different from one another. However, n 22 +n 23 n is 1 to 4, 22 and n 23 It is impossible for both to be 0 at the same time. That is, n 22 A methylene group with a label attached, and n 23 The nitrogen-containing rings that include the methylene group are 5-membered, 6-membered, 7-membered, or 8-membered rings. n 22 It is preferable that n is 1 or 2. 22 This range allows the catalytic activity of catalyst (b1) to be higher. n 23 n is preferably 0 or 1. 23 This range allows the catalytic activity of catalyst (b1) to be higher. n 22 +n 23 It is preferably 1 to 3, and more preferably 1 or 2. 22 +n 23 This range allows the catalytic activity of catalyst (b1) to be higher.

[0058] In the above general formula (22), n 24 x is an integer between 0 and 3, and may be, for example, 0 to 2, 0 or 1, 1 to 3, 2 or 3, or 1 or 2. n 24 If n is 2 or 3, 24 Individual R 252 They may be the same or different from each other. That is, n 24 Individual R 252 They may all be the same, they may all be different, or they may be partially the same.

[0059] n 22 +n 24 n is between 0 and 5, preferably between 0 and 4, more preferably between 0 and 3, even more preferably between 0 and 2, and particularly preferably between 1 or 2. 22 +n 24 This range allows the catalytic activity of catalyst (b1) to be higher.

[0060] In the above general formula (22), n 25 n is an integer between 0 and 6. 25 If R is between 1 and 6, 242 The bonding position is not particularly limited. For example, R 242 is, n 22 or n 23 It may be bonded to a carbon atom that has been marked (n 22 or n 23 (The hydrogen atoms in the methylene group to which the label is attached may be substituted.) 22 and n 23 It may be bonded to a carbon atom that does not have a label attached (n 22 and n 23 (The hydrogen atoms in the methylene group that are not marked may be substituted.) For example, n 25 If it is 2 or more, then 2 R 242 The two atoms may be bonded to the same carbon atom (they may both be substituted for the two hydrogen atoms in the same methylene group). In terms of the ease of manufacturing or obtaining compound (22), n 25 It is preferably 0 to 4, more preferably 0 to 2, and even more preferably 0 or 1. n 25 If n is 2 or greater (2 to 6), 25 Individual R 242 They may be the same or different from each other. That is, n 25 Individual R 242 They may all be the same, they may all be different, or they may be partially the same.

[0061] In the above general formula (21), R 231 , and R in the general formula (22) 232 These are a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 13 carbon atoms. The aforementioned R 231 and R 232 The alkyl groups with 1 to 10 carbon atoms, the aryl groups with 6 to 12 carbon atoms, and the aralkyl groups with 7 to 13 carbon atoms in each of these are, except that the number of carbon atoms is limited as described above, R 23 These are the same as alkyl, aryl, and aralkyl groups in [the relevant context]. In terms of increasing the catalytic activity of catalyst (b1), R 231 and R 232 It is preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and more preferably a hydrogen atom, a methyl group, or an ethyl group.

[0062] Among the compounds (2), preferred compound (21) is, for example, the R 211 and R 221 However, each is independently a hydrogen atom, a chain-like alkyl group having 1 to 4 carbon atoms, or an alkyl group having a cyclic structure with 5 to 7 carbon atoms, provided that R 211 and R 221 At least one of the members is the linear alkyl group or the alkyl group having a cyclic structure, and one or more hydrogen atoms in the linear alkyl group or the alkyl group having a cyclic structure may be substituted with halogen atoms or hydroxyl groups; The aforementioned R 241 and R 251 However, each is independently a hydrogen atom, a halogen atom, or a hydroxyl group; The aforementioned n 21 n is an integer between 0 and 2, and 21 If n is 2, 21 Individual R 251 They may be the same or different from each other; The aforementioned R 231However, examples of compounds (21) include a hydrogen atom, a chain-like alkyl group having 1 to 4 carbon atoms, a cyclic alkyl group having 5 to 7 carbon atoms, an aryl group having 6 to 8 carbon atoms, or an aralkyl group having 7 to 9 carbon atoms.

[0063] Among the compounds (2), a more preferred compound (21) is, for example, the R 211 and R 221 However, each is independently a hydrogen atom or a chain-like alkyl group having 1 to 4 carbon atoms, where R 211 and R 221 At least one of the members is the linear alkyl group, and one or more hydrogen atoms in the linear alkyl group may be substituted with halogen atoms or hydroxyl groups; The aforementioned R 241 and R 251 is a hydrogen atom; The aforementioned n 21 is 0 or 1; The aforementioned R 231 However, examples of compounds (21) include those which are hydrogen atoms or chain-like alkyl groups having 1 to 4 carbon atoms.

[0064] Among the compounds (2), preferred compounds (22) include, for example, the R 212 However, it is a hydrogen atom, a chain-like alkyl group having 1 to 4 carbon atoms, or an alkyl group having a cyclic structure with 5 to 7 carbon atoms; The aforementioned R 242 However, it is a halogen atom or a hydroxyl group; The aforementioned R 252 but is a hydrogen atom, a halogen atom, or a hydroxyl group; The aforementioned n 22 and n 23 However, each is an integer between 0 and 2, where n 22 +n 23 is 1 or 2; The aforementioned n 24 and n 25 However, each is independently either 0 or 1; The aforementioned R 232is a hydrogen atom, a chain alkyl group having 1 to 4 carbon atoms, an alkyl group having a cyclic structure with 5 to 7 carbon atoms, an aryl group having 6 to 8 carbon atoms, or an aralkyl group having 7 to 9 carbon atoms, and examples include the compound (22).

[0065] Among compounds (2), more preferred compounds (22) include, for example, the above R 212 is a hydrogen atom or a chain alkyl group having 1 to 4 carbon atoms; the above R 242 is a halogen atom or a hydroxyl group; the above R 252 is a hydrogen atom; the above n 22 and n 23 are each independently an integer of 0 to 2, provided that n 22 +n 23 is 1 or 2; the above n 24 and n 25 are each independently 0 or 1; the above R 232 is a hydrogen atom or a chain alkyl group having 1 to 4 carbon atoms, and examples include the compound (22).

[0066] More specific examples of preferred compound (2) include the compound (2) shown below, and compounds in which one or more hydrogen atoms in these compounds (2) are substituted with a halogen atom or a hydroxyl group. However, preferred compound (2) is not limited thereto.

[0067]

Chemical Formula

[0068]

Chemical Formula

[0069]

Chemical Formula

[0070]

Chem.

[0071]

Chem.

[0072]

Chem.

[0073]

Chem.

[0074]

Chem.

[0075] <<Method for producing compound (b10)>> As compound (b10), a commercially available product may be used, or a product produced by a known method may be used. The method for producing compound (b10) can be appropriately selected according to the structure of compound (b10), and is not particularly limited. For example, the target compound (b10) can be produced by using, as a raw material, an amino acid, an amino group-modified amino acid having a structure in which the amino group (-NH2) in the amino acid is substituted with a secondary amino group or a tertiary amino group, or a carboxy group-modified amino acid having a structure in which the carboxy group (-C(=O)-OH) in the amino acid is substituted with an alkoxycarbonyl group, an aryloxycarbonyl group or an aralkyloxycarbonyl group, and performing a known reaction on the raw material. For example, the target compound (b10) can be produced by using, as a raw material, a compound having no secondary amino group or tertiary amino group, introducing a secondary amino group or a tertiary amino group into the raw material, or after introducing an amino group (-NH2), substituting one or two hydrogen atoms in the amino group with a group other than a hydrogen atom. For example, the target compound (b10) can be produced by using a compound that does not have a carboxyl group, alkoxycarbonyl group, aryloxycarbonyl group, or aralkyloxycarbonyl group as a starting material, and then introducing a carboxyl group to it, or by introducing a carboxyl group and then esterifying the carboxyl group to convert it into an alkoxycarbonyl group, aryloxycarbonyl group, or aralkyloxycarbonyl group. For example, by using a compound having a secondary amino group and a tertiary amino group, and a compound having a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aralkyloxycarbonyl group as raw materials, and reacting these raw materials with each other, the target compound (b10) can be produced.

[0076] <<Leucoquinizarin or its derivatives (leucoquinizarins)>> Among the leucoquinizalins to which catalyst (b1) is applicable, the leucoquinizalin derivative is not particularly limited as long as it has a structure in which one or more hydrogen atoms in the leucoquinizalin are replaced by groups (substituents) other than hydrogen atoms. Preferred leucoquinizalin derivatives include, for example, those in which, among the three fused rings in leucoquinizalin, only one of the four hydrogen atoms bonded to the carbon dioxide adjacent to the carbonyl group in the ring containing the carbonyl group is substituted with a substituent.

[0077] Leucoquinizarin or its derivatives (leucoquinizarins) are defined by the following general formula (11)

[0078] [ka] (In the formula, R 11 and R 12 Each is independently a hydrogen atom or a monovalent organic group, however, R 11 and R 12 At least one of them is a hydrogen atom. It is preferable that the compound represented by (sometimes referred to as "compound (11)" in this specification) is used. Compound (11) provides a particularly good effect in promoting the reaction with aldehyde by catalyst (b1).

[0079] In the above general formula (11), R 11 and R 12 Each is independently a hydrogen atom or a monovalent organic group, however, R 11 and R 12 At least one of them is a hydrogen atom. That is, compound (11) is a compound represented by any of the following general formulas (11A), (11B), and (11)-101.

[0080] [ka] (In the formula, R 11a and R 12a (Each of these is independently the aforementioned organic group.)

[0081] The aforementioned R 11 , R 12 , R 11a and R 12a Examples of the monovalent organic group in this context include monovalent aliphatic hydrocarbon groups and aromatic hydrocarbon ring-containing hydrocarbon groups, which may have substituents. The aliphatic hydrocarbon group is a hydrocarbon group that does not have an aromatic hydrocarbon ring. More specifically, the aliphatic hydrocarbon group can be a monovalent saturated aliphatic hydrocarbon group (in other words, an alkyl group) or a monovalent unsaturated aliphatic hydrocarbon group. The aromatic hydrocarbon ring-containing hydrocarbon group is a hydrocarbon group having at least an aromatic hydrocarbon ring, and the carbon atoms having free valence may be present in the aromatic hydrocarbon ring skeleton or in the aliphatic hydrocarbon chain. More specifically, the aromatic hydrocarbon ring-containing hydrocarbon group includes a monovalent aromatic hydrocarbon group (in other words, an aryl group), a monovalent group having a structure in which one hydrogen atom in a monovalent saturated aliphatic hydrocarbon group is substituted with the monovalent aromatic hydrocarbon group (in other words, an aralkyl group), and a monovalent aromatic hydrocarbon ring-containing hydrocarbon group that does not fall under either an aryl group or an aralkyl group (which may be referred to as "aromatic hydrocarbon ring-containing hydrocarbon group (a1)" in this specification). In this specification, the term "aromatic hydrocarbon ring-containing hydrocarbon group" without "(a1)" refers to a concept that encompasses not only "aromatic hydrocarbon ring-containing hydrocarbon group (a1)" but also aryl groups and aralkyl groups.

