Method for producing compounds and apparatus for producing compounds

Abstract

To provide a novel manufacturing method that can efficiently produce different types of quinizalin derivatives from quinizalins via leucoquinizalins. [Solution] A method for producing a compound represented by the following formula (1), comprising: step (A) obtaining a compound represented by the following formula (11) from a compound represented by the following formula (12); and step (B) obtaining compound (1) by reacting compound (11) with a compound represented by the following formula (13), wherein in step (A), compound (11) is produced by continuously supplying a solution containing compound (12) and a reducing agent to a first reactor containing a noble metal solid catalyst; and in step (B), compound (11) obtained in step (A) is continuously supplied to a second reactor, and compound (11) and compound (13) are reacted in the second reactor. TIFF2026144679000031.tif43170

Description

[Technical Field]

[0001] This invention relates to a method for producing a compound and an apparatus for producing a compound. [Background technology]

[0002] Leucoquinizalins have many uses as raw materials or intermediates for pigments, dyes, physiologically active substances, pharmaceuticals, or redox flow battery materials. Leucoquinizalins can be produced, for example, from quinizalins.

[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 known method for producing leucoquinizarians from quinizarians is to use a stoichiometric amount of a reducing agent and a stoichiometric amount of a base. Furthermore, the following methods have been disclosed: one using sodium dithionite (also known as hydrosulfite sodium, Na2S2O4) as the reducing agent and potassium carbonate as the base (see Non-Patent Document 1); one using sodium dithionite as the reducing agent and sodium carbonate as the base (see Non-Patent Document 2); and one using sodium dithionite as the reducing agent and sodium hydroxide as the base (see Non-Patent Document 3).

[0005] Furthermore, a known method for producing leucoquinizarians from quinizarians is to use, for example, a stoichiometric amount of metal and a stoichiometric amount of acid. Furthermore, methods using tin chloride as the metal and hydrochloric acid as the acid (see Non-Patent Document 4) and methods using aluminum as the metal and acetic acid and indium chloride as the acids are disclosed (see Non-Patent Document 5). [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] G. Zagotto et al. “New 1,4-anthracene-9,10-dione derivatives as potential anticancer agents” IL Farmaco 55 (2000) pp.1-5. [Non-Patent Document 2] Bin Shan et al. “A new kind of H-acid monoazo-anthraquinone reactive dyes with surprising colour” Dyes and Pigments 123 (2015) pp.44-54. [Non-Patent Document 3] Tais Arthur Correa et al. “Synthesis of 1,4-Anthracene-9,10-dione Derivatives and Their Regulation of Nitric Oxide, IL-1β and TNF-αin Activated RAW264.7 Cells” Chemical Biology and Drug Design 2013, 82, pp.463-467. [Non-Patent Document 4] RAJENDRA P. MASKEYa et al. “Parimycin:Isolation and Structure Elucidation of a Novel Cytotoxic 2,3-Dihydroquinizarin Analogue of γ-Indomycinone from a Marine Streptomycete Isolate” THE JOURNAL OF ANTIBIOTICS VOL.55 NO.12 DEC. 2002, pp.1031-1035. [Non-Patent Document 5] Chunyan Wang et al. “A new InCl3-catalyzed reduction of anthrones and anthraquinones by using aluminum powder in aqueous media” Tetrahedron 63 (2007) pp.5071-5075. [Overview of the project] [Problems that the invention aims to solve]

[0007] In the manufacturing methods disclosed in Non-Patent Documents 1 to 5, stoichiometric amounts of by-products derived from various materials, including the base, acid, reducing agent, and metal, are easily generated, making the extraction or purification of the target product complicated.

[0008] Furthermore, it is known that leucoquinizalins can be subjected to a Marschalk reaction using an aldehyde to produce new quinizalin derivatives having a structure in which an alkyl group is introduced to the 2nd or 3rd carbon atom of the quinizalin. Such quinizalin derivatives are also expected to be used as raw materials or intermediates for pigments, dyes, physiologically active substances, pharmaceuticals, or redox flow battery materials.

[0009] The object of this invention is to provide a novel method for efficiently producing quinizalin derivatives of a different type from the quinizalin used as raw materials, via leucoquinizalins, from quinizalins.

Means for Solving the Problems

[0010] To solve the above problems, the present invention adopts the following constitution. [1] The following general formula (1)

[0011]

Chemical Formula

[0012]

Chemical Formula

[0013] [ka] (In the formula, R 11 and R 12 (This is the same as above.) Step (A) to obtain a compound represented by, The compound represented by the above general formula (11) and the following general formula (13)

[0014] [ka] (In the formula, R 13 (This is the same as above.) The process includes step (B) of reacting a compound represented by the above general formula (1) with a compound represented by the above general formula (1), In step (A) above, a solution containing the compound represented by general formula (12) and a reducing agent are continuously supplied to a first reactor containing a noble metal solid catalyst to produce the compound represented by general formula (11). A method for producing a compound, comprising: in step (B), continuously supplying the compound represented by general formula (11) obtained in step (A) to a second reactor, and reacting the compound represented by general formula (11) with the compound represented by general formula (13) in the second reactor.

[0015] [2] In step (B), the compound represented by general formula (11), the compound represented by general formula (13), and a solvent are continuously supplied to a heated second reactor, and the reaction is carried out while removing the solvent to produce the compound represented by general formula (1). A method for producing the compound according to [1], wherein in step (B), the reaction solution in the second reactor is further continuously supplied to a heated third reactor and the reaction is carried out to produce the compound represented by the general formula (1). [3] The aforementioned R 13 However, the group is an alkyl group having 1 to 10 carbon atoms, a phenyl group, a benzyl group, or a thienyl group, and one or more hydrogen atoms in the alkyl group, phenyl group, and benzyl group may be substituted with a halogen atom, a hydroxyl group, a carboxyl group, an amino group, a hydrazino group, a hydrazono group, a nitro group, a nitroso group, a cyano group, an isocyanone group, a cyanate group, an amidino group, a diazo group, a mercapto group, or a sulfo group, and one or more non-adjacent carbon atoms in the alkyl group, phenyl group, and benzyl 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 91 A group represented by -, or the general formula -N(-R 91 A method for producing the compound according to [1] or [2], which may be substituted with a group represented by )-C(=O)-. [4] In step (B), in the presence of a catalyst, the compound represented by general formula (11) and the compound represented by general formula (13) are reacted, A method for producing the compound according to any one of [1] to [3], wherein the catalyst comprises 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, or a mixture of a secondary amine or a tertiary amine and a carboxylic acid, an alkyl carboxylate, an aryl carboxylate, or an aralkyl carboxylate. [5] The catalyst is the following general formula (2)

[0016] [ka] (In the formula, X 1is 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 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.) A method for producing the compound described in [4], comprising the compound represented by .

[0017] [6] The R 11 and R 12 That is a hydrogen atom, The aforementioned 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 method for producing the compound described in any one of the items [1] to [5], which is represented by the group. [7] The following general formula (1)

[0018] [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.) A method for producing a compound represented by, The above manufacturing method is represented by the following general formula (11)

[0019] [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. Compounds represented by the following general formula (13)

[0020] [ka] (In the formula, R 13 (This is the same as above.) The process includes step (C) of reacting a compound represented by with to obtain a compound represented by the general formula (1), In step (C) above, the compound represented by general formula (11), the compound represented by general formula (13), and a solvent are continuously supplied to a heated second reactor, and the reaction is carried out while removing the solvent to produce the compound represented by general formula (1). A method for producing a compound, wherein in step (C) above, the reaction solution in the second reactor is continuously supplied to a heated third reactor and the reaction is carried out to produce the compound represented by the general formula (1).

[0021] [8] In step (C), the catalyst is further continuously supplied to the second reactor, A method for producing the compound according to [7], wherein the catalyst comprises 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, or a mixture of a secondary amine or a tertiary amine and a carboxylic acid, an alkyl carboxylate, an aryl carboxylate, or an aralkyl carboxylate. A compound manufacturing apparatus for producing the compound represented by the general formula (1) described in any one of the following items [9] [1] to [8], The manufacturing apparatus, the first reactor, A first supply means for continuously supplying a solution containing the compound represented by the general formula (12) to the first reactor, A second supply means for continuously supplying the reducing agent to the first reactor, The second reactor and, A first connecting means for connecting the first reactor and the second reactor, A compound manufacturing apparatus comprising a third supply means for continuously supplying the compound represented by the general formula (13) to the second reactor.

[10] The manufacturing apparatus further comprises a third reactor and A second connecting means for connecting the second reactor and the third reactor, The system comprises a fifth supply means for continuously supplying the reaction solution in the second reactor to the third reactor, The apparatus for producing the compound according to [9], wherein the third reactor is a reactor for producing the compound represented by the general formula (1).

[11] The manufacturing apparatus according to [9] or

[10] , further comprising a fourth supply means for continuously supplying the catalyst to the second reactor. [Effects of the Invention]

[0022] The present invention provides a novel method for efficiently producing quinizalin derivatives of a different type from the quinizalins used as raw materials, via leucoquinizalins, from quinizalins. [Brief explanation of the drawing]

[0023] [Figure 1] This is a schematic diagram showing an example of a compound manufacturing apparatus according to one embodiment of the present invention. [Figure 2] This is a schematic diagram showing another example of a compound manufacturing apparatus according to one embodiment of the present invention. [Figure 3] These are imaging data obtained by STEM-EDS for the precious metal solid catalyst obtained in Manufacturing Example 1. [Figure 4] These are imaging data obtained by STEM-EDS for the precious metal solid catalyst obtained in Manufacturing Example 2. [Figure 5] This graph shows the change in the yield of the compound in Example 4 over time. [Figure 6] This graph shows the change in the yield of the compound in Example 5 over time. [Modes for carrying out the invention]

[0024] In this specification, the unit of concentration "M" means "mol / L", and "mM" means "mmol / L".

[0025] ◎Method for producing compounds (Method (I)) A method for producing a compound according to one embodiment of the present invention is the following general formula (1)

[0026] [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)-; R91 (This is a hydrogen atom or an alkyl group.) A method for producing a compound represented by (which may be referred to as "compound (1)" in this specification), The above manufacturing method is represented by the following general formula (12)

[0027] [ka] (In the formula, R 11 and R 12 Each 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. From the compound represented by (which may be referred to as "compound (12)" in this specification), the following general formula (11)

[0028] [ka] (In the formula, R 11 and R 12 (This is the same as above.) Step (A) to obtain a compound represented by (which may be referred to as "compound (11)" in this specification), The compound represented by the above general formula (11) and the following general formula (13)

[0029] [ka] (In the formula, R 13 (This is the same as above.) The process includes step (B) of reacting a compound represented by (13) with a compound represented by the general formula (1) to obtain a compound represented by the general formula (1), In step (A) above, a solution containing the compound represented by general formula (12) and a reducing agent are continuously supplied to a first reactor containing a noble metal solid catalyst to produce the compound represented by general formula (11). In step (B), the compound represented by general formula (11) obtained in step (A) is continuously supplied to the second reactor, and the compound represented by general formula (11) and the compound represented by general formula (13) are reacted in the second reactor. In this specification, the manufacturing method of this embodiment may be referred to as "manufacturing method (I)".

[0030] According to the above manufacturing method (I), in step (A), a solution containing compound (12) and a reducing agent are continuously supplied to a first reactor containing a noble metal solid catalyst and reacted to produce compound (11). Furthermore, in step (B), compound (11) obtained in step (A) is continuously supplied to a second reactor, and compound (11) and compound (13) are reacted in the second reactor to produce compound (1), thereby efficiently obtaining compound (1) without placing a large burden on the environment.

[0031] In this specification, not only in the case of compound (1) above, but also when a compound is represented by a general formula or another formula (a non-generalized formula; in this specification, sometimes simply referred to as "formula"), a symbol may be assigned to these general formulas or other formulas. In such cases, as in the case of compound (1) above, a name with that symbol may be assigned to the compound.

[0032] <<Compound (1)>> First, we will explain compound (1), which is the target product of manufacturing method (I). Compound (1) is represented by the general formula (1) and is a quinizalin derivative.

[0033] 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 the present specification, the term "group" shall encompass not only an atomic group formed by bonding of a plurality of atoms but also a single atom, unless otherwise specified.

[0034] In the above general formula (1), R 101 and R 102 are each independently a hydrogen atom or a monovalent organic group, provided that at least one of R 101 and R 102 is, among the above organic groups, specifically a group represented by general formula -CH2-R 13 . That is, the compound (1) necessarily has a group represented by general formula -CH2-R 101 and R 102 as one or both of the organic groups, and necessarily has the group represented by general formula -CH2-R 13 .

[0035] More specifically, examples of the combination of R 101 and R 102 include: a combination of a hydrogen atom and a group represented by general formula -CH2-R 13 ; a combination of a group represented by general formula -CH2-R 13 and a hydrogen atom; a combination of two groups each represented by general formula -CH2-R 13 ; a combination of a monovalent organic group other than a group represented by general formula -CH2-R 13 and a group represented by general formula -CH2-R 13 ; and a combination of a group represented by general formula -CH2-R 13 and a monovalent organic group other than a group represented by general formula -CH2-R 13 . When the combination of R 101 and R 102 is a combination of two groups each represented by general formula -CH2-R 13 , R 101 and R 102 may be the same as or different from each other.

