JP2001261647A - Method for producing pyridine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method capable of producing a pyridine derivative useful as intermediates for medicinal agents, agrochemicals, electrophotographic photoreceptors, dyes, etc., in an industrial scale without using an expensive catalyst and a specific facility, further precisely, provide a method for producing a position-specific pyridine derivative generating no pollution problem and having high purity in high yield at a low cost. SOLUTION: This method for producing a pyridine derivative comprises a process for reacting a specific acetyl compound with a specific dialdehyde or its equivalent.

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 Many methods for synthesizing pyridine derivatives have been developed since ancient times, and they can be roughly classified into two. The first method is a method in which a pyridine ring already exists in the raw material and a new pyridine derivative is synthesized by converting a substituent thereof, and the second method is a method in which a pyridine ring is formed by a reaction. Examples of the first method include a coupling reaction using pyridine, halogenated pyridine, aminopyridine or the like as a raw material. However, in the case of coupling reaction of pyridine or halogenated pyridine,
Organometallic reagents such as organolithium, organotin, organomercury, Grignard reagents and organocopper reagents (for example, J. Am.C.
hem. Chem. , 79, pp. 6430 (195
7); Chem. Ind. Pp. 574 (197
4); Tetrahedron Lett. , 22, p
p. 5319 (1981); Heterocyc
l. Chem. , 16, pp. 1631 (1979);
Org. Synth. , VI, pp. 916 (198
8)) or a special catalyst such as a palladium complex, a cobalt complex, and a nickel complex (for example, J. Chem. Soc.
Perkin Trans. I, 1997, pp. 92
7 (1997); Appl. Organomet. Ch
em. , 10, pp. 415 (1996); USA P
attent, 5608071 (1997); Heter.
Cycles, 31, pp. 1543 (1990)
Etc.) and special equipment is required. In addition, these catalysts and reagents are very expensive, and the metal waste liquid requires special treatment. There are many problems and the method is not industrially advantageous. In the synthesis method using aminopyridine as a raw material, a method via a diazonium salt of pyridine (for example, Chem. Pharm. Bull., 32, pp. 1)
780 (1984); Org. Chem. , 40,
pp. 3183 (1975)). However, since the diazonium salt of pyridine is generally unstable, the yield and selectivity are low, and it is difficult to separate by-products.

[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,
pp. 600 (1975), Chem. Pharm.
Bull. , 33 pp. 4755 (1985)),
Further, a coupling reaction between an alkyltin derivative and a halogenated pyridine in the presence of a Pd catalyst (Tetrahedron)
Lett. , 33 pp. 2199 (199
2)), a coupling reaction between halogenated pyridine derivatives in the presence of a Ni metal catalyst (WO9852922), etc., are also known. There are many problems such as the need for special treatment and difficulty in separating by-products.
It is not an industrially advantageous method. In addition, synthesis of dipyridyl by a cross-coupling reaction utilizing a Grignard reaction (JP-A-64-3169, Tetrah
edron Lett. , 28 pp. 5845 (1
987)) or dipyridyl synthesis by the Wurtz reaction under irradiation of ultrasonic waves in the presence of Li metal between halogenated pyridine derivatives (Tetrahedron Lett., 3).
0, pp. 3567 (1989), Synthesi
s, pp. 564 (1986)) has been proposed, but requires dedicated equipment and has many problems in mass production.

The second method, the pyridine ring formation reaction,
Many methods have been developed since ancient times. One of them is
There is a method of synthesizing a pyridine ring using a carbonyl compound as a starting material, and is reviewed in Synthesis (Synthesis., Pp. 147-143).
1 (1976)). In this method, for example, an acetyl compound is halogenated and then converted into a pyridinium ion, and a pyridine ring is synthesized through a reaction with an α, β-unsaturated ketone derivative. It cannot be applied to the substrate that has it. 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.

Recently, a method of iodinating an acetylpyridine derivative to form a pyridine ring via a pyridinium ion (Synthesis, pp. 815 (1)
999)). 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 (Indian J. Chem., Sect.
B. Pp. 341 (1985), Indian
J. Chem. , Sect B .; Pp. 559
(1988)), but in this case, there were problems such as the necessity of removal in a multi-step reaction and a low yield.

