Amide compound production method, compound, and catalyst

Abstract

This catalyst is for use in condensation of a carboxylic acid and an amine compound having an amino group or a substituted amino group in which one hydrogen atom in the amino group is substituted with a substituent. The catalyst comprises a compound represented by general formula (1) (in the formula, R1, R2, R3, and R4 each independently represent a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group, or an acyl group, and X1 represents a hydrogen atom, a silyl-based protecting group, a sulfonyl-based protecting group, an alkyl group, an alkenyl group, an aralkyl group, or an acyl group). This amide compound production method comprises a step for obtaining an amide compound through condensation of the carboxylic acid and the amine compound by using the catalyst.

Description

Method for producing amide compounds, compounds and catalysts

[0001] The present invention relates to a method for producing an amide compound, the compound, and a catalyst. This application claims priority based on Japanese Patent Application No. 2024-117102, filed on July 22, 2024, the contents of which are incorporated herein by reference.

[0002] Many types of pharmaceuticals, agricultural chemicals, and other physiologically active natural products contain amide bonds. Therefore, there is a strong demand for the development of an efficient method for producing amide compounds containing amide bonds.

[0003] In the production of amide compounds, an amide bond is usually formed, and dehydration condensation between a carboxylic acid and an amine, which are relatively easily available, is widely used for this purpose. However, in the dehydration condensation, an expensive condensing agent must usually be used in an equimolar amount or more relative to the raw material compound, and after the reaction, waste products derived from the condensing agent are produced as by-products. Therefore, conventional methods for producing amide compounds have the problems of low resource utilization efficiency and the need to remove by-products after the reaction.

[0004] In contrast, it has been disclosed that diboronic acid derivatives having both a biphenyl skeleton and a dehydrated dimer structure of boronic acid effectively function as catalysts for the formation of amide bonds by dehydration condensation (see Non-Patent Document 1). The use of a small amount of such a catalyst relative to the raw material compounds results in high resource utilization efficiency and eliminates the need to remove by-products after the reaction. Meanwhile, a diboronic acid derivative having both a carbazole skeleton and a dehydrated dimer structure of boronic acid has been disclosed as a compound similar in structure to such diboronic acid derivatives (see Non-Patent Document 2).

[0005] Shimada, N.; Hirata, M.; Koshizuka, M.; Ohse, N.; Kaito, R.; Makino, K. Org .Lett. 2019, 21, 4303-4308.Ian A. Pocock, Alya M. Alotaibi, Kesar Jagdev, Connor Prior, Gregory R. Burgess, Louise Male and Richard S. Grainger, Chem. Commun., 2021, 57, 7252-7255.

[0006] However, the diboronic acid derivative disclosed in Non-Patent Document 1 requires many synthetic steps, and its production is problematic in that it is cumbersome. A synthetic route for a representative diboronic acid derivative, the compound represented by formula (9)-101, is shown below.

[0007]

[0008] Furthermore, Non-Patent Document 2 does not disclose any reaction for forming an amide bond.

[0009] An object of the present invention is to provide a novel catalyst that can be used in an amide bond-forming reaction by dehydration condensation, and a method for producing an amide compound using the catalyst.

[0010] In order to solve the above problems, the present invention employs the following configuration: [1] A method for producing an amide compound, the method comprising the step of condensing, in the presence of a catalyst, a carboxylic acid with an amine compound having an amino group or a substituted amino group in which one hydrogen atom in the amino group is substituted with a substituent, to obtain the amide compound, wherein the catalyst is a compound represented by the following general formula (1):

[0011] (In the formula, R １ , R ２ , R ３ and R ４ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group, or an acyl group; X １is a hydrogen atom, a silyl protecting group, a sulfonyl protecting group, an alkyl group, an alkenyl group, an aralkyl group, or an acyl group. １ , R ２ , R ３ and R ４ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group having 1 to 10 carbon atoms, or an acyl group having 2 to 10 carbon atoms. １ is a hydrogen atom, a trialkylsilyl group, a dialkylarylsilyl group, an alkyldiarylsilyl group, a triarylsilyl group, a dialkylaralkylsilyl group, an alkanesulfonyl group, a substituted alkanesulfonyl group, an arenesulfonyl group, a substituted arenesulfonyl group, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, or an acyl group having 2 to 10 carbon atoms. [4] The method for producing an amide compound according to any one of [1] to [3], wherein the carboxylic acid is a β-hydroxycarboxylic acid or an α-hydroxycarboxylic acid. [5] The method for producing an amide compound according to any one of [1] to [3], wherein the carboxylic acid is a carboxylic acid represented by the following general formula (2):

[0012] (In the formula, Q １ is a single bond or a divalent hydrocarbon group, in which one or more hydrogen atoms may be substituted with a protected amino group, and when the hydrocarbon group has a methylene group, one or more non-adjacent methylene groups in the hydrocarbon group may be substituted with a carbonyl group; Z １ is a hydrogen atom or a monovalent hydrocarbon group, in which one or more hydrogen atoms may be substituted with a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or a hydroxyl group, and when the hydrocarbon group has a methylene group, one or two or more non-adjacent methylene groups in the hydrocarbon group may be substituted with an oxygen atom or a group represented by the formula "-NH-"; R ９１is a hydrogen atom or an alkyl group. [6] The method for producing an amide compound according to any one of [1] to [3], wherein the carboxylic acid does not have a hydroxyl group. [7] The method for producing an amide compound according to [4], wherein the amine compound is a compound represented by the following general formula (3):

[0013] (In the formula, Z ２ and Z ３ are each independently a hydrogen atom or a monovalent hydrocarbon group, one or more hydrogen atoms in the hydrocarbon group may be substituted with an alkoxycarbonyl group or a protected amino group, one or more non-adjacent carbon atoms in the hydrocarbon group may be substituted alone or together with some or all of the hydrogen atoms bonded to the carbon atom with a nitrogen atom, an oxygen atom, a sulfur atom, a group represented by the formula "-NH-", a group represented by the formula "-NH-CO-", a group represented by the formula "-CO-NH-", a group represented by the formula "-CO-O-", or a group represented by the formula "-O-CO-", Z ２ and Z ３ When neither of the groups is a hydrogen atom, Z ２ and Z ３ may be bonded to each other to form a ring. [8] A method for producing an amide compound according to any one of [1] to [6], wherein the amide compound is a compound represented by the following general formula (1A):

[0014] (In the formula, R １Ａ , R ２Ａ , R ３Ａ and R ４Ａ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group, or an acyl group; X １Ａ represents a hydrogen atom, a silyl protecting group, a sulfonyl protecting group, an alkyl group, an alkenyl group, an aralkyl group, or an acyl group; １Ａ When R is a triisopropylsilyl group, １Ａ , R ２Ａ , R ３Ａ and R ４Ａ is not a hydrogen atom.１Ａ , R ２Ａ , R ３Ａ and R ４Ａ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group having 1 to 10 carbon atoms, or an acyl group having 2 to 10 carbon atoms. １Ａ is a hydrogen atom, a trialkylsilyl group, a dialkylarylsilyl group, an alkyldiarylsilyl group, a triarylsilyl group, a dialkylaralkylsilyl group, an alkanesulfonyl group, a substituted alkanesulfonyl group, an arenesulfonyl group, a substituted arenesulfonyl group, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, or an acyl group having 2 to 10 carbon atoms.

[11] A catalyst for use in the condensation of a carboxylic acid with an amine compound having an amino group or a substituted amino group in which one hydrogen atom in the amino group is substituted with a substituent, wherein the catalyst is a catalyst represented by the following general formula (1):

[0015] (In the formula, R １ , R ２ , R ３ and R ４ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group, or an acyl group; X １ is a hydrogen atom, a silyl protecting group, a sulfonyl protecting group, an alkyl group, an alkenyl group, an aralkyl group, or an acyl group.

[0016] According to the present invention, there are provided a novel catalyst that can be used in an amide bond-forming reaction by dehydration condensation, and a method for producing an amide compound using the catalyst.

[0017] In this specification, the concentration unit "M" means "mol / L". In this specification, when a compound is represented by a general formula or other formula, a symbol may be attached to the general formula or other formula. In such cases, the compound may be given a name with the symbol attached. For example, in this specification, a compound represented by the general formula (1) described below may be referred to as "compound (1)".

[0018] A method for producing an amide compound according to one embodiment of the present invention includes a step of condensing, using a catalyst, a carboxylic acid with an amine compound having an amino group or a substituted amino group in which one hydrogen atom in the amino group is substituted with a substituent, to obtain the amide compound (sometimes referred to as an "amidation step" in this specification), wherein the catalyst is a carboxylic acid represented by the following general formula (1):

[0019] (In the formula, R １ , R ２ , R ３ and R ４ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group, or an acyl group; X １ is a hydrogen atom, a silyl protecting group, a sulfonyl protecting group, an alkyl group, an alkenyl group, an aralkyl group, or an acyl group (compound (1)).

[0020] According to the production method of this embodiment, the use of the novel catalyst can promote the amide bond formation reaction by dehydration condensation with a small amount of the catalyst, and unlike the use of conventional condensing agents, the amount of by-products other than the target product (amide compound) can be reduced, resulting in high resource utilization efficiency. Furthermore, by using the catalyst, unlike the use of conventional condensing agents, it is possible to omit the removal of by-products after completion of the amide bond formation reaction, thereby obtaining an amide compound through a simplified process. Furthermore, due to its structure, compound (1) constituting the catalyst can be synthesized through a reduced number of steps, as described below, unlike the diboronic acid derivatives having a biphenyl skeleton described above, and can be produced through a simplified process.

[0021] It is known that in conventional methods for producing amide compounds, when a carboxylic acid having an aromatic cyclic group, such as an aromatic carboxylic acid, is used, the amide bond-forming reaction does not proceed easily. In contrast, according to the production method of the present embodiment, by using the novel catalyst, the amide bond-forming reaction easily proceeds even when such a carboxylic acid having an aromatic cyclic group is used, and therefore the method is particularly useful.

[0022] In this specification, unless otherwise specified, the term "amide bond-forming reaction" refers to an amide bond-forming reaction that proceeds by dehydration condensation.

[0023] <<Catalyst>> The catalyst comprises compound (1). Compound (1) will be described in detail below.

[0024] <Compound (1)> Compound (1) is represented by the general formula (1). In the general formula (1), R １ , R ２ , R ３ and R ４ each independently represents a hydrogen atom (—H), a fluorine atom (—F), a chlorine atom (—Cl), a bromine atom (—Br), an iodine atom (—I), a nitro group (—NO ２ ), amino group (-NH ２ ), sulfo group (—SO ３ H), an alkyl group or an acyl group. １ , R ２ , R ３ and R ４ (In this specification, these are collectively referred to as "R １ ~R ４ ") may be the same or different. １ ~R ４ Not limited to the above case, when multiple groups "may be the same or different from each other," it means that these multiple groups may all be the same, all be different, or only some of them may be the same.

[0025] R １ ~R ４The alkyl group in may be linear, branched, or cyclic, and may have both a linear structure (linear or branched) and a cyclic structure. When the alkyl group has a cyclic structure, including when the alkyl group is cyclic, the cyclic structure may be either monocyclic or polycyclic. The number of carbon atoms in the alkyl group is preferably 1 to 20, and more preferably 1 to 10.

[0026] The number of carbon atoms in the linear or branched alkyl group is preferably 1 to 20. Examples of such linear alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, and 3-methylhexyl. Examples of such groups include a hexyl group, a 2,2-dimethylpentyl group, a 2,3-dimethylpentyl group, a 2,4-dimethylpentyl group, a 3,3-dimethylpentyl group, a 3-ethylpentyl group, a 2,2,3-trimethylbutyl group, an n-octyl group, an isooctyl group, a 2-ethylhexyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, and an icosyl group. The number of carbon atoms in the chain alkyl group is more preferably 1 to 10, and may be, for example, any one of 1 to 8, 1 to 5, and 1 to 3.