[0036] In the above general formula (1), R 13 is an alkyl group, an aryl group, an aralkyl group, a heteroaryl group or a heteroarylalkyl group. The above R13 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. The number of carbon atoms in the alkyl group is preferably 1 to 30, and more preferably 1 to 20.

[0037] The number of carbon atoms in the linear or branched (i.e., chain-like) alkyl 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, for example, 1 to 8, 1 to 6, or 1 to 4.

[0038] The number of carbon atoms in the alkyl group having a cyclic structure, such as the cyclic alkyl group (cycloalkyl 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.

[0039] The aforementioned R 13 The aryl group in the above-mentioned material may be monocyclic or polycyclic. The number of carbon atoms in the aryl group is preferably 6 to 22.

[0040] Examples of the aryl 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 aforementioned aryl group may also include 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.

[0041] More preferably, the aryl group has 6 to 18 carbon atoms, and may be, for example, any of 6 to 14, 6 to 12, and 6 to 8. Examples of particularly preferred aryl groups include a phenyl group and the like.

[0042] The aforementioned R 13 Examples of the aralkyl group in include a monovalent group having a structure in which one hydrogen atom bonded to a carbon atom in the alkyl group is substituted with the aryl group. The aromatic ring in the aralkyl group may be either monocyclic or polycyclic. The aralkyl group preferably has 7 to 23 carbon atoms.

[0043] More preferably, the aralkyl group has 7 to 19 carbon atoms, and may be, for example, any of 7 to 15, 7 to 13, and 7 to 9. Examples of preferred aralkyl groups include a benzyl group (phenylmethyl group), a phenethyl group (2-phenylethyl group), a 3-phenylpropyl group, a 4-phenylbutyl group, a 1-naphthylmethyl group, a 2-naphthylmethyl group, and the like. Examples of particularly preferred aralkyl groups include a benzyl group and the like.

[0044] The aforementioned R 13 Examples of the heteroaryl group in include, among the aryl groups in R 13 , groups having aromaticity in which one or more carbon atoms constituting the aromatic ring skeleton are substituted with a hetero atom, either alone or together with a hydrogen atom bonded to said carbon atom; and groups having aromaticity obtained from the cyclic alkyl group in R 13 wherein one or more single bonds (C-C) between carbon atoms are substituted with a double bond (C=C), one hydrogen atom bonded to said carbon atom is removed, and further one or more carbon atoms constituting the ring skeleton are substituted with a hetero atom, either alone or together with a hydrogen atom bonded to said carbon atom, and the resulting group has aromaticity. For example, the heteroaryl group may be monocyclic or polycyclic.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] In the heteroaryl group, the number of heteroatoms constituting the aromatic ring skeleton is preferably 1 or 2.

[0049] 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.

[0050] The aforementioned R 13 The heteroarylalkyl group in the above is one that does not have a free valence in the alkyl group (in other words, R 13Examples include monovalent groups having a structure in which one hydrogen atom bonded to a carbon atom (which does not form a covalent bond with the methylene group (-CH2-) to which it is bonded) is substituted with the heteroaryl group. The aromatic ring in the heteroarylalkyl group may be monocyclic or polycyclic.

[0051] 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.

[0052] The aforementioned R 13 In the alkyl group, aryl group, aralkyl group, heteroaryl group, and heteroarylalkyl group (hereinafter, these groups may be collectively referred to as "alkyl groups, etc."), one or more hydrogen atoms may 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"), or they may not be substituted. Examples of the halogen atoms include fluorine (-F), chlorine (-Cl), bromine (-Br), and iodine (-I).

[0053] The aforementioned R 13 In the alkyl group, etc., where 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.

[0054] The substitution position of the hydrogen atom by the hydrogen atom substituent in the alkyl group, etc., is 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, in the aryl group or aralkyl group having 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.

[0055] The number of hydrogen atom substitutions by hydrogen atom substituents in the alkyl group, etc., is preferably 1 to 6, and may be any of 1 to 5, 1 to 4, and 1 to 3.

[0056] The aforementioned R 13 In the alkyl group etc. (the alkyl group, aryl group, aralkyl group, heteroaryl group and heteroarylalkyl group), one or more non-adjacent carbon atoms, either alone or together with the 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 91 A group represented by -, or the general formula -N(-R 91 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"). In this specification, a carbon atom being substituted with a substituent along with the hydrogen atom to which it is bonded includes, for example, a methylene group (-CH2-) or a methine group (-CH(-)-) being substituted with a substituent.

[0057] The aforementioned R 91 is a hydrogen atom or an alkyl group. R 91 The alkyl group in is R 13 Examples include alkyl groups similar to those in the above, however, R 91 The number of carbon atoms is preferably 1 to 6.

[0058] The aforementioned R 13 In the alkyl group, etc., where two or more carbon atoms are substituted with carbon substituents, these multiple carbon substituents may all be the same, may all be different, or may only some be the same.

[0059] The substitution position of carbon atoms by carbon substituents in the alkyl group, etc., is not particularly limited. The number of carbon atom substitutions by carbon substituents in the alkyl group, etc., is preferably 1 to 5, and may be, for example, 1 to 3 and 1 to 2.

[0060] R 13 The group is an alkyl group having 1 to 10 carbon atoms, a phenyl group, a benzyl group, or a thienyl group, and one or more hydrogen atoms in the alkyl group, phenyl group, and benzyl group may be substituted with a halogen atom, a hydroxyl group, a carboxyl group, an amino group, a hydrazino group, a hydrazono group, a nitro group, a nitroso group, a cyano group, an isocyanone group, a cyanate group, an amidino group, a diazo group, a mercapto group, or a sulfo group, and one or more non-adjacent carbon atoms in the alkyl group, phenyl group, and benzyl 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 91 A group represented by -, or the general formula -N(-R 91 ) may be substituted with a group represented by -C(=O)- (in these general formulas, R 91 The same as above. ) is preferable.

[0061] The aforementioned R 101 and R 102 In general formula -CH2-R 13 Other monovalent organic groups besides the group represented by include, for example, monovalent aliphatic hydrocarbon groups other than alkyl groups (i.e., monovalent unsaturated aliphatic hydrocarbon groups); monovalent hydrocarbon groups having an aromatic hydrocarbon ring that do not fall under either aryl groups or aralkyl groups (sometimes referred to as "aromatic hydrocarbon ring-containing hydrocarbon group (a1)" in this specification). R 101 and R 102 In the above, one or more hydrogen atoms in the unsaturated aliphatic hydrocarbon group and in the aromatic hydrocarbon ring-containing hydrocarbon group (a1) may or may not be substituted with the hydrogen atom substituent. R 101 and R 102 In the above, one or more non-adjacent carbon atoms in the unsaturated aliphatic hydrocarbon group and in the aromatic hydrocarbon ring-containing hydrocarbon group (a1) may be substituted with the carbon substituent, either individually or together with the hydrogen atom bonded to the carbon atom, or they may not be substituted.

[0062] Examples of the unsaturated aliphatic hydrocarbon group include R 13 Examples include monovalent groups having a structure in which one or more single bonds (CC) between carbon atoms in the alkyl group are replaced by double bonds (C=C) or triple bonds (C≡C), and one or two hydrogen atoms bonded to the carbon atoms are removed. 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.

[0063] 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).

[0064] 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, for example.

[0065] 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 R13 A monovalent group having a cyclic alkyl group substituted in the above structure; R 13 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.

[0066] 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 13 A monovalent group having a cyclic alkyl group substituted in the above structure; R 13 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.

[0067] The aromatic hydrocarbon ring-containing hydrocarbon group (a1) may be, for example, 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); or one or more hydrogen atoms in the unsaturated aliphatic hydrocarbon group may be R 13A monovalent group having the structure substituted with the aforementioned aryl group; R 13 Examples include monovalent groups having a structure in which one or more hydrogen atoms in the aryl group are substituted with the unsaturated aliphatic hydrocarbon group.

[0068] R 101 and R 102 The manner in which the hydrogen atom in the above-mentioned hydrogen atom substituent is substituted is as described above, R 13 This is similar to the substitution of a hydrogen atom in the alkyl group, etc., by the hydrogen atom substituent. R 101 and R 102 The manner in which carbon atoms are substituted by the carbon substituents in R is as described above. 13 This is similar to the manner in which carbon atoms in the alkyl group, etc., are substituted by the carbon substituents.

[0069] The aforementioned R 101 and R 102 One of them is a hydrogen atom, and the other is the one of the general formula -CH2-R 13 Compound (1), which is represented by the group, is also classified as compound (12). Therefore, by using such compound (1) as compound (12) and repeating steps (A) and (B), R 101 and R 102 All of the above are based on the general formula -CH2-R 13 Further different types of compounds (1) can be obtained, which are represented by the group (12)-101. In other words, a wider variety of compounds (1) can be produced by using quinizalin (compound (12)-101).

[0070] Next, we will explain the raw materials and other materials used in manufacturing method (I), as well as the details of each process.

[0071] <<Process (A)>> In step (A) described above, compound (11) is obtained from compound (12). At this time, compound (11) is produced by continuously supplying a solution containing compound (12) (sometimes referred to as "solution of compound (12)" in this specification) and a reducing agent to a first reactor containing a noble metal solid catalyst. The compound (11) obtained in step (A) is then continuously supplied to a second reactor for step (B) described later.

[0072] In this specification, not limited to the case of process (A), the method of continuously supplying raw materials to a reactor to carry out a reaction and continuously discharging the resulting reactant from the reactor may be referred to as the "flow method." On the other hand, not limited to the case of process (B) described later, a method in which the reaction is carried out without continuously supplying raw materials to the reactor, or in which the obtained reactants are not continuously discharged from the reactor, is sometimes called a "batch method."

[0073] The compound (12), the noble metal solid catalyst, and the reducing agent used in step (A) may each be one type or two or more types, and if there are two or more types, their combination and ratio can be arbitrarily selected according to the purpose.

[0074] <Compound (12)> The compound (12) used in step (A) is represented by the general formula (12) above and is quinizalin or its derivatives (quinizalins). Compound (12) is the starting material used in the production of compound (1). Compound (1) includes compounds classified as compound (12), and such compounds (1) can also be used as raw materials for producing other different types of compound (1). However, other different types of compound (1) cannot be obtained from the resulting compound (1).

[0075] In the above general formula (12), R 11 and R 12 Each of these is independently a hydrogen atom or the aforementioned organic group. However, R 11 and R 12at least one of which is a hydrogen atom. That is, the compound (12) is a compound represented by any one of the following general formula (12A), the following general formula (12B), and the following formula (12)-101.

[0076]

Chemical Formula

[0077] The aforementioned R 11 , R 12 , R 11a and R 12a The aforementioned organic group in is the same as the aforementioned monovalent organic group in R 101 and R 102 . Provided that it is not essential that R 11 or R 12 is a group represented by the aforementioned general formula -CH2-R 13 . That is, the aforementioned organic group in R 11 and R 12 (in other words, R 11a and R 12a ) is the same as the aforementioned organic group in R 13 except that it does not have to be a group represented by the general formula -CH2-R 101 and R 102 . Therefore, further detailed description of the aforementioned organic group in R is omitted. 11 and R 12 . Therefore, further detailed description of the aforementioned organic group in R 11 and R 12 is omitted. On the other hand, when the aforementioned organic group in R 11 or R 12 (in other words, R 11a or R 12a ) is a group represented by the general formula -CH2-R 13 , the compound (12) in this case is also classified as the compound (1).

[0078] The aforementioned R 11 and R 12is a hydrogen atom; that is, compound (12) is preferably quinizarin represented by formula (12)-101 above. In compound (1) obtained by using quinizarin (compound (12)-101), the aforementioned R 101 and R 102 one is a hydrogen atom, and the other is a group represented by the aforementioned general formula -CH2-R 13 , and this compound (1) is also classified as compound (12). Therefore, by using this compound (1) as compound (12) and carrying out step (A) and step (B) again, further different types of compound (1) can be obtained. That is, by using quinizarin (compound (12)-101), a greater variety of compounds (1) can be produced. That is, in the present embodiment, the aforementioned R 11 and R 12 are hydrogen atoms, and one of the aforementioned R 101 and R 102 is a hydrogen atom, and the other is preferably a group represented by the aforementioned general formula -CH2-R 13 .

[0079] <Compound (11)> Compound (11), which is produced in the aforementioned step (A) and used in the aforementioned step (B), is represented by the aforementioned general formula (11) and obtained from compound (12). In general formula (11), the aforementioned R 11 and R 12 are respectively the same as R 11 and R 12 in the aforementioned general formula (12). Compound (11) is leucoquinizarin or a derivative thereof (leucoquinizarins), and is the same as compound (12) except that apparently the positions of the ring skeleton of hydroquinone (1,4-dihydroxybenzene) and the ring skeleton of 1,4-benzoquinone are interchanged with each other. Therefore, further detailed description of compound (11) is omitted here.