[0007]

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.

[0008]

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) an acetyl compound represented by the following general formula (I):
A process for producing a pyridine derivative, which comprises reacting a dialdehyde compound represented by I) or a monoacetal compound or a diacetal compound which is an equivalent thereof, and then reacting the reaction product with an ammonia or ammonium salt.

[0009]

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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, hydroxy 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.

[0011]

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In the formula, R3 is 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 hydroxy group, an alkoxy group, an aryloxy group, an alkylthio group, an arylthio group, a carbonyl group, a sulfonyl group, a substituted or unsubstituted amino group, a nitro group, a cyano group, and a halogen atom.

[0013]

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 present invention is described below, but the content of the present invention is not limited thereto.

[0014]

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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.), hydroxy group, alkoxy group (methoxy, ethoxy, etc.), aryloxy group (phenoxy, 2-naphthyloxy, etc.), alkylthio group (methylthio, ethylthio, etc.), aryl- Ruthio group (phenylthio, naphthylthio etc.), carbonyl group [acyl group (acetyl, pivaloyl, benzoyl etc.), alkoxycarbonyl group (methoxycarbonyl, ethoxycarbonyl etc.), aryloxycarbonyl group (phenyloxycarbonyl etc.), carbamoyl group (none Substituted carbamoyl, N-methylcarbamoyl, N, N-diethylcarbamoyl, etc.]], sulfonyl group (methylsulfonyl, phenylsulfonyl, unsubstituted sulfamoyl, N-ethylsulfamoyl, N, N-
Dimethylsulfamoyl), a nitro group, a cyano group, and a halogen atom (chlorine, iodine, bromine, etc.). Preferably a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, 6 to 6 carbon atoms
An aryl group having 20 carbon atoms, an acyl group having 2 to 10 carbon atoms, an alkoxycarbonyl group having 2 to 10 carbon atoms, and a nitrogen-containing heterocyclic residue, more preferably a hydrogen atom and 1 to 4 carbon atoms.
Are a lower alkyl group, 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 nonmetal 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 present invention, the acetyl compound represented by the general formula (I) is reacted with a dialdehyde compound represented by the general formula (II) or a monoacetal compound or a diacetal compound which is an equivalent thereof. (Hereinafter, these are also simply referred to as “dialdehyde compounds”).

R3 is a substituted or unsubstituted linear, branched or cyclic alkyl group (methyl, ethyl, isopropyl, t-butyl, n-octyl, n-dodecyl, cyclopentyl, cyclohexyl, methoxyethyl, methoxyethyl, -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, 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),
Hydroxy 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), 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.

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 dialdehyde compound used in the method of the present invention can be obtained as a commercial product, or
J. Am. Chem. Soc. , 103, pp. 303
0 (1981) and the like.

Specific examples of the compound represented by the general formula (I), the compound represented by the general formula (II) and its equivalents (monoacetal compounds and diacetal compounds) are shown below. It is not limited to these compounds.

[0023]

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[0024]

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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 used is in the range of 1 to 30 times the weight of the acetyl compound,
More preferably 2 to 20 times the weight, more preferably 4 to 8 times
Double weight range.

In the present invention, it is preferable to add a base when reacting the acetyl compound with the dialdehyde compound. Although any base can be used for this reaction, usually, metal alkoxides such as potassium t-butoxide, sodium t-butoxide, and sodium ethoxide, sodium hydride, metal sodium, sodium hydroxide, potassium hydroxide Inorganic bases such as triethylamine and diisopropylamine are used, but potassium t-butoxide, sodium t-butoxide and sodium hydride are preferable, and potassium t-butoxide is more preferable. The amount of the base used is 0.1 mol per 1 mol of the acetyl compound.
It is good to carry out in the range of 10 to 10 mol, preferably 0.8 to 2.0 mol, more preferably 0.9 to 1.2 mol.

In the present invention, the reaction temperature when reacting the acetyl compound with the dialdehyde compound is 20 to 200.
C., preferably 30 to 100C, more preferably 40 to 80C. These reactions are usually completed within 24 hours, and in many cases, disappearance of raw materials is confirmed in 10 minutes to 12 hours.

