JP2003012650A - Method for producing heterocyclic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method with which a heterocyclic compound represented by general formula (I) and/or general formula (I)' can be efficiently produced by a short process. SOLUTION: A reaction is carried out in the presence of a metal catalyst to form a heterocyclic compound represented by general formula (I) and/or the general formula (I)' (R<1> , R<2> , R<3> , R<4> , and R<5> are each a hydrogen atom or a univalent substituent group or an atomic group in which two of these groups are mutually bonded to form a ring; X is an oxygen atom, a nitrogen atom, a sulfur atom, or a selenium atom; when X is an oxygen atom, a sulfur atom or a selenium atom, R<3> does not exist).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a heterocyclic compound.

[0002]

2. Description of the Related Art 1,2-azoles (isoxazole, pyrazole, isothiazole, isoselenazole, etc.) including heterocyclic compounds represented by the following general formula (I) have functions of dyes, pharmaceuticals, etc. It is useful as an intermediate and a raw material for a volatile compound. Among them, amino-1,2-azoles such as aminopyrazole are more useful because they also serve as synthetic intermediates for synthesizing other heterocyclic compounds, as described in US Pat. Is. Hironori Yamanaka et al., "Chemistry of Heterocyclic Compounds", Chapter 5 (1988, Kodansha Scientific), JA Joule, K. Mills.
Author, "Heterocyclic Chemistry Fourth edition", Cha
pter 22 (2000, Blackwell Science), AR Katrit
zky, AF Pozharskii, “Handbook of Heterocycli
c Chemistry 2nd edition ”, Chapter 4.3.2.3 (2000
Year, Pergamon), AR Katritzky, CW Rees, “Co
mprehensive Heterocyclic Chemistry ”, Volume 5, Ch
It is summarized in apter 4.04.3 (1984, Pergamon). For example, pyrazoles and isoxazoles can be easily synthesized by reacting a β-ketoester compound or a β-ketonitrile compound with hydrazines or hydroxylamines.

Of these 1,2-azoles, pyrazoles can be synthesized by referring to the above-mentioned books.
For example, if pivaloylacetonitrile and methylhydrazine are heated in an ethanol solvent for 5 hours, 5-amino-3-t-butyl-1-methylpyrazole can be easily synthesized with a yield of 79.4%. Chem. Pharm. Bull ., 35, pp. 3235, 1987
Reported in the year.

On the other hand, in the synthetic method of the heterocyclic compound represented by the general formula (I), the 3-oxo-2-cyanopropionitrile derivative is directly reacted with hydrazine or hydroxylamine in the same manner as in the above synthetic route. Even 3-substitution-5
-Amino-4-cyanopyrazole is not available, Bul
L. Chim. Soc. Fr., p. 3323, 1965. In fact, as compounds represented by the general formula (II) and the general formula (III), 2-cyanopivaloylacetonitrile and hydrazine are represented by the general formula (I) even when heated at 80 ° C. in an isopropanol solvent. No compound is obtained.

For example, among the compounds represented by the general formula (I), wherein R ² is a cyano group, the following synthetic methods have been reported. (A) A method of converting the compound of the general formula (II) into enol methyl ether with dimethylsulfate or diazomethane under basic conditions and reacting this with hydrazine. (J. H
eterocyclic Chem., 12, 1199, 1975, Bull. Ch.
im. Soc. Fr., page 3323, 1965, J. Chem. Soc., Perki
n Trans., Vol. 1, pp. 1545, 1996, U.S. Pat.No. 5294612)

(B) A method of reacting the compound of the general formula (II) with phosphorus pentachloride to convert it into a 3-chloro-2-cyanoacrylonitrile derivative, which is then reacted with hydrazine. (US Patent No. 5079213, EP-0492444A1 etc.)

(C) A method of synthesizing a 3-amino-2-cyanoacrylonitrile derivative and reacting it with hydrazine. (Liebigs Ann. Chem., P. 884, 1982, J. Hetero.
cyclic Chem., 29, 1067, 1992 etc.)

(D) A method of synthesizing a 3-alkoxy-2-cyanoacrylonitrile derivative from orthoester and malononitrile and reacting it with hydrazine. (J. Org.
Chem., 21, p. 1240, 1956, etc.)

