JP2001261646A - Method for producing pyridine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method capable of producing a pyridine derivative useful as an intermediate for medicinal agents, agrochemicals, electrophotographic photoreceptors, dyes, etc., without using an expensive catalyst and a specific facility in an industrial scale, 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 carbonyl compound with a specific 3- aminoacrolein.

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 Kovardo complex, or 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.

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 (Synthesis., Pp. 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.

Further, a method has been proposed in which an acetylpyridine derivative is iodinated to form a pyridine ring via a pyridinium ion (Synthesis, 815 (1999)). 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.

[0005]

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.

[0006]

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, a carbonyl compound represented by the following general formula (I) and a carbonyl compound represented by the following general formula (II)
Alternatively, a method for producing a pyridine derivative, comprising a step of reacting a 3-aminoacrolein represented by the following general formula (III).

[0007]

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(Wherein R 1 is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted oxygen atom and / or sulfur atom and / or selenium atom and / or phosphorus atom R2 represents a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted alkynyl group, a carbonyl group, a sulfonyl group, a cyano group. Unsubstituted aryl group, substituted or unsubstituted heterocyclic residue, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, hydroxyl group, alkoxy group, aryloxy group, alkylthio group, arylthio group, carbonyl group , A sulfonyl group, a nitro group, a cyano group, a halogen atom.
1, R2 may combine to form a substituted or unsubstituted ring of non-metallic atoms with the carbon atoms to which they are attached. )

[0009]

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(Wherein R3 and R4 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 may combine to form a substituted or unsubstituted ring consisting of a non-metallic atom together with the nitrogen atom to which they are attached, R5 represents a hydrogen atom, a substituted or unsubstituted alkyl group, Or unsubstituted aryl group, substituted or unsubstituted heterocyclic residue, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, hydroxyl group, alkoxy group, aryloxy group, alkylthio group, arylthio group, carbonyl Group, sulfonyl group, substituted or unsubstituted amino group, nitro group, cyano group, and halogen atom.)

[0011]

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 shown below as an example, but the content of the present invention is not limited thereto.

[0012]

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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., and substituted or unsubstituted aryl groups (phenyl, naphthyl, phenanthryl, tolyl, quinolyl, chlorophenyl) , Hydroxyphenyl, ethylaminophenyl, etc.), substituted or unsubstituted oxygen-containing heterocyclic residues (furyl, pyranyl, benzofuranyl, chromanyl, chromenyl, xanthenyl, 2-methylfuryl, 3-phenylxanthenyl, etc.), substituted or unsubstituted Substituted sulfur-containing heterocyclic residues (thienyl, benzothienyl, thianthrenyl, 3-
Methyl-thienyl, 2-phenylthianthrenyl, etc.), substituted or unsubstituted selenium-containing heterocyclic residues (selenolanyl, selenophenyl, 2-methylselenolanyl, etc.), and substituted or unsubstituted phosphorus-containing heterocyclic residues (phosphoranyl,
3-methylphosphorinyl, etc.), substituted or unsubstituted oxygen- and sulfur-containing heterocyclic residues (oxathiolanyl, phenoxazinyl, phenoxatinyl, 2-ethylphenoxatinyl, etc.), oxygen-containing and selenium-containing heterocyclic residues ( 1,2-oxaselenolanyl, 1,3-oxaselenolyl, 1,3
-Oxaselenanyl, etc.), sulfur-containing / selenium-containing heterocyclic residue (1,2-thiaselenolanyl, 1,3-thiaselenolyl, 1,4-thiaselenanyl, etc.), substituted or unsubstituted oxygen-containing / phosphorus-containing heterocyclic residue ( 1,4-oxaphosphorinyl, 5-chloro-1,3-oxaphospholinanyl and the like, and substituted or unsubstituted sulfur- and phosphorus-containing heterocyclic residues (1,4-thiaphospholinyl, 4-methyl-1, 2-thiaphospholinanyl, etc.), 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, etc.), sulfonyl group (methylsulfonyl, phenylsulfonyl, unsubstituted sulfamoyl, N-ethylsulfa Moyl, N, N-dimethylsulfamoyl, etc.), and a cyano group. Preferably a hydrogen atom, having 1 to 12 carbon atoms
Alkyl group, an aryl group having 6 to 20 carbon atoms, an oxygen-containing heterocyclic residue, a sulfur-containing heterocyclic residue, an oxygen-containing and sulfur-containing heterocyclic residue, more preferably an alkyl group having 1 to 6 carbon atoms. , An aryl group having 6 to 12 carbon atoms, and a sulfur-containing 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, 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.), hydroxyl groups, alkoxy groups (methoxy, ethoxy, etc.), aryloxy groups (phenoxy, etc.) , 2-naphthyloxy, etc.), alkylthio group (methylthio, ethylthio, etc.), arylthio group (phenylthio, naphthylthio, etc.), carbonyl group [acyl group (acetyl, pivaloyl, benzoyl, etc.), alkoxycarbonyl group (methoxycarbonyl, ethoxycarbonyl, etc.) ), An aryloxycarbonyl group (eg, phenyloxycarbonyl), a carbamoyl group (eg, unsubstituted carbamoyl, N-methylcarbamoyl, N, N-diethylcarbamoyl)], a sulfonyl group (methylsulfonyl, Nirusuruhoniru, unsubstituted sulfamoyl, N- ethylsulfamoyl, N, N-
Dimethylsulfamoyl, etc.), a nitro group, a cyano group, and a halogen atom (chlorine, iodine, bromine, etc.). Preferred are a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 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. And more preferably a hydrogen atom and carbon number 1
4 to lower alkyl groups, phenyl groups, and alkoxycarbonyl groups having 2 to 5 carbon atoms.