The ammonia or ammonium salt used in this reaction can be used in any form, but usually ammonia gas, aqueous ammonia, ammonium chloride, ammonium acetate, ammonium formate and the like are used. Ammonium acetate,
Ammonium formate, more preferably ammonium acetate, is used. The amount of these used is 1 to 30 times mol, preferably 3 to 15 times mol, more preferably 6 to 10 times mol per mol of the acetyl compound. 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 particularly required. However, when a reaction product of an acetyl compound and a dialdehyde compound is reacted with ammonia or an ammonium salt, an acid catalyst may be used as necessary. This is preferable because 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 such as amberlite and amberlyst. Resins and the like are used, preferably formic acid, acetic acid, and propionic acid, which can keep the reaction system weakly acidic, and more preferably acetic acid. The reaction temperature when reacting the reaction product of the acetyl compound and the dialdehyde compound with ammonia or an ammonium salt is usually in the range of 40 to 200 ° C., preferably 5 to 200 ° C.
It is 0-150 ° C, more preferably 60-110 ° C.
The reaction time is usually 1 to 20 hours, preferably 1.
It is 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.

[0031]

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 structure was analyzed by 1H-NMR and mass spectrum, and the purity was evaluated by high performance liquid chromatography (abbreviated as HPLC). Hereinafter, what was described as HPLC analysis is the condition (column ODS-80TM,
Detection UV: 254 nm, flow rate: 1.0 ml / min, eluent: methanol / water = 40/60 buffer, triethylamine and acetic acid 0.1%), and details are described only when the conditions are changed.

Example 1 Synthesis of 3-methyl-2,4'-dipyridyl (III-1) 3.63 g (0.030 mol) of 4-acetylpyridine and 2-methylpropanedialdehyde (IV-1) 60g
(0.030 mol) was dissolved in 14 ml of tetrahydrofuran, and 3.63 g (0.032 g) of potassium t-butoxide was dissolved.
Mol) and reacted at 60 ° C. for 30 minutes. 9.25 g (0.12 mol) of ammonium acetate and 7 ml of acetic acid were added,
After reacting at 60 ° C. for 2 hours, tetrahydrofuran is concentrated and removed while the internal temperature is raised to 85 ° C., and 85 ° C. to 100 ° C.
For 2 hours. After allowing the reaction mixture to cool, 30 ml of a 25% aqueous NaOH solution was added, and the mixture was extracted four times with 120 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, which was filtered and concentrated. It was recrystallized from a mixed solution of toluene / hexane to obtain 4.25 g (yield: 83.2%) of the desired product. HP
As a result of LC analysis, the purity was 99.5%.

Example 2 5-chloro-2- (4-pyridyl)
Synthesis of pyridine (III-2) 4.63 g (0.030 mol) of 4-acetylpyridine and 3.20 g of 2-chloropropanedialdehyde (IV-2)
(0.030 mol) was dissolved in 25 ml of tetrahydrofuran, and 3.63 g (0.032 mol) of potassium t-butoxide was dissolved.
Mol) was added and reacted at 60 ° C. for 10 minutes. Then 13.87 g (0.18 mol) of ammonium acetate and 10 m of acetic acid
After the reaction at 60 ° C. for 2 hours, tetrahydrofuran was concentrated and removed while the internal temperature was raised to 85 ° C.
Reaction was performed at １００100 ° C. for 2 hours. Cool to 25% NaOH
An aqueous solution (60 ml) was added, and the mixture was extracted four times with toluene (100 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. It was recrystallized from a mixed solution of toluene / hexane, and 4.63 g of colorless needle-like crystals were obtained as a target substance (yield 8).
1.0%). HPLC analysis (column ODS-8
0TM, detection UV 254nm, flow rate 1.0ml / mi
n, eluent acetonitrile / water = 70/30 buffer-triethylamine and acetic acid 0.1%). As a result, the purity was 99.9%.

