JP2001261653A - Method for synthesizing pyridine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing on an industrial scale a pyridine derivative useful as an intermediate for pharmaceutical preparations, agrochemicals, electrophotographic photoreceptors, dyestuffs, etc., without using any expensive catalyst and/or special equipment; more precisely, to provide a method for producing such a site-specific pyridine derivative in high purity and yield at low cost without causing any pollution problem. SOLUTION: This method for producing the subject pyridine derivative is characterized by comprising a process for reaction between a specific acetyl compound and a specific 3-amino-2-propenylideneammonium salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a process for producing a pyridine derivative which is an important intermediate in the fields of pharmaceuticals, agricultural chemicals, catalyst ligands, organic electroluminescent devices, charge transfer materials, electrophotographic photoreceptors, dyes and the like. About.

[0002]

2. Description of the Related Art A conventional method for forming a pyridine ring from an acetyl compound as a starting material has been reviewed (Synthesi).
s, pp. 1 (1976)). For example, a reaction has been reported in which a ketone of an acetyl compound is halogenated at the α-position and then converted to a pyridinium ion and reacted with an α, β-unsaturated ketone derivative to form a pyridine ring. Is not applicable when is in the molecule. This method is applicable to the synthesis of a pyridine ring having a substituent at the 2-position, but is not suitable for the synthesis of a pyridine ring having a substituent at the 3-position.

[0003] Further, taking an example of a synthesis method of a 2-pyridylpyridine derivative, an Ullmann reaction between 2-bromopyridine and 4-chloropyridine in nitrobenzene (Khim.
Geol. Nauk. Pp. 114 (1970)) and those utilizing a cobalt catalyst (Synthesis, p.
p. 600 (1975), Chem. Pharm. B
ull. , 33, pp. 4755 (1985)) and a coupling reaction between an alkyltin derivative and a halogenated pyridine in the presence of a Pd catalyst (Tetrahedron).
Lett. , 33, pp. 2199 (1992)), N
Coupling reaction between halogenated pyridine derivatives under i-metal catalyst (WO9852922) and the like are known, but the catalysts and reagents to be used are very expensive, and a special treatment is required for metal waste liquid and the like. There are many problems such as difficulty in separating by-products, and it cannot be said that this is an industrially advantageous method.

A cross-coupling reaction utilizing a Grignard reaction (JP-A-64-3169, Tetr
ahedron Lett. , 28, pp. 5845
(1987)) and Li of halogenated pyridine derivatives
Synthesis by Wurtz reaction under irradiation of ultrasonic waves in the presence of metal (Tetrahedron Lett., 30, p.
p. 3567 (1989), Synthesis, p.
p. 564 (1986)) has been proposed, but requires dedicated equipment and has many problems in mass production.

Also, a method of iodizing an acetylpyridine derivative to form a pyridine ring via a pyridinium ion (Synthesis, pp. 815 (199)
9)) has been proposed. However, in this case, if iodine remains during iodination, a by-product is generated in the next step, so a purification step is required after iodination, which is not suitable for mass synthesis. In addition, there is a concern about environmental problems due to halogenation.

Further, a pyridine ring formation reaction using a quaternary salt as shown below has been reported (India).
nJ. Chem. , Sect B .; , Pp. 341 (1
985), Indian J. et al. Chem. , Sect
B. , Pp. 559 (1988)), but in this case, there were problems such as the necessity of removal in a multi-stage reaction and a low yield.

[0007]

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[0008]

SUMMARY OF THE INVENTION An object of the present invention is to produce pyridine derivatives useful as intermediates for pharmaceuticals, agricultural chemicals, electrophotographic photoreceptors, dyes, etc. without using expensive catalysts or special equipment, and An object of the present invention is to provide a production method that can be produced on a large scale. More specifically, an object of the present invention is to provide a method for producing a regiospecific pyridine derivative which can be produced with high purity, high yield and low cost and does not cause a pollution problem.

[0009]

Means for Solving the Problems The present inventor has conducted intensive studies to achieve the above object, and as a result, has found that the above object is achieved by the following method. That is, (1) a pyridine derivative comprising a step of reacting an acetyl compound represented by the general formula (I) with a 3-amino-2-propenylidene ammonium salt represented by the general formula (II). Manufacturing method.

