JP2000044566A - Method for producing pyridine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for industrially and advantageously producing a pyridine derivative useful as an intermediate such as an antiviral agent under mild conditions with good yield. SOLUTION: General formula (I) (In the formula, X represents an alkoxyl group which may have a substituent, and A represents a divalent organic group containing 1 to 3 oxygen atoms, nitrogen atoms and / or sulfur atoms.) To a pyridine ester derivative represented by the general formula (II) in the presence of a base: (Wherein, R ¹ and R ² represent a hydrogen atom or a hydrocarbon group which may have a substituent, and R ³ represents a hydrocarbon group which may have a substituent.) By reacting an ester compound, the compound represented by the general formula (III) (Wherein R ⁴ represents a hydrocarbon group which may have a substituent). A pyridine β-ketoester derivative represented by the following formula: is obtained, and the obtained pyridine β-ketoester derivative is hydrolyzed and further decarboxylated. General formula (IV) (Wherein, R ⁵ represents —CHR ¹ R ² ).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing a pyridine derivative and a synthetic intermediate thereof. The pyridine derivative produced according to the present invention is useful as a synthetic intermediate of a compound having a pyridine skeleton in the molecule, such as a furopyridine derivative having antiviral activity [see WO 96/35678].

[0002]

2. Description of the Related Art Heretofore, several methods have been developed for synthesizing condensed pyridines such as furopyridine [Heterocycles, Vol. 45, No. 5, p. 975 (199).
7)), but a 5-substituted furo [2,3-c] convertible into the furopyridine derivative having the above antiviral activity.
As a method for producing pyridine, a 2-step synthesis using 2-chloro-3-hydroxypyridine as a raw material and a ring formation by aza-Diels-Alder reaction using furfural oxime as a raw material, followed by dehydrogenation to form 5- The only known method is to convert to substituted furo [2,3-c] pyridine-N-oxide [see WO 96/35678].

[0003]

However, of the above methods, the former method has many steps, the raw materials and the reactants are expensive and has a problem in availability, and the latter method requires 2,3-dichloro-5,5. An expensive dehydrogenating agent such as 6-dicyano-p-benzoquinone (DDQ) is required, and reduction from pyridine oxide to pyridine is required. Accordingly, an object of the present invention is to provide a method for producing a pyridine derivative capable of easily producing condensed pyridines such as a furopyridine derivative under mild conditions with good yield and industrial advantage. Another object of the present invention is to provide a synthetic intermediate which provides an industrially advantageous method for producing the pyridine derivative and a method for producing the same.

[0004]

According to the present invention, the above objects have been achieved by the general formula (I)

[0005]

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(Wherein X represents an optionally substituted alkoxyl, alkenyloxy, aryloxy or aralkyloxy group, and A represents an oxygen atom, a nitrogen atom and / or a sulfur atom A represents a divalent organic group containing three, and A together with the two carbon atoms to form a five-, six-, seven- or eight-membered ring; Which may form a condensed ring with one or more rings) (hereinafter abbreviated as pyridine ester derivative (I))
In the presence of a base, a compound of the general formula (II)

[0007]

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(Wherein R ¹ and R ² each independently represent a hydrogen atom or a hydrocarbon group which may have a substituent, and R ³ represents a hydrocarbon group which may have a substituent (Hereinafter referred to as ester (I)
Abbreviated as I)) to give a compound of the general formula (III)

[0009]

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(Wherein R ¹ , R ² and A are as defined above, and R ⁴ represents a hydrocarbon group which may have a substituent). Hereinafter, a pyridine β-ketoester derivative (II
Abbreviated as I)), and the resulting pyridine β-ketoester derivative (III) is hydrolyzed and further decarboxylated.

[0011]

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Wherein A is as defined above,
⁵ represents -CHR ¹ R ^2, and R ¹ and R ² are as defined above. A method for producing a pyridine derivative (hereinafter abbreviated as pyridine derivative (IV)) represented by the formula: pyridine derivative (IV) characterized by hydrolyzing pyridine β-ketoester derivative (III) and further decarboxylation reaction Production method, general formula (III-1)

[0013]

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(Wherein R ¹ and R ² each independently represent a hydrogen atom or a hydrocarbon group which may have a substituent, and R ⁴ represents a hydrocarbon group which may have a substituent And Z represents -ND- (D represents a hydrogen atom or a hydrocarbon group which may have a substituent), -O- and -S-.
Represents a divalent group selected from Pyridine β
A method for producing a pyridine β-keto ester derivative (III), characterized by reacting an ester (II) with a keto ester derivative or a pyridine ester derivative (I) in the presence of a base; A pyridine derivative (IV), a reducing agent, an alkylating agent, an alkenylating agent,
General formula (V) characterized by reacting an arylating agent or an aralkylating agent

[0015]

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(Wherein R ⁵ and A are as defined above, and R ⁶ represents a hydrogen atom, an alkyl group, an alkenyl group, an aryl group or an aralkyl group which may have a substituent). This is achieved by providing a method for producing the pyridine alcohol derivative (hereinafter abbreviated as pyridine alcohol derivative (V)).