R1 and R2 may be combined 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. Specifically, cyclopentanone, cyclohexanone, benzocyclobutane Pentannone, benzocyclohexanone, tetrahydropyran-4-none and the like.

In the compounds represented by formula (II) or (III), R3 and R4 are each independently a hydrogen atom, a substituted or unsubstituted linear, branched or cyclic alkyl group. Groups (methyl, ethyl, isopropyl, t-
Butyl, n-octyl, n-dodecyl, cyclopentyl, cyclohexyl, methoxyethyl, 2-chloroethyl, benzyl, 3-dimethylaminomethyl, bromocyclohexyl, 2-norbornyl, etc., and 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.), carbonyl group [acyl group (acetyl, pivaloyl, benzoyl, etc.), alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, etc.), aryloxycarbonyl (phenyloxycarbonyl, etc.), Carbamoyl group (unsubstituted carbamoyl, N-methylcarbamoyl, N, N-diethylcarbamoyl, etc.)]
Is mentioned. Preferred are lower alkyl groups having 1 to 4 carbon atoms, acyl groups having 2 to 5 carbon atoms, phenyl groups and naphthyl groups, and more preferred are methyl groups, ethyl groups and acetyl groups.

R3 and R4 may combine to form a substituted or unsubstituted ring composed of a nonmetallic atom together with the nitrogen atom to which they are attached. Specifically, a piperidine ring, a pyrrolidine ring, And a morpholine ring.

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.) 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.), hydroxyl groups, alkoxy groups (methoxy, ethoxy, etc.), aryloxy groups (phenoxy, etc.) , 2-naphthyloxy, etc.), alkylthio group (methylthio, ethylthio, etc.), arylthio group (phenylthio, naphthylthio, etc.), carbonyl group [acyl group (acetyl, pivaloyl, benzoyl, etc.), alkoxycarbonyl group (methoxycarbonyl, ethoxycarbonyl, etc.) ), An aryloxycarbonyl group (eg, phenyloxycarbonyl), a carbamoyl group (eg, unsubstituted carbamoyl, N-methylcarbamoyl, N, N-diethylcarbamoyl)], a sulfonyl group (methylsulfonyl, Nirusuruhoniru, 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.). Preferred are a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group having 1 to 4 carbon atoms, a phenyl group, a nitrogen-containing heterocyclic residue, a sulfur-containing heterocyclic residue, and a sulfonyl group having 1 to 8 carbon atoms. Preferred are a hydrogen atom, a methyl group, an ethyl group, a phenyl group, a halogen atom, and a sulfur-containing heterocyclic residue. In addition,
3- represented by the general formula (II) and the general formula (III)
The aminoacrolein compounds have a cis structure and a trans structure, respectively.