[0010]

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In the formula, R1 is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic residue, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted Represents a substituted alkynyl group, a carbonyl group, a sulfonyl group, or a cyano group. R2 is a hydrogen atom,
Substituted or unsubstituted alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heterocyclic residue, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, alkoxy group, aryloxy Group, hydroxyl group, alkylthio group, arylthio group, carbonyl group,
Represents a sulfonyl group, a nitro group, a cyano group, or a halogen atom. Further, R1 and R2 may combine to form a substituted or unsubstituted ring composed of a nonmetal atom together with the carbon atom to which they are attached.

[0012]

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In the formula, R3, R4, R6 and R7 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic residue, a carbonyl group. Represents R3 and R4, R6 and R7
May be joined together to form a substituted or unsubstituted ring consisting of non-metallic atoms together with the nitrogen atom to which they are attached. R5 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic residue, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, It represents a hydroxyl group, an alkylthio group, an arylthio group, an alkoxy group, an aryloxy group, a carbonyl group, a sulfonyl group, a substituted or unsubstituted amino group, a nitro group, a cyano group, or a halogen atom. X ^- is a counter ion of a quaternary ammonium salt, and represents a halide ion, a perhalate ion, an organic acid ion, or an inorganic ion. (2) a step of reacting the acetyl compound represented by the general formula (I) described in the above (1) with a 3-iminopropenylamino compound represented by the following general formula (III). A method for producing a pyridine derivative.

[0014]

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In the formula, R3, R4 and R6 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic residue, or an acyl group. . R3 and R4 may combine to form a substituted or unsubstituted ring consisting of a nonmetallic atom together with the nitrogen atom to which they are attached. R5 is a hydrogen atom,
Halogen, substituted or unsubstituted alkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heterocyclic residue, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, hydroxyl group, alkylthio group Group,
Represents an arylthio group, an alkoxy group, an aryloxy group, a carbonyl group, a sulfonyl group, a substituted or unsubstituted amino group, a nitro group, a cyano group, or a halogen atom.

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in more detail. To describe the method of the present invention in more detail,
One embodiment of the method of the invention (R3 and R4 or R6 and R7
Are shown below as an example, but the present invention is not limited thereto.

[0017]

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In the present invention, in the compound represented by the general formula (I), R1 is specifically a hydrogen atom, a substituted or unsubstituted linear, branched or cyclic alkyl group (methyl,
Ethyl, isopropyl, t-butyl, n-octyl, n
-Dodecyl, cyclopentyl, cyclohexyl, methoxyethyl, 2-chloroethyl, benzyl, 3-dimethylaminomethyl, bromocyclohexyl, 2-norbornyl, etc., substituted or unsubstituted aryl groups (phenyl, naphthyl, phenanthryl, tolyl, quinolyl, chlorophenyl) , Hydroxyphenyl, ethylaminophenyl, etc.), substituted or unsubstituted heterocyclic residues (pyrazolyl,
Imidazolyl, pyridyl, pyrimidinyl, thienyl, thiazolyl, furyl, isoxazolyl, benzothiazolyl, phenoxazinyl, 2-methylimidazolyl, 3-
Aminopyridyl, 4-phenylisoxazolyl, etc.) and substituted or unsubstituted alkenyl groups (vinyl, allyl, 2-
Butenyl, cinnamyl, 2-chloroethenyl, etc., substituted or unsubstituted alkynyl groups (ethynyl, 1-propynyl, 1-butynyl, trimethylsilylethynyl, etc.), carbonyl groups [acyl groups (acetyl, pivaloyl, benzoyl, etc.), alkoxycarbonyl ( Methoxycarbonyl, ethoxycarbonyl, etc.), aryloxycarbonyl (phenyloxycarbonyl, etc.), carbamoyl group (unsubstituted carbamoyl, N-methylcarbamoyl, N,
N-diethylcarbamoyl and the like), a sulfonyl group (methylsulfonyl, phenylsulfonyl, unsubstituted sulfamoyl, N-ethylsulfamoyl, N, N-dimethylsulfamoyl and the like), and a cyano group. Preferably a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, 6 to 2 carbon atoms
0 aryl group or heterocyclic residue, more preferably an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 12 carbon atoms, a 5- or 6-membered nitrogen-containing heterocyclic residue and a sulfur-containing residue. It is a heterocyclic residue.