[0017]

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the above general formula, specific examples of a ring formed by combining two carbon atoms to which A is bonded include a dihydrofuran ring, a furan ring, a pyrrole ring, a pyrroline ring and a dehydrodioxolane ring. A 5-membered ring such as a pyrazole ring, a pyrazoline ring, an imidazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, an oxadiazole ring, and a triazole ring; a pyran ring, a dihydropyran ring, a pyridine ring, a dihydropyridine ring, and a tetrahydropyridine ring. 6-membered ring such as dehydrodioxane ring, dehydromorpholine ring, pyridazine ring, dihydropyridazine ring, pyrimidine ring, dihydropyrimidine ring, tetrahydropyrimidine ring, pyrazine ring, dihydropyrazine ring; cycloheptatriene ring, cycloheptadiene ring, cycloheptene ring Each of A 7-membered ring such as a substituted, oxa-substituted or thia-substituted, thiazepine ring; a aza-substituted, oxa-substituted or thia-substituted cyclooctatetraene, cyclooctadiene or cyclooctene ring; 8-membered rings and the like. Specific examples of the condensed ring in the case where the ring formed together with the two carbon atoms to which A is bonded forms a condensed ring with one or more other rings include a benzofuran ring, an isobenzofuran ring, and a chromene ring. Ring, indolizine ring, indole ring, isoindole ring, quinolidine ring, indazole ring, isoquinoline ring,
Examples include a phthalazine ring, a naphthyridine ring, a quinoxaline ring, a benzothiophene ring, and a hydro form thereof. These rings may have a substituent.

The alkoxyl group represented by X includes, for example, a linear or branched chain alkoxyl group such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a hexyloxy group and an octyloxy group; And cycloalkyloxy groups such as a cyclopentyloxy group and a cyclohexyloxy group. These alkoxyl groups and cycloalkyloxy groups may have a substituent. Examples of such a substituent include a halogen atom such as a chlorine atom, a bromine atom, an iodine atom and a fluorine atom; a methoxy group, an ethoxy group,
Alkoxyl groups such as propoxy group and butoxy group; hydroxyl group; nitro group; phenyl group, p-methoxyphenyl group,
and an aryl group such as a p-chlorophenyl group.

The alkenyloxy group represented by X includes
For example, a propenyloxy group, a butenyloxy group, an octenyloxy group and the like can be mentioned. As the aryloxy group, for example, a phenyloxy group can be mentioned. As the aralkyloxy group, for example, a benzyloxy group can be mentioned. These alkenyloxy group, aryloxy group and aralkyloxy group may have a substituent. Examples of the substituent include a halogen atom such as a chlorine atom, a bromine atom, an iodine atom and a fluorine atom; a methoxy group; Alkoxyl groups such as ethoxy group, propoxy group and butoxy group; hydroxyl group; alkyl groups such as methyl group, ethyl group, propyl group and butyl group; nitro group; aryl such as phenyl group, p-methoxyphenyl group and p-chlorophenyl group And the like.

Examples of the hydrocarbon group represented by R ¹ , R ² , R ³ , R ⁴ and D include an alkyl group, an alkenyl group, an aryl group and an aralkyl group. Examples of the alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-
Linear or branched chain alkyl groups such as butyl group, pentyl group, isopentyl group, neopentyl group, hexyl group, heptyl group and octyl group; cycloalkyl groups such as cyclopropyl group, cyclopentyl group and cyclohexyl group; Can be These alkyl groups may have a substituent, such as a halogen atom such as a chlorine atom, a bromine atom, an iodine atom, and a fluorine atom; a methoxy group, an ethoxy group, a propoxy group, a butoxy group, and the like. A hydroxyl group; a nitro group; an aryl group such as a phenyl group, a p-methoxyphenyl group, and a p-chlorophenyl group. Examples of the alkenyl group include a vinyl group, a propenyl group, a butenyl group, and an octenyl group. Examples of the aryl group include a phenyl group. Examples of the aralkyl group include a benzyl group. These alkenyl group, aryl group and aralkyl group may have a substituent. Examples of the substituent include a halogen atom such as a chlorine atom, a bromine atom, an iodine atom and a fluorine atom; a methoxy group, an ethoxy group, Alkoxyl groups such as propoxy group and butoxy group; hydroxyl group; alkyl groups such as methyl group, ethyl group, propyl group and butyl group; nitro group; aryl groups such as phenyl group, p-methoxyphenyl group and p-chlorophenyl group. No.

Examples of the alkyl group represented by R ⁶ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, Straight-chain or branched chain alkyl groups such as hexyl group, heptyl group and octyl group; and cycloalkyl groups such as cyclopropyl group, cyclopentyl group and cyclohexyl group. These alkyl groups may have a substituent. Examples of the substituent include a halogen atom such as a chlorine atom, a bromine atom, an iodine atom and a fluorine atom; a hydroxyl group; a methoxy group, an ethoxy group, a propoxy group and a butoxy group. Nitro group; phenyl group, p-
And aryl groups such as a methoxyphenyl group and a p-chlorophenyl group.

The alkenyl group represented by R ⁶ includes, for example, a vinyl group, a propenyl group, a butenyl group and an octenyl group, and the aryl group includes, for example, a phenyl group and a naphthyl group, and the aralkyl group includes For example, a benzyl group and the like can be mentioned. These alkenyl group, aryl group and aralkyl group may have a substituent. Examples of the substituent include a halogen atom such as a chlorine atom, a bromine atom, an iodine atom and a fluorine atom; a hydroxyl group; a methyl group; Alkyl groups such as methoxy, ethoxy, propoxy and butoxy groups; nitro groups; aryl groups such as phenyl, p-methoxyphenyl and p-chlorophenyl groups. No.

Next, the production method of the present invention will be described in detail for each step.

Step 1: A step of producing a pyridine β-ketoester derivative (III) by reacting the ester (II) with the pyridine ester derivative (I) in the presence of a base.

Examples of the base include alkali metals such as sodium, lithium and potassium; alkaline earth metals such as calcium; sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, sodium butoxide, sodium t-butoxide. , Sodium benzyl oxide, potassium methoxide, potassium ethoxide, potassium propoxide,
Metal alcoholates such as potassium isopropoxide, potassium butoxide and potassium t-butoxide; organic magnesium halides such as methyl magnesium bromide, ethyl magnesium bromide, isopropyl magnesium bromide and mesityl magnesium bromide; metal hydrogen such as sodium hydride and potassium hydride And metal amides such as sodium amide, potassium amide, and lithium diisopropylamide. The amount of the base used is 0.1 to 1 mol of the pyridine ester derivative (I).
A range of 5 to 10 mol is preferable, and a range of 1 to 3 mol is more preferable.

