JP6418679B2 - Method for producing heteroaryl compound - Google Patents

Description

  The present invention relates to a method for producing a heteroaryl compound, which involves a reaction for introducing a heteroatom-containing group into an aromatic heterocyclic skeleton.

  Heteroaryl compounds having a structure in which various heteroatom-containing groups such as a substituted amino group in which a hydrogen atom is substituted with a substituent are bonded to an aromatic heterocyclic skeleton are used in pharmaceuticals and other various fields. It is useful as a highly functional material in

  In the production of such a heteroaryl compound, a starting material compound (for example, amine, alcohol, etc.) having a structure in which the heteroatom-containing group is bonded to a hydrogen atom instead of an aromatic heterocyclic skeleton, In general, a reaction for forming a bond with an aromatic heterocyclic skeleton is performed. The oldest known reaction of this kind is Ullmann condensation, in which a halogenated heteroaryl compound is reacted with an amine or alcohol in the presence of metallic copper. A Buchwald-Hartwig reaction has been found in which a halogenated heteroaryl compound and an amine are reacted in the presence of a transition metal catalyst such as palladium.

On the other hand, a method for obtaining the heteroaryl compound by performing a nucleophilic substitution reaction on the aromatic heterocyclic skeleton using the raw material compound has been studied for a long time. However, since this method requires an electron-deficient aromatic heterocyclic skeleton as an electrophile, the current level of attention has been low compared to the method using the above metal catalyst.
However, in recent years, by introducing a relatively strong electron-withdrawing substituent such as a nitro group or a cyano group into an aromatic heterocyclic skeleton, a nucleophilic substitution reaction is performed, and the target heteroaryl compound Is disclosed (see Non-Patent Documents 1 and 2).

Son T. Nguyen et al. , Synthesis 2013, 45, 1904-1908. Sebastian Lethu et al. , Eur. J. et al. Org. Chem. 2011, 3920-3931

  However, the above-described method for producing a heteroaryl compound, including the methods disclosed in Non-Patent Documents 1 and 2, has many restrictions on applicable conditions, and development of a production method involving a new reaction has been desired. .

  The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a method for producing a heteroaryl compound having a structure in which a heteroatom-containing group is bonded to an aromatic heterocyclic skeleton, accompanied by a novel reaction. To do.

In a first aspect of the present invention that solves the above problems, a compound represented by the following general formula (1α) or a salt thereof and a compound represented by the following general formula (2) are combined in the presence of a Lewis acid. In the method for producing a heteroaryl compound, the heteroaryl compound represented by the following general formula (3α) or (3β) is obtained , wherein the Lewis acid is an indium compound: is there.

（式中、Ｇは窒素原子、酸素原子又は硫黄原子であり；Ａは有機基であり；Ｅは芳香族複素環式基であり；Ｘは脱離基であり、前記脱離基は、アルコキシ基又はアルキルカルボニルオキシ基であり、ただし、ＸはＥの芳香族複素環骨格を構成する炭素原子と結合し；ｎ１は１〜３の整数であり、ｎ２は０〜２の整数であり、ただし、Ｇが窒素原子である場合には、ｎ１＋ｎ２は３であり、Ｇが酸素原子又は硫黄原子である場合には、ｎ１＋ｎ２は２であり；ｎ２’は０又は１であり、ただし、ｎ１＋ｎ２’は３であり；ｍは１以上の整数であり；ｑは１以上ｍ以下の整数であり；ｎ２が２である場合、一般式（１α）中の２個のＡは互いに同一でも異なっていてもよく、２個のＡは相互に結合して環を形成していてもよく；ｍが２以上である場合、一般式（２）中の複数個のＸは互いに同一でも異なっていてもよく；ｎ２が２であるか、又はｑが２以上である場合、一般式（３α）中の複数個のＡは互いに同一でも異なっていてもよく、ｎ２が２である場合、２個のＡは相互に結合して環を形成していてもよく；ｍ−ｑが２以上である場合、一般式（３α）中の複数個のＸは互いに同一でも異なっていてもよく；一般式（３β）中の２個のＥは互いに同一でも異なっていてもよく；一般式（３β）中の複数個のＸは互いに同一でも異なっていてもよく；ｑが２以上である場合、一般式（３α）中の複数個のｎ２及びｎ１−１の値は、それぞれ互いに同一でも異なっていてもよく；一般式（３β）中の２個のｍ−１の値は互いに同一でも異なっていてもよい。）

( Wherein G is a nitrogen atom, oxygen atom or sulfur atom; A is an organic group; E is an aromatic heterocyclic group; X is a leaving group; A group or an alkylcarbonyloxy group, wherein X is bonded to a carbon atom constituting the aromatic heterocyclic skeleton of E; n1 is an integer of 1 to 3, and n2 is an integer of 0 to 2, , When G is a nitrogen atom, n1 + n2 is 3, and when G is an oxygen atom or a sulfur atom, n1 + n2 is 2; n2 ′ is 0 or 1, provided that n1 + n2 ′ is M is an integer of 1 or more; q is an integer of 1 or more and m or less; and when n2 is 2, two A's in the general formula (1α) may be the same or different from each other Well, two A's may be bonded to each other to form a ring; when m is 2 or more A plurality of X in the general formula (2) may be the same or different from each other; when n2 is 2 or q is 2 or more, a plurality of A in the general formula (3α) is They may be the same or different from each other, and when n2 is 2, two A's may be bonded to each other to form a ring; when mq is 2 or more, the general formula (3α) And a plurality of X in the general formula (3β) may be the same as or different from each other; a plurality of X in the general formula (3β) may be They may be the same or different; when q is 2 or more, the values of a plurality of n2 and n1-1 in general formula (3α) may be the same or different from each other; general formula (3β) The two m-1 values may be the same or different from each other.)

In addition, in the second aspect of the present invention, a compound represented by the following general formula (1β) or a salt thereof and a compound represented by the following general formula (2) are reacted in the presence of a Lewis acid, It is a manufacturing method of the heteroaryl compound which obtains the heteroaryl compound represented by the following general formula (4 (alpha)) or (4 (beta)), Comprising: It is a manufacturing method of the heteroaryl compound whose said Lewis acid is an indium compound .

（式中、Ｇは窒素原子、酸素原子又は硫黄原子であり；Ａは有機基であり；Ｅは芳香族複素環式基であり；Ｘは脱離基であり、前記脱離基は、アルコキシ基又はアルキルカルボニルオキシ基であり、ただし、ＸはＥの芳香族複素環骨格を構成する炭素原子と結合し；ｎ１は、Ｇが窒素原子である場合には２であり、Ｇが酸素原子又は硫黄原子である場合には１であり；ｎ３は１以上の整数であり；ｍは１以上の整数であり；ｐは１以上ｎ３以下の整数であり；ｒはｎ１以下で且つ１又は２であり；ただし、ｐ及びｒが同時に１になることはなく；ｔは１以上ｍ以下の整数であり；ｎ３が２以上である場合、一般式（１β）中の複数個のＧは互いに同一でも異なっていてもよく；ｍが２以上である場合、一般式（２）中の複数個のＸは互いに同一でも異なっていてもよく；ｎ３−ｐが１以上である場合、一般式（４α）中の複数個のＧは互いに同一でも異なっていてもよく；ｍ−１若しくはｐが２以上であるか、又はｒが２である場合、一般式（４α）中の複数個のＸは互いに同一でも異なっていてもよく；ｐが２以上であるか、又はｒが２である場合、一般式（４α）中の複数個のＥは互いに同一でも異なっていてもよく；ｎ３−１が１以上であるか、又はｔが２以上である場合、一般式（４β）中の複数個のＧは互いに同一でも異なっていてもよく；ｔが２以上である場合、一般式（４β）中の複数個のＡは互いに同一でも異なっていてもよく；ｍ−ｔが２以上である場合、一般式（４β）中の複数個のＸは互いに同一でも異なっていてもよく；ｎ３が２以上である場合、一般式（１β）中の複数個のｎ１の値は互いに同一でも異なっていてもよく；ｎ３−ｐが２以上である場合、一般式（４α）中の複数個のｎ１の値は互いに同一でも異なっていてもよく；ｒが２であるか、又はｐが２以上である場合、一般式（４α）中の複数個のｍ−１の値は互いに同一でも異なっていてもよく；ｐが２以上である場合、一般式（４α）中の複数個のｒ及びｎ１−ｒの値は、それぞれは互いに同一でも異なっていてもよく；ｎ３−１が２以上であるか、又はｔが２以上である場合、一般式（４β）中の複数個のｎ１の値は互いに同一でも異なっていてもよく；ｔが２以上である場合、一般式（４β）中の複数個のｎ１−１及びｎ３−１の値は、それぞれ互いに同一でも異なっていてもよい。）

( Wherein G is a nitrogen atom, oxygen atom or sulfur atom; A is an organic group; E is an aromatic heterocyclic group; X is a leaving group; A group or an alkylcarbonyloxy group, wherein X is bonded to a carbon atom constituting the aromatic heterocyclic skeleton of E; n1 is 2 when G is a nitrogen atom, and G is an oxygen atom or 1 when it is a sulfur atom; n3 is an integer of 1 or more; m is an integer of 1 or more; p is an integer of 1 or more and n3 or less; r is n1 or less and 1 or 2 Yes; however, p and r are not 1 at the same time; t is an integer of 1 to m; and when n3 is 2 or more, a plurality of G in the general formula (1β) may be the same as each other They may be different; when m is 2 or more, a plurality of X in the general formula (2) are the same as each other. However, when n3-p is 1 or more, a plurality of G in the general formula (4α) may be the same or different from each other; m-1 or p is 2 or more, Alternatively, when r is 2, a plurality of X in the general formula (4α) may be the same or different from each other; when p is 2 or more, or when r is 2, the general formula (4α) A plurality of E may be the same or different from each other; when n3-1 is 1 or more, or t is 2 or more, a plurality of G in the general formula (4β) may be the same as each other They may be different; when t is 2 or more, a plurality of A's in general formula (4β) may be the same or different from each other; when mt is 2 or more, general formula (4β) A plurality of X may be the same or different from each other; when n3 is 2 or more, the general formula (1β A plurality of n1 values may be the same or different from each other; when n3-p is 2 or more, a plurality of n1 values in the general formula (4α) may be the same or different from each other. Well; when r is 2 or when p is 2 or more, a plurality of m-1 values in the general formula (4α) may be the same or different from each other; when p is 2 or more In the general formula (4α), the values of a plurality of r and n1-r may be the same or different from each other; when n3-1 is 2 or more, or t is 2 or more, A plurality of n1 values in the general formula (4β) may be the same or different from each other; when t is 2 or more, a plurality of n1-1 and n3-1 values in the general formula (4β) May be the same as or different from each other.)

In the first and second aspects of the present invention, E is preferably an aromatic heterocyclic group having one heteroatom in the aromatic heterocyclic skeleton.
In the 1st and 2nd aspect of this invention, it is preferable that the hetero atom in the aromatic heterocyclic skeleton which said E has is a sulfur atom, a nitrogen atom, or an oxygen atom.
In the 1st and 2nd aspect of this invention, it is preferable that said A is the alkyl group, aryl group, or arylalkyl group which may have a substituent.
In the first and second embodiments of the present invention, the Lewis acid is preferably di [bis (trifluoromethylsulfonyl) imide] indium.

In the first aspect of the present invention, m is preferably 1 or 2.
In the 2nd aspect of this invention, it is preferable that said n3 and m are 1 or 2 each independently.

  According to the present invention, a method for producing a heteroaryl compound having a structure in which a heteroatom-containing group is bonded to an aromatic heterocyclic skeleton is provided.