R2 is specifically a hydrogen atom, a substituted or unsubstituted linear, branched or cyclic alkyl group (methyl,
Ethyl, isopropyl, t-butyl, n-octyl, n
-Dodecyl, cyclopentyl, cyclohexyl, methoxyethyl, 2-chloroethyl, benzyl, 3-dimethylaminomethyl, bromocyclohexyl, 2-norbornyl, etc., substituted or unsubstituted aryl groups (phenyl, naphthyl, phenanthryl, tolyl, quinolyl, chlorophenyl) , Hydroxyphenyl, ethylaminophenyl, etc.), substituted or unsubstituted heterocyclic residues (pyrazolyl,
Imidazolyl, pyridyl, pyrimidinyl, thienyl, thiazolyl, furyl, isoxazolyl, 2-methylimidazolyl, 3-phenylpyridyl, 4-ethylisoxazolyl, etc.), substituted or unsubstituted alkenyl groups (vinyl,
Allyl, 2-butenyl, cinnamyl, 2-chloroethenyl and the like, substituted or unsubstituted alkynyl groups (ethynyl,
1-propynyl, 1-butynyl, trimethylsilylethynyl, etc.), hydroxyl group, alkoxy group (methoxy,
Ethoxy, etc.), aryloxy group (phenoxy, 2-naphthyloxy, etc.), alkylthio group (methylthio, ethylthio, etc.), arylthio group (phenylthio, naphthylthio, etc.), carbonyl group [acyl group (acetyl, pivaloyl, benzoyl, etc.) ), An alkoxycarbonyl group (methoxycarbonyl, ethoxycarbonyl, etc.), an aryloxycarbonyl group (phenyloxycarbonyl, etc.), a carbamoyl group (unsubstituted carbamoyl, N-methylcarbamoyl, N, N-diethylcarbamoyl, etc.)], a sulfonyl group ( Methylsulfonyl, phenylsulfonyl, unsubstituted sulfamoyl, N-ethylsulfamoyl, N, N
Dimethylsulfamoyl), a nitro group, a cyano group,
Represents a halogen atom (chlorine, iodine, bromine, etc.). Preferably a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, 6 carbon atoms
An aryl group having from 20 to 20 carbon atoms, an acyl group having from 2 to 10 carbon atoms, an alkoxycarbonyl group having from 2 to 10 carbon atoms, and a nitrogen-containing heterocyclic residue.
A lower alkyl group of 4; a phenyl group; and an alkoxycarbonyl group having 2 to 5 carbon atoms.

R1 and R2 may combine with each other to form a substituted or unsubstituted ring composed of a nonmetallic atom together with the carbon atom to which they are attached, and specific examples thereof include cyclopentanone, cyclohexanone, and benzocyclohexane. Examples include pentanone, benzocyclohexanone, and tetrahydropyran-4-none.

In the compound represented by formula (II) or (III), R3, R4, R6, and R7 are each independently a hydrogen atom, a substituted or unsubstituted straight chain, Branched or cyclic alkyl groups (methyl, ethyl, isopropyl, t-butyl, n-octyl, n-dodecyl,
Cyclopentyl, cyclohexyl, methoxyethyl, 2
-Chloroethyl, benzyl, 3-dimethylaminomethyl, bromocyclohexyl, 2-norbornyl, etc.), substituted or unsubstituted aryl groups (phenyl, naphthyl, phenanthryl, tolyl, quinolyl, chlorophenyl, hydroxyphenyl, ethylaminophenyl, etc.), substitution Or an unsubstituted heterocyclic residue (pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, thienyl, thiazolyl,
Furyl, isoxazolyl, 2-methylimidazolyl, 3
-Phenylpyridyl, 4-ethylisoxazolyl, etc.),
Carbonyl group [acyl group (acetyl, pivaloyl, benzoyl, etc.), alkoxycarbonyl group (methoxycarbonyl, ethoxycarbonyl, etc.), aryloxycarbonyl group (phenyloxycarbonyl, etc.), carbamoyl group (unsubstituted carbamoyl, N-methylcarbamoyl,
N, N-diethylcarbamoyl and the like)]. Preferably a lower alkyl group having 1 to 4 carbon atoms, 6 to 1 carbon atoms
An aryl group having 2 or an acyl group having 2 to 5 carbon atoms, more preferably a methyl group, a phenyl group, an acyl group, and particularly preferably a methyl group.

R3 and R4, R6 and R7 are each bonded,
They may form a substituted or unsubstituted ring consisting of a nonmetallic atom together with the nitrogen atom to which they are attached. Specific examples include a pyrrolidine ring, a piperidine ring and a morpholine ring, and a piperidine ring is preferred.