[0027] The number of carbon atoms of an 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, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, isobornyl, 1-adamantyl, 2-adamantyl, and tricyclodecyl. Examples of such alkyl groups having both a chain structure and a cyclic structure include monovalent groups having a structure in which one or more hydrogen atoms (—H) in the above-mentioned linear or branched alkyl group are substituted with the above-mentioned cyclic alkyl group. The number of carbon atoms of the alkyl group having a cyclic structure is more preferably 3 to 10, and may be, for example, 5 to 10.

[0028] R １ ~R ４ The acyl group in the formula (I) preferably has 2 to 20 carbon atoms, and more preferably has 2 to 10 carbon atoms.

[0029] R １ ~R ４ Examples of the alkyl group constituting the acyl group (bonded to the carbonyl group) in １ ~R ４ The number of carbon atoms in the acyl group containing an alkyl group is preferably 1 to 19, more preferably 1 to 9, and may be, for example, any one of 1 to 7, 1 to 4, and 1 to 2. That is, the number of carbon atoms in the acyl group containing an alkyl group is preferably 2 to 20, more preferably 2 to 10, and may be, for example, any one of 2 to 8, 2 to 5, and 2 to 3.

[0030] R １ ~R ４The aryl group constituting the acyl group (bonded to the carbonyl group) in the formula (I) may be either monocyclic or polycyclic. Examples of the aryl group include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 4-methylphenyl group (p-tolyl group), a 3-methylphenyl group (m-tolyl group), a 2-methylphenyl group (o-tolyl group), a 2,3-dimethylphenyl group (2,3-xylyl group), a 2,4-dimethylphenyl group (2,4-xylyl group), a 2,5-dimethylphenyl group (2,5-xylyl group), a 2,6-dimethylphenyl group (2,6-xylyl group), a 3,4-dimethylphenyl group (3,4-xylyl group), a 3,5-dimethylphenyl group (3,5-xylyl group), and a 2,4,6-trimethylphenyl group (mesityl group). The number of carbon atoms in the aryl group is preferably 6 to 19, more preferably 6 to 14, even more preferably 6 to 11, and particularly preferably 6 to 9. That is, the number of carbon atoms in the acyl group containing an aryl group is preferably 7 to 20, more preferably 7 to 15, even more preferably 7 to 12, and particularly preferably 7 to 10.

[0031] R １ ~R ４ Preferred acyl groups in the formula (I) include, for example, an acetyl group (—COCH ３ ), propionyl group (—COCH ２ CH ３ ), n-butyryl group (—COCH ２ CH ２ CH ３ ), isobutyryl group (-COCH(CH ３ ) ２ ), benzoyl group (-COC ６ CH ５ ) are just a few examples.

[0032] R １ , R ２ , R ３ and R ４are preferably each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group having 1 to 10 carbon atoms, or an acyl group having 2 to 10 carbon atoms. Such a compound (1) can be produced relatively easily, and the catalyst comprising compound (1) has a higher catalytic activity for the reaction of forming an amide bond by dehydration condensation.

[0033] In this specification, unless otherwise specified, the term "catalytic action" means the action of promoting the reaction of forming an amide bond by dehydration condensation.

[0034] In terms of ease of production of compound (1), in compound (1), R １ and R ４ are identical to each other, and R ２ and R ３ are preferably the same as each other, and R １ , R ２ , R ３ and R ４ may all be the same.

[0035] Compound (1) is more preferable in terms of the ease of production of compound (1) and the catalytic activity of the catalyst being higher, for example, R １ , R ２ , R ３ and R ４ Compound (1) in which R are all hydrogen atoms; １ , R ２ , R ３ and R ４ are all the same and are a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group having 1 to 10 carbon atoms, or an acyl group having 2 to 10 carbon atoms; １ and R ４ are all the same and are a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group having 1 to 10 carbon atoms, or an acyl group having 2 to 10 carbon atoms; R ２ and R ３ and the like.

[0036] In general formula (1), X １ is a hydrogen atom, a silyl protecting group, a sulfonyl protecting group, an alkyl group, an alkenyl group, an aralkyl group, or an acyl group. １ The alkyl group and the acyl group in １ ~R ４ Examples of the alkyl and acyl groups are the same as those described above.

[0037] X １ The number of carbon atoms in the alkyl group in X is preferably 1 to 20, and more preferably 1 to 10. １ The number of carbon atoms in the chain (straight-chain or branched-chain) alkyl group in X is preferably 1 to 20, more preferably 1 to 10, and may be, for example, 1 to 8, 1 to 5, or 1 to 3. １ The alkyl group having a cyclic structure preferably has 3 to 20 carbon atoms, more preferably 3 to 10 carbon atoms, and may be, for example, 5 to 10 carbon atoms.

[0038] X １ The number of carbon atoms in the acyl group in X is preferably 2 to 20, and more preferably 2 to 10. １ The number of carbon atoms in the acyl group containing the alkyl group in X is preferably 2 to 20, more preferably 2 to 10, and may be, for example, 2 to 8, 2 to 5, or 2 to 3. １ In the formula (I), the number of carbon atoms in the acyl group containing an aryl group is preferably 7 to 20, more preferably 7 to 15, even more preferably 7 to 12, and particularly preferably 7 to 10.

[0039] X １The alkenyl group in may be linear, branched, or cyclic, and may have both a linear structure (linear or branched) and a cyclic structure. When the alkenyl group has a cyclic structure, including when the alkenyl group is cyclic, the cyclic structure may be either monocyclic or polycyclic. The number of carbon atoms in the alkenyl group is preferably 2 to 20, and more preferably 2 to 10.

[0040] Examples of the alkenyl group include the above-mentioned R １ ~R ４ and monovalent groups having a structure in which one single bond (C—C) between carbon atoms in the alkyl group represented by the formula (I) is replaced with a double bond (C═C).

[0041] The number of carbon atoms in the linear or branched alkenyl group is preferably 2 to 20. Examples of such linear alkenyl groups include ethenyl (vinyl), 2-propenyl (allyl), 1-methylethenyl (isopropenyl), 2-methylethenyl (1-propenyl), butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, and decenyl. The number of carbon atoms in the linear alkenyl group is more preferably 2 to 10, and may be, for example, any of 2 to 8, 2 to 5, and 2 to 3.

[0042] The number of carbon atoms of an alkenyl group having a cyclic structure, such as the cyclic alkenyl group (cycloalkenyl group), is preferably 3 to 20. Examples of such cyclic alkenyl groups include a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, a cyclooctenyl group, a cyclononenyl group, and a cyclodecenyl group. Examples of such alkenyl groups having both a chain structure and a cyclic structure include those in which one or more hydrogen atoms (—H) in the above-mentioned linear or branched alkenyl group are replaced by the above-mentioned R １ ~R ４ and one or more hydrogen atoms (—H) in the cyclic alkenyl group are substituted with the above-mentioned R １ ~R ４The alkenyl group having a cyclic structure more preferably has 3 to 10 carbon atoms, and may, for example, have 5 to 10 carbon atoms.

[0043] X １ The aryl group constituting the aralkyl group (bonded to the alkylene group) in the formula (I) may be either monocyclic or polycyclic. The number of carbon atoms in the aralkyl group is preferably 7 to 20, more preferably 7 to 15, and even more preferably 7 to 12.

[0044] Examples of the aralkyl group include the above-mentioned R １ ~R ４ In the alkyl group as above, one hydrogen atom (—H) is １ ~R ４ and monovalent groups having a structure substituted with the aryl group constituting the acyl group as above.

[0045] Examples of the aralkyl group include a benzyl group (phenylmethyl group) and a phenethyl group (2-phenylethyl group).

[0046] X １ The silyl protecting group in the formula (I) may be a known protecting group having a silicon atom, and is preferably a group capable of protecting a group having a nitrogen atom, such as an amino group, a substituted amino group, or an imino group.

[0047] A preferred example of the silyl protecting group is a trimethylsilyl group (—Si(CH ３ ) ３ , TMS), triethylsilyl group (—Si(CH ２ CH ３ ) ３ , TES), triisopropylsilyl group (—Si(CH(CH ３ ) ２ ) ３ , TIPS), tert-butyldimethylsilyl group (—Si(CH ３ ) ２ C(CH ３ ) ３, TBS), dimethylisopropylsilyl group (—Si(CH ３ ) ２ CH (CH ３ ) ２ ), dimethyl n-propylsilyl group (—Si(CH ３ ) ２ CH ２ CH ２ CH ３ ), tri-n-butylsilyl group (—Si((CH ２ ) ３ CH ３ ) ３ ), diethylisopropylsilyl group (—Si(CH ２ CH ３ ) ２ CH (CH ３ ) ２ ), n-butyldimethylsilyl group (—Si(CH ３ ) ２ (CH ２ ) ３ CH ３ ), ethyldimethylsilyl group (—Si(CH ３ ) ２ CH ２ CH ３ a trialkylsilyl group such as a dimethylphenylsilyl group (—Si(CH ３ ) ２ C ６ H ５ ) and other dialkylarylsilyl groups; tert-butyldiphenylsilyl group (—Si(C ６ H ５ ) ２ C(CH ３ ) ３ , TBDPS), methyldiphenylsilyl group (—Si(C ６ H ５ ) ２ CH ３ alkyldiarylsilyl groups such as triphenylsilyl groups (—Si(C ６ H ５ ) ３ a triarylsilyl group such as a benzyldimethylsilyl group (—Si(CH ３ ) ２ CH ２ C ６ H ５) and the like; and the like.

[0048] X １ The sulfonyl protecting group in ２ The protecting group may be a known protecting group having a nitrogen atom, such as an amino group, a substituted amino group, or an imino group.

[0049] A preferred example of the sulfonyl protecting group is a methanesulfonyl group (—SO ２ CH ３ alkanesulfonyl groups such as (-Ms), (-Ms), etc.; trifluoromethanesulfonyl groups (-SO ２ CF ３ substituted alkanesulfonyl groups such as p-toluenesulfonyl groups (-SO ２ C ６ H ４ CH ３ , Ts), benzenesulfonyl group (—SO ２ C ６ H ５ arenesulfonyl groups such as o-nitrobenzenesulfonyl groups (-SO ２ C ６ H ４ NO ２ , Ns), p-nitrobenzenesulfonyl group (—SO ２ C ６ H ４ NO ２ , Nos), 2,4-dinitrobenzenesulfonyl group (—SO ２ C ６ H ３ (NO ２ ) ２ , DNs), pentafluorobenzenesulfonyl group (—SO ２ C ６ F ５ ) and the like; and the like.

[0050] As used herein, the term "substituted alkanesulfonyl group" refers to a monovalent group having a structure in which one or more hydrogen atoms in an alkanesulfonyl group have been replaced with a group other than a hydrogen atom. Similarly, the term "substituted arenesulfonyl group" refers to a monovalent group having a structure in which one or more hydrogen atoms in an arenesulfonyl group have been replaced with a group other than a hydrogen atom. As used herein, unless otherwise specified, the term "group" encompasses not only an atomic group formed by bonding multiple atoms but also a single atom.

[0051] X １ is preferably a hydrogen atom, a trialkylsilyl group, a dialkylarylsilyl group, an alkyldiarylsilyl group, a triarylsilyl group, a dialkylaralkylsilyl group, an alkanesulfonyl group, a substituted alkanesulfonyl group, an arenesulfonyl group, a substituted arenesulfonyl group, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, or an acyl group having 2 to 10 carbon atoms. Such a compound (1) can be produced relatively easily, and the catalyst consisting of compound (1) has a higher catalytic activity for the amide bond-forming reaction by dehydration condensation.

[0052] X １ When a catalyst comprising compound (1) in which is a hydrogen atom is used, the amide bond-forming reaction by dehydration condensation tends to proceed more easily (the catalytic activity is stronger) when a hydroxycarboxylic acid having a hydroxyl group is used as the carboxylic acid than when a carboxylic acid having no hydroxyl group is used. This tendency is stronger when the hydroxycarboxylic acid is a β-hydroxycarboxylic acid or an α-hydroxycarboxylic acid.

[0053] On the other hand, X １is a group other than a hydrogen atom (i.e., a silyl protecting group, a sulfonyl protecting group, an alkyl group, an alkenyl group, an aralkyl group, or an acyl group), the amide bond-forming reaction by dehydration condensation tends to proceed more easily (the catalytic action is stronger) when a carboxylic acid not having a hydroxyl group is used as the carboxylic acid than when a hydroxycarboxylic acid having a hydroxyl group is used.