[0082] R 11 , R 12 , R 11a and R 12a Among the monovalent aliphatic hydrocarbon groups in the above, saturated aliphatic hydrocarbon groups (alkyl groups) include the same alkyl groups as those listed above as being bonded to the oxygen atom in the alkoxycarbonyl group of compound (b10), and may be linear, branched, or cyclic, and may have both a linear structure (linear or branched structure) and a cyclic structure.

[0083] R 11 , R 12 , R 11a and R 12aAmong the monovalent aliphatic hydrocarbon groups in the above, unsaturated aliphatic hydrocarbon groups include, for example, monovalent groups having a structure in which one or more single bonds (CC) between carbon atoms in the alkyl group are replaced with double bonds (C=C) or triple bonds (C≡C), and one or two hydrogen atoms bonded to the carbon atoms are removed. The unsaturated aliphatic hydrocarbon group may be linear, branched, or cyclic, and may have both a linear structure (linear or branched structure) and a cyclic structure. The aforementioned unsaturated aliphatic hydrocarbon group may have only double bonds as unsaturated bonds, or only triple bonds, or both double and triple bonds. The number of unsaturated bonds in the aforementioned unsaturated aliphatic hydrocarbon group may be 1 or 2 or more. The position of the unsaturated bond in the unsaturated aliphatic hydrocarbon group is not particularly limited.

[0084] The aforementioned unsaturated aliphatic hydrocarbon group preferably has only double bonds or only triple bonds as unsaturated bonds, and the number of unsaturated bonds is 1 or 2. In other words, the unsaturated aliphatic hydrocarbon group is preferably an alkenyl group, an alkadienyl group (alkadienyl group), an alkynyl group, or an alkadinyl group (alkadiyneyl group).

[0085] The number of carbon atoms in the unsaturated aliphatic hydrocarbon group is preferably 2 to 30, more preferably 2 to 20, and more preferably 2 to 10, and may be any of 2 to 8, 2 to 6, and 2 to 4.

[0086] The number of carbon atoms in the alkenyl group is preferably 2 to 30, and more preferably 2 to 20. The number of carbon atoms in the linear or branched alkenyl group is preferably 2 to 20, more preferably 2 to 10, and may be any of 2 to 8, 2 to 6, or 2 to 4. Examples of such linear alkenyl groups include the ethenyl group (vinyl group), propenyl group (2-propenyl group (also known as allyl group), 1-methylethenyl group (also known as isopropenyl group), 2-methylethenyl group (also known as 1-propenyl group, isoallyl group)), butenyl group, pentenyl group, hexenyl group, heptenyl group, octenyl group, nonenyl group, decenyl group, and the like. The number of carbon atoms in the cyclic alkenyl group, such as the cyclic alkenyl group (cycloalkenyl group), is preferably 3 to 20, more preferably 4 to 10, and may be any of 4 to 8 and 4 to 6, for example. Examples of such cyclic alkenyl groups include monocyclic or polycyclic alkenyl groups such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, and cyclodecenyl groups. Examples of alkenyl groups having both chain-like and cyclic structures include those in which one or more hydrogen atoms in the above-mentioned linear or branched alkenyl group are R 11 , R 12 , R 11a and R 12a A monovalent group having a cyclic alkyl group substituted in the above structure; R 11 , R 12 , R 11a and R 12a Examples include monovalent groups having a structure in which one hydrogen atom in the alkyl group is substituted with the cyclic alkenyl group described above.

[0087] The number of carbon atoms in the alkynyl group is preferably 2 to 30, and more preferably 2 to 20. The number of carbon atoms in the linear or branched alkynyl group is preferably 2 to 20, more preferably 2 to 10, and may be any of 2 to 8, 2 to 6, or 2 to 4. Examples of such linear alkynyl groups include ethynyl group, propynyl group (1-propynyl group, 2-propynyl group (also known as propargyl group)), butynyl group, pentynyl group, hexynyl group, heptynyl group, octinyl group, noninyl group, decenyl group, etc. The number of carbon atoms in the cyclic alkynyl group, such as the cyclic alkynyl group (cycloalkynyl group), is preferably 8 to 20, more preferably 8 to 15, and may be, for example, 8 to 10. Examples of such cyclic alkynyl groups include monocyclic or polycyclic alkynyl groups such as cyclooctinyl, cyclononinyl, and cyclodecynyl groups. Examples of alkynyl groups having both chain-like and cyclic structures include those in which one or more hydrogen atoms in the above-mentioned linear or branched alkynyl group are R 11 , R 12 , R 11a and R 12a A monovalent group having a cyclic alkyl group substituted in the above structure; R 11 , R 12 , R 11a and R 12a Examples include monovalent groups having a structure in which one hydrogen atom in the alkyl group is substituted with the cyclic alkynyl group described above.

[0088] R 11 , R 12 , R 11a and R 12a Among the monovalent aromatic hydrocarbon ring-containing hydrocarbon groups in the above, the aryl group (monovalent aromatic hydrocarbon group) is the same as the aryl group listed above as being bonded to the oxygen atom in the aryloxycarbonyl group of compound (b10), and may be monocyclic or polycyclic.

[0089] R 11 , R 12, R 11a and R 12a Among the monovalent aromatic hydrocarbon ring-containing hydrocarbon groups in the above, the aralkyl group is the same as the aralkyl group listed above as being bonded to the oxygen atom in the aralkyloxycarbonyl group of compound (b10), and the aromatic hydrocarbon ring may be monocyclic or polycyclic.

[0090] R 11 , R 12 , R 11a and R 12a In the above monovalent aromatic hydrocarbon ring-containing hydrocarbon group, the aromatic hydrocarbon ring-containing hydrocarbon group (a1) is a monovalent group having a structure in which two or more hydrogen atoms in a monovalent saturated aliphatic hydrocarbon group are substituted with the aryl group (monovalent aromatic hydrocarbon group); one or more hydrogen atoms in the monovalent unsaturated aliphatic hydrocarbon group are R 11 , R 12 , R 11a and R 12a A monovalent group having the structure substituted with the aforementioned aryl group; R 11 , R 12 , R 11a and R 12a Examples include monovalent groups having a structure in which one or more hydrogen atoms in the aryl group are substituted with the monovalent unsaturated aliphatic hydrocarbon group.

[0091] R 11 , R 12 , R 11a and R 12aIn the monovalent aliphatic hydrocarbon group and aromatic hydrocarbon ring-containing hydrocarbon group, one or more hydrogen atoms may or may not be substituted with a halogen atom, a hydroxyl group (-OH), a carboxyl group (-COOH), an amino group (-NH2), a hydrazino group (-NHNH2), a hydrazono group, a nitro group (-NO2), a nitroso group (-N=O), a cyano group (-CN), an isocyanone group (-NC), a cyanate group (-O-CN), an amidino group, a diazo group (-N2), a mercapto group (-SH), or a sulfo group (-SO3H) (in this specification, these groups may be collectively referred to as "hydrogen atom substituents"). Examples of the halogen atoms include fluorine atoms (-F), chlorine atoms (-Cl), bromine atoms (-Br), and iodine atoms (-I).

[0092] In the monovalent aliphatic hydrocarbon group and the aromatic hydrocarbon ring-containing hydrocarbon group, if two or more hydrogen atoms are substituted with hydrogen atom substituents, these multiple hydrogen atom substituents may all be the same, may all be different, or may only some be the same.

[0093] The substitution positions of hydrogen atoms by hydrogen substituents in the monovalent aliphatic hydrocarbon group and the aromatic hydrocarbon ring-containing hydrocarbon group are not particularly limited. For example, if the number of hydrogen atom substitutions by hydrogen atom substituents is two or more, then two or more (two or three) hydrogen atoms bonded to the same carbon atom may be substituted with hydrogen atom substituents, or two or more hydrogen atoms bonded to different carbon atoms may be substituted with hydrogen atom substituents. For example, if the monovalent aromatic hydrocarbon ring-containing hydrocarbon group has both a chain structure and a cyclic structure, one or more hydrogen atoms bonded to the carbon atoms constituting the chain structure may be substituted with hydrogen substituents, or one or more hydrogen atoms bonded to the carbon atoms forming the cyclic structure may be substituted with hydrogen substituents.

[0094] The number of hydrogen atom substitutions by hydrogen atom substituents in the monovalent aliphatic hydrocarbon group and the aromatic hydrocarbon ring-containing hydrocarbon group is preferably 1 to 6, and may be any of 1 to 5, 1 to 4, and 1 to 3.

[0095] R 11 , R 12 , R 11a and R 12a In the monovalent aliphatic hydrocarbon group and aromatic hydrocarbon ring-containing hydrocarbon group, one or more non-adjacent carbon atoms, either alone or together with a hydrogen atom bonded to the carbon atom, are oxygen atoms (-O-), sulfur atoms (-S-), nitrogen atoms (-N=, (-N(-)-)), carbonyl groups (-C(=O)-), carbonyloxy groups (-C(=O)-O-), oxycarbonyl groups (-OC(=O)-), and general formula -C(=O)-N(-R 93 A group represented by -, or the general formula -N(-R 93 The atoms may be substituted with or unsubstituted with groups represented by )-C(=O)- (in this specification, these groups are sometimes collectively referred to as "carbon atom substituents").

[0096] In the above general formula, the R 93 is a hydrogen atom or an alkyl group. R 93 The alkyl group in is the same as the alkyl group listed above as being bonded to the oxygen atom in the alkoxycarbonyl group of compound (b10), and may be linear, branched, or cyclic, and may have both a linear structure (linear or branched structure) and a cyclic structure. However, R 93 The number of carbon atoms is preferably 1 to 6.

[0097] <<Aldehyde>> The aldehyde reacted with the leucoquinizalin or its derivative is not particularly limited as long as it has a formyl group (-C(=O)-H). The number of formyl groups in one molecule of the aldehyde may be only one, or two or more, and is not particularly limited, but it is preferable to have only one formyl group in order to easily control the reaction with leucoquinizarin or its derivatives.