The ester (II) is an ester compound derived from a carboxylic acid having a hydrogen atom at the alpha position, preferably acetic acid, propionic acid, butyric acid, isobutyric acid,
Ester compounds of carboxylic acids such as 2-methylpropionic acid, valeric acid, isovaleric acid, caproic acid and phenylacetic acid, for example, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, 2-methylpropyl ester , T-
Butyl ester, phenyl ester, benzyl ester, chlorophenyl ester and the like. Of these, esters of aliphatic lower alcohols such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, 2-methylpropyl ester, and t-butyl ester are preferred. The amount of the ester (II) used is preferably in the range of 0.5 to 10 mol, more preferably 1 to 3 mol, per 1 mol of the pyridine ester derivative (I).

The reaction in this step can be carried out in the absence of a solvent, but is preferably carried out in the presence of a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction. Examples thereof include aliphatic hydrocarbons such as pentane, hexane, cyclohexane, octane, and ligroin; aromatic hydrocarbons such as benzene, toluene, xylene, cumene, and mesitylene; Ethers such as ether, tetrahydrofuran and dioxane; polyethers such as ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol diethyl ether, triethylene glycol diethyl ether and tetraethylene glycol diethyl ether ; Methanol, ethanol, propanol, isopropanol, Nord, alcohols such as t- butanol. Among these, it is preferable to use an aromatic hydrocarbon, ether, or polyether as a solvent from the viewpoint of good reaction rate and good solubility of the pyridine ester derivative (I). The amount of the solvent used is not particularly limited as long as the pyridine ester derivative (I) dissolves under the reaction conditions, but is preferably in the range of 0.5 to 1000 times by weight based on the pyridine ester derivative (I). A range of 0.5 to 100 times by weight is more preferable.

[0028] The reaction temperature is preferably in the range of 0 ° C to 200 ° C, more preferably in the range of 10 ° C to 150 ° C.

The method for carrying out the reaction in this step is not particularly limited. For example, (1) a predetermined amount of a pyridine ester derivative (I), a base, an ester (II) and a solvent are mixed;
(2) dissolving a predetermined amount of pyridine ester derivative (I) in a solvent, adding a base to the solution to obtain a desired temperature, and then dissolving ester (II) as it is or in a solvent; (3) dissolving a predetermined amount of a base in a solvent, adding an ester (II) to the solution to obtain a desired temperature, and then preparing a pyridine ester derivative A method in which (I) is added as it is or dissolved in a solvent and added all at once, intermittently or continuously, and reacted.

The pyridine β-ketoester derivative (III) thus obtained is neutralized by adding an acid equivalent to the base used to the reaction solution, and then neutralized with methylene chloride, toluene, xylene, benzene, chloroform, Extraction with pentane, hexane, heptane, or the like, and isolation of the extract can be easily performed by concentrating the extract. Examples of acids that can be used in such an operation include carboxylic acids such as acetic acid and formic acid, and inorganic acids such as hydrochloric acid and sulfuric acid. Further, the purity of the obtained product can be further increased by performing a recrystallization operation as needed.

Depending on the combination of the pyridine ester derivative (I), the base and the ester (II) and the amount used, depending on the type of base, particularly when using a metal alcoholate as a base or using an alcohol as a solvent, Under the reaction conditions, the group represented by -X of the pyridine ester derivative (I), the -OR of the ester (II)
^A transesterification reaction may proceed between the group represented by ³ , the alcoholate portion of the metal alcoholate, and the alcohol. In this case, the product may be a mixture of a plurality of types of the moiety represented by —OR ⁴ of the pyridine β-ketoester derivative (III), and these mixtures are separated by ordinary isolation such as distillation, column chromatography, and recrystallization. -Purity can be easily increased by purification means. For the purpose of subjecting the mixture to the next step 2 for obtaining the pyridine derivative (IV), there is no problem if the mixture is used without purification.

Step 2: Step of hydrolyzing the pyridine β-ketoester derivative (III) and further decarboxylation to obtain the pyridine derivative (IV)

In the hydrolysis reaction, the amount of water used is not particularly limited. However, from the viewpoint of obtaining the desired pyridine derivative (IV) in good yield, the amount of water is preferably based on 1 mol of the pyridine β-ketoester derivative (III). Water is preferably used in an amount of 1 mol or more. In view of the reaction rate, extraction efficiency after the reaction, and volumetric efficiency of the apparatus, the amount of water used is usually 1 mol of the pyridine β-ketoester derivative (III). Is preferably 100 mol or less.

In the hydrolysis reaction, any of the known acids or bases used for the hydrolysis of esters can be used. Examples of the acid include an inorganic acid such as hydrochloric acid and sulfuric acid, and an acidic gas such as hydrogen chloride gas can also be used. Also, as a base, sodium hydroxide,
Examples include alkali metal hydroxides such as potassium hydroxide. The intermediate product obtained by hydrolyzing the pyridine β-ketoester derivative (III) is unstable under the reaction conditions, and the decarboxylation reaction proceeds rapidly to produce the pyridine derivative (IV). The carbonic acid reaction can be carried out in the same reactor using the acid or base used for the hydrolysis reaction as it is, and is usually carried out simultaneously with the hydrolysis reaction. In order to promote the progress of the hydrolysis reaction and the decarboxylation reaction, an acid or a base can be further added during the reaction. The kind of the acid or base added at that time may be the same as or different from the acid or base used for the hydrolysis reaction and the decarboxylation reaction first. The amount of the acid or base to be used is preferably in the range of 0.001 to 100 mol, more preferably 0.01 to 10 mol, per 1 mol of the pyridine β-ketoester derivative (III).