<< Method for producing heteroaryl compound >>
The method for producing a heteroaryl compound according to the present invention includes a group represented by the formula “—N (—) — H”, a group represented by the formula “—O—H”, and a formula “—S—H”. And a heteroatom-containing raw material compound having any one or more of these groups forming a salt with an aromatic heterocyclic raw material compound having a leaving group to react with the heteroatom-containing material. Between one or more of the nitrogen atom (N), oxygen atom (O) and sulfur atom (S) of the raw material compound and the carbon atom to which the leaving group of the aromatic heterocyclic raw material compound is bonded. In this way, a heteroaryl compound having a structure in which a heteroatom-containing group is bonded to an aromatic heterocyclic skeleton is obtained.

<First Embodiment>
The method for producing a heteroaryl compound according to the first embodiment of the present invention includes a compound represented by the following general formula (1α) (hereinafter sometimes abbreviated as “compound (1α)”) or a salt thereof, A heteroaryl represented by the following general formula (3α) is reacted with a compound represented by the general formula (2) (hereinafter sometimes abbreviated as “compound (2)”) in the presence of a Lewis acid. Compound (hereinafter sometimes abbreviated as “compound (3α)”) or heteroaryl compound represented by the following general formula (3β) (hereinafter sometimes abbreviated as “compound (3β)”) It is.
In this embodiment, various types of compounds (1α) and compounds (2) can be used, and various compounds (3α) or compounds (3β) can be easily obtained by a simplified process.

（式中、Ｇは窒素原子、酸素原子又は硫黄原子であり；Ａは有機基であり；Ｅは芳香族複素環式基であり；Ｘは脱離基であり、ただし、Ｅの芳香族複素環骨格を構成する炭素原子と結合し；ｎ１は１〜３の整数であり、ｎ２は０〜２の整数であり、ただし、Ｇが窒素原子である場合には、ｎ１＋ｎ２は３であり、Ｇが酸素原子又は硫黄原子である場合には、ｎ１＋ｎ２は２であり；ｎ２’は０又は１であり、ただし、ｎ１＋ｎ２’は３であり；ｍは１以上の整数であり；ｑは１以上ｍ以下の整数であり；ｎ２が２である場合、一般式（１α）中の２個のＡは互いに同一でも異なっていてもよく、２個のＡは相互に結合して環を形成していてもよく；ｍが２以上である場合、一般式（２）中の複数個のＸは互いに同一でも異なっていてもよく；ｎ２が２であるか、又はｑが２以上である場合、一般式（３α）中の複数個のＡは互いに同一でも異なっていてもよく、ｎ２が２である場合、２個のＡは相互に結合して環を形成していてもよく；ｍ−ｑが２以上である場合、一般式（３α）中の複数個のＸは互いに同一でも異なっていてもよく；一般式（３β）中の２個のＥは互いに同一でも異なっていてもよく；一般式（３β）中の複数個のＸは互いに同一でも異なっていてもよく；ｑが２以上である場合、一般式（３α）中の複数個のｎ２及びｎ１−１の値は、それぞれ互いに同一でも異なっていてもよく；一般式（３β）中の２個のｍ−１の値は互いに同一でも異なっていてもよい。）

Wherein G is a nitrogen atom, oxygen atom or sulfur atom; A is an organic group; E is an aromatic heterocyclic group; X is a leaving group, provided that E is an aromatic complex. Bonded to the carbon atom constituting the ring skeleton; n1 is an integer of 1 to 3, n2 is an integer of 0 to 2, provided that when G is a nitrogen atom, n1 + n2 is 3, Is an oxygen atom or a sulfur atom, n1 + n2 is 2; n2 ′ is 0 or 1, provided that n1 + n2 ′ is 3; m is an integer of 1 or more; and q is 1 or more of m. And when n2 is 2, two A's in the general formula (1α) may be the same or different from each other, and the two A's are bonded to each other to form a ring. When m is 2 or more, a plurality of X in the general formula (2) may be the same or different from each other; n2 Is 2 or q is 2 or more, a plurality of A in the general formula (3α) may be the same or different from each other, and when n2 is 2, two A's are mutually They may be bonded to form a ring; when mq is 2 or more, a plurality of X in the general formula (3α) may be the same or different from each other; in the general formula (3β) Two E's may be the same or different from each other; a plurality of X in the general formula (3β) may be the same or different from each other; and when q is 2 or more, in the general formula (3α) A plurality of n2 and n1-1 values may be the same or different from each other; two m-1 values in the general formula (3β) may be the same or different from each other.)

In the present embodiment, in the reaction with the compound (2), one or more selected from the group consisting of the compound (1α) and a salt thereof can be used, and the compound (1α) and a salt thereof can be used in combination. Good.
Similarly, in this embodiment, 1 or more types of compounds (2) can be used in reaction with a compound (1 (alpha)) or its salt.

[Compound (1α), salt of compound (1α)]
The compound (1α) is represented by the general formula (1α).
In the formula, G is a nitrogen atom, an oxygen atom or a sulfur atom.
A is an organic group.

The organic group in A is a monovalent group containing a carbon atom as a constituent atom. For example, one or more carbon atoms may be substituted with an atom other than a carbon atom, and the general formula “—G—H” As long as it can form a bond with the group represented by
Examples of the organic group include hydrocarbon groups that may have a substituent. Here, “the hydrocarbon group has a substituent” means that one or more hydrogen atoms constituting the hydrocarbon group are substituted with a group (substituent) other than a hydrogen atom, or constitute a hydrocarbon group One or more carbon atoms, or together with one or more hydrogen atoms to which the carbon atom is bonded, different from this (a carbon atom or a carbon atom to which one or more hydrogen atoms are bonded) It means being substituted with a group (substituent). And both the hydrogen atom and the carbon atom may be substituted with a substituent.

  The hydrocarbon group in A may be either an aliphatic hydrocarbon group or an aromatic hydrocarbon group (aryl group), and may be an aliphatic hydrocarbon group in which one or more hydrogen atoms are substituted with an aromatic hydrocarbon group. It may be a polycyclic hydrocarbon group formed by condensing a cyclic aliphatic hydrocarbon group and an aryl group.

  The aliphatic hydrocarbon group in A may be either a saturated aliphatic hydrocarbon group (alkyl group) or an unsaturated aliphatic hydrocarbon group.

  The alkyl group in A may be linear, branched or cyclic, and when it is cyclic, it may be monocyclic or polycyclic. The alkyl group preferably has 1 to 20 carbon atoms.

  The linear or branched alkyl group preferably has 1 to 20 carbon atoms. Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, Isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, n-hexyl group, 2-methylpentyl group, 3-methylpentyl group 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 2,2-dimethylpentyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 3,3-dimethylpentyl group, 3-ethylpentyl group, 2,2,3-trimethylbutyl group, n-octyl group, iso Corruptible group, 2-ethylhexyl group, nonyl group, decyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, heptadecyl group, octadecyl group, nonadecyl group, eicosyl group can be exemplified.

  The cyclic alkyl group preferably has 3 to 20 carbon atoms. Examples of the alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, and a cyclodecyl group. Group, norbornyl group, isobornyl group, 1-adamantyl group, 2-adamantyl group and tricyclodecyl group, and one or more hydrogen atoms of these cyclic alkyl groups may be linear, branched or The thing substituted by the cyclic alkyl group can be illustrated. Here, examples of the linear, branched and cyclic alkyl groups for substituting a hydrogen atom include those described above as examples of the alkyl group in A.

The unsaturated aliphatic hydrocarbon group for A may be linear, branched or cyclic, and when it is cyclic, it may be monocyclic or polycyclic. The unsaturated aliphatic hydrocarbon group preferably has 2 to 20 carbon atoms.
The unsaturated aliphatic hydrocarbon group for A includes a double bond (C═C) in which one or more single bonds (C—C) between carbon atoms in the alkyl group for A are unsaturated bonds. ) Or a group substituted by a triple bond (C≡C).
In the unsaturated aliphatic hydrocarbon group, the number of unsaturated bonds may be one, two or more, and when two or more, these unsaturated bonds may be only double bonds or triple bonds. Only a bond may be sufficient, and a double bond and a triple bond may be mixed.
In the unsaturated aliphatic hydrocarbon group, the position of the unsaturated bond is not particularly limited.

Preferred examples of the unsaturated aliphatic hydrocarbon group for A include linear or branched alkenyl and alkynyl groups corresponding to one unsaturated bond, and cyclic groups. Examples thereof include a cycloalkenyl group and a cycloalkynyl group.
Examples of the alkenyl group include an ethenyl group (vinyl group), a 2-propenyl group (allyl group), and a cyclohexenyl group.

  The aryl group in A may be either monocyclic or polycyclic, and preferably has 6 to 20 carbon atoms, and includes a phenyl group, a 1-naphthyl group, a 2-naphthyl group, an o-tolyl group, and an m-tolyl group. Group, p-tolyl group, xylyl group (dimethylphenyl group) and the like, and those in which one or more hydrogen atoms of these aryl groups are further substituted with these aryl groups or the alkyl group in A can be exemplified. . The aryl group having these substituents preferably has 6 to 20 carbon atoms including the substituents.

  Examples of the substituent in which one or more hydrogen atoms are substituted in the hydrocarbon group include an alkoxy group, an aryloxy group, a dialkylamino group, a diarylamino group, an alkylarylamino group, an alkylcarbonyl group, an arylcarbonyl group, and an alkyl group. Examples thereof include an oxycarbonyl group, an aryloxycarbonyl group, a cyano group (—CN), a hydroxyl group (—OH), and a halogen atom.

In the hydrocarbon group, the number of substituents replacing hydrogen atoms may be one, or two or more, and all hydrogen atoms may be substituted with the substituents.
In the hydrocarbon group, when there are two or more substituents replacing a hydrogen atom, these substituents may all be the same, may be all different, or only partially the same. Also good.

Examples of the alkoxy group as a substituent include monovalent groups formed by bonding the alkyl group in A to an oxygen atom, such as a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, and a cyclopropoxy group. .
Examples of the aryloxy group as a substituent include monovalent groups formed by bonding the aryl group in A to an oxygen atom, such as a phenyloxy group (phenoxy group) and 1-naphthyloxy group.

The dialkylamino group as a substituent is a monovalent group in which two hydrogen atoms of an amino group (—NH ₂ ) such as a dimethylamino group and a methylethylamino group are substituted with the alkyl group in A. Can be illustrated. In the dialkylamino group, two alkyl groups bonded to the nitrogen atom may be the same as or different from each other.
The diarylamino group which is a substituent is 1 in which two hydrogen atoms of an amino group (—NH ₂ ) such as a diphenylamino group and a phenyl-1-naphthylamino group are substituted with the aryl group in A. A valent group can be exemplified. In the diarylamino group, two aryl groups bonded to the nitrogen atom may be the same as or different from each other.
As the alkylarylamino group as a substituent, one hydrogen atom is substituted with the alkyl group in A out of two hydrogen atoms of an amino group (—NH ₂ ) such as a methylphenylamino group, A monovalent group formed by substituting one hydrogen atom with the aryl group in A can be exemplified.

Examples of the alkylcarbonyl group as a substituent include monovalent groups formed by bonding the alkyl group in A to a carbonyl group (—C (═O) —) such as a methylcarbonyl group (acetyl group).
Examples of the arylcarbonyl group as a substituent include monovalent groups formed by bonding the aryl group in A to a carbonyl group (—C (═O) —) such as a phenylcarbonyl group (benzoyl group).