(E) A methylthioamidium salt is prepared from a thioamide derivative and dimethylsulfate and reacted with malononitrile, or from thioamide or dithiocarboxylate and tetracyanoethylene oxide,
A method of synthesizing a 3-methylthio-2-cyanoacrylonitrile derivative and reacting it with hydrazine. (J. Heteroc
yclic Chem. 27, 647, 1990 etc.)

Like the above-mentioned examples, the synthesis of the compounds represented by the following general formula (I) and general formula (I) 'may not be easy unlike the above-mentioned synthesis of pyrazoles. I know there is. Further, each synthesis method has the following problems.
In (a) and (e), dimethylsulfate, which is highly toxic, or diazomethane, which is not easy to handle, must be used as the alkylating agent. In the method (a), J. Chem. Soc. Perkin Trans. 1, 1545, 1996.
Although a one-pot synthetic method that does not use an excess of reagents has been reported in the year, it is inevitable to use the minimum amount of the above alkylating agent. Further, there has been no report so far that the synthetic route of (a) was carried out using a reaction agent which is easier to handle than the above alkylating agent. Also, a method for synthesizing a pyrazole derivative while involving a ring-opening reaction as a similar reaction has been reported in J. Heterocyclic Chem. 28, 1257, 1991, etc. Several steps are required.

In (b), since a large amount of phosphorus pentachloride is used for chlorination, reaction charging and post-treatment are not easy. For example, in Example 1 of US Pat. No. 5,079,213, the yield is not described, but the general formula (II)
(R ²¹ : t-Bu) 57g and phosphorus pentachloride 86g, methylene chloride 500m
l react in That is, about 1.1 as phosphorus pentachloride
Equivalents are used and all chlorine atoms on phosphorus pentachloride are not used for chlorination. Further, the use of a halogen-based solvent is not preferable because it has a great influence on the environment.

In (c), the number of substrates whose substrates can be easily synthesized is limited. For example J. Am. Chem. Soc., 80, 2838, 1
In the case of malononitrile dimer as described in 958, and in the case of a substrate which can be easily synthesized from a specific nitrile and malononitrile as described in J. Chem. Res. Miniprint, 0958, 1988. Is. In many cases DE-A-2434922, Liebigs Ann. Chem. 884
P., 1982, J. Heterocyclic Chem. 29, 1067, 1
As described in 992 etc., several steps are required for synthesis. Further, when malononitrile is used, the reaction is often complicated by the formation of malononitrile dimer, and separation / purification is often difficult. In particular, when a nitrile having a lower reactivity than that of malononitrile is used, it is very difficult to suppress the production of malononitrile dimer. On the other hand, as described in Japanese Patent Laid-Open No. 2-3652, a synthetic method via imidate has been reported. In this method, imidate synthesis and / or reaction of imidate with malononitrile may be difficult depending on the substrate. Especially, when this method is applied using a nitrile having a bulky substituent such as a tertiary alkyl group as a raw material, The reaction with malononitrile is very slow and the inclusion of malononitrile dimer is unavoidable.

In (d), a limited number of orthoesters as raw materials can be easily obtained, but when the desired orthoester cannot be obtained, a step of synthesizing the orthoester is necessary, and the total number of steps is increased. Will increase.

Also in (e), it is difficult to obtain the starting thioamide derivative and dithiocarboxylate,
As in the case of (d), the number of steps increases. Also, tetracyanoethylene oxide is not an inexpensive raw material.

[0015]

The object of the present invention is to efficiently and efficiently produce a compound represented by the general formula (I) or the general formula (I) without using a toxic compound, a compound which is not easy to handle, or an expensive raw material. It is to provide a method capable of synthesizing a heterocyclic compound represented by I) ′.

[0016]

Means for Solving the Problems As a result of various studies conducted by the present inventor to overcome the above-mentioned drawbacks of the conventional method, a metal catalyst,
Especially by using a titanium catalyst, the following general formula (II)
It was also found that a heterocyclic compound represented by the following general formula (I) or general formula (I) ′ can be synthesized in a short step using a compound represented by the following general formula (III) as a raw material.
That is, the above object of the present invention was achieved by the following method. 1. In the presence of a metal catalyst, a compound represented by the following general formula (II) and a compound represented by the following general formula (III) are reacted to give a compound represented by the following general formula (I) and / or general formula (I) ′. A method for producing a heterocyclic compound, which comprises producing the represented heterocyclic compound.