[0098] In the aldehyde, the monovalent group bonded to the formyl group includes a hydrogen atom; a monovalent hydrocarbon group; a monovalent carbon-substituted hydrocarbon group having a structure in which one or more non-adjacent carbon atoms in the monovalent hydrocarbon group are substituted by a heteroatom, either alone or together with a hydrogen atom bonded to the carbon atom; and a monovalent hydrogen-substituted hydrocarbon group having a structure in which one or more hydrogen atoms in the monovalent hydrocarbon group or monovalent carbon-substituted hydrocarbon group are substituted by a group other than a hydrogen atom.

[0099] The aforementioned aldehyde is given by the following general formula (13)

[0100] [ka] (In the formula, R 13 The group is an alkyl group, aryl group, aralkyl group, heteroaryl group, or heteroarylalkyl group, and one or more hydrogen atoms in the alkyl group, aryl group, aralkyl group, heteroaryl group, and heteroarylalkyl group may be substituted with a halogen atom, hydroxyl group, carboxyl group, amino group, hydrazino group, hydrazono group, nitro group, nitroso group, cyano group, isocyano group, cyanate group, amidino group, diazo group, mercapto group, or sulfo group, and one or more non-adjacent carbon atoms in the alkyl group, aryl group, aralkyl group, heteroaryl group, and heteroarylalkyl group may, alone or together with a hydrogen atom bonded to the carbon atom, be an oxygen atom, sulfur atom, nitrogen atom, carbonyl group, carbonyloxy group, oxycarbonyl group, or a group of the general formula -C(=O)-N(-R 91 A group represented by -, or the general formula -N(-R 91 It may also be substituted with a group represented by )-C(=O)-; R 91(This is a hydrogen atom or an alkyl group.) It is preferable that the compound represented by (sometimes referred to as "compound (13)" in this specification) is used. Compound (13) provides particularly good acceleration of the reaction with leucoquinizarin or its derivatives by catalyst (b1).

[0101] In the above general formula (13), R 13 This is an alkyl group, an aryl group, an aralkyl group, a heteroaryl group, or a heteroarylalkyl group. The aforementioned R 13 The alkyl group in this compound (b10) is the same as the alkyl group listed above as being bonded to the oxygen atom in the alkoxycarbonyl group of the compound (b10). R 13 The alkyl group in may be linear, branched, or cyclic, and may have both a linear structure (linear or branched) and a cyclic structure. If the alkyl group is cyclic, including the case where it is cyclic, the cyclic structure may be monocyclic or polycyclic. R 13 The number of carbon atoms in the alkyl group is preferably 1 to 30, and more preferably 1 to 20. R 13 The number of carbon atoms in the linear or branched (i.e., chain-like) alkyl group is preferably 1 to 20, more preferably 1 to 10, and may be any of 1 to 8, 1 to 6, and 1 to 4, for example. R 13 The number of carbon atoms in the cyclic alkyl group (cycloalkyl group) or other alkyl group having a cyclic structure is preferably 3 to 20, more preferably 3 to 10, and may be any of 3 to 5, 5 to 7, or 7 to 10.

[0102] The aforementioned R 13The aryl group in this compound (b10) is the same as the aryl group listed above as being bonded to the oxygen atom in the aryloxycarbonyl group, and may be monocyclic or polycyclic. R 13 The number of carbon atoms in the aryl group is preferably 6 to 22, more preferably 6 to 18, and may be any of 6 to 14, 6 to 12, and 6 to 8, for example.

[0103] The aforementioned R 13 The aralkyl group in this compound (b10) is the same as the aralkyl group that is bonded to the oxygen atom in the aralkyloxycarbonyl group of the compound (b10) described above, and the aromatic ring in the aralkyl group may be monocyclic or polycyclic. R 13 The number of carbon atoms in the aralkyl group is preferably 7 to 23, more preferably 7 to 19, and may be any of 7 to 15, 7 to 13, and 7 to 9.

[0104] The aforementioned R 13 The heteroaryl group in is R 13 Among the aryl groups in which one or more carbon atoms constituting the aromatic ring skeleton are substituted with heteroatoms, either alone or together with hydrogen atoms bonded to the carbon atoms, and the group is aromatic, and R 13 Examples of aromatic groups include those in which, in the cyclic alkyl group, one or more single bonds (CC) between carbon atoms are substituted with double bonds (C=C), one hydrogen atom bonded to the carbon atom is removed, and one or more carbon atoms constituting the ring skeleton are substituted with heteroatoms, either alone or together with the hydrogen atom bonded to the carbon atom. For example, the heteroaryl group may be monocyclic or polycyclic.

[0105] Examples of the heteroatoms in the heteroaryl group include oxygen atoms, nitrogen atoms, sulfur atoms, selenium atoms, phosphorus atoms, and the like. In a heteroaryl group, the number of heteroatoms constituting the aromatic ring skeleton is not particularly limited; it may be 1, or 2 or more. If there are 2 or more heteroatoms, these multiple heteroatoms may all be the same, all be different, or only some be the same.

[0106] The heteroaryl group may, for example, have a structure in which a hydrocarbon ring (aliphatic hydrocarbon ring or aromatic hydrocarbon ring) is fused to an aromatic heterocycle.

[0107] The number of carbon atoms in the heteroaryl group is preferably 1 to 20, more preferably 1 to 15, and may be any of 1 to 12, 1 to 9, 1 to 6, and 1 to 3.

[0108] In the heteroaryl group, the number of heteroatoms constituting the aromatic ring skeleton is preferably 1 or 2.

[0109] Preferred heteroaryl groups include thienyl groups (2-thienyl group, 3-thienyl group), pyridyl groups (2-pyridyl group, 3-pyridyl group, 4-pyridyl group), furyl groups (2-furyl group, 3-furyl group), imidazolyl groups (2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group), thiazolyl groups (2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group), and the like. Particularly preferred heteroaryl groups include, for example, a thienyl group.

[0110] The aforementioned R 13 Examples of the heteroarylalkyl group in this context include monovalent groups having a structure in which one hydrogen atom bonded to a carbon atom in the alkyl group is substituted with the heteroaryl group. The aromatic ring in the heteroarylalkyl group may be monocyclic or polycyclic.

[0111] The number of carbon atoms in the heteroarylalkyl group is preferably 2 to 21, more preferably 2 to 16, and may be any of 2 to 13, 2 to 10, 2 to 7, and 2 to 4. In the heteroarylalkyl group, the number of heteroatoms constituting the aromatic ring skeleton is preferably 1 or 2.

[0112] The aforementioned R 13 In the alkyl group, aryl group, aralkyl group, heteroaryl group, and heteroarylalkyl group, one or more hydrogen atoms may be substituted with a halogen atom, hydroxyl group, carboxyl group, amino group, hydrazino group, hydrazono group, nitro group, nitroso group, cyano group, isocyano group, cyanate group, amidino group, diazo group, mercapto group, or sulfo group (the hydrogen atom substituent), or may not be substituted. Examples of the halogen atoms include fluorine atoms (-F), chlorine atoms (-Cl), bromine atoms (-Br), and iodine atoms (-I).

[0113] R 13 The manner in which the hydrogen atom in the above-mentioned hydrogen atom substituent is substituted is as described above, R 11 , R 12 , R 11a and R 12a This is similar to the substitution of hydrogen atoms by hydrogen atom substituents in the monovalent aliphatic hydrocarbon group and aromatic hydrocarbon ring-containing hydrocarbon group.

[0114] The aforementioned R 13 In the alkyl group, aryl group, aralkyl group, heteroaryl group, and heteroarylalkyl group, one or more non-adjacent carbon atoms, either alone or together with a hydrogen atom bonded to the carbon atom, are oxygen atoms, sulfur atoms, nitrogen atoms, carbonyl groups, carbonyloxy groups, oxycarbonyl groups, and groups of the general formula -C(=O)-N(-R 91 A group represented by -, or the general formula -N(-R 91The atom may be substituted with a group represented by )-C(=O)- (in this specification, these groups are also sometimes collectively referred to as "carbon atom substituents"), or it may not be substituted. R 13 The R in the carbon atom substituent in 91 This is a hydrogen atom or an alkyl group, and among these alkyl groups, R is as explained earlier. 11 , R 12 , R 11a and R 12a The R in the carbon atom substituent in 93 Examples include alkyl groups in the above context.

[0115] R 13 The manner in which carbon atoms are substituted by the carbon substituents in R is as described above. 11 , R 12 , R 11a and R 12a This is similar to the substitution of carbon atoms by carbon substituents in the monovalent aliphatic hydrocarbon group and aromatic hydrocarbon ring-containing hydrocarbon group.

[0116] <<Quinizarin derivative>> Quinizalin derivatives obtained by reacting leucoquinizalins with aldehydes using the catalyst (b1) (by performing a Marschalk reaction) have a structure in which a group derived from the aldehyde is introduced to the carbon atom at the 2nd or 3rd position of the quinizalin. For example, a preferred reaction using catalyst (b1) involves reacting compound (11) and compound (13) to produce the following general formula (1).

[0117] [ka] (In the formula, R 101 and R 102 Each is independently a hydrogen atom or a monovalent organic group, however, R 101 and R 102 At least one of them is the general formula -CH2-R 13 It is a base represented by; R13 The group is an alkyl group, aryl group, aralkyl group, heteroaryl group, or heteroarylalkyl group, and one or more hydrogen atoms in the alkyl group, aryl group, aralkyl group, heteroaryl group, and heteroarylalkyl group may be substituted with a halogen atom, hydroxyl group, carboxyl group, amino group, hydrazino group, hydrazono group, nitro group, nitroso group, cyano group, isocyano group, cyanate group, amidino group, diazo group, mercapto group, or sulfo group, and one or more non-adjacent carbon atoms in the alkyl group, aryl group, aralkyl group, heteroaryl group, and heteroarylalkyl group may, alone or together with a hydrogen atom bonded to the carbon atom, be an oxygen atom, sulfur atom, nitrogen atom, carbonyl group, carbonyloxy group, oxycarbonyl group, or a group of the general formula -C(=O)-N(-R 91 A group represented by -, or the general formula -N(-R 91 It may also be substituted with a group represented by )-C(=O)-; R 91 (This is a hydrogen atom or an alkyl group.) Examples of reactions include obtaining a compound represented by (which may be referred to as "compound (1)" in this specification). In other words, catalyst (b1) is preferably used in the reaction between compound (11) and compound (13). By selecting compound (11) and compound (13) as the targets for catalyst (b1), the amount of the target quinizalin derivative produced is further increased.