Examples of the alkyloxycarbonyl group as a substituent include monovalent groups formed by bonding the alkoxy group to a carbonyl group (—C (═O) —) such as a methyloxycarbonyl group (methoxycarbonyl group). .
Examples of the aryloxycarbonyl group as a substituent include monovalent groups formed by bonding the aryloxy group to a carbonyl group (—C (═O) —) such as a phenyloxycarbonyl group (phenoxycarbonyl group). it can.

  Examples of the halogen atom as a substituent include a fluorine atom (—F), a chlorine atom (—Cl), a bromine atom (—Br), and an iodine atom (—I).

  Examples of the substituent in which one or more carbon atoms or one or more hydrogen atoms bonded to the carbon atom are substituted in the hydrocarbon group include a nitrogen atom, an oxygen atom, and a sulfur atom. It can be illustrated.

In the hydrocarbon group, the substituent for substituting a carbon atom or a carbon atom to which a hydrogen atom is bonded may be only one, may be two or more, and all the carbon atoms are singly or the carbon atom. A hydrogen atom bonded to may be substituted with a substituent.
In the hydrocarbon group, when there are two or more substituents replacing a carbon atom or a carbon atom to which a hydrogen atom is bonded, these substituents may all be the same or different. Or only a part of them may be the same.

  A is preferably an alkyl group, aryl group or arylalkyl group which may have a substituent. The substituent here is the same as the above-described substituent described as having a hydrocarbon group.

In the formula, n1 is an integer of 1 to 3, and n2 is an integer of 0 to 2. However, the value of n1 + n2 is determined according to the type of G. That is, when G is a nitrogen atom, n1 + n2 is 3, and when G is an oxygen atom or a sulfur atom, n1 + n2 is 2.
n2 is preferably 1 when G is an oxygen atom or a sulfur atom.

When n2 is 2, two A in the general formula (1α) may be the same as or different from each other.
When n2 is 2, two A's in the general formula (1α) may be bonded to each other to form a ring together with G to which these A's are bonded. In this case, the bonding positions of the two A's are not particularly limited, and the formed ring may be either monocyclic or polycyclic.

The compound (1α) is an inorganic compound when n2 is 0, and is an organic compound when n2 is 1 or 2.
The compound (1α) can form a salt regardless of whether it is an inorganic compound or an organic compound.
In the present embodiment, a salt of the compound (1α) may be used instead of the compound (1α), or the compound (1α) and a salt thereof may be used in combination. That is, in this embodiment, 1 or more types selected from the group which consists of a compound (1 (alpha)) and its salt can be used.

  The salt of the compound (1α) is preferably an ammonium salt when G is a nitrogen atom, and more specifically, the compound (1α) when G is a nitrogen atom is selected from hydrochloric acid, sulfuric acid, phosphoric acid and the like. Examples thereof include salts formed by reacting with inorganic acids; salts formed by reacting with organic acids (carboxylic acids) such as acetic acid and propionic acid, and the like.

  It is preferable that the total amount of the compound (1α) and the salt thereof used in the reaction is appropriately adjusted according to the target reaction in consideration of the types of the compound (1α) and the salt thereof and the compound (2).

For example, when the compound (3α) in which “mq” is 0 is produced, the total amount of the compound (1α) and the salt thereof used is the number of moles of X in the compound (2) (compound (2) Is preferably 0.4 to 10 times the molar amount, more preferably 1 to 7.5 times the molar amount, and 1 to 6 times the molar amount. It is particularly preferred.
In addition, when the compound (3α) in which “mq” is 1 or more is produced, the total amount of the compound (1α) and the salt thereof used is the compound (3α) in which “mq” is 0. It is preferable to adjust appropriately according to the value of “m-q” with reference to the amount used in the production.

  On the other hand, when the compound (3β) is produced, the total amount of the compound (1α) and the salt thereof used is the number of moles of X in the compound (2) (number of moles m times the number of moles of the compound (2)). ) To 0.1 to 2.5 times the molar amount.

[Compound (2)]
The compound (2) is represented by the general formula (2).
In the formula, E is an aromatic heterocyclic group, and its valence is m (1 or more). m will be described later.
The aromatic heterocyclic group in E is not particularly limited as long as it has one or more hetero atoms as atoms constituting the aromatic heterocyclic skeleton, and may be monocyclic or polycyclic. The aromatic heterocyclic group may have, for example, a structure in which a ring other than the aromatic heterocyclic ring is condensed to the aromatic heterocyclic ring, and examples of the ring other than the aromatic heterocyclic ring include an aliphatic hydrocarbon ring, Examples include hydrocarbon rings such as aromatic hydrocarbon rings; non-aromatic heterocycles (rings having one or more heteroatoms as atoms constituting the ring skeleton and no aromaticity).

  In the aromatic heterocyclic group in E, the number of atoms constituting the aromatic heterocyclic skeleton is preferably 3 to 10, and more preferably 4 to 8. When the aromatic heterocyclic group has a structure in which an aromatic heterocyclic ring is condensed with a ring other than the aromatic heterocyclic ring, the above-mentioned “atom constituting the aromatic heterocyclic skeleton” includes aromatic It does not include atoms constituting the ring skeleton of a ring other than an aromatic heterocycle fused to a group heterocycle. In addition, when the aromatic heterocyclic group is a polycyclic structure having a structure in which the aromatic heterocycles are condensed with each other, the above-mentioned “number of atoms constituting the aromatic heterocyclic skeleton” is Means the number of atoms constituting the ring skeleton of each aromatic heterocycle.

Preferred examples of the hetero atom constituting the aromatic heterocyclic skeleton of the aromatic heterocyclic group in E include a sulfur atom, a nitrogen atom, an oxygen atom, a selenium atom, and a phosphorus atom.
The number of the heteroatoms constituting the aromatic heterocyclic skeleton is not particularly limited, but is preferably 1 or 2 and more preferably 1. When the number of the heteroatoms constituting the aromatic heterocyclic skeleton is two or more, the plurality of heteroatoms may be all the same, all different, or only partly the same. Good.
In the compound (2), the hetero atom in the aromatic heterocyclic skeleton of E is preferably a sulfur atom, a nitrogen atom or an oxygen atom.

  The aromatic heterocyclic group in E is, for example, a group formed by removing one or more hydrogen atoms bonded to carbon atoms constituting the ring skeleton from an aromatic heterocyclic compound, Preferred examples of the ring compound include sulfur-containing aromatic heterocyclic compounds (compounds having one or more sulfur atoms as atoms constituting the aromatic heterocyclic skeleton), nitrogen-containing aromatic heterocyclic compounds (aromatic heterocyclic skeletons). A compound having one or more nitrogen atoms as an atom constituting an oxygen), an oxygen-containing aromatic heterocyclic compound (a compound having one or more oxygen atoms as an atom constituting an aromatic heterocyclic skeleton), a sulfur atom, a nitrogen atom And a compound having two different heteroatoms selected from oxygen atoms as atoms constituting the aromatic heterocyclic skeleton.

  Examples of the sulfur-containing aromatic heterocyclic compound include thiophene and benzothiophene.

  Examples of the nitrogen-containing aromatic heterocyclic compound include pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazine, indole, isoindole, benzimidazole, purine, indazole, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline and the like. It can be illustrated.

  Examples of the oxygen-containing aromatic heterocyclic compound include furan, benzofuran (1-benzofuran), and isobenzofuran (2-benzofuran).

  Examples of the compound having two different hetero atoms as atoms constituting the aromatic heterocyclic skeleton include oxazole, isoxazole, thiazole, benzoxazole, benzoisoxazole, and benzothiazole.

More preferable compounds (2) include a sulfur-containing aromatic heterocyclic compound, a nitrogen-containing aromatic heterocyclic compound having a condensed ring structure of a nitrogen-containing aromatic heterocyclic ring and an aromatic hydrocarbon ring, and an oxygen-containing aromatic. An oxygen-containing aromatic heterocyclic compound having a condensed ring structure of a heterocyclic ring and an aromatic hydrocarbon ring can be exemplified.
Both nitrogen-containing aromatic heterocyclic compounds and oxygen-containing aromatic heterocyclic compounds are more reactive than sulfur-containing aromatic heterocyclic compounds if they do not have a condensed ring structure with a ring other than an aromatic heterocyclic ring. Although it tends to be low, those having a condensed ring structure with an aromatic hydrocarbon ring have good reactivity. The sulfur-containing aromatic heterocyclic compound usually has good reactivity regardless of the presence or absence of a condensed ring structure with a ring other than the aromatic heterocyclic ring.

  In the formula, X is a leaving group. However, X is bonded to a carbon atom constituting the aromatic heterocyclic skeleton of E, and is not bonded to an atom other than the carbon atom in E. The bonding position of X in E is not particularly limited as long as this condition is satisfied.

  X (leaving group) may be a known one, and preferred examples include an alkoxy group, an alkylcarbonyloxy group, an alkylthio group, a monoalkylamino group, a dialkylamino group, and the like.

Examples of the alkoxy group in X include the same alkoxy groups as the substituent in A, and a methoxy group is preferable.
Examples of the alkylcarbonyloxy group in X include a monovalent group formed by bonding the alkyl group in A to a carbon atom of the carbonyloxy group, such as a methylcarbonyloxy group (acetyloxy group).
Examples of the alkylthio group in X include monovalent groups formed by bonding the alkyl group in A to a sulfur atom, such as a methylthio group (CH ₃ —S—).
As the monoalkylamino group in X, one hydrogen atom of an amino group (—NH ₂ ) such as a methylamino group (CH ₃ —N (—H) —) is substituted with the alkyl group in A. And a monovalent group.
Examples of the dialkylamino group in X include the same dialkylamino groups as the substituent in A.

  X (leaving group) is preferably an alkoxy group or an alkylcarbonyloxy group.

  In the formula, m means the number of bonds of X in E, and is an integer of 1 or more, and the upper limit is determined according to the type of E, and is not particularly limited, but m is 1 to 3. 1 or 2 is more preferable.

  When m is 2 or more, the plurality of X in the general formula (2) may be the same or different from each other. That is, the plurality of Xs may all be the same, may all be different, or may be the same in part.

[Compound (3) (Compound (3α), Compound (3β))]
The compound (3α) is represented by the general formula (3α), and the compound (3β) is represented by the general formula (3β). In the present specification, the compound (3α) and the compound (3β) may be collectively referred to as “compound (3)”.
The target compound (3) can be obtained by reacting the compound (1α) and the compound (2), but one molecule or two or more compounds (1α) with respect to one molecule of the compound (2). Is obtained by reacting two molecules (2) with one molecule (1α) in which G is a nitrogen atom. (3β).

(Compound (3α))
In the formula, G, A, E, X, n1, n2 and m are the same as G, A, E, X, n1, n2 and m in the compound (1α) or the compound (2).

In the formula, q is an integer of 1 to m.
When mq is 2 or more, the plurality of Xs in the general formula (3α) may be the same as or different from each other.

When n2 is 2 or q is 2 or more, the plurality of A in the general formula (3α) may be the same as or different from each other.
When n2 is 2, two A's in the general formula (3α) may be bonded to each other to form a ring together with G to which these A's are bonded. That is, as in the case of the compound (1α), two A bonded to the same G may be bonded to each other to form a ring, and in this case, the two bonding positions of each other Is not particularly limited, and the formed ring may be either monocyclic or polycyclic.

When q is 2 or more, the plurality of n2 values in the general formula (3α) may be the same as or different from each other.
Similarly, when q is 2 or more, the plurality of n1-1 values in the general formula (3α) may be the same as or different from each other.

(Compound (3β))
In the formula, A, E, X, n1 and m are the same as A, E, X, n1 and m in the compound (1α) or the compound (2).