[0017]

[Chemical 4]

Wherein: R ¹ , R ² , R ³ , R ⁴ and R ⁵ are
Represents a hydrogen atom or a monovalent substituent, or represents R ¹ and R ² , R ¹ and R ³ , R ² and R ³ , R ¹ and R ⁴ or R ¹ and R ⁵ , R ² and R ⁴ or R ² and R ⁵ , R ³ and R ⁴ or R ³
And R ⁵ represent an atomic group for forming a ring by bonding with each other. X represents an oxygen atom, a nitrogen atom, a sulfur atom, or a selenium atom. However, when X is an oxygen atom, a sulfur atom or a selenium atom, R ³ does not exist. General formula (II)

[0019]

[Chemical 5]

In the formula, R ²¹ and R ²² represent a hydrogen atom or a monovalent substituent, or represent an atomic group for forming a ring by bonding with each other. General formula (III)

[0021]

[Chemical 6]

In the formula, R ³³ represents a hydrogen atom or a monovalent substituent. X ³ represents an oxygen atom, a nitrogen atom, a sulfur atom or a selenium atom. However, when X ³ is an oxygen atom, a sulfur atom or a selenium atom, R ³³ does not exist. 2. The method for producing a heterocyclic compound according to the above 1, wherein R ^{22 in the} general formula (II) is a cyano group. 3. 3. The method for producing a heterocyclic compound according to the above 1 or 2, wherein X in the general formula (I) and the general formula (I) ′ is a nitrogen atom. 4. R < ¹ > of General formula (I) and General formula (I) 'is a tertiary alkyl group, The manufacturing method of the heterocyclic compound in any one of said 1-3 characterized by the above-mentioned. 5. 5. The method for producing a heterocyclic compound according to any one of 1 to 4 above, wherein the metal catalyst is a titanium catalyst.

[0023]

BEST MODE FOR CARRYING OUT THE INVENTION Embodiments of the present invention will be described in detail. The present invention relates to a method for producing a heterocyclic compound represented by the general formula (I) and / or the general formula (I) ′, particularly a compound represented by the general formula (II) and a general formula (III). In the method for producing the compound using the compound, the reaction is performed in the presence of a metal catalyst. In addition, the method for producing the heterocyclic compound represented by the general formula (I) and / or the general formula (I) ′ means at least the heterocyclic compound represented by the general formula (I) and the general formula (I) ′. It is a method of manufacturing a kind. The metal catalyst preferably has Lewis acidity. This is because it is considered important that the metal catalyst having Lewis acidity is coordinated with the carbonyl group of the compound represented by the general formula (II) to activate the carbonyl group. However, it is not easy to understand how the properties of the metal catalyst actually used influence the reaction, and the properties and role of the metal catalyst used in the present invention are limited to this estimation. is not.

Any metal catalyst may be used as long as it has a metal atom or ion in the catalyst and has a function of promoting the reaction. The metal of the metal catalyst may be a typical metal or a transition metal. For example, boron, magnesium, aluminum, scandium, titanium, iron, nickel, zinc, tin, copper,
Examples include silver and lanthanoids. Boron, aluminum, titanium, tin and zinc are preferable, and titanium is particularly preferable.

Examples of the metal catalyst include organic metal compounds, metal alkoxides, metal halides, metal sulfonates, metal carboxylates and the like. Organic metal compounds, metal alkoxides, metal halides, metal sulfonates, and metal carboxylates are preferable, organic metal compounds, metal alkoxides, and metal halides are more preferable, and metal alkoxides are most preferable.

Specific examples of the organometallic compound include alkylaluminum and Grignard reagents. Specific examples of the metal alkoxide include trialkyl borate, aluminum alkoxide, and titanium tetraalkoxide. Specific examples of the metal halide include aluminum chloride, magnesium chloride, titanium tetrachloride, iron chloride, tin chloride, zinc chloride and the like. Specific examples of the metal sulfonate include scandium triflate, silver triflate, and lanthanoid triflate. Specific examples of the metal carboxylate include magnesium acetate and copper acetate. Among these, trialkyl borate, magnesium chloride, aluminum alkoxide, scandium triflate, titanium tetraalkoxide, zinc chloride, and tin chloride are preferable, and particularly preferably trimethyl borate, aluminum alkoxide, titanium tetraalkoxide, zinc chloride, Tin chloride, most preferably titanium tetraalkoxide.