R5 is specifically a hydrogen atom, a substituted or unsubstituted linear, branched or cyclic alkyl group (methyl,
Ethyl, isopropyl, t-butyl, n-octyl, n
-Dodecyl, cyclopentyl, cyclohexyl, methoxyethyl, 2-chloroethyl, benzyl, 3-dimethylaminomethyl, bromocyclohexyl, 2-norbornyl, etc., substituted or unsubstituted aryl groups (phenyl, naphthyl, phenanthryl, tolyl, quinolyl, chlorophenyl) , Hydroxyphenyl, ethylaminophenyl, etc.), substituted or unsubstituted heterocyclic residues (pyrazolyl,
Imidazolyl, pyridyl, pyrimidinyl, thienyl, thiazolyl, furyl, isoxazolyl, benzothiazolyl, phenoxazinyl, 2-methylimidazolyl, 3-
Aminopyridyl, 4-phenylisoxazolyl, etc.),
Substituted or unsubstituted alkenyl groups (vinyl, allyl, 2
-Butenyl, cinnamyl, 2-chloroethenyl and the like, substituted or unsubstituted alkynyl groups (ethynyl, 1-propynyl, 1-butynyl, trimethylsilylethynyl and the like),
Hydroxyl group, alkoxy group (methoxy, ethoxy, etc.), aryloxy group (phenoxy, 2-naphthyloxy, etc.), alkylthio group (methylthio, ethylthio, etc.), arylthio group (phenylthio, naphthylthio, etc.), carbonyl group [acyl Groups (acetyl, pivaloyl, benzoyl, etc.), alkoxycarbonyl groups (methoxycarbonyl, ethoxycarbonyl, etc.), aryloxycarbonyl groups (phenyloxycarbonyl, etc.), carbamoyl groups (unsubstituted carbamoyl, N-methylcarbamoyl, N, N-diethyl) Carbamoyl etc.)], a sulfonyl group (methylsulfonyl, phenylsulfonyl, unsubstituted sulfamoyl, N-ethylsulfamoyl, N, N-
Dimethylsulfamoyl, etc.), substituted or unsubstituted amino groups (amino, N-ethylamino, N, N-dimethylamino, N, N-diphenylamino, methoxycarbonylamino, phenoxycarbonylamino, acetylamino, ureido, methyl Sulfonylamino, phenylsulfonylamino, etc.), nitro group, cyano group, halogen atom (chlorine, iodine, bromine, etc.). Preferably, it is a lower alkyl group having 1 to 4 carbon atoms, an aryl group having 6 to 10 carbon atoms, a nitrogen-containing heterocyclic residue, a nitro group, a cyano group, or a halogen atom, and more preferably a methyl group, a phenyl group, or a pyridyl group. Group, nitro group, cyano group and halogen atom, particularly preferably methyl group, phenyl group and chlorine atom.

X ^- is a counter ion of a quaternary ammonium salt, specifically, a halide ion (fluoride ion,
Chloride ion, bromide ion, iodide ion, etc., perhalate ion (perchlorate ion, perbromate ion,
Periodate ion, etc.), organic acid ion (p-toluenesulfonic acid ion, 1,5-dinaphthalenesulfonic acid, etc.), and inorganic ion (sulfate ion, nitrate ion, tetrafluoroboron ion, hexafluorophosphate ion, etc.). Can be Preferably, they are easily isolated and inexpensive chloride ion, perchlorate ion, 1,5-dinaphthalenesulfonic acid, and tetrafluoroboron ion, and more preferably form a water-insoluble ion pair with a quaternary amine. It is a perchlorate ion that can be formed.

The acetyl compound used in the method of the present invention is easily available as a commercial product. An aromatic acetyl compound can be introduced by acylation by a Friedel-Crafts reaction (J. Org. Ch.).
em. , 38, pp. 1445 (1973); Am.
Chem. Soc. , 79, pp. 1445 (195
7); Am. Chem. Soc. , 84, pp. 81
3 (1962)). β-ketoesters and 1,3-diketones are described in Org. Synth. , III, pp. 379
(1955); Org. Synth. , IV, pp.41
5 (1963); Org. Chem. , 59, pp.
488 (1994) and the like, and can be easily synthesized, and Tetrahedron Lett. , 28
(44), pp. 5361 (1987),
It is also possible to prepare from nitro compounds by Nef reaction

The 3-amino-2 used in the method of the present invention
-Propenylidene ammonium salts are prepared by converting the corresponding acetal compound, vinyl ethers, carboxylic acid derivative to V
React with ilsmeier reagent (Tetrahed
ron, 43, pp. 171 (1987); Am.
Chem. Soc. , 103, pp. 3030 (198
1), Synthesis, pp. 641 (198
3), Zh. Org. Khim. , 8, pp. 139
4 (1972)), or thereafter, a suitable secondary amine is reacted with the treatment solution (J. Org. Chem., 5).
1, pp. 2961 (1986), Collect. C
zech. Chem. Commun, pp. 1637
(1996)).