As a method for carrying out the reaction, a hydrolysis reaction and a decarboxylation reaction are first started under basic conditions, and an excess acid is added to the reaction system during the reaction to drive the reaction under acidic conditions. Alternatively, a method in which a hydrolysis reaction and a decarboxylation reaction are first started under an acidic condition, and an excess base is added to the reaction system during the reaction to drive the reaction under a basic condition, may be employed.

For the purpose of obtaining the pyridine derivative (IV), a reaction solution containing the pyridine β-ketoester derivative (III) is obtained by the reaction in Step 1, and the pyridine β-ketoester derivative (III) is simply converted from the reaction solution. Without separation, it is also possible to add water and an acid or a base to the reaction solution and carry out the hydrolysis reaction and the decarboxylation reaction in step 2 to obtain the pyridine derivative (IV).

When the pyridine β-ketoester derivative (III) is not isolated from the reaction solution obtained in the reaction of the step 1 and the hydrolysis reaction and the decarboxylation reaction of the step 2 are subsequently carried out, the pyridine contained in the reaction solution The β-ketoester derivative (III) is quantitatively analyzed, and an acid or a base is used in an amount in the above-mentioned range based on the amount. The acid or base is preferably used in an amount in the range of 0.001 to 100 mol based on 1 mol of the pyridine ester derivative (I) used in Step 1, and in an amount of 0.01 to 10 mol. More preferably, it is used. Water is preferably used in an amount of 1 to 100 mol based on the amount of the pyridine β-ketoester derivative (III) contained in the reaction solution. Water may be used in an amount in the range of 1 to 100 mol based on the pyridine ester derivative (I).

Further, since a base is already present in the reaction solution containing the pyridine β-ketoester derivative (III) obtained in the step 1, by adding water, the base is directly hydrolyzed and decarboxylated. It can also act as a reaction accelerator. In this embodiment, the neutralization operation in Step 1 can be omitted.

The hydrolysis reaction and the decarboxylation reaction may be performed in the presence of an organic solvent. The type of the organic solvent is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include aliphatic hydrocarbons such as pentane, hexane, cyclohexane, octane, and ligroin; aromatic hydrocarbons such as benzene, toluene, xylene, cumene, and mesitylene; Ethers such as diethyl ether, tetrahydrofuran and dioxane; ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, ethylene glycol diethyl ether;
Polyethers such as diethylene glycol diethyl ether, triethylene glycol diethyl ether and tetraethylene glycol diethyl ether; methanol,
Examples include alcohols such as ethanol, propanol, isopropanol, butanol, and t-butanol. Among these, aromatic hydrocarbons, ethers, and polyethers are preferred from the viewpoints of good reaction rate and good solubility of the pyridine β-ketoester derivative (III). There is no particular limitation on the amount of solvent used,
It is preferably in the range of 0.5 to 100 parts by weight based on the pyridine β-keto ester derivative (III) or the pyridine ester derivative (I). In addition, the pyridine β-ketoester derivative (I
When the hydrolysis reaction and the decarboxylation reaction in Step 2 are performed without isolating II), the solvent used in Step 1 can be used in Step 2 as it is.

[0040] The reaction temperature is preferably in the range of 0 ° C to 200 ° C, more preferably in the range of 10 ° C to 150 ° C.

The pyridine derivative (IV) thus obtained is isolated and purified from the reaction mixture in the same manner as in a method generally used for isolating and purifying organic compounds. For example, cooling the reaction mixture to room temperature,
Extract with an organic solvent such as methylene chloride, toluene, xylene, benzene, chloroform, pentane, hexane, heptane, etc., wash the extract with brine, evaporate the solvent, and distill the residue, recrystallize, chromatograph, etc. Performed by purification.

Step 3: a step of reacting the pyridine derivative (IV) with a reducing agent, an alkylating agent, an alkenylating agent, an arylating agent or an aralkylating agent.

Examples of the reducing agent include borohydride compounds such as sodium borohydride and lithium borohydride; aluminum hydride compounds such as diisobutylaluminum hydride, lithium aluminum hydride and sodium bismethoxyethoxyaluminum. No. In addition, it is possible to reduce with hydrogen in the presence of a metal catalyst such as Raney nickel and Raney cobalt. A reduction method in which aluminum isopropoxide is allowed to act in isopropanol can also be employed. The amount of the reducing agent used is pyridine derivative (IV) 1
The amount is preferably in the range of 1.0 to 20 moles,
A range of 1.1 to 5 mol is more preferred.

Examples of the alkylating agent include alkyl metal compounds such as methyl lithium, n-butyl lithium, methyl magnesium chloride, methyl magnesium bromide, ethyl magnesium chloride and methyl cerium chloride. Examples include alkenyl metal compounds such as vinyl lithium, vinyl magnesium chloride, allyl lithium, and allyl magnesium chloride.Examples of the arylating agent include aryl metal compounds such as phenyllithium and phenylmagnesium bromide. And aralkyl metal compounds such as benzyllithium and benzylmagnesium bromide. The amount of the alkylating agent, the alkenylating agent, the arylating agent or the aralkylating agent to be used is preferably in the range of 0.5 to 20 mol, more preferably 1.1 to 2.0 mol, per 1 mol of the pyridine derivative (IV). Is more preferable.

The reaction can be carried out in the presence or absence of a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction. For example, alcohols such as methanol, ethanol, propanol and isopropanol; diethyl ether, diisopropyl ether,
Ethers such as dibutyl ether, tetrahydrofuran, 1,2-diethoxyethane and diethylene glycol dimethyl ether; and hydrocarbons such as hexane, heptane, cyclohexane, benzene, toluene and xylene. The amount of the solvent to be used is not particularly limited, but is preferably in the range of 1 to 200 times the weight of the pyridine derivative (IV).