[0080] <Solvent> In step (A), the solvent used to prepare the solution of compound (12) may be one type or two or more types. If there are two or more types, their combination and ratio can be arbitrarily selected according to the purpose.

[0081] The solvent is not particularly limited as long as it does not inhibit the reaction in step (A) and is capable of dissolving compound (12). In terms of the ease of dissolving compound (12), the solvent is preferably an organic solvent.

[0082] 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.

[0083] The organic solvent is preferably toluene, 1,4-dioxane, or tetrahydrofuran, as these have higher solubility for compound (12). The aforementioned organic solvent is preferably one with a boiling point of less than 100°C, as it is easily removed in step (B) described later. Examples of such organic solvents include tetrahydrofuran. Since the aforementioned organic solvent satisfies both of these conditions, tetrahydrofuran is more preferable.

[0084] Regardless of whether the solvent is a reducing agent as described below, in step (A), the concentration of compound (12) in the solution of compound (12) is preferably 0.1 to 100 mM, more preferably 0.5 to 20 mM, and even more preferably 2 to 10 mM. When the concentration of compound (12) (amount of solvent used) is within this range, the function of the solvent is more appropriately exerted, and the reaction to produce compound (11) from compound (12) proceeds more easily. In particular, when the concentration of compound (12) is above the lower limit, the fluidity of the solution of compound (12) becomes higher, and when the concentration of compound (12) is below the upper limit, excessive use of the solvent is suppressed. When the solvent is a reducing agent, when the amount of solvent used is within this range, in addition to the above effects, the amount of reducing agent used is also greatly in excess and sufficient.

[0085] In step (A), the supply rate (flow rate) of the compound (12) solution to the first reactor is preferably 0.06 to 120 mL / h, more preferably 0.6 to 60 mL / h, and even more preferably 1.2 to 30 mL / h. A supply rate of the compound (12) solution within this range facilitates the reaction that produces compound (11) from compound (12). Furthermore, a supply rate of the solution above the lower limit shortens the time required for step (A), while a supply rate below the upper limit increases the amount of compound (11) produced.

[0086] <Reducing agent> The reducing agent used in step (A) may be a known agent and may be in solid, liquid, or gaseous form. A solid reducing agent is preferably soluble in a solvent, and a liquid reducing agent is preferably homogeneous with a solvent. A liquid reducing agent may be a solvent.

[0087] In step (A), 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 gaseous form, 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.

[0088] 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).

[0089] 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.

[0090] In the reaction in step (A), hydrogen (hydrogen gas) is preferable as the reducing agent because it does not produce by-products derived from the reducing agent, the product compound (11) and the unreacted compound (12) are easily separated, the unreacted reducing agent is easily reused, and it exhibits good reactivity.

[0091] If the reducing agent is not a solvent, in step (A), the amount of reducing agent used is preferably 1 to 1000 times the molar amount of compound (12), and more preferably 2 to 100 times the molar amount. If the amount of reducing agent used is above the lower limit, the efficiency of compound (11) formation is increased. If the amount of reducing agent used is below the upper limit, the amount of unused reducing agent can be reduced further. When the reducing agent is a solvent, the amount of reducing agent used in step (A) is the same as the amount of solvent used as described above.

[0092] In step (A), the feed rate (flow rate) of the reducing agent to the first reactor is preferably 1 to 100 mL / min, more preferably 5 to 30 mL / min, and still more preferably 10 to 20 mL / min. When the feed rate of the reducing agent falls within this range, the reaction for producing compound (11) from compound (12) proceeds more easily. When the feed rate of the reducing agent is not less than the above lower limit, the time required for step (A) can be further shortened, and when the feed rate of the reducing agent is not more than the above upper limit, excessive use of the reducing agent can be suppressed.

[0093] <Noble Metal Solid Catalyst> The noble metal solid catalyst used in step (A) is classified as a heterogeneous catalyst used in flow-type reactions, and exhibits catalytic activity for the reaction of producing compound (11) from compound (12). The noble metal solid catalyst contains a noble metal and is solid, so it can be easily reused after use.

[0094] The noble metal solid catalyst is preferably a hydrogenation reduction catalyst.

[0095] The noble metal contained in the noble metal solid catalyst is preferably in the form of particles, and more preferably in the form of nanoparticles. In the present specification, particulate noble metals are referred to as "noble metal particles", and nanoparticulate noble metals are referred to as "noble metal nanoparticles". The activity of such a noble metal solid catalyst comprising noble metal particles (preferably noble metal nanoparticles) is higher because the surface area of the noble metal is large.

[0096] In the present specification, not limited to "noble metal nanoparticles", examples of "metal nanoparticles" include nano-sized particles formed by aggregation of about 10 to 10,000 metal atoms. The particle size of metal nanoparticles, not limited to noble metal nanoparticles, may be, for example, about 0.7 to 100 nm.

[0097] 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 in terms of higher catalytic activity.

[0098] Platinum is particularly suitable for use in combination with other precious metals and / or other metals (sometimes referred to as "other metals" in this specification) in a precious metal solid catalyst. In this case, the other metals (the "other metals") are preferably particulate, and more preferably nanoparticles, similar to the case of precious metals. In this specification, particulate other metals are referred to as "other metal particles," and nanoparticle other metals are referred to as "other metal nanoparticles." The activity of a noble metal solid catalyst containing two or more types of metal particles is increased. For example, in a noble metal solid catalyst containing both noble metal particles and the other metal particles, the particle size of the noble metal particles becomes smaller, increasing the surface area of ​​the noble metal particles. This further increases the activity of the noble metal solid catalyst because it allows the noble metal particles to be dispersed more uniformly over a wider area within the catalyst. Furthermore, in a noble metal solid catalyst containing both noble metal particles and the other metal particles, adjacent noble metal particles influence each other electronically, suppressing excessive reduction of compound (12) and improving the selectivity of compound (11) formation.

[0099] 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).

[0100] The precious metal contained in the precious metal solid catalyst and the other metals may each be one type or two or more types, and if there are two or more types, their combination and ratio can be arbitrarily selected according to the purpose.

[0101] When no other metals are used in combination with the noble metal, and when noble metals and other metals are used in combination, it is preferable to support these noble metals and other metals on a carrier. In other words, preferred noble metal solid catalysts include those containing a noble metal supported on a carrier, or a noble metal supported on a carrier and the other metal. The noble metal supported on the carrier and the other metal supported on the carrier are both preferably in particulate form, and more preferably in nanoparticle form. 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.

[0102] The aforementioned support is for supporting the catalyst and is not particularly limited as long as it does not inhibit the reaction in step (A). More specifically, examples of constituent materials for the support include 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. Among these, the support is preferably made of carbon, alumina, silica, or a composite of dimethylpolysilane and alumina, as these materials exhibit high physical and chemical stability.

[0103] The support material contained in the noble metal solid catalyst may be one type or two or more types, and if there are two or more types, their combination and ratio can be arbitrarily selected according to the purpose.

[0104] 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". In this embodiment, preferred noble metal solid catalysts, which are composed of a noble metal, or a noble metal and the other metals supported on a carrier, include Pt-Ni / DMPSi-Al2O3, Pt / DMPSi-Al2O3, Pt-Au / DMPSi-Al2O3, Pt-Fe / DMPSi-Al2O3, Pt-Co / DMPSi-Al2O3, Pd / C, Pt / C, Pt / Al2O3, Pt / SiO2, Pd / SiO2, Pt-Pd / DMPSi-Al2O3, and the like.

[0105] The shape of the noble metal solid catalyst can be cylindrical, extruded, spherical, granular, powdery, honeycomb-shaped, etc., regardless of its composition (components), and may also be an irregular shape where the shape cannot be clearly determined. The noble metal solid catalyst may be, for example, a granular form.

[0106] In step (A), a noble metal solid catalyst is placed in a first reactor for carrying out the reaction, and the solution of compound (12) and the like are supplied to the first reactor, thereby supplying the solution to the noble metal solid catalyst. Preferably, the first reactor contains packing materials such as carbon, Celite, diatomaceous earth, and silica along with the noble metal solid catalyst. Preferably, the first reactor contains a mixture of the noble metal solid catalyst and packing materials that has been prepared in advance, and after the mixture is placed in the reactor, additional packing materials may be added as needed to fill the voids in the first reactor. By placing the noble metal solid catalyst and packing materials in the first reactor, clogging of the liquid can be prevented when the solution of compound (12) and, if necessary, a liquid reducing agent or reducing agent solution are supplied to the first reactor.

[0107] In a mixture of a precious metal solid catalyst and a filler, the ratio of the amount of filler used to the total amount of precious metal solid catalyst and filler used ([amount of filler used (parts by mass)] / ([amount of precious metal solid catalyst used (parts by mass)] + [amount of filler used (parts by mass)]) × 100) is preferably 10 to 85% by mass, for example, 30 to 85% by mass, 50 to 85% by mass, and 70 to 85% by mass, or 10 to 65% by mass, 10 to 45% by mass, and 10 to 25% by mass, or 30 to 65% by mass. When the ratio is above the lower limit, the effect of using the filler is more pronounced. When the ratio is below the upper limit, excessive use of the filler is suppressed.

[0108] In this embodiment, the ratio of the volume of the noble metal solid catalyst contained in the first reactor to the volume of the containment section of the first reactor is preferably 20 to 100% by volume, more preferably 30 to 70% by volume, and even more preferably 40 to 60% by volume. When the ratio is above the lower limit, the amount of compound (11) produced increases further. The lower the ratio, the greater the effect of suppressing the overuse of the noble metal solid catalyst.

[0109] In step (A), the amount of precious metal solid catalyst used is preferably 0.01 to 10 mol%, and more preferably 0.1 to 5 mol%, relative to the molar amount of compound (12) passing through the first reactor per hour. When the amount of precious metal solid catalyst used is above the lower limit, the effect obtained by using the precious metal solid catalyst is enhanced. When the amount of precious metal solid catalyst used is below the upper limit, excessive use of the precious metal solid catalyst is suppressed.

[0110] Precious metal solid catalysts can be manufactured by known methods.

[0111] <Other conditions for process (A)> In step (A), other components that do not fall under any of the above-mentioned compound (12), solvent, reducing agent, noble metal solid catalyst, or filler may be used, or not used, as long as they do not impair the effects of the present invention. When using the aforementioned other components, in step (A), the ratio of the amount of the other components used to the amount of compound (12) 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 compound (11) production. On the other hand, the aforementioned ratio is 0% by mass or more.

[0112] In step (A), the reaction temperature in the reaction to obtain compound (11) from compound (12) in the first reactor is preferably 15 to 70°C, for example, it may be any of 15 to 55°C, 15 to 40°C, and 15 to 25°C, or any of 30 to 70°C, 45 to 70°C, and 60 to 70°C, or it may be 30 to 55°C, or the reaction may be carried out at room temperature, for example. If the reaction temperature is above the lower limit, the amount of residual compound (12) is further reduced and the amount of compound (11) produced is further increased. If the reaction temperature is below the upper limit, the amount of by-products is further reduced.

[0113] In this specification, "room temperature" means a temperature that is neither cooled nor heated, i.e., a normal temperature, such as 15-25°C.

[0114] In step (A), the reaction time in the reaction to obtain compound (11) from compound (12) in the first reactor is equivalent to the contact time between the noble metal solid catalyst and the solution of compound (12) in the presence of a reducing agent. The reaction time is preferably 0.5 to 20 minutes, and more preferably 1 to 10 minutes. When the reaction time is above the lower limit, the amount of compound (12) remaining is further reduced and the amount of compound (11) produced is further increased. When the reaction time is below the upper limit, the reaction time is prevented from becoming excessively long.

[0115] During the reaction in step (A), the inside of the first reactor may be pressurized using a back pressure regulating valve or other pressurizing means. By increasing the back pressure inside the first reactor in this way, the amount of compound (12) remaining may be further reduced and the amount of compound (11) produced may be further increased. The back pressure inside the first reactor is preferably 0.1 to 10 MPa, and when hydrogen gas is used as a reducing agent, it is preferably 0.1 to 0.9 MPa from a safety standpoint.

[0116] <<Process (B)>> In step (B), compound (11) obtained in step (A) is continuously supplied to the second reactor, and compound (1) is produced by reacting compound (11) with compound (13) in the second reactor. Step (B) can be carried out in a flow manner, in which not only compound (11) but also compound (13) is continuously supplied to the second reactor, and the reactant (compound (1)) obtained by reacting compound (11) and compound (13) is continuously discharged from the second reactor. On the other hand, step (B) can also be carried out in a batch manner, in which compound (13) is not continuously supplied to the second reactor by, for example, pre-filling the second reactor with compound (13), or the reactant (compound (1)) is not continuously discharged from the second reactor. The second reactor is a different reactor from the first reactor and is located downstream of the first reactor, for carrying out step (B).