The 3-iminopropenylamino compound used in the method of the present invention can be easily obtained as a commercial product. After reacting the corresponding acetal compound, vinyl ethers, and carboxylic acid derivative with the Vilsmeier reagent (Tetrahedron, 43, pp. 1).
71 (1987); Am. Chem. Soc. , 1
03, pp. 3030 (1981), Synthesi
s, pp. 641 (1983), Zh. Org. Kh
im. , 8, pp. 1394 (1972)) and can be adjusted by post-treatment with an appropriate amine.

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

[0029]

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[0030]

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[0031]

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Next, the production method will be described in detail. In the present invention, a reaction solvent may not be used throughout all steps, but if necessary, an aromatic solvent such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene, pyridine, acetonitrile, N, N-dimethylformamide, Polar solvents such as N, N-dimethylacetamide, N-methylpyrrolidone, methyl acetate, ethyl acetate,
Any organic solvent, whether polar or non-polar, such as an ester solvent such as butyl acetate, an alcohol solvent such as methanol, ethanol, isopropyl alcohol, butanol, and t-butanol can be used. Ether solvents such as ether, dibutyl ether, methyl t-butyl ether, and tetrahydrofuran (abbreviated as THF), and more preferably THF. In addition, two or more solvents can be used as a mixture, and the mixing ratio at the time of mixed use can be arbitrarily determined. The amount of the reaction solvent to be used is generally 1 to 50 times the weight of the acetyl compound, more preferably 2 to 30 times the weight, more preferably 4 to 8 times the weight.

In the present invention, the acetyl compound and 3-amino-2-propenylidene ammonium salt or 3-amino-2-propenylidene ammonium salt
When reacting with the iminopropenylamino compound, it is preferable to allow a base to be present. The base used in this reaction is
Any substance can be used, but usually potassium t
Metal alkoxides such as -butoxide, sodium t-butoxide and sodium ethoxide; inorganic bases such as sodium hydride, metal sodium, sodium hydroxide and potassium hydroxide; and organic bases such as triethylamine and diisopropylamine. Preferably potassium t-butoxide, sodium t-butoxide,
Sodium hydride, more preferably potassium t-
Butoxide. The amount of the base to be used is generally 0.1 to 10 mol, preferably 0.8 to 2.0 mol, more preferably 0.9 to 1.2 mol, per 1 mol of the acetyl compound.
It is in the molar range.

In the present invention, an acetyl compound and 3-amino-2-propenylidene ammonium salt or 3-amino-2-propenylidene ammonium salt
The reaction temperature at the time of reacting the iminopropenylamino compound is usually in the range of 20 to 200 ° C, preferably 3 to 200 ° C.
The temperature is 0 to 100 ° C, more preferably 40 to 80 ° C. These reactions are usually completed within 24 hours, and often 1
From 0 minutes to 12 hours, disappearance of the raw material is confirmed.

In the production method of the present invention, a catalyst is not particularly required. However, when an acetyl compound is reacted with a 3-iminopropenylamino compound, a method of activating with a secondary amine also gives good results. . Any secondary amine may be used as the secondary amine. Examples thereof include aliphatic secondary amines such as dimethylamine, diethylamine and dipropylamine; aliphatic cyclic secondary amines such as pyrrolidine and piperidine; and cyclic 6 such as morpholine. There are aliphatic secondary amines such as membered heteroaliphatic secondary amines, methylphenylamine and ethylphenylamine, and aromatic secondary amines such as diphenylamine and the like. Preferred are dimethylamine, diethylamine, pyrrolidine and piperidine, and more preferred are dimethylamine, pyrrolidine and piperidine. The amount of the secondary amine is usually 0.1 to 1 mol of the acetyl compound.
It is preferred to carry out the reaction in an amount of 1 to 10 mol, preferably 0.8 to 8.0 mol, more preferably 1.0 to 6.0 mol.

When reacting an acetyl compound with a 3-iminopropenylamino compound, good results can be obtained by using an acid anhydride or an acid halide together with a base, if necessary. Although any acid anhydride can be used, acetic anhydride and benzoic anhydride are inexpensive and give good results. Any acid halide can be used, but acetic chloride and benzoyl chloride are inexpensive and give good results. The amount of the acid anhydride to be used is usually 0.1 to 10.0 with respect to 1 mol of the acetyl compound.
It is good to use it in a molar amount, preferably in a range of 0.8 to 3.5 mol, more preferably in a range of 2.0 to 2.5 mol.
The amount of the acid chloride to be used is generally 0.1 to 10.0 mol, preferably 0.8 to 3.5 mol, per 1 mol of the acetyl compound.
It is preferable to use it in a molar amount, more preferably in a range of 2.0 to 2.5 molar amount.