The carbonyl compound used in the method of the present invention is easily available as a commercial product. The aromatic carbonyl compound can be introduced by acylation by Friedel-Crafts reaction or the like (J. Org.
Chem. , 38, pp. 1445 (1973); A
m. 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 derive carbonyl compounds from nitro compounds by Nef reaction.

The 3-aminoacroleins used in the method of the present invention are easily available as commercial products, or can be obtained from J. Am. Am. Chem. Soc. , 103, pp.3
030 (1981); Chem. Soc. PERK
IN TRANS. I, pp. 333 (1988); Co
llect. Czech. Chem. Commun. ,
61, pp. 1637 (1996); Collect. C
zech. Chem. Commun. , 49, pp. 26
02 (1984), Chem. Pharm. Bull. ,
29, pp. 308 (1981) and the like.

The specific examples of the compounds represented by formula (I), (II) or (III) are shown below, but the present invention is not limited to these compounds.

[0022]

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[0023]

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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 1 to 30 times the weight of the carbonyl compound, more preferably 2 to 20 times the weight, more preferably 4 to 20 times the weight of the carbonyl compound.
８8 times the weight.

In the present invention, the carbonyl compound and 3-
It is preferable to add a base when reacting aminoacroleins. 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 is preferable.
-Butoxide, sodium t-butoxide and sodium hydride, more preferably potassium t-butoxide. The amount of the base to be used is 0.1 to 10 mol, preferably 0.8 to 2.0 mol, per 1 mol of the carbonyl compound.
It is preferable to carry out the reaction in a molar amount, more preferably in the range of 0.9 to 1.2.

In the present invention, after the above-mentioned step of reacting a carbonyl compound with a 3-aminoacrolein, 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 is as follows: 1) a nitrogen atom-containing compound (preferably ammonia or ammonium salt) to be newly added to the reaction system; 2) the general formula (II) or A nitrogen atom in the compound represented by the general formula (III) (for example, when both R3 and R4 in the general formula (II) or the general formula (III) are hydrogen atoms) is exemplified.

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 preferred are ammonium acetate. These are used in an amount of 1 to 30 moles, preferably 3 to 15 moles, per mole of the carbonyl compound.
It is preferably carried out in a molar amount of, more preferably, 6 to 10 times the molar amount. 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 present invention, the reaction temperature of the reaction between the carbonyl compound and the 3-aminoacrolein is carried out at 20 to 200 ° C., preferably 40 to 8 ° C.
The temperature is in the range of 0 ° C, more preferably 40 to 60 ° C. These reactions are usually completed within 24 hours, often with 5
The disappearance of the raw material is confirmed in ~ 12 hours.

In the production method of the present invention, a catalyst is not particularly required. However, in the reaction for forming a pyridine ring in a reaction product of a carbonyl compound and a 3-aminoacrolein, an acid catalyst may be used as necessary. Is preferable because it is completed in a shorter time. Any acid catalyst can be used, but inorganic acids such as sulfuric acid and hydrochloric acid, p-
Toluenesulfonic acid, formic acid, acetic acid, organic acids such as propionic acid, Amberlite, strongly acidic ion exchange resins such as Amberlyst are used, preferably formic acid, acetic acid, which can keep the reaction system weakly acidic. Propionic acid, more preferably acetic acid.

In the present invention, the reaction temperature of the pyridine ring formation 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 pyridine derivative as the target substance 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.

[0032]

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%). The structure of the target compound synthesized in the examples is shown below.

Example 1 Synthesis of 2-phenylpyridine (c-1) 12.0 g (0.10 mol) of acetophenone and 10.4 g (0.105 mol) of 3-dimethylamino-propenal were dissolved in 50 ml of tetrahydrofuran. 12.35 g (0.11 mol) of potassium t-butoxide was added and 6
The reaction was performed at 0 ° C. for 30 minutes. To this mixture, 69.36 g (0.90 mol) of ammonium acetate and 70 ml of acetic acid were added, and after reacting at 60 ° C. for 2 hours, tetrahydrofuran was concentrated and removed while the internal temperature was raised to 105 ° C., and the mixture was heated at 105 ° C. for 2 hours. Reacted. After allowing the reaction solution to cool, 180 ml of a 25% aqueous NaOH solution was added, and the mixture was extracted four times with 300 ml of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, which was filtered and concentrated. 12.9 g of the target product by distillation under reduced pressure
(83.1% yield). As a result of HPLC analysis, the purity was 99.5%.