[0118] For example, as compound (11), the R 11 and R 12 When the reaction is carried out using a compound in which is a hydrogen atom, i.e., a leucoquinizarin represented by formula (11)-101 (compound (11)-101), compound (13) as the aldehyde, and catalyst (b1), compound (1) is used, the above R 101 and R 102 One of them is a hydrogen atom, and the other is the one of the general formula -CH2-R 13A compound (1) can be obtained that has a group represented by the above general formula (11). Such a compound (1) can be reduced to a leucoquinizalin derivative, and this leucoquinizalin derivative has the R in the above general formula (11). 11 and R 12 Either one of the above general formulas is -CH2-R 13 This corresponds to compound (11), which is a group represented by and whose other component is a hydrogen atom. By reacting such compound (11) with compound (13) again using catalyst (b1), even more different types of compound (1) can be obtained. In other words, by using leucoquinizarin (compound (11)-101), a wider variety of compound (1) can be produced. For convenience, the case where compound (13) is used as the aldehyde has been explained as an example, but the same result can be obtained when using aldehydes other than compound (13). Thus, leucoquinizarin (compound (11)-101) is preferred as compound (11) because it is possible to obtain a variety of target products.

[0119] ◎Method of using the catalyst (method of producing quinizalin derivatives) The catalyst (b1) can be used to obtain the quinizalin derivative by reacting the leucoquinizalins with the aldehyde. By using catalyst (b1), the reaction between the leucoquinizalins and the aldehyde is accelerated, the amount of residual leucoquinizalins is further reduced, and the amount of quinizalin derivative produced is further increased.

[0120] In other words, the method for producing quinizalin derivatives involves using a catalyst to react leucoquinizalin or its derivative with an aldehyde to obtain a quinizalin derivative. The quinizalin derivative has a structure in which the aldehyde-derived group is introduced to the carbon atom at position 2 or 3 of quinizalin. A production method is provided in which the catalyst comprises a compound (compound (b10)) having both a secondary amino group or a tertiary amino group and a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aralkyloxycarbonyl group.

[0121] In particular, a preferred method for producing quinizalin derivatives is a method of obtaining quinizalin derivatives by reacting leucoquinizalin or its derivative with an aldehyde using a catalyst. The quinizalin derivative is defined by the following general formula (1)

[0122] [ka] (In the formula, R 101 and R 102 Each is independently a hydrogen atom or a monovalent organic group, however, R 101 and R 102 At least one of them is the general formula -CH2-R 13 It is a base represented by; R 13 The group is an alkyl group, aryl group, aralkyl group, heteroaryl group, or heteroarylalkyl group, and one or more hydrogen atoms in the alkyl group, aryl group, aralkyl group, heteroaryl group, and heteroarylalkyl group may be substituted with a halogen atom, hydroxyl group, carboxyl group, amino group, hydrazino group, hydrazono group, nitro group, nitroso group, cyano group, isocyano group, cyanate group, amidino group, diazo group, mercapto group, or sulfo group, and one or more non-adjacent carbon atoms in the alkyl group, aryl group, aralkyl group, heteroaryl group, and heteroarylalkyl group may, alone or together with a hydrogen atom bonded to the carbon atom, be an oxygen atom, sulfur atom, nitrogen atom, carbonyl group, carbonyloxy group, oxycarbonyl group, or a group of the general formula -C(=O)-N(-R 91 A group represented by -, or the general formula -N(-R 91 It may also be substituted with a group represented by )-C(=O)-; R 91 (This is a hydrogen atom or an alkyl group.) The compound represented by (i.e., compound (1)) The catalyst is given by the following general formula (2)

[0123] [ka] (In the formula, X 1 is an alkylene group, and one or more hydrogen atoms in the alkylene group may be substituted with halogen atoms, hydroxyl groups, carboxyl groups, alkoxycarbonyl groups, aryloxycarbonyl groups, or aralkyloxycarbonyl groups; R 21 and R 22 Each is independently a hydrogen atom or an alkyl group, however, R 21 and R 22 At least one of the elements is the alkyl group, and one or more hydrogen atoms in the alkyl group may be substituted with a halogen atom or a hydroxyl group, and one or more non-adjacent carbon atoms in the alkyl group may, alone or together with a hydrogen atom bonded to the carbon atom, be an oxygen atom, a sulfur atom, a nitrogen atom, a carbonyl group, a carbonyloxy group, an oxycarbonyl group, or a group of the general formula -C(=O)-N(-R 92 A group represented by -, or the general formula -N(-R 92 It may also be substituted with a group represented by )-C(=O)-; R 92 is a hydrogen atom or an alkyl group; R 21 and R 22 If R is the alkyl group, 21 and R 22 They may be bonded to each other to form a ring; X 1 And the alkyl group R 21 or R 22 These elements may be joined to each other to form a ring; R 23 (This is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group.) It consists of a compound represented by (i.e., compound (2)) (i.e., catalyst (b1)), The leucoquinizalin or its derivative is the following general formula (11)

[0124] [ka] (In the formula, R 11 and R 12 Each is independently a hydrogen atom or a monovalent organic group, however, R 11 and R 12 At least one of them is a hydrogen atom. The compound represented by (i.e., compound (11)) The aforementioned aldehyde is given by the following general formula (13)

[0125] [ka] (In the formula, R 13 The group is an alkyl group, aryl group, aralkyl group, heteroaryl group, or heteroarylalkyl group, and one or more hydrogen atoms in the alkyl group, aryl group, aralkyl group, heteroaryl group, and heteroarylalkyl group may be substituted with a halogen atom, hydroxyl group, carboxyl group, amino group, hydrazino group, hydrazono group, nitro group, nitroso group, cyano group, isocyano group, cyanate group, amidino group, diazo group, mercapto group, or sulfo group, and one or more non-adjacent carbon atoms in the alkyl group, aryl group, aralkyl group, heteroaryl group, and heteroarylalkyl group may, alone or together with a hydrogen atom bonded to the carbon atom, be an oxygen atom, sulfur atom, nitrogen atom, carbonyl group, carbonyloxy group, oxycarbonyl group, or a group of the general formula -C(=O)-N(-R 91 A group represented by -, or the general formula -N(-R 91 It may also be substituted with a group represented by )-C(=O)-; R 91 (This is a hydrogen atom or an alkyl group.) A method for producing the compound represented by (i.e., compound (13)) is given.

[0126] In addition, it is preferable to use a solvent during the above reaction. Using a solvent allows the reaction to proceed more smoothly. During the above reaction, other components that do not fall under any of the following categories may be used or not, as long as they do not impair the effects of the present invention.

[0127] The catalyst (b1) used in the reaction, the leucoquinizalin derivative, the aldehyde, the solvent, and the other components may each be one or more, and if there are two or more, their combination and ratio can be arbitrarily selected according to the purpose.

[0128] <<Catalysts, leucoquinizarins, aldehydes>> The catalyst, leucoquinizarin or its derivatives (leucoquinizarins), and aldehyde used in the above reaction have all been explained previously, and therefore, a detailed explanation of these components will be omitted here.

[0129] During the reaction described above, the ratio of the amount of catalyst (b1) used to the total amount of leucoquinizarin and its derivatives used ([Amount of catalyst (b1) used (moles)] / ([Amount of leucoquinizarin used (moles)] + [Amount of leucoquinizarin derivative used (moles)]) × 100) is preferably 1 to 10 mol%, and may be, for example, 1 to 7 mol%, 1 to 5 mol%, or 1 to 3 mol%. If the ratio is above the lower limit, the effect of promoting the reaction between leucoquinizarins and aldehydes is further enhanced. If the ratio is below the upper limit, the overuse of catalyst (b1) is suppressed.

[0130] Furthermore, in the above reaction, if leucoquinizarin is not used, the amount of leucoquinizarin used is 0 moles, and if a leucoquinizarin derivative is not used, the amount of leucoquinizarin derivative used is 0 moles.

[0131] During the reaction described above, the amount of aldehyde used is preferably 1 to 8 times the molar amount of the total amount of leucoquinizarin and its derivatives used, and may be, for example, 1 to 6 times the molar amount or 1.5 to 4.5 times the molar amount. If the amount of aldehyde used is above the lower limit, the amount of quinizarin derivative produced will increase further. If the amount of aldehyde used is below the upper limit, the excessive use of aldehyde will be suppressed.

[0132] <<Solvent>> The solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction between the leucoquinizarins and the aldehyde, but it is preferably capable of dissolving at least a portion of the catalyst (b1), the leucoquinizarins, and the aldehyde, and more preferably capable of dissolving all of these components. In terms of the ease with which these components dissolve, the solvent is preferably an organic solvent.

[0133] Examples of the aforementioned organic solvents include aromatic hydrocarbons such as toluene, o-xylene, m-xylene, and p-xylene; Aliphatic hydrocarbons such as hexane and heptane; Ethers such as tetrahydrofuran (THF), 1,4-dioxane, cyclopentyl methyl ether, and 4-methyltetrahydropyran; Alcohols such as methanol, ethanol, and 2-propanol; Alcohol ethers such as 1-methoxy-2-propanol (compounds having both a hydroxyl group and an ether linkage); Esters such as ethyl acetate and butyl acetate; Examples include nitriles such as acetonitrile, chloroacetonitrile, dichloroacetonitrile, and trichloroacetonitrile.

[0134] When a solvent is used, the amount of solvent used during the reaction is preferably 3 to 30 mL per gram of the total amount of leucoquinizarin, leucoquinizarin derivative, aldehyde, and catalyst (b1), for example, it may be 4 to 20 mL or 5 to 10 mL. A solvent usage amount above the lower limit allows for a more pronounced solvent effect. A solvent usage amount below the upper limit prevents excessive solvent use.

[0135] <<Other ingredients>> The other components mentioned above are not particularly limited and can be selected as appropriate depending on the purpose. During the reaction described above, the ratio of the amount of the other components used to the total amount of leucoquinizalin and its derivatives used is preferably 10% by mass or less, and may be, for example, 8% by mass or less, 6% by mass or less, 4% by mass or less, or 2% by mass or less. The lower the ratio, the higher the efficiency of quinizalin derivative production. On the other hand, the aforementioned ratio is 0% by mass or more.

[0136] <<Other conditions>>

[0137] In the above reaction, the reaction temperature for obtaining a quinizalin derivative from leucoquinizalin or its derivative is preferably 100°C or higher, and may be, for example, 105°C or higher, or 115°C or higher. When the reaction temperature is above the lower limit, the amount of residual leucoquinizalin or its derivative is further reduced, and the amount of quinizalin derivative produced is further increased. On the other hand, in terms of further reducing the amount of by-products, the reaction temperature is preferably 140°C or lower.