The alkoxy group of the metal alkoxide may be any one, but commercially available ones are preferable because they are easily available. For example, in the case of titanium tetraalkoxide, titanium tetraisopropoxide, titanium tetramethoxide, titanium tetrabutoxide, etc. are commercially available. Those not commercially available can be synthesized by reacting titanium tetrachloride with a desired alcohol or by reacting another titanium tetraalkoxide with a desired alcohol. When the reaction is carried out in an alcohol solvent, titanium tetrachloride may be added to prepare titanium tetraalkoxide in the reaction system. The four alkoxy groups on titanium may be the same or different, but if the ligand exchange is very fast, it is difficult to describe the actual catalyst morphology.

In addition to the metal catalyst, a ligand that interacts with the metal catalyst may be added separately. As the ligand, one having an effect of further accelerating the activation of the reaction, one having an effect of position and stereocontrol, and the like can be used. In this case, it may be ligand-exchanged with the ligand initially bound to the metal catalyst, or may be newly coordinated to the vacant coordination site without ligand-exchange.

Then, the general formulas (I), (I) 'and (II)
The compounds represented by and (III) will be described.
R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ²¹ , R ²² , and R ³³ represent a hydrogen atom or a monovalent substituent. Examples of the monovalent substituent include a halogen atom, an alkyl group (including a cycloalkyl group and a bicycloalkyl group), an alkenyl group (including a cycloalkenyl group and a bicycloalkenyl group), an alkynyl group, an aryl group, a heterocyclic group, and a cyano group. Group, hydroxyl group, nitro group, carboxyl group, alkoxy group, aryloxy group, silyloxy group, heterocyclic oxy group, acyloxy group, carbamoyloxy group, alkoxycarbonyloxy group, aryloxycarbonyloxy, amino group (including anilino group ), Acylamino group, aminocarbonylamino group, alkoxycarbonylamino group, aryloxycarbonylamino group, sulfamoylamino group, alkyl and arylsulfonylamino group, mercapto group, alkylthio group, arylthio group, hetero Thio group, sulfamoyl group, sulfo group, alkyl and arylsulfinyl group, alkyl and arylsulfonyl group, acyl group, aryloxycarbonyl group, alkoxycarbonyl group, carbamoyl group, aryl and heterocyclic azo group, imide group, phosphino group, phosphinyl Examples include a group, a phosphinyloxy group, a phosphinylamino group, and a silyl group.

R ¹ , R ³ , R ²¹ and R ³³ are preferably
It is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group. The unsubstituted alkyl group has 1 to 1 carbon atoms.
20 alkyl groups are preferred. For example, methyl group, ethyl group, isopropyl group, t-butyl group, n-hexyl group,
Examples thereof include a cyclohexyl group and an adamantyl group.
These may have a substituent. As a substituent,
The above-mentioned monovalent substituents may be mentioned as examples. Examples of the unsubstituted aryl group include aryl groups having 6 to 18 carbon atoms. Examples thereof include a phenyl group, a naphthyl group and an anthracenyl group. These may have a substituent. Examples of the substituent include the above-mentioned monovalent substituents. The unsubstituted heterocyclic group has 4 to 1 carbon atoms.
And 8 heterocyclic groups. Examples thereof include a pyrrolyl group, a pyrrolidinyl group, a thienyl group, a furyl group, a pyridyl group, an imidazolyl group, an indolyl group, a quinolyl group, a pyranyl group, a morpholinyl group and a piperazinyl group. These may have a substituent. Examples of the substituent include the above-mentioned monovalent substituents.

R ¹ and R ²¹ are more preferably an alkyl group having 1 to 10 carbon atoms and an aryl group, and further preferably an alkyl group having 1 to 10 carbon atoms. Specifically, it is a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, a t-butyl group or an isoamyl group. Among them, the method of the present invention is preferably applied to the production of a heterocyclic compound having a substituent which is difficult to produce by a method different from the method of the present invention. For example, when R ¹ and R ²¹ are a methyl group or an ethyl group, the method using the orthoester according to (d) described in the section of the prior art can be adopted because the raw material is commercially available. , An alkyl group excluding a methyl group and an ethyl group facilitates the production of the corresponding heterocyclic compound by the method of the present invention,
This is an important advantage. In addition, R ¹ and R ²¹ are often limited in reaction by the conventional technique due to steric hindrance.
Even if it is a primary alkyl group (for example, t-butyl group or t-octyl group), the intended heterocyclic compound can be easily produced by the method of the present invention. From this point, it is particularly preferable that R ¹ and R ²¹ are tertiary alkyl groups.