  In the formula, n2 'is 0 or 1, provided that n1 + n2' is 3. n2 'corresponds to n2 excluding the case of 2.

Two Es in the general formula (3β) may be the same as or different from each other.
Moreover, several X in general formula (3 (beta)) may mutually be same or different.

  Two m-1 values in the general formula (3β) may be the same or different.

[Lewis acid]
The Lewis acid promotes the reaction of the compound (1α) and the compound (2), and is presumed to promote the reaction by coordination with E of the compound (2).
A Lewis acid is not specifically limited, A well-known thing can be used.
Among them, the Lewis acid is preferably an indium compound, preferably a metal sulfonimide, from the viewpoint that the electron withdrawing property is high and the yield of the target compound (3) is improved. Is more preferably di [bis (trifluoromethylsulfonyl) imide] indium (hereinafter, sometimes abbreviated as “In (NTf ₂ ) ₃ ”).

  A Lewis acid may be used individually by 1 type, may use 2 or more types together, and when using 2 or more types together, the combination and ratio can be adjusted suitably.

  The amount of Lewis acid used during the reaction is preferably a catalytic amount, preferably 0.5 to 30 mol%, and preferably 0.5 to 25 mol%, relative to compound (2). More preferably, it is particularly preferably 0.5 to 20 mol%. When the amount of Lewis acid used is equal to or greater than the lower limit, the reactivity is further improved, and when the amount of Lewis acid used is equal to or less than the upper limit, excessive use is suppressed, and post-treatment after the reaction is easier. It becomes.

[Other ingredients]
In the present invention, the reaction may be carried out using other components not corresponding to any of these, in addition to the compound (1α), the compound (2) and the Lewis acid, within a range not impairing the effects of the present invention. .

The other components can be arbitrarily selected according to the purpose, and the kind thereof is not particularly limited, but is dissolved in the reaction system (a mixture of raw materials containing compound (1α), compound (2), etc., or a reaction solution) during the reaction. What is possible is preferred.
As the other components, one kind may be used alone, two or more kinds may be used in combination, and when two or more kinds are used in combination, the combination and ratio can be adjusted as appropriate.
The amount of other components used during the reaction is not particularly limited, and may be appropriately adjusted according to the type and purpose.

[solvent]
In the present invention, the reaction of the compound (1α) and the compound (2) may be performed in the presence of a solvent, or may be performed in the absence of a solvent without the presence of a solvent.
Although the said solvent is not specifically limited, What does not prevent reaction of a compound (1 (alpha)) and a compound (2) is preferable, and the thing with the high solubility of the raw material used by reaction is preferable.
Examples of the solvent include chlorobenzene, 1,2-dichlorobenzene (o-dichlorobenzene), 1,3-dichlorobenzene (m-dichlorobenzene), 1,4-dichlorobenzene (p-dichlorobenzene), 1,2- Halogenated hydrocarbons such as dichloroethane (hydrocarbons having a halogen atom as a substituent); aromatic hydrocarbons such as toluene, o-xylene, m-xylene, and p-xylene; 1,4-dioxane, tetrahydrofuran (THF), Examples include ethers (compounds having an ether bond) such as diethyl ether, dibutyl ether, 1,2-dimethoxyethane, 1,2-diethoxyethane; nitroalkanes such as nitromethane and nitroethane. Among these, the solvent preferably has a small degree of interaction with a Lewis acid.

  A solvent may be used individually by 1 type, and may use 2 or more types together, and may use it as a mixed solvent, and when using 2 or more types together, the combination and ratio may be suitably selected according to the objective. Good.

  When the reaction is performed in the presence of a solvent, the amount of the solvent used in the reaction is preferably such that the concentration of the compound (2) is 0.05 to 4 mol / L, and 0.1 to 2 mol / L. It is more preferable that the amount is as follows.

[Other reaction conditions]
What is necessary is just to adjust suitably the temperature (reaction temperature) when making a compound (1 (alpha)) and a compound (2) react, according to the kind of these compounds. Especially, it is preferable that the said reaction temperature is 10 degreeC or more, and it is more preferable that it is 18 degreeC or more. The reaction temperature is usually not higher than the boiling point of the mixture of the raw materials used such as compound (1α), compound (2) and Lewis acid, preferably not higher than 180 ° C., more preferably not higher than 160 ° C. preferable.

  The time (reaction time) for reacting the compound (1α) and the compound (2) may be appropriately adjusted according to other conditions such as the reaction temperature, but is preferably 1 to 120 hours, preferably 2 to 100 hours. It is more preferable that

In the present embodiment, after completion of the reaction of the compound (1α) and the compound (2), the compound (3) that is the target product can be taken out by performing post-treatment as necessary by a known method. That is, after completion of the reaction, post-treatment operations such as filtration, washing, extraction, pH adjustment, dehydration, concentration, etc. are carried out as needed, either alone or in combination of two or more to concentrate, crystallize, reprecipitate The compound (3) can be taken out by column chromatography or the like. In addition, the extracted compound (3) is further subjected to operations such as crystallization, reprecipitation, column chromatography, extraction, and stirring and washing of crystals with a solvent, if necessary, or a combination of two or more. You may refine | purify by performing it more than once.
The compound (3) may be used for the intended purpose without being taken out after being subjected to post-treatment as necessary after completion of the reaction.

  The obtained compound (3) is publicly known, for example, nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), infrared spectroscopy (IR), ultraviolet / visible spectroscopy (UV-VIS absorption spectrum), etc. The structure can be confirmed by this method.

  In this embodiment, a bond is newly formed between G in the compound (1α) and E in the compound (2) to obtain at least one of the compound (3α) and the compound (3β). When it is desired to improve the production rate of either the compound (3α) or the compound (3β), each reaction condition including the use ratio of the compound (1α) and the compound (2) may be appropriately adjusted. .

Second Embodiment
The method for producing a heteroaryl compound according to the second embodiment of the present invention includes a compound represented by the following general formula (1β) (hereinafter sometimes abbreviated as “compound (1β)”) or a salt thereof, A compound represented by the general formula (2) (compound (2)) is reacted in the presence of a Lewis acid to form a heteroaryl compound represented by the following general formula (4α) (hereinafter, “compound (4α)”). Or a heteroaryl compound represented by the following general formula (4β) (hereinafter sometimes abbreviated as “compound (4β)”).
As in the first embodiment, various types of compounds (1β) and compounds (2) can be used in this embodiment, and various compounds (4α) or compounds ( 4β) is obtained.

（式中、Ｇは窒素原子、酸素原子又は硫黄原子であり；Ａは有機基であり；Ｅは芳香族複素環式基であり；Ｘは脱離基であり、ただし、Ｅの芳香族複素環骨格を構成する炭素原子と結合し；ｎ１は、Ｇが窒素原子である場合には２であり、Ｇが酸素原子又は硫黄原子である場合には１であり；ｎ３は１以上の整数であり；ｍは１以上の整数であり；ｐは１以上ｎ３以下の整数であり；ｒはｎ１以下で且つ１又は２であり；ただし、ｐ及びｒが同時に１になることはなく；ｔは１以上ｍ以下の整数であり；ｎ３が２以上である場合、一般式（１β）中の複数個のＧは互いに同一でも異なっていてもよく；ｍが２以上である場合、一般式（２）中の複数個のＸは互いに同一でも異なっていてもよく；ｎ３−ｐが１以上である場合、一般式（４α）中の複数個のＧは互いに同一でも異なっていてもよく；ｍ−１若しくはｐが２以上であるか、又はｒが２である場合、一般式（４α）中の複数個のＸは互いに同一でも異なっていてもよく；ｐが２以上であるか、又はｒが２である場合、一般式（４α）中の複数個のＥは互いに同一でも異なっていてもよく；ｎ３−１が１以上であるか、又はｔが２以上である場合、一般式（４β）中の複数個のＧは互いに同一でも異なっていてもよく；ｔが２以上である場合、一般式（４β）中の複数個のＡは互いに同一でも異なっていてもよく；ｍ−ｔが２以上である場合、一般式（４β）中の複数個のＸは互いに同一でも異なっていてもよく；ｎ３が２以上である場合、一般式（１β）中の複数個のｎ１の値は互いに同一でも異なっていてもよく；ｎ３−ｐが２以上である場合、一般式（４α）中の複数個のｎ１の値は互いに同一でも異なっていてもよく；ｒが２であるか、又はｐが２以上である場合、一般式（４α）中の複数個のｍ−１の値は互いに同一でも異なっていてもよく；ｐが２以上である場合、一般式（４α）中の複数個のｒ及びｎ１−ｒの値は、それぞれは互いに同一でも異なっていてもよく；ｎ３−１が２以上であるか、又はｔが２以上である場合、一般式（４β）中の複数個のｎ１の値は互いに同一でも異なっていてもよく；ｔが２以上である場合、一般式（４β）中の複数個のｎ１−１及びｎ３−１の値は、それぞれ互いに同一でも異なっていてもよい。）

Wherein G is a nitrogen atom, oxygen atom or sulfur atom; A is an organic group; E is an aromatic heterocyclic group; X is a leaving group, provided that E is an aromatic complex. N1 is 2 when G is a nitrogen atom; 1 when G is an oxygen atom or a sulfur atom; and n3 is an integer of 1 or more. M is an integer of 1 or more; p is an integer of 1 to n3; r is n1 or less and 1 or 2; provided that p and r are not 1 at the same time; An integer of 1 or more and m or less; when n3 is 2 or more, a plurality of G in the general formula (1β) may be the same or different from each other; when m is 2 or more, the general formula (2 A plurality of X may be the same as or different from each other; when n3-p is 1 or more, in general formula (4α) A plurality of G may be the same or different from each other; when m-1 or p is 2 or more, or r is 2, a plurality of X in the general formula (4α) may be the same as each other May be different; when p is 2 or more or r is 2, a plurality of E in the general formula (4α) may be the same or different from each other; n3-1 is 1 or more Or when t is 2 or more, a plurality of G in the general formula (4β) may be the same or different from each other; when t is 2 or more, a plurality of G in the general formula (4β) In the general formula (4β) may be the same or different from each other; when n3 is 2 or more, A may be the same or different from each other; In the general formula (1β), a plurality of n1 values may be the same or different from each other; When it is above, the values of a plurality of n1 in the general formula (4α) may be the same or different from each other; when r is 2 or p is 2 or more, in the general formula (4α) A plurality of m-1 values may be the same or different from each other; when p is 2 or more, a plurality of r and n1-r values in the general formula (4α) are the same as each other. However, when n3-1 is 2 or more, or t is 2 or more, a plurality of n1 values in the general formula (4β) may be the same or different from each other; When is 2 or more, the values of a plurality of n1-1 and n3-1 in the general formula (4β) may be the same as or different from each other.)

In the present embodiment, in the reaction with the compound (2), one or more selected from the group consisting of the compound (1β) and a salt thereof can be used, and the compound (1β) and a salt thereof can be used in combination. Good.
Similarly, in this embodiment, 1 or more types of compounds (2) can be used in reaction with a compound (1 (beta)) or its salt.

[Compound (1β), salt of compound (1β)]
The compound (1β) is represented by the general formula (1β).
In the formula, G is a nitrogen atom, an oxygen atom or a sulfur atom.
A is an organic group.
In the present embodiment, G and A are the same as G and A in the first embodiment.

  In the formula, n1 is determined according to the type of G. That is, when G is a nitrogen atom, it is 2. When G is an oxygen atom or a sulfur atom, it is 1.