[0117] Compounds (11) and (13) used in step (B) may be one type each, or two or more types. If there are two or more types, their combination and ratio can be arbitrarily selected according to the purpose.

[0118] <Compound (13)> The compound (13) used in process (B) is represented by the general formula (13) above, is an aldehyde, and is the other raw material used in the production of compound (1). The R in general formula (13) 13R in the general formula (1) is 13 This is the same as the above. In other words, by reacting compound (11) with compound (13), the R in compound (13) is released. 13 The compound (11) is introduced via a methylene group, and compound (1) is formed. This type of reaction carried out in step (B) is known as the Marschalk reaction.

[0119] In step (B), the amount of compound (13) used is preferably 1 to 6 times the molar amount of compound (12), for example, it may be 1 to 5 times the molar amount and 1 to 4 times the molar amount, or 2 to 6 times the molar amount and 3 to 6 times the molar amount, or 2 to 5 times the molar amount and 3 to 4 times the molar amount. If the amount of compound (13) used is above the lower limit, the production efficiency of compound (1) will be higher. If the amount of compound (13) used is below the upper limit, the amount of unused compound (13) can be further reduced.

[0120] <Solvent> In step (B), it is preferable to use the solid compound (13) as a solution dissolved in a solvent (which may be referred to as "solution of compound (13)" in this specification). On the other hand, the liquid compound (13) may be used as is without dissolving it in a solvent, or as a solution dissolved in a solvent (solution of compound (13)), but it is preferable to use it as a solution because it improves the suitability for manufacturing.

[0121] The solvent used in step (B), such as the solvent used to prepare the solution of compound (13), may be one type or two or more types, regardless of its intended use. If there are two or more types, their combination and ratio can be arbitrarily selected according to the purpose.

[0122] The solvent is not particularly limited, as long as it does not inhibit the reaction in step (B) and is capable of dissolving compound (13). In terms of the ease of dissolving compound (13), the solvent is preferably an organic solvent.

[0123] The organic solvent used in step (B) is the same as the organic solvent used in step (A). In particular, the boiling point of the organic solvent is preferably 100°C or higher, and more preferably 120°C or higher. By using such a high-boiling-point organic solvent, when the reaction between compound (11) and compound (13) is carried out in the second reactor, even if this reaction is a heating reaction, all or most of the amount of the organic solvent used can be kept in the second reactor, and the reaction can be carried out more smoothly. Examples of such high-boiling-point organic solvents include 1-methoxy-2-propanol.

[0124] In step (B), the amount of solvent used is preferably such that the concentration of compound (11) in the second reactor is 0.0001 to 2 M, more preferably 0.001 to 1 M, and even more preferably 0.01 to 0.5 M, regardless of the purpose of use of the solvent. When the amount of solvent used is within this range, the function of the solvent is more appropriately exhibited, and the reaction to produce compound (1) proceeds more easily. In particular, when the amount of solvent used is above the lower limit, the fluidity of the reaction solution is increased, and when the amount of solvent used is below the upper limit, excessive use of the solvent is suppressed.

[0125] In step (B), the supply rate (flow rate) when compound (13) is continuously supplied to the second reactor is preferably 0.06 to 120 mL / h, more preferably 0.6 to 60 mL / h, and even more preferably 1.2 to 30 mL / h. A supply rate of compound (13) within this range facilitates the reaction that produces compound (1). Furthermore, a supply rate above the lower limit shortens the time required for step (B), while a supply rate below the upper limit increases the amount of compound (1) produced. In this specification, unless otherwise specified, the supply rate of compound (13) refers to the supply rate of compound (13) itself when compound (13) is supplied without its solution, and refers to the supply rate of the solution of compound (13) when compound (13) is supplied.

[0126] <Catalyst> In step (B), it is preferable to react compound (11) and compound (13) in the presence of a catalyst. By using a catalyst to accelerate the reaction between compound (11) and compound (13), the amount of residual compound (11) is further reduced and the amount of compound (1) produced is further increased.

[0127] In this specification, unless otherwise specified, the term "catalyst" refers to the catalyst used in process (B), not the noble metal solid catalyst used in process (A).

[0128] If a catalyst is used in step (B), the catalyst may be continuously supplied to the second reactor, or it may not be necessary to continuously supply the catalyst to the second reactor by pre-loading the catalyst into the second reactor, for example. In step (B), when compound (13) is continuously supplied to the second reactor, it is preferable to continuously supply the catalyst to the second reactor as well. This allows compound (1) to be obtained more efficiently.

[0129] The catalyst used in step (B) may be one type or two or more types, and if there are two or more types, their combination and ratio can be arbitrarily selected according to the purpose.

[0130] Examples of catalysts used in step (B) include catalysts (sometimes referred to as "catalyst (b1)") comprising a compound having both a secondary or tertiary amino group and a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aralkyloxycarbonyl group (sometimes referred to as "compound (b10)" in this specification), and catalysts (sometimes referred to as "catalyst (b2)" in this specification) comprising a mixture of a secondary or tertiary amine and a carboxylic acid, an alkyl carboxylate, an aryl carboxylate, or an aralkyl carboxylate.

[0131] In other words, in step (B) above, the catalyst is continuously supplied to the second reactor, The catalyst is 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, 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, compounds having both a tertiary amino group and an aralkyloxycarbonyl group (all of the above, compound (b10)), A mixture of a secondary amine and a carboxylic acid, a mixture of a secondary amine and an alkyl carboxylate, a mixture of a secondary amine and an aryl carboxylate, a mixture of a secondary amine and an aralkyl carboxylate, Preferably, the mixture consists of a tertiary amine and a carboxylic acid, a tertiary amine and an alkyl carboxylate, a tertiary amine and an aryl carboxylate, or a tertiary amine and an aralkyl carboxylate.

[0132] 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.

[0133] The alkoxycarbonyl group in the catalyst (b1) (compound (b10)) is, for example, a methoxycarbonyl group, an ethoxycarbonyl group, an icosyloxycarbonyl group, a cyclopropyloxycarbonyl group, a cyclodecyloxycarbonyl group, a decahydro-2-naphthyloxycarbonyl group, etc. 13 Examples include monovalent groups having a structure in which the alkyl group is bonded to the oxygen atom in the oxycarbonyl group (-OC(=O)-). The number of carbon atoms in the alkoxycarbonyl group is preferably 2 to 31, and more preferably 2 to 21.

[0134] The aryloxycarbonyl group in catalyst (b1) (compound (b10)) is, for example, a phenyloxycarbonyl group, a 1-naphthyloxycarbonyl group, an indenyloxycarbonyl group, a phenantrenyloxycarbonyl group, a pyrenyloxycarbonyl group, etc. 13 Examples include monovalent groups having a structure in which the aryl group is bonded to the oxygen atom in the oxycarbonyl group. The number of carbon atoms in the aryloxycarbonyl group is preferably 7 to 23.

[0135] The aralkyloxycarbonyl group in catalyst (b1) (compound (b10)) is, for example, a benzyloxycarbonyl group, a phenethyloxycarbonyl group, a 2-naphthylmethyloxycarbonyl group, etc. 13 Examples include monovalent groups having a structure in which the aralkyl group is bonded to the oxygen atom in the oxycarbonyl group. The number of carbon atoms in the aralkyloxycarbonyl group is preferably 8 to 24.

[0136] The catalyst (b1) is based on the following general formula (2)

[0137] [ka] (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 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).

[0138] In the general formula (2), X 1 This is an alkylene group. Previous X 1 The alkylene group in is R 13 In the alkyl group mentioned above, a divalent group having a structure in which one hydrogen atom is removed is an example. More specifically, it is as follows:

[0139] X 1 The 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.

[0140] 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.

[0141] The number of carbon atoms in the cyclic alkylene group, 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. As an alkylene group having both a chain structure and a cyclic structure, one or more hydrogen atoms (-H) in the above-mentioned linear or branched alkylene group are R 13 Examples include divalent groups having a cyclic alkyl group substituted in the above structure.

[0142] X 1 In the alkylene group, one or more hydrogen atoms may be substituted with a halogen atom, a hydroxyl group, a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aralkyloxycarbonyl group, or may not be substituted. 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.

[0143] 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 R 22 The alkyl group in is R 13 Examples include those similar to the alkyl group in the above example.

[0144] However, R 21 and R 22 At least one of them is the alkyl group. That is, R 21 and R22 Examples of combinations include combinations of hydrogen atoms and alkyl groups, combinations of alkyl groups and hydrogen atoms, and combinations of alkyl groups.

[0145] R 21 and R 22 In the alkyl group, one or more hydrogen atoms may or may not be substituted with a halogen atom or a hydroxyl group. R 21 and R 22 The halogen atom as a substituent in 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.

[0146] R 21 and R 22 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 92 A group represented by -, or the general formula -N(-R 92 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 to 3.

[0147] In the above general formula, R 92 is a hydrogen atom or an alkyl group. The aforementioned R 92 The alkyl group in is R 13 Examples include those similar to the alkyl group in the above example.

[0148] R21 and R 22 If R is the alkyl group, 21 and R 22 These atoms may be bonded to each other, forming a ring together with the nitrogen atom to which they are bonded.

[0149] In this specification, when alkyl groups bond to each other to form a ring, it means that hydrogen atoms are removed from these alkyl groups, and the carbon atoms from which these hydrogen atoms have been removed bond to each other, thereby forming a ring with the group to which these alkyl groups are bonded (R 21 and R 22 In this case, it means forming a new ring structure together with the nitrogen atom. These alkyl groups may be bonded at one location or at two or more locations. If the alkyl groups are bonded at one location, the resulting ring is monocyclic; if the alkyl groups are bonded at two locations, the resulting ring is dicyclic.

[0150] R 21 and R 22 When the alkyl group in the compound forms a ring, it is preferable that the bonding between the alkyl groups occurs at one or two locations. 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.

[0151] 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.

[0152] In the above general formula (2), R 23 This is a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group. The aforementioned R 23 The alkyl group, aryl group, and aralkyl group in the above are, respectively, R 13 Examples include the same alkyl groups, aryl groups, and aralkyl groups as described above.

[0153] The aforementioned compound (2) is the following general formula (21) or (22)

[0154] [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 252Each 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 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.

[0155] 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, except that it is R 21 and R 22 This is the same as the alkyl group in the above.

[0156] However, R 211 and R 221 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.

[0157] R 211 , R 221 and R 212 In the alkyl group, one or more hydrogen atoms may or may not be substituted with a halogen atom or a hydroxyl group. R 211 , R 221 and R 212 The halogen atom as a substituent in 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.

[0158] 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.

[0159] 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, except that it is R 92 This is the same as the alkyl group in the above.

[0160] 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 252In 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, the carbon number is limited to these, except as described above for X 1 The substituents in are the same as the alkoxycarbonyl group, aryloxycarbonyl group, and aralkyloxycarbonyl group.

[0161] 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 251 They may all be the same, they may all be different, or they may be partially the same.

[0162] 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 23n 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.

[0163] 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.

[0164] 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.

[0165] 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 23It 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.

[0166] 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.

[0167] The alkyl carboxylate in the catalyst (b2) is, for example, methyl carboxylate, ethyl carboxylate, eicosyl carboxylate, cyclopropyl carboxylate, cyclodecyl carboxylate, decahydro-2-naphthyl carboxylate, etc., with R as the alkyl group. 13 Examples include alkyl carboxylates having the alkyl group in the above-mentioned region.

[0168] Examples of the aryl carboxylate in catalyst (b2) include phenyl carboxylate, 1-naphthyl carboxylate, indenyl carboxylate, phenantrenyl carboxylate, pyrenyl carboxylate, etc., where the aryl group is R 13 Examples include the aryl carboxylates having the aforementioned aryl group.

[0169] In catalyst (b2), the carboxylic acid aralkyl ester is, for example, benzyl carboxylate, phenethyl carboxylate, 2-naphthylmethyl carboxylate, etc., with R as the aralkyl group. 13 Examples include carboxylic acid aralkyl esters having the aralkyl group.

[0170] In catalyst (b2), the monovalent hydrocarbon group bonded to the carbonyl group in the alkyl carboxylate, aryl carboxylate, and aralkyl carboxylate may be either an aliphatic hydrocarbon group or an aromatic hydrocarbon ring-containing hydrocarbon group (A2).

[0171] The aliphatic hydrocarbon group in catalyst (b2) is a hydrocarbon group that does not have an aromatic hydrocarbon group. Among aliphatic hydrocarbon groups, saturated aliphatic hydrocarbon groups (in other words, alkyl groups) include R 13 Examples include those similar to the alkyl group in the above example. Among aliphatic hydrocarbon groups, the unsaturated aliphatic hydrocarbon group is R 101 and R 102Examples include those similar to the unsaturated aliphatic hydrocarbon group in the above-mentioned example.