[0054] An example of a preferred compound (1) is a compound represented by the following general formula (1)-1

[0055] (In the formula, R １１ , R ２１ , R ３１ and R ４１ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group having 1 to 10 carbon atoms, or an acyl group having 2 to 10 carbon atoms; X １１ is a trialkylsilyl group, a dialkylarylsilyl group, an alkyldiarylsilyl group, a triarylsilyl group, a dialkylaralkylsilyl group, an alkanesulfonyl group, a substituted alkanesulfonyl group, an arenesulfonyl group, a substituted arenesulfonyl group, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, or an acyl group having 2 to 10 carbon atoms.

[0056] Compound (1)-1 is R １ ~R ４ The number of carbon atoms in the alkyl group and the acyl group in X is limited. １ is limited to a group other than a hydrogen atom, and the types of silyl-based protecting groups and sulfonyl-based protecting groups, and the carbon numbers of the alkyl group, alkenyl group, aralkyl group, and acyl group are each limited. １１ ~R ４１ The alkyl group having 1 to 10 carbon atoms and the acyl group having 2 to 10 carbon atoms in １ ~R ４ This is the same as that explained above.１１ In the above, the trialkylsilyl group, dialkylarylsilyl group, alkyldiarylsilyl group, triarylsilyl group, dialkylaralkylsilyl group, alkanesulfonyl group, substituted alkanesulfonyl group, arenesulfonyl group, substituted arenesulfonyl group, alkyl group having 1 to 10 carbon atoms, alkenyl group having 2 to 10 carbon atoms, aralkyl group having 7 to 12 carbon atoms, and acyl group having 2 to 10 carbon atoms are each represented by X １ The preferred ones are the same as those described above in X １ The same as the preferred embodiment described above.

[0057] An example of a preferred compound (1)-1 is a compound represented by the following general formula (1)-1-1

[0058] (In the formula, R １１１ , R ２１１ , R ３１１ and R ４１１ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group having 1 to 10 carbon atoms, or an acyl group having 2 to 10 carbon atoms, provided that R １１１ and R ４１１ are identical to each other, and R ２１１ and R ３１１ are identical to each other; X １１ is the same as above.) (compound (1)-1-1)

[0059] Compound (1)-1-1 is R １１ and R ４１ are the same groups, and R ２１ and R ３１ Compound (1)-1-1 is the same as compound (1)-1, except that there is a structural restriction that R １１１ , R ２１１ , R ３１１ and R ４１１ may all be the same.

[0060] Preferable compound (1)-1-1 is, for example, R １１１ , R ２１１, R ３１１ and R ４１１ Compound (1)-1-1 in which all of R are hydrogen atoms; １１１ , R ２１１ , R ３１１ and R ４１１ are all the same and are a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group having 1 to 10 carbon atoms, or an acyl group having 2 to 10 carbon atoms; １１１ and R ４１１ are a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group having 1 to 10 carbon atoms, or an acyl group having 2 to 10 carbon atoms, and are all the same; R ２１１ and R ３１１ is a hydrogen atom.

[0061] Other examples of preferred compounds (1) include compounds represented by the following general formula (1)-2

[0062] (In the formula, R １２ , R ２２ , R ３２ and R ４２ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group having 1 to 10 carbon atoms, or an acyl group having 2 to 10 carbon atoms (compound (1)-2).

[0063] Compound (1)-2 is R １ ~R ４ The number of carbon atoms in the alkyl group and the acyl group in X is limited. １ It is the same as the compound (1) described above, except that R is limited to a hydrogen atom. １２ ~R ４２ The alkyl group having 1 to 10 carbon atoms and the acyl group having 2 to 10 carbon atoms in １ ~R ４ This is the same as that explained above.

[0064] An example of a preferred compound (1)-2 is a compound represented by the following general formula (1)-2-1

[0065] (In the formula, R １２１ , R ２２１ , R ３２１ and R ４２１ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group having 1 to 10 carbon atoms, or an acyl group having 2 to 10 carbon atoms, provided that R １２１ and R ４２１ are identical to each other, and R ２２１ and R ３２１ are the same as each other.) (compound (1)-2-1)

[0066] Compound (1)-2-1 is R １２ and R ４２ are the same groups, and R ２２ and R ３２ Compound (1)-2-1 is the same as compound (1)-2, except that there is a structural restriction that R １２１ , R ２２１ , R ３２１ and R ４２１ may all be the same.

[0067] Preferable compound (1)-2-1 is, for example, R １２１ , R ２２１ , R ３２１ and R ４２１ Compound (1)-2-1 in which all of R are hydrogen atoms; １２１ , R ２２１ , R ３２１ and R ４２１ are all the same and are a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group having 1 to 10 carbon atoms, or an acyl group having 2 to 10 carbon atoms; １２１ and R ４２１ are a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group having 1 to 10 carbon atoms, or an acyl group having 2 to 10 carbon atoms, and are all the same; R ２２１ and R ３２１is a hydrogen atom, and the like.

[0068] The catalyst may contain one or more compounds (1), and when two or more compounds are used, the combination and ratio of the compounds can be selected as desired depending on the intended purpose. Usually, the catalyst containing only one compound (1) is sufficient to achieve the intended catalytic action.

[0069] The catalyst (compound (1)) used in the amidation step may be one type or two or more types, and when two or more types are used, the combination and ratio thereof can be selected arbitrarily depending on the purpose. Usually, the use of one type of catalyst is sufficient to obtain the desired catalytic action.

[0070] In the amidation step, the amount of the catalyst (compound (1)) used is preferably 1 to 15 mol % relative to the number of moles of carboxy groups in the carboxylic acid used, and may be, for example, 1 to 10 mol % or 1 to 7 mol %. When the amount of the catalyst used is equal to or greater than the lower limit, the reaction rate of the condensation is increased. When the amount of the catalyst used is equal to or less than the upper limit, excessive use of the catalyst is suppressed.

[0071] Among the compounds (1), the compound (1)-101 shown below is publicly known and is disclosed in the aforementioned Non-Patent Document 2. The compounds (1) other than the compound (1)-101 are novel compounds.

[0072]

[0073] However, Non-Patent Document 2 does not disclose anything about the reaction of forming an amide bond, and the fact that compound (1)-101 can be used as a catalyst not only for the formation of an amide bond, is not disclosed in Non-Patent Document 2 or elsewhere. In other words, it has not been known that compound (1) can be used as a catalyst for the formation of an amide bond.

[0074] <Method for producing compound (1)> [Production method (I)] In compound (1), X １is a group other than a hydrogen atom, the compound represented by the following general formula (1α) (compound (1α)) can be converted into a compound represented by the following general formula (1a) (compound (1a)) by reacting a base with a compound represented by the following general formula (1b) (compound (1b)) and then reacting it with a compound represented by the following general formula (1c) (compound (1c)), and then reacting the compound (1a) with a lithiation agent to obtain trimethyl borate (B(OCH ３ ) ３ (In this specification, this production method may be referred to as "production method (I)"). Thus, due to its structure, compound (1) can be synthesized in fewer steps and produced in a simplified process, unlike the above-mentioned diboronic acid derivatives having a biphenyl skeleton.

[0075] (In the formula, R １ , R ２ , R ３ and R ４ is the same as above; X １α is a silyl protecting group, a sulfonyl protecting group, an alkyl group, an alkenyl group, an aralkyl group, or an acyl group; L １ is a leaving group.)

[0076] In compound (1c), L １ is a leaving group and may be a known group. １ Examples of the halogen atom include a halogen atom such as a chlorine atom and a bromine atom.

[0077] The base used when reacting compound (1b) with compound (1c) is preferably a strong base with low nucleophilicity. Examples of such strong bases include lithium bis(trimethylsilyl)amide (LiHMDS). The amount of base used is preferably 1 to 2 times the molar amount of compound (1b). The amount of compound (1c) used is preferably 1 to 2 times the molar amount of compound (1b). When reacting compound (1b) with a base and compound (1c), a solvent is preferably used. Examples of solvents used in this reaction include, but are not limited to, ethers such as tetrahydrofuran (THF). The reaction temperature when reacting compound (1b) with a base and compound (1c) is preferably 15 to 35°C, and may be ordinary temperature (e.g., room temperature). The reaction time is preferably 1 to 36 hours. When compound (1b) is reacted with a base and then reacted with compound (1c), these reactions are preferably carried out under an atmosphere of an inert gas such as nitrogen gas, helium gas, argon gas, etc. Compound (1a) can be isolated by a known method, and the isolated compound (1a) may be purified by a known method, if necessary.

[0078] Examples of the lithiation agent used when reacting compound (1a) with trimethyl borate include organolithium compounds (alkyllithiums) such as n-butyllithium. When using an organolithium compound, it is preferable to use a coordinating compound capable of coordinating with a metal ion, such as N,N,N',N'-tetramethylethylenediamine (TMEDA), hexamethylphosphoramide (HMPA), or dimethylpropyleneurea (DMPU). The amount of the lithiation agent used is preferably, for example, 1 to 8 times the molar amount of compound (1a). The amount of the coordinating compound used is preferably, for example, 1 to 8 times the molar amount of compound (1a). When reacting compound (1a) with a lithiation agent and trimethyl borate, it is preferable to use a solvent. Examples of the solvent include, but are not limited to, ethers such as tetrahydrofuran (THF). After reacting compound (1a) with the lithiation agent, it is preferable to cool the mixture to 0°C or below, such as -78°C, add trimethyl borate, and then react for 12 to 36 hours at a reaction temperature of preferably 15 to 35°C (e.g., ordinary temperature, room temperature). When reacting compound (1a) with the lithiation agent and reacting with trimethyl borate, these reactions are preferably carried out in an atmosphere of an inert gas such as nitrogen gas, helium gas, or argon gas. Compound (1α) can be isolated by known methods, and the isolated compound (1α) may be purified by known methods as needed.

[0079] [Production Method (II)] In the compound (1), X １ is a hydrogen atom, the compound represented by the following general formula (1β) (compound (1β)) can be obtained by converting the compound (1α) to the X １α (In this specification, this production method may be referred to as "production method (II)"). Even considering the steps up to this point, compound (1) can be synthesized in a fewer number of steps and produced in a simplified process, unlike the above-mentioned diboronic acid derivatives having a biphenyl skeleton.

[0080] (In the formula, R １ , R２ , R ３ , R ４ and X １α is the same as above.)

[0081] X from compound (1α) １α The removal method of X １α For example, X １α When X is a silyl protecting group, compound (1α) can be reacted with a fluorine atom-containing compound such as tetrabutylammonium fluoride (TBAF). １α The reaction conditions for removing X １α For example, the reaction can be carried out using an ether such as THF as a solvent, at a reaction temperature of 15 to 35°C, or alternatively at room temperature (e.g., room temperature), for a reaction time of 0.5 to 12 hours, but this is just one example.

[0082] [Production Method (III)] In the compound (1), R １ , R ２ , R ３ and R ４ The compound in which one or more of X is an amino group can be produced by the above-mentioned production method (I) or (II). １ is a hydrogen atom or not, R １ , R ２ , R ３ and R ４ or a nitro group, and converting the nitro group to an amino group (this production method may be referred to as "production method (III)" in this specification). Even considering the steps up to this point, compound (1) can be synthesized in a reduced number of steps, unlike the diboronic acid derivatives having a biphenyl skeleton described above, and can be produced in a simplified process. The reduction reaction in production method (III) can be carried out by a known method.

[0083] [Production Method (IV)] In the compound (1), R １ , R ２ , R ３ and R ４In the case where one or more of R １ , R ２ , R ３ and R ４ or a hydrogen atom) to compound (1) in which at least one of the following is a hydrogen atom (this production method may be referred to as "production method (IV)" in this specification). Even in consideration of the steps up to this point, compound (1) can be synthesized in a fewer number of steps and can be produced in a simplified process, unlike the above-mentioned diboronic acid derivatives having a biphenyl skeleton.

[0084] <<Carboxylic Acid>> The carboxylic acid is not particularly limited as long as it is an organic compound having a carboxy group (—C(═O)—OH).