As an acid anhydride or acid halide, if necessary, any base can be used, but triethylamine, pyridine, anhydrous sodium carbonate and the like are inexpensive and give good results. The amount of the base to be used is 0.1 to 0.1 mol per 1 mol of the acetyl compound.
It is good to use it in the range of 10 moles, preferably 0.8 to 8.0 moles, more preferably 2.1 to 4.1 moles.

In the present invention, after the above-mentioned step of reacting an acetyl compound with a 3-amino-2-propenylidene ammonium salt or 3-iminopropenylamino compound, a step of forming a pyridine ring in the reaction product is performed. . In the step of forming the pyridine ring, the source of the nitrogen atom of the pyridine ring may be: 1) a nitrogen atom-containing compound (preferably ammonia or ammonium salt) to be newly added to the reaction system; 2) the general formula (II) Alternatively, a nitrogen atom in the compound represented by the general formula (III) (general formula (II) or (II)
When R3 and R4 in I) are both hydrogen atoms, the general formula (I
When both R6 and R7 in I) are hydrogen atoms,
And / or when R6 in the general formula (III) is a hydrogen atom) 3).

In the present invention, in the case of the above 2), the reaction proceeds without adding ammonia or ammonium salt,
Although completed, ammonia or ammonium salt may be newly added. In the case of the above 1), it is necessary to add an ammonia or ammonium salt. Any form of ammonia or ammonium salt can be used, but usually ammonia gas, aqueous ammonia, ammonium chloride, ammonium acetate, ammonium formate and the like are used. Preferred are ammonium chloride, ammonium acetate, and ammonium formate, and more preferably, ammonium acetate. The amount of these additives is 1 to 30 times, preferably 3 to 1 mol per mol of the acetyl compound.
It is preferable to carry out in a range of from 15 to 15 times, more preferably in a range of from 6 to 10 times. In addition, two or more different forms of ammonia can be mixed and used, and the mixing ratio when mixed and used can be arbitrarily determined.

In the production method of the present invention, a catalyst is not required, but a pyridine ring is formed in a reaction product of an acetyl compound and a 3-amino-2-propenylidene ammonium salt or a 3-iminopropenylamino compound. In the reaction, it is preferable to use an acid catalyst if necessary, since the reaction is completed in a shorter time. Any acid catalyst can be used, but inorganic acids such as sulfuric acid and hydrochloric acid, organic acids such as p-toluenesulfonic acid, formic acid, acetic acid and propionic acid, and strongly acidic ion exchange resins such as Amberlite and Amberlyst And the like, preferably formic acid, acetic acid, and propionic acid, which can keep the reaction system weakly acidic, and more preferably acetic acid.

In the present invention, the reaction temperature of the pyridine ring forming reaction is usually in the range of 40 to 200 ° C., preferably 50 to 150 ° C., more preferably 60 to 110 ° C. The reaction time is usually 1 to 20 hours, preferably 1.5 to 10 hours, preferably 2 to 5 hours.

After completion of the reaction, the method of purifying the target pyridine derivative includes recrystallization using alcohol, hexane, toluene, etc., column purification using silica gel, and distillation under reduced pressure. By purifying these methods alone or in combination of two or more, the desired product can be obtained with high purity.

[0043]

EXAMPLES Next, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples. The purity was evaluated by high performance liquid chromatography (HPL).
C).

Example 1 4,4'-dimethyl-2,2 '
Synthesis of dipyridyl (V-1) 9.62 g of (2-methyl-3-piperidylprop-2-enylidene) piperidine perchlorate (IV-1)
(0.03 mol) and 4.06 g (0.030 mol) of 4-methyl-2-acetylpyridine were added to tetrahydrofuran 1
Dissolved in 4 ml, 3.63 g of potassium t-butoxide
(0.032 mol) and reacted at 60 ° C. for 30 minutes.
Next, 9.25 g (0.12 mol) of ammonium acetate and 7 ml of acetic acid were added, and the mixture was reacted at 60 ° C. for 2 hours.
The tetrahydrofuran was concentrated and removed while raising the temperature to 85 ° C, and the reaction was carried out at 85 ° C for 2 hours. After cooling, 40 ml of toluene and 30 ml of a 25% aqueous NaOH solution were added to the reaction solution, and the mixture was extracted four times with 20 ml of toluene. The organic layer was dried over anhydrous sodium sulfate, which was filtered and concentrated. Toluene was added for recrystallization, and 5.53 g of a pale yellow powder was obtained (yield: 75.
0%). HPLC analysis (column ODS-80T
M, detection UV: 254 nm, flow rate: 1.0 ml / min,
Eluent methanol / water = 40/60 buffer triethylamine and acetic acid 0.1%), resulting in a purity of 9
8.0%. 170-172 ° C.