The reaction temperature varies depending on the type of solvent, reducing agent, alkylating agent, alkenylating agent, arylating agent, and aralkylating agent used, but it should be within the range of -100 ° C. to the reflux temperature of the solvent. Is preferred. The reaction can be carried out under pressure or under reduced pressure. The reaction time varies depending on the reaction temperature, but is usually in the range of 30 minutes to 24 hours. Here, the reaction time can be adjusted by appropriately adjusting the reaction temperature.

The pyridine alcohol derivative (V) thus obtained is isolated and purified from the reaction mixture in the same manner as in a method generally used for isolating and purifying organic compounds. For example, the reaction mixture is returned to room temperature, then hydrolyzed by adding the reaction mixture to an acidic aqueous solution such as aqueous ammonium chloride, and then diethyl ether,
After extraction with an organic solvent such as ethyl acetate, the extract is washed with an aqueous solution of sodium hydrogen carbonate and brine, and the solvent is distilled off. The residue is purified by distillation, recrystallization, chromatography and the like.

The pyridine ester derivative (I), which is a starting material in the above reaction step, has the general formula (VI)

[0049]

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Wherein A is as defined above, and R ⁷
Represents an alkyl group, an alkenyl group, an aryl group or an aralkyl group which may have a substituent. ) (Hereinafter abbreviated as imine derivative (VI)) represented by general formula (VII):

[0051]

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(Wherein R ⁸ is a hydrogen atom or an optionally substituted alkyl, alkenyl, aryl, aralkyl, alkoxyl, alkenyloxy, aryloxy, aralkyloxy or amino A carbonylating agent (hereinafter abbreviated as carbonylating agent (VII)) represented by the formula (VIII):

[0053]

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(Wherein X is as defined above) (hereinafter, abbreviated as nitrile (VIII)).

Examples of the optionally substituted alkyl, alkenyl, aryl and aralkyl groups represented by R ⁷ and R ⁸ include the same groups as those represented by R ⁶ .

Examples of the optionally substituted alkoxyl group, alkenyloxy group, aryloxy group and aralkyloxy group represented by R ⁸ include the same groups as those represented by X.

The amino group which may have a substituent represented by R ⁸ includes, for example, amino group, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, dihexylamino group, dioctyl Examples thereof include a linear or branched chain amino group such as an amino group. These amino groups further include a halogen atom such as a chlorine atom, a bromine atom, an iodine atom and a fluorine atom; a hydroxyl group; an alkoxyl group such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group; a nitro group; It may have a substituent such as a phenyl group and a p-chlorophenyl group.

The leaving group represented by Y includes, for example, halogen atoms such as chlorine atom, bromine atom and iodine atom; and acyloxy groups such as acetoxy group, propionyloxy group, butyryloxy group and valeryloxy group.

Examples of the carbonylating agent (VII) include carboxylic anhydrides such as acetic anhydride, propionic anhydride, butyric anhydride, valeric anhydride and trifluoroacetic anhydride; acetyl chloride, acetyl bromide, propionyl chloride, and bromide. Carboxylic acid halides such as propionyl, butyryl chloride, isobutyryl chloride, valeryl chloride, isovaleryl chloride, pivaloyl chloride, benzoyl chloride, benzoyl bromide; methyl chloroformate, ethyl chloroformate, ethyl propyl chloroformate, propyl chloroformate, isopropyl chloroformate, butyl chloroformate, Halogenoformate esters such as allyl chloroformate, phenyl chloroformate, nitrophenyl chloroformate, and benzyl chloroformate; carbamic acid halides such as N, N-dimethylcarbamyl chloride; and chloroformate esters are preferred. It is needed. The amount of the carbonylating agent (VII) to be used is preferably in the range of 0.5 to 20 mol, and more preferably 1.1 to 20 mol, per 1 mol of the imine derivative (VI).
A range of 10 moles is more preferred.

Examples of the nitrile (VIII) include cyano formate such as methyl cyano formate, ethyl cyano formate, propyl cyano formate, isopropyl cyano formate, butyl cyano formate, allyl cyano formate, phenyl cyano formate, nitrophenyl cyano formate, and benzyl cyano formate. Acid esters. The amount of the nitrile (VIII) to be used is preferably in the range of 0.5 to 20 mol, more preferably in the range of 1.1 to 10 mol, per 1 mol of the imine derivative (VI).

The reaction can be carried out in the presence or absence of a solvent. The solvent is not particularly limited as long as it does not adversely affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene, xylene, mesitylene, and chlorobenzene; ethers such as tetrahydrofuran and dioxane; dimethylformamide, 1-methyl-2-pyrrolidinone Amides; dimethyl sulfoxide and the like. The amount of the solvent to be used is not particularly limited, but is preferably in the range of 1 to 200 times the weight of the imine derivative (VI).

The reaction temperature varies depending on the type of the solvent, the carbonylating agent (VII) and the nitrile (VIII), but is preferably in the range of 40 ° C. to the reflux temperature of the reaction system. The reaction can be carried out under pressure or under reduced pressure. The reaction time varies depending on the reaction temperature, but is usually in the range of 30 minutes to 24 hours. Here, the reaction time can be adjusted by appropriately adjusting the reaction temperature.

This reaction is carried out, for example, as follows. That is, the carbonylating agent (VII) is added dropwise to a mixed solution of the nitrile (VIII) and the imine derivative (VI) within a range from ice-cooling to the reflux temperature, and after the completion of the addition, the mixture loses the imine derivative (VI). This is done by heating at the desired temperature until the heating is complete.

The thus obtained pyridine ester derivative (I) is isolated and purified from the reaction mixture in the same manner as in a method generally used for isolating and purifying organic compounds. For example, after cooling the reaction mixture to room temperature, washed with aqueous sodium hydrogen carbonate solution and brine,
After evaporating the solvent, the residue is purified by recrystallization, chromatography and the like. When the product precipitates from the reaction mixture, the reaction may be carried out by cooling the reaction solution, adding a poor solvent as needed, and filtering the solution.