[0138] In the above reaction, the reaction time for obtaining a quinizalin derivative from leucoquinizalin or its derivative is preferably 1 hour or more, and may be, for example, 4 hours or more, or 12 hours or more. When the reaction time is above the lower limit, the amount of residual leucoquinizalin or its derivative is further reduced, and the amount of quinizalin derivative produced is further increased. The upper limit of the reaction time is not particularly limited. In terms of preventing the reaction time from becoming excessively long, it is preferable that the reaction time be 36 hours or less.

[0139] The reaction between leucoquinizalins and aldehydes may be carried out in an air atmosphere, but it is preferable to carry it out in an inert gas atmosphere because the amount of quinizalin derivative produced is increased. Examples of the aforementioned inert gases include nitrogen gas, helium gas, and argon gas.

[0140] In the method of using catalyst (b1) of this embodiment (method for producing quinizalin derivatives), after the reaction between leucoquinizalins and aldehydes is complete, the resulting reaction mixture can be post-treated as needed by known methods to extract the quinizalin derivative. That is, post-treatment operations such as filtration, washing, extraction, pH adjustment, dehydration, and concentration can be performed individually or in combination of two or more, and the quinizalin derivative can be extracted by concentration, crystallization, reprecipitation, thin-layer chromatography, column chromatography, etc. Furthermore, the extracted quinizalin derivative may be purified by performing crystallization, reprecipitation, thin-layer chromatography, column chromatography, extraction, stirring and washing of crystals with a solvent, individually or in combination of two or more, one or more times, as needed. Alternatively, after the completion of the above reaction, the resulting reaction mixture can be post-treated as needed, and the quinizalin derivative may be used for the following purposes without being extracted. For example, the quinizalin derivative may be used in the following reactions without being extracted.

[0141] <<Other Embodiments>> Up to this point, we have described a method for producing quinizalin derivatives using the so-called batch method. However, quinizalin derivatives may also be produced using the so-called flow method, in which raw materials (catalyst (b1), leucoquinizalins, and aldehydes) are continuously supplied to a reactor to carry out the reaction, and the resulting reaction product (quinizalin derivative) is continuously discharged from the reactor.

[0142] In other words, the method for producing quinizalin derivatives involves using a catalyst to react leucoquinizalin or its derivative with an aldehyde to obtain a quinizalin derivative. The quinizalin derivative has a structure in which the aldehyde-derived group is introduced to the carbon atom at position 2 or 3 of quinizalin. The catalyst consists of a compound having both a secondary amino group or a tertiary amino group and a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aralkyloxycarbonyl group. The leucoquinizalin or its derivative, the aldehyde, the catalyst, and the solvent are continuously supplied to the second reactor, and the reaction is carried out while removing the solvent to produce the quinizalin derivative. Furthermore, a manufacturing method is provided in which the reaction solution in the second reactor is continuously supplied to a heated third reactor and the reaction is carried out to produce the quinizalin derivative.

[0143] In the reaction solution in the second reactor, in addition to compound (1), there are usually unreacted compound (11), unreacted compound (13), a reaction intermediate that is formed before compound (1) by the reaction of compound (11) and compound (13), and water (by-product) produced in the reaction. In the third reactor, these unreacted compound (11) and unreacted compound (13) are reacted to further advance the reaction of the reaction intermediate, thereby increasing the amount of compound (1) produced.

[0144] In particular, a preferred method for producing quinizalin derivatives is a method of obtaining quinizalin derivatives by reacting leucoquinizalin or its derivative with an aldehyde using a catalyst. The quinizalin derivative is defined by the following general formula (1)

[0145] [ka] (In the formula, R 101 and R 102Each is independently a hydrogen atom or a monovalent organic group, however, R 101 and R 102 At least one of them is the general formula -CH2-R 13 It is a base represented by; R 13 The group is an alkyl group, aryl group, aralkyl group, heteroaryl group, or heteroarylalkyl group, and one or more hydrogen atoms in the alkyl group, aryl group, aralkyl group, heteroaryl group, and heteroarylalkyl group may be substituted with a halogen atom, hydroxyl group, carboxyl group, amino group, hydrazino group, hydrazono group, nitro group, nitroso group, cyano group, isocyano group, cyanate group, amidino group, diazo group, mercapto group, or sulfo group, and one or more non-adjacent carbon atoms in the alkyl group, aryl group, aralkyl group, heteroaryl group, and heteroarylalkyl group may, alone or together with a hydrogen atom bonded to the carbon atom, be an oxygen atom, sulfur atom, nitrogen atom, carbonyl group, carbonyloxy group, oxycarbonyl group, or a group of the general formula -C(=O)-N(-R 91 A group represented by -, or the general formula -N(-R 91 It may also be substituted with a group represented by )-C(=O)-; R 91 (This is a hydrogen atom or an alkyl group.) The compound represented by (i.e., compound (1)) The catalyst is given by the following general formula (2)

[0146] [ka] (In the formula, X 1 is an alkylene group, and one or more hydrogen atoms in the alkylene group may be substituted with halogen atoms, hydroxyl groups, carboxyl groups, alkoxycarbonyl groups, aryloxycarbonyl groups, or aralkyloxycarbonyl groups; R 21 and R 22 Each is independently a hydrogen atom or an alkyl group, however, R 21 and R 22At least one of the elements is the alkyl group, and one or more hydrogen atoms in the alkyl group may be substituted with a halogen atom or a hydroxyl group, and one or more non-adjacent carbon atoms in the alkyl group may, alone or together with a hydrogen atom bonded to the carbon atom, be an oxygen atom, a sulfur atom, a nitrogen atom, a carbonyl group, a carbonyloxy group, an oxycarbonyl group, or a group of the general formula -C(=O)-N(-R 92 A group represented by -, or the general formula -N(-R 92 It may also be substituted with a group represented by )-C(=O)-; R 92 is a hydrogen atom or an alkyl group; R 21 and R 22 If R is the alkyl group, 21 and R 22 They may be bonded to each other to form a ring; X 1 And the alkyl group R 21 or R 22 These elements may be joined to each other to form a ring; R 23 (This is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group.) It consists of a compound represented by (i.e., compound (2)) (i.e., catalyst (b1)), The leucoquinizalin or its derivative is the following general formula (11)

[0147] [ka] (In the formula, R 11 and R 12 Each is independently a hydrogen atom or a monovalent organic group, however, R 11 and R 12 At least one of them is a hydrogen atom. The compound represented by (i.e., compound (11)) The aforementioned aldehyde is given by the following general formula (13)

[0148] [ka] (In the formula, R 13 The group is an alkyl group, aryl group, aralkyl group, heteroaryl group, or heteroarylalkyl group, and one or more hydrogen atoms in the alkyl group, aryl group, aralkyl group, heteroaryl group, and heteroarylalkyl group may be substituted with a halogen atom, hydroxyl group, carboxyl group, amino group, hydrazino group, hydrazono group, nitro group, nitroso group, cyano group, isocyano group, cyanate group, amidino group, diazo group, mercapto group, or sulfo group, and one or more non-adjacent carbon atoms in the alkyl group, aryl group, aralkyl group, heteroaryl group, and heteroarylalkyl group may, alone or together with a hydrogen atom bonded to the carbon atom, be an oxygen atom, sulfur atom, nitrogen atom, carbonyl group, carbonyloxy group, oxycarbonyl group, or a group of the general formula -C(=O)-N(-R 91 A group represented by -, or the general formula -N(-R 91 It may also be substituted with a group represented by )-C(=O)-; R 91 (This is a hydrogen atom or an alkyl group.) The compound represented by (i.e., compound (13)) The leucoquinizalin or its derivative (compound (11)), the aldehyde (compound (13)), the catalyst (b1), and the solvent are continuously supplied to the second reactor, and the reaction is carried out while removing the solvent to produce the quinizalin derivative (compound (1)). Furthermore, a production method is provided in which the reaction solution in the second reactor is continuously supplied to a heated third reactor and the reaction is carried out to produce the quinizalin derivative (compound (1)).

[0149] Compound (11) (leucoquinizarin or its derivative) is converted using a noble metal solid catalyst to the following general formula (12)

[0150] [ka] (In the formula, R 11 and R 12Each is independently a hydrogen atom or the aforementioned organic group, however, R 11 and R 12 At least one of them is a hydrogen atom. It is obtained by the reduction of a compound represented by (sometimes referred to as "compound (12)" in this specification). This reaction can also be carried out in a flow manner. Therefore, in this embodiment, for example, compound (11) can be produced by continuously supplying a solution containing compound (12) and a reducing agent to a first reactor containing the noble metal solid catalyst, and then compound (11) can be continuously supplied to the second reactor. In this way, by carrying out both steps of the reaction using a flow system, a quinizalin derivative (compound (1)) can be obtained efficiently without placing a significant burden on the environment.

[0151] In this specification, a system in which raw materials are continuously supplied to a reactor to carry out a reaction and the resulting reactants are continuously discharged from the reactor may be referred to as a "flow system." On the other hand, a method in which the reaction is carried out without continuously supplying raw materials to the reactor, or in which the resulting reactants are not continuously discharged from the reactor, is sometimes called a "batch method."

[0152] R in the general formula (12) 11 and R 12 Each of these is independently a hydrogen atom or the aforementioned organic group. However, R 11 and R 12 At least one of them is a hydrogen atom. That is, compound (12) is a compound represented by any of the following general formulas (12A), (12B), and (12)-101.

[0153] [ka] (In the formula, R 11a and R 12a (Each of these is independently the aforementioned organic group.)

[0154] R in the general formula (12) 11and R 12 These are R in the general formula (11) mentioned above. 11 and R 12 It is the same as this. R in the above general formula (12A) 11a R in the general formula (11A) is 11a It is the same as this. In the above general formula (12B), R 12a R in the general formula (11B) is 12a It is the same as this.

[0155] ○ Steps to obtain compound (11) from compound (12) <Solvent> The solvent used to prepare the solution containing the compound (12) is the same as the organic solvents mentioned above that are used in the reaction between leucoquinizarins and aldehydes.

[0156] <Precious metal solid catalyst> The aforementioned noble metal solid catalyst is classified as a heterogeneous catalyst used in flow-type reactions and exhibits catalytic activity in the reaction that produces compound (11) from compound (12). The aforementioned precious metal solid catalyst contains a precious metal and, being a solid, can be easily reused after use. The aforementioned noble metal solid catalyst is preferably a hydrogenation reduction catalyst.

[0157] Examples of the noble metals that constitute the noble metal solid catalyst include palladium (Pd), platinum (Pt), rhodium (Rh), iridium (Ir), ruthenium (Ru), osmium (Os), and gold (Au). Among these, the noble metal is preferably palladium, platinum, or gold, as it exhibits higher catalytic activity. Platinum is particularly suitable for use in combination with other precious metals and / or other metals (which may be referred to as "other metals" in this specification) in a precious metal solid catalyst. The activity of a precious metal solid catalyst containing two or more such metal particles is increased. Examples of other metals (metals other than precious metals) included in the precious metal solid catalyst include transition metals such as iron (Fe), nickel (Ni), copper (Cu), silver (Ag), and zinc (Zn).