[0085] The carboxylic acid may be either a monocarboxylic acid having one carboxy group in one molecule or a polycarboxylic acid having two or more carboxy groups (e.g., a dicarboxylic acid, a tricarboxylic acid, etc.), and can be appropriately selected depending on the structure of the target amide compound. For example, the carboxylic acid is preferably a monocarboxylic acid, in that the amide bond-forming reaction can be easily controlled and the target amide compound can be easily obtained in high yield.

[0086] The carboxylic acid preferably has a hydrocarbon group, and preferably has a carboxy group directly bonded to the hydrocarbon group to form the carboxylic acid. In the carboxylic acid having a hydrocarbon group, the hydrocarbon group may be either an aliphatic hydrocarbon group or an aromatic cyclic group-containing hydrocarbon group, and the aliphatic hydrocarbon group may be either a saturated aliphatic hydrocarbon group or an unsaturated aliphatic hydrocarbon group. The aromatic cyclic group-containing hydrocarbon group is a hydrocarbon group having at least an aromatic cyclic group, and may be either an aromatic hydrocarbon group (a hydrocarbon group in which the carbon atoms constituting the aromatic ring have free valences) or a hydrocarbon group consisting of an aromatic hydrocarbon group and an aliphatic hydrocarbon group (a hydrocarbon group in which one or more hydrogen atoms in the aliphatic hydrocarbon group are substituted with an aromatic hydrocarbon group, and in which the carbon atoms constituting the aliphatic hydrocarbon group have free valences). The valence of the hydrocarbon group is determined, for example, depending on the number of carboxy groups in one carboxylic acid molecule, and may be monovalent or polyvalent (divalent or higher). The number of carbon atoms in the hydrocarbon group is not particularly limited and may be, for example, 1 to 30, any one of 1 to 25, 1 to 20, 1 to 15, and 1 to 10, or any one of 5 to 25, 5 to 20, 5 to 15, and 5 to 10.

[0087] The hydrocarbon group may have a substituent. In this specification, "a hydrocarbon group has a substituent" means that the hydrocarbon group has a structure in which one or more hydrogen atoms in the hydrocarbon group are substituted with a substituent other than a hydrogen atom, or has a structure in which one carbon atom in the hydrocarbon group is substituted alone or together with some or all of the hydrogen atoms bonded to the carbon atom with a substituent, or has a structure in which two or more carbon atoms that are not adjacent to each other in the hydrocarbon group are substituted alone or together with some or all of the hydrogen atoms bonded to the carbon atom with a substituent. The hydrocarbon group having a substituent may have both a structure in which a hydrogen atom is substituted with a substituent and a structure in which a carbon atom is substituted alone or together with the hydrogen atoms bonded to the carbon atom with a substituent.

[0088] Examples of the substituent that substitutes a hydrogen atom in a hydrocarbon group include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom; a hydroxyl group (—OH); a cyano group (—CN); a protected amino group; a nitro group; a sulfo group; an acyl group; and a formyl group (—C(═O)—H). Examples of the acyl group as the substituent include the above-mentioned R １ ~R ４ Examples of the acyl group include the same as the acyl group in the above.

[0089] The protected amino group may be an amino group protected with a known protecting group. Examples of the protecting group include a tert-butoxycarbonyl group (Boc group), a benzyloxycarbonyl group (Cbz group), a 9-fluorenylmethyloxycarbonyl group (Fmoc group), a phthaloyl group (Phth group), a benzyl group (Bn), an allyloxycarbonyl group (Alloc group), a silyl protecting group, and a sulfonyl protecting group. Examples of the silyl protecting group and the sulfonyl protecting group include, for example, the above-mentioned X １ Examples of the protecting groups include the same silyl-based protecting groups and sulfonyl-based protecting groups as those mentioned above.

[0090] Examples of the substituent that substitutes a carbon atom in a hydrocarbon group either alone or together with a hydrogen atom bonded to the carbon atom include heteroatoms such as an oxygen atom, a sulfur atom, and a nitrogen atom; and groups represented by the formulae "-NH-", "-CO-", "-NH-CO-", "-CO-NH-", "-CO-O-" and "-O-CO-".

[0091] A preferred example of the carboxylic acid is a hydroxycarboxylic acid having a hydroxyl group. When compound (1)-2 is used as compound (1), the reaction of forming an amide bond between the hydroxycarboxylic acid and the amine compound tends to proceed more easily.

[0092] The number of hydroxyl groups in one molecule of the hydroxycarboxylic acid may be 1 or 2 or more. That is, the hydroxycarboxylic acid may be a monohydroxycarboxylic acid or a polyhydroxycarboxylic acid such as a dihydroxycarboxylic acid or a trihydroxycarboxylic acid.

[0093] Preferred hydroxycarboxylic acids include β-hydroxycarboxylic acids (hydroxycarboxylic acids in which a hydroxyl group is bonded to the carbon atom adjacent to the carbon atom in which a carboxyl group is bonded); α-hydroxycarboxylic acids (hydroxycarboxylic acids in which a hydroxyl group is bonded to the carbon atom in which a carboxyl group is bonded); and protected amino acids having a hydroxyl group, which have an amino group protected with a protecting group (protected amino group) and a hydroxyl group, and which do not fall under either the β-hydroxycarboxylic acid or the α-hydroxycarboxylic acid. When compound (1)-2 is used as compound (1), the amide bond formation reaction between these hydroxycarboxylic acids and the amine compound tends to proceed more easily. That is, in the method for producing an amide compound of this embodiment, the carboxylic acid is preferably a hydroxycarboxylic acid, and examples of the hydroxycarboxylic acid include β-hydroxycarboxylic acids, α-hydroxycarboxylic acids, and protected amino acids having a hydroxyl group, with β-hydroxycarboxylic acids or α-hydroxycarboxylic acids being preferred. Protected amino acids will be described later, and examples of protected amino acids include those corresponding to the β-hydroxycarboxylic acids or the α-hydroxycarboxylic acids.

[0094] The hydroxycarboxylic acid is represented by the following general formula (2):

[0095] (In the formula, Q １ is a single bond or a divalent hydrocarbon group, in which one or more hydrogen atoms may be substituted with a protected amino group, and when the hydrocarbon group has a methylene group, one or more non-adjacent methylene groups in the hydrocarbon group may be substituted with a carbonyl group; Z １ is a hydrogen atom or a monovalent hydrocarbon group, in which one or more hydrogen atoms may be substituted with a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or a hydroxyl group, and when the hydrocarbon group has a methylene group, one or two or more non-adjacent methylene groups in the hydrocarbon group may be substituted with an oxygen atom or a group represented by the formula "-NH-"; R９１ is a hydrogen atom or an alkyl group.) Such hydroxycarboxylic acids (2) readily undergo an amide bond-forming reaction, and many of the resulting amide compounds are useful.

[0096] In general formula (2), Q １ is a single bond or a divalent hydrocarbon group, and when it is a single bond, it is １ and R ９１ is directly bonded to the carbon atom to which Q is bonded. １ When Q is a single bond, the hydroxycarboxylic acid (2) is an α-hydroxycarboxylic acid, and Q １ is a divalent hydrocarbon group, the hydroxycarboxylic acid (2) is a hydroxycarboxylic acid other than an α-hydroxycarboxylic acid, and an example thereof is a β-hydroxycarboxylic acid.

[0097] Q １ The divalent hydrocarbon group in Q may be the same as the hydrocarbon group described above, except that it has the same or less carbon atoms and its valence is limited to 2. １ One or more hydrogen atoms in the divalent hydrocarbon group in Q may be substituted with the above-mentioned protected amino group. １ where the divalent hydrocarbon group is a methylene group (-CH ２ When the hydrocarbon group has a carbonyl group (--CO--), one or two or more non-adjacent methylene groups in the hydrocarbon group may be substituted with a carbonyl group (--CO--).

[0098] Q １ The divalent hydrocarbon group in is preferably an aliphatic hydrocarbon group which may have a substituent, and more preferably a saturated aliphatic hydrocarbon group (i.e., an alkylene group) which may have a substituent. Examples of the substituted aliphatic hydrocarbon group include aliphatic hydrocarbon groups in which one or more hydrogen atoms are substituted with aryl groups. Examples of the aryl group in which a hydrogen atom is substituted include the above-mentioned X１ The aryl groups contained in the acyl groups in Q are the same as those in Q. １ When the divalent hydrocarbon group in is an aliphatic hydrocarbon group having a substituent, a hydrogen atom in the substituent may be substituted with a protected amino group as described above, and when the substituent has a methylene group, the methylene group in the substituent may be substituted with a carbonyl group as described above.

[0099] Q １ The number of carbon atoms in the aliphatic hydrocarbon group in the formula (I) is preferably 1 to 3, more preferably 1 or 2, and even more preferably 1. Here, in the case of an aliphatic hydrocarbon group having a substituent, the number of carbon atoms in the aliphatic hydrocarbon group does not include the number of carbon atoms in the substituent.

[0100] In general formula (2), Z １ is a hydrogen atom or a monovalent hydrocarbon group. １ The monovalent hydrocarbon group in Z may be the same as the hydrocarbon group described above, except that it has the same or less carbon atoms and its valence is limited to 1. １ One or more hydrogen atoms in the monovalent hydrocarbon group in Z may be substituted with a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or a hydroxyl group. １ When the monovalent hydrocarbon group in formula (I) contains a methylene group, one or two or more non-adjacent methylene groups in the hydrocarbon group may be substituted with an oxygen atom (—O—) or a group represented by the formula “—NH—”.

[0101] Z １ The monovalent hydrocarbon group in Z is preferably an alkyl group, an aryl group, or an aralkyl group which may have the above-mentioned substituent. １ The alkyl group and the aralkyl group in １ The alkyl and aralkyl groups in Z are the same as those in Z. １ The aryl group in the formula (I) is the same as that in the formula (I). １ Examples of the aryl group include the same as the aryl group constituting the acyl group in the above formula (I).

[0102] In general formula (2), R ９１ is a hydrogen atom or an alkyl group. ９１ The alkyl group in the formula (I) is the same as that in the formula (I). １ Examples of the alkyl group include the same as those in the alkyl group.

[0103] Preferred examples of the carboxylic acid include carboxylic acids having no hydroxyl group. When compound (1)-1 is used as compound (1), an amide bond-forming reaction between the carboxylic acid having no hydroxyl group and the amine compound tends to proceed easily.

[0104] The carboxylic acid having no hydroxyl group is not particularly limited as long as it satisfies these conditions. The carboxylic acid having no hydroxyl group is preferably the above-mentioned carboxylic acid having a hydrocarbon group, which has been specified to have no hydroxyl group. The carboxylic acid having no hydroxyl group is more preferably a carboxylic acid having the aromatic cyclic group-containing hydrocarbon group and having no hydroxyl group. In this case, the aromatic cyclic group-containing hydrocarbon group may be either the aromatic hydrocarbon group or a hydrocarbon group consisting of the aromatic hydrocarbon group and an aliphatic hydrocarbon group. It is known that the conventional amide bond formation reaction between such a carboxylic acid having an aromatic cyclic group-containing hydrocarbon group and the amine compound is difficult to proceed. In contrast, in this embodiment, the amide bond formation reaction proceeds easily, and is particularly facilitated by using compound (1)-1 as compound (1).

[0105] Preferred examples of the carboxylic acid include protected amino acids having an amino group protected with a protecting group (protected amino group). Such protected amino acids also facilitate the amide bond formation reaction, and many of the resulting amide compounds are useful. The protected amino acid corresponds to any of hydroxycarboxylic acid (2), hydroxycarboxylic acid other than hydroxycarboxylic acid (2), and carboxylic acid without a hydroxyl group.

[0106] Among the protected amino acids, examples of the other hydroxycarboxylic acids include serine, threonine, and tyrosine, whose amino groups are protected with protecting groups. Among the protected amino acids, examples of carboxylic acids without a hydroxyl group include glycine, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, histidine, leucine, isoleucine, lysine, methionine, phenylalanine, proline, tryptophan, and valine, whose amino groups are protected with protecting groups. However, these are merely examples of protected amino acids. Examples of protecting groups for the amino groups in the protected amino acids include those described above.