Example 2 Synthesis of 3- (2-pyridyl) quinoline (V-2) 5.14 g (0.030 mol) of 3-acetylquinoline and (3-piperidylprop-2-enylidene) piperidine perchlorate (IV-2) 9.20 g (0.030 mol)
Was dissolved in 15 ml of tetrahydrofuran, and potassium t-
3.64 g (0.032 mol) of butoxide was added and reacted at 60 ° C. for 10 minutes. Then ammonium acetate 9.25
g (0.12 mol) and 7 ml of acetic acid were added, and the mixture was reacted at 60 ° C for 2 hours. Then, tetrahydrofuran was concentrated and removed while the internal temperature was raised to 85 ° C, and the reaction was further performed at 85 ° C for 2 hours.
The mixture was allowed to cool, 60 ml of a 25% aqueous NaOH solution was added, and the mixture was extracted four times with 100 ml of toluene. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. Vacuum distillation (bp.
166-170 ° C / 0.1 Torr) to obtain 5.26 g (yield: 85.0%) of the target light yellow liquid. HP
LC analysis (column ODS-80TM, detection UV 264
nm, flow rate 1.0 ml / min, eluent acetonitrile / water = 80/20 buffer triethylamine and acetic acid 0.1%). As a result, the purity was 99.3%.

Example 3 2,4'-dipyridyl (V-
Synthesis of 3) 56.93 g (0.2) of (4-aza-4-phenylbut-1,3-dienyl) phenylamine hydrochloride (IV-3)
20 mol), 138 ml of piperidine and 120 ml of methanol were added, and the mixture was heated under reflux for 1 hour. The temperature was raised to 90 DEG C. and methanol was distilled off. It was allowed to cool to an internal temperature of 30 ° C., and 24.24 g of potassium t-butoxide (0.216 g) was added.
Mol), 24-23 g of 4-acetylpyridine (0.20 g)
0 mol) and reacted at 60 ° C. for 30 minutes. The mixture was allowed to cool to 40 ° C., and 92.50 g (1.20 mol) of ammonium acetate was added.
For 1.5 hours. After the reaction, the internal temperature was lowered to 80 ° C., and 140 ml of toluene was added. Internal temperature 30-50 ℃ 2
300 ml of a 5% aqueous NaOH solution was added dropwise. After completion of the dropwise addition, when the internal temperature reached 30 ° C., the mixture was filtered through celite, and the filtrate was extracted with 50 ml of toluene. 100m of toluene
The mixture was extracted twice with l, and the organic layers were combined, concentrated, and filtered through celite. The mixture was further concentrated and distilled under reduced pressure to obtain a light yellow solid (25.1 g).
(80.3% yield). HPLC analysis (column O
DS-80TM, UV detection 254 nm, flow rate 1.0 m
1 / min, eluent acetonitrile / water = 50/50
Buffer-triethylamine and acetic acid 0.1%)
As a result, the purity was 99.5%. Melting point 55.9-5
6.0 ° C

Example 4 5-Chloro-2- (4-pyridyl)
Synthesis of pyridine (V-4) 3.63 g (0.030 mol) of 4-acetylpyridine and 8.22 g of (3- (dimethylamino) prop-2-enylidene) dimethylamine perchlorate (IV-4) ( 0.
032 mol) in 23 ml of tetrahydrofuran,
3.63 g (0.032 mol) of potassium t-butoxide
Was added and reacted at 60 ° C. for 10 minutes. Next, 13.87 g (0.18 mol) of ammonium acetate and 10 ml of acetic acid were added and reacted at 60 ° C. for 2 hours. Then, tetrahydrofuran was concentrated and removed while raising the internal temperature to 85 ° C.
The reaction was carried out at 2 ° C. for 2 hours. Allow to cool, 25% NaOH aqueous solution 6
0 ml was added, and the mixture was extracted four times with 100 ml of toluene.
The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. Recrystallization was performed from a mixed solution of toluene / hexane to obtain 4.69 g of colorless needle crystals (yield: 82.0%). H
PLC analysis (column ODS-80TM, detection UV 25
4 nm, flow rate 1.0 ml / min, eluent acetonitrile / water = 70/30 buffer-triethylamine and acetic acid 0.1%). As a result, the purity was 99.9%.
3-Amino-2 with a melting point of 111.7-112.3 ° C.
The structures of -propenylidene ammonium salts or 3-iminopropenylamino compounds and the structures of the target compounds synthesized in Examples 1 to 4 are shown below.