Example 2 Synthesis of 2- (2-pyridyl) thiophene (c-2) 12.62 g (0.10 mol) of 2-acetylthiophene
And 10.41 g of 3-dimethylamino-propenal
(0.105 mol) was dissolved in 35 ml of tetrahydrofuran, and 12.35 g (0.11 g) of potassium t-butoxide was dissolved.
Mol) and reacted at 60 ° C. for 60 minutes. Subsequently, 69.36 g (0.90 mol) of ammonium acetate and 70 m of acetic acid were used.
and the reaction was carried out 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 105 ° C for 2 hours. Allow to cool to 25% N
Add 180 ml of aOH aqueous solution, and add 300 ml of ethyl acetate.
For a total of four extractions. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crystals were recrystallized from toluene-hexane to obtain 12.95 g (yield: 80.3%) of the target product.
As a result of HPLC analysis, the purity was 99.5%.

Example 3 Synthesis of 2,5-dimethyl-3-phenylpyridine (c-3) 13.42 g (0.10 mol) of methylbenzylketone and 2-methyl-3-piperidin-1-yl-propenal 16 .50 g (0.105 mol) were dissolved in 35 ml of tetrahydrofuran, and potassium t-butoxide was 12.35.
g (0.11 mol) was added and reacted at 60 ° C. for 60 minutes.
Subsequently, 69.36 g (0.90 mol) of ammonium acetate
And 70 ml of acetic acid, and reacted at 60 ° C. for 2 hours.
While raising the temperature to 05 ° C, tetrahydrofuran was concentrated and removed, and the reaction was further performed at 105 ° C for 2 hours. Allow to cool 25
180 ml of an aqueous NaOH solution and 300 ml of ethyl acetate are added.
It was extracted four times with ml. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The desired product 1 was obtained by distillation under reduced pressure.
4.84 g (81.0% yield) was obtained. As a result of HPLC analysis, the purity was 99.5%.

Example 4 Synthesis of 2-methyl-5-phenylpyridine (c-4) 5.81 g (0.10 mol) of acetone and 2-phenyl-
3-pyrrolidin-1-yl-propenal 21.13
g (0.105 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, 69.36 g (0.90 mol) of ammonium acetate and 70% of acetic acid
After adding 2 ml and reacting at 60 ° C. for 2 hours, tetrahydrofuran was concentrated and removed while raising the internal temperature to 105 ° C., and the reaction was further performed at 105 ° C. for 2 hours. Cool to 25% NaOH
Add 180 ml of aqueous solution, and add 300 ml of ethyl acetate for a total of 4
Extracted times. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. 14.90 g of the target product by distillation under reduced pressure
(88.0% yield). As a result of HPLC analysis, the purity was 99.8%.

Example 5 Synthesis of methyl-2-methylpyridine-3-carboxylate (c-5) 11.61 g (0.10 mol) of acetoacetic acid methyl ester and 3-morpholin-4-yl-propenal
82 g (0.105 mol) of tetrahydrofuran 35 m
l. of potassium t-butoxide 12.35 g
(0.11 mol) and reacted at 60 ° C. for 60 minutes.
Subsequently, 69.36 g (0.90 mol) of ammonium acetate
And 70 ml of acetic acid, and reacted at 60 ° C. for 2 hours.
While raising the temperature to 05 ° C, tetrahydrofuran was concentrated and removed, and the reaction was further performed at 105 ° C for 2 hours. Allow to cool 25
180 ml of an aqueous NaOH solution and 300 ml of ethyl acetate are added.
It was extracted four times with ml. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. Object 1 by vacuum distillation
0.82 g (yield 71.6%) was obtained. As a result of HPLC analysis, the purity was 99.0%.