[0065]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the present invention.

Reference Example 1 21.4 g (0.216 mol) of ethyl cyanoformate and 3-methylfuran-2-aldehydephenylimine 1
0.0 g (54.1 mmol) of xylene (50 ml)
After mixing at room temperature, the mixture was heated and stirred at 120 to 140 ° C. under reflux. Ethyl chloroformate 1 was added to the resulting mixture.
1.7 g (0.108 mol) of xylene (30 ml)
The solution was added dropwise over 1 hour. After completion of the dropwise addition, the reaction mixture was heated under reflux for 2 hours, allowed to cool to room temperature, and then the solvent was distilled off to obtain 14.0 g of a crude product. This was purified by silica gel column chromatography to obtain 5.40 g of 5-ethoxycarbonylfuro [2,3-c] pyridine (yield: 52.3%).

¹ H-NMR spectrum (270 MHz,
CDCl ₃ , TMS, ppm) δ: 1.47 (3H, t, J = 7.16 Hz), 4.5
1 (2H, q, J = 7.16 Hz), 6.94 (1H,
dd, J = 2.70 Hz, 1.08 Hz), 7.85
(1H, d, J = 2.70 Hz), 8.50 (1H,
d, J = 1.08 Hz), 8.99 (1H, s).

Example 1 5-ethoxycarbonylfuro [2, obtained in Reference Example 1
3-c] pyridine (956 mg, 5.0 mmol) was dissolved in toluene (10 ml), and sodium ethoxide 20% ethanol solution (2.55 g, 7.5 mm) was added to the solution.
ol) was added dropwise at room temperature, followed by stirring at room temperature.
661 mg (7.5 mmol) of ethyl acetate were added dropwise.
After completion of the dropwise addition, the temperature of the reaction mixture was raised to 80 ° C., and the reaction was performed for 8 hours. Thereafter, the reaction solution was cooled to 5 ° C and 450 mg of acetic acid (7.5 mm
ol), the mixture was stirred for 30 minutes while maintaining this temperature, and 1 ml of water was added to return to room temperature. The organic layer was separated, the aqueous layer was extracted twice with 5 ml of methylene chloride, and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator to obtain 851 mg of a solid. This solid was recrystallized in a toluene / hexane mixture,
Β-oxo-5-furo [2,3-c] with 99% LC purity
769 mg of ethyl pyridinepropionate (yield: 66
%).

The ¹ H-NMR spectrum (270 MHz,
CDCl ₃ , TMS, ppm) δ: 1.25 (3H, t, J = 7.17 Hz), 4.2
1 (2H, q, J = 7.17 Hz), 4.25 (2H,
s), 6.95 (1H, d, J = 2.46 Hz), 7.
85 (1H, d, J = 1.97 Hz), 8.42 (1
H, s), 8.88 (1H, s)

Example 2 5-ethoxycarbonylfuro [2,3-c] pyridine 9
56 mg (5.0 mmol) are dissolved in 10 ml of toluene, and 510 mg of sodium ethoxide is added to this solution.
(7.5 mmol) at room temperature, followed by 661 mg (7.5 mmol) of ethyl acetate while stirring at room temperature.
Was added dropwise. After the completion of the dropwise addition, the temperature of the reaction mixture was raised to 80 ° C., and the reaction was performed for 4 hours. Thereafter, the reaction solution was cooled to 5 ° C, and while maintaining the temperature at 5 to 10 ° C, 450 mg of acetic acid was added.
(7.5 mmol), and while maintaining this temperature, 3
After stirring for 0 minutes, 1 ml of water was added and the temperature was returned to room temperature. The organic layer was separated, the aqueous layer was extracted twice with 5 ml of methylene chloride, and the combined organic layers were dried over anhydrous magnesium sulfate.
The mixture was concentrated on a rotary evaporator, and the obtained solid was recrystallized in a toluene / hexane mixture, and 840 mg of ethyl β-oxo-5-furo [2,3-c] pyridinepropionate having a HPLC purity of 99% (yield) : 72%).

Example 3 While stirring 510 mg (7.5 mmol) of sodium ethoxide in 5 ml of toluene, 1.16 g (10.0 mmol) of t-butyl acetate was added dropwise to this solution at room temperature. In this solution, 5-ethoxycarbonylfuro [2,
A solution obtained by dissolving 956 mg (5.0 mmol) of 3-c] pyridine in 5 ml of toluene was added dropwise at room temperature. After the completion of the dropwise addition, the reaction mixture was heated to 60 ° C. and reacted for 3 hours. Thereafter, the reaction solution was cooled to 5 ° C and 450 mg of acetic acid (7.5 mm
ol), the mixture was stirred for 30 minutes while maintaining this temperature, and 1 ml of water was added to return to room temperature. The organic layer was separated, the aqueous layer was extracted twice with 5 ml of methylene chloride, and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated using a rotary evaporator. The obtained solid is dissolved in toluene /
Recrystallized in a hexane mixture to obtain a β
933 mg (yield: 80%) of ethyl-oxo-5-furo [2,3-c] pyridinepropionate was obtained.