R ² and R ²² are preferably a hydrogen atom, a cyano group, a carbamoyl group, a carboxyl group, an acyl group, a thioalkyl group, a sulfoalkyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, Examples thereof include a substituted or unsubstituted heterocyclic group. A cyano group, a carbamoyl group, an acyl group, a sulfoalkyl group, and an aryl group are more preferable, and a cyano group is still more preferable. Particularly, R ²² is preferably a cyano group.

R ⁴ and R ⁵ are preferably a hydrogen atom, an acyl group, a sulfoalkyl group or an alkyl group. More preferably, R ⁴ and R ⁵ are both hydrogen atoms.

X and X ³ represent a nitrogen atom, an oxygen atom, a sulfur atom or a selenium atom. A nitrogen atom, an oxygen atom and a sulfur atom are preferable, a nitrogen atom and an oxygen atom are more preferable, and a nitrogen atom is particularly preferable.
R ³ and R ³³ may not be present depending on X and X ³ . In this case, X and X ³ are either oxygen atom, sulfur atom or selenium atom. When X and X ³ are nitrogen atoms, R ³ and R ³³ are always present.

As R ³ and R ³³ , a hydrogen atom, an alkyl group having 1 to 40 carbon atoms, an aryl group and a heterocyclic group are more preferable, and a hydrogen atom and a carbon number of 1 are more preferable.
To 20 alkyl groups. Particularly preferred is a hydrogen atom.

R ¹ and R ² , R ¹ and R ³ , R ² and R ³ , R ¹ and R ⁴
Alternatively, R ¹ and R ⁵ , R ² and R ^4, R ² and R ⁵ , R ³ and R ^4, R ³ and R ⁵ , or R ⁴ and R ⁵ may be bonded to each other to form a ring. Good. In this case, these pairs represent an atomic group for forming a ring. The heterocyclic compound represented by the general formula (1) and the general formula (I) ′ having such a ring structure may be produced by using a compound having a ring formed in advance as a raw material. For example, R in the general formula (II)
²¹ and may be used in which R ²² is bonded to the each other to form a ring. Also, a ring may be formed during the reaction or the post-treatment. When R ¹ and R ³ and R ² and R ³ are bonded to each other to form a ring, the compound represented by the general formula (II) and the compound represented by the general formula (III) are bonded to each other in advance. hand,
That is, R ²¹ and R ³³ or R ²² and R ³³ may be bonded to each other to form one compound, and such a case is also included in the present invention.

In the reaction of the present invention, R ¹ and R ^{2 in} the general formulas (I) and (I) 'are respectively represented by R ²¹ and R ²² in the general formula (II) and the general formula (I), R ³ and X in (I) ′ are R ³³ and X in the general formula (III), respectively.
³ , but does not necessarily have to be the same. That is, the structure may be changed during the reaction of the present invention or by the post-treatment.

The compound represented by the general formula (II) may be synthesized by any method. For example, US Pat.
As described in 213, EP-0492444A1, etc.,
It can be easily synthesized by reacting a carboxylic acid derivative such as a carboxylic acid halide, a carboxylic acid ester or an acid anhydride with an acetonitrile derivative such as malononitrile in the presence of a base.

As the compound represented by the general formula (III), a commercially available compound may be used, or it may be separately synthesized so that R ³³ has a desired structure. For example, when X ³ is a nitrogen atom in the compound represented by the general formula (III) and is a hydrazine compound as the general formula (III), SR Sandler, W. K
aro, "Organic Functional Group Preparations Seco
nd Edition ", Chapter 14 (1983, Academic Press)
It can be synthesized with reference to.