[0107] The carboxylic acid used in the amidation step may be one kind or two or more kinds. When two or more kinds are used, the combination and ratio thereof can be arbitrarily selected depending on the purpose.

[0108] <<Amine Compound>> The amine compound is an amino (—NH ２ There are no particular limitations on the type of amino group, as long as it has a substituted amino group in which one hydrogen atom in the amino group has been substituted with a substituent.

[0109] The amine compound may be either a monovalent amine compound having one amino group or substituted amino group per molecule, or a polyvalent amine compound having a total of two or more amino groups or substituted amino groups, and can be appropriately selected depending on the structure of the target amide compound. The polyvalent amine compound may have two or more amino groups and no substituted amino groups per molecule, or may have two or more substituted amino groups and no amino groups, or may have both one or more amino groups and one or more substituted amino groups. For example, the amine compound is preferably a monovalent amine compound in that it is easy to control the amide bond formation reaction and can easily obtain the target amide compound in high yield.

[0110] The amine compound (the object of condensation with the carboxylic acid) is ammonia (NH ３For convenience, ammonia is considered to be a subordinate concept of amine compounds in this specification.

[0111] The substituent constituting the substituted amino group is not particularly limited as long as it is a group other than a hydrogen atom, but is preferably a hydrocarbon group, and one or more hydrogen atoms in the hydrocarbon group may be substituted with a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or a hydroxyl group. When the hydrocarbon group has a methylene group, one or two or more non-adjacent methylene groups in the hydrocarbon group may be substituted with an oxygen atom or a group represented by the formula "-NH-". The hydrocarbon group in the substituent may be any of the above-mentioned Z groups, including the fact that the hydrogen atom or methylene group may be substituted as described above. １ Examples of the hydrocarbon group include the same as those described above in the above.

[0112] The amine compound preferably has a hydrocarbon group, and preferably has an amino group or a substituted amino group directly bonded to the hydrocarbon group to form the amine compound. That is, the amine compound is preferably a primary amine or a secondary amine. When the amine compound has the substituted amino group, the substituent in the substituted amino group and the hydrocarbon group to which the substituted amino group is directly bonded may bond to each other to form a ring together with the nitrogen atom (nitrogen atom in the substituted amino group) to which they (the substituent in the substituted amino group and the hydrocarbon group to which the substituted amino group is directly bonded) are bonded.

[0113] Examples of the hydrocarbon group contained in the amine compound include the same hydrocarbon groups as those contained in the carboxylic acid. The valence of the hydrocarbon group is determined, for example, depending on the total number of amino groups and substituted amino groups in one molecule of the amine compound, and may be monovalent or polyvalent (divalent or higher). The number of carbon atoms in the hydrocarbon group is not particularly limited and may be, for example, 1 to 30, 1 to 25, 1 to 20, 1 to 15, or 1 to 10.

[0114] In this specification, unless otherwise specified, the hydrocarbon group contained in an amine compound means a hydrocarbon group to which an amino group or a substituted amino group is directly bonded.

[0115] The hydrocarbon group (a hydrocarbon group to which an amino group or a substituted amino group is directly bonded) may have a substituent. The hydrocarbon group having a substituent may have both a structure in which a hydrogen atom is substituted with a substituent and a structure in which one or more carbon atoms are substituted with a substituent, either alone or together with some or all of the hydrogen atoms bonded to the carbon atom.

[0116] Examples of the substituent with which a hydrogen atom in the hydrocarbon group of the amine compound is substituted include the same as the substituent with which a hydrogen atom in the hydrocarbon group of the carboxylic acid is substituted. Examples of the substituent with which a carbon atom in the hydrocarbon group of the amine compound is substituted alone or together with a hydrogen atom bonded to the carbon atom include the same as the substituent with which a carbon atom in the hydrocarbon group of the carboxylic acid is substituted alone or together with a hydrogen atom bonded to the carbon atom.

[0117] The amine compound is represented by the following general formula (3):

[0118] (In the formula, Z ２ and Z ３ are each independently a hydrogen atom or a monovalent hydrocarbon group, one or more hydrogen atoms in the hydrocarbon group may be substituted with an alkoxycarbonyl group or a protected amino group, one or more non-adjacent carbon atoms in the hydrocarbon group may be substituted alone or together with some or all of the hydrogen atoms bonded to the carbon atom with a nitrogen atom, an oxygen atom, a sulfur atom, a group represented by the formula "-NH-", a group represented by the formula "-NH-CO-", a group represented by the formula "-CO-NH-", a group represented by the formula "-CO-O-", or a group represented by the formula "-O-CO-", Z ２ and Z ３ When neither of the groups is a hydrogen atom, Z ２ and Z ３may be bonded to each other to form a ring (herein sometimes referred to as "amine compound (3)"). Such amine compound (3) easily undergoes an amide bond-forming reaction, and many of the resulting amide compounds are useful.

[0119] In general formula (3), Z ２ and Z ３ are each independently a hydrogen atom or a monovalent hydrocarbon group. ２ and Z ３ may be the same or different. ２ and Z ３ are both monovalent hydrocarbon groups, one of them is the substituent constituting the substituted amino group.

[0120] Z ２ and Z ３ The monovalent hydrocarbon group in １ For example, the monovalent hydrocarbon group may be the same as the monovalent hydrocarbon group in Z ２ and Z ３ The monovalent hydrocarbon group in may be either an aliphatic hydrocarbon group or an aromatic cyclic group-containing hydrocarbon group, and the aliphatic hydrocarbon group may be either a saturated aliphatic hydrocarbon group (in other words, an alkyl group) or an unsaturated aliphatic hydrocarbon group. As described above, the aromatic cyclic group-containing hydrocarbon group is a hydrocarbon group having at least an aromatic cyclic group, and may be either an aromatic hydrocarbon group or a hydrocarbon group consisting of an aromatic hydrocarbon group and an aliphatic hydrocarbon group.

[0121] In the unsaturated aliphatic hydrocarbon group, the number of unsaturated bonds between carbon atoms, i.e., the total number of double bonds (C═C) and triple bonds (C≡C), is not particularly limited and may be, for example, 1 to 3. The number of carbon atoms in the unsaturated aliphatic hydrocarbon group is preferably 2 to 20, and more preferably 2 to 10. The unsaturated aliphatic hydrocarbon group is preferably an alkenyl group or an alkynyl group.

[0122] Z ２ and Z ３The alkenyl group in the formula (I) is the same as that in the formula (I). １ The alkenyl group preferably has 2 to 20 carbon atoms, and more preferably has 2 to 10 carbon atoms.

[0123] Z ２ and Z ３ The alkynyl group in the above formula (I) is, for example, the above-mentioned R １ ~R ４ and the number of carbon atoms is preferably 2 to 20, more preferably 2 to 10. Preferred examples of the alkynyl group include an ethynyl group and a propargyl group.

[0124] Z ２ and Z ３ One or more hydrogen atoms in the monovalent hydrocarbon group in the formula (I) may be substituted with an alkoxycarbonyl group or a protected amino group. Examples of the protected amino group by which a hydrogen atom in the hydrocarbon group is substituted include the same protected amino groups as those by which a hydrogen atom in the hydrocarbon group of the above-mentioned carboxylic acid is substituted.

[0125] The alkoxycarbonyl group by which a hydrogen atom in the hydrocarbon group is substituted includes, for example, a monovalent group having a structure in which an alkoxy group is bonded to a carbon atom in a carbonyl group. １ ~R ４ The alkoxycarbonyl group preferably has 2 to 21 carbon atoms, more preferably 2 to 11 carbon atoms. Preferred examples of the alkoxycarbonyl group include a methoxycarbonyl group (—CO—O—CH ３ ), an ethoxycarbonyl group (—CO—O—CH ２ CH ３ ) etc.

[0126] Z ２ and Z ３In the monovalent hydrocarbon group, one or two or more non-adjacent carbon atoms may be substituted, either alone or together with some or all of the hydrogen atoms bonded to said carbon atoms, with a nitrogen atom, an oxygen atom, a sulfur atom, a group represented by the formula "-NH-", a group represented by the formula "-NH-CO-", a group represented by the formula "-CO-NH-", a group represented by the formula "-CO-O-", or a group represented by the formula "-O-CO-".

[0127] The positions of the hydrogen atoms and carbon atoms to be substituted are not particularly limited. For example, when a carbon atom is substituted, the carbon atom directly bonded to the nitrogen atom to which the hydrocarbon group is bonded may be substituted. Examples of such substituted hydrocarbon groups include alkoxy groups and aryloxy groups, but these are merely examples.

[0128] Z ２ and Z ３ The monovalent hydrocarbon group having a substituent in the formula (I) may have both a structure in which a hydrogen atom is substituted with a substituent and a structure in which one or more carbon atoms are substituted with a substituent, either alone or together with a hydrogen atom bonded to the carbon atom.

[0129] In this specification, the fact that a hydrocarbon group may have a structure in which at least a hydrogen atom or a carbon atom is substituted with a substituent may be simply referred to as "optionally having a substituent."

[0130] In the amine compound (3), Z ２ and Z ３ are not hydrogen atoms (in other words, they are all monovalent hydrocarbon groups which may have a substituent), Z ２ and Z ３ are mutually bonded to each other, and these (Z ２ and Z ３ ) may form a ring together with the nitrogen atom to which Z is bonded. ２ In the above, a carbon atom having a free valence obtained by removing a hydrogen atom is also present, and similarly, Z ３and a carbon atom having a free valence obtained by further removing a hydrogen atom in the above-mentioned formula (I), and the nitrogen-containing ring has a nitrogen atom as an atom constituting the ring skeleton.

[0131] The ring is Z ２ and Z ３ Depending on the number of bonds between Z and ２ and Z ３ When a carbon atom in at least one of the rings is substituted with the substituent, the ring further contains a heteroatom in addition to the nitrogen atom. The number of ring members (the number of atoms constituting the ring skeleton) of the ring is not particularly limited as long as it is 3 or more, but is preferably 5 to 12. Amine compound (3) having such a ring is highly versatile and has a high ring stability.

[0132] In the amine compound (3), Z ２ and Z ３ are each independently a monovalent hydrocarbon group which may have the above-mentioned substituent, or one is a hydrogen atom and the other is a monovalent hydrocarbon group which may have the above-mentioned substituent (in other words, Z ２ and Z ３ at least one of which is a monovalent hydrocarbon group), and it is more preferable that they are each independently an alkyl group, an aryl group, or an aralkyl group which may have the above-mentioned substituent, or that one is a hydrogen atom and the other is an alkyl group, an aryl group, or an aralkyl group which may have the above-mentioned substituent.

[0133] As the amine compound (3), Z ２ and Z ３ are each independently a monovalent hydrocarbon group which may have the above-mentioned substituent (i.e., a secondary amine), X １ When a catalyst consisting of the compound (1) in which Z is a hydrogen atom is used, the reaction of forming an amide bond by dehydration condensation tends to proceed more easily (the catalytic activity is higher) than when other catalysts are used. ２ and Z ３When one of the groups is a hydrogen atom and the other is a monovalent hydrocarbon group which may have the above-mentioned substituent (i.e., a primary amine), X １ When a catalyst comprising compound (1) in which is a group other than a hydrogen atom is used, the reaction of forming an amide bond by dehydration condensation tends to proceed more easily (the catalytic action is higher) than when other catalysts are used.

[0134] The amine compound used in the amidation step may be one type only, or two or more types may be used. When two or more types are used, the combination and ratio thereof can be selected arbitrarily depending on the purpose.

[0135] In the amidation step, the amount of the amine compound used is preferably 1 to 3 times the molar amount of the carboxy groups in the carboxylic acid used, and may be, for example, 1 to 2 times or 1 to 1.5 times the molar amount. When the amount of the amine compound used is equal to or greater than the lower limit, the reaction rate of the carboxylic acid and the yield of the amide compound are increased. When the amount of the amine compound used is equal to or less than the upper limit, excessive use of the amine compound is suppressed.

[0136] <<Solvent>> In the amidation step, the condensation (amidation reaction) of the carboxylic acid and the amine compound is preferably carried out in the presence of a solvent. Use of the solvent increases the condensation reaction rate even under mild conditions.