In the formula, n3 means the number of bonds of the group represented by the general formula “-G- (H) _n1 ” in A, is an integer of 1 or more, and the upper limit is determined according to the type of A. Although not particularly limited, n3 is preferably 1 to 3, and more preferably 1 or 2.

  When n3 is 2 or more, the plurality of Gs in the general formula (1β) may be the same as or different from each other. That is, the plurality of Gs may all be the same, may all be different, or may be the same for only a part.

  When n3 is 2 or more, a plurality of n1 values in the general formula (1β) may be the same as or different from each other.

Compound (1β) is an organic compound and can form a salt.
In the present embodiment, a salt of the compound (1β) may be used instead of the compound (1β), or the compound (1β) and a salt thereof may be used in combination. That is, in this embodiment, 1 or more types selected from the group which consists of a compound (1 (beta)) and its salt can be used.

  The salt of the compound (1β) is preferably an ammonium salt when G is a nitrogen atom, and more specifically, the compound (1β) when G is a nitrogen atom is selected from hydrochloric acid, sulfuric acid, phosphoric acid and the like. Examples thereof include salts formed by reacting with inorganic acids; salts formed by reacting with organic acids (carboxylic acids) such as acetic acid and propionic acid, and the like.

  The total amount of the compound (1β) and the salt thereof used in the reaction is preferably adjusted as appropriate according to the intended reaction in consideration of the types of the compound (1β) and the salt thereof and the compound (2). Usually, the total amount of the compound (1β) and the salt thereof used during the reaction is preferably 0.1 to 2.5 times the molar amount relative to the compound (2).

[Compound (2)]
The compound (2) is represented by the general formula (2).
The compound (2) in this embodiment is the same as the compound (2) in the first embodiment.

[Compound (4) (Compound (4α), Compound (4β))]
The compound (4α) is represented by the general formula (4α), and the compound (4β) is represented by the general formula (4β). In the present specification, the compound (4α) and the compound (4β) may be collectively referred to as “compound (4)”.
The target compound (4) is obtained by reacting the compound (1β) and the compound (2), but two or more molecules of the compound (2) react with one molecule of the compound (1β). The compound (4α) is obtained by reacting one molecule or two or more compounds (1β) with one molecule of the compound (2), which is the compound (4β). .

(Compound (4α))
In the formula, G, A, E, X, n1, n3 and m are the same as G, A, E, X, n1, n3 and m in the compound (1β) or the compound (2).

In the formula, p is an integer of 1 to n3.
R is n1 or less and 1 or 2.
However, p and r are not 1 at the same time.

  When n3-p is 1 or more (n3-p is not 0), a plurality of G in the general formula (4α) may be the same as or different from each other.

When m-1 or p is 2 or more, or r is 2, a plurality of X in the general formula (4α) may be the same as or different from each other.
When p is 2 or more or r is 2, a plurality of E in the general formula (4α) may be the same as or different from each other.

When n3-p is 2 or more, the plurality of n1 values in the general formula (4α) may be the same as or different from each other.
In addition, when r is 2 or p is 2 or more, a plurality of values of m−1 in the general formula (4α) may be the same as or different from each other.
When p is 2 or more, the plurality of r values in the general formula (4α) may be the same as or different from each other.
Similarly, when p is 2 or more, the plurality of n1-r values in the general formula (4α) may be the same as or different from each other.

(Compound (4β))
In the formula, G, A, E, X, n1, n3 and m are the same as G, A, E, X, n1, n3 and m in the compound (1β) or the compound (2).

  In the formula, t is an integer of 1 to m.

When n3-1 is 1 or more, or t is 2 or more, a plurality of G in the general formula (4β) may be the same as or different from each other.
When t is 2 or more, the plurality of A in the general formula (4β) may be the same as or different from each other.
When m−t is 2 or more, the plurality of Xs in the general formula (4β) may be the same as or different from each other.

When n3-1 is 2 or more, or t is 2 or more, a plurality of n1 values in the general formula (4β) may be the same or different from each other.
When t is 2 or more, the plurality of n1-1 values in the general formula (4β) may be the same as or different from each other.
Similarly, when t is 2 or more, the plurality of n3-1 values in the general formula (4β) may be the same as or different from each other.

[Lewis acid, other components, solvent]
The Lewis acid, other components and solvent in this embodiment, and the usage forms of these (Lewis acid, other components and solvent) are the same as the Lewis acid, other components and solvent in the first embodiment, and their usage forms. The same.

[Other reaction conditions]
What is necessary is just to adjust suitably the temperature (reaction temperature) when making a compound (1 (beta)) and a compound (2) react, according to the kind of these compounds. Especially, it is preferable that the said reaction temperature is 10 degreeC or more, and it is more preferable that it is 18 degreeC or more. The reaction temperature is usually not higher than the boiling point of the mixture of the raw materials used such as compound (1β), compound (2) and Lewis acid, preferably not higher than 180 ° C., more preferably not higher than 160 ° C. preferable.

  The time (reaction time) for reacting the compound (1β) and the compound (2) may be appropriately adjusted according to other conditions such as the reaction temperature, but is preferably 1 to 120 hours, preferably 2 to 100 hours. It is more preferable that

In the present embodiment, after completion of the reaction of the compound (1β) and the compound (2), the compound (4) that is the target product can be taken out by performing post-treatment as necessary by a known method. That is, after completion of the reaction, post-treatment operations such as filtration, washing, extraction, pH adjustment, dehydration, concentration, etc. are carried out as needed, either alone or in combination of two or more to concentrate, crystallize, reprecipitate Compound (4) can be removed by column chromatography or the like. In addition, the extracted compound (4) is further subjected to operations such as crystallization, reprecipitation, column chromatography, extraction, and stirring and washing of crystals with a solvent, if necessary, or a combination of two or more. You may refine | purify by performing it more than once.
The compound (4) may be used for the intended use without taking it out after performing a post-treatment as necessary after completion of the reaction.

  The obtained compound (4) is publicly known, for example, nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry (MS), infrared spectroscopy (IR), ultraviolet / visible spectroscopy (UV-VIS absorption spectrum), etc. The structure can be confirmed by this method.

  In the present embodiment, it is preferable to use a compound (1β) in which n3 is 1 or 2, and a compound (2) in which m is 1 or 2.

  In the present embodiment, as in the case of the first embodiment described above, a bond is newly formed between G in the compound (1β) and E in the compound (2) to form the compound (4α). And at least one of the compound (4β) is obtained. The reaction mechanism at this time is presumed to be the same as in the first embodiment. When it is desired to improve the production rate of either the compound (4α) or the compound (4β), each reaction condition including the use ratio of the compound (1β) and the compound (2) may be appropriately adjusted. .

  In the production method described above, the reaction for obtaining the compound (3α) or the compound (3β) from the compound (1α) and the compound (2), and the compound (4α) or the compound (4β) from the compound (1β) and the compound (2) The resulting reaction is a new reaction. In this reaction, by using a Lewis acid, E (aromatic heterocyclic group) of the compound (2) does not have a substituent having a relatively strong electron withdrawing property such as a nitro group or a cyano group. In E, the nucleophilic substitution reaction with the compound (1α) or the compound (1β) proceeds to obtain the target heteroaryl compound in which a heteroatom-containing group is newly introduced. As described above, the present invention has the advantage that there are few constraints such as various raw materials can be used and the target product can be obtained under mild conditions. It can be easily manufactured.

In the present invention, for example, by the reaction of the compound (1α) or the compound (1β) with the compound (2), X is eliminated from the compound (2), and the compound represented by the general formula “X—H” is obtained. By-product. This compound is, for example, an alcohol when X is an alkoxy group or the like. Moreover, this compound may exist as an anion represented by the general formula “X ⁻ ”. This by-produced compound can cause a nucleophilic substitution reaction in the same manner as the compound (1α) and the compound (1β). Therefore, as the reaction between the compound (1α) or the compound (1β) and the compound (2) proceeds, this compound may react with the unreacted compound (2). The reaction does not become the main reaction, and the target compound (3) can be obtained efficiently. This is quite surprising.

Hereinafter, the present invention will be described in more detail with reference to specific examples. However, the present invention is not limited to the following examples.
In addition, the usage-amount (mol%) of the Lewis acid shown below is the quantity on the basis of a compound (2) altogether. In addition, “isolation yield (%)” and “NMR conversion yield (%)” are the yields of the desired product (compound (3)) based on the compound (2) except for Example 20. The “NMR conversion yield (%)” is a yield obtained from NMR measurement data when methylene chloride is used as an internal standard. Only the “isolation yield (%)” in Example 20 is the yield (%) of the target product (compound (3)) based on the compound (1α). “Mmol” represents 10 ⁻³ mol. In addition, “−” in the column of the component means that the component is unused, and “−” in the column of the isolated yield (%) and the yield in terms of NMR (%) Means calculation.

<Production of Compound (3)>
[Example 1]
In (NTf ₂ ) ₃ (25 μmol) was heat-treated at 150 ° C. for 2 hours under reduced pressure in the container, and then cooled to room temperature, and the atmosphere was replaced with argon. Chlorobenzene (1 mL) was added thereto, and the contents were stirred at room temperature for 10 minutes. Furthermore, the compound (1α) (0.625 mmol) and the compound (2) (0.25 mmol) represented by the following formula were added thereto and reacted at 110 ° C. for 24 hours. The amount of each raw material compound used and the reaction conditions are shown in Tables 1 and 2. In Table 1, the amount of Lewis acid used is shown in “mol%” units.
After completion of the reaction, a saturated aqueous sodium hydrogen carbonate solution (0.5 mL) was added to the reaction solution, the aqueous layer was extracted three times with ethyl acetate (5 mL), and the organic layer was washed with saturated brine (2 mL), and anhydrous sodium sulfate. The resulting concentrate is purified by silica gel column chromatography (mobile phase: n-hexane / ethyl acetate (10/1, volume ratio)) and is the desired product. Compound (3101) was removed as a yellow liquid. The isolated yield of the compound (3101) was 63%, and the NMR conversion yield was 66%. The NMR conversion yield almost coincided with the isolated yield.
The NMR data and HRMS data of the obtained compound (3101) are shown below.

¹ H NMR (500 MHz, CDCl ₃ ) δ 3.10-3.16 (m, 4H), 3.81-3.87 (m, 4H), 6.15 (dd, J = 4.0, 1.1 Hz, 1H), 6.64 (dd, J = 5.7 , 1.1 Hz, 1H), 6.80 (dd, J = 5.5, 3.7 Hz, 1H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 51.9, 66.4, 105.6, 112.7, 126.1, 159.3.
HRMS (FI) Calcd for C ₈ H ₁₁ NOS: M +, 169.05613. Found: m / z 169.05824.

[Example 2]
The reaction was conducted under the conditions shown in Tables 1 and 2, and the concentrate was the same as Example 1 except that the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane / ethyl acetate (20/1, volume ratio)). The compound (3102) was obtained as a green liquid by the method (isolation yield 56%).
The NMR data and HRMS data of the obtained compound (3102) are shown below.

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.74-2.79 (m, 4H), 3.45-3.50 (m, 4H), 6.14 (dd, J = 3.7, 1.4, 1H), 6.63 (dd, J = 5.4, 1.4 Hz, 1H), 6.78 (dd, J = 5.4, 3.7 Hz, 1H).
HRMS (FI) Calcd for C ₈ H ₁₁ NS ₂ : M +, 185.03329. Found: m / z 185.03756.