In the present invention, depending on the reaction conditions and the like, the reaction positions of the general formula (II) and the general formula (III) are reversed together with the compound represented by the general formula (I). In some cases, the compound represented by the formula (1) is produced, but in the present invention, the case in which the general formula (I) ′ is produced is also included.
Either the general formula (I) or the general formula (I) 'may be selectively produced, or may be produced as a mixture in a certain ratio. However, when R ³ is a hydrogen atom, the compounds represented by the general formula (I) and the general formula (I) ′ are in a tautomeric relationship with each other. R in the general formula (I) '
¹ , R ² , R ³ , R ⁴ , R ⁵ , and X have the same meanings as in formula (I).
General formula (I) '

[0041]

[Chemical 7]

The compound represented by the general formula (II) may take a tautomer such as a keto form and an enol form depending on the environment in which it is placed. Although only the keto form is described in the present invention, the enol form and other tautomers may be used. The compounds represented by the general formulas (I) and (III) also have tautomers. In the present invention, one of the typical forms is described, but tautomers different from the description of the present invention are also included in the compound of the present invention.

The compounds represented by the general formulas (I), (I) ', (II) and (III) include those having a pair of salts depending on the synthetic process or isolation method. The counter salt may be any salt, and examples thereof include a halogen ion, a sulfate ion, a nitrate ion, a carbonate ion, a sulfonate ion, a phosphate ion, an acetate ion, a metal ion and an ammonium ion. Depending on the structure, an inner salt may be formed.

In the present invention, the general formula (I)
The compounds represented by (I) ′, (II) and (III) may contain isotopes (eg, ² H, ³ H, ¹³ C, ¹⁵ N).

Specific examples of the compounds represented by formulas (I), (I) ', (II) and (III) are shown below, but the invention is not limited thereto.

[0046]

[Table 1]

[0047]

[Table 2]

[0048]

[Table 3]

The reaction of the present invention may be carried out without using a solvent, but it is preferably carried out in the presence of a solvent. The solvent system may be water, a water-containing organic solvent, a homogeneous solvent of an organic solvent, or a two-phase solvent of water-organic solvent. As the organic solvent, a hydrocarbon solvent such as toluene, xylene and hexane, a halogen solvent such as methylene chloride, a sulfoxide solvent such as dimethylsulfoxide, an amide solvent such as dimethylformamide, an ether solvent such as tetrahydrofuran, dioxane and diglyme. Solvents, alcohol-based solvents such as methanol, ethanol, isopropanol, nitrile-based solvents such as acetonitrile, ketone-based solvents such as acetone and cyclohexanone, ester-based solvents such as acetic acid ethyl ester, and heterocyclic solvents such as pyridine and piperidine be able to. You may mix and use 2 or more types of organic solvents. Also, for example, J. Chem. Tech. Biotechno
It is also possible to use an ionic liquid as a reaction solvent as described in l.68,351, 1997, Science 269, 1065, 1
It is also possible to carry out the reaction using a supercritical fluid such as 995. The solvent used is preferably water, a hydrocarbon solvent, an ether solvent, an alcohol solvent, a nitrile solvent, an ester solvent, or a heterocyclic solvent. More preferred are hydrocarbon solvents and alcohol solvents. More preferred are aromatic hydrocarbon solvents such as toluene and lower alcohol solvents such as isopropanol.

The reaction of the present invention may be carried out in a homogeneous system or a heterogeneous system. General formula (I),
The compounds represented by (I) ′, (II) and (III) may be dissolved or sparingly soluble in the reaction solvent. The metal catalyst used in the present invention may be dissolved or hardly soluble in the reaction solvent. The intermediate product of the reaction of the present invention may be dissolved or hardly soluble in the reaction solvent. In addition, general formulas (I), (I) ′,
Due to the interaction between the compound represented by (II) and / or (III) and the metal catalyst, the solubility in the reaction solvent may be different from that in the case of using alone. Further, as the reaction proceeds, dissolution or precipitation may occur and the state of the reaction system may change depending on the progress of the reaction. When the compounds represented by the general formulas (I) and (I) 'are synthesized using the present invention, the reaction is carried out in a homogeneous system, but a reaction system in which a product is precipitated as the reaction proceeds Although desired to be constructed, the product can be obtained by any post-treatment even without such a reaction system.

The reaction temperature is preferably between 0 ° C and 200 ° C. More preferably from 20 ° C to 150 ° C,
Particularly preferably, it is between 60 ° C and 120 ° C.

The reaction of the present invention is carried out according to the general formulas (II) and (II
It is carried out by reacting the compound represented by I) with a metal catalyst in an arbitrary solvent, but it may be carried out by adding a compound or salt other than these.