Example 3 Synthesis of 2,5-dimethyl-3-phenylpyridine (III-3) 13.42 g (0.10 mol) of methyl benzyl ketone and 8.61 g (0.10 mol) of 2-methylpropanedialdehyde
Mol) was dissolved in 35 ml of tetrahydrofuran, 12.35 g (0.11 mol) of potassium t-butoxide was added, and the mixture was reacted at 60 ° C. for 60 minutes. Then ammonium acetate 3
0.83 g (0.40 mol) and 70 ml of acetic acid were added, and 60
After reacting at 2 ° C. for 2 hours, tetrahydrofuran was concentrated and removed while increasing the internal temperature to 95 to 105 ° C.
The reaction was performed at 05 ° C for 2 hours. The mixture was allowed to cool, 180 ml of a 25% aqueous solution of NaOH was added, and the mixture was extracted four times with 300 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. 15.18 g of the desired product (yield 8
2.8%). . As a result of HPLC analysis, the purity was 9
It was 9.5%.

Example 4 Synthesis of 2- (4-pyridyl) -3-phenylpyridine (III-4) 12.11 g (0.10 mol) of 4-acetylpyridine and 2-phenylpropanedialdehyde (IV-3) 14.8
2 g (0.10 mol) was dissolved in 35 ml of tetrahydrofuran, and 12.35 g (0.1%) of potassium t-butoxide was dissolved.
1 mol) and reacted at 60 ° C. for 60 minutes. Subsequently, 30.83 g (0.40 mol) of ammonium acetate and acetic acid 70
After reacting at 60 ° C for 2 hours, the internal temperature was adjusted to 95 to 105.
The tetrahydrofuran was concentrated and removed while the temperature was raised to 0 ° C, and the reaction was further performed at 95 to 105 ° C for 2 hours. Let cool 2
180 ml of a 5% aqueous NaOH solution is added, and ethyl acetate 30
Extraction was performed four times with 0 ml. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crystals were recrystallized from a mixture of toluene / hexane to give 18.35 g of the desired product (yield: 79.0).
%). As a result of HPLC analysis, the purity was 99.1%.

Example 5 Synthesis of 5-chloro-2-cyclohexylpyridine (III-5) 12.62 g (0.10 mol) of methylcyclohexyl ketone and 11.18 g of 2-chloropropanedialdehyde
(0.11 mol) was dissolved in 55 ml of tetrahydrofuran, and 12.35 g (0.11 mol) of potassium t-butoxide was added, followed by a reaction at 60 ° C. for 60 minutes. Subsequently, 30.83 g (0.40 mol) of ammonium acetate and 70 ml of acetic acid
After reacting at 60 ° C. for 2 hours, tetrahydrofuran was concentrated and removed while raising the internal temperature to 105 ° C.
The reaction was performed at 05 ° C for 2 hours. The mixture was allowed to cool, 180 ml of a 25% aqueous solution of NaOH was added, and the mixture was extracted four times with 300 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crystals were recrystallized from a mixed solution of toluene / hexane to obtain 15.85 g (yield: 81.0%) of the target product. H
As a result of PLC analysis, the purity was 99.2%.

Example 6 Synthesis of methyl 2,5-dimethylpyridine-3-carboxylate (III-6) 11.61 g (0.10 mol) of acetoacetic acid methyl ester and 8.61 g of 2-methylpropanedialdehyde
(0.10 mol) was dissolved in 65 ml of tetrahydrofuran, 12.35 g (0.11 mol) of potassium t-butoxide was added, and the mixture was reacted at 60 ° C. for 60 minutes. Subsequently, 30.83 g (0.40 mol) of ammonium acetate and 70 ml of acetic acid
After reacting at 60 ° C. for 2 hours, tetrahydrofuran was concentrated and removed while raising the internal temperature to 105 ° C.
The reaction was performed at 5 ° C. for 2 hours. The mixture was allowed to cool, 180 ml of a 25% aqueous solution of NaOH was added, and the mixture was extracted four times with 300 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. 12.40 g (yield: 7) of the target product was obtained by distillation under reduced pressure.
5.1%). As a result of HPLC analysis, the purity was 98.
7%.