Example 4 While stirring 405 mg (7.5 mmol) of sodium methoxide in 5 ml of toluene, 1.16 g (10.0 mmol) of t-butyl acetate was added dropwise to this solution at room temperature. In this solution, 5-ethoxycarbonylfuro [2,
A solution obtained by dissolving 956 mg (5.0 mmol) of 3-c] pyridine in 5 ml of toluene was added dropwise at room temperature. After the completion of the dropwise addition, the reaction mixture was heated to 60 ° C. and reacted for 3 hours. Thereafter, the reaction solution was cooled to 5 ° C and 450 mg of acetic acid (7.5 mm
ol), the mixture was stirred for 30 minutes while maintaining this temperature, and 1 ml of water was added to return to room temperature. The organic layer was separated, the aqueous layer was extracted twice with 5 ml of methylene chloride, and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated on a rotary evaporator to obtain 971 mg of a solid. When this was analyzed by NMR, methyl β-oxo-5-furo [2,3-c] pyridinepropionate, ethyl β-oxo-5-furo [2,3-c] pyridinepropionate and β-oxo- A mixture of t-butyl 5-furo [2,3-c] pyridinepropionate (mixing molar ratio = 55:
44: 1). The above β-oxo-
The NMR spectrum of ethyl 5-furo [2,3-c] pyridinepropionate shows the β-oxo- obtained in Example 1.
This was consistent with that of ethyl 5-furo [2,3-c] pyridine ethyl propionate.

Methyl β-oxo-5-furo [2,3-c] pyridinepropionate: ¹ H-NMR spectrum (270 MHz, CDCl ₃ , T
MS, ppm) [delta]: 3.75 (3H, s), 4.29
(2H, s), 6.95 (1H, d, J = 1.97H)
z), 7.85 (1H, d, J = 1.98 Hz), 8.
39 (1H, s), 8.88 (1H, s)

T-butyl β-oxo-5-furo [2,3-c] pyridinepropionate: ¹ H-NMR spectrum (270 MHz, CDCl ₃ , T
MS, ppm) [delta]: 1.42 (9H, s), 4.13.
(2H, s), 6.94 (1H, d, J = 1.98H)
z), 7.83 (1H, d, J = 1.98 Hz), 8.
40 (1H, s), 8.88 (1H, s)

Example 5 β-oxo-5-furo [2,3-c] obtained in Example 4
Methyl pyridine propionate, ethyl β-oxo-5-furo [2,3-c] pyridine propionate and β-oxo
Mixture of t-butyl oxo-5-furo [2,3-c] pyridine propionate (mixing molar ratio = 55: 44: 1) 9
71 mg was dissolved in 20 ml of toluene, and 1.04 g of 35% hydrochloric acid was added to this solution with stirring at room temperature. After completion of the addition, the reaction mixture was heated to 60 ° C. and reacted for 3 hours while stirring. Thereafter, the mixture was cooled to room temperature, and neutralized by adding 8.40 g of a 5% aqueous sodium hydroxide solution. The organic layer was separated, the aqueous layer was extracted twice with 5 ml of methylene chloride, and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated using a rotary evaporator. This was recrystallized from a toluene / hexane mixture, and 629 mg of 5-acetylfuro [2,3-c] pyridine having an HPLC purity of 99% (yield from 5-ethoxycarbonylfuro [2,3-c] pyridine:
78%).

Example 6 1.17 g (5.0 mmol) of ethyl β-oxo-5-furo [2,3-c] pyridinepropionate was added to toluene 2
The solution was dissolved in 0 ml, and 1.5 ml (7.5 mmol) of 10 N sulfuric acid was added to this solution at room temperature with stirring. After the addition was completed, the reaction mixture was heated to 80 ° C. and reacted for 6 hours while stirring. Thereafter, the mixture was cooled to room temperature and neutralized by adding 12 ml of a 5% aqueous sodium hydroxide solution. The organic layer was separated, the aqueous layer was extracted twice with 5 ml of methylene chloride, and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated using a rotary evaporator. This was recrystallized from a toluene / hexane mixture, and 580 mg of 5-acetylfuro [2,3-c] pyridine having a HPLC purity of 99% (yield: 72%).
%).

Example 7 583 mg of ethyl β-oxo-5-furo [2,3-c] pyridinepropionate obtained in Example 2 (2.5 mmol
l) was dissolved in 10 ml of toluene, and 3 g of a 10% aqueous sodium hydroxide solution was added to this solution while stirring. After completion of the addition, the reaction mixture was heated to 60 ° C. and stirred for 8 hours.
React for hours, then cool to room temperature, separate the organic layer,
The aqueous layer was extracted twice with 5 ml of methylene chloride, and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated using a rotary evaporator. The obtained solid was recrystallized from a toluene / hexane mixed solution, and 205 mg of 5-acetylfuro [2,3-c] pyridine having a HPLC purity of 99% (yield: 51%)
%).

Example 8 While stirring 405 mg (7.5 mmol) of sodium methoxide in 5 ml of toluene, 1.16 g (10.0 mmol) of t-butyl acetate was added dropwise to this solution at room temperature. In this solution, 5-ethoxycarbonylfuro [2,
A solution obtained by dissolving 956 mg (5.0 mmol) of 3-c] pyridine in 5 ml of toluene was added dropwise at room temperature. After completion of the dropwise addition, the reaction mixture was heated to 60 ° C. and reacted for 3 hours. Then, 450 mg of acetic acid was added to the obtained reaction mixture.
(7.5 mmol) was added to neutralize the mixture, and the mixture was stirred for 30 minutes. Then, 1.5 ml (7.5 mmol) of 5N hydrochloric acid was added, and the mixture was stirred and reacted at 60 ° C. for 5 hours. Thereafter, the reaction solution was cooled to room temperature, the organic layer was separated, the aqueous layer was extracted twice with 5 ml of methylene chloride, the combined organic layers were dried over anhydrous magnesium sulfate, and concentrated using a rotary evaporator. The obtained solid was recrystallized from a toluene / hexane mixture to give 5-acetylfuro [2,3-
c] Pyridine 580 mg (yield: 72%) was obtained.