[0137] The solvent is preferably one that does not interfere with the condensation, more preferably one that can dissolve at least one of the carboxylic acid and the amine compound, and even more preferably one that can dissolve both the carboxylic acid and the amine compound.

[0138] In this specification, unless otherwise specified, the term "solvent" is a concept that encompasses both a component that is liquid at room temperature and that dissolves a solute, and a component that is liquid at room temperature and that functions as a dispersion medium for dispersing a dispersoid.

[0139] The solvent is preferably an organic solvent. Examples of the organic solvent include aromatic hydrocarbons such as toluene, o-xylene (1,2-dimethylbenzene), m-xylene (1,3-dimethylbenzene), and p-xylene (1,4-dimethylbenzene); aliphatic hydrocarbons such as hexane; ethers (compounds having an ether bond) such as 1,4-dioxane, tetrahydrofuran (THF), diethyl ether, dibutyl ether, 1,2-dimethoxyethane, and 1,2-diethoxyethane; halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, and 1,2-dichloroethane; and halogenated aromatic hydrocarbons such as chlorobenzene, 1,2-dichlorobenzene (o-dichlorobenzene), 1,3-dichlorobenzene (m-dichlorobenzene), and 1,4-dichlorobenzene (p-dichlorobenzene).

[0140] The solvent used in the amidation step may be one type only, or two or more types may be used. When two or more types are used, the combination and ratio thereof can be selected arbitrarily depending on the purpose.

[0141] When the solvent is used, the amount of the solvent used in the amidation step is preferably 4 to 14 L per mole of the amount of the carboxylic acid used, and may be, for example, any one of 6 to 14 L, 6 to 11 L, 7.5 to 12.5 L, and 9 to 14 L, or any one of 4 to 12 L, 4 to 10 L, 4 to 8 L, and 4 to 6 L. When the amount of the solvent used is equal to or greater than the lower limit, the effect obtained by using the solvent is enhanced. When the amount of the solvent used is equal to or less than the upper limit, excessive use of the solvent is suppressed.

[0142] <<Other Component (i)>> In the amidation step, other components that do not fall under any of the carboxylic acid, the amine compound, the catalyst, and the solvent (hereinafter, sometimes referred to as “other component (i)”) may or may not be used, as long as the effects of the present invention are not impaired. The type of other component (i) is not particularly limited and can be selected as desired depending on the purpose.

[0143] When the other component (i) is used, the amount of the other component (i) used in the amidation step can be appropriately adjusted depending on the type of the other component (i). Typically, the ratio of the amount of the other component (i) used in the amidation step to the total amount of the carboxylic acid, the amine compound, and the catalyst used in the amidation step ([amount of the other component (i) used in the amidation step (parts by mass)] / ([amount of the carboxylic acid used in the amidation step (parts by mass)] + [amount of the amine compound used in the amidation step (parts by mass)] + [amount of the catalyst used in the amidation step (parts by mass)]) × 100) is preferably 20% by mass or less, and may be, for example, 10% by mass or less, 7% by mass or less, or 3% by mass or less. When the ratio is equal to or less than the upper limit, the effect obtained by using the catalyst, i.e., the effect of promoting the amide bond formation reaction by condensation with a small amount of catalyst used, is further enhanced. On the other hand, the ratio may be, for example, 1% by mass or more, in order to further enhance the effect obtained by using the other component (i).

[0144] <<Other Configurations>> In the amidation step, the temperature (reaction temperature) at which the condensation of the carboxylic acid and the amine compound is carried out is preferably 80 to 140°C, and may be, for example, any one of 90 to 130°C and 100 to 120°C. When the reaction temperature is equal to or higher than the lower limit, the reaction rate of the condensation is increased. When the reaction temperature is equal to or lower than the upper limit, excessive heating is suppressed.

[0145] In the amidation step, the time (reaction time) for condensing the carboxylic acid with the amine compound is preferably 1 to 48 hours, and may be, for example, 2 to 36 hours or 3 to 25 hours. When the reaction time is equal to or greater than the lower limit, the condensation reaction rate becomes higher. When the reaction time is equal to or less than the upper limit, the reaction time is prevented from becoming excessively long. The reaction time is particularly suitable when the reaction temperature is within the above-mentioned range.

[0146] In the amidation step, the condensation of the carboxylic acid and the amine compound may be carried out under an inert gas atmosphere, but can be carried out under an air atmosphere because strict dehydration conditions are not required. That is, according to the production method of the present embodiment, by using the catalyst, an amide compound can be obtained by a simplified method, unlike conventional production methods using a condensing agent that require strict dehydration conditions.

[0147] When condensation is performed in the amidation step, the order and method of mixing the carboxylic acid, the amine compound, the catalyst, and, if necessary, the solvent and the other component (i) are not particularly limited. For example, when a solvent is used, the carboxylic acid, the amine compound, the catalyst, and, if necessary, the other component (i) may be dissolved in a solvent to prepare a solution, and the solution may be mixed to perform condensation. Alternatively, the condensation may be performed by mixing the components separately without preparing a solution. When a solvent is used, for example, a first solution may be prepared by dissolving the carboxylic acid and the catalyst in a solvent, and the amine compound may be added to the first solution to perform condensation. In this case, if the amine compound is liquid, the amine compound may be added alone to the first solution. On the other hand, whether the amine compound is liquid or solid, a second solution may be prepared by dissolving the amine compound in a solvent, and the second solution may be added to the first solution. However, these are just examples of the blending of the raw materials when a solvent is used.

[0148] In the production method of this embodiment, after completion of the amidation step, the reaction solution can be post-treated as needed by known techniques to isolate the amide compound. That is, as needed, post-treatment procedures such as filtration, washing, extraction, pH adjustment, dehydration, and concentration can be performed alone or in combination of two or more, and the amide compound can be isolated by concentration, crystallization, reprecipitation, distillation, sublimation, column chromatography, and the like. Furthermore, the isolated amide compound can be further purified as needed by performing one or more operations such as crystallization, reprecipitation, distillation, sublimation, column chromatography, extraction, and stirring and washing of crystals with a solvent, either alone or in combination of two or more. Alternatively, after completion of the amidation step, the reaction solution can be post-treated as needed, and then used for the intended purpose without isolating the amide compound. For example, the amide compound can be subjected to the next intended reaction without being isolated.

[0149] The structure of the amide compound can be confirmed by known techniques such as nuclear magnetic resonance (NMR) spectroscopy, mass spectroscopy (MS), and infrared spectroscopy (IR).

[0150] An example of a preferred amide compound is a compound represented by the following general formula (4), which is obtained by condensing a hydroxycarboxylic acid (2) with an amine compound (3):

[0151] (In the formula, Q １ , Z １ , R ９１ , Z ２ and Z ３ is the same as above.) (sometimes referred to as "amide compound (4)" in this specification).

[0152] On the other hand, in this specification, an amide compound obtained by condensing a carboxylic acid having no hydroxyl group with an amine compound (3) may be referred to as an amide compound (5). Furthermore, an amide compound obtained by condensing a hydroxycarboxylic acid other than the hydroxycarboxylic acid (2) with an amine compound (3) may be referred to as an amide compound (6).

[0153] Catalyst The compound (1) is suitable as a catalyst for use in the condensation of the carboxylic acid and the amine compound. That is, the catalyst according to one embodiment of the present invention is a catalyst for use in the condensation of a carboxylic acid and an amine compound having an amino group or a substituted amino group in which one hydrogen atom in the amino group is substituted with a substituent, wherein the catalyst is a compound represented by the following general formula (1):

[0154] (In the formula, R １ , R ２ , R ３ and R ４ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group, or an acyl group; X １ is a hydrogen atom, a silyl protecting group, a sulfonyl protecting group, an alkyl group, an alkenyl group, an aralkyl group, or an acyl group (compound (1)).

[0155] Since the compound (1) and its use have already been described in detail, further detailed description of the catalyst of this embodiment will be omitted.

[0156] Compound The compound according to one embodiment of the present invention is represented by the following general formula (1A):

[0157] (In the formula, R １Ａ , R ２Ａ , R ３Ａ and R ４Ａ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group, or an acyl group; X １Ａ represents a hydrogen atom, a silyl protecting group, a sulfonyl protecting group, an alkyl group, an alkenyl group, an aralkyl group, or an acyl group; １Ａ When R is a triisopropylsilyl group, １Ａ , R ２Ａ , R ３Ａ and R ４Ａ is not a hydrogen atom.)

[0158] Compound (1A) can be prepared by reacting compound (1) with X １is a triisopropylsilyl group, and R １ , R ２ , R ３ and R ４ is a hydrogen atom, i.e., the compounds excluding the compound (1)-101. Such compound (1A) can be produced by the production method of compound (1) explained above. All of the compounds (1A) are novel compounds.

[0159] Compound (1A) is the same as compound (1) except for the above-mentioned restrictions and modifications. For example, in compound (1A), １Ａ , R ２Ａ , R ３Ａ and R ４Ａ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group having 1 to 10 carbon atoms, or an acyl group having 2 to 10 carbon atoms. １Ａ is preferably a hydrogen atom, a trialkylsilyl group, a dialkylarylsilyl group, an alkyldiarylsilyl group, a triarylsilyl group, a dialkylaralkylsilyl group, an alkanesulfonyl group, a substituted alkanesulfonyl group, an arenesulfonyl group, a substituted arenesulfonyl group, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, or an acyl group having 2 to 10 carbon atoms. Further detailed description of compound (1A) will be omitted.

[0160] The present invention will be described in more detail below with reference to specific examples, although the present invention is not limited to the examples shown below.

[0161] Of the components used in each example and comparative example, the commercially available products are as follows. Carbazole: manufactured by Tokyo Chemical Industry Co., Ltd. Tetrahydrofuran (THF): manufactured by Kanto Chemical Co., Ltd. Lithium bis(trimethylsilyl)amide (LiHMDS) THF solution (LiHMDS concentration 1.3 M): manufactured by Tokyo Chemical Industry Co., Ltd. Triisopropylsilyl chloride (TIPSCl): manufactured by Tokyo Chemical Industry Co., Ltd. Ethyl acetate: manufactured by Kanto Chemical Co., Ltd. n-Hexane: manufactured by Kanto Chemical Co., Ltd. N,N,N',N'-Tetramethylethylenediamine (TMEDA): manufactured by Tokyo Chemical Industry Co., Ltd. n-Butyllithium n-hexane solution (n-butyllithium concentration 1.56 M): manufactured by Kanto Chemical Co., Ltd. Trimethyl borate: manufactured by Aldrich Corporation Tetrabutylammonium fluoride (TBAF) THF solution (TBAF concentration 1 M): manufactured by Tokyo Chemical Industry Co., Ltd. Diethyl ether: manufactured by Nacalai Tesque, Inc. 3-Hydroxy-3-phenylpropionic acid: manufactured by Tokyo Chemical Industry Co., Ltd. Toluene: manufactured by Fujifilm Wako Pure Chemical Industries, Ltd. N-Methylbenzylamine: Tokyo Chemical Industry Co., Ltd. Dichloromethane: Nacalai Tesque, Inc. 4-Bromobenzoic acid: Tokyo Chemical Industry Co., Ltd. Benzylamine: Tokyo Chemical Industry Co., Ltd. Bromine: Fujifilm Wako Pure Chemical Industries, Ltd. Sodium thiosulfate: Fujifilm Wako Pure Chemical Industries, Ltd. Chloroform: Nacalai Tesque, Inc. 3-Phenylpropionic acid: Tokyo Chemical Industry Co., Ltd. p-Anisidine: Kanto Chemical Co., Ltd. N-Benzyloxycarbonyl-L-serine: Tokyo Chemical Industry Co., Ltd. N-(tert-butoxycarbonyl)-L-alanine: Tokyo Chemical Industry Co., Ltd. 1,2-Dichloroethane: Kanto Chemical Co., Ltd.