Example 7 Synthesis of 2- (5-methyl-2-pyridyl) thiophene (III-7) 12.62 g (0.10 mol) of 2-acetylthiophene
8.61 g of 2-methylpropanedialdehyde (0.1
0 mol) was dissolved in 65 ml of tetrahydrofuran, and 12.35 g (0.11 mol) of potassium t-butoxide was added, followed by a reaction at 60 ° C. for 60 minutes. Subsequently, 30.83 g (0.40 mol) of ammonium acetate and 70 ml of acetic acid were added, and 6
After reacting at 0 ° C. for 2 hours, tetrahydrofuran is concentrated and removed while the internal temperature is raised to 85 ° C., and further 85-105 ° C.
For 2 hours. Cool to 25% NaOH aqueous solution 18
0 ml was added, and the mixture was extracted four times with 300 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. 12.10 g (yield 6) of the target product was obtained by distillation under reduced pressure.
9.1%). As a result of HPLC analysis, the purity was 98.
2%.

Example 8 N, N'-dimethyl- (2,5
-Diphenylpyridin-3-yl) -formamide (II
Synthesis of I-8) 19.12 g of N, N'-dimethylbenzoylacetic acid amide
(0.10 mol) and 14.82 g (0.10 mol) of 2-phenylpropanedialdehyde in tetrahydrofuran 6
Dissolved in 5 ml, potassium t-butoxide 12.35 g
(0.11 mol) and reacted at 60 ° C. for 60 minutes. Subsequently, 30.83 g (0.40 mol) of ammonium acetate and 70 ml of acetic acid were added, and the mixture was reacted at 60 ° C. for 2 hours.
The tetrahydrofuran was concentrated and removed while the temperature was raised to 0 ° C, and the reaction was further performed at 85 to 105 ° C for 2 hours. Let cool 2
180 ml of a 5% aqueous NaOH solution is added, and ethyl acetate 30
Extraction was performed four times with 0 ml. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. Recrystallization from diethyl ether / hexane gave 21.45 g of the desired product (yield 70.9
%). As a result of HPLC analysis, the purity was 98.7%. The structures of the compounds synthesized in Examples 1 to 8 and the dialdehyde compound used are shown below.

[0040]

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[0041]

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In the same manner, the following compounds were also synthesized.

[0043]

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Comparative Example 1 Chem. Pharm. Bull. , 33, pp. 47
55 (1985).
-Methyl-pyridine and diethyl (4-pyridyl) borane are reacted in the presence of a palladium catalyst to give 3-methyl-2,
4′-Dipyridyl was synthesized. Table 1 shows the results.

[0045]

[Table 1]

Although the method of the comparative example can synthesize the target substance in a relatively short time, it has the problems described in the remarks and is not suitable for mass production. Also, when comparing the yield with Example 1 of the present invention, it is clear that the yield of the present invention is higher.

[0047]

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.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 213/82 C07D 213/82 401/04 401/04 405/04 405/04 409/04 409/04 471 / 04 113 471/04 113 // C07B 61/00 300 C07B 61/00 300 F term (reference) 4C055 AA01 BA01 BA02 BA05 BA07 BA08 BA27 BA57 BB01 CA02 CA03 CA05 CA08 CA27 CA39 CA42 CA47 CA57 CA58 CB01 DA01 DA27 DA33 DB01 EA01 FA22 FA23 FA24 4C063 BB01 CC12 CC14 CC75 CC92 DD06 DD12 EE01 4C065 AA01 AA05 BB09 CC01 DD02 EE02 HH09 JJ01 KK05 PP14 QQ02 4H039 CA42 CH10 CL25

Claims (1)

[Claims] An acetyl compound represented by the following general formula (I) is reacted with a dialdehyde compound represented by the general formula (II) or a monoacetal compound or a diacetal compound which is an equivalent thereof. A method for producing a pyridine derivative, comprising reacting a reactant with ammonia or an ammonium salt. 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, hydroxy 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 represents 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 alkoxy group, an aryloxy group, an alkylthio group, an arylthio group, a carbonyl group, a sulfonyl group, a substituted or unsubstituted amino group, a nitro group, a cyano group, and a halogen atom.