[0172] The aromatic hydrocarbon ring-containing hydrocarbon group (A2) in catalyst (b2) 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 (A2) can be an aromatic hydrocarbon group (in other words, an aryl group) or a monovalent group having a structure in which one or more hydrogen atoms in a monovalent aliphatic hydrocarbon group are substituted with the aromatic hydrocarbon group. The aforementioned aromatic hydrocarbon group (aryl group) is R 13 Examples include those similar to the aryl group in the above example. Among the monovalent aliphatic hydrocarbon groups, the saturated aliphatic hydrocarbon group (alkyl group) is R 13 Examples include those similar to the alkyl group in the above example. Among the monovalent aliphatic hydrocarbon groups, the unsaturated aliphatic hydrocarbon group is R 101 and R 102 Examples include those similar to the unsaturated aliphatic hydrocarbon group in the above-mentioned example.

[0173] In catalyst (b2), the monovalent hydrocarbon group constituting the substituted amino group in the secondary and tertiary amines and bonded to the nitrogen atom is the same as the monovalent hydrocarbon group bonded to the carbonyl group in the alkyl carboxylates and the like mentioned above.

[0174] The catalyst (b2) preferably consists of a mixture of dialkylamine, diarylamine, dialkylamine, monoalkylmonoarylamine, monoalkylmonoaralkylamine, monoarylmonoaralkylamine, trialkylamine, triarylamine, trialkylmonoarylamine, monoalkyldiarylamine, dialkylmonoaralkylamine, monoalkyldiarylamine, diarylmonoaralkylamine, or monoaryldiarylamine (in this specification, these components may be collectively referred to as "amine (b20)") and carboxyalkane, alkoxycarbonylalkane, aryloxycarbonylalkane, or aralkyloxycarbonylalkane (in this specification, these components may be collectively referred to as "carboxylic acid, etc. (b20)").

[0175] For example, the alkyl group in the amine (b20) is R 13 Examples include those similar to the alkyl group in the above example. The number of carbon atoms in the linear or branched alkyl group of the amine (b20) is preferably 1 to 10, and may be, for example, 1 to 8, 1 to 6, or 1 to 4. The number of carbon atoms in the alkyl group having a cyclic structure in the amine (b20) is preferably 3 to 10, and may be any of 3 to 5, 5 to 7, or 7 to 10.

[0176] For example, the aryl group in the amine (b20) is R 13 Examples include those similar to the aryl group in the above, and the number of carbon atoms is preferably 6 to 14, for example, it may be 6 to 12 and 6 to 8.

[0177] For example, R 13 Examples include those similar to the aralkyl group in the above, and the number of carbon atoms is preferably 7 to 15, for example, it may be 7 to 13 and 7 to 9.

[0178] In the carboxylic acid etc. (b20) mentioned above, the alkyl group to which the carboxyl group, alkoxycarbonyl group, aryloxycarbonyl group, and aralkyloxycarbonyl group are bonded in the carboxyalkane, alkoxycarbonylalkane, aryloxycarbonylalkane, and aralkyloxycarbonylalkane is R 13 Examples include those similar to the alkyl group in the above example. In the carboxylic acid, etc. (b20), the number of carbon atoms in the linear or branched alkyl group is preferably 1 to 10, and may be, for example, 1 to 8, 1 to 6, or 1 to 4. In the carboxylic acid, etc. (b20), the number of carbon atoms in the alkyl group having a cyclic structure is preferably 3 to 10, and may be any of 3 to 5, 5 to 7, or 7 to 10.

[0179] The alkoxycarbonyl group, aryloxycarbonyl group, and aralkyloxycarbonyl group in the carboxylic acid, etc. (b20) are the same as those in the compound (b10) described above. In the carboxylic acid, etc. (b20), the number of carbon atoms in the linear or branched alkoxy group in the alkoxycarbonyl group is preferably 1 to 10, and may be, for example, 1 to 8, 1 to 6, or 1 to 4. In the carboxylic acid, etc. (b20), the number of carbon atoms in the alkoxy group having a cyclic structure in the alkoxycarbonyl group is preferably 3 to 10, and may be any of 3 to 5, 5 to 7, or 7 to 10. In the carboxylic acid, etc. (b20), the number of carbon atoms in the aryloxy group of the aryloxycarbonyl group is preferably 6 to 14, and may be, for example, 6 to 12 and 6 to 8. In the carboxylic acid, etc. (b20), the number of carbon atoms in the aralkyloxy group in the aralkyloxycarbonyl group is preferably 7 to 15, and may be, for example, 7 to 13 and 7 to 9.

[0180] In step (B), the amount of catalyst used is preferably 4 to 40 mol% of the amount of compound (12) used, for example, it may be 4 to 10 mol% or 10 to 40 mol%. Using a catalyst amount above the lower limit increases the efficiency of compound (1) production. Using a catalyst amount below the upper limit prevents excessive catalyst use. In particular, the amount of catalyst (b1) used is preferably 4 to 10 mol% of the amount of compound (12) used, for example, it may be 4 to 7 mol%. The amount of catalyst (b2) used is preferably 10 to 40 mol% of the amount of compound (12) used, for example, it may be either 10 to 25 mol% or 25 to 40 mol%. In step (B), when the reaction is carried out in a flow manner, it is preferable that the ratio of the amount of catalyst supplied per hour to the amount of compound (12) supplied per hour is within the numerical range of the amount of catalyst used relative to the amount of compound (12) used as described above.

[0181] <Solvent> In step (B), the solid catalyst is preferably used as a solution dissolved in a solvent (sometimes referred to as the "catalyst solution" in this specification). On the other hand, the liquid catalyst may be used as is without dissolving it in a solvent, or as a solution dissolved in a solvent (catalyst solution), but it is preferable to use it as a solution because it improves manufacturability. In step (B), a solution in which both the catalyst and compound (13) are dissolved in the solvent may be used. The solvent used for dissolving the catalyst is the same solvent as described above for dissolving compound (13).

[0182] In step (B), the supply rate (flow rate) when the catalyst is continuously supplied to the second reactor is preferably the same as the supply rate (flow rate) of compound (13) to the second reactor, for the same reasons as in the case of compound (13). In this specification, unless otherwise specified, the supply rate of the catalyst refers to the supply rate of the catalyst itself when the catalyst is supplied without a solution, and to the supply rate of the catalyst solution when the catalyst solution is supplied.

[0183] <Other conditions for process (B)> In step (B), other components that do not fall under any of the above-mentioned compound (11), compound (13), solvent, or catalyst may be used, or not used, as long as they do not impair the effects of the present invention. When using the aforementioned other components, in step (B), the ratio of the amount of the other components used to the amount of compound (11) 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 compound (1) production. On the other hand, the aforementioned ratio is 0% by mass or more.

[0184] In step (B), the reaction temperature in the second reactor to obtain compound (1) from compound (11) is preferably 100°C or higher, and may be, for example, 105°C or higher and 115°C or higher. When the reaction temperature is above the lower limit, the amount of residual compound (11) is further reduced and the amount of compound (1) 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.

[0185] In step (B), the reaction time in the reaction to obtain compound (1) from compound (11) in the second reactor is equivalent to the contact time between compound (11) and compound (13). The reaction time is preferably 3 to 36 hours, and more preferably 5 to 24 hours. When the reaction time is above the lower limit, the amount of compound (11) remaining is further reduced and the amount of compound (1) produced is further increased. When the reaction time is below the upper limit, the reaction time is prevented from becoming excessively long.

[0186] In step (B), the reaction between compound (11) and compound (13) 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 compound (1) produced is increased. Examples of the aforementioned inert gases include nitrogen gas, helium gas, and argon gas.

[0187] When compound (13) and catalyst are supplied continuously to the second reactor, it is preferable to pre-fill the second reactor with a portion of the amount of compound (13) and catalyst to be used before supplying them to the second reactor. This shortens the time it takes for the reaction in the second reactor to reach a steady state, allowing step (B) to be carried out more quickly. Preferably, the amounts of compound (13) and catalyst to be placed in the second reactor beforehand are, for example, 50% by mass or more of the amount supplied to the second reactor per hour.

[0188] Step (B) is preferably carried out in a flow manner, in which case it is preferable to continuously supply a solvent to the second reactor in addition to compound (11) and compound (13). The solvent may be supplied on its own, but it is preferable to supply it as a solution of at least compound (13).

[0189] In step (B), when compound (13), catalyst, and solvent are continuously supplied to the second reactor in order to carry out the reaction in a flow manner, it is preferable to pre-fill a portion of the amounts of compound (13), catalyst, and solvent used in the second reactor before supplying them to the second reactor. In this specification, the solution which is a mixture of compound (13), catalyst, and solvent that is pre-filled in the second reactor in this manner may be referred to as the "first solution." The solution which is a mixture of compound (13), catalyst, and solvent that is subsequently supplied continuously to the second reactor may be referred to as the "second solution."

[0190] In step (B), compound (11), compound (13), and solvent are continuously supplied to a heated second reactor, and the reaction is carried out while removing the solvent from the second reactor to produce compound (1). Furthermore, in step (B), it is preferable to continuously supply the reaction solution from the second reactor to a heated third reactor and carry out the reaction to produce compound (1). By carrying out the reaction in two stages in this way, the yield of compound (1) is further increased. The solvent may be supplied on its own, but it is preferable to supply it as a solution of at least compound (13). The third reactor is a reactor different from the first and second reactors, located downstream of the second reactor (on the opposite side from the first reactor), and is used for carrying out step (B).

[0191] In step (B), the solvent to be removed from the second reactor may include, for example, the solvent used to dissolve compound (12) in step (A), the solvent used to dissolve compound (13) in step (B), and the solvent used to dissolve the catalyst in step (B). In step (B), the reaction is carried out while removing the solvent from the second reactor, which increases the rate of compound (1) formation.

[0192] However, in step (B), it is preferable to leave at least some of the solvent in the second reactor. Doing so increases the amount of compound (1) produced.

[0193] The solvent used to dissolve compound (12) in step (A) is solvent S. 12 The solvent used to dissolve compound (13) in step (B) is solvent S. 13 The solvent used to dissolve the catalyst in step (B) is solvent S. C In this case, the solvent S in process (A) 12 The amount of solvent S used in process (B) 12 Percentage of removal amount ([Solvent S in step (B) 12 [Amount of removal of solvent S in step (A)] / [Amount of solvent S in step (A)] 12 [Amount used] × 100 (volume %) R 12 This refers to the solvent S in process (B). 13 and solvent S C Solvent S in process (B) relative to the total amount used 13 and solvent S C The percentage of the total amount removed (([Solvent S in step (B) 13 [Amount of removal] + [Solvent S in step (B)] C [Amount of removal of solvent S in step (B)]) / ([Amount of solvent S in step (B)] 13 [Amount of solvent used] + [Solvent S in step (B)] C [Amount used] × 100 (volume %) R 13+C It is preferable that the solvent S is higher than the given value. In step (B), the solvent S is used in this manner. 12 solvent S 13 and solvent S C By prioritizing the removal of R, the reactions in the first and second reactors can be carried out more smoothly, and the amount of by-products can be reduced. 12 is solvent S 12 This can be adjusted by adjusting the boiling point of R. 13+C is solvent S 13 and solvent S C This can be adjusted by changing the boiling point. Note that solvent S is used here. 12 solvent S 13 and solvent S C If neither of these is used, the amount of solvent used and removed is 0 (zero).

[0194] The reaction solution in the second reactor typically contains, in addition to compound (1), unreacted compound (11), unreacted compound (13), a reaction intermediate formed by the reaction of compound (11) and compound (13) before becoming compound (1), and water (by-product) produced in the reaction. The reaction solution typically also contains the solvent, which is not one of the raw materials or reaction products, and the catalyst.

[0195] The supply rate (flow rate) of the reaction solution in the second reactor to the third reactor is preferably the same as the supply rate (flow rate) of compound (13) to the second reactor, for the same reasons as described earlier for compound (13).

[0196] In step (B), the reaction temperature in the reaction to obtain compound (1) from compound (11) in the third reactor is preferably 95°C or higher, and may be the same as or different from the reaction temperature in the reaction to obtain compound (1) from compound (11) in the second reactor. When the reaction temperature is above the lower limit, the amount of residual compound (11) is further reduced and the amount of compound (1) 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.

[0197] In manufacturing method (I), after the completion of step (B), the resulting reaction mixture may be post-treated as needed by known methods to isolate compound (1). That is, post-treatment operations such as filtration, washing, extraction, pH adjustment, dehydration, and concentration may be performed individually or in combination of two or more, and compound (1) may be isolated by concentration, crystallization, reprecipitation, thin-layer chromatography, column chromatography, etc. Furthermore, the isolated compound (1) may be purified by performing operations such as crystallization, reprecipitation, thin-layer chromatography, column chromatography, extraction, and stirring and washing of crystals with a solvent one or more times, individually or in combination of two or more, as needed. Alternatively, after the completion of step (B), the resulting reaction mixture may be post-treated as needed, and compound (1) may be used for the following intended use without being isolated. For example, compound (1) may be subjected to the following intended reaction without being isolated.

[0198] The structure of compound (1) obtained by manufacturing method (I) can be confirmed by known methods such as nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), and infrared spectroscopy (IR).