[0162] Example 1 <<Production of Compound (1) (Production Method (I))>> <Production of Compound (1a)> Carbazole (1.5 g, 8.97 mmol) was dissolved in tetrahydrofuran (THF) (90 mL) under a nitrogen gas atmosphere to prepare a 0.1 M carbazole solution. The above-described THF solution of LiHMDS (9 mL, 11.7 mmol as LiHMDS, 1.3 times the molar amount relative to carbazole) was added to the carbazole solution at room temperature under a nitrogen gas atmosphere. After stirring for 15 minutes, triisopropylsilyl chloride (TIPSCl) (2.5 mL, 11.7 mmol, 1.3 times the molar amount relative to carbazole) was added at room temperature and stirred for 18 hours. The reaction was terminated by adding water to the resulting reaction solution, and ethyl acetate was added to the resulting mixture to extract the organic layer. The resulting organic layer was washed with saturated saline, and the washed organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered and concentrated under reduced pressure to obtain a crude product, which was purified by flash column chromatography using n-hexane as a mobile phase to obtain compound (1a)-101 as a colorless solid (yield: 2.75 g (8.5 mmol), 95%).

[0163] The compound obtained is compound (1a)-101. １ The obtained spectrum data is shown below. 1 H NMR (270 MHz, CDCl3) δ8.06 (d, J = 7.6 Hz, 2H), 7.69 (d, J = 7.6 Hz, 2H), 7.36 (m, 2H), 7.21 (t, J = 7.6 Hz, 2H), 2.01 (hept, J = 7.3 Hz, 3H), 1.20 (d, J = 7.3 Hz, 18H).

[0164] <Production of Compound (1)> At room temperature under a nitrogen gas atmosphere, compound (1a)-101 (2 g, 6.18 mmol) obtained above was dissolved in N,N,N',N'-tetramethylethylenediamine (TMEDA) (3.7 mL, 24.8 mmol, 4-fold molar amount relative to compound (1a)-101) to prepare a TMEDA solution. At room temperature under a nitrogen gas atmosphere, the above n-hexane solution of n-butyllithium (15.9 mL, 24.8 mmol as n-butyllithium, 4-fold molar amount relative to compound (1a)-101) was added to the TMEDA solution, and the resulting mixture was heated to 68°C and stirred at 68°C for 3 hours. The resulting reaction solution was cooled to -78°C, and THF (28 mL) was added to dilute the reaction solution. To the diluted reaction solution at −78° C., trimethyl borate (6.9 mL, 61.8 mmol, 10-fold molar amount relative to compound (1a)-101) was added and stirred for 10 minutes. The resulting mixture was then warmed to room temperature. The mixture was further stirred at room temperature for 18 hours to carry out the reaction. 3 M hydrochloric acid and water were added to the resulting reaction solution to terminate the reaction. Ethyl acetate was added to the resulting mixture to extract an organic layer. The resulting organic layer was washed with saturated brine, and the washed organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered and concentrated under reduced pressure to obtain a viscous liquid crude product. n-Hexane was added to the crude product and stirred to produce a solid. The liquid containing this solid was then allowed to stand. The supernatant was then removed, and the resulting solid was dried to obtain the target compound (1)-101 (corresponding to compound (1α)) as a beige solid (yield: 1.8 g (4.57 mmol), 74%).

[0165] The compound obtained is compound (1)-101. １ H NMR and １３ The obtained spectral data are shown below. 1H NMR (270 MHz, CDCl3) δ7.92 (d, J = 7.8 Hz, 4H), 7.49 (t, J = 7.8 Hz, 2H), 4.47 (s, 2H), 2.01 (hept, J = 7.3 Hz, 3H), 1.20 (d, J = 7.3 Hz, 18H). 13 C NMR (125 MHz, CDCl3) δ145.0, 132.2, 127.8, 125.2, 117.4, 18.7, 14.0, One quaternary carbon signal with symmetry was not detected.

[0166]

[0167] Example 2 Production of Compound (1) (Production Method (II)) Compound (1)-101 (0.1 g, 0.25 mmol) obtained above was dissolved in THF at room temperature under a nitrogen gas atmosphere to prepare a 0.2 M THF solution. The above-mentioned TBAF THF solution (0.5 mL, 0.5 mmol as TBAF, twice the molar amount relative to compound (1)-101) was added to the THF solution of compound (1)-101 at room temperature under a nitrogen gas atmosphere, and the reaction was carried out by stirring for 1 hour. Water was then added to the resulting reaction solution to terminate the reaction, and diethyl ether was added to the resulting mixture to extract the organic layer. The resulting organic layer was washed with saturated saline, and the washed organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered and concentrated under reduced pressure to obtain a viscous liquid crude product. n-Hexane was added to this crude product and the mixture was stirred to produce a solid, and the liquid containing this solid was then allowed to stand. Next, the supernatant was removed from this liquid, and the resulting solid was dried to obtain the target compound (1)-201 (corresponding to compound (1β)) as a light beige solid (yield: 47.2 mg (0.199 mmol), 80%).

[0168] The compound obtained is compound (1)-201. １ H NMR, １３ C NMR, １１The obtained spectral data are shown below. 1 H NMR (270 MHz, CDCl3) δ11.33 (s, 1H), 8.85 (s, 2H), 7.80 (d, J = 7.6 Hz, 2H), 7.64 (d, J = 7.6 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6) δ139.7, 128.8, 126.8, 125.6, 113.9, missing two quaternary carbon signals. 11 B NMR (160 MHz, DMSO-d6) δ 28.258. HRMS (ESI) m / z calcd for C 14 H 12 B2NO3 [M + 2MeOH-2HO-H] - 264.1082, found for 264.0997.

[0169]

[0170] <<Production of Amide Compound (4)>> [Example 3] At room temperature and in an air atmosphere, 3-hydroxy-3-phenylpropionic acid (41.6 mg, 0.25 mmol) and the compound (1)-201 obtained above (1.2 mg, 5 μmol, 2 mol % relative to 3-hydroxy-3-phenylpropionic acid) were dissolved in toluene (2.5 mL) to prepare a toluene solution. At room temperature and in an air atmosphere, N-methylbenzylamine (32 μL, 0.25 mmol, 1 molar amount relative to 3-hydroxy-3-phenylpropionic acid) was added to the toluene solution, and the resulting mixture was heated to 110°C and further stirred at 110°C for 4 hours. Next, the resulting reaction solution was diluted with dichloromethane, and the organic layer was washed with 1 M hydrochloric acid, 1 M aqueous sodium hydroxide solution, and saturated saline, in that order. The washed organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain the target amide compound (4)-101 as a yellow oil (yield: 60.5 mg (0.225 mmol), 90%).

[0171] The obtained product is amide compound (4)-101. １ The obtained spectrum data is shown below. 1 H NMR (270 MHz, CDCl3) δ7.45-7.10 (m, 10H), 5.21-5.12 (m, 1H), 4.59 (d, J = 14.3 Hz, 0.4H), 4.48 (d, J = 14.3 Hz, 0.6H), 4.39 (d, J = 3.2 Hz, 1H), 2.96 (s, 1.2H), 2.83 (s, 1.8H), 2.67-2.63 (m, 2H).

[0172]

[0173] Example 4 A carboxylic acid and an amine compound were condensed, followed by post-treatment and isolation in the same manner as in Example 3, except that the compound (1)-201 was replaced with the same molar amount of compound (1)-101, to obtain amide compound (4)-101 (yield: 38.4 mg (0.143 mmol), 57%). The compound obtained was confirmed to be amide compound (4)-101 by the following: １ This was confirmed by H NMR analysis, and the spectral data obtained was the same as in Example 3.

[0174]

[0175] Comparative Example 1 Condensation of a carboxylic acid and an amine compound was attempted in the same manner as in Example 3, except that compound (1)-201 was not used. However, the condensation reaction did not proceed, and the target amide compound (4)-101 was not obtained.

[0176] <<Production of Amide Compound (5)>> [Example 5] A carboxylic acid and an amine compound were condensed, post-treated, and isolated in the same manner as in Example 3, except that the same molar amount of 4-bromobenzoic acid was used instead of 3-hydroxy-3-phenylpropionic acid, the amount of compound (1)-201 was changed from 5 μmol to 12.55 μmol (5 mol % relative to 4-bromobenzoic acid), the same molar amount of benzylamine was used instead of N-methylbenzylamine, and the stirring time at 110°C was changed from 4 hours to 24 hours, thereby obtaining amide compound (5)-101 (yield: 18.9 mg (0.065 mmol), 26%). The fact that the obtained compound was amide compound (5)-101 can be confirmed by the following: １ The obtained spectrum data is shown below. 1 H NMR (270 MHz, CDCl3) δ7.66 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.35 (s, 5H), 6.44 (br, 1H), 4.62 (d, J = 5.7 Hz, 2H).

[0177]

[0178] Example 6 A carboxylic acid and an amine compound were condensed, followed by post-treatment and isolation in the same manner as in Example 5, except that the same molar amount of compound (1)-101 was used instead of compound (1)-201, to obtain amide compound (5)-101 (yield: 58 mg (10.2 mmol), 80%). The compound obtained was confirmed to be amide compound (5)-101 by the following: １ This was confirmed by H NMR analysis, and the spectral data obtained was the same as in Example 5.

[0179]

[0180] Comparative Example 2 Condensation of a carboxylic acid and an amine compound was attempted in the same manner as in Example 5, except that compound (1)-201 was not used. However, the condensation reaction did not proceed, and the target amide compound (5)-101 was not obtained.

[0181] Example 7 Production of Compound (1) (Production Method (IV)) Compound (1)-101 (1.0 g, 2.54 mmol) obtained above was dissolved in chloroform at room temperature under an air atmosphere to prepare a chloroform solution with a concentration of 0.1 M. Bromine (0.27 mL, 2.1 times the molar amount relative to compound (1)-101) was added to the chloroform solution of compound (1)-101 at room temperature under an air atmosphere, and the reaction was carried out by stirring for 10 minutes. A saturated aqueous solution of sodium thiosulfate was then added to the resulting reaction solution to terminate the reaction, and chloroform was added to the resulting mixture to extract the organic layer. The resulting organic layer was washed with water and saturated brine in this order, and the washed organic layer was dried over anhydrous sodium sulfate. The dried organic layer was filtered and concentrated under reduced pressure to obtain a viscous liquid crude product. The crude product was purified by flash column chromatography using a mixture of dichloromethane and ethyl acetate (dichloromethane:ethyl acetate = 20:1, volume ratio) as the mobile phase, yielding a viscous liquid product. n-Hexane was added to this product and stirred to produce a solid, and the liquid containing this solid was allowed to stand. The supernatant was then removed from the liquid, and the resulting solid was dried to obtain the target compound (1)-102 as a white solid (yield: 841 mg (1.52 mmol), 60%).

[0182] The compound obtained is compound (1)-102. １ H NMR, and １３ The obtained spectral data are shown below. 1 H NMR (270 MHz, CDCl3) δ7.73 (d, J = 9.0 Hz, 2H), 7.65 (d, J = 9.0 Hz, 2H), 6.24 (s, 2H), 1.95 (hept, J = 7.6 Hz, 3H), 1.17 (d, J = 7.6 Hz, 18H). 13C NMR (125 MHz, CDCl3) δ144.5, 132.4, 130.8, 120.2, 117.8, 18.6, 13.9, missing two quaternary carbon signals.

[0183]

[0184] <<Production of Amide Compound (4)>> [Example 8] At room temperature and in an air atmosphere, 3-hydroxy-3-phenylpropionic acid (33.2 mg, 0.2 mmol) and the compound (1)-102 obtained above (2.2 mg, 4 μmol, 2 mol % relative to 3-hydroxy-3-phenylpropionic acid) were dissolved in toluene (2 mL) to prepare a toluene solution. At room temperature and in an air atmosphere, N-methylbenzylamine (26 μL, 0.2 mmol, 1 molar amount relative to 3-hydroxy-3-phenylpropionic acid) was added to the toluene solution, and the resulting mixture was heated to 110°C and further stirred at 110°C for 4 hours. Thereafter, the resulting reaction solution was post-treated in the same manner as in Example 3 to obtain a crude product, and the crude product was purified by silica gel column chromatography to obtain the target amide compound (4)-101 as a yellow oil (yield: 52.8 mg (0.196 mmol), 98%).