Example 9 5-acetylfuro [2,3- obtained by the method of Example 8
c] Pyridine 2.42 g (15.0 mmol) was dissolved in toluene (30 ml) and cooled to 0 ° C. To the cooled solution, 16.0 ml (16.0 mmol) of a 1.0 M diisobutylaluminum hydride / toluene solution was added, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into 100 ml of an ice-cooled 5% aqueous ammonium chloride solution. Ethyl acetate 1
Extracted twice with 00 ml. The extract was washed with 100 ml of a saturated aqueous solution of sodium hydrogencarbonate and 100 ml of a saturated saline solution, and then the solvent was concentrated to obtain 2.36 g of a crude product. This is purified by silica gel column chromatography,
2.25 g (yield: 92.0%) of 5- (1-hydroxyethyl) -furo [2,3-c] pyridine was obtained.

The ¹ H-NMR spectrum (270 MHz,
CDCl ₃ , TMS, ppm) δ: 1.55 (3H,
s), 4.03 (1H, s), 4.99 (1H, q, J
= 5.93 Hz), 6.80 (1H, d, J = 1.98)
Hz), 7.53 (1H, s), 7.77 (1H, d,
J = 2.47 Hz), 8.80 (1H, s)

[0081]

Industrial Applicability The present invention provides a method for efficiently and industrially producing a pyridine derivative useful as an intermediate such as an antiviral agent under mild conditions. Also provided are synthetic intermediates that provide such methods and methods for their preparation.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Manzo Shiono 2045, Sazu, Kurashiki-shi, Okayama Prefecture Kuraray Co., Ltd. F-term (reference) 4C065 AA05 BB04 CC01 DD02 EE02 HH04 JJ01 KK01 4C071 AA01 BB01 CC01 CC11 CC21 EE04 EE13 FF06 GG03 LL07

Claims (5)

[Claims] 1. A compound of the general formula (I) (In the formula, X represents an optionally substituted alkoxyl group, alkenyloxy group, aryloxy group or aralkyloxy group, and A contains 1 to 3 oxygen atoms, nitrogen atoms and / or sulfur atoms. Represents a divalent organic group,
And A forms a 5-, 6-, 7- or 8-membered ring together with the two carbon atoms to be bonded, and this ring forms a condensed ring with one or more other rings. It may be. ) To a pyridine ester derivative represented by the general formula (II) in the presence of a base: (Wherein, R ¹ and R ² each independently represent a hydrogen atom or a hydrocarbon group which may have a substituent, and R ³ represents a hydrocarbon group which may have a substituent. ) To give an ester compound of the general formula (III) (Wherein R ¹ , R ² and A are as defined above,
R ⁴ represents a hydrocarbon group which may have a substituent. ), And the resulting pyridine β-ketoester derivative is hydrolyzed and further decarboxylated. (Wherein A is as defined above, and R ⁵ is —CHR ¹
Represents R ² and R ¹ and R ² are as defined above. )). 2. A compound of the general formula (III) (Wherein, R ¹ and R ² each independently represent a hydrogen atom or a hydrocarbon group which may have a substituent, R ⁴ represents a hydrocarbon group which may have a substituent, A represents a divalent organic group containing 1 to 3 oxygen atoms, nitrogen atoms and / or sulfur atoms, and A is a 5-membered ring, a 6-membered ring, a 7-membered ring together with two carbon atoms to be bonded. A ring or an eight-membered ring, and this ring may form a condensed ring with one or more other rings.)
General formula (IV) wherein the ketoester derivative is subjected to hydrolysis and further decarboxylation. (Wherein A is as defined above, and R ⁵ is —CHR ¹
Represents R ² and R ¹ and R ² are as defined above. )). 3. A compound of the general formula (III-1) (Wherein, R ¹ and R ² each independently represent a hydrogen atom or a hydrocarbon group which may have a substituent, R ⁴ represents a hydrocarbon group which may have a substituent, Z is-
ND- (D represents a hydrogen atom or a hydrocarbon group which may have a substituent), represents a divalent group selected from -O- and -S-. A pyridine β-ketoester derivative represented by the formula: 4. A compound of the general formula (I) (In the formula, X represents an optionally substituted alkoxyl group, alkenyloxy group, aryloxy group or aralkyloxy group, and A contains 1 to 3 oxygen atoms, nitrogen atoms and / or sulfur atoms. Represents a divalent organic group,
And A forms a 5-, 6-, 7- or 8-membered ring together with the two carbon atoms to be bonded, and this ring forms a condensed ring with one or more other rings. It may be. ) To the pyridine ester derivative represented by the general formula (II) in the presence of a base: (Wherein, R ¹ and R ² each independently represent a hydrogen atom or a hydrocarbon group which may have a substituent, and R ³ represents a hydrocarbon group which may have a substituent. Wherein an ester compound represented by the general formula (III) is acted on: (Wherein R ¹ , R ² and A are as defined above,
R ⁴ represents a hydrocarbon group which may have a substituent. The method for producing a pyridine β-ketoester derivative represented by the following formula: 5. A compound of the general formula (IV) obtained by the method according to claim 1 or 2. Wherein R ⁵ represents —CHR ¹ R ² and R ¹ and R
² independently represents a hydrogen atom or a hydrocarbon group which may have a substituent; A represents an oxygen atom, a divalent organic group containing 1 to 3 nitrogen atoms and / or sulfur atoms, And A is 5 together with the two carbon atoms to which it is attached.
A 6-membered ring, a 7-membered ring or an 8-membered ring may be formed, and this ring may form a condensed ring with one or more other rings. Wherein a reducing agent, an alkylating agent, an alkenylating agent, an arylating agent or an aralkylating agent is allowed to act on the pyridine derivative represented by the general formula (V). (Wherein R ⁵ and A are as defined above, and R ⁶ represents a hydrogen atom, an alkyl group, an alkenyl group, an aryl group or an aralkyl group which may have a substituent.) A method for producing an alcohol derivative.