[Example 3]
The reaction was conducted under the conditions shown in Tables 1 and 2, and the concentrate was the same as Example 1 except that the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane / ethyl acetate (20/1, volume ratio)). By the method, the compound (3103) was obtained as a white solid (isolation yield: 66%).
The NMR data, HRMS data and melting point of the obtained compound (3103) are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.29-3.35 (m, 8H), 6.20 (dd, J = 3.7, 1.4 Hz, 1H), 6.65 (dd, J = 5.5, 1.4 Hz, 1H), 6.81 ( dd, J = 5.5, 3.7 Hz, 1H), 6.90 (tt, J = 7.3, 1.1, 1H), 6.95-7.01 (m, 2H), 7.26-7.33 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 49.1, 51.9, 106.1, 112.9, 116.6, 120.3, 126.1, 129.2, 151.1, 159.1.
HRMS (FI) Calcd for C ₁₄ H ₁₆ N ₂ S: M +, 244.10342. Found: m / z 244.10816.
mp: 120-122 ° C.

[Example 4]
The compound (3104) was obtained as a yellow solid in the same manner as in Example 1 except that the reaction was carried out under the conditions shown in Tables 1 and 2 and the concentrate was purified by silica gel column chromatography (mobile phase: ethyl acetate). (Isolation yield 80%).
The NMR data, HRMS data and melting point of the obtained compound (3104) are shown below.

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.14 (s, 3H), 3.11 (t, J = 5.4 Hz, 2H), 3.15 (t, J = 5.1 Hz, 2H), 3.62 (t, J = 5.1 Hz , 2H), 3.77 (t, J = 5.1 Hz, 2H), 6.19 (dd, J = 3.7, 1.4 Hz, 1H), 6.68 (dd, J = 5.2, 1.1 Hz), 6.80 (dd, J = 5.5, 3.7).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 21.3, 40.9, 45.8, 51.8, 52.1, 107.0, 113.6, 126.1, 158.6, 169.0.
HRMS (FI) Calcd for C ₁₀ H ₁₄ N ₂ OS: M +, 210.08268. Found: m / z 210.07912.
mp: 57-59 ° C.

[Example 5]
The reaction was conducted under the conditions shown in Tables 1 and 2, and the concentrate was the same as Example 1 except that the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane / ethyl acetate (20/1, volume ratio)). By the method, a compound (3105) was obtained as a white solid (isolation yield: 74%).
The NMR data, HRMS data and melting point of the obtained compound (3105) are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.14 (s, 3H), 3.11 (t, J = 5.4 Hz, 2H), 3.15 (t, J = 5.1 Hz, 2H), 3.62 (t, J = 5.1 Hz , 2H), 3.77 (t, J = 5.1 Hz, 2H), 6.19 (dd, J = 3.7, 1.4 Hz, 1H), 6.68 (dd, J = 5.2, 1.1 Hz), 6.80 (dd, J = 5.5, 3.7)
¹³ C NMR (100 MHz, CDCl ₃ ) δ 21.3, 40.9, 45.8, 51.8, 52.1, 107.0, 113.6, 126.1, 158.6, 169.0.
HRMS (FI) Calcd for C ₁₀ H ₁₄ N ₂ OS: M +, 210.08268. Found: m / z 210.07912.
mp: 72-74 ° C.

[Example 6]
The reaction was conducted under the conditions shown in Tables 1 and 2, and the concentrate was the same as Example 1 except that the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane / ethyl acetate (20/1, volume ratio)). By the method, the compound (3106) was obtained as a white solid (isolation yield 67%).
The NMR data, HRMS data and melting point of the obtained compound (3106) are shown below.

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.37 (d, J = 1.1 Hz, 3H), 3.04-3.08 (m, 4H), 3.81-3.84 (m, 4H), 5.95 (d, J = 4.0, 1H ), 6.41 (dq, J = 3.4, 1.1, 1H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 15.3, 52.2, 66.5, 105.8, 123.3, 127.6, 157.0.
HRMS (FI) Calcd for C ₉ H ₁₃ NOS: M +, 183.07178. Found: m / z 183.07460.
mp: 54-56 ° C.

[Example 7]
The reaction was carried out under the conditions shown in Tables 1 and 2, and the concentrate was the same as Example 1 except that the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane / ethyl acetate (50/1, volume ratio)). By the method, a compound (3107) was obtained as a white solid (isolation yield 93%).
The NMR data, HRMS data and melting point of the obtained compound (3107) are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 2.43 (s, 3H), 3.15 (t, J = 8.5 Hz, 2H), 3.89 (t, J = 8.5 Hz, 2H), 6.34 (d, J = 3.7 Hz , 1H), 6.52-6.56 (m, 1H), 6.76 (t, J = 7.3, Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 7.16-7.07 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 15.4, 28.2, 54.5, 108.2, 111.8, 119.1, 123.1, 124.7, 127.4, 129.2, 130.1, 146.1, 147.9.
HRMS (FI) Calcd for C ₁₃ H ₁₃ NS: M +, 215.07687. Found: m / z 215.07659.
mp: 70-72 ° C.

[Example 8]
The reaction was performed under the conditions shown in Tables 1 and 2, and the concentrate was the same as Example 1 except that the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane / ethyl acetate (40/1, volume ratio)). By the method, the compound (3108) was obtained as a red liquid (isolation yield 91%).
The NMR data and HRMS data of the obtained compound (3108) are shown below.

¹ H NMR (500 MHz, CDCl ₃ ) δ 2.27 (s, 3H), 2.41 (d, J = 1.1, 3H), 3.25 (s, 3H), 6.41 (d, J = 3.4, 1H), 6.50-6.52 (m, 1H), 6.84 (dt, J = 9.0, 2.3, 2H), 7.04 (d, J = 8.0, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 15.8, 20.4, 42.0, 116.2, 118.6, 123.1, 129.1, 129.4, 133.7, 147.3, 151.5.
HRMS (FI) Calcd for C ₁₃ H ₁₅ NS: M +, 217.09252. Found: m / z 217.09203.

[Example 9]
The reaction was performed under the conditions shown in Tables 1 and 2, and the concentrate was the same as Example 1 except that the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane / ethyl acetate (5/1, volume ratio)). By the method, the compound (3109) was obtained as a white solid (isolation yield 73%).
The NMR data, HRMS data and melting point of the obtained compound (3109) are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.06-3.11 (m, 4H), 3.82-3.87 (m, 4H), 6.20 (dd, J = 3.2, 1.4 Hz, 1H), 6.86 (dd, J = 5.3 , 1.6 Hz, 1H), 7.26 (dd, J = 5.3, 3.2 Hz, 1H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 50.7, 66.6, 100.4, 119.6, 125.6, 152.4.
HRMS (FI) Calcd for C ₈ H ₁₁ NOS: M +, 169.05613. Found: m / z 169.05862.
mp: 75-77 ° C.

[Example 10]
The reaction was performed under the conditions shown in Tables 1 and 2, and the concentrate was the same as Example 1 except that the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane / ethyl acetate (40/1, volume ratio)). By the method, compound (3110) was obtained as a white solid (isolation yield 85%).
The NMR data, HRMS data and melting point of the obtained compound (3110) are shown below.

¹ H NMR (500 MHz, CDCl ₃ ) δ 3.14 (t, J = 8.3 Hz, 2H), 3.92 (t, J = 8.6 Hz, 2H), 6.63 (dd, 3.4, 1.7 Hz, 1H), 6.74 (td , J = 7.4, 1.1 Hz, 1H), 7.01 (d, J = 8.1 Hz, 1H), 7.09 (td, J = 14.3, 3.9 Hz, 1H), 7.15 (dd, J = 7.4, 1.1 Hz, 1H) , 7.18 (dd, J = 5.1, 1.7 Hz, 1H), 7.32 (dd, J = 5.1, 3.4 Hz, 1H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 28.2, 52.8, 103.7, 107.9, 118.6, 120.6, 124.9, 125.0, 127.3, 130.4, 143.4, 147.5.
HRMS (FI) Calcd for C ₁₂ H ₁₁ NS: M +, 201.06122. Found: m / z 201.06455.
mp: 44-46 ° C.

[Example 11]
The reaction was conducted under the conditions shown in Tables 1 and 2, and the concentrate was the same as Example 1 except that the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane / ethyl acetate (20/1, volume ratio)). By the method, a compound (3111) was obtained as a brown solid (isolation yield 93%).
The NMR data, HRMS data, and melting point of the obtained compound (3111) are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.90 (s, 3H), 5.97 (bs, 1H), 6.23 (d, J = 3.2 Hz, 1H), 6.65 (d, J = 2.8 Hz, 1H), 6.89 (tt, J = 7.3, 1.1 Hz, 1H), 7.07-7.12 (m, 2H), 7.23-7.30 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 57.5, 95.5, 100.1, 116.0, 120.2, 129.3, 131.6, 143.2, 149.0.
HRMS (FI) Calcd for C ₁₁ H ₁₁ NOS: M +, 205.05613. Found: m / z 205.06016.
mp: 57-59 ° C.

[Example 12]
The reaction was carried out under the conditions shown in Tables 1 and 2 without using a solvent, and the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane / ethyl acetate / triethylamine (100/50/3, volume ratio)). Except for the above, Compound (3401) was obtained as a brown solid in the same manner as in Example 1 (isolation yield: 93%).
The NMR data, HRMS data and melting point of the obtained compound (3401) are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.51 (bs, 2H), 6.84-6.90 (m, 4H), 6.90-6.95 (m, 4H), 7.20-7.27 (m, 4H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 107.92, 107.94, 115.57, 115.60, 120.11, 120.12, 129.39, 129.41, 135.2, 144.5.
HRMS (FI) Calcd for C ₁₆ H ₁₄ N ₂ S: M +, 266.08777. Found: m / z 266.08708.
mp: 171-173 ° C.

[Example 13]
The reaction was performed under the conditions shown in Tables 1 and 2, and the concentrate was the same as Example 1 except that the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane / ethyl acetate (30/1, volume ratio)). The compound (3112) was obtained as a red solid by the method (isolation yield 94%).
The NMR data, HRMS data and melting point of the obtained compound (3112) are shown below.

¹ H NMR (500 MHz, CDCl ₃ ) δ 5.76 (bs, 1H), 6.89 (tt, J = 7.6, 1.1 Hz, 1H), 6.98-7.04 (m, 3H), 7.26 (tt, J = 7.9, 1.8 Hz, 2H), 7.34-7.42 (m, 2H), 7.64-7.69 (m, 1H), 7.81-7.87 (m, 1H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 109.1, 116.1, 120.2, 120.6, 123.2, 123.9, 124.9, 129.4, 134.6, 135.0, 138.9, 144.7.
HRMS (FI) Calcd for C ₁₄ H ₁₁ NS: M +, 225.06122. Found: m / z 225.06597.
mp: 81-83 ° C.

［実施例１４］
表１及び２に示す条件で反応を行った点以外は、実施例１と同じ方法で、赤色個体として化合物（３１１３）を得た（単離収率９４％）。
得られた化合物（３１１３）のＮＭＲデータ、ＨＲＭＳデータ及び融点を以下に示す。

[Example 14]
A compound (3113) was obtained as a red solid in the same manner as in Example 1 except that the reaction was carried out under the conditions shown in Tables 1 and 2 (isolation yield 94%).
The NMR data, HRMS data and melting point of the obtained compound (3113) are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.80 (s, 3H), 5.62 (bs, 1H), 6.74 (s, 1H), 6.86 (dt, J = 9.2, 3.0 Hz, 2H), 7.04 (dt, J = 9.2, 2.7 Hz, 2H), 7.37 (dd, J = 6.0, 3.2 Hz, 2H), 7.63-7.68 (m, 1H), 7.79-7.85 (m, 1H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 55.6, 104.7, 114.8 119.5, 120.2, 123.2, 123.8, 124.8, 134.0, 137.0, 137.6, 139.0, 154.5.
HRMS (FI) Calcd for C ₁₅ H ₁₃ NOS: M +, 255.07178. Found: m / z 255.07643.
mp: 100-102 ° C.