[0185] The obtained product is amide compound (4)-101. １ This was confirmed by H NMR analysis, and the spectral data obtained was the same as in Example 3.

[0186]

[0187] Example 9 At room temperature and in an air atmosphere, 4-bromobenzoic acid (40.2 mg, 0.2 mmol) and the compound (1)-102 obtained above (5.5 mg, 10 μmol, 5 mol % relative to 4-bromobenzoic acid) were dissolved in toluene (2 mL) to prepare a toluene solution. Benzylamine (22 μL, 0.2 mmol, 1 molar amount relative to 4-bromobenzoic acid) was added to the toluene solution at room temperature and in an air atmosphere, and the resulting mixture was heated to 110°C and further stirred at 110°C for 24 hours. The resulting reaction solution was then post-treated in the same manner as in Example 3 to obtain a crude product, which was then purified by silica gel column chromatography to obtain the target amide compound (5)-101 as a white solid (yield: 47.6 mg (0.164 mmol), 82%).

[0188] The obtained product is amide compound (5)-101. １ This was confirmed by H NMR analysis, and the spectral data obtained was the same as in Example 5.

[0189]

[0190] Example 10 At room temperature and in an air atmosphere, 3-phenylpropionic acid (30.0 mg, 0.2 mmol) and the compound (1)-102 obtained above (11 mg, 20 μmol, 10 mol % relative to the 3-phenylpropionic acid) were dissolved in toluene (1 mL) to prepare a toluene solution. At room temperature and in an air atmosphere, N-methylbenzylamine (26 μL, 0.2 mmol, 1 molar amount relative to the 3-phenylpropionic acid) was added to the toluene solution, and the resulting mixture was heated to 110°C and further stirred at 110°C for 24 hours. Thereafter, the resulting reaction solution was post-treated in the same manner as in Example 3 to obtain a crude product, which was then purified by silica gel column chromatography to obtain the target amide compound (5)-102 as a yellow oil (yield: 41 mg (0.162 mmol), 81%).

[0191] The obtained product is amide compound (5)-102.１ The obtained spectrum data is shown below. 1 H NMR (270 MHz, CDCl3) δ7.38-7.11 (m, 10H), 4.63 (s, 1.2H), 4.50 (s, 0.8H), 3.10-3.01 (m, 2H), 2.90 (s, 1.2H), 2.88 (s, 1.8H), 2.75-2.69 (m, 2H).

[0192]

[0193] Example 11 A carboxylic acid and an amine compound were condensed, followed by post-treatment and isolation in the same manner as in Example 10, except that the amount of compound (1)-102 was changed from 20 μmol to 4 μmol (2 mol % relative to 3-phenylpropionic acid) and that the same molar amount of p-anisidine was used instead of N-methylbenzylamine, to obtain amide compound (5)-103 as a white solid (yield: 51.1 mg (0.20 mmol), over 99%).

[0194] The obtained product is amide compound (5)-103. １ The obtained spectrum data is shown below. 1 H NMR (270 MHz, CDCl3) δ7.32-7.21 (m, 7H), 6.93 (br s, 1H), 6.83 (d, J = 8.1 Hz, 2H), 3.77 (s, 3H), 3.04 (t, J = 8.1 Hz, 2H), 2.63 (t, J = 8.1Hz, 2H).

[0195]

[0196] Example 12 N-benzyloxycarbonyl-L-serine (47.8 mg, 0.2 mmol) and the compound (1)-102 obtained above (11 mg, 20 μmol, 10 mol % relative to N-benzyloxycarbonyl-L-serine) were dissolved in 1,2-dichloroethane (2 mL) at room temperature under an air atmosphere to prepare a dichloroethane solution. Benzylamine (22 μL, 0.2 mmol, 1 molar amount relative to N-benzyloxycarbonyl-L-serine) was added to the dichloroethane solution at room temperature under an air atmosphere, and the resulting mixture was heated to 90°C and further stirred at 90°C for 24 hours. Next, the resulting reaction solution was diluted with dichloromethane, and the organic layer was washed with 1 M hydrochloric acid, 1 M aqueous sodium hydroxide solution, and saturated saline, in that order. The washed organic layer was then dried over anhydrous sodium sulfate. The dried organic layer was filtered and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain the target amide compound (6)-101 as a white solid (yield: 40.7 mg (0.124 mmol), 62%).

[0197] The obtained product is amide compound (6)-101. １ The obtained spectrum data is shown below. 1 H NMR (270 MHz, DMSO-d6) δ8.43 (br t, 1H), 7.36-7.23 (m, 10H), 5.02 (d, J = 5.9 Hz, 2H), 4.91 (br t, 1H), 4.31 (d, J = 5.9 Hz, 2H), 4.15-4.08 (m, 1H), 3.65-3.60 (m, 2H).

[0198]

[0199] Example 13 N-(tert-butoxycarbonyl)-L-alanine (37.8 mg, 0.2 mmol) and the compound (1)-102 obtained above (11 mg, 20 μmol, 10 mol % relative to N-(tert-butoxycarbonyl)-L-alanine) were dissolved in toluene (2 mL) at room temperature under an air atmosphere to prepare a toluene solution. Benzylamine (22 μL, 0.2 mmol, 1 molar amount relative to N-(tert-butoxycarbonyl)-L-alanine) was added to the toluene solution at room temperature under an air atmosphere, and the resulting mixture was heated to 90°C and further stirred at 90°C for 24 hours. Next, the resulting reaction solution was diluted with dichloromethane, and the organic layer was washed with 1 M hydrochloric acid, 1 M aqueous sodium hydroxide solution, and saturated saline, in this order. The washed organic layer was then dried over anhydrous sodium sulfate. The dried organic layer was filtered and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography to obtain the target amide compound (5)-104 as a white solid (yield: 35.1 mg (0.126 mmol), 63%).

[0200] The obtained product is amide compound (5)-104. １ The obtained spectrum data is shown below. 1 H NMR (270 MHz, CDCl3) δ7.34-7.23 (m, 5H), 6.72 (br s, 1H), 5.13 (br s, 1H), 4.43 (br s, 2H), 4.20 (m, 1H), 1.40 (s, 9H), 1.36 (d, J = 7.0Hz, 3H).

[0201]

[0202] Example 14 A carboxylic acid and an amine compound were condensed, followed by post-treatment and isolation in the same manner as in Example 11, except that the compound (1)-102 was replaced with the same molar amount of compound (1)-101, to give amide compound (5)-103 as a white solid (yield: 17.4 mg (0.068 mmol), 34%).

[0203] The obtained product is amide compound (5)-103. １ This was confirmed by H NMR analysis, and the spectral data obtained was the same as in Example 11.

[0204]

[0205] As is clear from the above examples, by using a catalyst comprising compound (1), the target amide compound was obtained in good yield when an aromatic carboxylic acid having no hydroxyl group, an aromatic hydroxycarboxylic acid, a protected amino acid having an aromatic cyclic group, or a protected amino acid having no aromatic cyclic group was used as the carboxylic acid, and a primary amine or a secondary amine was used as the amine compound. For example, even when an aromatic carboxylic acid was used, the amide compound was obtained in good yield, unlike in conventional production methods. Thus, it was confirmed that the catalyst is useful for reactions between a wide range of carboxylic acids and amine compounds and is highly versatile.

[0206] From the comparison between Example 4 and Example 8, the comparison between Example 6 and Example 9, and the comparison between Example 11 and Example 14, it is clear that in compound (1), R １ and R ４ It was confirmed that the activity of the catalyst tends to be improved by making the group other than a hydrogen atom.

[0207] The present invention can be used to produce amide compounds.

Claims

1. A method for producing an amide compound, the method comprising the step of condensing, in the presence of a catalyst, a carboxylic acid with an amine compound having an amino group or a substituted amino group in which one hydrogen atom in the amino group is substituted with a substituent, to obtain the amide compound, wherein the catalyst is a compound represented by the following general formula (1): (In the formula, R １ , R ２ , R ３ and R ４ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group, or an acyl group; X １ and R is a hydrogen atom, a silyl protecting group, a sulfonyl protecting group, an alkyl group, an alkenyl group, an aralkyl group, or an acyl group.

2. The above R １ , R ２ , R ３ and R ４ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group having 1 to 10 carbon atoms, or an acyl group having 2 to 10 carbon atoms.

3. The above X １ is a hydrogen atom, a trialkylsilyl group, a dialkylarylsilyl group, an alkyldiarylsilyl group, a triarylsilyl group, a dialkylaralkylsilyl group, an alkanesulfonyl group, a substituted alkanesulfonyl group, an arenesulfonyl group, a substituted arenesulfonyl group, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, or an acyl group having 2 to 10 carbon atoms.

4. The method for producing an amide compound according to claim 1 or 2, wherein the carboxylic acid is a β-hydroxycarboxylic acid or an α-hydroxycarboxylic acid.

5. The carboxylic acid is represented by the following general formula (2): (In the formula, Q １ is a single bond or a divalent hydrocarbon group, in which one or more hydrogen atoms may be substituted with a protected amino group, and when the hydrocarbon group has a methylene group, one or more non-adjacent methylene groups in the hydrocarbon group may be substituted with a carbonyl group; Z １ is a hydrogen atom or a monovalent hydrocarbon group, in which one or more hydrogen atoms may be substituted with a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, or a hydroxyl group, and when the hydrocarbon group has a methylene group, one or two or more non-adjacent methylene groups in the hydrocarbon group may be substituted with an oxygen atom or a group represented by the formula "-NH-"; R ９１ The method for producing an amide compound according to claim 4, wherein the compound is a compound represented by the formula:

6. The method for producing an amide compound according to claim 1 or 2, wherein the carboxylic acid does not have a hydroxyl group.

7. The amine compound is represented by the following general formula (3): (In the formula, Z ２ and Z ３ are each independently a hydrogen atom or a monovalent hydrocarbon group, one or more hydrogen atoms in the hydrocarbon group may be substituted with an alkoxycarbonyl group or a protected amino group, one or more non-adjacent carbon atoms in the hydrocarbon group may be substituted alone or together with some or all of the hydrogen atoms bonded to the carbon atom with a nitrogen atom, an oxygen atom, a sulfur atom, a group represented by the formula "-NH-", a group represented by the formula "-NH-CO-", a group represented by the formula "-CO-NH-", a group represented by the formula "-CO-O-", or a group represented by the formula "-O-CO-", Z ２ and Z ３ When neither of the groups is a hydrogen atom, Z ２ and Z ３ may be bonded to each other to form a ring.

8. The following general formula (1A): (In the formula, R １Ａ , R ２Ａ , R ３Ａ and R ４Ａ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group, or an acyl group; X １Ａ represents a hydrogen atom, a silyl protecting group, a sulfonyl protecting group, an alkyl group, an alkenyl group, an aralkyl group, or an acyl group; １Ａ When R is a triisopropylsilyl group, １Ａ , R ２Ａ , R ３Ａ and R ４Ａ is not a hydrogen atom.) A compound represented by the formula:

9. The above R １Ａ , R ２Ａ , R ３Ａ and R ４Ａ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group having 1 to 10 carbon atoms, or an acyl group having 2 to 10 carbon atoms.

10. The above X １Ａ is a hydrogen atom, a trialkylsilyl group, a dialkylarylsilyl group, an alkyldiarylsilyl group, a triarylsilyl group, a dialkylaralkylsilyl group, an alkanesulfonyl group, a substituted alkanesulfonyl group, an arenesulfonyl group, a substituted arenesulfonyl group, an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to 10 carbon atoms, an aralkyl group having 7 to 12 carbon atoms, or an acyl group having 2 to 10 carbon atoms.

11. A catalyst for use in the condensation of a carboxylic acid with an amine compound having an amino group or a substituted amino group in which one hydrogen atom in the amino group is substituted with a substituent, wherein the catalyst is represented by the following general formula (1): (In the formula, R １ , R ２ , R ３ and R ４ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a nitro group, an amino group, a sulfo group, an alkyl group, or an acyl group; X １ is a hydrogen atom, a silyl protecting group, a sulfonyl protecting group, an alkyl group, an alkenyl group, an aralkyl group, or an acyl group.

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