The compounds represented by the general formulas (II) and (III) may be used after isolation and purification when they are separately synthesized, or they may not be isolated after the synthesis. May be used for. For example, after synthesizing the compound represented by the general formula (II), the compound represented by the general formula (III) and a metal catalyst are added and reacted without isolation and purification to give the compound represented by the general formula (I ) And a compound represented by the general formula (I) ′ are also possible.

The amount of the metal catalyst used depends on the kind of the raw material, the reaction temperature and other factors, but it is usually the general formula (II)
It is used in an amount of 0.1 to 2 equivalents, preferably 0.8 to 1.2 equivalents, relative to the compound represented by. The amount of the compound represented by the general formula (III) used is preferably 0.5 equivalent to 2 equivalents relative to the compound represented by the general formula (II).

[0055]

EXAMPLES The present invention will be described in more detail below by way of examples, but the present invention is not construed as being limited to the examples.

<Example 1-1> (Synthesis of Compound Example 2-8) Malononitrile 66.06
g (1 mol) was dispersed in 500 ml of toluene, and 123.2 ml (1 mol) of pivaloyl chloride was added thereto. This mixture was cooled to an internal temperature of 5 ° C. or lower, and 279 ml (2 mol) of triethylamine was added dropwise while stirring while maintaining the internal temperature of 10 ° C. or lower. 30 in an ice bath after dropping
Stirring was continued for 5 minutes, and 500 g of ice water was added to the reaction mixture. Further, 132 ml of concentrated sulfuric acid was added dropwise while keeping the internal temperature at 20 ° C or lower. Stir for 30 minutes in an ice bath, filter the resulting solid and wash the solid with water. The solid was dried to obtain 126.3 g (84%) of a white solid of Compound Example 2-8. FAB MS (posi) 151 (MH ⁺ ). ¹ H NMR (DMSO-d ₆ ) 1.15 (s, 9H, C ₄ H ₉ ), 9.45-9.65 (b
r, 1H).

<Example 1-2> (Synthesis of Compound Example 1-8) Compound Example 2-8 1.5 g
(10 mmol) was dispersed in 10 ml of toluene, and 2.95 ml of titanium tetraisopropoxide (10 mmo)
1) was slowly added dropwise. After stirring at room temperature for about 10 minutes, 0.58 m of hydrazine monohydrate (Compound Example 3-1)
1 (12 mmol) was slowly added dropwise. The obtained reaction mixture was reacted for 6 hours in an oil bath set at 80 ° C.
After the reaction was completed, the precipitate was filtered off and the solid was washed with toluene and methanol. Purify by mixing the filtrate and washing solution,
1.2g of compound examples 1-8 were obtained (yield 73%). FAB MS (posi) 165 (MH ⁺ ). ¹ H NMR (DMSO-d ₆ ) 1.27 (s, 9H, C ₄ H ₉ ), 5.50-6.30
_{(Br, 2H, NH 2)} , 11.20-11.90 (br, 1H, NH).

Comparative Example 1 Compound Example 2-8 and Compound Example 3
-1 in toluene or isopropanol at 80 ° C for 3
When reacted for a time, Compound Example 2-8 was not consumed,
It was confirmed by HPLC that Compound Example 1-8 was not produced. EP-492444 is a synthetic example of the compound example 1-8 reported so far, but the compound example 2-8 is treated with phosphorus pentachloride and then reacted with hydrazine. This method requires the use of various reactive agents. According to another method for synthesizing pyrazoles, Compound Example 2-8 was methylated with dimethylsulfate and subsequently reacted with hydrazine to give Compound Example 1-8 in a total yield of 23%. The use of dimethylsulfate is unavoidable and the number of steps is large compared to the present invention.

<Example 2> (Synthesis of Compound Example 1-2) Compound Example 2-2 (Example 1-
0.49 g (4.5 mmol) synthesized in the same manner as in 1) was dispersed in 9 ml of toluene, and 1.3 ml (4.5 mmol) of titanium tetraisopropoxide was slowly added dropwise.
After stirring at room temperature for about 10 minutes, 0.26 ml (5.4 mmol) of hydrazine monohydrate (Compound Example 3-1) was slowly added dropwise. The obtained reaction mixture was reacted for 6 hours in an oil bath set at 80 ° C. After the reaction was completed, the precipitate was filtered off and the solid was washed with toluene and methanol. The filtrate and the washing liquid were mixed and purified, and Compound Example 1-2 was 0.30.
g was obtained (yield 55%). FAB MS (posi) 123 (MH ⁺ ). ¹ H NMR (DMSO-d ₆ ) 2.22 (s, 3H, CH ₃ ), 5.20-5.90 (br,
2H, NH ₂ ), 9.60-9.80 (br, 1H, NH).