[Example 15]
The reaction was carried out under the conditions shown in Tables 1 and 2, and the concentrate was the same as Example 1 except that the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane / ethyl acetate (4/1, volume ratio)). The compound (3114) was obtained as a red solid by the method (isolation yield 88%).
The NMR data, HRMS data and melting point of the obtained compound (3114) are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.43 (bs, 1H), 5.80 (bs, 1H), 6.58 (s, 1H), 6.86-7.00 (m, 3H), 7.17 (dd, J = 7.8, 1.4 Hz, 1H), 7.36-7.43 (m, 2H), 7.67-7.73 (m, 1H), 7.80-78.6 (m 1H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 105.2, 115.3, 120.1, 120.4, 121.3, 123.2, 123.4, 123.9, 124.9, 131.2, 133.7, 136.4, 139.1, 147.3.
HRMS (FI) Calcd for C ₁₄ H ₁₁ NOS: M +, 241.05613. Found: m / z 241.05549.
mp: 81-83 ° C.

[Example 16]
The reaction was performed under the conditions shown in Tables 1 and 2, and the concentrate was the same as Example 1 except that the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane / ethyl acetate (5/1, volume ratio)). The compound (3115) was obtained as a red solid by the method (isolation yield 84%).
The NMR data, HRMS data and melting point of the obtained compound (3115) are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.03 (bs, 1H), 6.85 (dt, J = 8.7, 2.2 Hz, 2H), 7.24 (s, 1H), 7.38 (td, J = 7.2, 1.5 Hz, 1H), 7.42 (td, J = 7.2, 1.7 Hz, 1H), 7.47 (dt, J = 6.9, 2.3 Hz, 2H), 7.57-7.61 (m, 1H), 7.85-7.89 (m, 1H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 101.2, 114.3, 116.4, 120.0, 120.9, 123.3, 124.4, 125.2, 132.2, 133.8, 134.7, 138.9, 149.2.
HRMS (FI) Calcd for C ₁₅ H ₁₀ N ₂ S: M +, 250.05647. Found: m / z 250.05788.
mp: 158-160 ° C.

[Example 17]
The reaction was performed under the conditions shown in Tables 3 and 4, and the concentrate was the same as Example 1 except that the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane / ethyl acetate (6/1, volume ratio)). By the method, a compound (3116) was obtained as a brown solid (isolation yield 91%).
The NMR data, HRMS data, and melting point of the obtained compound (3116) are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 1.37 (t, J = 7.1 Hz, 3H), 4.33 (q, J = 7.2 Hz, 2H), 6.01 (bs, 1H), 6.88 (dt, J = 8.7, 2.3 Hz, 2H), 7.20 (s, 1H), 7.37 (td, J = 7.2, 1.5 Hz, 1H), 7.40 (td, J = 7.0, 1.7 Hz, 1H), 7.62 (dd, J = 7.1, 2.1 Hz, 1H), 7.86 (dd, J = 6.9, 1.4 Hz, 1H), 7.92 (dt, J = 9.2, 2.2 Hz, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 14.4, 60.4, 113.9, 114.2, 120.9, 121.1, 123.3, 124.2, 125.1, 131.5, 133.1, 134.7, 138.8, 149.2, 166.6.
HRMS (FI) Calcd for C ₁₇ H ₁₅ NO ₂ S: M +, 297.08235. Found: m / z 297.08403.
mp: 127-129 ° C.

[Example 18]
A compound (3117) was obtained as a red solid in the same manner as in Example 1 except that the reaction was carried out under the conditions shown in Tables 3 and 4 (isolation yield 81%).
The NMR data, HRMS data and melting point of the obtained compound (3117) are shown below.

¹ H NMR (500 MHz, CDCl ₃ ) δ 1.40 (bs, 1H), 2.82 (t, J = 6.6 Hz, 2H), 3.84 (q, J = 6.1 Hz, 2H), 5.74 (bs, 1H), 6.975 (d, J = 8.0, 2H), 6.975 (s, 1H), 7.34-7.41 (m, 2H), 7.63-7.68 (m, 1H), 7.82-7.86 (m, 1H).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 38.4, 63.8, 108.3, 116.5, 120.5, 123.2, 123.9, 124.9, 129.9, 130.0, 134.5, 135.2, 138.9, 143.2.
HRMS (FI) Calcd for C ₁₆ H ₁₅ NOS: M +, 269.08743. Found: m / z 269.09014.
mp: 65-67 ° C.

[Example 19]
The compound (3118) was obtained as a red solid in the same manner as in Example 1 except that the reaction was carried out under the conditions shown in Tables 3 and 4 (isolation yield 89%).
The NMR data, HRMS data and melting point of the obtained compound (3118) are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.72 (bs, 1H), 6.73 (dt, J = 8.7, 2.5 Hz, 2H), 7.05 (s, 1H), 7.34-7.42 (m, 2H), 7.50 ( dt, J = 8.7, 2.5 Hz, 2H), 7.59-7.64 (m, 1H), 7.82-7.87 (m, 1H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 81.1, 111.4, 117.8, 120.7, 123.3, 124.1, 125.0, 134.2, 134.6, 138.0, 138.9, 144.7.
HRMS (FI) Calcd for C ₁₄ H ₁₀ INS: M +, 350.95786. Found: m / z 350.95491.
mp: 105-107 ° C.

[Example 20]
The compound (3119) was obtained as a brown solid in the same manner as in Example 1 except that the reaction was carried out under the conditions shown in Tables 3 and 4 (isolation yield 66%).
The NMR data, HRMS data and melting point of the obtained compound (3119) are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.16 (td, J = 7.7, 1.2 Hz, 1H), 7.33 (td, J = 7.8, 1.2 Hz, 1H), 7.40-7.46 (m, 2H), 7.58 ( d, J = 8.7 Hz, 1H), 7.63 (dd, J = 7.8, 0.9 Hz, 1H), 7.73-7.78 (m, 1H), 7.79 (s, 1H), 7.86-7.91 (m, 1H), 8.10 (bs, 1H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 113.7, 119.6, 120.0, 121.0, 122.6, 123.3, 124.4, 125.3, 126.2, 130.5, 131.6, 133.4, 138.7, 151.6, 164.9.
HRMS (FI) Calcd for C ₁₅ H ₁₀ N ₂ S ₂ : M +, 282.02977. Found: m / z 282.02854.
mp: 202-204 ° C.

[Example 21]
The reaction was performed under the conditions shown in Tables 3 and 4, and the concentrate was the same as Example 1 except that the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane / ethyl acetate (30/1, volume ratio)). The compound (3120) was obtained as a yellow liquid by the method (isolation yield 75%).
The NMR data and HRMS data of the obtained compound (3120) are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.88 (t, J = 6.9 Hz, 3H), 1.24-1.40 (m, 6H), 1.60-1.70 (m, 2H), 2.85 (s, 3H), 3.06- 3.12 (m, 2H), 6.53 (s, 1H), 7.29-7.38 (m, 2H), 7.76-7.81 (m, 2H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 14.1, 22.7, 26.9, 27.3, 31.8, 41.1, 56.3, 106.2, 122.2, 123.2, 123.5, 124.3, 135.1, 139.3, 147.6.
HRMS (FI) Calcd for C ₁₅ H ₂₁ NS: M +, 247.13947. Found: m / z 247.14262.

[Example 22]
The reaction was performed under the conditions shown in Tables 3 and 4, and the concentrate was the same as Example 1 except that the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane / ethyl acetate (20/1, volume ratio)). By the method, a compound (3201) was obtained as a white solid (isolation yield 97%).
The NMR data, HRMS data and melting point of the obtained compound (3201) are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.25 (t, J = 8.7 Hz, 2H), 4.04 (t, J = 8.7 Hz, 2H), 5.72 (s, 1H), 6.87 (td, J = 7.3, 0.9 Hz, 1H), 7.05-7.11 (m, 1H), 7.14-7.23 (m, 3H), 7.34-7.40 (m, 2H), 7.52 (d, J = 7.8 Hz, 1H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 28.0, 49.8, 80.9, 109.8, 110.8, 118.3, 120.5, 120.6, 123.0, 124.9, 127.7, 130.1, 130.4, 144.2, 150.6, 154.7.
HRMS (FI) Calcd for C ₁₆ H ₁₃ NO: M +, 235.09971. Found: m / z 235.10175.
mp: 96-98 ° C.

[Example 23]
The reaction was performed under the conditions shown in Tables 3 and 4, and the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane / triethylamine (30/1, volume ratio)), and further purified by gas chromatography. Gave the compound (3202) as a white solid in the same manner as in Example 1 (isolation yield 39%).
The NMR data, HRMS data and melting point of the obtained compound (3202) are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.04 (s, 1H), 7.11 (tt, J = 7.3, 1.2 Hz, 2H), 7.14-7.25 (m, 6H), 7.28-7.36 (m, 5H), 7.37-7.41 (m, 1H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 92.7, 110.6, 119.5, 122.6, 122.9, 123.4, 124.1, 129.3, 129.5, 145.2, 151.2, 156.2.
HRMS (FI) Calcd for C ₂₀ H ₁₅ NO: M +, 285.11538. Found: m / z 285.12028.
mp: 70-72 ° C.

[Example 24]
The reaction was performed under the conditions shown in Tables 3 and 4, and the concentrate was the same as Example 1 except that the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane / ethyl acetate (2/1, volume ratio)). By the method, the compound (3301) was obtained as a yellow-brown solid (isolation yield 61%).
The NMR data, HRMS data and melting point of the obtained compound (3301) are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 3.06-3.13 (m, 4H), 3.90-3.97 (m, 4H), 6.74 (d, J = 2.8 Hz, 1H), 7.09 (td, J = 7.6, 1.1 Hz, 1H), 7.19 (td, J = 7.7, 1.2 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.71 (bs, 1H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 53.1, 67.1, 110.2, 111.4, 119.0, 122.0, 122.4, 132.5, 135.7 (one signal overlapped with another signal and could not be clearly confirmed).
HRMS (FI) Calcd for C ₁₂ H ₁₄ N ₂ O: M +, 202.11061.Found: m / z 202.11246.
mp: 140-142 ° C.

[Example 25]
The reaction was performed under the conditions shown in Tables 3 and 4, and the concentrate was the same as Example 1 except that the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane / ethyl acetate (5/1, volume ratio)). By the method, the compound (3302) was obtained as a brown solid (isolation yield 69%).
The NMR data, HRMS data, and melting point of the obtained compound (3302) are shown below.

¹ H NMR (500 MHz, CDCl ₃ ) δ 3.17 (t, J = 8.6 Hz, 2H), 3.91 (t, J = 8.6 Hz, 2H), 6.52 (d, J = 8.0 Hz, 1H), 6.69 (t , J = 7.4 Hz, 1H), 6.99 (t, J = 7.7 Hz, 1H), 7.08 (t, J = 7.4 Hz, 1H), 7.14-7.18 (m, 2H), 7.22 (t, J = 7.5 Hz , 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.90 (bs, 1H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 28.9, 55.4, 108.3, 111.5, 116.9, 117.8, 119.3, 119.7, 122.4, 123.1, 123.5, 124.5, 127.3, 129.7, 135.2, 151.4.
HRMS (FI) Calcd for C ₁₆ H ₁₄ N ₂ : M +, 234.11570. Found: m / z 234.11989.
mp: 84-86 ° C.