[0158] When no other metals are used in combination with the precious metals, and when no other metals are used in combination with the precious metals, it is preferable to support these precious metals and other metals on a carrier. In a noble metal solid catalyst in which a noble metal, or a noble metal and the aforementioned other metals, are supported on a carrier, the reducing agent can easily pass through the voids between these metals, and the reaction to produce compound (11) from compound (12) is easily promoted.

[0159] The aforementioned support is for supporting a catalyst, and its constituent materials include, for example, carbon (C), alumina (aluminum oxide, Al2O3), silica (SiO2), a composite of dimethylpolysilane (DMPSi) and alumina (sometimes referred to as "DMPSi-Al2O3" in this specification), zeolite, Celite®, diatomaceous earth, and the like.

[0160] In this specification, a noble metal solid catalyst composed of a metal supported on a carrier will be expressed as "metal species / carrier composition" by listing the metal species and the carrier composition. For example, a platinum-nickel solid catalyst composed of platinum and nickel supported on a carrier made of a composite of dimethylpolysilane and alumina will be expressed as "Pt-Ni / DMPSi-Al2O3".

[0161] In this specification, unless otherwise specified, the term "catalyst" refers to a catalyst used in the process of obtaining compound (1) from compound (11), and not to a noble metal solid catalyst used in the process of obtaining compound (11) from compound (12).

[0162] <Reducing agent> The reducing agent may be a known agent and may be in solid, liquid, or gaseous form. A solid reducing agent is preferably soluble in the solvent, and a liquid reducing agent is preferably homogeneous with the solvent. The liquid reducing agent may also be the solvent itself. For example, solid and liquid reducing agents (except when the reducing agent is a solvent) can be supplied to the noble metal solid catalyst as a solution obtained by dissolving them in a solvent. Gaseous reducing agents can be supplied to the noble metal solid catalyst in their gaseous state, and liquid reducing agents (except when the reducing agent is a solvent) can be supplied to the noble metal solid catalyst as is, without dilution with a solvent.

[0163] The reducing agent is preferably a component that can be dehydrogenated. Examples of such reducing agents include hydrogen (H2), primary alcohols, secondary alcohols, hydrazine (NH2-NH2), hydroxylamine (NH2-OH), and ammonia (NH3).

[0164] A liquid reducing agent capable of dissolving compound (12) may also be used as a solvent. Examples of components that can be used as both a reducing agent and a solvent include methanol, ethanol, 2-propanol, and 1-methoxy-2-propanol, as mentioned above, but these are only examples.

[0165] In the reaction to obtain compound (11) from compound (12), hydrogen (hydrogen gas) is preferable as the reducing agent because it does not produce by-products derived from the reducing agent, allows for easy separation of the product compound (11) from the unreacted compound (12), facilitates the reuse of the unreacted reducing agent, and exhibits good reactivity.

[0166] <Other conditions> When a solution containing compound (12) is continuously supplied to the first reactor, the supply rate (flow rate) of the solution is preferably 0.001 to 2 mL / min. When a solution containing a reducing agent is continuously supplied to the first reactor, the supply rate (flow rate) of the reducing agent is preferably 1 to 100 mL / min.

[0167] In the first reactor, the reaction temperature for the reaction to obtain compound (11) from compound (12) is preferably 15 to 70°C.

[0168] ○ Steps to obtain compound (1) from compound (11) In the second reactor, the amounts of compound (13) and catalyst (b1) used, as well as the reaction temperature, in the reaction to obtain compound (1) from compound (11) may be the same as those of the aldehyde and catalyst (b1) used, and the reaction temperature, in the reaction to obtain a quinizalin derivative from leucoquinizalin or its derivative in the batch process described above, for the same reasons as in the batch process described above.

[0169] In the third reactor, the reaction temperature for the reaction to obtain compound (1) is preferably 95°C or higher and preferably 140°C or lower, for the same reasons as in the second reactor where compound (1) is obtained from compound (11).

[0170] When compound (13) is continuously supplied to the second reactor, the supply rate (flow rate) of compound (13), when the catalyst is continuously supplied to the second reactor, the supply rate (flow rate) of the catalyst, and when the reaction solution in the second reactor is continuously supplied to the third reactor, the supply rate (flow rate) of the reaction solution are preferably 0.001 to 2 mL / min.

[0171] After the reaction between compound (11) and compound (13) is complete, the resulting reaction mixture can be handled in the same manner as in the batch method described above. That is, the resulting reaction mixture can be subjected to post-treatment operations such as filtration, washing, extraction, pH adjustment, dehydration, and concentration, either individually or in combination of two or more, and compound (1) can be isolated by concentration, crystallization, reprecipitation, thin-layer chromatography, column chromatography, etc. The isolated compound (1) may be further purified by performing operations such as crystallization, reprecipitation, thin-layer chromatography, column chromatography, extraction, and stirring and washing of crystals with a solvent, either individually or in combination of two or more, one or more times, if necessary. Alternatively, after the completion of the reaction, the resulting reaction mixture may be used for the following intended purpose without isolating compound (1). For example, compound (1) may be used in the following intended reaction without isolating it.

[0172] The structure of the quinizalin derivative (compound (1)) obtained by the above-described manufacturing method can be confirmed by known methods such as nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), and infrared spectroscopy (IR). [Examples]

[0173] The present invention will be described in more detail below with reference to specific examples. However, the present invention is not limited in any way to the examples shown below.

[0174] The main raw materials and reagents used in each example are shown below. [Catalyst (compound (2))] 3-Piperidinecarboxylic acid: Manufactured by Tokyo Chemical Industry Co., Ltd. 4-Piperidinecarboxylic acid: Manufactured by Tokyo Chemical Industry Co., Ltd. 2-Piperidinecarboxylic acid: Manufactured by Tokyo Chemical Industry Co., Ltd. 3-Ethyl piperidinecarboxylate: Manufactured by Tokyo Chemical Industry Co., Ltd. 3-(methylamino)propionic acid: Manufactured by Tokyo Chemical Industry Co., Ltd. N-methylglycine: Manufactured by Tokyo Chemical Industry Co., Ltd. 2-Pyrrolidinecarboxylic acid: Manufactured by Tokyo Chemical Industry Co., Ltd. (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid: Manufactured by Tokyo Chemical Industry Co., Ltd. 1-Methylpyrrolidine-2-carboxylic acid: Manufactured by Tokyo Chemical Industry Co., Ltd. [Compound (11)] Leucoquinizalin: Manufactured by Tokyo Chemical Industry Co., Ltd. [Compound (13)] 4-Methoxybenzaldehyde (also known as p-anisaldehyde): Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. [Other catalysts] Piperidinium acetate (salt formed by the reaction of piperidine and acetic acid): Manufactured by Tokyo Chemical Industry Co., Ltd. [solvent] 1-Methoxy-2-propanol: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. THF: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. [Other raw materials or reagents] Dimethylpolysilane: Manufactured by Nippon Soda Co., Ltd. Digrim: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. Sodium borohydride: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. Sodium hexachloroplatinate(IV) hexahydrate (Na2PtCl6·6H2O): Manufactured by Sigma-Aldrich. Basic alumina: Manufactured by Merck. Nickel(II) chloride hexahydrate (NiCl2·6H2O): Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.

[0175] <<Production of Compound (1)>> [Example 1] 3-Piperidinecarboxylic acid (compound (2)-101) (2.1 mg, 0.016 mmol), 4-Methoxybenzaldehyde (compound (13)-101) (337.6 mg, 2.480 mmol), leucoquinizarin (compound (11)-101) (200.6 mg, 0.828 mmol), and 1-Methoxy-2-propanol (4 mL) were placed in a flask. The air in the flask was replaced with argon gas, and the mixture in the flask was stirred at 110°C for 3 hours under an argon gas atmosphere to carry out the reaction. Next, the temperature of the reaction mixture in the flask was allowed to cool to room temperature, and then 1,3,5-trimethoxybenzene (38.6 mg), an internal standard, and dichloromethane (4 mL) were added to the reaction mixture.

[0176] Next, a minute sample is taken from the resulting mixture, diluted with deuterated chloroform (CDCl3), and then analyzed using a nuclear magnetic resonance spectrometer (Bruker "Advance NEO 400MHz"). 1 The 1H NMR spectrum was observed, and the obtained product was confirmed to be compound (1)-101. From the acquired data, the yield of compound (1)-101 was calculated from the integral ratio of the signals of 1,3,5-trimethoxybenzene (internal standard, δ 6.09 ppm (s, 3H)) and the target compound (1)-101 (2-(4-(methoxybenzyl)quinizalin) (7.23-7.16 (m, 2H)), which was 67%.

[0177] Acquired at this time 1 H NMR spectral data and separately acquired data 13 The 13C NMR spectral data is shown below. 1 H NMR (400 MHz, Chloroform-d)δ13.44 (d, J = 0.6 Hz, 1H), 12.92 (s, 1H), 8.39 - 8.28 (m, 2H), 7.85 - 7.77 (m, 2H), 7.23 - 7.16 (m, 2H), 7.03 (d, J = 0.8 Hz, 1H), 6.90 - 6.84 (m, 2H), 4.02 (s, 2H), 3.80 (s, 3H). 13 C NMR (101 MHz, Chloroform-d)δ187.18, 186.39, 158.48, 157.82, 156.79, 144.19, 134.41, 134.28, 133.68, 133.55, 130.29, 130.02, 128.54, 127.04, 126.94, 114.21, 112.24, 111.34, 55.30, 35.04. HRMS calc.: 360.0998, found: 360.1001 (+0.9 ppm). IR (ATR, ν max / cm -1 ) 3074, 2933, 2842, 1626, 1606, 1586, 1566, 1510, 1429, 1421, 1368, 1346, 1332, 1299, 1270, 1241, 1216, 1177, 1162, 1122, 1108, 1043, 1025, 959, 901, 848, 788, 775, 735, 726, 715, 683, 669, 650, 636, 609, 555, 518, 511, 469, 449, 426. Mp. 142℃.

[0178] [ka]

[0179] [Example 2] Compound (1)-101 was prepared in the same manner as in Example 1, except that 4-piperidinecarboxylic acid (compound (2)-102) (0.016 mmol) was used instead of 3-piperidinecarboxylic acid (compound (2)-101) (0.016 mmol). The NMR yield of compound (1)-101, calculated in the same manner as in Example 1, was 34%.