[0199] ◎Method for producing compounds (Method of production (II)) A method for producing a compound according to one embodiment of the present invention is the following general formula (1)

[0200] [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 13The 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 a compound represented by (i.e., compound (1)), The above manufacturing method is represented by the following general formula (11)

[0201] [ka] (In the formula, R 11 and R 12 Each 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. A compound represented by (i.e., compound (11)) and the following general formula (13)

[0202] [ka] (In the formula, R 13 (This is the same as above.) The process includes step (C) of reacting a compound represented by (i.e., compound (13)) with a compound represented by the general formula (1) (compound (1)), In step (C) above, the compound represented by general formula (11), the compound represented by general formula (13), and a solvent are continuously supplied to a heated second reactor, and the reaction is carried out while removing the solvent to produce the compound represented by general formula (1). In step (C) above, the reaction solution in the second reactor is further continuously supplied to the heated third reactor to carry out the reaction, thereby producing the compound represented by the general formula (1). In this specification, the manufacturing method of this embodiment may be referred to as "manufacturing method (II)".

[0203] The above-mentioned manufacturing method (II) is the same as the above-mentioned manufacturing method (I), except that it is not specified that compound (11) used in step (B) is obtained in step (A), and in step (B), compound (11), compound (13), and solvent are continuously supplied to a heated second reactor, and the reaction is carried out while removing the solvent to produce compound (1), and in step (B), the reaction solution in the second reactor is further continuously supplied to a heated third reactor, and the reaction is carried out to produce compound (1). According to manufacturing method (II), compound (1) can be obtained efficiently.

[0204] In other words, step (C) is the same as step (B) in the above-described manufacturing method (I), except that the compound (11) used is not specified as the one obtained in step (A), and that compound (11), compound (13), and solvent are continuously supplied to a heated second reactor, and the reaction is carried out while removing the solvent to produce compound (1), and further, the reaction solution in the second reactor is continuously supplied to a heated third reactor, and the reaction is carried out to produce compound (1).

[0205] The compounds (11) used in step (C) that are not obtained in step (A) described above are not particularly limited. Examples of such compounds (11) used in step (C) include compounds (11) obtained by carrying out a reaction using a noble metal solid catalyst, compound (12), a solvent, and a reducing agent, provided that the solution containing compound (12) and the reducing agent are not continuously supplied to the noble metal solid catalyst; and compounds (11) obtained by other methods that do not involve using a noble metal solid catalyst, compound (12), a solvent, and a reducing agent.

[0206] In step (C), compound (11) can be used in the same manner as in step (B) described above. The conditions for generating compound (1) in the second reactor and the conditions for generating compound (1) in the third reactor in step (C) are the same as those in step (B) described above. For example, in step (C), a catalyst to further promote the reaction between compound (11) and compound (13) is continuously supplied to the second reactor. Preferably, the catalyst consists of a compound having both a secondary or tertiary amino group and a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, or an aralkyloxycarbonyl group, or consists of a mixture of a secondary or tertiary amine and a carboxylic acid, an alkyl carboxylate, an aryl carboxylate, or an aralkyl carboxylate.

[0207] In manufacturing method (II), as in manufacturing method (I), after the completion of step (C), the reaction mixture obtained may be post-treated as needed to isolate compound (1). The isolated compound (1) may then be further purified as needed in the same manner as in manufacturing method (I). Alternatively, after post-treating the reaction mixture obtained after the completion of step (C) as needed in the same manner as in manufacturing method (I), compound (1) may be used for the following intended purpose without being isolated.

[0208] Further detailed explanation of manufacturing method (II) is omitted.

[0209] ◎ Compound manufacturing equipment A compound manufacturing apparatus according to one embodiment of the present invention is a compound manufacturing apparatus for manufacturing a compound represented by the general formula (1) (i.e., compound (1)) by the manufacturing method (I) described above, The manufacturing apparatus, the first reactor, A first supply means for continuously supplying a solution containing the compound represented by the general formula (12) (i.e., compound (12)) to the first reactor, A second supply means for continuously supplying the reducing agent to the first reactor, The second reactor and, A first connecting means for connecting the first reactor and the second reactor, The system includes a third supply means for continuously supplying the compound represented by the general formula (13) (i.e., compound (13)) to the second reactor.

[0210] The manufacturing apparatus of this embodiment further includes a third reactor, The first connecting means and the second connecting means for connecting the third reactor, The system comprises a fifth supply means for continuously supplying the reaction solution in the second reactor to the third reactor, Preferably, the third reactor is a reactor for producing the compound represented by the general formula (1).

[0211] Preferably, the manufacturing apparatus of this embodiment further includes a fourth supply means for continuously supplying the catalyst to the second reactor.

[0212] The manufacturing apparatus of this embodiment will be described below with reference to the drawings. Figure 1 is a schematic diagram showing an example of a manufacturing apparatus for the compound of this embodiment. The manufacturing apparatus 1 shown here is suitable for carrying out both process (A) and process (B) in a flow manner.

[0213] The manufacturing apparatus 1 includes a first reactor 11 containing a noble metal solid catalyst and for carrying out a reaction to obtain compound (11) from compound (12), and a second reactor 12 for reacting compound (11) with compound (13). The manufacturing apparatus 1 includes a first supply means 91 for continuously supplying a solution containing compound (12) to a first reactor 11, and a flow path 90 connecting the first supply means 91 and the first reactor 11. The manufacturing apparatus 1 includes a second supply means 92 for continuously supplying a reducing agent to the first reactor 11, and a flow path 90 connecting the second supply means 92 and the first reactor 11. The manufacturing apparatus 1 includes a first connecting means 81 that connects the first reactor 11 and the second reactor 12. The manufacturing apparatus 1 includes a third supply means 93 for continuously supplying the compound (13) to the second reactor 12, and a flow path 90 connecting the third supply means 93 and the first connecting means 81.

[0214] The manufacturing apparatus 1 further includes a third reactor 13, which is another reactor for reacting compound (11) and compound (13). The manufacturing apparatus 1 further includes a second connecting means 82 for connecting the second reactor 12 and the third reactor 13. Of the second connecting means 82, the end portion on the second reactor 12 side extends into the interior of the second reactor 12, preferably to an area near the bottom surface inside the second reactor 12, and the end portion can be easily immersed in the reaction liquid inside the second reactor 12. The manufacturing apparatus 1 further includes, separately from the third supply means 93, a fourth supply means 94 for continuously supplying an optional component to the second reactor 12, and a flow path 90 connecting the fourth supply means 94 and the first connecting means 81. The manufacturing apparatus 1 further includes a fifth supply means 95 in the middle of the second connecting means 82 for continuously supplying the reaction liquid in the second reactor 12 to the third reactor 13. The manufacturing apparatus 1 further includes a flow path 90 for removing the liquid substance inside the third reactor 13 from the third reactor 13.

[0215] During the production of compound (1), the first supply means 91 is activated to continuously supply a solution of compound (12) to the first reactor 11 containing the noble metal solid catalyst via the flow path 90. The first supply means 91 may be, for example, a liquid transfer pump or the like, and may be a known device. The first reactor 11 is preferably a column-shaped container into which the liquid flows in from one end and out from the other. Since the reaction in step (A) proceeds rapidly, even if a container with two openings and one-way flow of the liquid is used, compound (11) can be obtained with sufficiently high efficiency, and step (A) can be carried out quickly. Examples of materials for the first reactor 11 include metal, resin, and glass. The flow path 90 is not limited to those provided here, but is not particularly limited as long as it allows for the flow of liquids, and may be a pipe made of metal, resin, glass, etc., and may be a known type.

[0216] During the production of compound (1), the second supply means 92 is further activated to continuously supply the reducing agent to the first reactor 11 containing the noble metal solid catalyst via the flow path 90. When using a gaseous reducing agent, the second supply means 92 can be, for example, a gas supply means such as a mass flow controller. When using a liquid reducing agent, or a solution obtained by dissolving a solid or liquid reducing agent in a solvent, the second supply means 92 can be, for example, a liquid transfer pump.

[0217] In Figure 1, the flow path 90 to which the first supply means 91 is connected and the flow path 90 to which the second supply means 92 is connected are separately connected to the first reactor 11. However, in the manufacturing apparatus of this embodiment, these flow paths may merge and then the merged flow path may be connected to the first reactor 11.

[0218] In this way, compound (12) and the reducing agent are continuously supplied to the first reactor 11, and the reaction is carried out in the first reactor 11, thereby obtaining compound (11) in the first reactor 11.

[0219] During the production of compound (1), the reaction solution is then continuously supplied from the first reactor 11 to the second reactor 12 via the first connecting means 81, thereby continuously supplying compound (11) to the second reactor 12.

[0220] Since the reaction in step (B) is slower than the reaction in step (A), the second reactor 12, unlike the first reactor 11, is preferably capable of storing liquid for carrying out a normal liquid-phase reaction. The material used for the second reactor 12 is the same as the material used for the first reactor 11. The first connecting means 81 is similar to the flow path 90.

[0221] During the production of compound (1), compound (13) can be continuously supplied to the second reactor 12 via the flow path 90 by activating the third supply means 93. The third supply means 93 is the same as the second supply means 92.

[0222] During the production of compound (1), the catalyst can be continuously supplied to the second reactor 12 via the flow path 90 by activating the fourth supply means 94. The fourth supply means 94 is the same as the second supply means 92.

[0223] When continuously supplying a solvent to the second reactor 12, for example, the solution of compound (13) may be continuously supplied to the second reactor 12 using the third supply means 93, or the catalyst solution may be continuously supplied to the second reactor 12 using the fourth supply means 94, or both the solution of compound (13) and the catalyst solution may be continuously supplied together.

[0224] As described above, the reaction between compound (11) and compound (13) is preferably carried out under an inert gas atmosphere. To this end, it is preferable to replace the gas inside the flow channels 90 connected to the first connecting means 81, the second reactor 12, the second connecting means 82, the third reactor 13, and the third supply means 93 and the fourth supply means 94 with an inert gas.

[0225] In this way, compound (11) is continuously supplied to the second reactor 12, preferably compound (13) is also continuously supplied to the second reactor 12, and preferably the catalyst is also continuously supplied to the second reactor 12, and the reaction is carried out in the second reactor 12, thereby obtaining compound (1) in the second reactor 12.

[0226] Furthermore, compound (13) does not need to be continuously supplied to the second reactor 12, for example, by pre-loading it into the second reactor 12. In other words, compound (1) can be produced even if a manufacturing apparatus 1 is used that does not include a third supply means 93 and a flow path 90 connecting the third supply means 93 and the first connecting means 81.

[0227] In this description, the case in which compound (13) is supplied to the second reactor 12 using the third supply means 93 and the catalyst is supplied using the fourth supply means 94 has been explained. However, in this embodiment, for example, a mixture of compound (13) and catalyst may be supplied to the second reactor 12 using the third supply means 93. Examples of the mixture of compound (13) and catalyst include a solution in which both compound (13) and catalyst are dissolved in a solvent. Furthermore, a catalyst may not be used. If a catalyst is used, it does not need to be continuously supplied to the second reactor 12, for example, by pre-loading it into the second reactor 12. Therefore, the manufacturing apparatus 1 does not necessarily have to include a fourth supply means 94 and a flow path 90 connecting the fourth supply means 94 and the first connecting means 81.

[0228] In Figure 1, the flow path 90 to which the third supply means 93 is connected and the flow path 90 to which the fourth supply means 94 is connected are separately connected to the first connecting means 81. However, in the manufacturing apparatus of this embodiment, these flow paths may merge and then the merged flow path may be connected to the first connecting means 81.

[0229] During the production of compound (1), the fifth supply means 95 is then activated to continuously supply the reaction solution in the second reactor 12 to the third reactor 13 via the second connecting means 82. As a result, the reaction takes place in the third reactor 13, and compound (1) is obtained in the third reactor 13 as well.

[0230] The fifth supply means 95 is the same as the first supply means 91.

[0231] The first connecting means 81 may be without branching, but as shown in Figure 1, it is preferable that it comprises a starting point 810 at an intermediate point, a first branching section 812 branching from this starting point 810, and a second branching section 813 branching linearly in two vertical directions at a point on the first branching section 812 away from the starting point 810, and further comprising a first valve 71 near the upper end of the second branching section 813, through which the connecting passage in the first connecting means 81 can be released, and further comprising a second valve 72 near the lower end of the second branching section 813, through which the connecting passage in the first connecting means 81 can be released. In such a first connecting means 81, the composite structure of the end 811 on the second reactor 12 side of the starting point 810, the first branching section 812, and the second branching section 813 has a structure similar to that of the Dean-Stark apparatus. Therefore, a manufacturing apparatus 1 equipped with a first connecting means 81 including a first branch 812 and a second branch 813 can be used as a manufacturing apparatus incorporating a Dean Stark apparatus. The first branch 812 preferably has an inclined region in which its height decreases as it approaches the starting point 810, and more preferably consists of such an inclined region. Having the inclined region in the first branch 812 makes the composite structure closer to the structure of the Dean-Stark device.