[Example 26]
The compound (3121) was obtained as a colorless liquid in the same manner as in Example 1 except that the reaction was carried out under the conditions shown in Tables 3 and 4 and the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane). Obtained (isolation yield 61%).
The NMR data and HRMS data of the obtained compound (3121) are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.88 (t, J = 6.9, 3H), 1.19-1.38 (m, 12H), 1.38-1.48 (m, 2H), 1.77 (quint, J = 7.0, 2H) , 4.02 (t, J = 6.6, 2H), 6.19 (dd, J = 3.7, 1.4 Hz, 1H), 6.53 (dd, J = 5.5, 1.4 Hz, 1H), 6.70 (dd, J = 5.9, 3.7 Hz , 1H).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 14.1, 22.7, 25.9, 29.2, 29.3, 29.5, 31.9, 74.0, 104.5, 111.7, 124.7, 165.9 (The two signals overlap each other, so they are clearly identified. could not.).
HRMS (FI) Calcd for C ₁₄ H ₂₄ OS: M +, 240.15479. Found: m / z 240.15264.

[Example 27]
The compound (3122) was obtained as a colorless liquid in the same manner as in Example 1 except that the reaction was carried out under the conditions shown in Tables 3 and 4 and the concentrate was purified by silica gel column chromatography (mobile phase: n-hexane). Obtained (isolation yield 82%).
The NMR data and HRMS data of the obtained compound (3122) are shown below.

¹ H NMR (400 MHz, CDCl ₃ ) δ 0.88 (t, J = 6.9, 3H), 1.19-1.33 (m, 12H), 1.33-1.44 (m, 2H), 1.56-1.65 (m, 2H), 2.79 (t, J = 7.6, 2H), 6.97 (dd, J = 5.3, 3.4 Hz, 1H), 7.10 (dd, J = 3.4, 1.1 Hz, 1H), 7.32 (dd, J = 5.3, 1.1 Hz, 1H ).
¹³ C NMR (100 MHz, CDCl ₃ ) δ 14.1, 22.7, 28.4, 29.2, 29.3, 29.4, 29.50, 29.54, 31.9, 39.0, 127.4, 128.8, 133.2, 135.0.
HRMS (FI) Calcd for C ₁₄ H ₂₄ S ₂ : M +, 256.13194.Found: m / z 256.1349.

[Example 28]
Compound (3123) was obtained in the same manner as in Example 1 except that the reaction was performed under the conditions shown in Tables 3 and 4. The NMR conversion yield of the compound (3123) was 42%.
The structure of the compound (3123) was confirmed by NMR data and HRMS data.

[Example 29]
Compound (3124) was obtained in the same manner as in Example 5 except that Compound (1α) (0.625 mmol) and Compound (2) (0.25 mmol) represented by the following formula were used (yield: 76). %).
The structure of the compound (3124) was confirmed by NMR data and HRMS data.

[Example 30]
Compound (3125) was obtained in the same manner as in Example 4 except that compound (1α) (0.3 mmol) and compound (2) (0.25 mmol) represented by the following formula were used (yield 60 %).
The structure of the compound (3125) was confirmed by NMR data and HRMS data.

[Example 31]
Compound (3126) was obtained in the same manner as in Example 19 except that compound (1α) (0.3 mmol) and compound (2) (0.25 mmol) represented by the following formula were used (yield: 85 %).
The structure of the compound (3126) was confirmed by NMR data and HRMS data.

[Comparative Example 1]
The production of the compound (3101) was attempted in the same manner as in Example 1 except that In (NTf ₂ ) ₃ was not used. However, the reaction hardly proceeded, and the NMR conversion yield of the compound (3101) was 1 %.

[Example 32]
Compound (3101) was obtained in the same manner as in Example 1, except that 1,4-dioxane (1 mL) was used instead of chlorobenzene (1 mL). The NMR conversion yield of the compound (3101) was 29%.
The NMR data of the obtained compound (3101) were the same as those in Example 1.

[Example 33]
Compound (3101) was obtained in the same manner as in Example 1, except that 1,2-diethoxyethane (1 mL) was used instead of chlorobenzene (1 mL). The NMR conversion yield of the compound (3101) was 21%.
The NMR data of the obtained compound (3101) were the same as those in Example 1.

[Example 34]
Compound (3101) was obtained in the same manner as in Example 1, except that dibutyl ether (1 mL) was used instead of chlorobenzene (1 mL). The NMR conversion yield of the compound (3101) was 59%.
The NMR data of the obtained compound (3101) were the same as those in Example 1.

[Example 35]
Compound (3101) was obtained in the same manner as in Example 1 except that p-xylene (1 mL) was used instead of chlorobenzene (1 mL). The NMR conversion yield of the compound (3101) was 59%.
The NMR data of the obtained compound (3101) were the same as those in Example 1.

[Example 36]
Compound (3101) was obtained in the same manner as in Example 1 except that nitromethane (1 mL) was used instead of chlorobenzene (1 mL). The NMR conversion yield of the compound (3101) was 26%.
The NMR data of the obtained compound (3101) were the same as those in Example 1.

[Example 37]
Compound (3101) was obtained in the same manner as in Example 1 except that the reaction time was changed to 48 hours instead of 24 hours. The NMR conversion yield of the compound (3101) was 39%.
The NMR data of the obtained compound (3101) were the same as those in Example 1.

[Example 38]
Compound (3101) was obtained in the same manner as in Example 1 except that the reaction temperature was changed to 110 ° C instead of 110 ° C and the reaction time was changed to 48 hours instead of 24 hours. The NMR conversion yield of the compound (3101) was 39%.
The NMR data of the obtained compound (3101) were the same as those in Example 1.

[Example 39]
Compound (3101) was obtained in the same manner as in Example 1, except that the amount of compound (1α) used was 0.375 mmol instead of 0.625 mmol. The NMR conversion yield of the compound (3101) was 61%.
The NMR data of the obtained compound (3101) were the same as those in Example 1.

[Example 40]
Compound (3101) was obtained in the same manner as in Example 1 except that the amount of compound (1α) used was changed to 0.5 mmol instead of 0.625 mmol. The NMR conversion yield of the compound (3101) was 63%.
The NMR data of the obtained compound (3101) were the same as those in Example 1.

[Example 41]
Compound (3101) was obtained in the same manner as in Example 1 except that the amount of compound (1α) used was changed to 0.75 mmol instead of 0.625 mmol. The NMR conversion yield of the compound (3101) was 61%.
The NMR data of the obtained compound (3101) were the same as those in Example 1.

  The present invention can be used for the production of pharmaceuticals, highly functional materials and the like.

Claims (8)

A compound represented by the following general formula (1α) or a salt thereof and a compound represented by the following general formula (2) are reacted in the presence of a Lewis acid, and the following general formula (3α) or (3β) A method for producing a heteroaryl compound to obtain a heteroaryl compound represented by:
A method for producing a heteroaryl compound, wherein the Lewis acid is an indium compound .

( Wherein G is a nitrogen atom, oxygen atom or sulfur atom; A is an organic group; E is an aromatic heterocyclic group; X is a leaving group; A group or an alkylcarbonyloxy group, wherein X is bonded to a carbon atom constituting the aromatic heterocyclic skeleton of E; n1 is an integer of 1 to 3, and n2 is an integer of 0 to 2, , When G is a nitrogen atom, n1 + n2 is 3, and when G is an oxygen atom or a sulfur atom, n1 + n2 is 2; n2 ′ is 0 or 1, provided that n1 + n2 ′ is M is an integer of 1 or more; q is an integer of 1 or more and m or less; and when n2 is 2, two A's in the general formula (1α) may be the same or different from each other Well, two A's may be bonded to each other to form a ring; when m is 2 or more A plurality of X in the general formula (2) may be the same or different from each other; when n2 is 2 or q is 2 or more, a plurality of A in the general formula (3α) is They may be the same or different from each other, and when n2 is 2, two A's may be bonded to each other to form a ring; when mq is 2 or more, the general formula (3α) And a plurality of X in the general formula (3β) may be the same as or different from each other; a plurality of X in the general formula (3β) may be They may be the same or different; when q is 2 or more, the values of a plurality of n2 and n1-1 in general formula (3α) may be the same or different from each other; general formula (3β) The two m-1 values may be the same or different from each other.) A compound represented by the following general formula (1β) or a salt thereof and a compound represented by the following general formula (2) are reacted in the presence of a Lewis acid, and the following general formula (4α) or (4β) A method for producing a heteroaryl compound to obtain a heteroaryl compound represented by:
A method for producing a heteroaryl compound, wherein the Lewis acid is an indium compound .

( Wherein G is a nitrogen atom, oxygen atom or sulfur atom; A is an organic group; E is an aromatic heterocyclic group; X is a leaving group; A group or an alkylcarbonyloxy group, wherein X is bonded to a carbon atom constituting the aromatic heterocyclic skeleton of E; n1 is 2 when G is a nitrogen atom, and G is an oxygen atom or 1 when it is a sulfur atom; n3 is an integer of 1 or more; m is an integer of 1 or more; p is an integer of 1 or more and n3 or less; r is n1 or less and 1 or 2 Yes; however, p and r are not 1 at the same time; t is an integer of 1 to m; and when n3 is 2 or more, a plurality of G in the general formula (1β) may be the same as each other They may be different; when m is 2 or more, a plurality of X in the general formula (2) are the same as each other. However, when n3-p is 1 or more, a plurality of G in the general formula (4α) may be the same or different from each other; m-1 or p is 2 or more, Alternatively, when r is 2, a plurality of X in the general formula (4α) may be the same or different from each other; when p is 2 or more, or when r is 2, the general formula (4α) A plurality of E may be the same or different from each other; when n3-1 is 1 or more, or t is 2 or more, a plurality of G in the general formula (4β) may be the same as each other They may be different; when t is 2 or more, a plurality of A's in general formula (4β) may be the same or different from each other; when mt is 2 or more, general formula (4β) A plurality of X may be the same or different from each other; when n3 is 2 or more, the general formula (1β A plurality of n1 values may be the same or different from each other; when n3-p is 2 or more, a plurality of n1 values in the general formula (4α) may be the same or different from each other. Well; when r is 2 or when p is 2 or more, a plurality of m-1 values in the general formula (4α) may be the same or different from each other; when p is 2 or more In the general formula (4α), the values of a plurality of r and n1-r may be the same or different from each other; when n3-1 is 2 or more, or t is 2 or more, A plurality of n1 values in the general formula (4β) may be the same or different from each other; when t is 2 or more, a plurality of n1-1 and n3-1 values in the general formula (4β) May be the same as or different from each other.)   The method for producing a heteroaryl compound according to claim 1 or 2, wherein E is an aromatic heterocyclic group having one heteroatom in the aromatic heterocyclic skeleton.   The manufacturing method of the heteroaryl compound as described in any one of Claims 1-3 whose hetero atom in the aromatic heterocyclic skeleton which said E has is a sulfur atom, a nitrogen atom, or an oxygen atom.   The manufacturing method of the heteroaryl compound as described in any one of Claims 1-4 whose said A is the alkyl group, aryl group, or arylalkyl group which may have a substituent. The method for producing a heteroaryl compound according to any one of claims 1 to 5 , wherein the Lewis acid is di [bis (trifluoromethylsulfonyl) imide] indium. The method for producing a heteroaryl compound according to any one of claims 1 and 3 to 6 , wherein m is 1 or 2. The method for producing a heteroaryl compound according to any one of claims 2 to 6 , wherein n3 and m are each independently 1 or 2.