[0180] [ka]

[0181] [Example 3] Compound (1)-101 was prepared in the same manner as in Example 1, except that 2-piperidinecarboxylic acid (compound (2)-103) (0.016 mmol) was used instead of 3-piperidinecarboxylic acid (compound (2)-101) (0.016 mmol), and the reaction time at 110°C was changed from 3 hours to 18 hours. The NMR yield of compound (1)-101, calculated in the same manner as in Example 1, was 21%.

[0182] [ka]

[0183] [Example 4] Compound (1)-101 was prepared in the same manner as in Example 1, except that ethyl 3-piperidinecarboxylate (compound (2)-104) (0.016 mmol) was used instead of 3-piperidinecarboxylic acid (compound (2)-101) (0.016 mmol). The NMR yield of compound (1)-101, calculated in the same manner as in Example 1, was 20%.

[0184] [ka]

[0185] [Example 5] Compound (1)-101 was prepared in the same manner as in Example 1, except that 3-(methylamino)propionic acid (compound (2)-201) (0.016 mmol) was used instead of 3-piperidinecarboxylic acid (compound (2)-101) (0.016 mmol). The NMR yield of compound (1)-101, calculated in the same manner as in Example 1, was 56%.

[0186] [ka]

[0187] [Example 6] Compound (1)-101 was prepared in the same manner as in Example 1, except that N-methylglycine (compound (2)-202) (0.016 mmol) was used instead of 3-piperidinecarboxylic acid (compound (2)-101) (0.016 mmol). The NMR yield of compound (1)-101, calculated in the same manner as in Example 1, was 38%.

[0188] [ka]

[0189] [Example 7] Compound (1)-101 was prepared in the same manner as in Example 1, except that 2-pyrrolidinecarboxylic acid (compound (2)-105) (0.016 mmol) was used instead of 3-piperidinecarboxylic acid (compound (2)-101) (0.016 mmol), and the reaction time at 110°C was changed from 3 hours to 18 hours. The NMR yield of compound (1)-101, calculated in the same manner as in Example 1, was 17%.

[0190] [ka]

[0191] [Example 8] Compound (1)-101 was prepared in the same manner as in Example 1, except that (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (compound (2)-106) (0.016 mmol) was used instead of 3-piperidinecarboxylic acid (compound (2)-101) (0.016 mmol), and the reaction time at 110°C was changed from 3 hours to 18 hours. The NMR yield of compound (1)-101, calculated in the same manner as in Example 1, was 16%.

[0192] [ka]

[0193] [Example 9] Compound (1)-101 was prepared in the same manner as in Example 1, except that 1-methylpyrrolidine-2-carboxylic acid (compound (2)-107) (0.016 mmol) was used instead of 3-piperidinecarboxylic acid (compound (2)-101) (0.016 mmol), and the reaction time at 110°C was changed from 3 hours to 18 hours. The NMR yield of compound (1)-101, calculated in the same manner as in Example 1, was 16%.

[0194] [ka]

[0195] [Comparative Example 1] Compound (1)-101 was prepared in the same manner as in Example 1, except that piperidinium acetate (0.016 mmol) was used instead of 3-piperidinecarboxylic acid (compound (2)-201) (0.016 mmol). The NMR yield of compound (1)-101, calculated in the same manner as in Example 1, was 19%.

[0196] [ka]

[0197] Furthermore, the compound (1)-101 obtained in Examples 2 to 9 and Comparative Example 1 1 The 1H NMR spectral data is from compound (1)-101 obtained in Example 1. 1 The spectral data was similar to that obtained from 1H NMR.

[0198] As is clear from the above results, in Examples 1 to 9, by reacting leucoquinizarin (compound (11)-101) with 4-methoxybenzaldehyde (compound (13)-101) using various catalysts (b1), a quinizarin derivative (compound (1)-101) having a structure in which a group derived from 4-methoxybenzaldehyde is introduced to the carbon atom at position 2 of quinizarin was obtained. The NMR yields of the quinizarin derivatives in Examples 1 to 9 were equivalent to or better than the NMR yield of the quinizarin derivative in Comparative Example 1.

[0199] From a comparison of Examples 1, 2 and 4 and Examples 3, 7-9, it was found that in compound (2) (compound (b10)), the group linking the secondary or tertiary amino group with the carboxyl group or alkoxycarbonyl group (the X 1 A tendency was observed for catalyst (b1) to have higher catalytic activity when the number of carbon atoms in the linking direction (corresponding to) was 2 or 3 compared to when it was 1. A comparison of Example 5 and Example 6 also shows that the X in compound (2) (compound (b10)) 1 A tendency was observed for catalyst (b1) to have higher catalytic activity when the number of carbon atoms in the linking direction of the corresponding group was 2 compared to when it was 1. In other words, in compound (2) (compound (b10)), regardless of the presence or absence of a nitrogen-containing ring, the above X 1 It was confirmed that having approximately 2 to 3 carbon atoms in the corresponding group is advantageous in that it increases the catalytic activity of catalyst (b1).

[0200] From a comparison of Example 6 with Examples 3, 7-9, the X in compound (2) (compound (b10)) 1 Even when the number of carbon atoms in the corresponding group was the same (1), catalyst (b1) tended to have higher catalytic activity when it did not have a nitrogen-containing ring than when it did. This was thought to be because when compound (2) does not have a nitrogen-containing ring, its molecular structure is more flexible, and the arrangement of the substituted amino group and carboxyl group becomes a more desirable arrangement in the transition state of the catalytic reaction.

[0201] From a comparison between Example 1 and Example 4, in compound (2) (compound b10), the aforementioned R 23 It was observed that the catalytic activity of catalyst (b1) tends to be higher when R is a hydrogen atom than when R is a group other than a hydrogen atom. This suggests that when compound (2) (compound b10) is a carboxylic acid rather than a carboxylic ester, it more easily interacts with the carbonyl group of the substrate aldehyde in the transition state of the catalytic reaction.

[0202] From a comparison between Example 3 and Examples 7 to 9, in compound (2) (compound b10), the aforementioned X 1 It was observed that when the number of carbon atoms in the group corresponding to X is the same, and compound (2) has a nitrogen-containing ring, the catalytic activity of catalyst (b1) tends to be higher when the number of ring members of the nitrogen-containing ring is 6 than when it is 5. This is considered to be because when the number of ring members of the nitrogen-containing ring is 6, the arrangement of the substituted amino group and the carboxy group becomes a more favorable arrangement in the transition state of the catalytic reaction.

[0203] In Examples 3 and 7 to 9, the yield of the quinisarine derivative (compound (1)-101) is lower than that in Examples 1, 2 and 4 to 6, but it was expected that the yield would be further improved by extending the reaction time.

[0204] <<Production of Noble Metal Solid Catalyst>> [Production Example 1] <Production of Pt-Ni / DMPSi-Al₂O₃ (i)> Dimethylpolysilane (0.501 g) was mixed with THF (8 mL), and sodium borohydride (163.4 mg) dissolved in diglym (6 mL) was added. The mixture was stirred at room temperature under an argon atmosphere for 1 hour. A solution obtained by dissolving Na2PtCl6·6H2O (134.4 mg, 0.24 mmol) and NiCl2·6H2O (59.0 mg, 0.24 mmol) in THF (4 mL) was slowly added, and the mixture was stirred at room temperature under an argon atmosphere for 3 hours. Basic alumina (2.50 g) was then added, and the mixture was stirred at room temperature under an argon atmosphere for 24 hours. Methanol (400 mL) was then added dropwise, and the mixture was stirred at room temperature under an argon atmosphere for 1 hour. The resulting reaction mixture was then filtered by suction, and the solid was collected. This solid was dried under reduced pressure at 100 °C for 3 hours to obtain a gray solid. This gray solid was sequentially washed with acetone, water, and dichloromethane (200 mL each), and the washed solid was dried under reduced pressure for 5 hours to obtain the target product, Pt-Ni / DMPSi-Al2O3(i) (precious metal solid catalyst), as a gray solid (yield 2.60 g, platinum content 0.0122 mmol / g, nickel content 0.27 mmol / g).

[0205] Using a scanning transmission electron microscope (TECNAI OSIRIS, manufactured by FEI), the gray solid catalyst (Pt-Ni / DMPSi-Al2O3(i)) obtained above was analyzed by scanning transmission electron microscopy-energy dispersive X-ray spectroscopy (STEM-EDS) under conditions of an accelerating current of 200 kV and a magnification of 450,000x. The acquired imaging data is shown in Figure 1. Of the imaging data, Figure 1(a) is the imaging data in observation mode, Figure 1(b) is the distribution data of platinum (Pt), Figure 1(c) is the distribution data of nickel (Ni), Figure 1(d) is the distribution data of aluminum (Al), and Figure 1(e) is the distribution data of silicon (Si). From these imaging data, it was confirmed that platinum nanoparticles and nickel nanoparticles were immobilized on a composite support composed of dimethylpolysilane and aluminum oxide. Furthermore, since the distribution of platinum and nickel was consistent, it was inferred that these metal nanoparticles constituted binary metal nanoparticles. In addition, from Figures 1(b) to 1(e), it is clear that platinum and nickel are present in the regions where silicon is distributed, and from this, it was confirmed that platinum nanoparticles and nickel nanoparticles are mainly distributed in the regions where the polysilane support in the composite support is present.

[0206] [Example 10] At room temperature, quinizalin (compound (12)-101) and the internal standard 1,3,5-trimethoxybenzene were dissolved in THF to prepare THF solutions with a quinizalin concentration of 0.03 M and a 1,3,5-trimethoxybenzene concentration of 0.01 M. The Pt-Ni / DMPSi-Al2O3(i) (0.5g, platinum content 0.008 mmol) obtained in Production Example 1 and Celite® (2g) were uniformly mixed. The resulting mixture was packed into a glass column (first reactor) with an inner diameter of 10 mm and a length of 10 cm, and the remaining voids inside the column were filled with Celite®. Furthermore, polytetrafluoroethylene (PTFE) filters were attached to both ends of the column to create a catalyst cartridge (first reactor containing a precious metal solid catalyst). This catalyst cartridge was installed in a flow reactor (Tokyo Rikakikai Co., Ltd. "Synple Flow MCR-1000") equipped with a double-tube gas-liquid mixing column head.

[0207] At room temperature, a 1-methoxy-2-propanol solution (27 mL) was prepared with a concentration of 0.133 M 4-methoxybenzaldehyde (compound (13)-101) and a concentration of 0.0028 M 3-piperidinecarboxylic acid (compound (2)-101).