Comparative Example 2 Compound Example 2-2 and Compound Example 3
-1 in toluene or isopropanol at 80 ° C for 3
When reacted for time, Compound Example 2-2 was not consumed,
It was confirmed that Compound Example 1-2 was not produced.

<Example 3> (Synthesis of Compound Example 1-18) 0.17 g (1 mmol) of Compound Example 2-12 (synthesized in the same manner as in Example 1-1) was dispersed in 2 ml of toluene to prepare titanium tetraisohydrate. 0.295 ml (1 mmol) of propoxide was slowly added dropwise.
After stirring at room temperature for about 10 minutes, 0.073 ml (1.5 mmol) of hydrazine monohydrate (Compound Example 3-1) was slowly added dropwise. The obtained reaction mixture was reacted for 6 hours in an oil bath set at 80 ° C. After the reaction was completed, the precipitate was filtered off and the solid was washed with toluene and methanol. The filtrate and the washing solution were mixed and purified, and Compound Example 1-18 was purified to 0.
13 g was obtained (68% yield). FAB MS (posi) 185 (MH ⁺ ). ¹ H NMR (DMSO-d ₆ ) 6.10-6.70 (br, 2H, NH ₂ ), 7.35
7.60 (m, 3H, Ar), 7.75-7.90 (m, 2H, Ar), 12.00-12.45
(br, 1H, NH).

Comparative Example 3 When Compound Example 2-12 and Compound Example 3-1 were reacted in toluene or isopropanol at 80 ° C. for 3 hours, Compound Example 2-12 was not consumed, and Compound Example 1-18. Was not generated.

[0063]

INDUSTRIAL APPLICABILITY By using the method of the present invention, a heterocyclic compound represented by the general formula (I) or the general formula (I) 'can be efficiently synthesized in a shorter step than the conventionally known production method. it can. Furthermore, the step of converting into an active group is unnecessary, and the reaction reagent used in this step is unnecessary.

Claims (5)

[Claims] 1. A compound represented by the following general formula (II) in the presence of a metal catalyst:
A compound represented by the following general formula (III) is reacted with to produce a heterocyclic compound represented by the following general formula (I) and / or general formula (I) ′. A method for producing a characterized heterocyclic compound. [Chemical 1] In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent a hydrogen atom or a monovalent substituent, or R ¹ and R ² , R ¹ and R ³ , R ² and R ³ , R ¹ and R ⁴ or R ¹ and R ⁵ , R ² and R ⁴
Alternatively, R ² and R ⁵ , R ³ and R ^4, or R ³ and R ⁵ are bonded to each other to form an atomic group. X represents an oxygen atom, a nitrogen atom, a sulfur atom, or a selenium atom. However,
When X is an oxygen atom, a sulfur atom or a selenium atom, R ³
Does not exist. General formula (II) In the formula, R ²¹ and R ²² represent a hydrogen atom or a monovalent substituent, or represent an atomic group for bonding with each other to form a ring. General formula (III): In the formula, R ³³ represents a hydrogen atom or a monovalent substituent. X
³ represents an oxygen atom, a nitrogen atom, a sulfur atom, or a selenium atom. However, when X ³ is an oxygen atom, a sulfur atom or a selenium atom, R ³³ does not exist. 2. The method for producing a heterocyclic compound according to claim 1, wherein R ^{22 in the} general formula (II) is a cyano group. 3. X in the general formula (I) and the general formula (I) ′.
Is a nitrogen atom, The manufacturing method of the heterocyclic compound of Claim 1 or 2 characterized by the above-mentioned. 4. R in the general formula (I) and the general formula (I) ′.
¹ is a tertiary alkyl group.
4. The method for producing the heterocyclic compound according to any one of 3 above. 5. The method for producing a heterocyclic compound according to claim 1, wherein the metal catalyst is a titanium catalyst.