[0048]

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[0049]

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Examples 5 to 9 The same operations as in Example 4 were performed to synthesize compounds V-5 to V-9. Table 1 shows the results. The structures of the compounds synthesized in Examples 5 to 9 are shown below.

[0051]

[Table 1]

[0052]

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In the same manner, compound V-10 shown below
~ V-20 were also synthesized.

[0054]

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Comparative Example 1 Khim. Geol. Nauk. , Pp. 114 (197
According to the method described in (0), 2,4-dipyridyl (V-3) was synthesized from 2-bromopyridine and 4-chloropyridine by an Ullmann reaction, and compared with Example 3. Table 2 shows the results, and the structures of the by-products are shown below.

[0056]

[Table 2]

[0057]

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As is clear from the table, the method of the comparative example can be synthesized by the reaction of relatively simple compounds, but the selectivity is low and the present invention has high selectivity.

[0059]

According to the present invention, pyridine derivatives useful as intermediates for pharmaceuticals, agricultural chemicals, electrophotographic photoreceptors, dyes, etc. are produced on an industrial scale without using expensive catalysts or special equipment. be able to. More specifically, it is possible to produce a regiospecific pyridine derivative which can be produced with high purity, high yield and low cost and does not cause a pollution problem.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) C07D 213/80 C07D 213/80 213/84 213/84 Z 401/04 401/04 405/04 405/04 409/04 409/04 471/04 113 471/04 113 F term (reference) 4C055 AA01 BA02 BA06 BA07 BA08 BA16 BA25 BA57 BA59 BB17 CA01 CA02 CA03 CA06 CA08 CA25 CA39 CA42 CA47 CA57 DA01 DA06 DA08 DA25 EA01 FA23 FA37 4C063 AA01 BB01 CC75 CC92 DD12 EE01 EE03 EE05 4C065 AA04 BB09 CC01 DD02 EE02 HH02 PP14 QQ01

Claims (2)

[Claims] 1. A pyridine derivative comprising a step of reacting an acetyl compound represented by the general formula (I) with a 3-amino-2-propenylidene ammonium salt represented by the general formula (II). Manufacturing method. Embedded image In the formula, R1 is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic residue, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl Represents a group, a carbonyl group, a sulfonyl group, or a cyano group. R2 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group,
Substituted or unsubstituted heterocyclic residue, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, alkoxy group, aryloxy group, hydroxyl group, alkylthio group, arylthio group, carbonyl group, sulfonyl group , A nitro group, a cyano group, or a halogen atom. Further, R1 and R2 may combine to form a substituted or unsubstituted ring composed of a nonmetal atom together with the carbon atom to which they are attached. Embedded image In the formula, R3, R4, R6, and R7 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic residue, or a carbonyl group. R3 and R4, and R6 and R7 may be respectively bonded to form a substituted or unsubstituted ring composed of a nonmetallic atom together with the nitrogen atom to which they are bonded. R5
Is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic residue, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, Represents a group, an alkylthio group, an arylthio group, an alkoxy group, an aryloxy group, a carbonyl group, a sulfonyl group, a substituted or unsubstituted amino group, a nitro group, a cyano group, and a halogen atom.
X ^- is a counter ion of a quaternary ammonium salt, and represents a halide ion, a perhalate ion, an organic acid ion, or an inorganic ion. 2. A process comprising reacting an acetyl compound represented by the general formula (I) according to claim 1 with a 3-iminopropenylamino compound represented by the following general formula (III). For producing a pyridine derivative. Embedded image In the formula, R3, R4, and R6 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic residue, or an acyl group. R3 and R4 may combine to form a substituted or unsubstituted ring consisting of a nonmetallic atom together with the nitrogen atom to which they are attached. R5 represents a hydrogen atom, a halogen, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group.
Group, substituted or unsubstituted heterocyclic residue, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, hydroxyl group, alkoxy group, aryloxy group, carbonyl group, sulfonyl group, substituted or unsubstituted Represents an amino group, a nitro group, a cyano group, and a halogen atom.