[0208] The first solution was placed inside a test tube reactor (second reactor) with an inner diameter of 25 mm and a length of 15 cm. The fractional distillation section of the front stage of the Dean-Stark apparatus was connected to this test tube reactor, and an air cooling tube (cooling tube) was connected to the top of the liquid reservoir section of the rear stage of the Dean-Stark apparatus. Furthermore, the air inside these connections was replaced with nitrogen gas, and the outlet piping of the flow reactor was connected to the top of the front stage of the Dean-Stark apparatus via a Schlenk line.

[0209] At room temperature, a second solution of 1-methoxy-2-propanol with a concentration of 4-methoxybenzaldehyde at 0.2 M and a second solution of methanol with a concentration of 3-piperidinecarboxylic acid at 0.0042 M were prepared.

[0210] Using a liquid transfer pump (Minato Concept Co., Ltd. peristaltic pump "MCRP204", first supply means), the THF solution was continuously supplied to the catalyst cartridge at room temperature at a flow rate of 14 mL / h. Simultaneously, using a mass flow controller (Tokyo Rikakikai Co., Ltd. simple flow gas addition unit "MFC-11GU", second supply means), hydrogen gas was continuously supplied to the catalyst cartridge at room temperature at a flow rate of 10 mL / min via the double-tube gas-liquid mixing column head.

[0211] Separately, an empty glass column (third reactor) with an inner diameter of 10 mm and a length of 10 cm was installed in a flow reactor (Tokyo Rikakikai Co., Ltd. "Synple Flow MCR-1000"), and the glass column was heated to 100°C. The test tube reactor was heated to 125°C while stirring the first solution inside it. Separately, using a liquid transfer pump (Minato Concept Co., Ltd. peristaltic pump "MCRP204", third supply means), the 1-methoxy-2-propanol second solution and the methanol second solution were each added separately at a flow rate of 6 mL / h to the solution discharged from the catalyst cartridge (flow reactor). This combined solution was then supplied via a Schlenk line from the upper part of the upstream section in the Dean-Stark apparatus into the heated and stirred test tube reactor. Furthermore, simultaneously, a separate liquid transfer pump (Minato Concept Co., Ltd. peristaltic pump "MCRP204", fifth supply means) was used to supply the reaction solution from the test tube reactor at a flow rate of 6 mL / h into the heated glass column (third reactor) through its lower opening, and the solution that flowed out through its upper opening was stored in an Erlenmeyer flask at room temperature. During this time, solvents such as THF and methanol, along with water, were extracted and recovered from the downstream liquid reservoir in the Dean-Stark apparatus via the second valve. Simultaneously, the excess hydrogen gas supplied to the catalyst cartridge in process (A) was recovered from the upper part of the air-cooling tube (on the opposite side from where the Dean-Stark apparatus was connected) via the first valve.

[0212] Over time, a minute sample is taken from this accumulated solution, diluted with deuterated chloroform (CDCl3), and then analyzed using a nuclear magnetic resonance spectrometer (Bruker "Advance NEO 400MHz"). 1 1H NMR spectra were observed. From the acquired data, the yield of compound (1)-101 was calculated from the integral ratio of the signals of 1,3,5-trimethoxybenzene (internal standard, δ 6.09 ppm (s, 3H)) and the target compound (1)-101 (2-(4-(methoxybenzyl)quinizalin) (7.23-7.16 (m, 2H)). A graph showing the change in yield over time is shown in Figure 2.

[0213] At intervals of approximately 3 hours and 5 hours of storage, hexane (10 mL) was added to the solution, and the resulting precipitated solid was separated by suction filtration to obtain the target compound (1)-101 as a pure product. Furthermore, the solvent was removed from the filtrate under reduced pressure using a rotary evaporator, and the remaining solid was dissolved in dichloromethane (3 mL). The mixture was then purified by thin-layer chromatography (developing solvent: toluene) to obtain the target compound (1)-101. As a result, the total yield of these obtained compounds (1)-101 was 87% at the 3-hour storage stage and 84% at the 5-hour storage stage.

[0214] Furthermore, the compound (1)-101 in the above-mentioned stored solution and the isolated compound (1)-101 are 1 The 1H NMR spectral data was the same as in Example 1.

[0215] [ka] [Industrial applicability]

[0216] This invention can be used for the production of quinizalin derivatives.

Claims

1. A catalyst for use in the reaction of leucoquinizalin or its derivative with an aldehyde, The catalyst is a catalyst comprising a compound having both a secondary amino group or a tertiary amino group and a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aralkyloxycarbonyl group.

2. The leucoquinizalin or its derivative is the following general formula (11) 【Chemistry 1】 (In the formula, R １１ and R １２ Each is independently a hydrogen atom or a monovalent organic group, however, R １１ and R １２ At least one of them is a hydrogen atom. The catalyst according to claim 1, which is a compound represented by [the compound name].

3. The aforementioned aldehyde is given by the following general formula (13) 【Chemistry 2】 (In the formula, R １３ The group is an alkyl group, aryl group, aralkyl group, heteroaryl group, or heteroarylalkyl group, and one or more hydrogen atoms in the alkyl group, aryl group, aralkyl group, heteroaryl group, and heteroarylalkyl group may be substituted with a halogen atom, hydroxyl group, carboxyl group, amino group, hydrazino group, hydrazono group, nitro group, nitroso group, cyano group, isocyano group, cyanate group, amidino group, diazo group, mercapto group, or sulfo group, and one or more non-adjacent carbon atoms in the alkyl group, aryl group, aralkyl group, heteroaryl group, and heteroarylalkyl group may, alone or together with a hydrogen atom bonded to the carbon atom, be an oxygen atom, sulfur atom, nitrogen atom, carbonyl group, carbonyloxy group, oxycarbonyl group, or a group of the general formula -C(=O)-N(-R ９１ A group represented by )- or the general formula -N(-R ９１ It may also be substituted with a group represented by )-C(=O)-; R ９１ (This is a hydrogen atom or an alkyl group.) The catalyst according to claim 1, which is a compound represented by [the compound name].

4. The aforementioned aldehyde is given by the following general formula (13) 【Transformation 3】 (wherein R １３ is an alkyl group, an aryl group, an aralkyl group, a heteroaryl group or a heteroarylalkyl group, and one or two or more hydrogen atoms in said alkyl group, aryl group, aralkyl group, heteroaryl group and heteroarylalkyl group may be substituted with a halogen atom, a hydroxyl group, a carboxy group, an amino group, a hydrazino group, a hydrazono group, a nitro group, a nitroso group, a cyano group, an isocyano group, a cyanate group, an amidino group, a diazo group, a mercapto group or a sulfo group, and one carbon atom, or two or more carbon atoms not adjacent to each other, in said alkyl group, aryl group, aralkyl group, heteroaryl group and heteroarylalkyl group may, alone or together with hydrogen atoms bonded to said carbon atom, be substituted with an oxygen atom, a sulfur atom, a nitrogen atom, a carbonyl group, a carbonyloxy group, an oxycarbonyl group, a group represented by general formula -C(=O)-N(-R ９１ )-, or a group represented by general formula -N(-R ９１ )-C(=O)-; R ９１ (This is a hydrogen atom or an alkyl group.) The catalyst according to claim 2, which is a compound represented by

5. The catalyst is defined by the following general formula (2) 【Chemistry 4】 (In the formula, X １ is an alkylene group, and one or more hydrogen atoms in the alkylene group may be substituted with a halogen atom, a hydroxyl group, a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aralkyloxycarbonyl group; R ２１ and R ２２ Each is independently a hydrogen atom or an alkyl group, however R ２１ and R ２２ At least one of the elements is the alkyl group, and one or more hydrogen atoms in the alkyl group may be substituted with a halogen atom or a hydroxyl group, and one or more non-adjacent carbon atoms in the alkyl group may, alone or together with a hydrogen atom bonded to the carbon atom, be an oxygen atom, a sulfur atom, a nitrogen atom, a carbonyl group, a carbonyloxy group, an oxycarbonyl group, or a group of the general formula -C(=O)-N(-R ９２ A group represented by )- or the general formula -N(-R ９２ It may also be substituted with a group represented by )-C(=O)-; R ９２ is a hydrogen atom or an alkyl group; R ２１ and R ２２ If R is the alkyl group, ２１ and R ２２ They may be bonded to each other to form a ring; X １ And the alkyl group R ２１ or R ２２ These may be joined to each other to form a ring; R ２３ (This is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group.) A catalyst according to any one of claims 1 to 4, comprising a compound represented by the above.

6. The compound represented by the above general formula (2) is the following general formula (21) or (22) 【Transformation 5】 (In the formula, R ２１１ , R ２２１ and R ２１２ Each is independently a hydrogen atom or an alkyl group having 1 to 10 carbon atoms, however, R ２１１ and R ２２１ At least one of the elements is the alkyl group, and one or more hydrogen atoms in the alkyl group may be substituted with a halogen atom or a hydroxyl group, and one or more non-adjacent carbon atoms in the alkyl group may, alone or together with a hydrogen atom bonded to the carbon atom, be an oxygen atom, a sulfur atom, a nitrogen atom, a carbonyl group, a carbonyloxy group, an oxycarbonyl group, or a group of the general formula -C(=O)-N(-R ９２１ A group represented by )- or the general formula -N(-R ９２１ It may also be substituted with a group represented by )-C(=O)-; R ９２１ is a hydrogen atom or an alkyl group having 1 to 10 carbon atoms; R ２４１ , R ２５１ and R ２５２ Each of these is independently a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, an alkoxycarbonyl group having 2 to 11 carbon atoms, an aryloxycarbonyl group having 7 to 13 carbon atoms, or an aralkyloxycarbonyl group having 8 to 14 carbon atoms; R ２４２ These are halogen atoms, hydroxyl groups, carboxyl groups, alkoxycarbonyl groups having 2 to 11 carbon atoms, aryloxycarbonyl groups having 7 to 13 carbon atoms, or aralkyloxycarbonyl groups having 8 to 14 carbon atoms; n ２１ n is an integer between 0 and 5. ２１ If n is 2 or more, ２１ Individual R ２５１ They may be the same or different from each other; n ２２ and n ２３ Each of these is an independent integer between 0 and 2, where n ２２ +n ２３ The ranges from 1 to 4; n ２４ n is an integer between 0 and 3. ２４ If n is 2 or 3, ２４ Individual R ２５２ They may be the same or different from each other; n ２５ n is an integer between 0 and 6. ２５ If n is 2 or more, ２５ Individual R ２４２ They may be the same or different from each other; R ２３１ and R ２３２ (These are a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an aryl group having 6 to 12 carbon atoms, or an aralkyl group having 7 to 13 carbon atoms.) The catalyst according to claim 5, which is a compound represented by .

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