Example 6 Synthesis of 5-chloro-2-cyclohexylpyridine (c-6) 12.62 g (0.10 mol) of methylcyclohexyl ketone and 14.02 g (0.02 mol) of 2-chloro-3-dimethylamino-propenal. 105 mol) in 55 ml of tetrahydrofuran, and 12.35 of potassium t-butoxide.
g (0.11 mol) was added and reacted at 60 ° C. for 60 minutes.
Subsequently, 69.36 g (0.90 mol) of ammonium acetate
And 70 ml of acetic acid, and reacted at 60 ° C. for 2 hours.
While raising the temperature to 05 ° C, tetrahydrofuran was concentrated and removed, and the reaction was further performed at 105 ° C for 2 hours. Allow to cool 25
180 ml of an aqueous NaOH solution and 300 ml of ethyl acetate are added.
It was extracted four times with ml. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crystals were recrystallized from toluene-hexane to obtain 16.55 g (yield: 84.6%) of the desired product. As a result of HPLC analysis, the purity was 99.5%.

Example 7 Synthesis of 3,5-dimethylpyridine (c-7) 5.81 g (0.10 mol) of propylaldehyde and 2-
Methyl-3-piperidin-1-yl-propenal 1
6.50 g (0.105 mol) of tetrahydrofuran 5
Dissolved in 5 ml and potassium t-butoxide 12.35.
g (0.11 mol) was added and reacted at 60 ° C. for 60 minutes.
Subsequently, 69.36 g (0.90 mol) of ammonium acetate
And 70 ml of acetic acid, and reacted at 60 ° C. for 2 hours.
While raising the temperature to 05 ° C, tetrahydrofuran was concentrated and removed, and the reaction was further performed at 105 ° C for 2 hours. Allow to cool 25
180 ml of an aqueous NaOH solution and 300 ml of ethyl acetate are added.
It was extracted four times with ml. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. 9.9 g of the target product by distillation
(92.4% yield). As a result of HPLC analysis, the purity was 99.5%. The structures of the compounds c-1 to c-7 are shown below.

[0040]

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Compounds c-8 to c-17 were synthesized in the same manner.

[0042]

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Comparative Example 1 Synthesis of 2- (2-pyridyl) thiophene (c-2) 9.41 g (0.10 mol) of 2-aminopyridine was dissolved in 500 ml of thiophene, and then isoamyl nitrite 1
9.9 g (0.17 mol) was added dropwise and reacted at room temperature for 24 hours. After refluxing for 2 hours, thiophene and isoamino alcohol were removed by distillation. The residue was purified by a silica gel column to obtain 2.28 g of the desired product (14.1% yield). As a result of the structural analysis, 3- (2-pyridyl) thiophene (HPLC content: 9.3%) was confirmed as a by-product.
Table 1 shows the results.

[0044]

[Table 1]

In the method of Comparative Example, both the yield and the selectivity were low.
It is clear that the present invention has a higher selectivity as compared with the present invention.

[0046]

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.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07D 213/803 C07D 213/803 213/84 213/84 Z 401/04 401/04 405/04 405/04 409/04 409/04 471/04 113 471/04 113 F term (reference) 4C055 AA01 BA01 BA02 BA05 BA06 BA07 BA08 BA16 BA26 BA57 BA59 BB01 BB02 CA01 CA02 CA03 CA05 CA06 CA08 CA39 CA46 CA47 CA57 CB01 CB02 DA01 DA05 DA08 DA13 DA33 DB01 DB02 EA01 FA03 FA22 FA23 FA24 FA25 FA37 4C063 AA01 BB01 CC14 CC75 CC92 DD12 EE01 EE03 4C065 AA01 AA05 BB09 CC01 DD02 EE02 HH09 JJ01 KK06 PP14 QQ01

Claims (1)

[Claims] 1. A method for producing a pyridine derivative, comprising a step of reacting a carbonyl compound represented by the general formula (I) with a 3-aminoacrolein represented by the general formula (II) or (III). Method. Embedded image (Wherein R1 contains a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted oxygen atom and / or a sulfur atom and / or a selenium atom and / or a phosphorus atom Represents a heterocyclic residue, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a carbonyl group, a sulfonyl group, and a cyano group.
R2 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, a hydroxyl group, Represents an alkoxy group, an aryloxy group, an alkylthio group, an arylthio group, a carbonyl group, 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. ) (Wherein, R3 and R4 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. R4 may combine to form a substituted or unsubstituted ring consisting of a non-metallic atom 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, substituted or unsubstituted heterocyclic residue, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group,
Represents a hydroxyl 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. )