[0232] More specifically, while the reaction is taking place in the second reactor 12, the gas component that flows out of the second reactor 12, passes through the end portion 811 of the first connecting means 81 and the first branch portion 812, and reaches the second branch portion 813 can be extracted and recovered through the first valve 71, which is in an open state. Examples of this gas component include excess hydrogen gas supplied to the first reactor 11. The recovered gas, such as hydrogen gas, can be reused.

[0233] Furthermore, while the reaction is taking place in the second reactor 12, any low-boiling-point components that flow out of the second reactor 12, pass through the terminal portion 811 of the first connecting means 81 and the first branch portion 812, and reach the second branch portion 813 can be extracted and recovered as a liquid through the second valve 72, which is left open. Examples of these low-boiling-point components include the solvent, which has a relatively low boiling point, and water newly produced by the reaction in the second reactor 12. By carrying out the reaction in the second reactor 12 while extracting the solvent and water in this way, the rate of compound (1) formation is increased, as explained earlier.

[0234] The third reactor 13 may be the same as the second reactor 12, but it is preferable that it be the same as the first reactor 11.

[0235] The reaction solution (liquid) in the third reactor 13 contains both compound (1) produced in the second reactor 12 and compound (1) produced in the third reactor 13, as compound (1).

[0236] If a column-shaped container similar to that used in the first reactor 11 is used as the third reactor 13, the reaction solution (liquid) in the third reactor 13 can be continuously removed from the third reactor 13 via the flow path 90, and all processes can be carried out in a flow manner.

[0237] Figure 2 is a schematic diagram showing another example of the compound manufacturing apparatus of this embodiment. The manufacturing apparatus 2 shown here is suitable for performing process (A) in a flow manner and process (B) in a batch manner. More specifically, manufacturing apparatus 2 is the same as manufacturing apparatus 1, except that it does not have a third reactor 13, and furthermore, it does not have a configuration connected to the third reactor 13, namely the fifth supply means 95, the second connecting means 82, and the flow path 90 connected to the third reactor 13.

[0238] When using manufacturing apparatus 2, the reaction in the first reactor 11 and the reaction in the second reactor 12 can both be carried out in the same manner as when using manufacturing apparatus 1 during the production of compound (1). When manufacturing apparatus 2 is used, during the production of compound (1), the reaction solution (liquid) containing compound (1), etc., in the second reactor 12 is then discontinuously removed from the second reactor 12. In other words, when manufacturing apparatus 2 is used, the reaction solution (liquid) obtained in step (B) is not continuously discharged from the second reactor 12, so step (B) is a batch process. When using manufacturing apparatus 2, compound (1) can be produced in the same manner as when using manufacturing apparatus 1, except that the operations after the continuous supply of the reaction solution in the second reactor 12 to the third reactor are omitted. [Examples]

[0239] 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.

[0240] The main raw materials and reagents used in each example are shown below. [Precious metal solid catalyst] Pt / DMPSi-Al2O3(i): A platinum solid catalyst composed of platinum nanoparticles supported on a carrier made of a composite of dimethylpolysilane (DMPSi) and alumina (Al2O3). Pt-Ni / DMPSi-Al2O3(i): A platinum-nickel solid catalyst composed of platinum nanoparticles and nickel nanoparticles supported on a carrier made of a composite of dimethylpolysilane and alumina. [Compound (12)] Quinizalin: Manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. [Compound (13)] 4-Methoxybenzaldehyde (alias: p-anisaldehyde): manufactured by FUJIFILM Wako Pure Chemical Corporation Hexanal (alias: n-hexyl aldehyde): manufactured by FUJIFILM Wako Pure Chemical Corporation [Catalyst] Piperidinium acetate (salt formed by the reaction of piperidine and acetic acid): manufactured by FUJIFILM Wako Pure Chemical Corporation [Solvent] 1-Methoxy-2-propanol: manufactured by FUJIFILM Wako Pure Chemical Corporation THF: manufactured by FUJIFILM Wako Pure Chemical Corporation [Other Raw Materials or Reagents] Dimethylpolysilane: manufactured by Nippon Soda Co., Ltd. Diglyme: manufactured by FUJIFILM Wako Pure Chemical Corporation Sodium borohydride: manufactured by FUJIFILM Wako Pure Chemical Corporation Sodium hexachloroplatinate(IV) hexahydrate (Na₂PtCl₆·6H₂O): manufactured by Sigma-Aldrich Co. LLC Basic alumina: manufactured by Merck KGaA Nickel(II) chloride hexahydrate (NiCl₂·6H₂O): manufactured by FUJIFILM Wako Pure Chemical Corporation Chloro(triphenylphosphine)gold(I) (AuCl[P(C₆H₅)₃]): manufactured by FUJIFILM Wako Pure Chemical Corporation Iron(II) chloride (anhydrous) (FeCl₂): manufactured by FUJIFILM Wako Pure Chemical Corporation Cobalt(II) chloride hexahydrate (CoCl₂·6H₂O): manufactured by FUJIFILM Wako Pure Chemical Corporation Celite (registered trademark): manufactured by FUJIFILM Wako Pure Chemical Corporation

[0241] <<Production of Precious Metal Solid Catalyst>> [Production Example 1] <Production of Pt / DMPSi-Al₂O₃ (i)> Dimethylpolysilane (0.501 g) was mixed with THF (8 mL), and sodium borohydride (163.6 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 (134.8 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 at 150°C for 5 hours to obtain the target product, Pt / DMPSi-Al2O3(i) (precious metal solid catalyst), as a gray solid (yield 2.90 g, platinum content 0.016 mmol / g).

[0242] Using a scanning transmission electron microscope (FEI's "TECNAI OSIRIS"), the gray solid catalyst (Pt / 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 3. Of the imaging data, Figure 3(a) is the imaging data in observation mode, Figure 3(b) is the distribution data of platinum (Pt), Figure 3(c) is the distribution data of aluminum (Al), and Figure 3(d) is the distribution data of silicon (Si). From these imaging data, it was confirmed that platinum nanoparticles were immobilized on a composite support composed of dimethylpolysilane and aluminum oxide. From Figures 3(b) to 3(d), it is clear that platinum is present in the regions where silicon is distributed, and from this, it was confirmed that the platinum nanoparticles are mainly distributed in the regions where the polysilane support in the composite support is present.

[0243] [Manufacturing Example 2] <Preparation of Pt-Ni / DMPSi-Al2O3(i)> THF (8 mL) was added to dimethylpolysilane (0.501 g), followed by addition of sodium borohydride (163.4 mg) dissolved in diglyme (6 mL), and the mixture was stirred for 1 hour at room temperature under an argon atmosphere. 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 thereto, and the mixture was stirred for 3 hours at room temperature under an argon atmosphere. Basic alumina (2.50 g) was further added thereto, and the mixture was stirred for 24 hours at room temperature under an argon atmosphere. Then, methanol (400 mL) was added dropwise thereto, and the mixture was stirred for 1 hour at room temperature under an argon atmosphere. Subsequently, the obtained reaction solution was subjected to suction filtration to recover a solid, and the solid was dried under reduced pressure at 100°C for 3 hours, thereby obtaining a gray solid. This gray solid was washed sequentially 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) (a noble metal solid catalyst) as a gray solid (yield: 2.60 g, platinum content: 0.0122 mmol / g, nickel content: 0.27 mmol / g).

[0244] The gray solid catalyst (Pt-Ni / DMPSi-Al2O3(i)) obtained above was analyzed by the same method as in Production Example 1. The imaging data acquired at this time are shown in Figure 4. Among the imaging data, Figure 4(a) is imaging data in observation mode, Figure 4(b) is distribution data of platinum (Pt), Figure 4(c) is distribution data of nickel (Ni), Figure 4(d) is distribution data of aluminum (Al), and Figure 4(e) is 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 4(b) to 4(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.

[0245] <<Manufacturing of Compound (1) (Process (A) Flow method, Process (B) Batch method)>> [Example 1] Compound (1) was produced using the manufacturing apparatus shown in Figure 2. Specifically, quinizalin (compound (12)-101) (0.15 g, 0.62 mmol) was dissolved in THF (50 mL) to prepare a THF solution (quinizalin concentration 12.4 mM). The Pt / DMPSi-Al2O3(i) (0.5 g, platinum content 0.008 mmol) obtained in Production Example 1 and Celite® (2 g) were uniformly mixed, and the resulting mixture was packed into the interior of a glass column (first reactor) with an inner diameter of 10 mm and a length of 10 cm. The remaining voids inside this column were filled with Celite®. Furthermore, by attaching polytetrafluoroethylene (PTFE) filters to both ends of this column, a catalyst cartridge (first reactor containing a precious metal solid catalyst) was prepared. 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.

[0246] A 1-methoxy-2-propanol solution was prepared by dissolving 4-methoxybenzaldehyde (compound (13)-101) (0.25 g, 1.84 mmol) and piperidinium acetate (0.0306 g, 0.21 mmol) in 1-methoxy-2-propanol (3 g, 3.3 mL) at room temperature.

[0247] The 1-methoxy-2-propanol 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 upstream part of the Dean-Stark apparatus was connected to this test tube reactor via a PTFE cap, and an air cooling tube (cooling tube) was connected to the top of the liquid reservoir section of the downstream part 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 upstream part of the Dean-Stark apparatus via a Schlenk line.

[0248] 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 10 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 (step (A)).

[0249] The test tube reactor was heated to 110°C while stirring the 1-methoxy-2-propanol solution inside it. The solution discharged from the catalyst cartridge (flow reactor) was continuously supplied to the inside of the test tube reactor in this state. After supplying the entire amount of the THF solution to the catalyst cartridge, another 10 mL of THF was supplied to the catalyst cartridge. Then, the mixture was stirred at 110°C for 12 hours to carry out the reaction. During this time, solvents such as THF and water were collected from the downstream liquid reservoir in the Dean-Stark apparatus via the second valve. At the same time, the excess hydrogen gas supplied to the catalyst cartridge in step (A) was collected from the upper part of the air cooling tube (opposite the side to which the Dean-Stark apparatus was connected) via the first valve (step (B)). The solvent components that were removed and recovered were collected and analyzed by gas chromatography. The results showed that 1-methoxy-2-propanol was not detected, confirming that 1-methoxy-2-propanol remained in the test tube reactor where the reaction took place.

[0250] The reaction solution in the test tube reactor and a mixture of toluene (15 mL) were transferred to a separatory funnel, and a saturated sodium bicarbonate aqueous solution (15 mL) was added to wash the reaction solution. Next, the organic layer separated from the aqueous layer was dried using anhydrous sodium sulfate (10 g), the sodium sulfate was removed from the organic layer by filtration, and the solvent was removed by vacuum distillation using a rotary evaporator. The resulting solid was dissolved in dichloromethane (5 mL) and purified by thin-layer chromatography (eluent: toluene) to obtain the target compound (1)-101(2-(4-(methoxybenzyl)quinizalin) (yield 168.4 mg, yield 75%).

[0251] The obtained compound is compound (1)-101. 1 1H NMR, 13 The melting point (Mp) was confirmed by 13C NMR, HRMS, IR, and 13C NMR. The data obtained at this time are 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), 7.83 - 7.80 (m, 2H), 7.21 - 7.19 (m, 2H), 7.03 (d, J = 0.8 Hz, 1H), 6.89 - 6.85 (m, 2H), 4.02 (s, 2H), 3.80 (s, 3H). 13C 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℃.

[0252] [ka]

[0253] [Example 2] Compound (1)-102 was obtained in the same manner as in Example 1 (yield 61%), except that in step (B), the same molar amount of hexanal (compound (13)-102) was used instead of 4-methoxybenzaldehyde, and the amount of piperidinium acetate used was changed from 0.21 mmol to 0.07 mmol.

[0254] The obtained compound is compound (1)-102. 1 1H NMR, 13 The melting point (Mp) was confirmed by 13C NMR, HRMS, IR, and 13C NMR. The data obtained at this time are shown below. 1 ¹H NMR (400 MHz, Chloroform-d)δ13.43 (d, J = 0.6 Hz, 1H), 13.00 (s, 1H), 8.40 - 8.30 (m, 2H), 7.87 - 7.78 (m, 2H), 7.16 (d, J = 0.7 Hz, 1H), 2.80 - 2.70 (m, 2H), 1.75 - 1.61 (m, 2H), 1.46 - 1.36 (m, 2H), 1.36 - 1.27 (m, 4H), 0.98 - 0.83 (m, 3H). 13 ¹³C NMR (101 MHz, Chloroform-d)δ187.25, 186.34, 157.91, 157.27, 145.58, 134.34, 134.23, 133.75, 133.62, 128.09, 127.02, 126.90, 112.03, 111.07, 31.64, 30.18, 29.12, 28.73, 22.58, 14.08. HRMS calc.: 324.1362, found: 324.1355 (-2.0 ppm). IR (ATR, ν max / cm -1 ) 3068, 2946, 2930, 2854, 1620, 1581, 1442, 1425, 1401, 1383, 1373, 1343, 1305, 1279, 1261, 1238, 1213, 1179, 1157, 1132, 1118, 1013, 1003, 960, 916, 903, 834, 813, 792, 785, 753, 734, 719, 680, 649, 626, 548, 518, 485, 445, 438, 423. Mp. 99 °C.

[0255] [Chemical]

[0256] [Example 3] Compound (1)-103 was obtained in the same manner as in Example 1 (yield 72%), except that in step (A), compound (1)-102 (0.46 mmol) obtained in Example 2 was used instead of quinizalin (0.62 mmol).

[0257] The obtained compound is compound (1)-103. 1 1H NMR, 13 The findings were confirmed by 13C NMR, HRMS, and IR. The data obtained at this time are shown below. 1 H NMR (400 MHz, Chloroform-d)δ13.70 (s,1H), 13.61 (s, 1H), 8.45 - 8.29 (m, 2H), 7.81 (dd, J = 5.9, 3.4 Hz, 2H), 7.18 - 7.06 (m, 2H), 6.88 - 6.72 (m, 2H), 4.14 (s, 2H), 3.76 (s, 3H), 2.87 - 2.76 (m, 2H), 1.52 - 1.35 (m, 4H), 1.28 (dp, J = 6.6, 2.8 Hz, 4H), 0.89 (dt, J = 8.6, 4.0 Hz, 3H). 13 C NMR (101 MHz, Chloroform-d)δ186.60, 186.40, 158.06, 157.52, 157.47, 143.88, 140.14, 134.18, 134.15, 133.70, 133.67, 131.06, 129.20, 126.88, 113.94, 110.69, 110.49, 55.25, 31.61, 30.85, 29.77, 29.01, 27.33, 22.58, 14.10. HRMS calc.: 444.1937, found: 444.1932 (-1.1 ppm). IR (ATR, ν max / cm -1) 3073, 3035, 3007, 2955, 2928, 2862, 2847, 1880, 1619, 1584, 1564, 1511, 1462, 1451, 1422, 1417, 1391, 1342, 1330, 1313, 1300, 1292, 1259, 1240, 1204, 1181, 1173, 1137, 1112, 1099, 1072, 1036, 1017, 1007, 996, 983, 956, 898, 841, 818, 797, 786, 775, 746, 730, 710, 689, 673, 643, 639, 619, 557, 538, 524, 511, 484, 452, 434, 415.

[0258] [ka]

[0259] <<Manufacturing of Compound (1) (Process (A) Flow Schema, Process (B) Flow Schema)>> [Example 4] Compound (1) was produced from quinizalin using the manufacturing apparatus shown in Figure 1. Specifically, quinizalin (compound (12)-101) and the internal standard 1,3,5-trimethoxybenzene were dissolved in THF at room temperature to prepare a THF solution with a quinizalin concentration of 0.03 M and a 1,3,5-trimethoxybenzene concentration of 0.01 M. Using the Pt / DMPSi-Al2O3(i) (0.5g, platinum content 0.008 mmol) obtained in Production Example 1 and Celite (registered trademark) (2g), a catalyst cartridge (first reactor containing a precious metal solid catalyst) similar to that in Example 1 was prepared, and this was installed in the flow reactor (Tokyo Rikakikai Co., Ltd. "Synple Flow MCR-1000" model) in the same manner as in Example 1.

[0260] At room temperature, a 1-methoxy-2-propanol solution (12 mL) was prepared with a concentration of 0.1 M 4-methoxybenzaldehyde (compound (13)-101) and a concentration of 0.005 M piperidinium acetate.

[0261] A test tube-type reactor (second reactor) with an inner diameter of 25 mm and a length of 15 cm was filled with the 1-methoxy-2-propanol solution 1. The fractional distillation section of the front stage of the Dean-Stark apparatus was connected to this test tube-type reactor, and an air-cooling tube (cooling tube) was connected to the upper part 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 upper part of the front stage of the Dean-Stark apparatus via a Schlenk line.

[0262] A second 1-methoxy-2-propanol solution was prepared at room temperature with a concentration of 0.2 M 4-methoxybenzaldehyde and a concentration of 0.01 M piperidinium acetate.

[0263] 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 15 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 (step (A)).

[0264] 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 120°C while stirring the 1-methoxy-2-propanol solution 1 inside it. Separately, the 1-methoxy-2-propanol solution 2 was added to the solution discharged from the catalyst cartridge (flow reactor) at a flow rate of 7 mL / h using a liquid transfer pump (Minato Concept peristaltic pump "MCRP204", third supply means). This combined solution was then supplied from the upper part of the upstream section of the Dean-Stark apparatus through a Schlenk line 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 7 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 a conical flask at room temperature. During this time, solvents such as THF and water were extracted and recovered from the downstream liquid reservoir in the Dean-Stark apparatus via the second valve, and at the same time, the excess hydrogen gas supplied to the catalyst cartridge in step (A) was recovered from the upper part of the air-cooling tube (opposite the side to which the Dean-Stark apparatus was connected) via the first valve (step (B)).

[0265] 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)). Figure 5 shows a graph illustrating the change in yield over time.

[0266] After the solution had been stored for 50 minutes, decane, an internal standard, was added. The sample after the addition of decane was then analyzed by gas chromatography, and the amount of 1,3,5-trimethoxybenzene in the stored solution was calculated from the analysis results. The amount of quinizalin that passed through the glass column (third reactor) during the 50 minutes was also calculated.

[0267] After the solution had been stored for 50 minutes, hexane (10 mL) was added, and the resulting precipitated solid was separated by suction filtration to obtain the target compound (1)-101 as a pure product (yield 85.7 mg, yield 66%). 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 compound was then purified by thin-layer chromatography (eluent: toluene) to obtain the target compound (1)-101 (yield 20.9 mg, yield 16%). In other words, the total yield of these compounds (1)-101 at this stage was 106.6 mg (total yield was 82%).

[0268] 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.

[0269] [Example 5] Compound (1) was produced from quinizalin using the manufacturing apparatus shown in Figure 1. Specifically, quinizalin (compound (12)-101) and the internal standard 1,3,5-trimethoxybenzene were dissolved in THF at room temperature to prepare a THF solution with a quinizalin concentration of 0.03 M and a 1,3,5-trimethoxybenzene concentration of 0.01 M. Using the Pt-Ni / DMPSi-Al2O3(i) (0.5g, platinum content 0.008 mmol) obtained in Production Example 2 and Celite (registered trademark) (2g), a catalyst cartridge (first reactor containing a precious metal solid catalyst) similar to that in Example 1 was prepared, and this was installed in the flow reactor (Tokyo Rikakikai Co., Ltd. "Synple Flow MCR-1000" model) in the same manner as in Example 1.

[0270] 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).

[0271] 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.

[0272] 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.

[0273] 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 (step (A)).

[0274] 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 step (A) was recovered from the upper part of the air-cooling tube (opposite the side to which the Dean-Stark apparatus was connected) via the first valve (step (B)).

[0275] As time progresses, a minute sample is taken from this stored solution, and, as in Example 4, 1 The yield of compound (1)-101 was calculated from the integral ratio of the signals in the 1H NMR spectrum. Figure 6 shows a graph illustrating the change in yield over time.

[0276] After approximately 3 hours and 5 hours of storage, compound (1)-101 was isolated in the same manner as in Example 4, with yields of 87% and 84%, respectively.

[0277] 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.

[0278] [ka] [Industrial applicability]

[0279] This invention can be used in the production of quinizalin derivatives. [Explanation of Symbols]

[0280] 1,2... Manufacturing equipment 11. Reactor No. 1 12. Reactor No. 2 13. Third Reactor 91...first supply means 92...Second supply means 93...Third supply means 94...Fourth supply means 95...Fifth supply means 81...first connection means 82...Second connection means

Claims

1. The following general formula (1) 【Chemistry 1】 (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 -CH ２ -R １３ It is a base represented by; R １３ represents an alkyl group, an aryl group, an aralkyl group, a heteroaryl group or a heteroarylalkyl group, and one 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 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 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.) A method for producing a compound represented by, The above manufacturing method is as follows: General formula (12) 【Chemistry 2】 (In the formula, R １１ and R １２ Each 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. From the compound represented by the following general formula (11) 【Transformation 3】 (In the formula, R １１ and R １２ (This is the same as above.) Step (A) to obtain a compound represented by, The compound represented by the above general formula (11) and the following general formula (13) 【Chemistry 4】 (In the formula, R １３ (This is the same as above.) The process includes step (B) of reacting a compound represented by with to obtain a compound represented by the general formula (1), In step (A) above, a solution containing the compound represented by general formula (12) and a reducing agent are continuously supplied to a first reactor containing a noble metal solid catalyst to produce the compound represented by general formula (11). A method for producing a compound, comprising: in step (B), continuously supplying the compound represented by general formula (11) obtained in step (A) to a second reactor, and reacting the compound represented by general formula (11) with the compound represented by general formula (13) in the second reactor.

2. In step (B) above, the compound represented by general formula (11), the compound represented by general formula (13), and a solvent are continuously supplied to a heated second reactor, and the reaction is carried out while removing the solvent to produce the compound represented by general formula (1). The method for producing the compound according to claim 1, further comprising the step (B) above, continuously supplying the reaction solution in the second reactor to a heated third reactor and carrying out the reaction to produce the compound represented by the general formula (1).

3. The aforementioned R １３ However, the group is an alkyl group having 1 to 10 carbon atoms, a phenyl group, a benzyl group, or a thienyl group, and one or more hydrogen atoms in the alkyl group, phenyl group, and benzyl group may be substituted with a halogen atom, a hydroxyl group, a carboxyl group, an amino group, a hydrazino group, a hydrazono group, a nitro group, a nitroso group, a cyano group, an isocyanone group, a cyanate group, an amidino group, a diazo group, a mercapto group, or a sulfo group, and one or more non-adjacent carbon atoms in the alkyl group, phenyl group, and benzyl 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 ９１ A group represented by )- or the general formula -N(-R ９１ A method for producing the compound according to claim 1 or 2, wherein the compound may be substituted with a group represented by )-C(=O)-.

4. In step (B) above, in the presence of a catalyst, the compound represented by general formula (11) and the compound represented by general formula (13) are reacted, A method for producing the compound according to claim 1 or 2, wherein the catalyst comprises 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, or comprises a mixture of a secondary amine or a tertiary amine and a carboxylic acid, an alkyl carboxylate, an aryl carboxylate, or an aralkyl carboxylate.

5. The catalyst is defined by the following general formula (2) 【Transformation 5】 (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 method for producing the compound according to claim 4, comprising the compound represented by [the specified formula].

6. The aforementioned R １１ and R １２ That is a hydrogen atom, The aforementioned R １０１ and R １０２ Either one is a hydrogen atom, and the other is the general formula -CH ２ -R １３ A method for producing the compound according to claim 1 or 2, wherein the group is represented by .

7. The following general formula (1) 【Transformation 6】 (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 -CH ２ -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.) A method for producing a compound represented by, The above manufacturing method is as follows: General formula (11) 【Transformation 7】 (In the formula, R １１ and R １２ Each 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. A compound represented by the following general formula (13) 【Transformation 8】 (In the formula, R １３ (This is the same as above.) The process includes step (C) of reacting a compound represented by with to obtain a compound represented by the general formula (1), In step (C) above, the compound represented by general formula (11), the compound represented by general formula (13), and a solvent are continuously supplied to a heated second reactor, and the reaction is carried out while removing the solvent to produce the compound represented by general formula (1). A method for producing a compound, wherein in step (C) above, the reaction solution in the second reactor is continuously supplied to a heated third reactor and the reaction is carried out to produce the compound represented by the general formula (1).

8. In step (C) above, the catalyst is further continuously supplied to the second reactor, A method for producing the compound according to claim 7, wherein the catalyst comprises 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, or comprises a mixture of a secondary amine or a tertiary amine and a carboxylic acid, an alkyl carboxylate, an aryl carboxylate, or an aralkyl carboxylate.

9. A compound manufacturing apparatus for producing the compound represented by the general formula (1) according to the compound manufacturing method described in claim 1, The manufacturing apparatus, the first reactor, A first supply means for continuously supplying a solution containing the compound represented by the general formula (12) to the first reactor, A second supply means for continuously supplying the reducing agent to the first reactor, The second reactor and, A first connecting means for connecting the first reactor and the second reactor, A compound manufacturing apparatus comprising a third supply means for continuously supplying the compound represented by the general formula (13) to the second reactor.

10. The manufacturing apparatus further comprises a third reactor and A second connecting means for connecting the second reactor and the third reactor, The system comprises a fifth supply means for continuously supplying the reaction solution in the second reactor to the third reactor, The apparatus for producing a compound according to claim 9, wherein the third reactor is a reactor for producing a compound represented by the general formula (1).

11. The compound manufacturing apparatus according to claim 9 or 10, further comprising a fourth supply means for continuously supplying a catalyst to the second reactor.

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